{"slug":"melatonin","name":"Melatonin","csvName":"Melatonin","rank":13,"rankingBasis":"Added from Patrick's pull list 2026-10-31 (keyword demand sheet); second PDF bundle","rankingSourceUrl":"","commonForms":["Immediate-release tablet / capsule","Prolonged / extended-release","Liquid / oral solution","Sublingual / oral spray"],"forms":[{"slug":"immediate-release","label":"Immediate-release tablet / capsule","studyIds":["pmid-27566320","pmid-24650045","pmid-25046730","pmid-20070489","pmid-18490497","pmid-10690873","pmid-26300641"]},{"slug":"extended-release","label":"Prolonged / extended-release","studyIds":["pmid-37150895","pmid-39174857","pmid-39458580","pmid-37438493","pmid-31381847","pmid-10085470","pmid-18982259","pmid-3994899","pmid-30731257","pmid-30286985","pmid-32673769","pmid-29702366","pmid-26440286","pmid-38769992"]},{"slug":"liquid","label":"Liquid / oral solution","studyIds":["pmid-36046952","pmid-29194416","pmid-11360039","pmid-39771491","pmid-29109369"]},{"slug":"sublingual","label":"Sublingual / oral spray","studyIds":["pmid-37438493"]}],"pairs":[{"anchor":"immediate-release-vs-extended-release","a":"immediate-release","b":"extended-release","aLabel":"Immediate-release tablet / capsule","bLabel":"Prolonged / extended-release","studyIds":[],"evidence":{"grade":null,"basis":"no_data","rationale":"No relevant studies in the database for this question.","counts":{}}},{"anchor":"sublingual-vs-immediate-release","a":"sublingual","b":"immediate-release","aLabel":"Sublingual / oral spray","bLabel":"Immediate-release tablet / capsule","studyIds":[],"evidence":{"grade":null,"basis":"no_data","rationale":"No relevant studies in the database for this question.","counts":{}}}],"studies":[{"id":"pmid-42325096","title":"Pharmacokinetics of Intravenous Melatonin in Preschool-Aged Pediatric Surgical Patients.","year":"2026","journal":"Paediatric anaesthesia","pmid":"42325096","pmcid":null,"doi":"10.1002/pan.70248","url":"https://pubmed.ncbi.nlm.nih.gov/42325096/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/42325096/","doiUrl":"https://doi.org/10.1002/pan.70248","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13551265/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"single-arm","n":"20","formsStudiedRaw":"Melatonin (intravenous solution for injection 1 mg/mL, GMP investigational product)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Administering intravenous melatonin in a dose of 0.15 mg·kg−1 in 1–6-year-olds yielded pharmacokinetic characteristics comparable to those reported in adults.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"Cmax of 416 298 [IQR 322 230–508 006] pg·mL −1","source":"fulltext","location":"Table 2","truncated":false},{"metric":"AUC","text":"AUC0–∞ was 8 352 522 [7 287 183–9 181 133] pg·min·mL −1","source":"fulltext","location":"Table 2","truncated":false}]},{"id":"pmid-40608082","title":"Melatonin for prevention of delirium in patients receiving mechanical ventilation in the intensive care unit: a multiarm multistage adaptive randomized controlled clinical trial (DEMEL).","year":"2025","journal":"Intensive care medicine","pmid":"40608082","pmcid":null,"doi":"10.1007/s00134-025-08002-z","url":"https://pubmed.ncbi.nlm.nih.gov/40608082/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40608082/","doiUrl":"https://doi.org/10.1007/s00134-025-08002-z","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12283818/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"RCT (multiarm multistage adaptive phase 2b/3, placebo-controlled, double-blind)","n":"355 randomized; 334 ITT; 75 in activity-stage PK analysis","formsStudiedRaw":"Melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"This randomized clinical trial found that the low-dose of melatonin (0.3 mg nightly) achieved a better pharmacokinetic profile than the high-dose (3 mg nightly), but did not change the incidence of delirium compared to placebo in mechanically ventilated critically-ill patients.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"12/24, 50% ... 6/25, 24% ... 0/26, 0%","source":"fulltext","location":"Abstract; Results Activity stage","truncated":false}]},{"id":"pmid-37150895","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","year":"2024","journal":"Journal of dietary supplements","pmid":"37150895","pmcid":null,"doi":"10.1080/19390211.2023.2206475","url":"https://pubmed.ncbi.nlm.nih.gov/37150895/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37150895/","doiUrl":"https://doi.org/10.1080/19390211.2023.2206475","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","formsStudiedRaw":"Melatonin (extended-release vs immediate-release bi-layer tablets)","formTags":["extended-release"],"food":true,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In conclusion, this extended-release melatonin formulation quickly raised plasma melatonin levels and sustained levels above 300 pg/mL for 6 h before falling below 50 pg/mL by 9 h.","source":"fulltext","location":"Conclusion p.11","truncated":false},{"metric":"Tmax","text":"longer time to peak concentration (1.56 vs 0.6 h)","source":"fulltext","location":"Table 2; Abstract","truncated":false},{"metric":"Cmax","text":"7581 pg/mL vs 13120 pg/mL","source":"fulltext","location":"Table 2; Abstract","truncated":false},{"metric":"Comparison","text":"The extended-release melatonin had a lower maximum concentration (Cmax, p < 0.002)","source":"fulltext","location":"Table 2; Results p.9","truncated":false},{"metric":"Comparison","text":"longer time to reach maximum concentration in the blood (Tmax = 1.56 h, p < 0.001)","source":"fulltext","location":"Table 2; Results p.9","truncated":false},{"metric":"Comparison","text":"no significant differences in AUC and iAUC(0-10h)","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Comparison","text":"lower for extended-release melatonin ... indicating a slower rate of absorption (77% less)","source":"fulltext","location":"Results p.9; Table 2","truncated":false},{"metric":"Comparison","text":"terminal disposition rate constant (λ) (p < 0.001) were lower for extended-release","source":"fulltext","location":"Results p.9; Table 2","truncated":false},{"metric":"Comparison","text":"absorption half-life (ta1/2) (p < 0.002) was greater with the immediate-release formulation","source":"fulltext","location":"Results p.9; Table 2","truncated":false},{"metric":"Comparison","text":"terminal half-life (t1/2) however, was greater with the extended-release formulation","source":"fulltext","location":"Results p.9; Table 2","truncated":false}]},{"id":"pmid-39174857","title":"Melatonin Bioavailability After Oral Administration of a New Delayed-Release Form in Healthy Male Volunteers.","year":"2024","journal":"Drugs in R&D","pmid":"39174857","pmcid":null,"doi":"10.1007/s40268-024-00482-6","url":"https://pubmed.ncbi.nlm.nih.gov/39174857/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39174857/","doiUrl":"https://doi.org/10.1007/s40268-024-00482-6","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11456059/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"open-label, single-arm, single-centre bioavailability study (compared with historical prolonged-release data from a previous study)","n":"14 included; 12 in PK analysis","formsStudiedRaw":"Melatonin 1.9 mg delayed-release tablet (with 10 mg zinc and 200 mg lemon balm extract, baobab pulp, sodium alginate)","formTags":["extended-release"],"food":true,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The melatonin release profile of the newly developed delayed-release form is in line with what was anticipated for this formulation, with a peak observed 3 h after intake and significant release up to 7 h after intake.","source":"fulltext","location":"Conclusions p.421","truncated":false},{"metric":"Cmax","text":"Cmax 740 ± 824 pg/mL; Tmax 179 ± 60 min","source":"fulltext","location":"Abstract; Results 3.2","truncated":false},{"metric":"Tmax","text":"Tmax: 179 ± 60 min","source":"fulltext","location":"Abstract; Results 3.2","truncated":false},{"metric":"AUC","text":"Melatonin relative AUC0/720 was 2328 ± 2721 pg × h/mL","source":"fulltext","location":"Results 3.2","truncated":false},{"metric":"AUC","text":"2295 ± 2649 versus 3070 ± 1452 pg × h/mL, p < 0.05","source":"fulltext","location":"Discussion p.420","truncated":false},{"metric":"AUC","text":"3070 ± 1452 pg × h/mL","source":"fulltext","location":"Discussion p.420","truncated":false},{"metric":"Cmax","text":"Cmax 1151 ± 565 pg/mL, Tmax of 64 ± 44 min","source":"fulltext","location":"Introduction p.416; Discussion p.420","truncated":false},{"metric":"Tmax","text":"Tmax of 64 ± 44 min","source":"fulltext","location":"Introduction p.416; Discussion p.420","truncated":false},{"metric":"Comparison","text":"the peak of the DR form was significantly lower (Cmax 740 ± 824 versus 1151 ± 565 pg/mL, p < 0.05)","source":"fulltext","location":"Discussion p.420","truncated":false},{"metric":"Comparison","text":"delayed (Tmax 179 ± 60 versus 64 ± 44 min, p < 0.001)","source":"fulltext","location":"Discussion p.420","truncated":false}]},{"id":"pmid-39458580","title":"Comparative Pharmacokinetics of Sustained-Release versus Immediate-Release Melatonin Capsules in Fasting Healthy Adults: A Randomized, Open-Label, Cross-Over Study.","year":"2024","journal":"Pharmaceutics","pmid":"39458580","pmcid":null,"doi":"10.3390/pharmaceutics16101248","url":"https://pubmed.ncbi.nlm.nih.gov/39458580/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39458580/","doiUrl":"https://doi.org/10.3390/pharmaceutics16101248","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11510348/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover (open-label, balanced, two-treatment, two-sequence, two-period)","n":"16","formsStudiedRaw":"Melatonin 5 mg sustained-release (Melatonin-SR, Melotime) vs 5 mg immediate-release (Melatonin-IR)","formTags":["extended-release"],"food":true,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Melatonin-SR capsules, on a single oral dose administration, elevated plasma melatonin levels and sustained them over an extended period (up to 8 h) as compared to immediate release products.","source":"fulltext","location":"Conclusions p.9","truncated":false},{"metric":"AUC","text":"Five participants were excluded from the calculation of AUC0–∞","source":"fulltext","location":"Table 2 (footnote a)","truncated":false},{"metric":"AUC","text":"One participant was excluded from the calculation of AUC0–∞","source":"fulltext","location":"Table 2 (footnote b)","truncated":false},{"metric":"Tmax","text":"1.26 [0.59] h vs. 0.87 [0.42] h","source":"fulltext","location":"Table 3","truncated":false},{"metric":"Comparison","text":"Melatonin-SR reported a lower Cmax (11,446.87 pg/mL) compared to Melatonin-IR (22,786.30 pg/mL)","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Comparison","text":"noteworthy though not significant (p > 0.05)","source":"fulltext","location":"Results p.7","truncated":false}]},{"id":"pmid-37438493","title":"Bioavailability of Melatonin after Administration of an Oral Prolonged-Release Tablet and an Immediate-Release Sublingual Spray in Healthy Male Volunteers.","year":"2023","journal":"Drugs in R&D","pmid":"37438493","pmcid":null,"doi":"10.1007/s40268-023-00431-9","url":"https://pubmed.ncbi.nlm.nih.gov/37438493/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37438493/","doiUrl":"https://doi.org/10.1007/s40268-023-00431-9","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10439092/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover (single-center, open-label)","n":"14 included; PK in 13 per form (text); Table 1 states 12 volunteers","formsStudiedRaw":"Melatonin (oral prolonged-release tablet vs immediate-release sublingual spray); metabolite 6-sulfatoxymelatonin (6-SMT)","formTags":["extended-release","sublingual"],"food":true,"timing":true,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Overall, our results suggest that the galenic forms containing melatonin assessed in this study are suitable for the management of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form.","source":"fulltext","location":"Conclusions (p.7)","truncated":false},{"metric":"Cmax","text":"Cmax: 1151 ± 565 pg/mL; Tmax: 64.2 ± 44.2 min","source":"fulltext","location":"Table 1; Abstract; Results 3.3","truncated":false},{"metric":"Cmax","text":"1151 versus 2380 pg/mL on average","source":"fulltext","location":"Table 1; Discussion","truncated":false},{"metric":"Cmax","text":"Cmax: 2332 ± 950 pg/mL; Tmax: 23.3 ± 6.5 min","source":"fulltext","location":"Abstract; Results 3.3","truncated":false},{"metric":"Tmax","text":"Tmax: 64.2 ± 44.2 min","source":"fulltext","location":"Table 1; Abstract","truncated":false},{"metric":"Tmax","text":"Tmax: 23.3 ± 6.5 min","source":"fulltext","location":"Table 1; Abstract","truncated":false},{"metric":"AUC","text":"3070 ± 1452 pg⋅h/mL for PR form versus 2903 ± 867 pg⋅h/mL for IR form","source":"fulltext","location":"Table 1; Results 3.3; Discussion","truncated":false},{"metric":"Relative bioavailability","text":"Taking into consideration the doses, IR form bioavailability was nearly twice (1.89) as high as that of the PR form.","source":"fulltext","location":"Results 3.3","truncated":false},{"metric":"Comparison","text":"tablet intake produced a lower peak (Cmax: 1151 ± 565 pg/mL ...; p < 0.001 for comparison of Cmax and Tmax)","source":"fulltext","location":"Table 1; Abstract","truncated":false},{"metric":"Comparison","text":"AUCs were of the same order of magnitude for both galenic forms","source":"fulltext","location":"Table 1","truncated":false}]},{"id":"pmid-36046952","title":"Dose assessment of melatonin in sepsis (DAMSEL2) study: Pharmacokinetics of two doses of oral melatonin in patients with sepsis.","year":"2022","journal":"Journal of pineal research","pmid":"36046952","pmcid":null,"doi":"10.1111/jpi.12830","url":"https://pubmed.ncbi.nlm.nih.gov/36046952/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36046952/","doiUrl":"https://doi.org/10.1111/jpi.12830","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9787748/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"open-label","n":"10","formsStudiedRaw":"Melatonin (oral liquid)","formTags":["liquid"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"We conclude that 20 mg seems a suitable dose of liquid melatonin in patients with sepsis.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"Cmax ... median [range] concentration of 1465 [986−1928] ng/ml","source":"fulltext","location":"Table 3; Results 3.3.1","truncated":false},{"metric":"Cmax","text":"Cmax levels ... 240 [146−350] ng/ml, p = .008","source":"fulltext","location":"Table 3; Results 3.3.1","truncated":false},{"metric":"Cmax","text":"49.5 ng/ml compared to 74.6 ng/ml after a dose of 20 or 50 mg","source":"fulltext","location":"Results p.7","truncated":false},{"metric":"Cmax","text":"268 ng/ml compared to 1440 ng/ml after 20 or 50 mg doses","source":"fulltext","location":"Results p.7","truncated":false},{"metric":"Comparison","text":"Cmax levels in patients with sepsis were significantly lower than levels seen after the higher dose (240 [146−350] ng/ml, p = .008, Figure 2)","source":"fulltext","location":"Results 3.3.1, p.5","truncated":false},{"metric":"Comparison","text":"not significantly different from Cmax in the 20 mg dose cohort (p = .22, Figure 2)","source":"fulltext","location":"Results 3.3.1, p.6","truncated":false},{"metric":"Comparison","text":"relative bioavailability (Frel) and the absorption rate constant (ka) for capsules were lower compared to the liquid melatonin formulation (Frel = 19% vs. 100%, ka = 0.11 vs. 0.28/min)","source":"fulltext","location":"Results p.7; Table 4","truncated":false}]},{"id":"pmid-32937627","title":"Pharmacokinetics and Safety of Intravenous, Intravesical, Rectal, Transdermal, and Vaginal Melatonin in Healthy Female Volunteers: A Cross-Over Study.","year":"2021","journal":"Pharmacology","pmid":"32937627","pmcid":null,"doi":"10.1159/000510252","url":"https://pubmed.ncbi.nlm.nih.gov/32937627/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32937627/","doiUrl":"https://doi.org/10.1159/000510252","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover (route order not stated in extracted text; 5 sessions)","n":"10","formsStudiedRaw":"Melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Rectally and vaginally administered melatonin may serve as relevant alternatives to standard oral melatonin therapy. Transdermal delivery of melatonin displayed an extended absorption and can be applied if prolonged effects are intended. Intravesical administration displayed, as expected, a very limited bioavailability. Melatonin administered by these routes of administration was safe.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Tmax","text":"21 (8) h for transdermal","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Tmax","text":"Transdermal administration reached tmax between 16 and 24 h, with most participants showing tmax at 24 h","source":"fulltext","location":"Results p.172","truncated":false},{"metric":"Absolute bioavailability","text":"3 participants reaching a bioavailability of over 100%","source":"fulltext","location":"Results p.172; Discussion p.174","truncated":false},{"metric":"Comparison","text":"KSS score following transdermal administration was significantly increased compared to baseline values (p = 0.028)","source":"fulltext","location":"Table 4; Results p.172","truncated":false},{"metric":"Comparison","text":"Pre- and post-administration SRT scores did not differ for any of the routes of administration (p > 0.05)","source":"fulltext","location":"Results p.172","truncated":false}]},{"id":"pmid-30734962","title":"Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia.","year":"2019","journal":"Journal of pineal research","pmid":"30734962","pmcid":null,"doi":"10.1111/jpi.12565","url":"https://pubmed.ncbi.nlm.nih.gov/30734962/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/30734962/","doiUrl":"https://doi.org/10.1111/jpi.12565","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"single-arm","n":"5","formsStudiedRaw":"Melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Melatonin half‐life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"The peak plasma concentration reached 0.25 µg/mL.","source":"fulltext","location":"Abstract; Results 3.3","truncated":false},{"metric":"Cmax","text":"maximal serum concentration (Cmax) was 0.27 ± 0.04 μg/mL (0.25 μg/mL in the population analysis)","source":"fulltext","location":"Results 3.3","truncated":false},{"metric":"Cmax","text":"The measured peak concentration varied greatly among patients (0.08‐0.28 μg/mL)","source":"fulltext","location":"Results 3.3","truncated":false},{"metric":"AUC","text":"The area under the curve in 24 hours was 4.35 µg/mL*h.","source":"fulltext","location":"Abstract; Results 3.3","truncated":false},{"metric":"Tmax","text":"individual mean time to maximal concentration (Tmax) was 8.66 ± 1.12 hours (6.8 hours in the population analysis)","source":"fulltext","location":"Results 3.3","truncated":false},{"metric":"AUC","text":"AUC calculated for the entire study period was 17.44 ± 9.92 μg/mL*h","source":"fulltext","location":"Results 3.3","truncated":false},{"metric":"AUC","text":"The expected AUC at the steady state after the 4th virtual infusion is 9.71 μg/mL*h","source":"fulltext","location":"Results 3.4","truncated":false},{"metric":"Comparison","text":"AUC was lower compared to the AUC of 10.48 μg/mL*h found in a previous study that administered the same dose of melatonin as a single bolus","source":"fulltext","location":"Discussion","truncated":false}]},{"id":"pmid-31381847","title":"A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation.","year":"2019","journal":"The primary care companion for CNS disorders","pmid":"31381847","pmcid":null,"doi":"10.4088/PCC.19m02450","url":"https://pubmed.ncbi.nlm.nih.gov/31381847/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/31381847/","doiUrl":"https://doi.org/10.4088/PCC.19m02450","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover","n":"10","formsStudiedRaw":"Melatonin","formTags":["extended-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The novel, well-tolerated CRA-melatonin was shown to achieve quick release and then continuous release and absorption of melatonin for up to 7 hours, making it a significant advancement in the pharmacokinetic release profile of exogenous melatonin delivery and, therefore, an important potential consideration as a baseline therapy for sleep.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"Within the first hour of dosing, a median Cmax of 4,690 pg/mL was reached for CRA-melatonin","source":"fulltext","location":"Abstract; Results","truncated":false},{"metric":"Cmax","text":"compared to a median Cmax of 23,352 pg/mL for IR-melatonin","source":"fulltext","location":"Abstract; Results","truncated":false},{"metric":"Comparison","text":"median Cmax of 4,690 pg/mL ... compared to ... 23,352 pg/mL; ... median of 6.7 hours ... compared with ... 3.7 hours","source":"fulltext","location":"Results","truncated":false}]},{"id":"pmid-28368352","title":"Melatonin Pharmacological Blood Levels Increase Total Antioxidant Capacity in Critically Ill Patients.","year":"2017","journal":"International journal of molecular sciences","pmid":"28368352","pmcid":null,"doi":"10.3390/ijms18040759","url":"https://pubmed.ncbi.nlm.nih.gov/28368352/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/28368352/","doiUrl":"https://doi.org/10.3390/ijms18040759","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5412344/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"RCT","n":"64 enrolled (placebo 29, melatonin 35 per Table 1)","formsStudiedRaw":"Melatonin (oral/enteral tablet)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Enteral administration of melatonin was adequate to obtain pharmacological levels even in the early phase of critically-illnesses, with a favourable pharmacokinetic profile.","source":"fulltext","location":"Conclusions (section 5)","truncated":false},{"metric":"AUC","text":"53,413 vs. 1221 pg·h·mL−1 for the melatonin vs. placebo (p < 0.001)","source":"fulltext","location":"Results 2.2 p.5","truncated":false},{"metric":"Comparison","text":"melatonin levels increased to 2514 ... vs. 20.3 ... (p < 0.001)","source":"fulltext","location":"Abstract; Results 2.2; Discussion 3.1","truncated":false},{"metric":"Comparison","text":"the differences with endogenous levels were statistically significant also after 14 h","source":"fulltext","location":"Results 2.2 p.3","truncated":false},{"metric":"Comparison","text":"no accumulative effect was observed either at midnight or at 14:00 h","source":"fulltext","location":"Results 2.2 p.5","truncated":false},{"metric":"Comparison","text":"afternoon: p = 0.208","source":"fulltext","location":"Results 2.2 p.5","truncated":false},{"metric":"Comparison","text":"in group P nocturnal secretion (00:00) was impaired","source":"fulltext","location":"Abstract; Results 2.2","truncated":false},{"metric":"Comparison","text":"similar in the two randomized groups","source":"fulltext","location":"Results 2.2","truncated":false}]},{"id":"pmid-29194416","title":"Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates.","year":"2017","journal":"Molecules (Basel, Switzerland)","pmid":"29194416","pmcid":null,"doi":"10.3390/molecules22122115","url":"https://pubmed.ncbi.nlm.nih.gov/29194416/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/29194416/","doiUrl":"https://doi.org/10.3390/molecules22122115","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6149762/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"RCT","n":"15","formsStudiedRaw":"Melatonin (oral solution, Melamil 5 mg/mL, intragastric via nasogastric tube)","formTags":["liquid"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Results point out the possibility to obtain and maintain neuroprotective concentrations of melatonin in blood using a single oral administration of the indoleamine repeated every 12/24 h.","source":"fulltext","location":"Conclusions (section 5)","truncated":false},{"metric":"Comparison","text":"These Tmax values are higher compared to adults, and do not appear to depend on the dose","source":"fulltext","location":"Discussion p.6","truncated":false}]},{"id":"pmid-27566320","title":"Pharmacokinetics of Repeated Melatonin Drug Administrations Prior to and After Surgery.","year":"2016","journal":"Clinical drug investigation","pmid":"27566320","pmcid":null,"doi":"10.1007/s40261-016-0452-5","url":"https://pubmed.ncbi.nlm.nih.gov/27566320/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/27566320/","doiUrl":"https://doi.org/10.1007/s40261-016-0452-5","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"other (prospective two-phase cohort, same patients dosed twice)","n":"12","formsStudiedRaw":"Melatonin (oral capsule)","formTags":["immediate-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"These preliminary results indicate that postoperative melatonin dose should be augmented compared with preoperative administration if corresponding melatonin plasma levels are intended.","source":"fulltext","location":"Abstract (Conclusions)","truncated":false},{"metric":"Comparison","text":"t absorption and Tmax were significantly increased during the postoperative phase","source":"fulltext","location":"Abstract; Results p.1047","truncated":false},{"metric":"Comparison","text":"Cmax values were significantly higher during surgery compared with postoperative values","source":"fulltext","location":"Abstract; Results p.1047","truncated":false},{"metric":"Comparison","text":"t elimination was significantly extended during the postoperative phase","source":"fulltext","location":"Abstract; Results p.1048","truncated":false},{"metric":"Comparison","text":"AUC? did not differ between the study phases (p > 0.05)","source":"fulltext","location":"Abstract; Results p.1048","truncated":false},{"metric":"Comparison","text":"Baseline melatonin plasma concentrations did not differ significantly","source":"fulltext","location":"Results p.1047","truncated":false}]},{"id":"pmid-24650045","title":"Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis.","year":"2014","journal":"Journal of pineal research","pmid":"24650045","pmcid":null,"doi":"10.1111/jpi.12134","url":"https://pubmed.ncbi.nlm.nih.gov/24650045/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/24650045/","doiUrl":"https://doi.org/10.1111/jpi.12134","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC4279949/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"open-label","n":"20","formsStudiedRaw":"Melatonin","formTags":["immediate-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Melatonin was rapidly cleared at all doses with a median [range] elimination half-life of 51.7 [29.5–63.2] min across all doses. There was considerable variability in maximum melatonin levels within each dose cohort, but 6-hydoxymelatonin sulfate levels were less variable and remained stable for several hours.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Tmax","text":"maximum levels reached at 30–60 min (Table 4)","source":"fulltext","location":"Results p.431","truncated":false},{"metric":"Tmax","text":"maximum levels reached at a median of 120 min","source":"fulltext","location":"Results p.431","truncated":false},{"metric":"Comparison","text":"significant effect of melatonin dose on both the area under the concentration curve (AUC, P = 0.0065)","source":"fulltext","location":"Results p.431 text","truncated":false},{"metric":"Comparison","text":"Significant effect of dose (P = 0.006)","source":"fulltext","location":"Table 4 footnote a","truncated":false},{"metric":"Comparison","text":"maximum concentration (Cmax, P = 0.0018)","source":"fulltext","location":"Results p.431 text","truncated":false},{"metric":"Comparison","text":"There was a significant dose effect (P = 0.0018)","source":"fulltext","location":"Results p.431; Table 5 footnote a","truncated":false},{"metric":"Comparison","text":"levels after 30, 50, or 100 mg were significantly higher than after 20 mg (all P < 0.001)","source":"fulltext","location":"Fig. 2 legend","truncated":false}]},{"id":"pmid-25046730","title":"Soft gel capsules improve melatonin's bioavailability in humans.","year":"2014","journal":"Expert opinion on drug metabolism & toxicology","pmid":"25046730","pmcid":null,"doi":"10.1517/17425255.2014.943183","url":"https://pubmed.ncbi.nlm.nih.gov/25046730/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/25046730/","doiUrl":"https://doi.org/10.1517/17425255.2014.943183","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"parallel","n":"60","formsStudiedRaw":"Melatonin","formTags":["immediate-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Soft gel capsules improved the bioavailability of melatonin in humans even when administered dose was reduced.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Tmax","text":"60 ± 6.15","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Tmax","text":"60 ± 5.20","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Tmax","text":"40 ± 8.85","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Cmax","text":"799.1 ± 39.03","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Cmax","text":"2620 ± 93.30","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Cmax","text":"2405 ± 278.9","source":"fulltext","location":"Table 1","truncated":false},{"metric":"AUC","text":"90516 ± 6579","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Comparison","text":"There are no significant differences between Tmax values of 1 mg of melatonin powder and 1 mg of melatonin soft gel capsule","source":"fulltext","location":"Table 1; Results p.1195-1196","truncated":false},{"metric":"Comparison","text":"Both are significantly higher than Tmax values of 3 mg of melatonin powder","source":"fulltext","location":"Table 1 footnote (‡ p<0.01 ANOVA Bonferroni)","truncated":false}]},{"id":"pmid-22804755","title":"Plasma insulin, leptin, adiponectin, resistin, ghrelin, and melatonin in nonalcoholic steatohepatitis patients treated with melatonin.","year":"2013","journal":"Journal of pineal research","pmid":"22804755","pmcid":null,"doi":"10.1111/j.1600-079X.2012.01023.x","url":"https://pubmed.ncbi.nlm.nih.gov/22804755/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/22804755/","doiUrl":"https://doi.org/10.1111/j.1600-079X.2012.01023.x","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"other (single-arm open-label treatment study with healthy control group for baseline only)","n":"16 NASH patients + 15 controls","formsStudiedRaw":"Melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"the results of the current study demonstrate that 4-wk melatonin treatment leads to an attenuation of insulin resistance, a rise in reduced plasma levels of adipokines including adiponectin, ghrelin, and leptin and an improvement of plasma liver enzymes in patients with NASH.","source":"fulltext","location":"Discussion, final paragraph","truncated":false},{"metric":"Comparison","text":"Median melatonin levels between controls and patients did not differ significantly","source":"fulltext","location":"Results p.5","truncated":false},{"metric":"Comparison","text":"Melatonin therapy was associated with a several-fold increase above baseline","source":"fulltext","location":"Table 3; Results p.5","truncated":false}]},{"id":"pmid-22348451","title":"Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults.","year":"2012","journal":"Journal of pineal research","pmid":"22348451","pmcid":null,"doi":"10.1111/j.1600-079X.2011.00958.x","url":"https://pubmed.ncbi.nlm.nih.gov/22348451/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/22348451/","doiUrl":"https://doi.org/10.1111/j.1600-079X.2011.00958.x","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC3682489/","pdfLink":null,"openAccess":"open access: yes (free in PMC)","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized, double-blind, placebo-controlled parallel PK substudy","n":"27 (8 placebo, 9 low dose, 10 high dose)","formsStudiedRaw":"Melatonin surge-sustained release (25% immediate release + 75% controlled release), 0.4 mg and 4.0 mg","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The findings from this study suggest that melatonin half-life, Tmax, apparent total clearance, and apparent volume of distribution are similar for both low- and high-dose surge-sustained melatonin formulations in older adults, consistent with linear pharmacokinetic behavior.","source":"fulltext","location":"Discussion p.443","truncated":false},{"metric":"Tmax","text":"Mean (S.E.)","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Tmax","text":"Maximal concentration was reached in 1.3 ± 0.19 hrs in the low-dose arm and 1.5 ± 0.24 hrs in the high-dose arm (Tmax)","source":"fulltext","location":"Results p.440","truncated":false},{"metric":"Tmax","text":"1.3 ± 0.19 hrs in the low-dose arm and 1.5 ± 0.24 hrs in the high-dose arm (Tmax)","source":"fulltext","location":"Results p.440","truncated":false},{"metric":"Cmax","text":"The maximum concentration was 405 ± 93 pg/mL for the low-dose arm and 3999 ± 700 pg/mL for the high-dose arm","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"3999 ± 700 pg/mL for the high-dose arm","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"The median peak concentrations pretreatment was 46.7 pg/mL (range: 23.6–118 pg/mL)","source":"fulltext","location":"Results p.440","truncated":false},{"metric":"Comparison","text":"with no significant difference between the two arms (P = 0.6)","source":"fulltext","location":"Results p.440","truncated":false},{"metric":"Comparison","text":"The average maximal serum concentration was significantly greater in the high-dose arm (P < 0.001).","source":"fulltext","location":"Results p.440","truncated":false},{"metric":"Comparison","text":"mean half-life (t1/2) of 1.8 and 2.1 hrs in the low-dose and high-dose arms, respectively (P = 0.4)","source":"fulltext","location":"Results p.440","truncated":false}]},{"id":"pmid-20070489","title":"Pharmacokinetics of orally administered melatonin in critically ill patients.","year":"2010","journal":"Journal of pineal research","pmid":"20070489","pmcid":null,"doi":"10.1111/j.1600-079X.2009.00737.x","url":"https://pubmed.ncbi.nlm.nih.gov/20070489/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/20070489/","doiUrl":"https://doi.org/10.1111/j.1600-079X.2009.00737.x","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"open-label, single-arm, two sequential cohorts (prospective interventional)","n":"12","formsStudiedRaw":"Melatonin 3 mg (crushed oral tablet via enteral tube)","formTags":["immediate-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Exogenous orally administered melatonin proved to be readily and adequately absorbed, even in the early phase of a critical illness.","source":"fulltext","location":"Discussion p.146","truncated":false},{"metric":"AUC","text":"Pharmacokinetic parameters calculated in the patients of Cohort 1.","source":"fulltext","location":"Table 3","truncated":false},{"metric":"Tmax","text":"Maximal serum melatonin concentration, as measured in Cohort 2, was reached 16 min 52 s (Tmax) after melatonin administration.","source":"fulltext","location":"Results p.144","truncated":false},{"metric":"Comparison","text":"this difference was not statistically significant (P = 0.0547)","source":"fulltext","location":"Discussion p.146","truncated":false},{"metric":"Comparison","text":"melatonin levels after 48–60 hr from ICU admission were significantly depressed (Table 2) compared with the values reported in the literature for healthy volunteers","source":"fulltext","location":"Results p.143","truncated":false}]},{"id":"pmid-18289163","title":"Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men.","year":"2008","journal":"Journal of pineal research","pmid":"18289163","pmcid":null,"doi":"10.1111/j.1600-079X.2007.00499.x","url":"https://pubmed.ncbi.nlm.nih.gov/18289163/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/18289163/","doiUrl":"https://doi.org/10.1111/j.1600-079X.2007.00499.x","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"RCT (single-blind, placebo-controlled, parallel)","n":"46","formsStudiedRaw":"melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later. There might be a dose–response relationship between the plasma concentration of melatonin and coagulation activity.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"Melatonin levels were expectedly higher in subjects who received melatonin than in those under placebo medication","source":"fulltext","location":"Table 1; Results para 1","truncated":false}]},{"id":"pmid-18423009","title":"Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.","year":"2008","journal":"Critical care (London, England)","pmid":"18423009","pmcid":null,"doi":"10.1186/cc6871","url":"https://pubmed.ncbi.nlm.nih.gov/18423009/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/18423009/","doiUrl":"https://doi.org/10.1186/cc6871","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2447606/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"RCT (double-blind, placebo-controlled) with PK sub-analysis in melatonin group","n":"24","formsStudiedRaw":"Melatonin","formTags":[],"food":false,"timing":true,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"A 10-mg nocturnal dose of melatonin is excessive in this patient population and reduced doses of 1 to 2 mg could be used in future chronotherapeutic studies.","source":"fulltext","location":"Conclusion p.7","truncated":false},{"metric":"Tmax","text":"Data are presented as mean (standard deviation).","source":"fulltext","location":"Table 3","truncated":false},{"metric":"AUC","text":"AUC(0-24), area under the concentration time curve between time 0 and 24 hours","source":"fulltext","location":"Table 3","truncated":false}]},{"id":"pmid-18490497","title":"The effect of oral contraceptives on the pharmacokinetics of melatonin in healthy subjects with CYP1A2 g.-163C>A polymorphism.","year":"2008","journal":"Journal of clinical pharmacology","pmid":"18490497","pmcid":null,"doi":"10.1177/0091270008318669","url":"https://pubmed.ncbi.nlm.nih.gov/18490497/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/18490497/","doiUrl":"https://doi.org/10.1177/0091270008318669","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"open-label, single-dose, parallel-group, 4 study groups","n":"29","formsStudiedRaw":"Melatonin (6 mg, 2 x 3 mg tablets)","formTags":["immediate-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In conclusion, a significant inhibitory effect of OCs on the CYP1A2-catalyzed melatonin metabolism was seen; thereby, OC use can alter CYP1A2-phenotyping results.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"AUC","text":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","source":"fulltext","location":"Table I","truncated":false},{"metric":"Tmax","text":"tmax data, which are given as median and range","source":"fulltext","location":"Table I","truncated":false},{"metric":"Comparison","text":"about a 5-fold difference in the AUC (P < .0001)","source":"fulltext","location":"Results p.989","truncated":false},{"metric":"Comparison","text":"a 4-fold difference in the Cmax (P < .0001)","source":"fulltext","location":"Results p.989","truncated":false},{"metric":"Comparison","text":"about an 8-fold difference in the weight-corrected apparent oral clearance","source":"fulltext","location":"Results p.989","truncated":false},{"metric":"Comparison","text":"no statistically significant differences in the pharmacokinetic values of melatonin between representatives of the wild-type (n = 14) and the variant (n = 15) genotypes","source":"fulltext","location":"Results p.989","truncated":false},{"metric":"Comparison","text":"the AUC of melatonin was equal in the nonusers of OCs of the wild-type and of the variant genotypes (P = .97)","source":"fulltext","location":"Results p.989","truncated":false},{"metric":"Comparison","text":"The tmax (P = .71) and t1/2 (P = .90) values did not differ significantly between the groups.","source":"fulltext","location":"Results p.989","truncated":false},{"metric":"Comparison","text":"no statistically significant differences in the AUC, Cmax, t1/2, and tmax values of 6-OH-melatonin between the study groups","source":"fulltext","location":"Results p.989","truncated":false}]},{"id":"pmid-11360039","title":"Determination of exogenous melatonin and its 6-hydroxy metabolite in human plasma by liquid chromatography-mass spectrometry.","year":"2001","journal":"Therapeutic drug monitoring","pmid":"11360039","pmcid":null,"doi":"10.1097/00007691-200106000-00017","url":"https://pubmed.ncbi.nlm.nih.gov/11360039/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/11360039/","doiUrl":"https://doi.org/10.1097/00007691-200106000-00017","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"single-arm","n":"1","formsStudiedRaw":"Melatonin (and 6-hydroxymelatonin metabolite)","formTags":["liquid"],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"From the analysis of our volunteer sample an extremely high first-pass metabolism of orally given melatonin could be demonstrated with metabolite concentrations exceeding those of the parent drug by more than 30-fold.","source":"fulltext","location":"Discussion","truncated":false},{"metric":"Cmax","text":"The maximum concentration (Cmax) of melatonin was 19.2 ng/mL","source":"fulltext","location":"Results, Volunteer Sample p.285","truncated":false},{"metric":"Cmax","text":"that of 6-hydroxymelatonin 694 ng/mL","source":"fulltext","location":"Results, Volunteer Sample p.285","truncated":false},{"metric":"Tmax","text":"Both analytes reached Cmax at the same time, 1.5 hours after melatonin intake.","source":"fulltext","location":"Results, Volunteer Sample p.285","truncated":false}]},{"id":"pmid-10690873","title":"Measurement of urinary melatonin: a useful tool for monitoring serum melatonin after its oral administration.","year":"2000","journal":"The Journal of clinical endocrinology and metabolism","pmid":"10690873","pmcid":null,"doi":"10.1210/jcem.85.2.6349","url":"https://pubmed.ncbi.nlm.nih.gov/10690873/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/10690873/","doiUrl":"https://doi.org/10.1210/jcem.85.2.6349","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"single-arm (Study 2 exogenous); observational (Study 1 endogenous)","n":"Study 1: 16; Study 2: 17","formsStudiedRaw":"Melatonin 3 mg tablet (provided by Novartis Consumer Health)","formTags":["immediate-release"],"food":true,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"After oral application of MLT, however, only measurement of MLT excretion is a reliable marker of serum concentrations. Determination of MLT in urine may prove to be a useful tool for drug monitoring after oral administration of the pineal hormone.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"peak serum MLT concentrations 60 min after its application","source":"fulltext","location":"Table 2 (Exp 2)","truncated":false},{"metric":"Tmax","text":"resulted in peak serum MLT concentrations 60 min after its application","source":"fulltext","location":"Results, Study 2","truncated":false},{"metric":"AUC","text":"AUCMLT differed 16-fold among subjects","source":"fulltext","location":"Table 2 (Exp 2)","truncated":false}]},{"id":"pmid-10883420","title":"The absolute bioavailability of oral melatonin.","year":"2000","journal":"Journal of clinical pharmacology","pmid":"10883420","pmcid":null,"doi":"10.1177/00912700022009422","url":"https://pubmed.ncbi.nlm.nih.gov/10883420/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/10883420/","doiUrl":"https://doi.org/10.1177/00912700022009422","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover","n":"13 enrolled; 12 completed","formsStudiedRaw":"Melatonin (oral tablets 2 mg and 4 mg; IV 2 mg)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Oral melatonin tablets in dosages of 2 and 4 mg show poor absolute bioavailability, either due to poor oral absorption, large first-pass metabolism, or a combination of both.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Absolute bioavailability","text":"Both the 2 and the 4 mg oral dosages showed an absolute bioavailability of approximately 15%.","source":"fulltext","location":"Abstract / Results","truncated":false},{"metric":"Comparison","text":"The AUC0-inf and Cmax for the 2 mg and 4 mg oral doses were not significantly different from each other (p = 0.07).","source":"fulltext","location":"Results p.782","truncated":false},{"metric":"Comparison","text":"the AUC0-inf and Cmax for the oral doses differed significantly from the 2 mg IV dose (p < 0.0001)","source":"fulltext","location":"Results p.782","truncated":false},{"metric":"Comparison","text":"showed no statistically significant difference among doses or routes of administration","source":"fulltext","location":"Results p.782","truncated":false}]},{"id":"pmid-11038434","title":"Bioavailability of melatonin in humans after day-time administration of D(7) melatonin.","year":"2000","journal":"Biopharmaceutics & drug disposition","pmid":"11038434","pmcid":null,"doi":"10.1002/1099-081x(200001)21:1<15::aid-bdd215>3.0.co;2-h","url":"https://pubmed.ncbi.nlm.nih.gov/11038434/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/11038434/","doiUrl":"https://doi.org/10.1002/1099-081x(200001)21:1<15::aid-bdd215>3.0.co;2-h","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover (two-way crossover; randomization not explicitly stated)","n":"12","formsStudiedRaw":"D7 (deuterated) melatonin, oral solution vs IV infusion","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The absolute bioavailability of MLT was from 1 to 37%: mean = 8.6 ± 3.9% and 16.8 ± 12.7% for male and female subjects, respectively.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"The mean MLT Cmax value 243.7 ± 124.6 pg/mL in male subjects","source":"fulltext","location":"Abstract / Results p.19","truncated":false},{"metric":"Cmax","text":"623.6 ± 575.1 pg/mL in females","source":"fulltext","location":"Abstract / Results p.19","truncated":false},{"metric":"AUC","text":"AUCs: 236 ± 107 pg.h/mL","source":"fulltext","location":"Abstract / Results p.19","truncated":false},{"metric":"AUC","text":"701 ± 645 pg.h/mL","source":"fulltext","location":"Abstract / Results p.19","truncated":false},{"metric":"Absolute bioavailability","text":"mean values: 8.6 ± 3.6% for males and 16.8 ± 12.7% for females","source":"fulltext","location":"Abstract / Results p.19","truncated":false},{"metric":"Absolute bioavailability","text":"mean =8.6 ± 3.9% and 16.8 ± 12.7% for male and female subjects","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Absolute bioavailability","text":"The absolute bioavailability of MLT was from 1 to 37%","source":"fulltext","location":"Abstract / Results p.19","truncated":false},{"metric":"Comparison","text":"Cmax and AUC values were significantly different in male and female subjects","source":"fulltext","location":"Abstract / Results p.19","truncated":false},{"metric":"Comparison","text":"There was no significant gender difference in total body clearance normalized to body weight","source":"fulltext","location":"Results p.19","truncated":false}]},{"id":"pmid-10085470","title":"A melatonin preparation with a pulsatile liberation pattern: a new form of melatonin in replacement therapy.","year":"1999","journal":"Biological signals and receptors","pmid":"10085470","pmcid":null,"doi":"10.1159/000014576","url":"https://pubmed.ncbi.nlm.nih.gov/10085470/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/10085470/","doiUrl":"https://doi.org/10.1159/000014576","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover (open, single-dose, 3-way crossover; sequences ABC, BCA, CAB); Abstract says \"randomised, single-dose, threefold cross-over\"","n":"15 humans; 6 dogs","formsStudiedRaw":"Melatonin (oral pulsatile controlled-release capsule vs fast-release)","formTags":["extended-release"],"food":true,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The kinetic profile of the delivery system is adjusted to the pattern of sleep maintenance disturbances.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"Cmax 1 20.7 (A), 16.4 (B), 9.7 (C) ... Cmax 2 of 13.0 and 17.5 pmol/ml, respectively","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Urinary excretion","text":"the amounts of renally excreted aMT6s were about 3.40 mg (capsule A), 6.60 mg (capsule B) and 6.72 mg (capsule C)","source":"fulltext","location":"Results p.6","truncated":false},{"metric":"Cmax","text":"Cmax 1 ≅ 80 pmol/ml, at tmax 1 of approximately 1 h","source":"fulltext","location":"Results p.4 (in vivo studies)","truncated":false},{"metric":"Cmax","text":"the second peak, Cmax 2 ≅ 40 pmol/ml, at tmax 2 of approximately 5 h","source":"fulltext","location":"Results p.4 (in vivo studies)","truncated":false},{"metric":"Comparison","text":"the AUC ratios of A (5 mg MLT) to B or C (10 mg MLT each) are 0.51 for A/B and 0.43 for A/C","source":"fulltext","location":"Results p.6","truncated":false},{"metric":"Comparison","text":"The controlled-release forms B and C produce a second serum peak (Cmax 2 between about 13 and 18 pmol/ml) after about 3.5 h (tmax 2).","source":"fulltext","location":"Results p.4-6","truncated":false}]},{"id":"pmid-10407218","title":"Exercise-induced GH secretion is enhanced by the oral ingestion of melatonin in healthy adult male subjects.","year":"1999","journal":"European journal of endocrinology","pmid":"10407218","pmcid":null,"doi":"10.1530/eje.0.1410022","url":"https://pubmed.ncbi.nlm.nih.gov/10407218/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/10407218/","doiUrl":"https://doi.org/10.1530/eje.0.1410022","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"randomized crossover (randomised, double-blind, placebo-controlled)","n":"7","formsStudiedRaw":"Melatonin 5 mg oral","formTags":[],"food":true,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Since exercise-induced GH secretion is thought to be mediated predominantly through a hypothalamic pathway, it seems likely that melatonin facilitates GH secretion at a hypothalamic level.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"levels reached a mean peak value of 1638 ± 61.9 pg/ml 30 min after ingestion.","source":"fulltext","location":"Results p.24 (para 1)","truncated":false}]},{"id":"pmid-18982259","title":"Batch variation and pharmacokinetics of oral sustained release melatonin-loaded sugar spheres in human subjects.","year":"1997","journal":"Archives of pharmacal research","pmid":"18982259","pmcid":null,"doi":"10.1007/BF02975211","url":"https://pubmed.ncbi.nlm.nih.gov/18982259/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/18982259/","doiUrl":"https://doi.org/10.1007/BF02975211","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"parallel (two groups of subjects, one batch each); in vitro dissolution of 3 batches","n":"10","formsStudiedRaw":"Melatonin (sustained-release sugar spheres in gelatin capsules, 0.2 mg total, 10% immediate release fraction)","formTags":["extended-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The current oral sustained release MT delivery system may be utilized to treat circadian rhythm disorders if it is proven to be more clinically useful when compared to immediate release MT.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"AUC","text":"The calculated AUC of B1 and B2 were 515.5±206.2 and 555.6±334.9 pg-h/ml, respectively.","source":"fulltext","location":"Table I; Results p.558","truncated":false},{"metric":"AUC","text":"No statistically significant difference of AUC between two batches was observed.","source":"fulltext","location":"Table I; Results p.558","truncated":false},{"metric":"Cmax","text":"The Tmax and Cmax of B1 and B2 were found to be 0.5 h and 1.0h; 117±21 pg/ml and 108±33 pg/ml, respectively.","source":"fulltext","location":"Table I; Results p.557","truncated":false},{"metric":"Cmax","text":"There was no significant difference of Cmax between B1 and B2.","source":"fulltext","location":"Table I; Results p.557","truncated":false},{"metric":"Tmax","text":"Tmax ... 0.5 h and 1.0h","source":"fulltext","location":"Table I","truncated":false},{"metric":"Comparison","text":"The Tmax was more advanced in case of B1 when compared to B2","source":"fulltext","location":"Results p.557","truncated":false},{"metric":"Comparison","text":"There was a statistically significant difference in T50% between B1 and B2, and also between B1 and B3.","source":"fulltext","location":"Results p.557; Table I","truncated":false}]},{"id":"pmid-2071448","title":"PET and plasma pharmacokinetic studies after bolus intravenous administration of [11C]melatonin in humans.","year":"1991","journal":"International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology","pmid":"2071448","pmcid":null,"doi":"10.1016/0883-2897(91)90132-5","url":"https://pubmed.ncbi.nlm.nih.gov/2071448/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/2071448/","doiUrl":"https://doi.org/10.1016/0883-2897(91)90132-5","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"single-arm (n=1), PET plus plasma PK","n":"1","formsStudiedRaw":"Melatonin ([11C]melatonin tracer with 42 µg carrier), intravenous bolus","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The results confirmed that melatonin readily crosses the blood-brain barrier and that 6-sulfatoxymelatonin is the main plasma metabolite.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Tmax","text":"Plasma radioactivity ... peaked at 3.5 min","source":"fulltext","location":"Results p.358; Abstract","truncated":false},{"metric":"Tmax","text":"Immunoreactive plasma melatonin and 6-sulfatoxymelatonin peaked at 3.5 and 20 min, respectively","source":"fulltext","location":"Results p.358","truncated":false},{"metric":"Tmax","text":"maximum activity in the brain 8.5min following injection","source":"fulltext","location":"Abstract","truncated":false}]},{"id":"pmid-3994899","title":"Plasma concentrations of melatonin in man following oral absorption of different preparations.","year":"1985","journal":"British journal of clinical pharmacology","pmid":"3994899","pmcid":null,"doi":"10.1111/j.1365-2125.1985.tb02679.x","url":"https://pubmed.ncbi.nlm.nih.gov/3994899/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/3994899/","doiUrl":"https://doi.org/10.1111/j.1365-2125.1985.tb02679.x","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC1463812/","pdfLink":null,"openAccess":"open access: yes (free in PMC)","textUsed":"full text (PDF extraction)","species":"human","speciesRaw":"human","design":"open-label, non-randomized (order of treatments not randomised), fed vs fasted within each preparation","n":"12","formsStudiedRaw":"Melatonin 2 mg (gelatine capsule, corn oil solution, slow-release pill)","formTags":["extended-release"],"food":true,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The slow-release preparation usefully extended high plasma melatonin concentrations for 5-7 h after ingestion but the timing of peak concentrations was very dependent on nutritional status. These preparations should be of use in the study of timed melatonin administration in man.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Tmax","text":"tmax varied from 0.46 ± 0.07 h (gelatine capsule fed), to 0.95 ± 0.42 h (corn oil, fasting","source":"fulltext","location":"Results p.519","truncated":false},{"metric":"Tmax","text":"to 0.95 ± 0.42 h (corn oil, fasting, mean ± s.e. mean)","source":"fulltext","location":"Results p.519","truncated":false},{"metric":"Comparison","text":"Mean melatonin concentrations were higher in the fed than in the fasted state with both preparations","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Comparison","text":"No significant differences were found in the timing of peak plasma melatonin levels between these preparations in either the fasted or the fed state","source":"fulltext","location":"Results p.519","truncated":false},{"metric":"Comparison","text":"no significant differences were present between fasting and fed plasma profiles","source":"fulltext","location":"Results p.519","truncated":false}]},{"id":"pmid-9062870","title":"Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications.","year":"1997","journal":"Journal of pineal research","pmid":"9062870","pmcid":null,"doi":"10.1111/j.1600-079x.1997.tb00302.x","url":"https://pubmed.ncbi.nlm.nih.gov/9062870/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/9062870/","doiUrl":"https://doi.org/10.1111/j.1600-079x.1997.tb00302.x","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"primate","speciesRaw":"other animal (rat, dog, cynomolgus monkey) plus in vitro (Caco-2, rat and human liver slices)","design":"other (IV/oral crossover in dogs and monkeys with washout; parallel groups in rats)","n":"rat 6 per route; dog 2; monkey 2","formsStudiedRaw":"Melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In conclusion, the absolute bioavailability of oral melatonin following a 10 mg/kg dose is moderate in rats and high in dogs and monkeys. However, the bioavailability appears to be dose dependent, at least in dogs and monkeys. Limited in vitro studies indicate the potential for high oral absorption and low first-pass hepatic extraction of melatonin in humans.","source":"fulltext","location":"Discussion, final paragraph","truncated":false},{"metric":"AUC","text":"the plasma AUC was calculated to be 3.53 mg*h/L","source":"fulltext","location":"Results p.49","truncated":false},{"metric":"Absolute bioavailability","text":"dose-normalized intraperitoneal bioavailability of melatonin was 74.0%","source":"fulltext","location":"Results p.49; Abstract","truncated":false},{"metric":"Absolute bioavailability","text":"The mean oral bioavailability of a 10 mg/kg dose of melatonin was found to be 53.5% in rats","source":"fulltext","location":"Table 1; Abstract; Results p.49","truncated":false},{"metric":"Fractional absorption","text":"about 72% of the oral dose was actually absorbed","source":"fulltext","location":"Discussion p.50","truncated":false},{"metric":"Absolute bioavailability","text":"oral bioavailability of melatonin in dogs decreased to 16.9% following a 1 mg/kg oral dose","source":"fulltext","location":"Table 1; Abstract","truncated":false},{"metric":"Absolute bioavailability","text":"in excess of 100% in dogs and monkeys","source":"fulltext","location":"Table 1; Abstract","truncated":false},{"metric":"Comparison","text":"significant dose dependency in the pharmacokinetics","source":"fulltext","location":"Table 1; Discussion","truncated":false},{"metric":"Comparison","text":"suggesting the lack of substantial first-pass hepatic extraction of melatonin in rats","source":"fulltext","location":"Abstract; Results","truncated":false},{"metric":"Comparison","text":"roughly half of that obtained in rats","source":"fulltext","location":"Results; Discussion","truncated":false}]},{"id":"pmid-37969335","title":"Dietary effects of melatonin on growth performance by modulation of protein bioavailability and behavior in early weaned rats and pigs.","year":"2023","journal":"Journal of animal science and technology","pmid":"37969335","pmcid":null,"doi":"10.5187/jast.2023.e44","url":"https://pubmed.ncbi.nlm.nih.gov/37969335/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37969335/","doiUrl":"https://doi.org/10.5187/jast.2023.e44","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10640933/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"pig","speciesRaw":"pig","design":"parallel","n":"Pigs 120; rats: 24 in Methods (abstract says 42)","formsStudiedRaw":"Melatonin (dietary, 50 ppm / 50 mg per kg diet)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Collectively, early weaned animals given dietary melatonin supplementation showed improved growth through upregulation of hepatic antioxidant capacity and minimization of energy-wasting behavior, including roaming and fight states, after pigs' social hierarchy establishment.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"the concentration of melatonin in serum was not different as a result of dietary melatonin supplementation","source":"fulltext","location":"Results p.12; Fig. 3A","truncated":false}]},{"id":"pmid-1617960","title":"Lack of a nocturnal rise of serum melatonin in prepubertal gilts.","year":"1992","journal":"Domestic animal endocrinology","pmid":"1617960","pmcid":null,"doi":"10.1016/0739-7240(92)90029-w","url":"https://pubmed.ncbi.nlm.nih.gov/1617960/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/1617960/","doiUrl":"https://doi.org/10.1016/0739-7240(92)90029-w","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"pig","speciesRaw":"pig","design":"other (four animal experiments; Exp 4 exogenous melatonin vs one control gilt)","n":"Exp 4: 4 gilts (3 melatonin, 1 control)","formsStudiedRaw":"melatonin","formTags":[],"food":false,"timing":true,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Data from experiment 4 indicates that a nocturnal rise in serum melatonin can be measured when melatonin is supplied exogenously to the gilt.","source":"fulltext","location":"Discussion para 1","truncated":false},{"metric":"Comparison","text":"similar serum concentrations of melatonin were measured in samples taken after feeding regardless of whether gilts were in the dark or light (P > 05)","source":"fulltext","location":"Results, Experiment 4","truncated":false},{"metric":"Comparison","text":"Serum concentrations of melatonin were similar (P > .05) in blood samples collected hourly during light and dark periods","source":"fulltext","location":"Results, Experiment 1","truncated":false}]},{"id":"pmid-42306921","title":"Dissolving Microneedles for Transdermal Delivery of Melatonin: Fabrication, Characterization, and In Vivo Pharmacokinetic Evaluation in Mice.","year":"2026","journal":"ACS applied bio materials","pmid":"42306921","pmcid":null,"doi":"10.1021/acsabm.6c00235","url":"https://pubmed.ncbi.nlm.nih.gov/42306921/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/42306921/","doiUrl":"https://doi.org/10.1021/acsabm.6c00235","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"single-arm","n":null,"formsStudiedRaw":"Melatonin (transdermal dissolving microneedles)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Taken together, MEL MNs hold promise as a viable transdermal delivery modality. However, further investigation is warranted to comprehensively evaluate their therapeutic efficacy.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"mean Cmax of 35.06 ± 11.06 ng/mL","source":"fulltext","location":"Results (in vivo PK) para","truncated":false},{"metric":"Cmax","text":"reaching a Cmax of 6.08 ± 3.65 ng/g","source":"fulltext","location":"Abstract; Results","truncated":false}]},{"id":"pmid-42589559","title":"Effects of Melatonin Formulations on Caffeine-Evoked Cortical Activity and Pentobarbital-Induced Sleep in Mice.","year":"2026","journal":"International journal of molecular sciences","pmid":"42589559","pmcid":null,"doi":"10.3390/ijms27156906","url":"https://pubmed.ncbi.nlm.nih.gov/42589559/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/42589559/","doiUrl":"https://doi.org/10.3390/ijms27156906","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13466267/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"parallel (randomized groups, two experiments)","n":"84 (both experiments)","formsStudiedRaw":"Melatonin (standard vs lipid-multiparticulate, LMP)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"LMP-melatonin produced greater formulation-dependent effects than conventional melatonin on caffeine-evoked cortical electrical activity, pentobarbital-induced sedative-hypnotic responses, and selected biochemical and molecular outcomes. However, pharmacokinetic exposure, physiological sleep stages, sleep architecture, sleep quality, and direct measures of neuronal injury were not assessed. Therefore, the findings do not directly establish enhanced bioavailability, physiological sleep promotion, or neuroprotection.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"serum melatonin, serotonin, and dopamine significantly lower in the C group compared with controls","source":"fulltext","location":"Results 2.3; Fig. 3A","truncated":false},{"metric":"Comparison","text":"Standard melatonin dose-dependently restored serum melatonin (C vs. C+M1, C+M2; both p < 0.0001)","source":"fulltext","location":"Results 2.3","truncated":false},{"metric":"Comparison","text":"LMP-melatonin led to significantly greater peak levels at similar doses, with the maximal level observed in the high-dose LMP group (C+M2 vs. C+LMP-M2; p < 0.0001)","source":"fulltext","location":"Results 2.3","truncated":false}]},{"id":"pmid-39722474","title":"Preclinical Evidence for a Drug-Drug Interaction Between Cannabinol and Melatonin.","year":"2025","journal":"Basic & clinical pharmacology & toxicology","pmid":"39722474","pmcid":null,"doi":"10.1111/bcpt.14120","url":"https://pubmed.ncbi.nlm.nih.gov/39722474/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39722474/","doiUrl":"https://doi.org/10.1111/bcpt.14120","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"parallel, randomized (terminal sampling, separate mice per time point)","n":"48 mice (in total, both experiments)","formsStudiedRaw":"Melatonin (10 mg/kg p.o.) with or without cannabinol (CBN, 50 mg/kg p.o.)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"We found CBN potently inhibited CYP1A2-mediated metabolism of melatonin and increased the apparent oral bioavailability of melatonin in mice with a four-fold increase in the plasma melatonin exposure.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"Cmax ng/mL 265 ± 49","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Cmax","text":"184 ± 62","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Tmax","text":"tmax 15 vs 30 min","source":"fulltext","location":"Table 1","truncated":false},{"metric":"AUC","text":"Total melatonin exposure (AUC) was over four times greater (2.54 vs. 10.28 µg*min/mL) when coadministered with CBN","source":"fulltext","location":"Table 1; Results 3.2","truncated":false},{"metric":"Comparison","text":"Total melatonin exposure (AUC) was over four times greater","source":"fulltext","location":"Table 1; Results 3.2","truncated":false},{"metric":"Comparison","text":"there was no significant change in the elimination half-life of melatonin","source":"fulltext","location":"Discussion p.4","truncated":false}]},{"id":"pmid-39065568","title":"Development, Characterization, and Evaluation of Potential Systemic Toxicity of a Novel Oral Melatonin Formulation.","year":"2024","journal":"Pharmaceutics","pmid":"39065568","pmcid":null,"doi":"10.3390/pharmaceutics16070871","url":"https://pubmed.ncbi.nlm.nih.gov/39065568/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39065568/","doiUrl":"https://doi.org/10.3390/pharmaceutics16070871","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11279405/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"single-dose animal PK / in vitro release study","n":"Control n:3 and MEL n:3 (as printed)","formsStudiedRaw":"Melatonin (IT-AA-NVC copolymer chitosan-coated nanoparticle formulation, SM)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Encapsulation in a polymeric carrier can significantly reduce many disadvantages, both by stabilizing the molecule and by providing a sustained release.","source":"fulltext","location":"Conclusions p.15","truncated":false},{"metric":"Cmax","text":"Cmax 7.15271 µg/mL","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Cmax","text":"mean plasma level of melatonin was found to demonstrate a Cmax value of 7.12 µg/mL within 75 min","source":"fulltext","location":"Results p.12-13 (3.2)","truncated":false},{"metric":"Tmax","text":"tmax 75 min","source":"fulltext","location":"Table 2; text p.13","truncated":false},{"metric":"AUC","text":"AUC0→120 450.9 µg.min/mL","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Cmax","text":"Cmax 47 µg/mL (In Vitro)","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Tmax","text":"tmax 40 min (In Vitro)","source":"fulltext","location":"Table 2","truncated":false}]},{"id":"pmid-39771491","title":"LC-MS/MS-Based Concurrent Quantification of Cannabidiol and Melatonin in Mouse Plasma to Elucidate Complex PK Interactions.","year":"2024","journal":"Pharmaceutics","pmid":"39771491","pmcid":null,"doi":"10.3390/pharmaceutics16121511","url":"https://pubmed.ncbi.nlm.nih.gov/39771491/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39771491/","doiUrl":"https://doi.org/10.3390/pharmaceutics16121511","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11728601/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"parallel, randomized (5 groups)","n":"30","formsStudiedRaw":"Melatonin (with or without cannabidiol)","formTags":["liquid"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"High oral doses of CBD inhibit both the intestinal absorption and metabolic clearance of MT, resulting in a more smooth PK profile.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Absolute bioavailability","text":"The bioavailability of MT was determined to be 10.7%.","source":"fulltext","location":"Table 5; Results 3.2.1","truncated":false},{"metric":"Comparison","text":"oral administration of a high dose of CBD (40 mg/kg) considerably reduced the Cmax of MT","source":"fulltext","location":"Table 5; Fig. 5A","truncated":false},{"metric":"Comparison","text":"the change in AUC(0–∞), reflecting overall exposure, was not substantial","source":"fulltext","location":"Table 5; Results 3.2.2","truncated":false},{"metric":"Comparison","text":"co-administration of a low dose of CBD orally did not change the oral concentration–time curve and pharmacokinetic parameters of MT","source":"fulltext","location":"Table 5; Discussion","truncated":false}]},{"id":"pmid-32178261","title":"Bioavailability of Melatonin from Lentil Sprouts and Its Role in the Plasmatic Antioxidant Status in Rats.","year":"2020","journal":"Foods (Basel, Switzerland)","pmid":"32178261","pmcid":null,"doi":"10.3390/foods9030330","url":"https://pubmed.ncbi.nlm.nih.gov/32178261/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32178261/","doiUrl":"https://doi.org/10.3390/foods9030330","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7143261/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"other (single-arm PK study in group 1; parallel groups 2-5 for 90-min bioavailability/bioactivity study)","n":"8 (PK) + 10 per group x 4 groups (bioavailability)","formsStudiedRaw":"Melatonin (from lentil sprout extract; synthetic melatonin comparator)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In view of the results, lentil sprouts can be considered as a source of bioavailable melatonin, whose intake could modulate plasmatic oxidative stress and defend the organism from aging and related diseases, among other potential health benefits.","source":"fulltext","location":"Conclusions (p.14)","truncated":false},{"metric":"Tmax","text":"Tmax (min) 90.0 ± 0.0","source":"fulltext","location":"Table 4","truncated":false},{"metric":"Cmax","text":"Cmax (pg/mL) 45.4 ± 3.5","source":"fulltext","location":"Table 4","truncated":false},{"metric":"Comparison","text":"significantly (p < 0.05) increased melatonin concentration (1.7-fold in contrast to control","source":"fulltext","location":"Results 3.3, p.11","truncated":false},{"metric":"Comparison","text":"2.9-fold in comparison to the Fasting group","source":"fulltext","location":"Results 3.3, p.11","truncated":false},{"metric":"Comparison","text":"22% lower than that of the Lentil Sprouts group","source":"fulltext","location":"Results 3.3, p.11","truncated":false},{"metric":"Comparison","text":"the excretion of aMT6s was significantly (p < 0.05) different","source":"fulltext","location":"Results 3.3, p.13","truncated":false},{"metric":"Comparison","text":"did not suffer significant (p > 0.05) during the fasting period","source":"fulltext","location":"Results 3.3, p.13","truncated":false},{"metric":"Comparison","text":"did not show any significant (p > 0.05) change in the 90 min posttreatment","source":"fulltext","location":"Results 3.3, p.13","truncated":false}]},{"id":"pmid-32439308","title":"In vitro and in vivo evaluation of organic solvent-free injectable melatonin nanoformulations.","year":"2020","journal":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V","pmid":"32439308","pmcid":null,"doi":"10.1016/j.ejpb.2020.05.003","url":"https://pubmed.ncbi.nlm.nih.gov/32439308/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32439308/","doiUrl":"https://doi.org/10.1016/j.ejpb.2020.05.003","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"other (IV formulation comparison, repeated-measures microdialysis in same animals on days 7, 14, 21)","n":null,"formsStudiedRaw":"Melatonin (liposomal LP, MCT nanoemulsion NE, vs DMSO or EtOH solutions)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In this study we have demonstrated a successful production of an injectable melatonin nanoformulation, which consists solely of clinically approved lipids, is stable over time, improves melatonin solubilization, and prolongs in vitro melatonin release in comparison to conventional formulations with organic solvents.","source":"fulltext","location":"Conclusion (p.254)","truncated":false},{"metric":"AUC","text":"AUC were the highest in melatonin-LP (3523.27 mg*min/mL), and the lowest in melatonin-EtOH (1513.92 mg*min/mL)","source":"fulltext","location":"Results 3.4, p.251","truncated":false},{"metric":"Comparison","text":"melatonin-LP had longer time above 1 nM (P = 0.0028)","source":"fulltext","location":"Results 3.7, p.251","truncated":false},{"metric":"Comparison","text":"100 nM (P = 0.021)","source":"fulltext","location":"Results 3.7, p.252","truncated":false},{"metric":"Comparison","text":"200 nM (P = 0.034)","source":"fulltext","location":"Results 3.7, p.252","truncated":false},{"metric":"Comparison","text":"Melatonin-MCT had longer time above 100 nM (P = 0.0051)","source":"fulltext","location":"Results 3.7, p.252","truncated":false},{"metric":"Comparison","text":"and 200 nM (P = 0.034)","source":"fulltext","location":"Results 3.7, p.252","truncated":false},{"metric":"Comparison","text":"All three melatonin-formulations were found to display a comparable PK behavior in circulation","source":"fulltext","location":"Results 3.7 p.251; Discussion p.253","truncated":false},{"metric":"Comparison","text":"The PK parameters, T1/2, Cmax, Tmax, AUC in brain were superior for both melatonin-NPs in comparison to the melatonin dissolved in DMSO.","source":"fulltext","location":"Discussion p.253","truncated":false},{"metric":"Comparison","text":"Melatonin release was slowest from LP","source":"fulltext","location":"Results 3.4; Fig. 2f","truncated":false}]},{"id":"pmid-30625289","title":"PK-PD based optimal dose and time for orally administered supra-pharmacological dose of melatonin to prevent radiation induced mortality in mice.","year":"2019","journal":"Life sciences","pmid":"30625289","pmcid":null,"doi":"10.1016/j.lfs.2019.01.007","url":"https://pubmed.ncbi.nlm.nih.gov/30625289/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/30625289/","doiUrl":"https://doi.org/10.1016/j.lfs.2019.01.007","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"parallel","n":null,"formsStudiedRaw":"Melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"PK parameters at 250 mg/kg dose were qualitatively similar to low dose of melatonin, thus preventing chances of unexpected toxicity.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"Cmax attained was 87.23 ± 9.03 μg/mL at 5 min (Tmax)","source":"fulltext","location":"Results 3.2 (p.33)","truncated":false},{"metric":"Cmax","text":"mean Cmax was 59.82 ± 3.3 μg/mL at 10 ± 4.1 min (Tmax)","source":"fulltext","location":"Results 3.2 (p.33)","truncated":false},{"metric":"Absolute bioavailability","text":"oral bioavailability ... aqueous suspension and PEG formulation were 29% and 98.5% respectively","source":"fulltext","location":"Results 3.2 (p.33)","truncated":false},{"metric":"Absolute bioavailability","text":"29% and 98.5% respectively","source":"fulltext","location":"Results 3.2 (p.33)","truncated":false},{"metric":"Tmax","text":"Tmax at 5 min with closely spaced another distinct concentration peak at 20 min","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"caused a threefold rise in Cmax and AUC as compared to oral suspension (29% bioavailability)","source":"fulltext","location":"Discussion p.36","truncated":false}]},{"id":"pmid-30731257","title":"Melatonin loaded with bacterial cellulose nanofiber by Pickering-emulsion solvent evaporation for enhanced dissolution and bioavailability.","year":"2019","journal":"International journal of pharmaceutics","pmid":"30731257","pmcid":null,"doi":"10.1016/j.ijpharm.2019.01.059","url":"https://pubmed.ncbi.nlm.nih.gov/30731257/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/30731257/","doiUrl":"https://doi.org/10.1016/j.ijpharm.2019.01.059","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"18","formsStudiedRaw":"Melatonin","formTags":["extended-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The bioavailability of MLT-BCNs in rat was much higher than the commercially available MLT. In conclusion, melatonin loaded with BC could be considered as a promising system for improving water solubility and bioavailability of it.","source":"fulltext","location":"Conclusion (p.400)","truncated":false},{"metric":"Cmax","text":"peak concentration ... MLT-BCNs, the commercially available MLT and the physical mixture with raw MLT and BCNs were 299.7 ng/mL, 148.8 ng/mL and 120.1 ng/mL and the peak time was 15 min","source":"fulltext","location":"Results 3.5 (p.400)","truncated":false},{"metric":"Tmax","text":"the peak time was 15 min after oral administration, respectively","source":"fulltext","location":"Results 3.5 (p.400)","truncated":false},{"metric":"Relative bioavailability","text":"AUC of MLT-BCNs was 2.4-fold and 2.6-fold higher than ... commercially available MLT ... and the physical mixture","source":"fulltext","location":"Results 3.5 (p.400); Abstract","truncated":false},{"metric":"Relative bioavailability","text":"AUC of MLT-BCNs was 2.4-fold and 2.6-fold higher","source":"fulltext","location":"Results 3.5 (p.400)","truncated":false},{"metric":"Comparison","text":"The peak concentration of MLT of the commercially available MLT and the physical mixture ... was significantly lower than that of MLT-BCNs (p < 0.05).","source":"fulltext","location":"Results 3.5","truncated":false},{"metric":"Comparison","text":"significantly lower than that of MLT-BCNs (p < 0.05)","source":"fulltext","location":"Results 3.5","truncated":false},{"metric":"Comparison","text":"AUC of MLT-BCNs was 2.4-fold and 2.6-fold higher ... (p < 0.05)","source":"fulltext","location":"Results 3.5","truncated":false},{"metric":"Comparison","text":"The equilibrium solubility of the freeze-dried MLT-BCNs was [higher than] the commercially available MLT (p < 0.05)","source":"fulltext","location":"Results 3.4","truncated":false}]},{"id":"pmid-30286985","title":"Preparation, characterization and in vitro evaluation of melatonin-loaded porous starch for enhanced bioavailability.","year":"2018","journal":"Carbohydrate polymers","pmid":"30286985","pmcid":null,"doi":"10.1016/j.carbpol.2018.08.127","url":"https://pubmed.ncbi.nlm.nih.gov/30286985/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/30286985/","doiUrl":"https://doi.org/10.1016/j.carbpol.2018.08.127","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"12 rats (as printed)","formsStudiedRaw":"Melatonin","formTags":["extended-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The AUC0–360min of the group treated with formulation MPS was approximately 2.34-fold higher than that of raw MLT. Therefore, this study offers a new and simple approach to improve the solubility and bioavailability of MLT.","source":"fulltext","location":"Conclusion (p.132)","truncated":false},{"metric":"Cmax","text":"The Cmax of commercially available MLT, MLT and MPS in rats were 120.11, 134.26 and 291.77 ng/mL, respectively.","source":"fulltext","location":"Results 3.4 (p.131)","truncated":false},{"metric":"Cmax","text":"plasma concentrations of MLT and MPS reached a Cmax of 134.26 and 291.77 ng/mL at 15 and 20 min, respectively","source":"fulltext","location":"Results 3.4 (p.131); Abstract","truncated":false},{"metric":"Tmax","text":"reached a Cmax of 134.26 and 291.77 ng/mL at 15 and 20 min, respectively","source":"fulltext","location":"Abstract; Results 3.4","truncated":false},{"metric":"Tmax","text":"commercially available MLT and MLT reached a maximum concentration within 15 min, followed by a rapid fall","source":"fulltext","location":"Results 3.4 (p.131)","truncated":false},{"metric":"Tmax","text":"The plasma concentration of MPS reaching Cmax at 20 min","source":"fulltext","location":"Abstract; Results 3.4","truncated":false},{"metric":"Relative bioavailability","text":"The AUC0–360min of the formulated MPS-treated group was approximately 2.34-fold higher than that of raw MLT.","source":"fulltext","location":"Abstract; Results 3.4; Conclusion","truncated":false},{"metric":"Comparison","text":"The plasma concentration of MPS-treated rats was always higher than that of those treated with MLT and the market drug Circadin","source":"fulltext","location":"Results 3.4","truncated":false}]},{"id":"pmid-27644893","title":"Melatonin pharmacokinetics after transdermal administration changes according to the time of the day.","year":"2017","journal":"European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences","pmid":"27644893","pmcid":null,"doi":"10.1016/j.ejps.2016.09.020","url":"https://pubmed.ncbi.nlm.nih.gov/27644893/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/27644893/","doiUrl":"https://doi.org/10.1016/j.ejps.2016.09.020","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"other (within-animal repeated-measures at two Zeitgeber times; not described as randomized)","n":"5","formsStudiedRaw":"Melatonin (transdermal 2% emulsion; also IV and oral comparators) and metabolite AFMK","formTags":[],"food":false,"timing":true,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Results indicate that time of day is a variable that should be taken into account when melatonin is transdermally administered.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Absolute bioavailability","text":"The bioavailability, in percentage, was 2.1% (±0.9%) at ZT16 and 5.9% (±3.6%) at ZT4","source":"fulltext","location":"Results p.167 (text)","truncated":false},{"metric":"Tmax","text":"tmax for the IV route had the values of 27 (± 9) min at ZT16 and 18 (± 7) min at ZT4","source":"fulltext","location":"Results 3.2 (text)","truncated":false},{"metric":"Tmax","text":"values ranging from 15 to 139 min at ZT16","source":"fulltext","location":"Results 3.2 (text)","truncated":false},{"metric":"Tmax","text":"from 62 to 183 min at ZT4","source":"fulltext","location":"Results 3.2 (text)","truncated":false},{"metric":"Comparison","text":"C0 and AUC values were more than twice higher at ZT4 than at ZT16, whereas CLP and Vdss values were more than twice lower at ZT4","source":"fulltext","location":"Results 3.1; Table 1","truncated":false},{"metric":"Comparison","text":"AUC was much higher at ZT4 than at ZT16, but also MRT and bioavailability (F) values were higher at ZT4","source":"fulltext","location":"Results 3.1; Table 1","truncated":false},{"metric":"Comparison","text":"Ka was significantly higher at ZT16 than at ZT4, that the tmax at ZT16 occurred earlier than at ZT4","source":"fulltext","location":"Results 3.1; Table 2","truncated":false},{"metric":"Comparison","text":"the bioavailability of the oral route was tenfold higher than the transdermal route","source":"fulltext","location":"Results 3.1; Table 1","truncated":false},{"metric":"Comparison","text":"parameters obtained from the non-compartmental study were not different according to the studied ZTs","source":"fulltext","location":"Results 3.2; Table 3","truncated":false}]},{"id":"pmid-27865856","title":"Melatonin-loaded silica coated with hydroxypropyl methylcellulose phthalate for enhanced oral bioavailability: Preparation, and in vitro-in vivo evaluation.","year":"2017","journal":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V","pmid":"27865856","pmcid":null,"doi":"10.1016/j.ejpb.2016.11.003","url":"https://pubmed.ncbi.nlm.nih.gov/27865856/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/27865856/","doiUrl":"https://doi.org/10.1016/j.ejpb.2016.11.003","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"other (parallel groups, randomised per Methods; preclinical formulation comparison)","n":"9 (Methods text) / '3 groups of six' (inconsistent)","formsStudiedRaw":"Melatonin (raw, MLT-SiO2, MLT-SiO2-HP55 enteric nanosphere)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Our in vitro release and in vivo absorption studies indicated that the proposed preparation of MLT-SiO2-HP55 is an effective method to facilitate the controlled and sustained release of MLT with enhanced bioavailability.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"reached the maximum value of 168.86, 195.33, and 383.71 ng/mL after 15, 15, and 30 min","source":"fulltext","location":"Abstract; Results 3.4","truncated":false},{"metric":"Relative bioavailability","text":"The AUC values of MLT-SiO2 were 1.4 times higher than those of raw MLT.","source":"fulltext","location":"Results 3.4 p.65; Discussion","truncated":false},{"metric":"Relative bioavailability","text":"The corresponding area under the curve (AUC) of MLT-SiO2-HP55 was 3.5 times higher than that of raw MLT.","source":"fulltext","location":"Abstract; Discussion p.65 (oral bioavailability sentence)","truncated":false},{"metric":"Relative bioavailability","text":"AUC values of MLT-SiO2-HP55 were 2.4 and 3.5 times higher than that of raw MLT and MLT-SiO2, respectively","source":"fulltext","location":"Results 3.4 p.65","truncated":false},{"metric":"Comparison","text":"MLT-SiO2-HP55 prolonged Tmax from 15 min to 30 min and increased Cmax from 168.86 ng/mL to 383.71 ng/mL","source":"fulltext","location":"Abstract; Results 3.4","truncated":false},{"metric":"Comparison","text":"Cmax of MLT-SiO2 increased from 168.86 ng/mL to 195.33 ng/mL","source":"fulltext","location":"Discussion p.65","truncated":false},{"metric":"Comparison","text":"The oral bioavailabilities of MLT-SiO2 and MLT-SiO2-HP55 were 1.4 and 3.5 times greater than those of raw MLT, respectively.","source":"fulltext","location":"Abstract; Results 3.4; Discussion","truncated":false}]},{"id":"pmid-29109369","title":"Effects of Melatonin on Glucose Homeostasis, Antioxidant Ability, and Adipokine Secretion in ICR Mice with NA/STZ-Induced Hyperglycemia.","year":"2017","journal":"Nutrients","pmid":"29109369","pmcid":null,"doi":"10.3390/nu9111187","url":"https://pubmed.ncbi.nlm.nih.gov/29109369/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/29109369/","doiUrl":"https://doi.org/10.3390/nu9111187","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5707659/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"other (randomized parallel groups for efficacy; same-animal two-dose PK sub-study)","n":"40 (efficacy); 6 (PK)","formsStudiedRaw":"Melatonin (oral gavage, in 6% alcohol aqueous solution)","formTags":["liquid"],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In conclusion, in this study, six-week oral melatonin administration at 10 mg/kg of BW was able to decrease plasma and liver cholesterol and plasma MDA levels, and increase the adiponectin level.","source":"fulltext","location":"Conclusions (section 5)","truncated":false},{"metric":"Comparison","text":"the 50-mg/kg of BW group had significantly higher serum melatonin concentrations at 10, 30, 60, and 120 min","source":"fulltext","location":"Results 3.8; Table 8","truncated":false},{"metric":"Comparison","text":"no significant difference in the half life and Ke between the 10- and 50-mg/kg BW groups","source":"fulltext","location":"Results 3.8; Table 8","truncated":false},{"metric":"Comparison","text":"The melatonin-treated groups had significantly higher plasma melatonin levels compared to Group D.","source":"fulltext","location":"Results 3.7; Table 7","truncated":false}]},{"id":"pmid-19465096","title":"New findings on melatonin absorption and alterations by pharmaceutical excipients using the Ussing chamber technique with mounted rat gastrointestinal segments.","year":"2009","journal":"International journal of pharmaceutics","pmid":"19465096","pmcid":null,"doi":"10.1016/j.ijpharm.2009.05.024","url":"https://pubmed.ncbi.nlm.nih.gov/19465096/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/19465096/","doiUrl":"https://doi.org/10.1016/j.ijpharm.2009.05.024","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"other (in vitro Ussing chamber, ex vivo rat tissue)","n":null,"formsStudiedRaw":"Melatonin (solution, 0.01% w/v = 100 µg/mL)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Melatonin absorption occurs throughout the GI tract but shows absorption site dependency. The extent of absorption was highest in the rectum followed by the ileum.","source":"fulltext","location":"Conclusions p.15","truncated":false},{"metric":"Comparison","text":"The cumulative absorption was the highest in the rectum (157.4 ± 20 ng/mL) followed by the ileum (104.8 ± 5.2 ng/mL)","source":"fulltext","location":"Results 3.1 p.11","truncated":false},{"metric":"Comparison","text":"*p < 0.05 compared with the control.","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Comparison","text":"**p < 0.01 compared with the control.","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Comparison","text":"The transport of melatonin between SM and MS of the all three areas were almost identical for 90 min","source":"fulltext","location":"Results 3.2 p.11; Fig. 2","truncated":false},{"metric":"Comparison","text":"The transport of 10 µg/mL rhodamine 123 in the efflux direction was greater than that in the absorption way","source":"fulltext","location":"Results 3.2 p.11","truncated":false},{"metric":"Comparison","text":"significantly increased by the addition of 1.0% sodium oleate","source":"fulltext","location":"Results 3.4 p.13","truncated":false}]},{"id":"pmid-17014690","title":"Preclinical evaluation of pharmacokinetics and safety of melatonin in propylene glycol for intravenous administration.","year":"2006","journal":"Journal of pineal research","pmid":"17014690","pmcid":null,"doi":"10.1111/j.1600-079X.2006.00372.x","url":"https://pubmed.ncbi.nlm.nih.gov/17014690/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/17014690/","doiUrl":"https://doi.org/10.1111/j.1600-079X.2006.00372.x","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"other (two-dose parallel preclinical IV PK and safety study)","n":"16 (PK substudy)","formsStudiedRaw":"melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In conclusion, melatonin in propylene glycol markedly elevates plasma levels of melatonin with no serious toxicity. This preparation should be further evaluated in human patients.","source":"fulltext","location":"Abstract","truncated":false}]},{"id":"pmid-8412502","title":"Primary pharmaco-toxicological evaluation of 2-iodomelatonin, a potent melatonin agonist.","year":"1993","journal":"Life sciences","pmid":"8412502","pmcid":null,"doi":"10.1016/0024-3205(93)90596-u","url":"https://pubmed.ncbi.nlm.nih.gov/8412502/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/8412502/","doiUrl":"https://doi.org/10.1016/0024-3205(93)90596-u","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"rodent","speciesRaw":"rodent","design":"other (animal pharmaco-toxicological experiments)","n":null,"formsStudiedRaw":"2-iodomelatonin (melatonin analogue); melatonin used as comparator in ovulation studies only","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: off-target analyte (PK of 2-iodomelatonin (synthetic melatonin analogue) in rats after 30 mg/animal i.p.; not melatonin itself. Native melatonin appears only in ovulation-inhibition dose-response (not PK).)","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In the rat, 2-iodomelatonin was slowly metabolized in vivo; its apparent elimination half-life was about 60 minutes, much longer than that reported for melatonin.","source":"fulltext","location":"Summary","truncated":false},{"metric":"Comparison","text":"about 60 minutes on the average) than that of melatonin (approximately 30 minutes, see ref. 24)","source":"fulltext","location":"Discussion","truncated":false}]},{"id":"pmid-32673769","title":"Design of multi-particulate \"Dome matrix\" with sustained-release melatonin and delayed-release caffeine for jet lag treatment.","year":"2020","journal":"International journal of pharmaceutics","pmid":"32673769","pmcid":null,"doi":"10.1016/j.ijpharm.2020.119618","url":"https://pubmed.ncbi.nlm.nih.gov/32673769/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32673769/","doiUrl":"https://doi.org/10.1016/j.ijpharm.2020.119618","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"other_animal","speciesRaw":"other animal (rabbit)","design":"parallel (2 groups, n=3/group)","n":"6","formsStudiedRaw":"Melatonin (sustained-release) with caffeine (delayed-release) in Dome matrix","formTags":["extended-release"],"food":true,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"A Dome matrix with dual drug release kinetics and controlled pharmacokinetics responses can be produced through appropriate choice of polymer and formulation designs. The Dome matrix of melatonin and caffeine is envisaged to introduce melatonin-induced sleep phase followed by caffeine-stimulated wake phase in jet lag cases.","source":"fulltext","location":"Conclusion (p.9)","truncated":false},{"metric":"Comparison","text":"Formulation of neat melatonin and caffeine in the form of a Dome matrix reduced their Ka and Ke ... a reduction in Cmax and prolonged Tmax","source":"fulltext","location":"Results 3.4, p.9","truncated":false},{"metric":"Comparison","text":"The cumulative melatonin and caffeine fractions were higher when the drugs were administered in the form of a Dome matrix than neat compounds","source":"fulltext","location":"Results 3.4, p.9","truncated":false}]},{"id":"pmid-29702366","title":"Effects of melatonin administration on seminal plasma metabolites and sperm fertilization competence during the non-reproductive season in ram.","year":"2018","journal":"Theriogenology","pmid":"29702366","pmcid":null,"doi":"10.1016/j.theriogenology.2018.04.018","url":"https://pubmed.ncbi.nlm.nih.gov/29702366/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/29702366/","doiUrl":"https://doi.org/10.1016/j.theriogenology.2018.04.018","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"other_animal","speciesRaw":"other animal (sheep, Sarda breed rams)","design":"other (randomized two-group parallel; treated vs untreated)","n":"8","formsStudiedRaw":"Melatonin (subcutaneous slow-release implants)","formTags":["extended-release"],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In conclusion, melatonin treatment during the non-breeding season improves the concentration of several metabolites in seminal plasma and sperm fertilization competence in Sarda breed ram.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"the concentration of melatonin in seminal plasma increased from 3.34 ± 1.70 at day 0 e9.65 ± 2.89 AU after 90 days, then decreased to reach the level of the untreated ram after 120 days (p < 0.05)","source":"fulltext","location":"Abstract; Table 2","truncated":false}]},{"id":"pmid-26440286","title":"A novel LC-MS/MS assay for the simultaneous determination of melatonin and its two major metabolites, 6-hydroxymelatonin and 6-sulfatoxymelatonin in dog plasma: Application to a pharmacokinetic study.","year":"2016","journal":"Journal of pharmaceutical and biomedical analysis","pmid":"26440286","pmcid":null,"doi":"10.1016/j.jpba.2015.09.028","url":"https://pubmed.ncbi.nlm.nih.gov/26440286/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/26440286/","doiUrl":"https://doi.org/10.1016/j.jpba.2015.09.028","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"other_animal","speciesRaw":"other animal (Beagle dog)","design":"single-arm","n":"6","formsStudiedRaw":"melatonin","formTags":["extended-release"],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"S-O-MEL was the predominant component circulating in blood after ingestion of MEL. 6-O-MEL and MEL exhibited similar pharmacokinetic characteristics.","source":"fulltext","location":"Abstract / Section 3.3","truncated":false},{"metric":"Comparison","text":"The data was significantly different from that of MEL according to Student's t test (p < 0.05).","source":"fulltext","location":"Table 4 footnote a","truncated":false}]},{"id":"pmid-26300641","title":"Caenorhabditis elegans as an alternative in vivo model to determine oral uptake, nanotoxicity, and efficacy of melatonin-loaded lipid-core nanocapsules on paraquat damage.","year":"2015","journal":"International journal of nanomedicine","pmid":"26300641","pmcid":null,"doi":"10.2147/IJN.S84909","url":"https://pubmed.ncbi.nlm.nih.gov/26300641/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/26300641/","doiUrl":"https://doi.org/10.2147/IJN.S84909","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC4536844/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"other_animal","speciesRaw":"other animal (Caenorhabditis elegans, N2 wild type, L1 larvae)","design":"other (in vivo nematode model)","n":"20 worms analyzed per uptake time point; three independent experiments","formsStudiedRaw":"melatonin-loaded lipid-core nanocapsules (Mel-LNC), rhodamine B-labeled","formTags":["immediate-release"],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In this study, we demonstrated the oral absorption of LNC in an in vivo alternative model based on C. elegans. Fluorescence microscopic analysis confirmed the oral uptake of LNC by nematodes and that it was distributed in the body of the worm.","source":"fulltext","location":"Conclusion","truncated":false}]},{"id":"pmid-15019067","title":"Intranasal administration of melatonin starch microspheres.","year":"2004","journal":"International journal of pharmaceutics","pmid":"15019067","pmcid":null,"doi":"10.1016/j.ijpharm.2003.11.028","url":"https://pubmed.ncbi.nlm.nih.gov/15019067/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/15019067/","doiUrl":"https://doi.org/10.1016/j.ijpharm.2003.11.028","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"other_animal","speciesRaw":"other animal (rabbit)","design":"parallel (three groups) animal PK; also in vitro release and gamma scintigraphy nasal clearance (6 rabbits)","n":"12 rabbits in vivo PK (Methods 2.5.4)","formsStudiedRaw":"melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"The absolute bioavailability of melatonin starch microspheres after intranasal administration was 84.07%. A significant correlation between in vivo and in vitro was disclosed.","source":"fulltext","location":"Conclusions (section 4)","truncated":false},{"metric":"Tmax","text":"absorption rate was rapid (Tmax = 7.8 min), and the absolute bioavailability was high, 84.07%","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Fractional absorption","text":"A relatively good correlation exists between f and drug release percentage in vitro","source":"fulltext","location":"Fig. 6; Results 3.5","truncated":false},{"metric":"Comparison","text":">80% of the starch microspheres could be detected in the nasal tissue 2 h after administration, compared to 30% for a solution","source":"fulltext","location":"Abstract; Results 3.3","truncated":false}]},{"id":"pmid-10332069","title":"Intranasal absorption of melatonin in vivo bioavailability study.","year":"1999","journal":"International journal of pharmaceutics","pmid":"10332069","pmcid":null,"doi":"10.1016/s0378-5173(99)00019-8","url":"https://pubmed.ncbi.nlm.nih.gov/10332069/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/10332069/","doiUrl":"https://doi.org/10.1016/s0378-5173(99)00019-8","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"other_animal","speciesRaw":"other animal (rabbit)","design":"other (modified crossover, n=6, three legs with 7-day washout: nasal, i.v., nasal)","n":"6","formsStudiedRaw":"Melatonin (intranasal formulations in 40% PEG 300 with or without 1% sodium glycocholate vs i.v.)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"However, the relatively high bioavailability without GC shows that it might not be necessary to use an enhancer for a clinical relevant formulation.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Absolute bioavailability","text":"the bioavailability after nasal administration of melatonin is 55% (S.D. ± 17 %, n = 6) for -GC and 94% (S.D. ± 29%, n = 4) for +GC","source":"fulltext","location":"Table 1; Abstract; Results","truncated":false},{"metric":"Comparison","text":"These results indicate that GC has an enhancer effect (P < 0.05).","source":"fulltext","location":"Abstract; Results p.3; Table 1 asterisk","truncated":false}]},{"id":"pmid-10535761","title":"A method of achieving physiological plasma levels of melatonin in the chicken by oral administration.","year":"1999","journal":"Journal of pineal research","pmid":"10535761","pmcid":null,"doi":"10.1111/j.1600-079x.1999.tb00607.x","url":"https://pubmed.ncbi.nlm.nih.gov/10535761/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/10535761/","doiUrl":"https://doi.org/10.1111/j.1600-079x.1999.tb00607.x","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"other_animal","speciesRaw":"other animal (chicken: broilers and laying hens)","design":"other (three separate dose/delivery-method experiments; E2 placebo-controlled)","n":"E1 15; E2 16; E3 9","formsStudiedRaw":"Melatonin","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"It was concluded that melatonin-treated, ethanol-rinsed cracked wheat grains can be used to experimentally mimic long-night plasma melatonin patterns. Injections may be useful for mimicking the melatonin patterns of very short nights in chickens experiencing constant light.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"high dose of 267-371 µg/kg body weight applied to 50 g feed pellets forced plasma levels up to 12,960-15,880 pM","source":"fulltext","location":"Results, Experiment 1 p.132","truncated":false},{"metric":"Cmax","text":"A low dose of 31-80 µg/kg body weight increased levels to 2,530-5,570 pM","source":"fulltext","location":"Results, Experiment 1 p.132","truncated":false},{"metric":"Cmax","text":"the level rose to 530-1,460 pM if the low dose had been absorbed into 50 g wheat","source":"fulltext","location":"Results, Experiment 1 p.132","truncated":false},{"metric":"Cmax","text":"doses of 300 µg/kg produced 15 nM, which is more than ten times higher than the nocturnal peak concentration","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Cmax","text":"When injected (2 µg/bird), concentrations peaked (610 pM) within 30 min","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"The lower the dose, the lower the initial peak, and it was further lowered if the low dose was absorbed in whole wheat grains.","source":"fulltext","location":"Results, Experiment 1","truncated":false},{"metric":"Comparison","text":"In the grape seed oil/melatonin-injected birds, clearance was slightly slower","source":"fulltext","location":"Discussion","truncated":false}]},{"id":"pmid-9787493","title":"Diurnal rhythm of melatonin in bovine milk: pharmacokinetics of exogenous melatonin in lactating cows and goats.","year":"1998","journal":"Acta veterinaria Scandinavica","pmid":"9787493","pmcid":null,"doi":"10.1186/BF03547778","url":"https://pubmed.ncbi.nlm.nih.gov/9787493/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/9787493/","doiUrl":"https://doi.org/10.1186/BF03547778","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8050655/","pdfLink":null,"openAccess":"open access: yes (free in PMC)","textUsed":"full text (PDF extraction)","species":"other_animal","speciesRaw":"other animal (lactating Ayrshire cows and Finnish landrace goats)","design":"single-arm","n":"4 cows + 4 goats (PK)","formsStudiedRaw":"Melatonin (IV bolus)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"Our results suggest that milk melatonin levels reflect blood concentrations of melatonin with a short delay.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"steady state distribution volume 1.0 ± 0.3 l/kg and 0.6 ± 0.1 l/kg (p<0.05)","source":"fulltext","location":"Table 2 footnote a; Abstract","truncated":false}]},{"id":"pmid-41599679","title":"Unraveling Cannabidiol's Bidirectional Regulation of Melatonin Pharmacokinetics via PEPT1/CYP1A2: Mechanistic Insights and Quantitative Projections.","year":"2025","journal":"Pharmaceuticals (Basel, Switzerland)","pmid":"41599679","pmcid":null,"doi":"10.3390/ph19010080","url":"https://pubmed.ncbi.nlm.nih.gov/41599679/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41599679/","doiUrl":"https://doi.org/10.3390/ph19010080","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12845078/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"in_vitro","speciesRaw":"other animal (beagle dog, Sprague-Dawley rat) and in vitro","design":"other (animal PK drug-interaction study; randomized groups, parallel)","n":"beagles 12; rats 24 (methods) + 12 (ABT)","formsStudiedRaw":"Melatonin (with cannabidiol as interacting compound)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"This study identifies the critical role of PEPT1 in MT absorption and elucidates the dual mechanisms of CBD; namely, absorption inhibition and metabolic delay in regulating MT pharmacokinetics, which exhibits interspecies differences.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Absolute bioavailability","text":"an oral bioavailability of 20.5% for MT","source":"fulltext","location":"Results 2.2 para 1","truncated":false},{"metric":"Comparison","text":"2536 (458.7) ** vs 601.9 (219.1)","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Comparison","text":"1355 (239.6) vs 1082 (356.7) with no asterisk","source":"fulltext","location":"Table 1","truncated":false},{"metric":"Comparison","text":"99.05 (36.63) ** vs 588.3 (371.2)","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Comparison","text":"212.5 (118.9) *","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Comparison","text":"121.4 (38.04) *","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Comparison","text":"138.1 (76.76) with no asterisk","source":"fulltext","location":"Table 2","truncated":false},{"metric":"Comparison","text":"there were no statistically significant differences in its pharmacokinetic parameters","source":"fulltext","location":"Results 2.3","truncated":false},{"metric":"Comparison","text":"903.1 (432.9) ##","source":"fulltext","location":"Table 4","truncated":false}]},{"id":"pmid-38769992","title":"Designing an effective dissolution test for bilayer tablets tailored for optimal melatonin release in sleep disorder management.","year":"2024","journal":"Frontiers in nutrition","pmid":"38769992","pmcid":null,"doi":"10.3389/fnut.2024.1394330","url":"https://pubmed.ncbi.nlm.nih.gov/38769992/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38769992/","doiUrl":"https://doi.org/10.3389/fnut.2024.1394330","pmcUrl":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11102985/","pdfLink":null,"openAccess":"open access: yes","textUsed":"full text (PDF extraction)","species":"in_vitro","speciesRaw":"in vitro","design":"other (specify)","n":null,"formsStudiedRaw":"Melatonin (bilayer fast/slow-release tablet with Eschscholzia californica and Melissa officinalis extracts) vs monolayer tablet","formTags":["extended-release"],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"the inclusion of retarding agents in the BL-Tablet's formulation does not have an adverse impact on melatonin absorption.","source":"fulltext","location":"Conclusion p.10","truncated":false},{"metric":"Comparison","text":"no significant variations (p > 0.05) in bioaccessibility between the BL-Tablet and the ML-Tablet","source":"fulltext","location":"Results 3.3 p.8","truncated":false},{"metric":"Comparison","text":"gradual and sustained releases were observed, spanning 2.5 h for the EU Pharmacopoeia method and 8 h for the new SIFC-biorelevant dissolution method","source":"fulltext","location":"Abstract; Results 3.2.1","truncated":false},{"metric":"Comparison","text":"there are no significant differences observed between the two dissolution tests","source":"fulltext","location":"Results 3.2.1 p.7","truncated":false}]},{"id":"pmid-26445481","title":"The Effect of Melatonin Adsorbed to Polyethylene Glycol Microspheres on the Survival of MCF-7 Cells.","year":"2016","journal":"Neuroimmunomodulation","pmid":"26445481","pmcid":null,"doi":"10.1159/000439277","url":"https://pubmed.ncbi.nlm.nih.gov/26445481/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/26445481/","doiUrl":"https://doi.org/10.1159/000439277","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"in_vitro","speciesRaw":"in vitro","design":"other (in vitro)","n":"3 (release assay, Fig. 1); 5 (cell assays)","formsStudiedRaw":"melatonin adsorbed to PEG microspheres","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: partial","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"In conclusion, melatonin neurohormone adsorbed to PEG microspheres has antitumor effects against human MCF-7 breast cancer cells and is therefore a possible therapeutic alternative for treating this disease.","source":"fulltext","location":"Discussion, final paragraph","truncated":false}]},{"id":"pmid-10467952","title":"Effect of fatty acids on the permeation of melatonin across rat and pig skin in-vitro and on the transepidermal water loss in rats in-vivo.","year":"1999","journal":"The Journal of pharmacy and pharmacology","pmid":"10467952","pmcid":null,"doi":"10.1211/0022357991773140","url":"https://pubmed.ncbi.nlm.nih.gov/10467952/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/10467952/","doiUrl":"https://doi.org/10.1211/0022357991773140","pmcUrl":null,"pdfLink":null,"openAccess":"open access: no","textUsed":"full text (PDF extraction)","species":"in_vitro","speciesRaw":"in vitro","design":"other (in vitro Franz diffusion cell study)","n":null,"formsStudiedRaw":"Melatonin (transdermal, with fatty acid penetration enhancers)","formTags":[],"food":false,"timing":false,"relevance":"full-text extraction: complete","verification":"values extracted verbatim from the full-text PDF (bundle 2, 2026-11-02); reviewer check pending","quotes":[{"metric":"Authors' conclusion","text":"We conclude that saturated fatty acids such as undecanoic acid or lauric acid which showed maximum permeation across rat and porcine skin, respectively, may be used as potential penetration enhancers in the development of a transdermal delivery system for melatonin.","source":"fulltext","location":"Abstract","truncated":false},{"metric":"Comparison","text":"steady-state flux of melatonin with linolenic acid was significantly higher than that with oleic acid (P < 0.05)","source":"fulltext","location":"Results, rat unsaturated fatty acids","truncated":false},{"metric":"Comparison","text":"no significant difference in the flux values of linoleic acid and linolenic acid (P > 0.05)","source":"fulltext","location":"Results, rat unsaturated fatty acids","truncated":false},{"metric":"Comparison","text":"not statistically different from that of undecanoic acid (C-11) (P > 0.05)","source":"fulltext","location":"Results, porcine saturated fatty acids","truncated":false},{"metric":"Comparison","text":"flux values of linoleic acid and linolenic acid were not significantly different from that of oleic acid (P > 0.05)","source":"fulltext","location":"Results, porcine unsaturated fatty acids","truncated":false}]}],"sections":{"forms":{"studyIds":["pmid-37150895","pmid-39174857","pmid-39458580","pmid-37438493","pmid-36046952","pmid-31381847","pmid-29194416","pmid-27566320","pmid-24650045","pmid-25046730","pmid-20070489","pmid-18490497","pmid-11360039","pmid-10690873","pmid-10085470","pmid-18982259","pmid-3994899","pmid-39771491","pmid-30731257","pmid-30286985","pmid-29109369","pmid-32673769","pmid-29702366","pmid-26440286","pmid-26300641","pmid-38769992"],"evidence":{"grade":"B","basis":"mixed","rationale":"6 human randomized/crossover studies; A-eligible only once the reviewer confirms they agree (capped at B until then). Auto-computed draft grade — pending reviewer review.","counts":{"human":17,"rodent":4,"other_animal":4,"in_vitro":1}}},"with-food":{"studyIds":["pmid-37150895","pmid-39174857","pmid-39458580","pmid-37438493","pmid-10690873","pmid-10085470","pmid-10407218","pmid-3994899","pmid-32673769"],"evidence":{"grade":"B","basis":"mixed","rationale":"6 human randomized/crossover studies; A-eligible only once the reviewer confirms they agree (capped at B until then). Auto-computed draft grade — pending reviewer review.","counts":{"human":8,"other_animal":1}}},"best-time":{"studyIds":["pmid-37438493","pmid-18423009","pmid-1617960","pmid-27644893"],"evidence":{"grade":"B","basis":"mixed","rationale":"1 human randomized/crossover and 2 human studies in total. 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Talk to a clinician about what's right for you."}],"evidence_grade":"A","evidence_grade_status":"draft — pending reviewer (rubric v2)","form_grades":{"immediate-release":{"label":"Immediate-release tablet / capsule","grade":"A","basis":"11 human studies, total n=124, 6 randomized/crossover; median CV 41.5% across 4 matched set(s) (consistent)","studies":11,"total_n":124,"randomized":6,"median_cv":41.5,"cv_sets":[{"set":"Cmax / melatonin / serum/plasma / fasted / single /  / pg/ml","studies":["10883420","18982259","31381847","39458580"],"cv":97.5},{"set":"Cmax / melatonin / serum/plasma / fed / single /  / pg/ml","studies":["10690873","20070489","37150895"],"cv":45.6},{"set":"Tmax / melatonin / serum/plasma / fasted / single /  / h","studies":["10085470","18490497","18982259","39458580"],"cv":27.3},{"set":"Tmax / melatonin / serum/plasma / fed / single /  / h","studies":["20070489","37150895","3994899"],"cv":37.4}],"pmids":["10085470","10690873","10883420","18490497","18982259","20070489","27566320","31381847","37150895","39458580","3994899"]},"extended-release":{"label":"Prolonged / extended-release","grade":"B","basis":"7 human studies, total n=93, 6 randomized/crossover; median CV 59.2% across 7 matched set(s) (consistent)","studies":7,"total_n":93,"randomized":6,"median_cv":59.2,"cv_sets":[{"set":"Cmax / 6-sulfatoxymelatonin / serum/plasma / fed / single /  / pg/ml","studies":["37438493","39174857"],"cv":14.6},{"set":"Cmax / melatonin / serum/plasma / fasted / single /  / pg/ml","studies":["31381847","39458580"],"cv":59.2},{"set":"Cmax / melatonin / serum/plasma / fed / single /  / pg/ml","studies":["22348451","37150895","37438493","39174857"],"cv":142.4},{"set":"Tmax / 6-sulfatoxymelatonin / serum/plasma / fed / single /  / min","studies":["37438493","39174857"],"cv":43.8},{"set":"Tmax / melatonin / serum/plasma / fasted / single /  / h","studies":["10085470","39458580"],"cv":66.6},{"set":"Tmax / melatonin / serum/plasma / fed / single /  / h","studies":["22348451","37150895"],"cv":73.1},{"set":"Tmax / melatonin / serum/plasma / fed / single /  / min","studies":["37438493","39174857"],"cv":43.6}],"pmids":["10085470","22348451","31381847","37150895","37438493","39174857","39458580"]},"liquid":{"label":"Liquid / oral solution","grade":"B","basis":"3 human studies, total n=21, 1 randomized/crossover; consistency not evaluable (no matched set with ≥2 studies)","studies":3,"total_n":21,"randomized":1,"median_cv":null,"cv_sets":[],"pmids":["11038434","18423009","29194416"]},"sublingual":{"label":"Sublingual / oral spray","grade":"C","basis":"1 human study, total n=13, 1 randomized/crossover; consistency not evaluable (no matched set with ≥2 studies)","studies":1,"total_n":13,"randomized":1,"median_cv":null,"cv_sets":[],"pmids":["37438493"]}},"measured_pk":{"slug":"melatonin","name":"Melatonin","source":"PDF full-text extraction bundle 2 (1,666 papers), merged 2026-11-02","gradeStatus":"draft — pending reviewer (Dr. Colin Reily)","counts":{"papers":119,"withData":61,"rejected":58,"species":{"human":30,"rodent":16,"other_animal":8,"in_vitro":4,"pig":2,"primate":1},"pkValues":663},"forms":[{"slug":"immediate-release","label":"Immediate-release tablet / capsule","n_studies":16,"species":{"human":15,"other_animal":1},"n_values":170,"pmids":["10085470","10690873","10883420","18490497","18982259","20070489","24650045","25046730","27566320","28368352","31381847","32673769","36046952","37150895","39458580","3994899"]},{"slug":"extended-release","label":"Prolonged / extended-release","n_studies":10,"species":{"human":7,"rodent":2,"other_animal":1},"n_values":71,"pmids":["10085470","22348451","26440286","30286985","30731257","31381847","37150895","37438493","39174857","39458580"]},{"slug":"liquid","label":"Liquid / oral solution","n_studies":6,"species":{"human":4,"rodent":2},"n_values":89,"pmids":["11038434","18423009","27644893","29194416","36046952","39771491"]},{"slug":"sublingual","label":"Sublingual / oral spray","n_studies":1,"species":{"human":1},"n_values":6,"pmids":["37438493"]}],"pairs":[{"grade":"C","basis":"4 human studies (4 randomized/crossover); majority: first form higher (1 agree, 1 contradict)","majority":"A_better","tally":{"unclear":2,"A_better":1,"no_difference":1},"pmids":["10085470","31381847","37150895","39458580"],"anchor":"immediate-release-vs-extended-release","a":"immediate-release","b":"extended-release","aLabel":"Immediate-release tablet / capsule","bLabel":"Prolonged / extended-release","status":"draft — pending reviewer (Dr. Colin Reily)","rows":[{"pair":"immediate-release-vs-extended-release","pmid":"10085470","species":"human","design":"randomized crossover (open, single-dose, 3-way crossover; sequences ABC, BCA, CAB); Abstract says \"randomised, single-dose, threefold cross-over\"","n":"15 humans; 6 dogs","title":"A melatonin preparation with a pulsatile liberation pattern: a new form of melatonin in replacement therapy.","journal":"Biological signals and receptors","year":"1999","comparison":"A vs B and C (dose proportionality)","parameter":"AUC","direction_text":"AUC ratio A/B 0.51, A/C 0.43 (5 mg vs 10 mg); authors assume dose proportionality","significant":"NR","p_value":"","direction_DERIVED":"unclear","location":"Results p.6","quote":"the AUC ratios of A (5 mg MLT) to B or C (10 mg MLT each) are 0.51 for A/B and 0.43 for A/C"},{"pair":"immediate-release-vs-extended-release","pmid":"10085470","species":"human","design":"randomized crossover (open, single-dose, 3-way crossover; sequences ABC, BCA, CAB); Abstract says \"randomised, single-dose, threefold cross-over\"","n":"15 humans; 6 dogs","title":"A melatonin preparation with a pulsatile liberation pattern: a new form of melatonin in replacement therapy.","journal":"Biological signals and receptors","year":"1999","comparison":"B, C vs A (release pattern)","parameter":"Cmax 2 / tmax 2","direction_text":"B and C produce a second serum peak at about 3.5 h; A does not","significant":"NR","p_value":"","direction_DERIVED":"unclear","location":"Results p.4-6","quote":"The controlled-release forms B and C produce a second serum peak (Cmax 2 between about 13 and 18 pmol/ml) after about 3.5 h (tmax 2)."},{"pair":"immediate-release-vs-extended-release","pmid":"31381847","species":"human","design":"randomized crossover","n":"10","title":"A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation.","journal":"The primary care companion for CNS disorders","year":"2019","comparison":"CRA vs IR","parameter":"Cmax and time above 1,000 pg/mL","direction_text":"CRA lower Cmax (4,690 vs 23,352 pg/mL) and longer time above threshold (6.7 vs 3.7 h)","significant":"NR","p_value":"","direction_DERIVED":"unclear","location":"Results","quote":"median Cmax of 4,690 pg/mL ... compared to ... 23,352 pg/mL; ... median of 6.7 hours ... compared with ... 3.7 hours"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"Cmax","direction_text":"ER < IR","significant":"yes","p_value":"0.002","direction_DERIVED":"A_better","location":"Table 2; Results p.9","quote":"The extended-release melatonin had a lower maximum concentration (Cmax, p < 0.002)"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"Tmax","direction_text":"ER > IR","significant":"yes","p_value":"<0.001","direction_DERIVED":"B_better","location":"Table 2; Results p.9","quote":"longer time to reach maximum concentration in the blood (Tmax = 1.56 h, p < 0.001)"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"AUC0-10h","direction_text":"no difference","significant":"no","p_value":"0.417","direction_DERIVED":"no_difference","location":"Table 2","quote":"no significant differences in AUC and iAUC(0-10h)"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"iAUC0-10h","direction_text":"no difference (values not reported)","significant":"no","p_value":"","direction_DERIVED":"no_difference","location":"Results p.9","quote":"no significant differences in AUC and iAUC(0-10h)"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"ka","direction_text":"ER < IR","significant":"yes","p_value":"<0.001","direction_DERIVED":"A_better","location":"Results p.9; Table 2","quote":"lower for extended-release melatonin ... indicating a slower rate of absorption (77% less)"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"lambda (ke)","direction_text":"ER < IR","significant":"yes","p_value":"<0.001","direction_DERIVED":"A_better","location":"Results p.9; Table 2","quote":"terminal disposition rate constant (λ) (p < 0.001) were lower for extended-release"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"ta1/2","direction_text":"text: IR > ER; Table 2 values: ER > IR","significant":"yes","p_value":"0.002","direction_DERIVED":"unclear","location":"Results p.9; Table 2","quote":"absorption half-life (ta1/2) (p < 0.002) was greater with the immediate-release formulation"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"t1/2","direction_text":"ER > IR","significant":"yes","p_value":"<0.001","direction_DERIVED":"B_better","location":"Results p.9; Table 2","quote":"terminal half-life (t1/2) however, was greater with the extended-release formulation"},{"pair":"immediate-release-vs-extended-release","pmid":"37150895","species":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","journal":"Journal of dietary supplements","year":"2024","comparison":"ER vs IR","parameter":"mean plasma melatonin at individual timepoints","direction_text":"differed at 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6 h","significant":"yes","p_value":"0.25 h <0.001; 0.5 h <0.001; 0.75 h 0.003; 1 h 0.038; 2 h 0.031; 3 h 0.006; 4 h 0.004; 5 h 0.005; 6 h 0.011","direction_DERIVED":"unclear","location":"Results p.8","quote":"differences in the mean plasma melatonin concentrations were noted at timepoints 0.25 h (p < 0.001), 0.5 h (p < 0.001), 0.75 h (p = 0.003)"},{"pair":"immediate-release-vs-extended-release","pmid":"39458580","species":"human","design":"randomized crossover (open-label, balanced, two-treatment, two-sequence, two-period)","n":"16","title":"Comparative Pharmacokinetics of Sustained-Release versus Immediate-Release Melatonin Capsules in Fasting Healthy Adults: A Randomized, Open-Label, Cross-Over Study.","journal":"Pharmaceutics","year":"2024","comparison":"SR vs IR","parameter":"Cmax","direction_text":"SR lower","significant":"yes","p_value":"<0.05","direction_DERIVED":"unclear","location":"Table 2","quote":"Melatonin-SR reported a lower Cmax (11,446.87 pg/mL) compared to Melatonin-IR (22,786.30 pg/mL)"},{"pair":"immediate-release-vs-extended-release","pmid":"39458580","species":"human","design":"randomized crossover (open-label, balanced, two-treatment, two-sequence, two-period)","n":"16","title":"Comparative Pharmacokinetics of Sustained-Release versus Immediate-Release Melatonin Capsules in Fasting Healthy Adults: A Randomized, Open-Label, Cross-Over Study.","journal":"Pharmaceutics","year":"2024","comparison":"SR vs IR","parameter":"AUC0-t","direction_text":"SR lower","significant":"yes","p_value":"<0.05","direction_DERIVED":"unclear","location":"Table 2","quote":""},{"pair":"immediate-release-vs-extended-release","pmid":"39458580","species":"human","design":"randomized crossover (open-label, balanced, two-treatment, two-sequence, two-period)","n":"16","title":"Comparative Pharmacokinetics of Sustained-Release versus Immediate-Release Melatonin Capsules in Fasting Healthy Adults: A Randomized, Open-Label, Cross-Over Study.","journal":"Pharmaceutics","year":"2024","comparison":"SR vs IR","parameter":"AUC0-inf","direction_text":"SR lower","significant":"yes","p_value":"<0.05","direction_DERIVED":"unclear","location":"Table 2","quote":""},{"pair":"immediate-release-vs-extended-release","pmid":"39458580","species":"human","design":"randomized crossover (open-label, balanced, two-treatment, two-sequence, two-period)","n":"16","title":"Comparative Pharmacokinetics of Sustained-Release versus Immediate-Release Melatonin Capsules in Fasting Healthy Adults: A Randomized, Open-Label, Cross-Over Study.","journal":"Pharmaceutics","year":"2024","comparison":"SR vs IR","parameter":"plasma concentration 4-8 h","direction_text":"SR higher","significant":"no","p_value":">0.05","direction_DERIVED":"no_difference","location":"Results p.7","quote":"noteworthy though not significant (p > 0.05)"}],"old_grade":"C","grade_v2":"C","grade_v2_basis":"head-to-head and matched single-form evidence agree. 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geometric mean per table footnote"},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 2.5 mg MLT + controlled-release tablet 2.5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Cmax","detail":"Cmax 2","value":"17.41","variance":"","units":"pmol/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":"second peak; Abstract and Discussion print 17.5 for capsule C (Table 1: 17.41)"},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 2.5 mg MLT + controlled-release tablet 2.5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Tmax","detail":"tmax 1","value":"0.50","variance":"","units":"h","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 2.5 mg MLT + controlled-release tablet 2.5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Tmax","detail":"tmax 2","value":"3.50","variance":"","units":"h","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 2.5 mg MLT + controlled-release tablet 2.5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"AUC","detail":"AUC0-tlast","value":"42.38","variance":"","units":"pmol/ml×h","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 2.5 mg MLT + controlled-release tablet 2.5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"AUC","detail":"AUC0-inf","value":"42.67","variance":"","units":"pmol/ml×h","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 5 mg MLT (Jenapharm (hard gelatine capsule containing tablets))","forms":["immediate-release"],"dose":"5 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Cmax","detail":"Cmax 1 (Abstract)","value":"20.7","variance":"","units":"pmol/ml","location":"Abstract","quote":"Cmax 1 20.7 (A), 16.4 (B), 9.7 (C) ... Cmax 2 of 13.0 and 17.5 pmol/ml, respectively","quoteCheck":"supported","note":"rounded value printed in Abstract/Discussion"},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Cmax","detail":"Cmax 1 (Abstract)","value":"16.4","variance":"","units":"pmol/ml","location":"Abstract","quote":"","quoteCheck":"no quote","note":"rounded value printed in Abstract/Discussion"},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 2.5 mg MLT + controlled-release tablet 2.5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Cmax","detail":"Cmax 1 (Abstract)","value":"9.7","variance":"","units":"pmol/ml","location":"Abstract","quote":"","quoteCheck":"no quote","note":"rounded value printed in Abstract/Discussion"},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Cmax","detail":"Cmax 2 (Abstract)","value":"13.0","variance":"","units":"pmol/ml","location":"Abstract","quote":"","quoteCheck":"no quote","note":"rounded value printed in Abstract/Discussion"},{"pmid":"10085470","species":"human","arm":"","form":"fast-release tablet 2.5 mg MLT + controlled-release tablet 2.5 mg MLT + enteric coated controlled-release tablet 5 mg MLT (pulsatile) (Jenapharm (hard gelatine capsule containing tablets))","forms":["extended-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"fasted 10 h, with 150 ml mineral water","n":"15","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Cmax","detail":"Cmax 2 (Abstract)","value":"17.5","variance":"","units":"pmol/ml","location":"Abstract","quote":"","quoteCheck":"no quote","note":"rounded value printed in Abstract/Discussion; Table 1 prints 17.41 for capsule C Cmax 2"},{"pmid":"10085470","species":"human","arm":"","form":"capsule B (as above) (Jenapharm (hard gelatine capsule containing tablets))","forms":["immediate-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"food withheld 36 h; water ad libitum","n":"6","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Cmax","detail":"Cmax 1 (dogs)","value":"80","variance":"","units":"pmol/ml","location":"Results p.4 (in vivo studies)","quote":"Cmax 1 ≅ 80 pmol/ml, at tmax 1 of approximately 1 h","quoteCheck":"supported","note":"printed as approximate (≅) in text; dogs, capsule B (10 mg); mean n=6 per Fig. 2 legend"},{"pmid":"10085470","species":"human","arm":"","form":"capsule B (as above) (Jenapharm (hard gelatine capsule containing tablets))","forms":["immediate-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"food withheld 36 h; water ad libitum","n":"6","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Cmax","detail":"Cmax 2 (dogs)","value":"40","variance":"","units":"pmol/ml","location":"Results p.4 (in vivo studies)","quote":"the second peak, Cmax 2 ≅ 40 pmol/ml, at tmax 2 of approximately 5 h","quoteCheck":"supported","note":"printed as approximate (≅) in text"},{"pmid":"10085470","species":"human","arm":"","form":"capsule B (as above) (Jenapharm (hard gelatine capsule containing tablets))","forms":["immediate-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"food withheld 36 h; water ad libitum","n":"6","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Tmax","detail":"tmax 1 (dogs)","value":"1","variance":"","units":"h","location":"Results p.4","quote":"","quoteCheck":"no quote","note":"printed as \"approximately 1 h\""},{"pmid":"10085470","species":"human","arm":"","form":"capsule B (as above) (Jenapharm (hard gelatine capsule containing tablets))","forms":["immediate-release"],"dose":"10 mg melatonin","doseBasis":"active compound","fed":"food withheld 36 h; water ad libitum","n":"6","analyte":"melatonin (MLT)","matrix":"serum","parameter":"Tmax","detail":"tmax 2 (dogs)","value":"5","variance":"","units":"h","location":"Results p.4","quote":"","quoteCheck":"no quote","note":"printed as \"approximately 5 h\""},{"pmid":"10407218","species":"human","arm":"","form":"melatonin (formulation NR)","forms":[],"dose":"5 mg","doseBasis":"active compound","fed":"light breakfast 0800 h then fasted; dosed at -60 min before exercise (study began 1400 h)","n":"7","analyte":"melatonin","matrix":"serum/plasma (see note)","parameter":"Cmax","detail":"mean peak value after oral ingestion","value":"1638","variance":"± 61.9 (SEM)","units":"pg/ml","location":"Results p.24 (para 1)","quote":"levels reached a mean peak value of 1638 ± 61.9 pg/ml 30 min after ingestion.","quoteCheck":"supported","note":"Methods say results are means ± SEM; matrix not explicitly stated for the melatonin measurement (blood sampled; plasma separated and stored, but abstract/methods mention serum for GH); n inferred from study design of 7 subjects, not stated beside this value"},{"pmid":"10690873","species":"human","arm":"","form":"tablet (Novartis Consumer Health tablet (manufacturer given))","forms":["immediate-release"],"dose":"3 mg","doseBasis":"active compound","fed":"overnight fast, light breakfast 0700-0800 h, dose at 1000 h","n":"17","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"peak serum MLT 60 min after 3 mg","value":"4,701","variance":"± 6,415 (SD)","units":"pg/mL","location":"Table 2 (Exp 2)","quote":"peak serum MLT concentrations 60 min after its application","quoteCheck":"value not in quote","note":"Abstract: peak levels differing 28-fold among subjects (940-27,240 pg/mL; range)"},{"pmid":"10690873","species":"human","arm":"","form":"tablet (Novartis Consumer Health tablet (manufacturer given))","forms":["immediate-release"],"dose":"3 mg","doseBasis":"active compound","fed":"overnight fast, light breakfast 0700-0800 h, dose at 1000 h","n":"17","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"time of peak","value":"60","variance":"","units":"min","location":"Results, Study 2","quote":"resulted in peak serum MLT concentrations 60 min after its application","quoteCheck":"supported","note":"statistic not specified; also Table 2 footnote b"},{"pmid":"10690873","species":"human","arm":"","form":"tablet (Novartis Consumer Health tablet (manufacturer given))","forms":["immediate-release"],"dose":"3 mg","doseBasis":"active compound","fed":"overnight fast, light breakfast 0700-0800 h, dose at 1000 h","n":"17","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUCMLT","value":"9,514","variance":"± 9,152 (SD)","units":"pg/h·mL","location":"Table 2 (Exp 2)","quote":"AUCMLT differed 16-fold among subjects","quoteCheck":"value not in quote","note":"AUC integration interval not stated explicitly"},{"pmid":"10690873","species":"human","arm":"","form":"none (NA)","forms":[],"dose":"0","doseBasis":"NR","fed":"NR","n":"16","analyte":"endogenous melatonin","matrix":"serum","parameter":"AUC","detail":"overnight AUCMLT","value":"557.9","variance":"± 178.4 (SD)","units":"pg/h·mL","location":"Table 2 (Exp 1)","quote":"","quoteCheck":"no quote","note":"endogenous, no supplement"},{"pmid":"10883420","species":"human","arm":"","form":"oral tablet (Nature's Bounty, lot 38798 01)","forms":["immediate-release"],"dose":"2 mg","doseBasis":"active compound","fed":"fasted","n":"12","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0-inf","value":"237.77","variance":"± 149.79 (SD)","units":"ng·min/mL","location":"Table I","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10883420","species":"human","arm":"","form":"oral tablet (Nature's Bounty, lot 38798 01)","forms":["immediate-release"],"dose":"2 mg","doseBasis":"active compound","fed":"fasted","n":"12","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"peak serum concentration","value":"2175","variance":"± 1645 (SD)","units":"pg/ml","location":"Table I","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10883420","species":"human","arm":"","form":"oral tablet (Nature's Bounty, lot 38798 01)","forms":["immediate-release"],"dose":"2 mg","doseBasis":"active compound","fed":"fasted","n":"12","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"tmax","value":"52.0","variance":"± 31.5 (SD)","units":"min","location":"Table I","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10883420","species":"human","arm":"","form":"oral tablet (Nature's Bounty, lot 38798 01)","forms":["immediate-release"],"dose":"4 mg","doseBasis":"active compound","fed":"fasted","n":"12","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0-inf","value":"530.57","variance":"± 267.29 (SD)","units":"ng·min/mL","location":"Table I","quote":"","quoteCheck":"no quote","note":"Methods: AUC0-inf for 4 mg dose was 'dose adjusted' (reduced by 50%) for comparison; unclear whether Table I 4 mg value is dose-adjusted"},{"pmid":"10883420","species":"human","arm":"","form":"oral tablet (Nature's Bounty, lot 38798 01)","forms":["immediate-release"],"dose":"4 mg","doseBasis":"active 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(SD)","units":"ng·min/mL","location":"Table I","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10883420","species":"human","arm":"","form":"IV bolus over 3 min, 100 µg/ml prepared from powder (Regis Technologies) (NA (IND #53,749))","forms":[],"dose":"2 mg","doseBasis":"active compound","fed":"fasted","n":"12","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"peak serum concentration","value":"96,850","variance":"± 55,024 (SD)","units":"pg/ml","location":"Table I","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10883420","species":"human","arm":"","form":"IV bolus over 3 min, 100 µg/ml prepared from powder (Regis Technologies) (NA (IND #53,749))","forms":[],"dose":"2 mg","doseBasis":"active compound","fed":"fasted","n":"12","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"tmax","value":"1.79","variance":"± 1.41 (SD)","units":"min","location":"Table I","quote":"","quoteCheck":"no 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compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"0.38","variance":"± 0.14 (SD)","units":"h","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"11038434","species":"human","arm":"","form":"oral solution with 200 mL water, midday (Besins-Iscovesco, Montrouge, France)","forms":["liquid"],"dose":"250 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"236.0","variance":"± 107.3 (SD)","units":"pg.h/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"11038434","species":"human","arm":"","form":"oral solution with 200 mL water, midday (Besins-Iscovesco)","forms":["liquid"],"dose":"250 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"623.6","variance":"± 575.1 (SD)","units":"pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"11038434","species":"human","arm":"","form":"oral solution with 200 mL water, midday (Besins-Iscovesco)","forms":["liquid"],"dose":"250 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"0.38","variance":"± 0.14 (SD)","units":"h","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"11038434","species":"human","arm":"","form":"oral solution with 200 mL water, midday (Besins-Iscovesco)","forms":["liquid"],"dose":"250 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"701.4","variance":"± 644.8 (SD)","units":"pg.h/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"11038434","species":"human","arm":"","form":"oral solution with 200 mL water, midday (Besins-Iscovesco, Montrouge, France)","forms":["liquid"],"dose":"250 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"Cmax","detail":"text, mean ± SD","value":"243.7","variance":"± 124.6 (SD)","units":"pg/mL","location":"Abstract / Results p.19","quote":"The mean MLT Cmax value 243.7 ± 124.6 pg/mL in male subjects","quoteCheck":"supported","note":""},{"pmid":"11038434","species":"human","arm":"","form":"oral solution with 200 mL water, midday (Besins-Iscovesco)","forms":["liquid"],"dose":"250 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"Cmax","detail":"text, mean ± SD","value":"623.6","variance":"± 575.1 (SD)","units":"pg/mL","location":"Abstract / Results p.19","quote":"623.6 ± 575.1 pg/mL in females","quoteCheck":"supported","note":""},{"pmid":"11038434","species":"human","arm":"","form":"oral solution with 200 mL water, midday (Besins-Iscovesco, Montrouge, France)","forms":["liquid"],"dose":"250 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"AUC","detail":"text, mean ± SD","value":"236","variance":"± 107 (SD)","units":"pg.h/mL","location":"Abstract / Results p.19","quote":"AUCs: 236 ± 107 pg.h/mL","quoteCheck":"supported","note":""},{"pmid":"11038434","species":"human","arm":"","form":"oral solution with 200 mL water, midday (Besins-Iscovesco)","forms":["liquid"],"dose":"250 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"AUC","detail":"text, mean ± SD","value":"701","variance":"± 645 (SD)","units":"pg.h/mL","location":"Abstract / Results p.19","quote":"701 ± 645 pg.h/mL","quoteCheck":"supported","note":""},{"pmid":"11038434","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"D7 melatonin","matrix":"plasma","parameter":"Tmax","detail":"mean oral Tmax","value":"23","variance":"","units":"min","location":"Results p.19","quote":"MLT was rapidly absorbed, with mean Tmax at 23 min","quoteCheck":"supported","note":""},{"pmid":"11038434","species":"human","arm":"","form":"IV infusion in 500 mL isotonic solution, 10:00-12:00 h (Besins-Iscovesco (D7 MLT))","forms":[],"dose":"23 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"Cmax","detail":"range of concentrations at end of infusion","value":"88.8 to 164.4","variance":"","units":"pg/mL","location":"Results p.19","quote":"plasma concentrations ranged from 88.8 to 164.4 pg/mL for male subjects","quoteCheck":"supported","note":"range 88.8-164.4"},{"pmid":"11038434","species":"human","arm":"","form":"IV infusion (Besins-Iscovesco)","forms":[],"dose":"23 µg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"D7 melatonin","matrix":"plasma","parameter":"Cmax","detail":"range of concentrations at end of infusion","value":"102.7 to 195.3","variance":"","units":"pg/mL","location":"Results p.19","quote":"102.7 to 195.3 for females","quoteCheck":"supported","note":"range 102.7-195.3"},{"pmid":"11360039","species":"human","arm":"","form":"oral melatonin (formulation NR)","forms":[],"dose":"25 mg","doseBasis":"NR","fed":"NR","n":"1","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"19.2","variance":"","units":"ng/mL","location":"Results, Volunteer Sample p.285","quote":"The maximum concentration (Cmax) of melatonin was 19.2 ng/mL","quoteCheck":"supported","note":"single volunteer; text says both analytes reached Cmax at 1.5 h, but Fig. 1 legend gives 34 ng/mL melatonin at 30 min (inconsistent)"},{"pmid":"11360039","species":"human","arm":"","form":"oral melatonin (formulation NR)","forms":[],"dose":"25 mg","doseBasis":"NR","fed":"NR","n":"1","analyte":"6-hydroxymelatonin (total, after hydrolysis)","matrix":"plasma","parameter":"Cmax","detail":"","value":"694","variance":"","units":"ng/mL","location":"Results, Volunteer Sample p.285","quote":"that of 6-hydroxymelatonin 694 ng/mL","quoteCheck":"supported","note":"single volunteer; Fig. 1 legend gives 484 ng/mL at 30 min"},{"pmid":"11360039","species":"human","arm":"","form":"oral melatonin (formulation NR)","forms":[],"dose":"25 mg","doseBasis":"NR","fed":"NR","n":"1","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.5","variance":"","units":"h","location":"Results, Volunteer Sample p.285","quote":"Both analytes reached Cmax at the same time, 1.5 hours after melatonin intake.","quoteCheck":"supported","note":"single volunteer; applies to both melatonin and 6-OHM"},{"pmid":"11360039","species":"human","arm":"","form":"oral melatonin (formulation NR)","forms":[],"dose":"25 mg","doseBasis":"NR","fed":"NR","n":"1","analyte":"6-hydroxymelatonin (total, after hydrolysis)","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.5","variance":"","units":"h","location":"Results, Volunteer Sample p.285","quote":"Both analytes reached Cmax at the same time, 1.5 hours after melatonin intake.","quoteCheck":"supported","note":"single volunteer"},{"pmid":"18423009","species":"human","arm":"","form":"Oral liquid melatonin (immediate release) given enterally","forms":["liquid"],"dose":"10 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"0.5","variance":"± 0 (SD)","units":"hours","location":"Table 3","quote":"Data are presented as mean (standard deviation).","quoteCheck":"value not in quote","note":"Plasma concentrations corrected by subtracting 9 p.m. baseline value; n=9 from Methods text"},{"pmid":"18423009","species":"human","arm":"","form":"Oral liquid melatonin (immediate release) given enterally","forms":["liquid"],"dose":"10 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"14,974","variance":"± 3,200 (SD)","units":"pg/mL","location":"Table 3","quote":"Data are presented as mean (standard deviation).","quoteCheck":"value not in quote","note":""},{"pmid":"18423009","species":"human","arm":"","form":"Oral liquid melatonin (immediate release) given enterally","forms":["liquid"],"dose":"10 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-24h","value":"29,979","variance":"± 8,205 (SD)","units":"ng-hours/L","location":"Table 3","quote":"AUC(0-24), area under the concentration time curve between time 0 and 24 hours","quoteCheck":"value not in quote","note":"Units printed as ng-hours/L"},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"11.4","variance":"± 4.3 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"2.3","variance":"± 2.1 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"10.9","variance":"± 6.0 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"8","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"2.4","variance":"± 1.5 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"6.6","variance":"± 5.8 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":"p-value is between-study-groups difference (Table I), printed in separate column"},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"7.9","variance":"± 3.0 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"1.8","variance":"± 1.9 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"7.2","variance":"± 5.2 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"8","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"1.7","variance":"± 1.2 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"4.5","variance":"± 4.2 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":"p-value is between-study-groups difference (Table I), printed in separate column"},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"12.4","variance":"± 4.0 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"11.0","variance":"± 4.0 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"11.6","variance":"± 3.5 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"8","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"10.3","variance":"± 3.8 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-∞","value":"11.3","variance":"± 3.7 (SD)","units":"ng ×h/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":"p-value is between-study-groups difference (Table I), printed in separate column"},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"6.8","variance":"± 2.8 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"5.5","variance":"± 2.6 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"4.7","variance":"± 1.5 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"8","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"5.8","variance":"± 1.8 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"5.7","variance":"± 2.2 (SD)","units":"ng/mL","location":"Table I","quote":"Data are given as arithmetic mean ± arithmetic SD, except for tmax data","quoteCheck":"value not in quote","note":"p-value is between-study-groups difference (Table I), printed in separate column"},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.0","variance":"± 0.5–1.5 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.0","variance":"± 0.5–2.0 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.0","variance":"± 0.5–1.5 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"8","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"0.75","variance":"± 0.5–1.5 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.0","variance":"± 0.5–2.0 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":"p-value is between-study-groups difference (Table I), printed in separate column"},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.5","variance":"± 1.0–2.0 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.5","variance":"± 1.0–2.0 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"7","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.5","variance":"± 0.5–2.0 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"Melatonin tablets (2 x 3 mg) (Yliopiston apteekki, Helsinki)","forms":["immediate-release"],"dose":"6 mg","doseBasis":"active compound","fed":"overnight fast; 200 mL water; standard lunch 4 h after dose","n":"8","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.0","variance":"± 1.0–2.0 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":""},{"pmid":"18490497","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"6-OH-melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.5","variance":"± 0.5–2.0 (range)","units":"h","location":"Table I","quote":"tmax data, which are given as median and range","quoteCheck":"value not in quote","note":"p-value is between-study-groups difference (Table I), printed in separate column"},{"pmid":"18982259","species":"human","arm":"","form":"20% Aquacoat-coated MT-loaded sugar spheres in gelatin capsule (NR (laboratory prepared))","forms":["immediate-release"],"dose":"0.2 mg","doseBasis":"active compound","fed":"fasted","n":"4","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC (calculated, RSTRIP; interval NR)","value":"515.5","variance":"± 206.2 (SD)","units":"pg-h/ml","location":"Table I; Results p.558","quote":"The calculated AUC of B1 and B2 were 515.5±206.2 and 555.6±334.9 pg-h/ml, respectively.","quoteCheck":"supported","note":"Page image checked; Table printed 'Mean ± standard deviation'"},{"pmid":"18982259","species":"human","arm":"","form":"20% Aquacoat-coated MT-loaded sugar spheres in gelatin capsule (NR (laboratory prepared))","forms":["immediate-release"],"dose":"0.2 mg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC (calculated, RSTRIP; interval NR)","value":"555.6","variance":"± 334.9 (SD)","units":"pg-h/ml","location":"Table I; Results p.558","quote":"No statistically significant difference of AUC between two batches was observed.","quoteCheck":"value not in quote","note":""},{"pmid":"18982259","species":"human","arm":"","form":"20% Aquacoat-coated MT-loaded sugar spheres in gelatin capsule (NR (laboratory prepared))","forms":["immediate-release"],"dose":"0.2 mg","doseBasis":"active compound","fed":"fasted","n":"4","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"117","variance":"± 21 (SD)","units":"pg/ml","location":"Table I; Results p.557","quote":"The Tmax and Cmax of B1 and B2 were found to be 0.5 h and 1.0h; 117±21 pg/ml and 108±33 pg/ml, respectively.","quoteCheck":"supported","note":""},{"pmid":"18982259","species":"human","arm":"","form":"20% Aquacoat-coated MT-loaded sugar spheres in gelatin capsule (NR (laboratory prepared))","forms":["immediate-release"],"dose":"0.2 mg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"108","variance":"± 33 (SD)","units":"pg/ml","location":"Table I; Results p.557","quote":"There was no significant difference of Cmax between B1 and B2.","quoteCheck":"value not in quote","note":""},{"pmid":"18982259","species":"human","arm":"","form":"20% Aquacoat-coated MT-loaded sugar spheres in gelatin capsule (NR (laboratory prepared))","forms":["immediate-release"],"dose":"0.2 mg","doseBasis":"active compound","fed":"fasted","n":"4","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"0.5","variance":"± 0.05 (SD)","units":"h","location":"Table I","quote":"Tmax ... 0.5 h and 1.0h","quoteCheck":"supported","note":"Table prints 0.5±0.05; statistic type not stated (footnote says mean±SD)"},{"pmid":"18982259","species":"human","arm":"","form":"20% Aquacoat-coated MT-loaded sugar spheres in gelatin capsule (NR (laboratory prepared))","forms":["immediate-release"],"dose":"0.2 mg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.0","variance":"","units":"h","location":"Table I","quote":"Tmax ... 0.5 h and 1.0h","quoteCheck":"supported","note":"No variance printed"},{"pmid":"20070489","species":"human","arm":"","form":"125 mg tablet (3 mg melatonin; microcrystalline cellulose, calcium phosphate, Mg stearate, Na CMC), crushed in 20 mL water via nasogastric/naso-jejunal tube + 20 mL flush (Procemsa (Torino, Italy); melatonin Helsinn)","forms":["immediate-release"],"dose":"3 mg","doseBasis":"active compound","fed":"continuous enteral nutrition or combined enteral + parenteral nutrition","n":"6","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC","value":"28231.29","variance":"","units":"pg/mL*hr","location":"Table 3","quote":"Pharmacokinetic parameters calculated in the patients of Cohort 1.","quoteCheck":"value not in quote","note":"Fitted by non-linear regression to baseline-corrected data of Cohort 1; statistic type (individual/pooled/mean curve) not stated."},{"pmid":"20070489","species":"human","arm":"","form":"125 mg tablet (3 mg melatonin; microcrystalline cellulose, calcium phosphate, Mg stearate, Na CMC), crushed in 20 mL water via nasogastric/naso-jejunal tube + 20 mL flush (Procemsa (Torino, Italy); melatonin Helsinn)","forms":["immediate-release"],"dose":"3 mg","doseBasis":"active compound","fed":"continuous enteral nutrition or combined enteral + parenteral nutrition","n":"6","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"Tmax","value":"0.27","variance":"","units":"hr","location":"Table 3","quote":"Pharmacokinetic parameters calculated in the patients of Cohort 1.","quoteCheck":"value not in quote","note":"Fitted by non-linear regression to baseline-corrected data of Cohort 1; statistic type (individual/pooled/mean curve) not stated. Results text and Abstract give 16 min 52 s (Cohort 2) / 16 min; 0.27 hr = 16.2 min"},{"pmid":"20070489","species":"human","arm":"","form":"125 mg tablet (3 mg melatonin; microcrystalline cellulose, calcium phosphate, Mg stearate, Na CMC), crushed in 20 mL water via nasogastric/naso-jejunal tube + 20 mL flush (Procemsa (Torino, Italy); melatonin Helsinn)","forms":["immediate-release"],"dose":"3 mg","doseBasis":"active compound","fed":"continuous enteral nutrition or combined enteral + parenteral nutrition","n":"6","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"Cmax","value":"11039.84","variance":"","units":"pg/mL","location":"Table 3","quote":"Pharmacokinetic parameters calculated in the patients of Cohort 1.","quoteCheck":"value not in quote","note":"Fitted by non-linear regression to baseline-corrected data of Cohort 1; statistic type (individual/pooled/mean curve) not stated. Abstract: 11040 pg/mL"},{"pmid":"20070489","species":"human","arm":"","form":"same crushed 3 mg tablet via enteral tube (Procemsa (Torino, Italy); melatonin Helsinn)","forms":["immediate-release"],"dose":"3 mg","doseBasis":"active compound","fed":"continuous enteral nutrition or combined enteral + parenteral nutrition","n":"6","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"Tmax measured in Cohort 2","value":"16 min 52 s","variance":"","units":"min:s as printed","location":"Results p.144","quote":"Maximal serum melatonin concentration, as measured in Cohort 2, was reached 16 min 52 s (Tmax) after melatonin administration.","quoteCheck":"supported","note":"value printed as 16 min 52 s; not converted; inconsistent in format with Table 3 Tmax 0.27 hr (Cohort 1 fit); Abstract says 'peak after 16 min'"},{"pmid":"2071448","species":"human","arm":"","form":"[11C]melatonin in saline with 2% ethanol","forms":[],"dose":"42 µg carrier (13 mCi radioactivity)","doseBasis":"active compound","fed":"NR","n":"1","analyte":"plasma radioactivity ([11C]melatonin plus radiolabelled metabolites)","matrix":"plasma","parameter":"Tmax","detail":"time of peak plasma radioactivity","value":"3.5","variance":"","units":"min","location":"Results p.358; Abstract","quote":"Plasma radioactivity ... peaked at 3.5 min","quoteCheck":"supported","note":"IV bolus"},{"pmid":"2071448","species":"human","arm":"","form":"[11C]melatonin in saline with 2% ethanol","forms":[],"dose":"42 µg carrier (13 mCi radioactivity)","doseBasis":"active compound","fed":"NR","n":"1","analyte":"immunoreactive plasma melatonin","matrix":"plasma","parameter":"Tmax","detail":"time of peak plasma melatonin after IV bolus","value":"3.5","variance":"","units":"min","location":"Results p.358","quote":"Immunoreactive plasma melatonin and 6-sulfatoxymelatonin peaked at 3.5 and 20 min, respectively","quoteCheck":"supported","note":"IV bolus"},{"pmid":"2071448","species":"human","arm":"","form":"[11C]melatonin in saline with 2% ethanol","forms":[],"dose":"42 µg carrier (13 mCi radioactivity)","doseBasis":"active compound","fed":"NR","n":"1","analyte":"immunoreactive plasma 6-sulfatoxymelatonin","matrix":"plasma","parameter":"Tmax","detail":"time of peak plasma 6-sulfatoxymelatonin","value":"20","variance":"","units":"min","location":"Results p.358","quote":"Immunoreactive plasma melatonin and 6-sulfatoxymelatonin peaked at 3.5 and 20 min, respectively","quoteCheck":"supported","note":""},{"pmid":"2071448","species":"human","arm":"","form":"[11C]melatonin in saline with 2% ethanol","forms":[],"dose":"42 µg carrier (13 mCi radioactivity)","doseBasis":"active compound","fed":"NR","n":"1","analyte":"melatonin (brain, PET)","matrix":"brain","parameter":"Tmax","detail":"time of maximum brain activity","value":"8.5","variance":"","units":"min","location":"Abstract","quote":"maximum activity in the brain 8.5min following injection","quoteCheck":"supported","note":"Brain activity in Abstract; Results text describes regional peaks 'around 5-10 min'"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%, ethyl cellulose, release over 3-5 h) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"0.4 mg","doseBasis":"active compound","fed":"NR (dim light, supine, no caffeine/smoking during 24-h sampling)","n":"9","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"","value":"4.7","variance":"± 0.96 (SEM)","units":"hr","location":"Table 2","quote":"Mean (S.E.)","quoteCheck":"value not in quote","note":"Visit 1 = endogenous pre-treatment profile (no exogenous melatonin)"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"4.0 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"","value":"5.1","variance":"± 1.4 (SEM)","units":"hr","location":"Table 2","quote":"Mean (S.E.)","quoteCheck":"value not in quote","note":"Visit 1 = endogenous pre-treatment profile (no exogenous melatonin)"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%, ethyl cellulose, release over 3-5 h) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"0.4 mg","doseBasis":"active compound","fed":"NR (dim light, supine, no caffeine/smoking during 24-h sampling)","n":"9","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"","value":"52","variance":"± 8.1 (SEM)","units":"pg/mL","location":"Table 2","quote":"Mean (S.E.)","quoteCheck":"value not in quote","note":"Visit 1 = endogenous pre-treatment profile (no exogenous melatonin)"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"4.0 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"","value":"61","variance":"± 11 (SEM)","units":"pg/mL","location":"Table 2","quote":"Mean (S.E.)","quoteCheck":"value not in quote","note":"Visit 1 = endogenous pre-treatment profile (no exogenous melatonin)"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%, ethyl cellulose, release over 3-5 h) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"0.4 mg","doseBasis":"active compound","fed":"NR (dim light, supine, no caffeine/smoking during 24-h sampling)","n":"9","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0–tlast","value":"337","variance":"± 64 (SEM)","units":"pg/mL•hr","location":"Table 2","quote":"Mean (S.E.)","quoteCheck":"value not in quote","note":"Visit 1 = endogenous pre-treatment profile (no exogenous melatonin)"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"4.0 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0–tlast","value":"418","variance":"± 73 (SEM)","units":"pg/mL•hr","location":"Table 2","quote":"Mean (S.E.)","quoteCheck":"value not in quote","note":"Visit 1 = endogenous pre-treatment profile (no exogenous melatonin)"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%, ethyl cellulose, release over 3-5 h) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"0.4 mg","doseBasis":"active compound","fed":"NR (dim light, supine, no caffeine/smoking during 24-h sampling)","n":"9","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0–inf (extrapolated to infinity)","value":"350","variance":"± 65 (SEM)","units":"pg/mL•hr","location":"Table 2","quote":"Mean (S.E.)","quoteCheck":"value not in quote","note":"Visit 1 = endogenous pre-treatment profile (no exogenous melatonin)"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"4.0 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0–inf (extrapolated to infinity)","value":"438","variance":"± 79 (SEM)","units":"pg/mL•hr","location":"Table 2","quote":"Mean (S.E.)","quoteCheck":"value not in quote","note":"Visit 1 = endogenous pre-treatment profile (no exogenous melatonin)"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%, ethyl cellulose, release over 3-5 h) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"0.4 mg","doseBasis":"active compound","fed":"NR (dim light, supine, no caffeine/smoking during 24-h sampling)","n":"9","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"Tmax text","value":"1.3","variance":"± 0.19 (SEM (presumed; text prints ±))","units":"hrs","location":"Results p.440","quote":"Maximal concentration was reached in 1.3 ± 0.19 hrs in the low-dose arm and 1.5 ± 0.24 hrs in the high-dose arm (Tmax)","quoteCheck":"supported","note":"text prints ±; Table 2 labels SE"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"4.0 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"Tmax text","value":"1.5","variance":"± 0.24 (SEM (presumed; text prints ±))","units":"hrs","location":"Results p.440","quote":"1.3 ± 0.19 hrs in the low-dose arm and 1.5 ± 0.24 hrs in the high-dose arm (Tmax)","quoteCheck":"supported","note":"text prints ±; Table 2 labels SE"},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%, ethyl cellulose, release over 3-5 h) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"0.4 mg","doseBasis":"active compound","fed":"NR (dim light, supine, no caffeine/smoking during 24-h sampling)","n":"9","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"Abstract: maximum concentration","value":"405 ± 93","variance":"± 93 (SEM (presumed; Table 2 labels S.E.))","units":"pg/mL","location":"Abstract","quote":"The maximum concentration was 405 ± 93 pg/mL for the low-dose arm and 3999 ± 700 pg/mL for the high-dose arm","quoteCheck":"supported","note":""},{"pmid":"22348451","species":"human","arm":"","form":"Immediate release tablet (25%) + controlled release tablet (75%) taken together (Custom-made by ABCO Labs; melatonin Regis Technologies)","forms":["extended-release"],"dose":"4.0 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"Abstract: maximum concentration","value":"3999 ± 700","variance":"± 700 (SEM (presumed; Table 2 labels S.E.))","units":"pg/mL","location":"Abstract","quote":"3999 ± 700 pg/mL for the high-dose arm","quoteCheck":"supported","note":""},{"pmid":"22348451","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"endogenous peak concentration pre-treatment (median)","value":"46.7","variance":"","units":"pg/mL","location":"Results p.440","quote":"The median peak concentrations pretreatment was 46.7 pg/mL (range: 23.6–118 pg/mL)","quoteCheck":"supported","note":"Baseline endogenous; pooled all subjects"},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 1 (AUC window not stated; table footnote a)","value":"1102","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 1","value":"12.80","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 1","value":"30.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 2 (AUC window not stated; table footnote a)","value":"3266","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 2","value":"35.70","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 2","value":"60.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 3 (AUC window not stated; table footnote a)","value":"3405","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 3","value":"30.33","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 3","value":"60.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 4 (AUC window not stated; table footnote a)","value":"1564","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 4","value":"20.86","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 4","value":"30.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 5 (AUC window not stated; table footnote a)","value":"13616","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 5","value":"147.68","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 5","value":"30.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 6 (AUC window not stated; table footnote a)","value":"2491","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 6","value":"30.09","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 6","value":"30.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 7 (AUC window not stated; table footnote a)","value":"1866","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 7","value":"33.67","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 7","value":"30.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; 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lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 9 (AUC window not stated; table footnote a)","value":"822","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 9","value":"6.25","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 9","value":"60.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 10 (AUC window not stated; table footnote a)","value":"1640","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 10","value":"8.51","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"30 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 10","value":"120.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; 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lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 13 (AUC window not stated; table footnote a)","value":"8915","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 13","value":"113.78","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 13","value":"30.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 14 (AUC window not stated; table footnote a)","value":"4234","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 14","value":"67.84","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 14","value":"30.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 15 (AUC window not stated; table footnote a)","value":"6554","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 15","value":"91.38","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 15","value":"30.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"100 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"subject 16 (AUC window not stated; table footnote a)","value":"9570","variance":"","units":"ng/ml/min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"100 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"subject 16","value":"103.22","variance":"","units":"ng/ml","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"100 mg","doseBasis":"active compound","fed":"fasted; lunch 3 h post-dose","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"subject 16","value":"60.00","variance":"","units":"min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"24650045","species":"human","arm":"","form":"10 mg melatonin capsules (Nu-Pharm Laboratories, melatonin from Flamma s.p.a.)","forms":["immediate-release"],"dose":"100 mg","doseBasis":"active compound","fed":"fasted; 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individual Tmax in Table 4 include 120.00 (subject 10)"},{"pmid":"24650045","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"6-hydroxymelatonin sulfate","matrix":"serum","parameter":"Tmax","detail":"time to maximum serum level","value":"120","variance":"","units":"min","location":"Results p.431","quote":"maximum levels reached at a median of 120 min","quoteCheck":"supported","note":""},{"pmid":"25046730","species":"human","arm":"","form":"melatonin powder (commercially available)","forms":[],"dose":"1 mg","doseBasis":"active compound","fed":"NR","n":"20","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"60","variance":"± 6.15 (SD)","units":"min","location":"Table 1","quote":"60 ± 6.15","quoteCheck":"supported","note":""},{"pmid":"25046730","species":"human","arm":"","form":"soft gelatin capsule (LO.LI. Pharma, Rome) (LO.LI. 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Pharma, Rome) (LO.LI. Pharma)","forms":["immediate-release"],"dose":"1 mg","doseBasis":"active compound","fed":"NR","n":"20","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"2620","variance":"± 93.30 (SD)","units":"pg/ml","location":"Table 1","quote":"2620 ± 93.30","quoteCheck":"supported","note":"Column header says pg/ml; Table 1 footnote says Cmax in µmol/l"},{"pmid":"25046730","species":"human","arm":"","form":"melatonin powder (commercially available)","forms":[],"dose":"3 mg","doseBasis":"active compound","fed":"NR","n":"20","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"2405","variance":"± 278.9 (SD)","units":"pg/ml","location":"Table 1","quote":"2405 ± 278.9","quoteCheck":"supported","note":"Column header says pg/ml; Table 1 footnote says Cmax in µmol/l"},{"pmid":"25046730","species":"human","arm":"","form":"melatonin powder (commercially available)","forms":[],"dose":"1 mg","doseBasis":"active compound","fed":"NR","n":"20","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-360 min (trapezoidal)","value":"90516","variance":"± 6579 (SD)","units":"µmol·min/l (per Table 1 footnote; no unit in column)","location":"Table 1","quote":"90516 ± 6579","quoteCheck":"supported","note":"Units not stated in AUC row; footnote gives µmol·min/l, which is inconsistent with Cmax in pg/ml. Value as printed."},{"pmid":"25046730","species":"human","arm":"","form":"soft gelatin capsule (LO.LI. Pharma, Rome) (LO.LI. 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Internally inconsistent; value as printed."},{"pmid":"27566320","species":"human","arm":"","form":"melatonin capsule","forms":["immediate-release"],"dose":"10 mg","doseBasis":"active compound","fed":"fasted (standard preoperative fasting)","n":"12","analyte":"plasma melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"30.0","variance":"± 15.0–30.0 (IQR)","units":"min","location":"Table 1; Abstract","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27566320","species":"human","arm":"","form":"melatonin capsule","forms":["immediate-release"],"dose":"10 mg","doseBasis":"active compound","fed":"NR","n":"12","analyte":"plasma melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"90.0","variance":"± 48.8–120.0 (IQR)","units":"min","location":"Table 1; Abstract","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27566320","species":"human","arm":"","form":"melatonin capsule","forms":["immediate-release"],"dose":"10 mg","doseBasis":"active compound","fed":"fasted (standard preoperative fasting)","n":"12","analyte":"plasma melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"5497.5","variance":"± 2077.1–13,233.8 (IQR)","units":"pg/ml","location":"Abstract; Results p.1047","quote":"","quoteCheck":"no quote","note":"Table 1 prints 5497.5 (2077.1–13,233.8) too; Cmax pre-dose baseline not subtracted"},{"pmid":"27566320","species":"human","arm":"","form":"melatonin capsule","forms":["immediate-release"],"dose":"10 mg","doseBasis":"active compound","fed":"NR","n":"12","analyte":"plasma melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"2340.5","variance":"± 1672.4–8871.4 (IQR)","units":"pg/ml","location":"Table 1; Abstract","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27566320","species":"human","arm":"","form":"melatonin capsule","forms":["immediate-release"],"dose":"10 mg","doseBasis":"active compound","fed":"fasted (standard preoperative fasting)","n":"12","analyte":"plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"0.673 × 10^6","variance":"± 0.212 × 10^6–1.074 × 10^6 (IQR)","units":"pg/ml·min","location":"Table 1","quote":"","quoteCheck":"no quote","note":"value printed as 0.673 x 10^6 (not converted); AUC0-inf not significantly different between phases (p>0.05)"},{"pmid":"27566320","species":"human","arm":"","form":"melatonin capsule","forms":["immediate-release"],"dose":"10 mg","doseBasis":"active compound","fed":"NR","n":"12","analyte":"plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"0.545 × 10^6","variance":"± 0.178 × 10^6–1.038 × 10^6 (IQR)","units":"pg/ml·min","location":"Table 1","quote":"","quoteCheck":"no quote","note":"value printed as 0.545 x 10^6 (not converted)"},{"pmid":"27566320","species":"human","arm":"","form":"melatonin capsule","forms":["immediate-release"],"dose":"10 mg","doseBasis":"active compound","fed":"fasted (standard preoperative 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variance not stated (Fig. S1 supplementary, not in PDF)"},{"pmid":"28368352","species":"human","arm":"","form":"identical-looking placebo tablet without melatonin (Procemsa (Torino, Italy))","forms":[],"dose":"0 mg","doseBasis":"NR","fed":"NR","n":"29","analyte":"serum melatonin","matrix":"serum","parameter":"AUC","detail":"concentration/time profile, early phase (AUC)","value":"1221","variance":"","units":"pg·h/mL","location":"Results 2.2 p.5","quote":"","quoteCheck":"no quote","note":"statistic type and variance not stated; Fig. S1 supplementary; verified on page image (manager QA); corrected"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution 5 mg/mL via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding (formula/mother's milk)","n":"6","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment) - patient 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(Milte Italia))","forms":["liquid"],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding (formula/mother's milk)","n":"6","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment) - patient E","value":"14.54","variance":"","units":"µg·mL−1·h","location":"Table 2","quote":"","quoteCheck":"no quote","note":"individual patient E"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution 5 mg/mL via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding (formula/mother's milk)","n":"6","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment) - patient F","value":"10.75","variance":"","units":"µg·mL−1·h","location":"Table 2","quote":"","quoteCheck":"no quote","note":"individual patient F"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral 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H","value":"6.10","variance":"","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":"individual patient H"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"1 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"4","analyte":"melatonin","matrix":"plasma/serum","parameter":"Tmax","detail":"Tmax - patient I","value":"1.88","variance":"","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":"individual patient I"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"1 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"4","analyte":"melatonin","matrix":"plasma/serum","parameter":"Tmax","detail":"Tmax - patient L","value":"1.40","variance":"","units":"h","location":"Table 3","quote":"","quoteCheck":"no 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G"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"1 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"4","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax - patient H","value":"1.78","variance":"","units":"µg·mL−1","location":"Table 3","quote":"","quoteCheck":"no quote","note":"individual patient H"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"1 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"4","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax - patient I","value":"0.50","variance":"","units":"µg·mL−1","location":"Table 3","quote":"","quoteCheck":"no quote","note":"individual patient I"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"1 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"4","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax - patient L","value":"0.97","variance":"","units":"µg·mL−1","location":"Table 3","quote":"","quoteCheck":"no quote","note":"individual patient L"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"1 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"4","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax","value":"1.03","variance":"± 0.27 (SEM)","units":"µg·mL−1","location":"Table 3; Results 2.2","quote":"","quoteCheck":"no quote","note":"Mean ± SE across patients"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment) - patient M","value":"53.87","variance":"","units":"µg·mL−1·h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient M"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment) - patient N","value":"89.21","variance":"","units":"µg·mL−1·h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient N"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment) - patient O","value":"245.24","variance":"","units":"µg·mL−1·h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient O"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment) - patient P","value":"94.66","variance":"","units":"µg·mL−1·h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient P"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment) - patient Q","value":"110.59","variance":"","units":"µg·mL−1·h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient Q"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"AUC (extrapolated, one-compartment)","value":"118.77","variance":"± 33.02 (SEM)","units":"µg·mL−1·h","location":"Table 4; Results 2.2","quote":"","quoteCheck":"no quote","note":"Mean ± SE across patients"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Tmax","detail":"Tmax - patient M","value":"3.01","variance":"","units":"h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient M"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Tmax","detail":"Tmax - patient N","value":"3.30","variance":"","units":"h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient N"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Tmax","detail":"Tmax - patient O","value":"1.40","variance":"","units":"h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient O"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Tmax","detail":"Tmax - patient P","value":"8.70","variance":"","units":"h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient P"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Tmax","detail":"Tmax - patient Q","value":"7.10","variance":"","units":"h","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient Q"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Tmax","detail":"Tmax","value":"4.70","variance":"± 1.37 (SEM)","units":"h","location":"Table 4; Results 2.2","quote":"","quoteCheck":"no quote","note":"Mean ± SE across patients"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax - patient M","value":"3.54","variance":"","units":"µg·mL−1","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient M"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax - patient N","value":"5.20","variance":"","units":"µg·mL−1","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient N"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax - patient O","value":"12.25","variance":"","units":"µg·mL−1","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient O"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax - patient P","value":"8.21","variance":"","units":"µg·mL−1","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient P"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax - patient Q","value":"6.02","variance":"","units":"µg·mL−1","location":"Table 4","quote":"","quoteCheck":"no quote","note":"individual patient Q"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"Cmax","detail":"Cmax","value":"7.04","variance":"± 1.50 (SEM)","units":"µg·mL−1","location":"Table 4; Results 2.2","quote":"","quoteCheck":"no quote","note":"Mean ± SE across patients"},{"pmid":"29194416","species":"human","arm":"","form":"Melamil oral solution via nasogastric tube (Melamil (Milte Italia))","forms":["liquid"],"dose":"5 mg/kg","doseBasis":"active compound","fed":"given 1 h after feeding","n":"5","analyte":"melatonin","matrix":"plasma/serum","parameter":"AUC","detail":"Abstract value of AUC (upper end of range)","value":"118.17","variance":"","units":"µg·mL−1·h","location":"Abstract","quote":"","quoteCheck":"no quote","note":"INCONSISTENT: Abstract prints 118.17; Table 4 and Results print 118.77"},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"individual-analysis mean ± SE - AUC for entire study period (individual analysis)","value":"17.44","variance":"± 9.92 (SE)","units":"µg/mL/h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"individual-analysis mean ± SE","value":"8.66","variance":"± 1.12 (SE)","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"individual-analysis mean ± SE","value":"0.27","variance":"± 0.04 (SE)","units":"µg/mL","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"patient M001","value":"56.92","variance":"","units":"µg/mL/h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"patient M002","value":"8.76","variance":"","units":"µg/mL/h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"patient M003","value":"8.68","variance":"","units":"µg/mL/h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"patient M004","value":"3.64","variance":"","units":"µg/mL/h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"patient M005","value":"9.20","variance":"","units":"µg/mL/h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"patient M001","value":"7.8","variance":"","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"patient M002","value":"7.9","variance":"","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"patient M003","value":"13","variance":"","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"patient M004","value":"6.5","variance":"","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"patient M005","value":"8.1","variance":"","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"patient M001","value":"0.19","variance":"","units":"µg/mL","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"patient M002","value":"0.43","variance":"","units":"µg/mL","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"patient M003","value":"0.26","variance":"","units":"µg/mL","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"patient M004","value":"0.22","variance":"","units":"µg/mL","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"patient M005","value":"0.27","variance":"","units":"µg/mL","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"population analysis estimate (Fig. 3B, whole period)","value":"9.54","variance":"","units":"μg/mL*h","location":"Fig. 3B (population analysis)","quote":"","quoteCheck":"no quote","note":"Fig. 3B prints AUC 9.54; abstract/text give AUC 4.35 μg/mL*h in 24 h (population)"},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"population analysis estimate (Fig. 3B)","value":"6.8","variance":"","units":"h","location":"Fig. 3B (population analysis)","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"population analysis estimate (Fig. 3B)","value":"0.25","variance":"","units":"μg/mL","location":"Fig. 3B (population analysis)","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"population analysis; peak plasma concentration","value":"0.25","variance":"","units":"µg/mL","location":"Abstract; Results 3.3","quote":"The peak plasma concentration reached 0.25 µg/mL.","quoteCheck":"supported","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"individual mean; text calls dispersion '±' without type (Table 3 says SE)","value":"0.27","variance":"± 0.04 (SD)","units":"μg/mL","location":"Results 3.3","quote":"maximal serum concentration (Cmax) was 0.27 ± 0.04 μg/mL (0.25 μg/mL in the population analysis)","quoteCheck":"supported","note":"variance type not specified in text; Table 3 header says Mean ± SE"},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"measured peak concentration range among patients","value":"0.08-0.28","variance":"","units":"μg/mL","location":"Results 3.3","quote":"The measured peak concentration varied greatly among patients (0.08‐0.28 μg/mL)","quoteCheck":"value not in quote","note":"Table 3 lists individual Cmax up to 0.43 (M002), inconsistent with this range; modelled vs measured not distinguished"},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-24h (population)","value":"4.35","variance":"","units":"µg/mL*h","location":"Abstract; Results 3.3","quote":"The area under the curve in 24 hours was 4.35 µg/mL*h.","quoteCheck":"supported","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC in 24 hours (individual analysis section, no variance given)","value":"4.35","variance":"","units":"µg/mL*h","location":"Results 3.3","quote":"","quoteCheck":"no quote","note":"same value printed in individual-analysis paragraph"},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"population analysis","value":"6.8","variance":"","units":"hours","location":"Results 3.3","quote":"individual mean time to maximal concentration (Tmax) was 8.66 ± 1.12 hours (6.8 hours in the population analysis)","quoteCheck":"supported","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC entire study period, individual analysis","value":"17.44","variance":"± 9.92 (NR)","units":"μg/mL*h","location":"Results 3.3","quote":"AUC calculated for the entire study period was 17.44 ± 9.92 μg/mL*h","quoteCheck":"supported","note":""},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"in silico steady state (highest)","value":"0.48","variance":"","units":"μg/mL","location":"Results 3.4; Discussion","quote":"","quoteCheck":"no quote","note":"simulation, not measured"},{"pmid":"30734962","species":"human","arm":"","form":"Aqueous melatonin solution 0.4 mg/mL, excipient-free (diluted with saline to 6 mL), infused over 4 h at 1.5 mL/h via OG tube (NR (Industria Farmaceutica Galenica Senese))","forms":[],"dose":"0.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"in silico expected AUC at steady state after 4th virtual infusion","value":"9.71","variance":"","units":"μg/mL*h","location":"Results 3.4","quote":"The expected AUC at the steady state after the 4th virtual infusion is 9.71 μg/mL*h","quoteCheck":"supported","note":"simulation, not measured"},{"pmid":"30734962","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"previous study: same dose as single bolus in preterm neonates (ref 20)","value":"0.44","variance":"","units":"μg/mL","location":"Discussion","quote":"","quoteCheck":"no quote","note":"cited from another study, not this study's arm"},{"pmid":"30734962","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"previous study: same dose as single bolus in preterm neonates (ref 20)","value":"10.48","variance":"","units":"μg/mL*h","location":"Discussion","quote":"","quoteCheck":"no quote","note":"cited from another study, not this study's arm"},{"pmid":"31381847","species":"human","arm":"","form":"Continuous release and absorption melatonin tablet (hydrogel matrix with citric acid) (REMfresh)","forms":["extended-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"4,690","variance":"","units":"pg/mL","location":"Abstract; Results","quote":"Within the first hour of dosing, a median Cmax of 4,690 pg/mL was reached for CRA-melatonin","quoteCheck":"supported","note":""},{"pmid":"31381847","species":"human","arm":"","form":"Immediate-release melatonin (Natrol)","forms":["immediate-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"23,352","variance":"","units":"pg/mL","location":"Abstract; Results","quote":"compared to a median Cmax of 23,352 pg/mL for IR-melatonin","quoteCheck":"supported","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 2 mL 99.9% ethanol + 23 mL 0.9% saline, infused over 10 min (2.5 mL/min) (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"752,616","variance":"± 334,359 (SD)","units":"pg mL-1","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 2 mL 99.9% ethanol + 23 mL 0.9% saline, infused over 10 min (2.5 mL/min) (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"0","variance":"± 0 (SD)","units":"min","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 2 mL 99.9% ethanol + 23 mL 0.9% saline, infused over 10 min (2.5 mL/min) (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"371,328","variance":"± 164,858 (SD)","units":"pg mL-1 min","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 50 mL of 50% w/w DMSO in 0.9% saline; no urination for first hour (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"6,987","variance":"± 6,113 (SD)","units":"pg mL-1","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 50 mL of 50% w/w DMSO in 0.9% saline; no urination for first hour (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"51","variance":"± 29 (SD)","units":"min","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 50 mL of 50% w/w DMSO in 0.9% saline; no urination for first hour (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"13,691","variance":"± 9,048 (SD)","units":"pg mL-1 min","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 2.5 mL of 20% w/w glycofurol, 40% w/w DMSO, 40% w/w 0.9% saline (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"62,449","variance":"± 33,816 (SD)","units":"pg mL-1","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 n=9 (superscript a); text says rectal PK data excluded for 1 participant"},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 2.5 mL of 20% w/w glycofurol, 40% w/w DMSO, 40% w/w 0.9% saline (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"24","variance":"± 20 (SD)","units":"min","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 n=9 (superscript a); text says rectal PK data excluded for 1 participant"},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in 2.5 mL of 20% w/w glycofurol, 40% w/w DMSO, 40% w/w 0.9% saline (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"9","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"117,742","variance":"± 73,222 (SD)","units":"pg mL-1 min","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 n=9 (superscript a); text says rectal PK data excluded for 1 participant"},{"pmid":"32937627","species":"human","arm":"","form":"1 g skin lotion containing 25 mg melatonin and 150 mg DMSO over 20 x 20-cm chest area (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"897","variance":"± 551 (SD)","units":"pg mL-1","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"1 g skin lotion containing 25 mg melatonin and 150 mg DMSO over 20 x 20-cm chest area (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"20.5","variance":"± 8.0 (SD)","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Abstract: 21 (8) h; text p.172: 'mean tmax of 20.5 h'; Table 3: 20.5 h (8.0 h)"},{"pmid":"32937627","species":"human","arm":"","form":"1 g skin lotion containing 25 mg melatonin and 150 mg DMSO over 20 x 20-cm chest area (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"32,644","variance":"± 10,046 (SD)","units":"pg mL-1 min","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in suppository of 2.2 mL hard fat (WITEPSOL H-15) (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"50,828","variance":"± 22,813 (SD)","units":"pg mL-1","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in suppository of 2.2 mL hard fat (WITEPSOL H-15) (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"147","variance":"± 56 (SD)","units":"min","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"25 mg melatonin in suppository of 2.2 mL hard fat (WITEPSOL H-15) (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"377,237","variance":"± 163,559 (SD)","units":"pg mL-1 min","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32937627","species":"human","arm":"","form":"1 g skin lotion containing 25 mg melatonin and 150 mg DMSO over 20 x 20-cm chest area (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"as printed in abstract","value":"21","variance":"± 8 (SD)","units":"h","location":"Abstract","quote":"21 (8) h for transdermal","quoteCheck":"supported","note":"inconsistent with Table 3 / Results text (20.5 h (8.0 h))"},{"pmid":"32937627","species":"human","arm":"","form":"1 g skin lotion containing 25 mg melatonin and 150 mg DMSO over 20 x 20-cm chest area (melatonin API Flamma S.p.A.; formulations prepared by hospital pharmacies)","forms":[],"dose":"25 mg","doseBasis":"active compound","fed":"NR","n":"10","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"range of individual tmax","value":"between 16 and 24","variance":"","units":"h","location":"Results p.172","quote":"Transdermal administration reached tmax between 16 and 24 h, with most participants showing tmax at 24 h","quoteCheck":"supported","note":""},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"50 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"","value":"1465","variance":"± 986–1928 (range)","units":"ng/ml","location":"Table 3; Results 3.3.1","quote":"Cmax ... median [range] concentration of 1465 [986−1928] ng/ml","quoteCheck":"supported","note":"Table 3 values are median [range]"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"50 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"","value":"30","variance":"± 10–60 (range)","units":"min","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 values are median [range]"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"50 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"6-hydroxymelatonin sulfate (6-OHMS)","matrix":"serum","parameter":"Cmax","detail":"","value":"6.6","variance":"± 6.4–8.6 (range)","units":"ng/ml","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 values are median [range]"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"50 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"6-hydroxymelatonin sulfate (6-OHMS)","matrix":"serum","parameter":"Tmax","detail":"","value":"120","variance":"± 60–120 (range)","units":"min","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 values are median [range]"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"20 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"","value":"240","variance":"± 146–350 (range)","units":"ng/ml","location":"Table 3; Results 3.3.1","quote":"Cmax levels ... 240 [146−350] ng/ml, p = .008","quoteCheck":"supported","note":"Table 3 values are median [range]"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"20 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"","value":"30","variance":"± 10–60 (range)","units":"min","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 values are median [range]"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"20 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"6-hydroxymelatonin sulfate (6-OHMS)","matrix":"serum","parameter":"Cmax","detail":"","value":"4.7","variance":"± 3.8–8.0 (range)","units":"ng/ml","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 values are median [range]"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"20 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"6-hydroxymelatonin sulfate (6-OHMS)","matrix":"serum","parameter":"Tmax","detail":"","value":"60","variance":"± 30–120 (range)","units":"min","location":"Table 3","quote":"","quoteCheck":"no quote","note":"Table 3 values are median [range]"},{"pmid":"36046952","species":"human","arm":"","form":"oral gelatine capsule","forms":["immediate-release"],"dose":"20 mg","doseBasis":"active compound","fed":"NR","n":"NR","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"mean Cmax healthy subjects (DAMSEL1, previously published)","value":"49.5","variance":"","units":"ng/ml","location":"Results p.7","quote":"49.5 ng/ml compared to 74.6 ng/ml after a dose of 20 or 50 mg","quoteCheck":"supported","note":"Healthy subjects given capsules in DAMSEL1 [ref 26], cited here for comparison; dose 20 mg"},{"pmid":"36046952","species":"human","arm":"","form":"oral gelatine capsule","forms":["immediate-release"],"dose":"50 mg","doseBasis":"active compound","fed":"NR","n":"NR","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"mean Cmax healthy subjects (DAMSEL1, previously published)","value":"74.6","variance":"","units":"ng/ml","location":"Results p.7","quote":"49.5 ng/ml compared to 74.6 ng/ml after a dose of 20 or 50 mg","quoteCheck":"supported","note":"Healthy subjects given capsules in DAMSEL1 [ref 26], cited here for comparison; dose 50 mg"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"20 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"average Cmax (text)","value":"268","variance":"","units":"ng/ml","location":"Results p.7","quote":"268 ng/ml compared to 1440 ng/ml after 20 or 50 mg doses","quoteCheck":"supported","note":"Text gives average Cmax 268 (20 mg); Table 3 gives median 240 [146-350]"},{"pmid":"36046952","species":"human","arm":"","form":"oral liquid melatonin 1 mg/ml (liquid) (Apotek Produktion & Laboratorier (liquid))","forms":["liquid"],"dose":"50 mg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"average Cmax (text)","value":"1440","variance":"","units":"ng/ml","location":"Results p.7","quote":"268 ng/ml compared to 1440 ng/ml after 20 or 50 mg doses","quoteCheck":"supported","note":"Text gives average Cmax 1440 (50 mg); Table 3 gives median 1465 [986-1928]"},{"pmid":"36046952","species":"human","arm":"","form":"NR","forms":[],"dose":"NR mg","doseBasis":"active compound","fed":"NR","n":"NR","analyte":"melatonin","matrix":"serum","parameter":"relative_bioavailability","detail":"Frel capsules relative to solution (theta1; solution = 100%)","value":"0.19","variance":"","units":"fraction","location":"Table 4","quote":"","quoteCheck":"no quote","note":"Typical value (population model, 95% CI by log-likelihood profiling). Table 4 prints Frel capsules = theta1*100%; text says 'Frel = 19% vs. 100%'"},{"pmid":"37150895","species":"human","arm":"","form":"bi-layer tablet, extended-release","forms":["extended-release"],"dose":"4 mg","doseBasis":"active compound","fed":"fasted (8 h), meals from 1 h post-dose","n":"17","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-10h","value":"17181","variance":"± 19217 (SD)","units":"pg.h/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"p-value is ER vs IR"},{"pmid":"37150895","species":"human","arm":"","form":"bi-layer tablet, immediate-release","forms":["immediate-release"],"dose":"4 mg","doseBasis":"active compound","fed":"fasted (8 h), meals from 1 h post-dose","n":"17","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-10h","value":"16711","variance":"± 11353 (SD)","units":"pg.h/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"p-value is ER vs IR"},{"pmid":"37150895","species":"human","arm":"","form":"bi-layer tablet, extended-release","forms":["extended-release"],"dose":"4 mg","doseBasis":"active compound","fed":"fasted (8 h), meals from 1 h post-dose","n":"17","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.56","variance":"± 0.55 (SD)","units":"h","location":"Table 2; Abstract","quote":"longer time to peak concentration (1.56 vs 0.6 h)","quoteCheck":"supported","note":"Table 2 header says mean (SD)"},{"pmid":"37150895","species":"human","arm":"","form":"bi-layer tablet, immediate-release","forms":["immediate-release"],"dose":"4 mg","doseBasis":"active compound","fed":"fasted (8 h), meals from 1 h post-dose","n":"17","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"0.60","variance":"± 0.40 (SD)","units":"h","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Abstract and text print 0.6"},{"pmid":"37150895","species":"human","arm":"","form":"bi-layer tablet, extended-release","forms":["extended-release"],"dose":"4 mg","doseBasis":"active compound","fed":"fasted (8 h), meals from 1 h post-dose","n":"17","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"7581","variance":"± 9743 (SD)","units":"pg/mL","location":"Table 2; Abstract","quote":"7581 pg/mL vs 13120 pg/mL","quoteCheck":"supported","note":"Text prints Cmax p < 0.002 while Table 2 prints 0.002"},{"pmid":"37150895","species":"human","arm":"","form":"bi-layer tablet, immediate-release","forms":["immediate-release"],"dose":"4 mg","doseBasis":"active compound","fed":"fasted (8 h), meals from 1 h post-dose","n":"17","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"13120","variance":"± 9959 (SD)","units":"pg/mL","location":"Table 2; Abstract","quote":"","quoteCheck":"no quote","note":""},{"pmid":"37438493","species":"human","arm":"","form":"oral prolonged-release tablet (Chronobiane LP)","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"1151","variance":"± 565 (SD)","units":"pg/mL","location":"Table 1; Abstract; Results 3.3","quote":"Cmax: 1151 ± 565 pg/mL; Tmax: 64.2 ± 44.2 min","quoteCheck":"supported","note":""},{"pmid":"37438493","species":"human","arm":"","form":"sublingual spray, two sprays (Chronobiane Immediat)","forms":["sublingual"],"dose":"1 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"2380","variance":"± 950 (SD)","units":"pg/mL","location":"Table 1; Discussion","quote":"1151 versus 2380 pg/mL on average","quoteCheck":"supported","note":"Inconsistent with Abstract and Results 3.3, which print 2332 ± 950 pg/mL (see next row)."},{"pmid":"37438493","species":"human","arm":"","form":"oral prolonged-release tablet (Chronobiane LP)","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"64.2","variance":"± 44.2 (SD)","units":"min","location":"Table 1; Abstract","quote":"Tmax: 64.2 ± 44.2 min","quoteCheck":"supported","note":"Discussion rounds to 60 min on average; Results 3.3 says Cmax reached on average 1 h"},{"pmid":"37438493","species":"human","arm":"","form":"sublingual spray, two sprays (Chronobiane Immediat)","forms":["sublingual"],"dose":"1 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"23.3","variance":"± 6.5 (SD)","units":"min","location":"Table 1; Abstract","quote":"Tmax: 23.3 ± 6.5 min","quoteCheck":"supported","note":"Results 3.3 text also says Cmax reached at T20; Discussion says 20 min on average"},{"pmid":"37438493","species":"human","arm":"","form":"oral prolonged-release tablet (Chronobiane LP)","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-540 (baseline-subtracted per Methods)","value":"3070","variance":"± 1452 (SD)","units":"pg⋅h/mL","location":"Table 1; Results 3.3; Discussion","quote":"3070 ± 1452 pg⋅h/mL for PR form versus 2903 ± 867 pg⋅h/mL for IR form","quoteCheck":"supported","note":"Methods 2.7: AUC attributable to supplementation = AUC with baseline (T-15 min) value subtracted"},{"pmid":"37438493","species":"human","arm":"","form":"sublingual spray, two sprays (Chronobiane Immediat)","forms":["sublingual"],"dose":"1 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-420 (baseline-subtracted per Methods)","value":"2903","variance":"± 867 (SD)","units":"pg⋅h/mL","location":"Table 1; Results 3.3; Discussion","quote":"3070 ± 1452 pg⋅h/mL for PR form versus 2903 ± 867 pg⋅h/mL for IR form","quoteCheck":"supported","note":"Doses differ (1 mg vs 1.9 mg)"},{"pmid":"37438493","species":"human","arm":"","form":"","forms":[],"dose":"","doseBasis":"","fed":"","n":"","analyte":"melatonin","matrix":"plasma","parameter":"relative_bioavailability","detail":"IR vs PR dose-adjusted bioavailability (author statement)","value":"1.89","variance":"","units":"fold (ratio)","location":"Results 3.3","quote":"Taking into consideration the doses, IR form bioavailability was nearly twice (1.89) as high as that of the PR form.","quoteCheck":"supported","note":"Derived by authors from AUCs and doses; not computed by extractor"},{"pmid":"37438493","species":"human","arm":"","form":"oral prolonged-release tablet (Chronobiane LP)","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"Cmax","detail":"6-SMT","value":"9395","variance":"± 2894 (SD)","units":"pg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"37438493","species":"human","arm":"","form":"sublingual spray, two sprays (Chronobiane Immediat)","forms":["sublingual"],"dose":"1 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"Cmax","detail":"6-SMT","value":"12776","variance":"± 3541 (SD)","units":"pg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"37438493","species":"human","arm":"","form":"oral prolonged-release tablet (Chronobiane LP)","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"Tmax","detail":"6-SMT","value":"97.5","variance":"± 40 (SD)","units":"min","location":"Table 1; Results 3.3","quote":"97.5 ± 40 min versus 36.7 ± 12.3 min, p < 0.001","quoteCheck":"supported","note":"Results text says Cmax reached on average 100 min after PR"},{"pmid":"37438493","species":"human","arm":"","form":"sublingual spray, two sprays (Chronobiane Immediat)","forms":["sublingual"],"dose":"1 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"Tmax","detail":"6-SMT","value":"36.7","variance":"± 12.3 (SD)","units":"min","location":"Table 1; Results 3.3","quote":"97.5 ± 40 min versus 36.7 ± 12.3 min, p < 0.001","quoteCheck":"supported","note":""},{"pmid":"37438493","species":"human","arm":"","form":"oral prolonged-release tablet (Chronobiane LP)","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"AUC","detail":"6-SMT AUC0-540","value":"31967","variance":"± 6554 (SD)","units":"pg⋅h/mL","location":"Table 1; Results 3.3","quote":"31967 ± 6554 pg⋅h/mL and 18815 ± 4224 pg⋅h/mL for the PR and IR form, respectively (p < 0.001)","quoteCheck":"supported","note":""},{"pmid":"37438493","species":"human","arm":"","form":"sublingual spray, two sprays (Chronobiane Immediat)","forms":["sublingual"],"dose":"1 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"13","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"AUC","detail":"6-SMT AUC0-420","value":"18815","variance":"± 4224 (SD)","units":"pg⋅h/mL","location":"Table 1; Results 3.3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39174857","species":"human","arm":"","form":"Delayed-release tablet with zinc and lemon balm (Chronobiane Protect LD 1.9 mg (PiLeJe))","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"12","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"740","variance":"± 824 (SD)","units":"pg/mL","location":"Abstract; Results 3.2","quote":"Cmax 740 ± 824 pg/mL; Tmax 179 ± 60 min","quoteCheck":"supported","note":""},{"pmid":"39174857","species":"human","arm":"","form":"Delayed-release tablet with zinc and lemon balm (Chronobiane Protect LD 1.9 mg (PiLeJe))","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"12","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"179","variance":"± 60 (SD)","units":"min","location":"Abstract; Results 3.2","quote":"Tmax: 179 ± 60 min","quoteCheck":"supported","note":""},{"pmid":"39174857","species":"human","arm":"","form":"Delayed-release tablet with zinc and lemon balm (Chronobiane Protect LD 1.9 mg (PiLeJe))","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"12","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"relative AUC0-720","value":"2328","variance":"± 2721 (SD)","units":"pg × h/mL","location":"Results 3.2","quote":"Melatonin relative AUC0/720 was 2328 ± 2721 pg × h/mL","quoteCheck":"supported","note":"Methods: AUC attributable to supplementation obtained by subtraction of baseline (T-15 min). Discussion prints 2295 ± 2649 for DR AUC (see next row)."},{"pmid":"39174857","species":"human","arm":"","form":"Delayed-release tablet with zinc and lemon balm (Chronobiane Protect LD 1.9 mg (PiLeJe))","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"12","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC for comparison with prolonged-release form (stated AUC0-540 for PR)","value":"2295","variance":"± 2649 (SD)","units":"pg × h/mL","location":"Discussion p.420","quote":"2295 ± 2649 versus 3070 ± 1452 pg × h/mL, p < 0.05","quoteCheck":"supported","note":"Inconsistent with Results value 2328 ± 2721 (relative AUC0-720); the time window for the DR value in this comparison is not stated."},{"pmid":"39174857","species":"human","arm":"","form":"prolonged-release tablet","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"NR","n":"12","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-540","value":"3070","variance":"± 1452 (SD)","units":"pg × h/mL","location":"Discussion p.420","quote":"3070 ± 1452 pg × h/mL","quoteCheck":"supported","note":"Previous study's prolonged-release form, per Supplementary Table 1 (not available)."},{"pmid":"39174857","species":"human","arm":"","form":"prolonged-release tablet","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"NR","n":"12","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"1151","variance":"± 565 (SD)","units":"pg/mL","location":"Introduction p.416; Discussion p.420","quote":"Cmax 1151 ± 565 pg/mL, Tmax of 64 ± 44 min","quoteCheck":"supported","note":"Historical comparator from previous study [17]."},{"pmid":"39174857","species":"human","arm":"","form":"prolonged-release tablet","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"NR","n":"12","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"64","variance":"± 44 (SD)","units":"min","location":"Introduction p.416; Discussion p.420","quote":"Tmax of 64 ± 44 min","quoteCheck":"supported","note":"Historical comparator."},{"pmid":"39174857","species":"human","arm":"","form":"Delayed-release tablet with zinc and lemon balm (Chronobiane Protect LD 1.9 mg (PiLeJe))","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"12","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"7635","variance":"± 1161 (SD)","units":"pg/mL","location":"Results 3.2","quote":"For plasma 6-SMT, the Cmax was 7635 ± 1161 pg/mL","quoteCheck":"supported","note":""},{"pmid":"39174857","species":"human","arm":"","form":"Delayed-release tablet with zinc and lemon balm (Chronobiane Protect LD 1.9 mg (PiLeJe))","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"12","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"185","variance":"± 32 (SD)","units":"min","location":"Results 3.2","quote":"Tmax 185 ± 32 min","quoteCheck":"supported","note":""},{"pmid":"39174857","species":"human","arm":"","form":"Delayed-release tablet with zinc and lemon balm (Chronobiane Protect LD 1.9 mg (PiLeJe))","forms":["extended-release"],"dose":"1.9 mg","doseBasis":"active compound","fed":"fed (breakfast 2 h before)","n":"12","analyte":"6-sulfatoxymelatonin","matrix":"plasma","parameter":"AUC","detail":"relative AUC0-720","value":"27657","variance":"± 4178 (SD)","units":"pg × h/mL","location":"Results 3.2","quote":"Relative AUC0/720 was 27657 ± 4178 pg × h/mL","quoteCheck":"supported","note":""},{"pmid":"39458580","species":"human","arm":"","form":"sustained-release capsule (Melotime (Nutriventia))","forms":["extended-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"11,446.87","variance":"± 7804.98 (SD)","units":"pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"immediate-release capsule (Huanggang Saikang Pharmaceutical)","forms":["immediate-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"22,786.30","variance":"± 13,772.70 (SD)","units":"pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"sustained-release capsule (Melotime (Nutriventia))","forms":["extended-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"geometric least square mean","value":"9681.86","variance":"","units":"pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"immediate-release capsule (Huanggang Saikang Pharmaceutical)","forms":["immediate-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"geometric least square mean","value":"19,587.29","variance":"","units":"pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"sustained-release capsule (Melotime (Nutriventia))","forms":["extended-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"30,004.59","variance":"± 21,291.97 (SD)","units":"h×pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"immediate-release capsule (Huanggang Saikang Pharmaceutical)","forms":["immediate-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"43,078.8322","variance":"± 35,854.20 (SD)","units":"h×pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Printed with four decimals in the table (others have two)."},{"pmid":"39458580","species":"human","arm":"","form":"sustained-release capsule (Melotime (Nutriventia))","forms":["extended-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t geometric least square mean","value":"24,065.72","variance":"","units":"h×pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"immediate-release capsule (Huanggang Saikang Pharmaceutical)","forms":["immediate-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t geometric least square mean","value":"33,483.50","variance":"","units":"h×pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"sustained-release capsule (Melotime (Nutriventia))","forms":["extended-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"35,812.98","variance":"± 28,295.06 (SD)","units":"h×pg/mL","location":"Table 2 (footnote a)","quote":"Five participants were excluded from the calculation of AUC0–∞","quoteCheck":"value not in quote","note":"n not printed; footnote says five participants excluded."},{"pmid":"39458580","species":"human","arm":"","form":"immediate-release capsule (Huanggang Saikang Pharmaceutical)","forms":["immediate-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"43,539.37","variance":"± 37,146.72 (SD)","units":"h×pg/mL","location":"Table 2 (footnote b)","quote":"One participant was excluded from the calculation of AUC0–∞","quoteCheck":"value not in quote","note":"n not printed; footnote says one participant excluded."},{"pmid":"39458580","species":"human","arm":"","form":"sustained-release capsule (Melotime (Nutriventia))","forms":["extended-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf geometric least square mean","value":"24,565.12","variance":"","units":"h×pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"immediate-release capsule (Huanggang Saikang Pharmaceutical)","forms":["immediate-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf geometric least square mean","value":"34,464.67","variance":"","units":"h×pg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39458580","species":"human","arm":"","form":"sustained-release capsule (Melotime (Nutriventia))","forms":["extended-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"1.26","variance":"± 0.59 (SD)","units":"h","location":"Table 3","quote":"1.26 [0.59] h vs. 0.87 [0.42] h","quoteCheck":"supported","note":""},{"pmid":"39458580","species":"human","arm":"","form":"immediate-release capsule (Huanggang Saikang Pharmaceutical)","forms":["immediate-release"],"dose":"5 mg","doseBasis":"active compound","fed":"fasted","n":"16","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"0.87","variance":"± 0.42 (SD)","units":"h","location":"Table 3","quote":"","quoteCheck":"no quote","note":""},{"pmid":"3994899","species":"human","arm":"","form":"gelatine-coated capsule, 2 mg melatonin in 250 mg lactose (Sigma melatonin)","forms":["immediate-release"],"dose":"2 mg","doseBasis":"active compound","fed":"fed","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"above basal, to limit of detectability","value":"8036","variance":"± 2455 (SEM)","units":"pg ml-1 h","location":"Table 1","quote":"","quoteCheck":"no quote","note":"P<0.05 fed vs fasting (paired t-test)."},{"pmid":"3994899","species":"human","arm":"","form":"gelatine-coated capsule","forms":["immediate-release"],"dose":"2 mg","doseBasis":"active compound","fed":"fasted","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"above basal, to limit of detectability","value":"3712","variance":"± 703 (SEM)","units":"pg ml-1 h","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"3994899","species":"human","arm":"","form":"0.04% w/v melatonin in corn oil with 2% v/v ethanol, 5 mL dispersed in 50 mL milk","forms":[],"dose":"2 mg","doseBasis":"active compound","fed":"fed","n":"4","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"above basal, to limit of detectability","value":"5826","variance":"± 2644 (SEM)","units":"pg ml-1 h","location":"Table 1","quote":"","quoteCheck":"no quote","note":"P<0.05 fed vs fasting."},{"pmid":"3994899","species":"human","arm":"","form":"corn oil solution","forms":[],"dose":"2 mg","doseBasis":"active compound","fed":"fasted","n":"4","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"above basal, to limit of detectability","value":"3953","variance":"± 1533 (SEM)","units":"pg ml-1 h","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"3994899","species":"human","arm":"","form":"gelatine-coated capsule, 2 mg melatonin in 250 mg lactose (Sigma melatonin)","forms":["immediate-release"],"dose":"2 mg","doseBasis":"active compound","fed":"fed","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"lowest of reported range (gelatine capsule fed)","value":"0.46","variance":"± 0.07 (SEM)","units":"h","location":"Results p.519","quote":"tmax varied from 0.46 ± 0.07 h (gelatine capsule fed), to 0.95 ± 0.42 h (corn oil, fasting","quoteCheck":"supported","note":"Only the range endpoints are printed; other arms' tmax NR."},{"pmid":"3994899","species":"human","arm":"","form":"corn oil solution","forms":[],"dose":"2 mg","doseBasis":"active compound","fed":"fasted","n":"4","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"highest of reported range (corn oil fasting)","value":"0.95","variance":"± 0.42 (SEM)","units":"h","location":"Results p.519","quote":"to 0.95 ± 0.42 h (corn oil, fasting, mean ± s.e. mean)","quoteCheck":"supported","note":"Range endpoint only."},{"pmid":"42325096","species":"human","arm":"","form":"aqueous solution for injection 1 mg/mL (Glostrup Pharmacy)","forms":[],"dose":"0.15 mg·kg−1 (max 5 mg)","doseBasis":"active compound","fed":"NR","n":"20","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"416 719.80","variance":"± 170 557.51 (SD)","units":"pg·mL−1","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 prints thin-space thousands separators"},{"pmid":"42325096","species":"human","arm":"","form":"aqueous solution for injection 1 mg/mL (Glostrup Pharmacy)","forms":[],"dose":"0.15 mg·kg−1 (max 5 mg)","doseBasis":"active compound","fed":"NR","n":"20","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0–∞","value":"8 568 258.31","variance":"± 1 925 910.79 (SD)","units":"pg·min·mL−1","location":"Table 2","quote":"","quoteCheck":"no quote","note":""},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin in 25% DMSO/water (Sigma)","forms":[],"dose":"5 mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"2.38","variance":"","units":"mg.hr/L","location":"Table 1","quote":"","quoteCheck":"no quote","note":"AUC time zero to last detectable time point"},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin in 25% DMSO/water (Sigma)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"3.53","variance":"","units":"mg*h/L","location":"Results p.49","quote":"the plasma AUC was calculated to be 3.53 mg*h/L","quoteCheck":"supported","note":"Text only (Table 1 has no IP column)"},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin in 10% DMSO/water (3.25 mg/mL) (Sigma)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"2.49","variance":"","units":"mg.hr/L","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Oral dosing section"},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin in 10% DMSO/water (3.25 mg/mL) (Sigma)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"fractional_absorption","detail":"fraction absorbed (Fabs = F/Fip, author-derived)","value":"72","variance":"","units":"%","location":"Discussion p.50","quote":"about 72% of the oral dose was actually absorbed","quoteCheck":"supported","note":"Author estimate assuming complete absorption of the IP dose; hepatic extraction about 26% (100-Fip)"},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin 5.0 mg/mL in 30% propylene glycol, over 6 min (Sigma)","forms":[],"dose":"ca. 3 (Table 1: 2.95) mg/kg","doseBasis":"active compound","fed":"NR","n":"2","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"0.81","variance":"","units":"mg.hr/L","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin 1.0 mg/mL in 20% propylene glycol (Sigma)","forms":[],"dose":"1 (Table 1: 0.98) mg/kg","doseBasis":"active compound","fed":"NR","n":"2","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"0.05","variance":"","units":"mg.hr/L","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Oral 0.98 mg/kg (text: 1 mg/kg); analysed by LC/MS/MS only"},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin 3.5 mg/mL in 20% propylene glycol, oral intubation (Sigma)","forms":[],"dose":"ca. 10 (Table 1: 10.30) mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"2","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"3.44","variance":"","units":"mg.hr/L","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Oral 10.30 mg/kg (text: ca. 10 mg/kg)"},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin 4.0 mg/mL in 20% propylene glycol, over 5-6 min (Sigma)","forms":[],"dose":"ca. 3 (Table 1: 2.98) mg/kg","doseBasis":"active compound","fed":"NR","n":"2","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"1.78","variance":"","units":"mg.hr/L","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"9062870","species":"primate","arm":"","form":"melatonin 4.0 mg/mL in 20% propylene glycol (Sigma)","forms":[],"dose":"ca. 10 (Table 1: 10.00) mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"2","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"","value":"8.85","variance":"","units":"mg.hr/L","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Oral 10.00 mg/kg"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution (0.25% melatonin, 11% ethanol, saline), 0.2 mL, caudal lateral vein","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"0.88","variance":"± 0.47 (SD)","units":"h·μg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":"p<0.05 IV ZT4 vs ZT16"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution, 0.2 mL","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"2.18","variance":"± 0.96 (SD)","units":"h·μg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":"p<0.05 IV ZT4 vs ZT16"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"0.31","variance":"± 0.11 (SD)","units":"h·μg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Table 2 (one-compartment) prints 0.34 ± 0.08 for TD ZT16; p<0.05 TD ZT4 vs ZT16"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"2.16","variance":"± 1.40 (SD)","units":"h·μg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Table 2 prints 1.98 ± 1.07 for TD ZT4 (compartmental); p<0.05 TD ZT4 vs ZT16"},{"pmid":"27644893","species":"rodent","arm":"","form":"oral solution (0.67% melatonin, 13% ethanol, saline), 1.5 mL by gastric cannula","forms":["liquid"],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"4","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"3.66","variance":"± 2.07 (SD)","units":"h·μg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":"p<0.05 TD ZT16 vs oral ZT16"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"0.30","variance":"± 0.08 (SD)","units":"μg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"0.64","variance":"± 0.41 (SD)","units":"μg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27644893","species":"rodent","arm":"","form":"oral solution (0.67% melatonin, 13% ethanol, saline), 1.5 mL by gastric cannula","forms":["liquid"],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"4","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"2.05","variance":"± 1.21 (SD)","units":"μg/mL","location":"Table 1","quote":"","quoteCheck":"no quote","note":"p<0.05 TD ZT16 vs oral ZT16"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Tmax","detail":"tmax","value":"32","variance":"± 18 (SD)","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Tmax","detail":"tmax","value":"151","variance":"± 127 (SD)","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27644893","species":"rodent","arm":"","form":"oral solution (0.67% melatonin, 13% ethanol, saline), 1.5 mL by gastric cannula","forms":["liquid"],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"4","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Tmax","detail":"tmax","value":"46","variance":"± 18 (SD)","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution (0.25% melatonin, 11% ethanol, saline), 0.2 mL, caudal lateral vein","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf (compartmental)","value":"1.00","variance":"± 0.34 (SD)","units":"h·μg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 (compartmental analysis); * p<0.05 ZT4 vs ZT16 (paired t-test)"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution, 0.2 mL","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf (compartmental)","value":"2.36","variance":"± 0.94 (SD)","units":"h·μg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 (compartmental analysis); * p<0.05 ZT4 vs ZT16 (paired t-test)"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf (compartmental)","value":"0.34","variance":"± 0.08 (SD)","units":"h·μg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 (compartmental analysis); * p<0.05 ZT4 vs ZT16 (paired t-test)"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf (compartmental)","value":"1.98","variance":"± 1.07 (SD)","units":"h·μg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 (compartmental analysis; column labelled 'TD IV ZT4' in paper, read as TD ZT4); * p<0.05 ZT4 vs ZT16 (paired t-test)"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Tmax","detail":"tmax (one-compartment TD)","value":"29.70","variance":"± 10.14 (SD)","units":"min","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 (compartmental analysis); * p<0.05 ZT4 vs ZT16 (paired t-test); Table 1 non-compartmental tmax = 32 ± 18 min"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Tmax","detail":"tmax (one-compartment TD)","value":"98.78","variance":"± 33.06 (SD)","units":"min","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 (compartmental analysis; column labelled 'TD IV ZT4' in paper, read as TD ZT4); * p<0.05 ZT4 vs ZT16 (paired t-test); Table 1 non-compartmental tmax = 151 ± 127 min"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax (one-compartment TD)","value":"0.18","variance":"± 0.03 (SD)","units":"μg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 (compartmental analysis); Table 1 Cmax = 0.30 ± 0.08"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"unbound plasma melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax (one-compartment TD)","value":"0.44","variance":"± 0.30 (SD)","units":"μg/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 (compartmental analysis; column labelled 'TD IV ZT4' in paper, read as TD ZT4); Table 1 Cmax = 0.64 ± 0.41"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution (0.25% melatonin, 11% ethanol, saline), 0.2 mL, caudal lateral vein","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Cmax","detail":"Cmax/D dose-normalised","value":"30.90","variance":"± 37.28 (SD)","units":"ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution, 0.2 mL","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Cmax","detail":"Cmax/D dose-normalised","value":"15.23","variance":"± 9.60 (SD)","units":"ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Cmax","detail":"Cmax/D dose-normalised","value":"3.88","variance":"± 1.67 (SD)","units":"ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Cmax","detail":"Cmax/D dose-normalised","value":"2.84","variance":"± 1.16 (SD)","units":"ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"oral solution (0.67% melatonin, 13% ethanol, saline), 1.5 mL by gastric cannula","forms":["liquid"],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"4","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Cmax","detail":"Cmax/D dose-normalised","value":"1.68","variance":"± 1.33 (SD)","units":"ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution (0.25% melatonin, 11% ethanol, saline), 0.2 mL, caudal lateral vein","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf/D dose-normalised","value":"17.55","variance":"± 15.52 (SD)","units":"h·ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution, 0.2 mL","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf/D dose-normalised","value":"9.92","variance":"± 5.17 (SD)","units":"h·ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf/D dose-normalised","value":"12.45","variance":"± 5.92 (SD)","units":"h·ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf/D dose-normalised","value":"9.68","variance":"± 1.87 (SD)","units":"h·ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"oral solution (0.67% melatonin, 13% ethanol, saline), 1.5 mL by gastric cannula","forms":["liquid"],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"4","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf/D dose-normalised","value":"2.72","variance":"± 2.29 (SD)","units":"h·ng/mL·mg","location":"Table 3","quote":"","quoteCheck":"no quote","note":"AFMK parameters not different between ZTs (text p.167); dose-normalised route comparisons p<0.05 (text)"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution (0.25% melatonin, 11% ethanol, saline), 0.2 mL, caudal lateral vein","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Tmax","detail":"tmax","value":"27","variance":"± 9 (SD)","units":"min","location":"Results 3.2 (text)","quote":"tmax for the IV route had the values of 27 (± 9) min at ZT16 and 18 (± 7) min at ZT4","quoteCheck":"supported","note":"no significant ZT difference for AFMK tmax"},{"pmid":"27644893","species":"rodent","arm":"","form":"IV bolus solution, 0.2 mL","forms":[],"dose":"0.5 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Tmax","detail":"tmax","value":"18","variance":"± 7 (SD)","units":"min","location":"Results 3.2 (text)","quote":"","quoteCheck":"no quote","note":""},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g applied to lower back skin","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Tmax","detail":"tmax range","value":"15–139","variance":"","units":"min","location":"Results 3.2 (text)","quote":"values ranging from 15 to 139 min at ZT16","quoteCheck":"value not in quote","note":"range of individual tmax; mean NR"},{"pmid":"27644893","species":"rodent","arm":"","form":"2% melatonin emulsion, 0.5 g","forms":[],"dose":"10 mg","doseBasis":"active compound","fed":"NR (rats had ad libitum food)","n":"5","analyte":"AFMK (melatonin metabolite)","matrix":"plasma","parameter":"Tmax","detail":"tmax range","value":"62–183","variance":"","units":"min","location":"Results 3.2 (text)","quote":"from 62 to 183 min at ZT4","quoteCheck":"value not in quote","note":"range of individual tmax; mean NR"},{"pmid":"27865856","species":"rodent","arm":"","form":"raw melatonin dispersed in distilled water (Nanjing Zelang Medical Technological (raw material))","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"Cmax","detail":"","value":"168.86","variance":"","units":"ng/mL","location":"Abstract; Results 3.4","quote":"reached the maximum value of 168.86, 195.33, and 383.71 ng/mL after 15, 15, and 30 min","quoteCheck":"supported","note":"value read from mean concentration-time curve per text; SD/n not stated (Abstract gives raw MLT 168.86 and MLT-SiO2-HP55 383.71; Results text gives all three)"},{"pmid":"27865856","species":"rodent","arm":"","form":"raw melatonin dispersed in distilled water (Nanjing Zelang Medical Technological (raw material))","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"Tmax","detail":"","value":"15","variance":"","units":"min","location":"Abstract; Results 3.4","quote":"","quoteCheck":"no quote","note":"value read from mean concentration-time curve per text; SD/n not stated"},{"pmid":"27865856","species":"rodent","arm":"","form":"melatonin adsorbed on silica nanospheres, dispersed in water","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"Cmax","detail":"","value":"195.33","variance":"","units":"ng/mL","location":"Abstract; Results 3.4","quote":"","quoteCheck":"no quote","note":"value read from mean concentration-time curve per text; SD/n not stated (Abstract gives raw MLT 168.86 and MLT-SiO2-HP55 383.71; Results text gives all three)"},{"pmid":"27865856","species":"rodent","arm":"","form":"melatonin adsorbed on silica nanospheres, dispersed in water","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"Tmax","detail":"","value":"15","variance":"","units":"min","location":"Abstract; Results 3.4","quote":"","quoteCheck":"no quote","note":"value read from mean concentration-time curve per text; SD/n not stated"},{"pmid":"27865856","species":"rodent","arm":"","form":"melatonin-loaded silica coated with HPMCP HP55 (15.41% HP55)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"Cmax","detail":"","value":"383.71","variance":"","units":"ng/mL","location":"Abstract; Results 3.4","quote":"","quoteCheck":"no quote","note":"value read from mean concentration-time curve per text; SD/n not stated (Abstract gives raw MLT 168.86 and MLT-SiO2-HP55 383.71; Results text gives all three)"},{"pmid":"27865856","species":"rodent","arm":"","form":"melatonin-loaded silica coated with HPMCP HP55 (15.41% HP55)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"Tmax","detail":"","value":"30","variance":"","units":"min","location":"Abstract; Results 3.4","quote":"","quoteCheck":"no quote","note":"value read from mean concentration-time curve per text; SD/n not stated"},{"pmid":"27865856","species":"rodent","arm":"","form":"melatonin adsorbed on silica nanospheres, dispersed in water","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"relative_bioavailability","detail":"AUC ratio MLT-SiO2 / raw MLT","value":"1.4","variance":"","units":"fold (times)","location":"Results 3.4 p.65; Discussion","quote":"The AUC values of MLT-SiO2 were 1.4 times higher than those of raw MLT.","quoteCheck":"supported","note":"stated ratio, absolute AUC values not printed (figure only); Discussion also states oral bioavailability of MLT-SiO2 was 1.4 times raw MLT"},{"pmid":"27865856","species":"rodent","arm":"","form":"melatonin-loaded silica coated with HPMCP HP55 (15.41% HP55)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"relative_bioavailability","detail":"AUC ratio MLT-SiO2-HP55 / raw MLT","value":"3.5","variance":"","units":"fold (times)","location":"Abstract; Discussion p.65 (oral bioavailability sentence)","quote":"The corresponding area under the curve (AUC) of MLT-SiO2-HP55 was 3.5 times higher than that of raw MLT.","quoteCheck":"supported","note":"INCONSISTENT: Results p.65 states AUC of MLT-SiO2-HP55 was 2.4 and 3.5 times higher than that of raw MLT and MLT-SiO2, respectively (i.e. 2.4 vs raw MLT, 3.5 vs MLT-SiO2); Abstract and Discussion final paragraph say 3.5 vs raw MLT"},{"pmid":"27865856","species":"rodent","arm":"","form":"melatonin-loaded silica coated with HPMCP HP55 (15.41% HP55)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"relative_bioavailability","detail":"AUC ratio MLT-SiO2-HP55 / raw MLT (alternative printed value)","value":"2.4","variance":"","units":"fold (times)","location":"Results 3.4 p.65","quote":"AUC values of MLT-SiO2-HP55 were 2.4 and 3.5 times higher than that of raw MLT and MLT-SiO2, respectively","quoteCheck":"supported","note":"inconsistent with Abstract (3.5 vs raw MLT); ordering of the two comparators as printed"},{"pmid":"27865856","species":"rodent","arm":"","form":"melatonin-loaded silica coated with HPMCP HP55 (15.41% HP55)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted overnight","n":"NR","analyte":"melatonin","matrix":"rat plasma","parameter":"relative_bioavailability","detail":"AUC ratio MLT-SiO2-HP55 / MLT-SiO2","value":"3.5","variance":"","units":"fold (times)","location":"Results 3.4 p.65","quote":"AUC values of MLT-SiO2-HP55 were 2.4 and 3.5 times higher than that of raw MLT and MLT-SiO2, respectively","quoteCheck":"supported","note":"as printed order; inconsistent with Abstract/Discussion (3.5 vs raw MLT). Arithmetic from 1.4 x 2.4 not performed"},{"pmid":"29109369","species":"rodent","arm":"","form":"melatonin in 6% alcohol solution (Sigma)","forms":[],"dose":"10 mg/kg BW","doseBasis":"active compound","fed":"starved 4 h","n":"6","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC (window NR; 0-120 min presumed not stated)","value":"102.0","variance":"± 4.8 (SD)","units":"µg·min/mL","location":"Table 8","quote":"","quoteCheck":"no quote","note":"AUC integration window not stated"},{"pmid":"29109369","species":"rodent","arm":"","form":"melatonin in 6% alcohol solution (Sigma)","forms":[],"dose":"50 mg/kg BW","doseBasis":"active compound","fed":"starved 4 h","n":"6","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC (window NR)","value":"455.1","variance":"± 25.2 (SD)","units":"µg·min/mL","location":"Table 8","quote":"","quoteCheck":"no quote","note":"AUC integration window not stated"},{"pmid":"30286985","species":"rodent","arm":"","form":"Commercially available melatonin (Circadin) dispersed in water (Circadin)","forms":["extended-release"],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"120.11","variance":"","units":"ng/mL","location":"Results 3.4 (p.131)","quote":"The Cmax of commercially available MLT, MLT and MPS in rats were 120.11, 134.26 and 291.77 ng/mL, respectively.","quoteCheck":"supported","note":"order in sentence taken as commercial, raw MLT, MPS"},{"pmid":"30286985","species":"rodent","arm":"","form":"Raw melatonin dispersed in water","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"134.26","variance":"","units":"ng/mL","location":"Results 3.4 (p.131); Abstract","quote":"plasma concentrations of MLT and MPS reached a Cmax of 134.26 and 291.77 ng/mL at 15 and 20 min, respectively","quoteCheck":"supported","note":""},{"pmid":"30286985","species":"rodent","arm":"","form":"Melatonin adsorbed in porous starch (drug loading 12.30%)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"291.77","variance":"","units":"ng/mL","location":"Results 3.4 (p.131); Abstract","quote":"plasma concentrations of MLT and MPS reached a Cmax of 134.26 and 291.77 ng/mL at 15 and 20 min, respectively","quoteCheck":"supported","note":""},{"pmid":"30286985","species":"rodent","arm":"","form":"Raw melatonin dispersed in water","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"15","variance":"","units":"min","location":"Abstract; Results 3.4","quote":"reached a Cmax of 134.26 and 291.77 ng/mL at 15 and 20 min, respectively","quoteCheck":"supported","note":""},{"pmid":"30286985","species":"rodent","arm":"","form":"Commercially available melatonin (Circadin) dispersed in water (Circadin)","forms":["extended-release"],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"'within 15 min'","value":"within 15 min","variance":"","units":"min","location":"Results 3.4 (p.131)","quote":"commercially available MLT and MLT reached a maximum concentration within 15 min, followed by a rapid fall","quoteCheck":"supported","note":"approximate statement, not a point value"},{"pmid":"30286985","species":"rodent","arm":"","form":"Melatonin adsorbed in porous starch (drug loading 12.30%)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"20","variance":"","units":"min","location":"Abstract; Results 3.4","quote":"The plasma concentration of MPS reaching Cmax at 20 min","quoteCheck":"supported","note":""},{"pmid":"30286985","species":"rodent","arm":"","form":"Melatonin adsorbed in porous starch (drug loading 12.30%)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"relative_bioavailability","detail":"AUC0-360min fold, MPS vs raw MLT","value":"2.34","variance":"","units":"fold","location":"Abstract; Results 3.4; Conclusion","quote":"The AUC0–360min of the formulated MPS-treated group was approximately 2.34-fold higher than that of raw MLT.","quoteCheck":"supported","note":"'approximately'; absolute AUC values not printed"},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin in water, tail vein","forms":[],"dose":"62.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"87.92","variance":"± 9.03 (SD)","units":"ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin in water, tail vein","forms":[],"dose":"62.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"5.00","variance":"± 0.00 (SD)","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin in water, tail vein","forms":[],"dose":"62.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"1503.08","variance":"± 298.8 (SD)","units":"min·ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin in water, tail vein","forms":[],"dose":"62.5 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"1528.28","variance":"± 301.83 (SD)","units":"min·ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin suspension in water by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"59.82","variance":"± 4.00 (SD)","units":"ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin suspension in water by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"10.00","variance":"± 4.08 (SD)","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin suspension in water by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"1766.05","variance":"± 325.6 (SD)","units":"min·ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin suspension in water by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"1773.89","variance":"± 330.79 (SD)","units":"min·ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin 15 mg/mL in 20% PEG-400 by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"199.10","variance":"± 37.51 (SD)","units":"ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin 15 mg/mL in 20% PEG-400 by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"7.00","variance":"± 4.47 (SD)","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin 15 mg/mL in 20% PEG-400 by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"6006.33","variance":"± 644.4 (SD)","units":"min·ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin 15 mg/mL in 20% PEG-400 by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"6026.69","variance":"± 641.77 (SD)","units":"min·ug/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin 15 mg/mL in 20% PEG-400 by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"second plasma concentration peak","value":"20","variance":"","units":"min","location":"Abstract","quote":"Tmax at 5 min with closely spaced another distinct concentration peak at 20 min","quoteCheck":"supported","note":"abstract describes Tmax 5 min and a second peak at 20 min; formulation not stated in abstract; Table 1 gives Tmax 7.00 for PEG"},{"pmid":"30625289","species":"rodent","arm":"","form":"Melatonin 15 mg/mL in 20% PEG-400 by gavage","forms":[],"dose":"250 mg/kg","doseBasis":"active compound","fed":"NR","n":"5","analyte":"melatonin","matrix":"Intestine tissue","parameter":"AUC","detail":"tissue AUC0-t","value":"51.98","variance":"± 29.14 (SD)","units":"min·ug/ml","location":"Table 2","quote":"","quoteCheck":"no quote","note":"units as printed in Table 2"},{"pmid":"30731257","species":"rodent","arm":"","form":"Melatonin-loaded bacterial cellulose nanofiber, freeze-dried (MLT content 33.5%/ drug loading 34.2% as printed)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"299.7","variance":"","units":"ng/mL","location":"Results 3.5 (p.400)","quote":"peak concentration ... MLT-BCNs, the commercially available MLT and the physical mixture with raw MLT and BCNs were 299.7 ng/mL, 148.8 ng/mL and 120.1 ng/mL and the peak time was 15 min","quoteCheck":"supported","note":"order MLT-BCNs, commercial, physical mixture per sentence"},{"pmid":"30731257","species":"rodent","arm":"","form":"Melatonin-loaded bacterial cellulose nanofiber, freeze-dried (MLT content 33.5%/ drug loading 34.2% as printed)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"15","variance":"","units":"min","location":"Results 3.5 (p.400)","quote":"the peak time was 15 min after oral administration, respectively","quoteCheck":"supported","note":"stated for all three groups"},{"pmid":"30731257","species":"rodent","arm":"","form":"Commercially available melatonin (Circadin)","forms":["extended-release"],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"148.8","variance":"","units":"ng/mL","location":"Results 3.5 (p.400)","quote":"peak concentration ... MLT-BCNs, the commercially available MLT and the physical mixture with raw MLT and BCNs were 299.7 ng/mL, 148.8 ng/mL and 120.1 ng/mL and the peak time was 15 min","quoteCheck":"supported","note":"order MLT-BCNs, commercial, physical mixture per sentence"},{"pmid":"30731257","species":"rodent","arm":"","form":"Commercially available melatonin (Circadin)","forms":["extended-release"],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"15","variance":"","units":"min","location":"Results 3.5 (p.400)","quote":"the peak time was 15 min after oral administration, respectively","quoteCheck":"supported","note":"stated for all three groups"},{"pmid":"30731257","species":"rodent","arm":"","form":"Physical mixture of raw MLT and BCNs","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"120.1","variance":"","units":"ng/mL","location":"Results 3.5 (p.400)","quote":"peak concentration ... MLT-BCNs, the commercially available MLT and the physical mixture with raw MLT and BCNs were 299.7 ng/mL, 148.8 ng/mL and 120.1 ng/mL and the peak time was 15 min","quoteCheck":"supported","note":"order MLT-BCNs, commercial, physical mixture per sentence"},{"pmid":"30731257","species":"rodent","arm":"","form":"Physical mixture of raw MLT and BCNs","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"15","variance":"","units":"min","location":"Results 3.5 (p.400)","quote":"the peak time was 15 min after oral administration, respectively","quoteCheck":"supported","note":"stated for all three groups"},{"pmid":"30731257","species":"rodent","arm":"","form":"Melatonin-loaded bacterial cellulose nanofiber, freeze-dried (MLT content 33.5%/ drug loading 34.2% as printed)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"relative_bioavailability","detail":"AUC fold, MLT-BCNs vs commercial MLT","value":"2.4","variance":"","units":"fold","location":"Results 3.5 (p.400); Abstract","quote":"AUC of MLT-BCNs was 2.4-fold and 2.6-fold higher than ... commercially available MLT ... and the physical mixture","quoteCheck":"supported","note":""},{"pmid":"30731257","species":"rodent","arm":"","form":"Melatonin-loaded bacterial cellulose nanofiber, freeze-dried (MLT content 33.5%/ drug loading 34.2% as printed)","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"relative_bioavailability","detail":"AUC fold, MLT-BCNs vs physical mixture raw MLT + BCNs","value":"2.6","variance":"","units":"fold","location":"Results 3.5 (p.400)","quote":"AUC of MLT-BCNs was 2.4-fold and 2.6-fold higher","quoteCheck":"supported","note":""},{"pmid":"32178261","species":"rodent","arm":"","form":"Ethanol extract of 6-day lentil sprouts in PBS","forms":[],"dose":"50 µg melatonin/kg","doseBasis":"active compound","fed":"12 h fasted","n":"8","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"90.0","variance":"± 0.0 (SD)","units":"min","location":"Table 4","quote":"Tmax (min) 90.0 ± 0.0","quoteCheck":"supported","note":""},{"pmid":"32178261","species":"rodent","arm":"","form":"Ethanol extract of 6-day lentil sprouts in PBS","forms":[],"dose":"50 µg melatonin/kg","doseBasis":"active compound","fed":"12 h fasted","n":"8","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"45.4","variance":"± 3.5 (SD)","units":"pg/mL","location":"Table 4","quote":"Cmax (pg/mL) 45.4 ± 3.5","quoteCheck":"supported","note":""},{"pmid":"32178261","species":"rodent","arm":"","form":"Ethanol extract of 6-day lentil sprouts in PBS","forms":[],"dose":"50 µg melatonin/kg","doseBasis":"active compound","fed":"12 h fasted","n":"8","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"6560","variance":"± 963 (SD)","units":"pg/mL min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32178261","species":"rodent","arm":"","form":"Ethanol extract of 6-day lentil sprouts in PBS","forms":[],"dose":"50 µg melatonin/kg","doseBasis":"active compound","fed":"12 h fasted","n":"8","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t/dose","value":"131.2","variance":"± 19.3 (SD)","units":"(pg/mL min)/(µg/kg)","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32178261","species":"rodent","arm":"","form":"Ethanol extract of 6-day lentil sprouts in PBS","forms":[],"dose":"50 µg melatonin/kg","doseBasis":"active compound","fed":"12 h fasted","n":"8","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"9381","variance":"± 2008 (SD)","units":"pg/mL min","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"32439308","species":"rodent","arm":"","form":"liposomes","forms":[],"dose":"1 mL formulation (3 mg/mL theoretical)","doseBasis":"NR","fed":"","n":"3","analyte":"melatonin","matrix":"in vitro dialysis (PBS)","parameter":"AUC","detail":"AUC of released melatonin","value":"3523.27","variance":"","units":"mg*min/mL","location":"Results 3.4, p.251","quote":"AUC were the highest in melatonin-LP (3523.27 mg*min/mL), and the lowest in melatonin-EtOH (1513.92 mg*min/mL)","quoteCheck":"supported","note":"units as printed (mg*min/mL)"},{"pmid":"32439308","species":"rodent","arm":"","form":"solution","forms":[],"dose":"NR NR","doseBasis":"NR","fed":"","n":"3","analyte":"melatonin","matrix":"in vitro dialysis (PBS)","parameter":"AUC","detail":"AUC of released melatonin","value":"1513.92","variance":"","units":"mg*min/mL","location":"Results 3.4, p.251","quote":"AUC were the highest in melatonin-LP (3523.27 mg*min/mL), and the lowest in melatonin-EtOH (1513.92 mg*min/mL)","quoteCheck":"supported","note":"units as printed (mg*min/mL)"},{"pmid":"39065568","species":"rodent","arm":"","form":"IT-AA-NVC copolymer/melatonin nanoparticles coated with chitosan","forms":[],"dose":"1 mg/kg BW","doseBasis":"active compound","fed":"fasted 24 h","n":"3","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"7.15271","variance":"","units":"µg/mL","location":"Table 2","quote":"Cmax 7.15271 µg/mL","quoteCheck":"supported","note":"Text p.12-13 prints 7.12 µg/mL; Fig. 6 y-axis labelled ng/L (peak about 7.5 by eye, not recorded). Unit inconsistency Table vs Fig."},{"pmid":"39065568","species":"rodent","arm":"","form":"IT-AA-NVC copolymer/melatonin nanoparticles coated with chitosan","forms":[],"dose":"1 mg/kg BW","doseBasis":"active compound","fed":"fasted 24 h","n":"3","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"text value","value":"7.12","variance":"","units":"µg/mL","location":"Results p.12-13 (3.2)","quote":"mean plasma level of melatonin was found to demonstrate a Cmax value of 7.12 µg/mL within 75 min","quoteCheck":"supported","note":"Inconsistent with Table 2 (7.15271)."},{"pmid":"39065568","species":"rodent","arm":"","form":"IT-AA-NVC copolymer/melatonin nanoparticles coated with chitosan","forms":[],"dose":"1 mg/kg BW","doseBasis":"active compound","fed":"fasted 24 h","n":"3","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"75","variance":"","units":"min","location":"Table 2; text p.13","quote":"tmax 75 min","quoteCheck":"supported","note":""},{"pmid":"39065568","species":"rodent","arm":"","form":"IT-AA-NVC copolymer/melatonin nanoparticles coated with chitosan","forms":[],"dose":"1 mg/kg BW","doseBasis":"active compound","fed":"fasted 24 h","n":"3","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-120 min","value":"450.9","variance":"","units":"µg.min/mL","location":"Table 2","quote":"AUC0→120 450.9 µg.min/mL","quoteCheck":"supported","note":"Text calls it AUC0-120h but the table unit is min."},{"pmid":"39065568","species":"rodent","arm":"","form":"SM micro/nanoparticles","forms":[],"dose":"10 mg","doseBasis":"NR","fed":"NR","n":"triplicate","analyte":"melatonin","matrix":"in vitro phosphate buffer pH 7.4","parameter":"Cmax","detail":"in vitro maximum released","value":"47","variance":"","units":"µg/mL","location":"Table 2","quote":"Cmax 47 µg/mL (In Vitro)","quoteCheck":"supported","note":"Text p.10 says maximum of 47 µg within the first hour."},{"pmid":"39065568","species":"rodent","arm":"","form":"SM micro/nanoparticles","forms":[],"dose":"10 mg","doseBasis":"NR","fed":"NR","n":"triplicate","analyte":"melatonin","matrix":"in vitro phosphate buffer pH 7.4","parameter":"Tmax","detail":"in vitro","value":"40","variance":"","units":"min","location":"Table 2","quote":"tmax 40 min (In Vitro)","quoteCheck":"supported","note":""},{"pmid":"39722474","species":"rodent","arm":"","form":"melatonin in ethanol:Tween-80:saline (Sigma-Aldrich M5250)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"NR","n":"4-5 per time point","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"265","variance":"± 49 (NR)","units":"ng/mL","location":"Table 1","quote":"Cmax ng/mL 265 ± 49","quoteCheck":"supported","note":"Variance type not stated in table (error bars in Fig. 1 are SEM)."},{"pmid":"39722474","species":"rodent","arm":"","form":"melatonin with cannabinol 50 mg/kg (CBN from THC Pharm GmbH)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"NR","n":"4-5 per time point","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"184","variance":"± 62 (NR)","units":"ng/mL","location":"Table 1","quote":"184 ± 62","quoteCheck":"supported","note":"Variance type not stated in table."},{"pmid":"39722474","species":"rodent","arm":"","form":"melatonin in ethanol:Tween-80:saline (Sigma-Aldrich M5250)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"NR","n":"4-5 per time point","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"15","variance":"","units":"min","location":"Table 1","quote":"tmax 15 vs 30 min","quoteCheck":"supported","note":"Sparse sampling; plasma concentrations at each time point averaged."},{"pmid":"39722474","species":"rodent","arm":"","form":"melatonin with cannabinol 50 mg/kg (CBN from THC Pharm GmbH)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"NR","n":"4-5 per time point","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"30","variance":"","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39722474","species":"rodent","arm":"","form":"melatonin in ethanol:Tween-80:saline (Sigma-Aldrich M5250)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"NR","n":"4-5 per time point","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"total exposure","value":"2.54","variance":"","units":"µg•minutes/mL","location":"Table 1; Results 3.2","quote":"Total melatonin exposure (AUC) was over four times greater (2.54 vs. 10.28 µg*min/mL) when coadministered with CBN","quoteCheck":"supported","note":"Computed from averaged concentrations; no variance."},{"pmid":"39722474","species":"rodent","arm":"","form":"melatonin with cannabinol 50 mg/kg (CBN from THC Pharm GmbH)","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"NR","n":"4-5 per time point","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"total exposure","value":"10.28","variance":"","units":"µg•minutes/mL","location":"Table 1; Results 3.2","quote":"","quoteCheck":"no quote","note":"Abstract: four-fold increase in plasma melatonin exposure; Discussion: 4-fold."},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin p.o. with CBD i.v.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"0.08","variance":"± 0.00 (SD)","units":"h","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin oral solution","forms":["liquid"],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"0.08","variance":"± 0.00 (SD)","units":"h","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"0.08","variance":"± 0.00 (SD)","units":"h","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"0.11","variance":"± 0.07 (SD)","units":"h","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin p.o. with CBD i.v.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"884.1","variance":"± 596.1 (SD)","units":"ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin oral solution","forms":["liquid"],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"1061.9","variance":"± 430.0 (SD)","units":"ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"1200.2","variance":"± 576.0 (SD)","units":"ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"454.9","variance":"± 227.6 (SD)","units":"ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin p.o. with CBD i.v.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-0.5h)","value":"163.1","variance":"± 108.5 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin oral solution","forms":["liquid"],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-0.5h)","value":"178.54","variance":"± 69.38 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-0.5h)","value":"209.3","variance":"± 101.26 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-0.5h)","value":"103.3","variance":"± 30.9 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin p.o. with CBD i.v.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0.5-8h)","value":"67.64","variance":"± 16.57 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin oral solution","forms":["liquid"],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0.5-8h)","value":"43.94","variance":"± 9.11 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0.5-8h)","value":"50.63","variance":"± 19.06 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0.5-8h)","value":"125.3","variance":"± 48.15 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin i.v.","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-8h)","value":"402.1","variance":"± 117.1 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin p.o. with CBD i.v.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-8h)","value":"210.8","variance":"± 96.5 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin oral solution","forms":["liquid"],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-8h)","value":"210.3","variance":"± 71.0 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-8h)","value":"242.2","variance":"± 103.7 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-8h)","value":"207.2","variance":"± 66.8 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin i.v.","forms":[],"dose":"2 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-inf)","value":"403.5","variance":"± 117.2 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin p.o. with CBD i.v.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-inf)","value":"218.6","variance":"± 94.2 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin oral solution","forms":["liquid"],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-inf)","value":"215.4","variance":"± 69.8 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-inf)","value":"247.2","variance":"± 101.6 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC(0-inf)","value":"242.8","variance":"± 71.6 (SD)","units":"h × ng/mL","location":"Table 5","quote":"","quoteCheck":"no quote","note":""},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"0.42","variance":"± 0.20 (SD)","units":"h","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"0.63","variance":"± 0.26 (SD)","units":"h","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"103.52","variance":"± 25.67 (SD)","units":"ng/mL","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"1820.4","variance":"± 823.7 (SD)","units":"ng/mL","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin p.o. with CBD i.v.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"AUC","detail":"AUC(0-8h)","value":"279.36","variance":"± 41.69 (SD)","units":"h × ng/mL","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"AUC","detail":"AUC(0-8h)","value":"134.80","variance":"± 28.69 (SD)","units":"h × ng/mL","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"AUC","detail":"AUC(0-8h)","value":"2156.5","variance":"± 574.5 (SD)","units":"h × ng/mL","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin p.o. with CBD i.v.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"AUC","detail":"AUC(0-inf)","value":"288.58","variance":"± 38.60 (SD)","units":"h × ng/mL","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"AUC","detail":"AUC(0-inf)","value":"138.12","variance":"± 29.05 (SD)","units":"h × ng/mL","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"39771491","species":"rodent","arm":"","form":"melatonin + cannabidiol p.o.","forms":[],"dose":"10 mg/kg","doseBasis":"active compound","fed":"fasted 12 h before oral dosing","n":"6","analyte":"cannabidiol (CBD)","matrix":"plasma","parameter":"AUC","detail":"AUC(0-inf)","value":"2186.8","variance":"± 578.2 (SD)","units":"h × ng/mL","location":"Table 6","quote":"","quoteCheck":"no quote","note":"CBD PK (interacting compound, not the target supplement)"},{"pmid":"42306921","species":"rodent","arm":"","form":"dissolving microneedle patch, transdermal","forms":[],"dose":"1.83 mg per MN patch (drug loading)","doseBasis":"active compound","fed":"NR","n":"3 per time point","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"35.06","variance":"± 11.06 (NR)","units":"ng/mL","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 prints value ± second number; variance type (SD/SEM) not stated; 'mean' per Results text"},{"pmid":"42306921","species":"rodent","arm":"","form":"dissolving microneedle patch, transdermal","forms":[],"dose":"1.83 mg per MN patch (drug loading)","doseBasis":"active compound","fed":"NR","n":"3 per time point","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUClast","value":"1152.11","variance":"± 169.97 (NR)","units":"ng/mL*min","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 prints value ± second number; variance type (SD/SEM) not stated; 'mean' per Results text"},{"pmid":"42306921","species":"rodent","arm":"","form":"dissolving microneedle patch, transdermal","forms":[],"dose":"1.83 mg per MN patch (drug loading)","doseBasis":"active compound","fed":"NR","n":"3 per time point","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUCinf","value":"1160.89","variance":"± 171.76 (NR)","units":"ng/mL*min","location":"Table 2","quote":"","quoteCheck":"no quote","note":"Table 2 prints value ± second number; variance type (SD/SEM) not stated; 'mean' per Results text"},{"pmid":"42306921","species":"rodent","arm":"","form":"dissolving microneedle patch, transdermal","forms":[],"dose":"1.83 mg per MN patch (drug loading)","doseBasis":"active compound","fed":"NR","n":"3 per time point","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"text","value":"35.06","variance":"± 11.06 (NR)","units":"ng/mL","location":"Results (in vivo PK) para","quote":"mean Cmax of 35.06 ± 11.06 ng/mL","quoteCheck":"supported","note":"same as Table 2"},{"pmid":"8412502","species":"rodent","arm":"","form":"2-iodomelatonin (RBI)","forms":[],"dose":"30 mg/animal","doseBasis":"active compound","fed":"NR","n":"NR","analyte":"2-iodomelatonin","matrix":"plasma","parameter":"Cmax","detail":"","value":"12.37","variance":"","units":"mg/L","location":"Table VI","quote":"","quoteCheck":"no quote","note":""},{"pmid":"8412502","species":"rodent","arm":"","form":"2-iodomelatonin (RBI)","forms":[],"dose":"30 mg/animal","doseBasis":"active compound","fed":"NR","n":"NR","analyte":"2-iodomelatonin","matrix":"plasma","parameter":"Tmax","detail":"","value":"20","variance":"","units":"min","location":"Table VI","quote":"","quoteCheck":"no quote","note":""},{"pmid":"8412502","species":"rodent","arm":"","form":"2-iodomelatonin (RBI)","forms":[],"dose":"30 mg/animal","doseBasis":"active compound","fed":"NR","n":"NR","analyte":"major metabolite (RT 4.89 min)","matrix":"plasma","parameter":"Cmax","detail":"","value":"72.00","variance":"","units":"µg/L","location":"Table VI","quote":"","quoteCheck":"no quote","note":"Footnote marks this value as in µg/L (the column otherwise mg/L); verified on page image."},{"pmid":"8412502","species":"rodent","arm":"","form":"2-iodomelatonin (RBI)","forms":[],"dose":"30 mg/animal","doseBasis":"active compound","fed":"NR","n":"NR","analyte":"major metabolite (RT 4.89 min)","matrix":"plasma","parameter":"Tmax","detail":"","value":"30","variance":"","units":"min","location":"Table VI","quote":"","quoteCheck":"no quote","note":""},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 3 mg/ml in 10% PEG 300 / isotonic saline, 0.5 ml over 30 s","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"","value":"5","variance":"","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":"printed without SD"},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 3 mg/ml in 10% PEG 300 / isotonic saline, 0.5 ml over 30 s","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"weight corrected","value":"478","variance":"± 105 (SD)","units":"ng/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Cmax weight corrected per table title"},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 3 mg/ml in 10% PEG 300 / isotonic saline, 0.5 ml over 30 s","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0-60 min","value":"9228","variance":"± 916 (SD)","units":"NR","location":"Table 1","quote":"","quoteCheck":"no quote","note":"AUC units not printed in Table 1; serum concentrations corrected for body weight per Methods 2.5"},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 30 mg/ml in 40% PEG 300, 50 µl","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"","value":"5","variance":"","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":"printed without SD"},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 30 mg/ml in 40% PEG 300, 50 µl","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"weight corrected","value":"249","variance":"± 125 (SD)","units":"ng/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Cmax weight corrected per table title"},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 30 mg/ml in 40% PEG 300, 50 µl","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0-60 min","value":"4834","variance":"± 2004 (SD)","units":"NR","location":"Table 1","quote":"","quoteCheck":"no quote","note":"AUC units not printed in Table 1; serum concentrations corrected for body weight per Methods 2.5"},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 30 mg/ml in 40% PEG 300 containing 1% sodium glycocholate, 50 µl","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"4","analyte":"melatonin","matrix":"serum","parameter":"Tmax","detail":"","value":"5","variance":"","units":"min","location":"Table 1","quote":"","quoteCheck":"no quote","note":"printed without SD"},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 30 mg/ml in 40% PEG 300 containing 1% sodium glycocholate, 50 µl","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"4","analyte":"melatonin","matrix":"serum","parameter":"Cmax","detail":"weight corrected","value":"493","variance":"± 290 (SD)","units":"ng/ml","location":"Table 1","quote":"","quoteCheck":"no quote","note":"Cmax weight corrected per table title"},{"pmid":"10332069","species":"other_animal","arm":"","form":"melatonin 30 mg/ml in 40% PEG 300 containing 1% sodium glycocholate, 50 µl","forms":[],"dose":"1.5 mg","doseBasis":"active compound","fed":"NR","n":"4","analyte":"melatonin","matrix":"serum","parameter":"AUC","detail":"AUC0-60 min","value":"7637","variance":"± 2581 (SD)","units":"NR","location":"Table 1","quote":"","quoteCheck":"no quote","note":"AUC units not printed in Table 1; serum concentrations corrected for body weight per Methods 2.5"},{"pmid":"10535761","species":"other_animal","arm":"","form":"melatonin in 95% ethanol applied to feed pellets (50 g)","forms":[],"dose":"500 µg per bird (267-371 µg/kg bw)","doseBasis":"active compound","fed":"time-restricted feeding (1.5 h access from 09:30), melatonin feed eaten first, up to 50 g","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"range of individual peak plasma levels","value":"12,960-15,880","variance":"","units":"pM","location":"Results, Experiment 1 p.132","quote":"high dose of 267-371 µg/kg body weight applied to 50 g feed pellets forced plasma levels up to 12,960-15,880 pM","quoteCheck":"supported","note":""},{"pmid":"10535761","species":"other_animal","arm":"","form":"melatonin in 95% ethanol applied to feed pellets (50 g)","forms":[],"dose":"114 µg per bird (31-80 µg/kg bw)","doseBasis":"active compound","fed":"time-restricted feeding","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"range of individual peak plasma levels","value":"2,530-5,570","variance":"","units":"pM","location":"Results, Experiment 1 p.132","quote":"A low dose of 31-80 µg/kg body weight increased levels to 2,530-5,570 pM","quoteCheck":"supported","note":""},{"pmid":"10535761","species":"other_animal","arm":"","form":"melatonin soaked into whole wheat grains (50 g eaten)","forms":[],"dose":"114 µg per bird (31-80 µg/kg bw)","doseBasis":"active compound","fed":"time-restricted feeding","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"range of individual peak plasma levels","value":"530-1,460","variance":"","units":"pM","location":"Results, Experiment 1 p.132","quote":"the level rose to 530-1,460 pM if the low dose had been absorbed into 50 g wheat","quoteCheck":"supported","note":""},{"pmid":"10535761","species":"other_animal","arm":"","form":"melatonin in 95% ethanol applied to feed pellets (50 g)","forms":[],"dose":"500 µg per bird (267-371 µg/kg bw)","doseBasis":"active compound","fed":"time-restricted feeding (1.5 h access from 09:30), melatonin feed eaten first, up to 50 g","n":"5","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"abstract summary","value":"15","variance":"","units":"nM","location":"Abstract","quote":"doses of 300 µg/kg produced 15 nM, which is more than ten times higher than the nocturnal peak concentration","quoteCheck":"supported","note":"Abstract; Results give 12,960-15,880 pM for 267-371 µg/kg"},{"pmid":"10535761","species":"other_animal","arm":"","form":"melatonin in 0.5 mL grape seed oil, s.c. neck","forms":[],"dose":"2 µg per bird (1.01-1.42 µg/kg bw per Fig. 3)","doseBasis":"active compound","fed":"NR","n":"3","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"abstract summary","value":"610","variance":"","units":"pM","location":"Abstract","quote":"When injected (2 µg/bird), concentrations peaked (610 pM) within 30 min","quoteCheck":"supported","note":"both vehicles"},{"pmid":"15019067","species":"other_animal","arm":"","form":"melatonin solution, intravenous","forms":[],"dose":"0.1 mg/kg","doseBasis":"active compound","fed":"NR","n":"4","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-inf","value":"2203","variance":"","units":"ng min ml-1","location":"Table 2","quote":"","quoteCheck":"no 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compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"0.50","variance":"± 0.47 (SD)","units":"h","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"41599679","species":"in_vitro","arm":"","form":"1-aminobenzotriazole 200 mg/kg intragastric, then MT + CBD 2 h later","forms":[],"dose":"5 (MT) + 20 (CBD) mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"1.68","variance":"± 0.78 (SD)","units":"h","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"41599679","species":"in_vitro","arm":"","form":"1-aminobenzotriazole 200 mg/kg intragastric, then MT 2 h later","forms":[],"dose":"5 (MT) mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"2097","variance":"± 614.8 (SD)","units":"ng/mL","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"41599679","species":"in_vitro","arm":"","form":"1-aminobenzotriazole 200 mg/kg intragastric, then MT + CBD 2 h later","forms":[],"dose":"5 (MT) + 20 (CBD) mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"903.1","variance":"± 432.9 (SD)","units":"ng/mL","location":"Table 4","quote":"","quoteCheck":"no quote","note":"p vs ABT + MT 5 mg/kg group (# / ##)"},{"pmid":"41599679","species":"in_vitro","arm":"","form":"1-aminobenzotriazole 200 mg/kg intragastric, then MT 2 h later","forms":[],"dose":"5 (MT) mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"8845","variance":"± 3485 (SD)","units":"h × ng/mL","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"41599679","species":"in_vitro","arm":"","form":"1-aminobenzotriazole 200 mg/kg intragastric, then MT + CBD 2 h later","forms":[],"dose":"5 (MT) + 20 (CBD) mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"melatonin","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"3859","variance":"± 1678 (SD)","units":"h × ng/mL","location":"Table 4","quote":"","quoteCheck":"no quote","note":"p vs ABT + MT 5 mg/kg group (# / ##)"},{"pmid":"41599679","species":"in_vitro","arm":"","form":"1-aminobenzotriazole 200 mg/kg intragastric, then MT + CBD 2 h later","forms":[],"dose":"5 (MT) + 20 (CBD) mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"cannabidiol","matrix":"plasma","parameter":"Tmax","detail":"Tmax","value":"1.67","variance":"± 0.52 (SD)","units":"h","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"41599679","species":"in_vitro","arm":"","form":"1-aminobenzotriazole 200 mg/kg intragastric, then MT + CBD 2 h later","forms":[],"dose":"5 (MT) + 20 (CBD) mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"cannabidiol","matrix":"plasma","parameter":"Cmax","detail":"Cmax","value":"514.4","variance":"± 507.5 (SD)","units":"ng/mL","location":"Table 4","quote":"","quoteCheck":"no quote","note":""},{"pmid":"41599679","species":"in_vitro","arm":"","form":"1-aminobenzotriazole 200 mg/kg intragastric, then MT + CBD 2 h later","forms":[],"dose":"5 (MT) + 20 (CBD) mg/kg","doseBasis":"active compound","fed":"NR","n":"6","analyte":"cannabidiol","matrix":"plasma","parameter":"AUC","detail":"AUC0-t","value":"2691","variance":"± 2127 (SD)","units":"h × ng/mL","location":"Table 4","quote":"","quoteCheck":"no quote","note":""}],"studies":{"1617960":{"pmid":"1617960","title":"Lack of a nocturnal rise of serum melatonin in prepubertal gilts.","authors":"Diekman MA, Brandt KE, Green ML, Clapper JA, Malayer JR","journal":"Domestic animal endocrinology","year":"1992","volume":"9","issue":"2","pages":"161-7","doi":"10.1016/0739-7240(92)90029-w","url":"https://pubmed.ncbi.nlm.nih.gov/1617960/","species":"pig","speciesRaw":"pig","design":"other (four animal experiments; Exp 4 exogenous melatonin vs one control gilt)","n":"Exp 4: 4 gilts (3 melatonin, 1 control)","status":"partial","statusNote":"Mostly endogenous melatonin rhythm study in gilts (Exp 1-3). Only Exp 4 involves oral exogenous melatonin and its serum result is figure-only (Fig. 4); no numeric absorption values printed.","conclusion":"Data from experiment 4 indicates that a nocturnal rise in serum melatonin can be measured when melatonin is supplied exogenously to the gilt.","limitations":"only 3 gilts per melatonin condition, 1 control; exogenous results figure-only; actual ingested dose unmeasured; primarily an endogenous rhythm study"},"2071448":{"pmid":"2071448","title":"PET and plasma pharmacokinetic studies after bolus intravenous administration of [11C]melatonin in humans.","authors":"Le Bars D, Thivolle P, Vitte PA, Bojkowski C, Chazot G, Arendt J, Frackowiak RS, Claustrat B","journal":"International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology","year":"1991","volume":"18","issue":"3","pages":"357-62","doi":"10.1016/0883-2897(91)90132-5","url":"https://pubmed.ncbi.nlm.nih.gov/2071448/","species":"human","speciesRaw":"human","design":"single-arm (n=1), PET plus plasma PK","n":"1","status":"complete","statusNote":"Single-subject intravenous [11C]melatonin PET and plasma PK study; no oral absorption data (IV reference-type PK only).","conclusion":"The results confirmed that melatonin readily crosses the blood-brain barrier and that 6-sulfatoxymelatonin is the main plasma metabolite.","limitations":"n=1; intravenous route only; no oral absorption; preliminary study; no absolute concentrations tabulated (normalized figures); no PK variability"},"2300680":{"pmid":"2300680","title":"Moclobemide, an inhibitor of MAO-A, does not increase daytime plasma melatonin levels in normal humans.","authors":"Scheinin M, Koulu M, Vakkuri O, Vuorinen J, Zimmer RH","journal":"Progress in neuro-psychopharmacology & biological psychiatry","year":"1990","volume":"14","issue":"1","pages":"73-82","doi":"10.1016/0278-5846(90)90065-o","url":"https://pubmed.ncbi.nlm.nih.gov/2300680/","species":"human","speciesRaw":"human","design":"randomized crossover (double-blind, Latin square, placebo-controlled; later open deprenyl session)","n":"8","status":"not absorption-related","statusNote":"Pharmacodynamic study of moclobemide (100/200/300 mg) and deprenyl (10 mg) on endogenous daytime plasma melatonin; no melatonin was administered, so no melatonin absorption/PK data.","conclusion":"Daytime human plasma melatonin concentrations do not accurately reflect MAO-A inhibition in acute drug studies.","limitations":"melatonin not administered"},"3994899":{"pmid":"3994899","title":"Plasma concentrations of melatonin in man following oral absorption of different preparations.","authors":"Aldhous M, Franey C, Wright J, Arendt J","journal":"British journal of clinical pharmacology","year":"1985","volume":"19","issue":"4","pages":"517-21","doi":"10.1111/j.1365-2125.1985.tb02679.x","url":"https://pubmed.ncbi.nlm.nih.gov/3994899/","species":"human","speciesRaw":"human","design":"open-label, non-randomized (order of treatments not randomised), fed vs fasted within each preparation","n":"12","status":"complete","statusNote":"1985 short report; limited numeric data (AUC table, ranges of tmax and half-life). Slow-release preparation shown only as individual profiles (Fig. 2).","conclusion":"The slow-release preparation usefully extended high plasma melatonin concentrations for 5-7 h after ingestion but the timing of peak concentrations was very dependent on nutritional status. These preparations should be of use in the study of timed melatonin administration in man.","limitations":"small n (4-5 per preparation); order of treatments not randomised; very large interindividual variability; slow-release data individual/figure only; AUC for slow-release not reported; Cmax values not printed"},"7800718":{"pmid":"7800718","title":"8-methoxypsoralen increases daytime plasma melatonin levels in humans through inhibition of metabolism.","authors":"Garde E, Micic S, Knudsen K, Angelo HR, Wulf HC","journal":"Photochemistry and photobiology","year":"1994","volume":"60","issue":"5","pages":"475-80","doi":"10.1111/j.1751-1097.1994.tb05137.x","url":"https://pubmed.ncbi.nlm.nih.gov/7800718/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Oral 8-methoxypsoralen (0.6 mg/kg) given to 15 PUVA patients; endogenous plasma melatonin, 6-sulfatoxymelatonin and 8-MOP were measured. No melatonin supplement administered. Melatonin/8-MOP/aMT6s time-courses are shown only in Fig. 1 (means with 95% CI); no tabulated PK values. Could alternatively be classed off-target analyte (8-MOP).","conclusion":"In summary, the results of this clinical study demonstrate that 8-MOP intake is followed by correlated changes in daytime aMT levels and an independent decrease in serum aMT6s levels, suggesting a competitive inhibition of hepatic aMT metabolism.","limitations":""},"8412502":{"pmid":"8412502","title":"Primary pharmaco-toxicological evaluation of 2-iodomelatonin, a potent melatonin agonist.","authors":"Stankov B, Gervasoni M, Scaglione F, Perego R, Cova D, Marabini L, Fraschini F","journal":"Life sciences","year":"1993","volume":"53","issue":"17","pages":"1357-65","doi":"10.1016/0024-3205(93)90596-u","url":"https://pubmed.ncbi.nlm.nih.gov/8412502/","species":"rodent","speciesRaw":"rodent","design":"other (animal pharmaco-toxicological experiments)","n":"NR","status":"off-target analyte","statusNote":"PK of 2-iodomelatonin (synthetic melatonin analogue) in rats after 30 mg/animal i.p.; not melatonin itself. Native melatonin appears only in ovulation-inhibition dose-response (not PK).","conclusion":"In the rat, 2-iodomelatonin was slowly metabolized in vivo; its apparent elimination half-life was about 60 minutes, much longer than that reported for melatonin.","limitations":"analogue not melatonin; n not reported for PK; no variance reported; metabolite structure unconfirmed; single dose, single route (i.p.); route stated inconsistently (i.v. vs i.p.) in text"},"8791041":{"pmid":"8791041","title":"Nocturnal plasma melatonin levels after flunitrazepam administration in healthy subjects.","authors":"Hajak G, Rodenbeck A, Bandelow B, Friedrichs S, Huether G, Rüther E","journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology","year":"1996","volume":"6","issue":"2","pages":"149-53","doi":"10.1016/0924-977x(96)00005-3","url":"https://pubmed.ncbi.nlm.nih.gov/8791041/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Effect of IV flunitrazepam (1 mg) vs placebo on endogenous nocturnal plasma melatonin in 10 healthy men. No melatonin supplement administered; no absorption/PK of exogenous melatonin.","conclusion":"These results show that, although the benzodiazepine flunitrazepam improves sleep, it reduces the nocturnal secretion of melatonin, and therefore alters the circadian rhythm of a hormone which is supposed to play a special role in circadian sleep-wake rhythmicity.","limitations":""},"9062870":{"pmid":"9062870","title":"Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications.","authors":"Yeleswaram K, McLaughlin LG, Knipe JO, Schabdach D","journal":"Journal of pineal research","year":"1997","volume":"22","issue":"1","pages":"45-51","doi":"10.1111/j.1600-079x.1997.tb00302.x","url":"https://pubmed.ncbi.nlm.nih.gov/9062870/","species":"primate","speciesRaw":"other animal (rat, dog, cynomolgus monkey) plus in vitro (Caco-2, rat and human liver slices)","design":"other (IV/oral crossover in dogs and monkeys with washout; parallel groups in rats)","n":"rat 6 per route; dog 2; monkey 2","status":"complete","statusNote":"Primary preclinical PK study (rat, dog, monkey) plus in vitro Caco-2 and liver slice data; no human in vivo data.","conclusion":"In conclusion, the absolute bioavailability of oral melatonin following a 10 mg/kg dose is moderate in rats and high in dogs and monkeys. However, the bioavailability appears to be dose dependent, at least in dogs and monkeys. Limited in vitro studies indicate the potential for high oral absorption and low first-pass hepatic extraction of melatonin in humans.","limitations":"n=2 per species for dog and monkey; no variance reported for PK; oral 10 mg/kg vs IV 3 mg/kg dose mismatch (bioavailability >100%); no human in vivo data; human liver slices from 3 donors only"},"9787493":{"pmid":"9787493","title":"Diurnal rhythm of melatonin in bovine milk: pharmacokinetics of exogenous melatonin in lactating cows and goats.","authors":"Eriksson L, Valtonen M, Laitinen JT, Paananen M, Kaikkonen M","journal":"Acta veterinaria Scandinavica","year":"1998","volume":"39","issue":"3","pages":"301-10","doi":"10.1186/BF03547778","url":"https://pubmed.ncbi.nlm.nih.gov/9787493/","species":"other_animal","speciesRaw":"other animal (lactating Ayrshire cows and Finnish landrace goats)","design":"single-arm","n":"4 cows + 4 goats (PK)","status":"complete","statusNote":"Primary study; diurnal endogenous melatonin rhythm in cow milk/serum (not recorded as absorption data) plus IV bolus PK in cows and goats.","conclusion":"Our results suggest that milk melatonin levels reflect blood concentrations of melatonin with a short delay.","limitations":"n=4 per species; different doses in cows (270 µg/kg) and goats (30 µg/kg); milk concentration-time data figure-only; IV route only, no oral absorption; harmonic means used for most parameters"},"10085470":{"pmid":"10085470","title":"A melatonin preparation with a pulsatile liberation pattern: a new form of melatonin in replacement therapy.","authors":"Hoffmann A, Farker K, Dittgen M, Hoffmann H","journal":"Biological signals and receptors","year":"1999","volume":"8","issue":"1-2","pages":"96-104","doi":"10.1159/000014576","url":"https://pubmed.ncbi.nlm.nih.gov/10085470/","species":"human","speciesRaw":"human","design":"randomized crossover (open, single-dose, 3-way crossover; sequences ABC, BCA, CAB); Abstract says \"randomised, single-dose, threefold cross-over\"","n":"15 humans; 6 dogs","status":"complete","statusNote":"","conclusion":"The kinetic profile of the delivery system is adjusted to the pattern of sleep maintenance disturbances.","limitations":"statistical analysis descriptive only (no statistical tests); male subjects only; dog values approximate (text); no variance reported in Table 1; RIA assay; dose differs between capsules (5 vs 10 mg)"},"10332069":{"pmid":"10332069","title":"Intranasal absorption of melatonin in vivo bioavailability study.","authors":"Bechgaard E, Lindhardt K, Martinsen L","journal":"International journal of pharmaceutics","year":"1999","volume":"182","issue":"1","pages":"1-5","doi":"10.1016/s0378-5173(99)00019-8","url":"https://pubmed.ncbi.nlm.nih.gov/10332069/","species":"other_animal","speciesRaw":"other animal (rabbit)","design":"other (modified crossover, n=6, three legs with 7-day washout: nasal, i.v., nasal)","n":"6","status":"complete","statusNote":"","conclusion":"However, the relatively high bioavailability without GC shows that it might not be necessary to use an enhancer for a clinical relevant formulation.","limitations":"animal (rabbit) study; two +GC rabbits excluded (sneezing), n=4; single dose 1.5 mg, 6 animals; AUC0-60 min only; AUC units not printed"},"10407218":{"pmid":"10407218","title":"Exercise-induced GH secretion is enhanced by the oral ingestion of melatonin in healthy adult male subjects.","authors":"Meeking DR, Wallace JD, Cuneo RC, Forsling M, Russell-Jones DL","journal":"European journal of endocrinology","year":"1999","volume":"141","issue":"1","pages":"22-6","doi":"10.1530/eje.0.1410022","url":"https://pubmed.ncbi.nlm.nih.gov/10407218/","species":"human","speciesRaw":"human","design":"randomized crossover (randomised, double-blind, placebo-controlled)","n":"7","status":"partial","statusNote":"Primarily a pharmacodynamic study (exercise-induced GH and IGFBP-1 after oral melatonin). The only absorption/PK data are a mean peak melatonin level and undetectable baseline; no AUC, Tmax series or other PK parameters.","conclusion":"Since exercise-induced GH secretion is thought to be mediated predominantly through a hypothalamic pathway, it seems likely that melatonin facilitates GH secretion at a hypothalamic level.","limitations":"pharmacodynamic study, minimal PK data; n=7 males; melatonin sampling matrix and timepoints not fully described; formulation not specified"},"10459702":{"pmid":"10459702","title":"Amplitude reduction of plasma melatonin rhythm in association with an internal desynchronization in a subject with non-24-hour sleep-wake syndrome.","authors":"Masubuchi S, Hashimoto S, Endo T, Honma S, Honma K","journal":"Psychiatry and clinical neurosciences","year":"1999","volume":"53","issue":"2","pages":"249-51","doi":"10.1046/j.1440-1819.1999.00535.x","url":"https://pubmed.ncbi.nlm.nih.gov/10459702/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Single-subject case report of endogenous plasma melatonin rhythm amplitude/AUC in non-24-h sleep-wake syndrome; exogenous melatonin (1 or 3 mg) was given for 5 weeks but not sampled on dosing days, so no absorption/PK of the supplement is reported.","conclusion":"These results suggest a causal relationship between the reduction of circadian oscillation and internal desynchronization in this subject.","limitations":"single subject; no PK of administered melatonin"},"10467952":{"pmid":"10467952","title":"Effect of fatty acids on the permeation of melatonin across rat and pig skin in-vitro and on the transepidermal water loss in rats in-vivo.","authors":"Kandimalla K, Kanikkannan N, Andega S, Singh M","journal":"The Journal of pharmacy and pharmacology","year":"1999","volume":"51","issue":"7","pages":"783-90","doi":"10.1211/0022357991773140","url":"https://pubmed.ncbi.nlm.nih.gov/10467952/","species":"in_vitro","speciesRaw":"in vitro","design":"other (in vitro Franz diffusion cell study)","n":"NR","status":"complete","statusNote":"In vitro skin permeation (rat and pig skin) of melatonin with fatty acid enhancers; also in vivo rat TEWL (not recorded, unrelated outcome).","conclusion":"We conclude that saturated fatty acids such as undecanoic acid or lauric acid which showed maximum permeation across rat and porcine skin, respectively, may be used as potential penetration enhancers in the development of a transdermal delivery system for melatonin.","limitations":"in vitro excised animal skin; n=3 per condition; no human data; no statistics printed for most comparisons vs control"},"10535761":{"pmid":"10535761","title":"A method of achieving physiological plasma levels of melatonin in the chicken by oral administration.","authors":"Nøddegaard F, Kennaway DJ","journal":"Journal of pineal research","year":"1999","volume":"27","issue":"3","pages":"129-38","doi":"10.1111/j.1600-079x.1999.tb00607.x","url":"https://pubmed.ncbi.nlm.nih.gov/10535761/","species":"other_animal","speciesRaw":"other animal (chicken: broilers and laying hens)","design":"other (three separate dose/delivery-method experiments; E2 placebo-controlled)","n":"E1 15; E2 16; E3 9","status":"complete","statusNote":"Three experiments in chickens (oral via feed; subcutaneous); mostly plasma concentrations at times, no formal PK parameters; individual curves figure-only.","conclusion":"It was concluded that melatonin-treated, ethanol-rinsed cracked wheat grains can be used to experimentally mimic long-night plasma melatonin patterns. Injections may be useful for mimicking the melatonin patterns of very short nights in chickens experiencing constant light.","limitations":"small n; animal study; no formal PK parameters or statistics; figure-only individual curves; exact dose unknown in E2; endogenous melatonin confounds dark-period values"},"10690873":{"pmid":"10690873","title":"Measurement of urinary melatonin: a useful tool for monitoring serum melatonin after its oral administration.","authors":"Kovács J, Brodner W, Kirchlechner V, Arif T, Waldhauser F","journal":"The Journal of clinical endocrinology and metabolism","year":"2000","volume":"85","issue":"2","pages":"666-70","doi":"10.1210/jcem.85.2.6349","url":"https://pubmed.ncbi.nlm.nih.gov/10690873/","species":"human","speciesRaw":"human","design":"single-arm (Study 2 exogenous); observational (Study 1 endogenous)","n":"Study 1: 16; Study 2: 17","status":"complete","statusNote":"Study 1 is endogenous melatonin (no supplement); Study 2 gives 3 mg oral melatonin PK (serum) plus urinary excretion.","conclusion":"After oral application of MLT, however, only measurement of MLT excretion is a reliable marker of serum concentrations. Determination of MLT in urine may prove to be a useful tool for drug monitoring after oral administration of the pineal hormone.","limitations":"small n; single dose, single product; inter-individual variability very large (28-fold Cmax); serum time-course figure-only; no bioavailability computed"},"10877005":{"pmid":"10877005","title":"Fluvoxamine but not citalopram increases serum melatonin in healthy subjects-- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin.","authors":"von Bahr C, Ursing C, Yasui N, Tybring G, Bertilsson L, Röjdmark S","journal":"European journal of clinical pharmacology","year":"2000","volume":"56","issue":"2","pages":"123-7","doi":"10.1007/s002280050729","url":"https://pubmed.ncbi.nlm.nih.gov/10877005/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Randomized blinded crossover in 7 healthy subjects of placebo, citalopram 40 mg or fluvoxamine 50 mg on endogenous nocturnal serum melatonin (MT-AUC0-20, urinary MT); no exogenous melatonin given. Plasma citalopram/fluvoxamine levels are PK of other drugs, not the listed supplement. Data sections skipped.","conclusion":"The serum MT level increased markedly after ingestion of FLU but not after CIT.","limitations":"endogenous melatonin only; n=7"},"10883420":{"pmid":"10883420","title":"The absolute bioavailability of oral melatonin.","authors":"DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS Jr","journal":"Journal of clinical pharmacology","year":"2000","volume":"40","issue":"7","pages":"781-4","doi":"10.1177/00912700022009422","url":"https://pubmed.ncbi.nlm.nih.gov/10883420/","species":"human","speciesRaw":"human","design":"randomized crossover","n":"13 enrolled; 12 completed","status":"complete","statusNote":"","conclusion":"Oral melatonin tablets in dosages of 2 and 4 mg show poor absolute bioavailability, either due to poor oral absorption, large first-pass metabolism, or a combination of both.","limitations":"small n; single product/lot; no dose above 4 mg; endogenous baseline not subtracted (NR)"},"11038434":{"pmid":"11038434","title":"Bioavailability of melatonin in humans after day-time administration of D(7) melatonin.","authors":"Fourtillan JB, Brisson AM, Gobin P, Ingrand I, Decourt JP, Girault J","journal":"Biopharmaceutics & drug disposition","year":"2000","volume":"21","issue":"1","pages":"15-22","doi":"10.1002/1099-081x(200001)21:1<15::aid-bdd215>3.0.co;2-h","url":"https://pubmed.ncbi.nlm.nih.gov/11038434/","species":"human","speciesRaw":"human","design":"randomized crossover (two-way crossover; randomization not explicitly stated)","n":"12","status":"complete","statusNote":"IV (A) individual-subject values not entered row-by-row (group mean ± SD entered); oral (B) individual-subject values entered.","conclusion":"The absolute bioavailability of MLT was from 1 to 37%: mean = 8.6 ± 3.9% and 16.8 ± 12.7% for male and female subjects, respectively.","limitations":"small n (6 per sex); very large inter-individual variability; single oral dose level; exogenous dose far below supplement doses"},"11168905":{"pmid":"11168905","title":"Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients.","authors":"Siegrist C, Benedetti C, Orlando A, Beltrán JM, Tuchscherr L, Noseda CM, Brusco LI, Cardinali DP","journal":"Journal of pineal research","year":"2001","volume":"30","issue":"1","pages":"34-42","doi":"10.1034/j.1600-079x.2001.300105.x","url":"https://pubmed.ncbi.nlm.nih.gov/11168905/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Open pilot clinical safety/efficacy study of 3 mg melatonin nightly for 6 months in 22 insomniac patients (serum prolactin, FSH, TSH, estradiol, blood chemistry, sleep scores). Only pre-treatment urinary aMT6s (endogenous) was measured; no melatonin PK/absorption data.","conclusion":"The results of this open, subacute administration trial indicate that melatonin is a safe and useful treatment for sleep disturbances in middle-aged or elderly patients, either by itself or together with benzodiazepines.","limitations":"no PK data; open label, no control"},"11360039":{"pmid":"11360039","title":"Determination of exogenous melatonin and its 6-hydroxy metabolite in human plasma by liquid chromatography-mass spectrometry.","authors":"Härtter S, Morita S, Bodin K, Ursing C, Tybring G, Bertilsson L","journal":"Therapeutic drug monitoring","year":"2001","volume":"23","issue":"3","pages":"282-6","doi":"10.1097/00007691-200106000-00017","url":"https://pubmed.ncbi.nlm.nih.gov/11360039/","species":"human","speciesRaw":"human","design":"single-arm","n":"1","status":"partial","statusNote":"Analytical method (LC/MS) paper; PK limited to a single healthy volunteer given 25 mg oral melatonin.","conclusion":"From the analysis of our volunteer sample an extremely high first-pass metabolism of orally given melatonin could be demonstrated with metabolite concentrations exceeding those of the parent drug by more than 30-fold.","limitations":"n=1; method validation paper; figure-only profile; single dose (25 mg)"},"12644393":{"pmid":"12644393","title":"Effect of melatonin on estrogen and progesterone receptors in relation to uterine contraction in rats.","authors":"Abd-Allah AR, El-Sayed el SM, Abdel-Wahab MH, Hamada FM","journal":"Pharmacological research","year":"2003","volume":"47","issue":"4","pages":"349-54","doi":"10.1016/s1043-6618(03)00014-8","url":"https://pubmed.ncbi.nlm.nih.gov/12644393/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Rat pharmacology study: melatonin 0.8 mg/kg/day i.p. for 15 days; effects on uterine estrogen/progesterone receptor staining and oxytocin-induced uterine contraction. No melatonin PK or absorption data.","conclusion":"The data, so far obtained, may indicate a possible relationship of melatonin-induced modulation of the number of estrogen and progesterone receptors and its inhibitory effect on uterine contraction.","limitations":"pharmacodynamic study only; intraperitoneal route"},"12661062":{"pmid":"12661062","title":"Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist.","authors":"Vachharajani NN, Yeleswaram K, Boulton DW","journal":"Journal of pharmaceutical sciences","year":"2003","volume":"92","issue":"4","pages":"760-72","doi":"10.1002/jps.10348","url":"https://pubmed.ncbi.nlm.nih.gov/12661062/","species":"primate","speciesRaw":"other animal (rat, cynomolgus monkey) and in vitro","design":"other (preclinical PK studies)","n":"NR","status":"off-target analyte","statusNote":"Absorption/PK study of BMS-214778, a synthetic melatonin receptor agonist drug (rats, monkeys, in vitro), not melatonin supplement. Listed supplement: Melatonin; list species/form (human, IV) do not match paper. Data sections skipped.","conclusion":"()","limitations":"off-target analyte"},"15019067":{"pmid":"15019067","title":"Intranasal administration of melatonin starch microspheres.","authors":"Mao S, Chen J, Wei Z, Liu H, Bi D","journal":"International journal of pharmaceutics","year":"2004","volume":"272","issue":"1-2","pages":"37-43","doi":"10.1016/j.ijpharm.2003.11.028","url":"https://pubmed.ncbi.nlm.nih.gov/15019067/","species":"other_animal","speciesRaw":"other animal (rabbit)","design":"parallel (three groups) animal PK; also in vitro release and gamma scintigraphy nasal clearance (6 rabbits)","n":"12 rabbits in vivo PK (Methods 2.5.4)","status":"complete","statusNote":"","conclusion":"The absolute bioavailability of melatonin starch microspheres after intranasal administration was 84.07%. A significant correlation between in vivo and in vitro was disclosed.","limitations":"animal study (rabbit); small n (4 per group for PK); no statistical tests for PK differences; group allocation described ambiguously"},"15302228":{"pmid":"15302228","title":"A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog beta-methyl-6-chloromelatonin.","authors":"Mulchahey JJ, Goldwater DR, Zemlan FP","journal":"Life sciences","year":"2004","volume":"75","issue":"15","pages":"1843-56","doi":"10.1016/j.lfs.2004.03.023","url":"https://pubmed.ncbi.nlm.nih.gov/15302228/","species":"human","speciesRaw":"human","design":"other (single blind, placebo controlled, across-groups dose escalation)","n":"NR","status":"off-target analyte","statusNote":"Human PK/safety study of beta-methyl-6-chloromelatonin, a synthetic melatonin analog/agonist (20, 35, 50, 100 mg oral), not melatonin itself. Data sections skipped.","conclusion":"()","limitations":"off-target analyte"},"16432265":{"pmid":"16432265","title":"Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia.","authors":"Karim A, Tolbert D, Cao C","journal":"Journal of clinical pharmacology","year":"2006","volume":"46","issue":"2","pages":"140-8","doi":"10.1177/0091270005283461","url":"https://pubmed.ncbi.nlm.nih.gov/16432265/","species":"human","speciesRaw":"human","design":"RCT","n":"NR","status":"off-target analyte","statusNote":"Human PK/tolerance study of ramelteon (MT1/MT2 melatonin receptor agonist drug), not melatonin. Identified from title and PubMed metadata; data sections skipped.","conclusion":"()","limitations":"off-target analyte"},"16914418":{"pmid":"16914418","title":"Nitric oxide synthase inhibition in rats: melatonin reduces blood pressure and ischemia/reperfusion-induced infarct size.","authors":"Deniz E, Sahna E, Aksulu HE","journal":"Scandinavian cardiovascular journal : SCJ","year":"2006","volume":"40","issue":"4","pages":"248-52","doi":"10.1080/14017430600833116","url":"https://pubmed.ncbi.nlm.nih.gov/16914418/","species":"rodent","speciesRaw":"rodent","design":"other (animal pharmacodynamic study)","n":"NR","status":"not absorption-related","statusNote":"Rat study of melatonin effects on blood pressure and ischemia/reperfusion infarct size after NOS inhibition; no melatonin concentration, absorption or PK data found (text searched for plasma/serum/concentration/absorption/PK terms).","conclusion":"()","limitations":""},"17014690":{"pmid":"17014690","title":"Preclinical evaluation of pharmacokinetics and safety of melatonin in propylene glycol for intravenous administration.","authors":"Cheung RT, Tipoe GL, Tam S, Ma ES, Zou LY, Chan PS","journal":"Journal of pineal research","year":"2006","volume":"41","issue":"4","pages":"337-43","doi":"10.1111/j.1600-079X.2006.00372.x","url":"https://pubmed.ncbi.nlm.nih.gov/17014690/","species":"rodent","speciesRaw":"rodent","design":"other (two-dose parallel preclinical IV PK and safety study)","n":"16 (PK substudy)","status":"complete","statusNote":"IV-only rat PK; numeric PK values printed only in text/abstract (plasma concentration at 2 and 120 min, half-lives); full curve is figure-only (Fig. 1). Safety tables (Tables 2-4) not extracted as unrelated.","conclusion":"In conclusion, melatonin in propylene glycol markedly elevates plasma levels of melatonin with no serious toxicity. This preparation should be further evaluated in human patients.","limitations":"animal study (rat), anesthetized; IV only, no bioavailability; no AUC/Cmax/CL reported; plasma levels in first 60 min from 10^5-10^6-fold dilutions, authors note possible dilution errors; no vehicle/anesthesia control group; concentrations figure-only apart from 2 and 120 min"},"17389558":{"pmid":"17389558","title":"Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2.","authors":"Greenblatt DJ, Harmatz JS, Karim A","journal":"Journal of clinical pharmacology","year":"2007","volume":"47","issue":"4","pages":"485-96","doi":"10.1177/0091270006298602","url":"https://pubmed.ncbi.nlm.nih.gov/17389558/","species":"human","speciesRaw":"human","design":"RCT","n":"NR","status":"off-target analyte","statusNote":"Human age/gender PK and PD study of ramelteon (MT1/MT2 melatonin receptor agonist drug), not melatonin. Identified from title and PubMed metadata; data sections skipped.","conclusion":"()","limitations":"off-target analyte"},"18277460":{"pmid":"18277460","title":"Pinealectomy and melatonin administration in rats: their effects on plasma leptin levels and relationship with zinc.","authors":"Baltaci AK, Mogulkoc R","journal":"Acta biologica Hungarica","year":"2007","volume":"58","issue":"4","pages":"335-43","doi":"10.1556/ABiol.58.2007.4.1","url":"https://pubmed.ncbi.nlm.nih.gov/18277460/","species":"rodent","speciesRaw":"rodent","design":"other (animal controlled experiment)","n":"NR","status":"not absorption-related","statusNote":"Rat study of pinealectomy and ip melatonin on plasma leptin and zinc; no melatonin absorption/PK data. PDF contains only first 2 pages (335-336) of the 335-343 article; abstract and intro readable.","conclusion":"()","limitations":"PDF truncated to 2 of 9 pages"},"18289163":{"pmid":"18289163","title":"Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men.","authors":"Wirtz PH, Spillmann M, Bärtschi C, Ehlert U, von Känel R","journal":"Journal of pineal research","year":"2008","volume":"44","issue":"2","pages":"127-33","doi":"10.1111/j.1600-079X.2007.00499.x","url":"https://pubmed.ncbi.nlm.nih.gov/18289163/","species":"human","speciesRaw":"human","design":"RCT (single-blind, placebo-controlled, parallel)","n":"46","status":"partial","statusNote":"Pharmacodynamic (coagulation) RCT; only a single post-dose plasma melatonin value per group (60 min) is reported, no PK curve. Coagulation outcomes not extracted.","conclusion":"A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later. There might be a dose–response relationship between the plasma concentration of melatonin and coagulation activity.","limitations":"single timepoint only, no Cmax/Tmax/AUC; large inter-individual variability; study aimed at coagulation outcomes, not PK; single-blind"},"18423009":{"pmid":"18423009","title":"Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.","authors":"Bourne RS, Mills GH, Minelli C","journal":"Critical care (London, England)","year":"2008","volume":"12","issue":"2","pages":"R52","doi":"10.1186/cc6871","url":"https://pubmed.ncbi.nlm.nih.gov/18423009/","species":"human","speciesRaw":"human","design":"RCT (double-blind, placebo-controlled) with PK sub-analysis in melatonin group","n":"24","status":"complete","statusNote":"Primary RCT of sleep outcomes with a PK sub-analysis in 9 melatonin-group patients; only PK data extracted.","conclusion":"A 10-mg nocturnal dose of melatonin is excessive in this patient population and reduced doses of 1 to 2 mg could be used in future chronotherapeutic studies.","limitations":"small n (PK in 9 patients); critically ill population, altered CYP1A2 likely; no placebo or healthy comparator PK; baseline (9 p.m.) subtracted; bioavailability not measured; sampling times not listed; Cmax/AUC-ALT correlations exploratory"},"18490497":{"pmid":"18490497","title":"The effect of oral contraceptives on the pharmacokinetics of melatonin in healthy subjects with CYP1A2 g.-163C>A polymorphism.","authors":"Hilli J, Korhonen T, Turpeinen M, Hokkanen J, Mattila S, Laine K","journal":"Journal of clinical pharmacology","year":"2008","volume":"48","issue":"8","pages":"986-94","doi":"10.1177/0091270008318669","url":"https://pubmed.ncbi.nlm.nih.gov/18490497/","species":"human","speciesRaw":"human","design":"open-label, single-dose, parallel-group, 4 study groups","n":"29","status":"complete","statusNote":"Drug-interaction/pharmacogenetic PK study (OC x CYP1A2 genotype) of 6 mg oral melatonin.","conclusion":"In conclusion, a significant inhibitory effect of OCs on the CYP1A2-catalyzed melatonin metabolism was seen; thereby, OC use can alter CYP1A2-phenotyping results.","limitations":"small n per group (7-8); men included in non-OC groups (6 men each); OC preparations heterogeneous; baseline-subtracted concentrations; parallel not crossover"},"18982259":{"pmid":"18982259","title":"Batch variation and pharmacokinetics of oral sustained release melatonin-loaded sugar spheres in human subjects.","authors":"Lee BJ, Ryu SG, Choi HG, Kim CK, Parrott KA, Ayres JW, Sack RL","journal":"Archives of pharmacal research","year":"1997","volume":"20","issue":"6","pages":"555-9","doi":"10.1007/BF02975211","url":"https://pubmed.ncbi.nlm.nih.gov/18982259/","species":"human","speciesRaw":"human","design":"parallel (two groups of subjects, one batch each); in vitro dissolution of 3 batches","n":"10","status":"complete","statusNote":"Batch-variation study of sustained-release melatonin sugar spheres: in vitro release for 3 batches plus in vivo PK of B1 and B2 in human subjects. B3 not tested in vivo.","conclusion":"The current oral sustained release MT delivery system may be utilized to treat circadian rhythm disorders if it is proven to be more clinically useful when compared to immediate release MT.","limitations":"very small n (4 and 6); no immediate-release comparator in the study; sampling times and age/sex NR; no p-values printed for in vivo comparisons; Fig. 3 values figure-only; low dose (0.2 mg)"},"19465096":{"pmid":"19465096","title":"New findings on melatonin absorption and alterations by pharmaceutical excipients using the Ussing chamber technique with mounted rat gastrointestinal segments.","authors":"Tran HT, Tran PH, Lee BJ","journal":"International journal of pharmaceutics","year":"2009","volume":"378","issue":"1-2","pages":"9-16","doi":"10.1016/j.ijpharm.2009.05.024","url":"https://pubmed.ncbi.nlm.nih.gov/19465096/","species":"rodent","speciesRaw":"rodent","design":"other (in vitro Ussing chamber, ex vivo rat tissue)","n":"NR","status":"complete","statusNote":"In vitro (ex vivo) Ussing chamber study using excised rat GI segments; no in vivo PK.","conclusion":"Melatonin absorption occurs throughout the GI tract but shows absorption site dependency. The extent of absorption was highest in the rectum followed by the ileum.","limitations":"in vitro/ex vivo rat tissue; not human PK; small n (4); cumulative values given as concentration (ng/mL), not amounts; single melatonin concentration (100 µg/mL) for most experiments; excipient concentrations high relative to typical dosage forms; Fig. 6 caption (ileum) conflicts with text (jejunum); n NR for several experiments; many values figure-only"},"20070489":{"pmid":"20070489","title":"Pharmacokinetics of orally administered melatonin in critically ill patients.","authors":"Mistraletti G, Sabbatini G, Taverna M, Figini MA, Umbrello M, Magni P, Ruscica M, Dozio E, Esposti R, DeMartini G, Fraschini F, Rezzani R, Reiter RJ, Iapichino G","journal":"Journal of pineal research","year":"2010","volume":"48","issue":"2","pages":"142-7","doi":"10.1111/j.1600-079X.2009.00737.x","url":"https://pubmed.ncbi.nlm.nih.gov/20070489/","species":"human","speciesRaw":"human","design":"open-label, single-arm, two sequential cohorts (prospective interventional)","n":"12","status":"complete","statusNote":"","conclusion":"Exogenous orally administered melatonin proved to be readily and adequately absorbed, even in the early phase of a critical illness.","limitations":"small n (6 per cohort); two different cohorts needed to describe PK; K2 from Cohort 2 applied to Cohort 1; baseline correction assumed unchanged endogenous secretion; healthy-volunteer PK values taken from literature, no in-study comparator; heterogeneous critically ill patients; no absolute bioavailability measured"},"20140668":{"pmid":"20140668","title":"Melatonin modulates hippocampus NMDA receptors, blood and brain oxidative stress levels in ovariectomized rats.","authors":"Dilek M, Naziroğlu M, Baha Oral H, Suat Ovey I, Küçükayaz M, Mungan MT, Kara HY, Sütçü R","journal":"The Journal of membrane biology","year":"2010","volume":"233","issue":"1-3","pages":"135-42","doi":"10.1007/s00232-010-9233-x","url":"https://pubmed.ncbi.nlm.nih.gov/20140668/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Pharmacodynamic/antioxidant study in ovariectomized rats (intraperitoneal melatonin 10 mg/kg/day for 30 days; oxidative stress markers, vitamins, GSH, NMDA receptor subunits). No melatonin concentrations or PK/absorption parameters measured; entire text including pages 5-8 searched for absorption/PK content.","conclusion":"NR","limitations":""},"21709095":{"pmid":"21709095","title":"Melatonin attenuates colistin-induced nephrotoxicity in rats.","authors":"Yousef JM, Chen G, Hill PA, Nation RL, Li J","journal":"Antimicrobial agents and chemotherapy","year":"2011","volume":"55","issue":"9","pages":"4044-9","doi":"10.1128/AAC.00328-11","url":"https://pubmed.ncbi.nlm.nih.gov/21709095/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"off-target analyte","statusNote":"Nephroprotection study in rats (IV melatonin 5 mg/kg twice daily with IV colistin for 7 days). PK reported is of colistin (effect of melatonin on colistin clearance), not melatonin absorption; melatonin concentrations not measured. IV route.","conclusion":"NR","limitations":""},"22348451":{"pmid":"22348451","title":"Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults.","authors":"Gooneratne NS, Edwards AY, Zhou C, Cuellar N, Grandner MA, Barrett JS","journal":"Journal of pineal research","year":"2012","volume":"52","issue":"4","pages":"437-45","doi":"10.1111/j.1600-079X.2011.00958.x","url":"https://pubmed.ncbi.nlm.nih.gov/22348451/","species":"human","speciesRaw":"human","design":"randomized, double-blind, placebo-controlled parallel PK substudy","n":"27 (8 placebo, 9 low dose, 10 high dose)","status":"complete","statusNote":"","conclusion":"The findings from this study suggest that melatonin half-life, Tmax, apparent total clearance, and apparent volume of distribution are similar for both low- and high-dose surge-sustained melatonin formulations in older adults, consistent with linear pharmacokinetic behavior.","limitations":"small n (8-10 per arm); no IV arm, so no bioavailability; subjects excluded from NCA (2) and Ka (2); custom-made tablets, not commercial products; baseline correction for Visit 2 not stated; stated as SE; text uses ±; sleep outcome comparisons underpowered"},"22642804":{"pmid":"22642804","title":"Pharmacokinetics, oral bioavailability and metabolism of a novel isoquinolinone-based melatonin receptor agonist in rats.","authors":"Zhu J, Hu Y, Ho MK, Wong YH","journal":"Xenobiotica; the fate of foreign compounds in biological systems","year":"2012","volume":"42","issue":"11","pages":"1138-50","doi":"10.3109/00498254.2012.691186","url":"https://pubmed.ncbi.nlm.nih.gov/22642804/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"off-target analyte","statusNote":"Absorption/PK study of IS0042, a novel synthetic isoquinolinone MT2 melatonin-receptor agonist in rats (IV 10 or 25 mg/kg, oral 100 mg/kg), not melatonin itself. Melatonin not administered or measured; melatonin only mentioned in the introduction.","conclusion":"NR","limitations":""},"22804755":{"pmid":"22804755","title":"Plasma insulin, leptin, adiponectin, resistin, ghrelin, and melatonin in nonalcoholic steatohepatitis patients treated with melatonin.","authors":"Gonciarz M, Bielański W, Partyka R, Brzozowski T, Konturek PC, Eszyk J, Celiński K, Reiter RJ, Konturek SJ","journal":"Journal of pineal research","year":"2013","volume":"54","issue":"2","pages":"154-61","doi":"10.1111/j.1600-079X.2012.01023.x","url":"https://pubmed.ncbi.nlm.nih.gov/22804755/","species":"human","speciesRaw":"human","design":"other (single-arm open-label treatment study with healthy control group for baseline only)","n":"16 NASH patients + 15 controls","status":"partial","statusNote":"Pharmacodynamic/clinical trial in NASH patients (insulin resistance, adipokines, liver enzymes); only plasma melatonin concentrations (baseline vs day 28, pre-dose morning sample) are absorption-relevant. No PK parameters.","conclusion":"the results of the current study demonstrate that 4-wk melatonin treatment leads to an attenuation of insulin resistance, a rise in reduced plasma levels of adipokines including adiponectin, ghrelin, and leptin and an improvement of plasma liver enzymes in patients with NASH.","limitations":"no PK parameters (Cmax, AUC, Tmax) reported; single fasting morning sample only; no placebo group; no randomization or blinding stated; small n; dose-timing relative to sampling not explicitly stated; pharmacodynamic focus; formulation not described"},"23352467":{"pmid":"23352467","title":"Antioxidant activity of melatonin in diabetes in relation to the regulation and levels of plasma Cu, Zn, Fe, Mn, and Se in Zucker diabetic fatty rats.","authors":"Navarro-Alarcon M, Ruiz-Ojeda FJ, Blanca-Herrera RM, Agil A","journal":"Nutrition (Burbank, Los Angeles County, Calif.)","year":"2013","volume":"29","issue":"5","pages":"785-9","doi":"10.1016/j.nut.2012.11.005","url":"https://pubmed.ncbi.nlm.nih.gov/23352467/","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"60","status":"not absorption-related","statusNote":"Rat study of oral melatonin (10 mg/kg/d in drinking water, 6 wk) on plasma Cu, Zn, Fe, Mn, Se in ZDF and lean rats; no melatonin absorption/PK measured. Paper only mentions an earlier report that melatonin increases Zn absorption, not supported by present plasma Zn results.","conclusion":"Melatonin administration enhances plasma Se levels in M-ZDF and M-ZL rats.","limitations":"melatonin absorption not measured"},"24120727":{"pmid":"24120727","title":"A physiologically based pharmacokinetics model for melatonin--effects of light and routes of administration.","authors":"Peng HT, Bouak F, Vartanian O, Cheung B","journal":"International journal of pharmaceutics","year":"2013","volume":"458","issue":"1","pages":"156-68","doi":"10.1016/j.ijpharm.2013.09.033","url":"https://pubmed.ncbi.nlm.nih.gov/24120727/","species":"other_animal","speciesRaw":"other animal (specify)","design":"other (computational PBPK model)","n":"NR","status":"review/non-primary","statusNote":"PBPK modeling study (MATLAB Simulink) of endogenous and exogenous melatonin (IV, oral IR/CR, transdermal); compares model simulations with PK data re-used or re-calculated from previously published studies (Demuro 2000, Mallo 1990, Hughes 1998, Benes 1997, Gooneratne 2012, Aeschbach 2009 etc.). No new human PK data; Table 4 gives model-predicted vs literature-observed PK parameters (data not extracted).","conclusion":"()","limitations":"modeling study, no new primary PK data; observed values taken from other publications"},"24441643":{"pmid":"24441643","title":"Melatonin administration in diabetes: regulation of plasma Cr, V, and Mg in young male Zucker diabetic fatty rats.","authors":"Navarro-Alarcon M, Ruiz-Ojeda FJ, Blanca-Herrera RM, Kaki A, Adem A, Agil A","journal":"Food & function","year":"2014","volume":"5","issue":"3","pages":"512-6","doi":"10.1039/c3fo60389j","url":"https://pubmed.ncbi.nlm.nih.gov/24441643/","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"60","status":"not absorption-related","statusNote":"Rat study of oral melatonin (10 mg/kg/d in drinking water, 6 wk) on plasma Cr, V and Mg in ZDF and lean rats; melatonin was not measured and no absorption/PK of any supplement was assessed.","conclusion":"melatonin treatment increases plasma Cr and V levels in young male ZDF rats but not in young male ZL rats, and it does not affect plasma Mg levels in either ZDF or ZL rats.","limitations":"no melatonin absorption/PK data"},"24650045":{"pmid":"24650045","title":"Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis.","authors":"Galley HF, Lowes DA, Allen L, Cameron G, Aucott LS, Webster NR","journal":"Journal of pineal research","year":"2014","volume":"56","issue":"4","pages":"427-38","doi":"10.1111/jpi.12134","url":"https://pubmed.ncbi.nlm.nih.gov/24650045/","species":"human","speciesRaw":"human","design":"open-label","n":"20","status":"complete","statusNote":"","conclusion":"Melatonin was rapidly cleared at all doses with a median [range] elimination half-life of 51.7 [29.5–63.2] min across all doses. There was considerable variability in maximum melatonin levels within each dose cohort, but 6-hydoxymelatonin sulfate levels were less variable and remained stable for several hours.","limitations":"small n (5 per dose cohort); young healthy males only; open-label, non-randomized sequential cohorts; high inter-individual variability; only individual-subject values printed; no cohort means or GMs; serum 6-hydroxymelatonin sulfate values figure-only; no absolute bioavailability measured; AUC time window not stated"},"24756186":{"pmid":"24756186","title":"Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial.","authors":"Hansen MV, Andersen LT, Madsen MT, Hageman I, Rasmussen LS, Bokmand S, Rosenberg J, Gögenur I","journal":"Breast cancer research and treatment","year":"2014","volume":"145","issue":"3","pages":"683-95","doi":"10.1007/s10549-014-2962-2","url":"https://pubmed.ncbi.nlm.nih.gov/24756186/","species":"human","speciesRaw":"human","design":"RCT","n":"54 randomized (28 melatonin, 26 placebo)","status":"not absorption-related","statusNote":"RCT of 6 mg oral melatonin daily vs placebo for depressive symptoms in breast cancer surgery patients; no melatonin concentrations or PK/absorption data reported (searched pages 5-13 for plasma/serum/concentration/absorption terms: none).","conclusion":"Melatonin significantly reduced the risk of depressive symptoms in women with breast cancer during a three-month period after surgery.","limitations":"no PK data"},"25046730":{"pmid":"25046730","title":"Soft gel capsules improve melatonin's bioavailability in humans.","authors":"Proietti S, Carlomagno G, Dinicola S, Bizzarri M","journal":"Expert opinion on drug metabolism & toxicology","year":"2014","volume":"10","issue":"9","pages":"1193-8","doi":"10.1517/17425255.2014.943183","url":"https://pubmed.ncbi.nlm.nih.gov/25046730/","species":"human","speciesRaw":"human","design":"parallel","n":"60","status":"complete","statusNote":"","conclusion":"Soft gel capsules improved the bioavailability of melatonin in humans even when administered dose was reduced.","limitations":"industry-affiliated (manufacturer employee, product supplied); parallel groups with allocation method NR; fed/fasted state and blinding NR; units inconsistent (pg/ml vs µmol/l; AUC unit not stated in row); AUC value for 3 mg powder inconsistent with reported statistics; no baseline correction for endogenous melatonin stated; no absolute bioavailability measured; 'bioavailability' judged from AUC/Cmax"},"25197811":{"pmid":"25197811","title":"Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening.","authors":"Rubio-Sastre P, Scheer FA, Gómez-Abellán P, Madrid JA, Garaulet M","journal":"Sleep","year":"2014","volume":"37","issue":"10","pages":"1715-9","doi":"10.5665/sleep.4088","url":"https://pubmed.ncbi.nlm.nih.gov/25197811/","species":"human","speciesRaw":"human","design":"randomized crossover (single-blind, placebo-controlled; 4 OGTT sessions)","n":"21","status":"not absorption-related","statusNote":"Pharmacodynamic study of 5 mg oral melatonin (liquid) on glucose tolerance (OGTT) in the morning and evening; plasma melatonin was not measured (only the dosing solution was assayed: 5.5 mg/mL). Reported Cmax/AUC refer to plasma glucose and insulin.","conclusion":"Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening.","limitations":"no melatonin PK/absorption data"},"25243731":{"pmid":"25243731","title":"Melatonin and clonidine premedication has similar impact on the pharmacokinetics and pharmacodynamics of propofol target controlled-infusions.","authors":"Bienert A, Wawrzyniak K, Wiczling P, Przybyłowski K, Kokot ZJ, Matysiak J, Pachutko A, Józefowicz M, Kusza K, Grześkowiak E","journal":"Journal of clinical pharmacology","year":"2015","volume":"55","issue":"3","pages":"307-16","doi":"10.1002/jcph.401","url":"https://pubmed.ncbi.nlm.nih.gov/25243731/","species":"human","speciesRaw":"human","design":"parallel","n":"32","status":"off-target analyte","statusNote":"Population PK/PD study of propofol (plasma propofol concentrations) in patients premedicated with oral melatonin (5 mg night before + 5 mg 60 min pre-op) or clonidine; melatonin concentrations/absorption not measured. Analyte of PK is propofol, not melatonin.","conclusion":"No significant differences in the PK/PD of propofol were noted due to the premedication with clonidine and melatonin.","limitations":"melatonin not measured"},"25450415":{"pmid":"25450415","title":"Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment.","authors":"Torres R, Kramer WG, Baroldi P","journal":"Journal of clinical pharmacology","year":"2015","volume":"55","issue":"5","pages":"525-33","doi":"10.1002/jcph.440","url":"https://pubmed.ncbi.nlm.nih.gov/25450415/","species":"human","speciesRaw":"human","design":"open-label, single-dose, parallel-group phase I (2 studies)","n":"29 (hepatic); 32 (renal)","status":"off-target analyte","statusNote":"PK of tasimelteon (synthetic dual melatonin receptor agonist drug), not melatonin supplement; hepatic and renal impairment studies, single 20 mg oral dose. Data sections skipped.","conclusion":"NR (data sections skipped; off-target analyte)","limitations":"off-target analyte"},"25579320":{"pmid":"25579320","title":"Therapeutic uses of melatonin and melatonin derivatives: a patent review (2012 - 2014).","authors":"Rivara S, Pala D, Bedini A, Spadoni G","journal":"Expert opinion on therapeutic patents","year":"2015","volume":"25","issue":"4","pages":"425-41","doi":"10.1517/13543776.2014.1001739","url":"https://pubmed.ncbi.nlm.nih.gov/25579320/","species":"unclear","speciesRaw":"other","design":"other (patent review)","n":"NR","status":"review/non-primary","statusNote":"Patent review (2012-2014) of therapeutic uses of melatonin and derivatives; no primary PK data.","conclusion":"NR","limitations":"review"},"25677201":{"pmid":"25677201","title":"Dietary proanthocyanidins modulate melatonin levels in plasma and the expression pattern of clock genes in the hypothalamus of rats.","authors":"Ribas-Latre A, Del Bas JM, Baselga-Escudero L, Casanova E, Arola-Arnal A, Salvadó MJ, Arola L, Bladé C","journal":"Molecular nutrition & food research","year":"2015","volume":"59","issue":"5","pages":"865-78","doi":"10.1002/mnfr.201400571","url":"https://pubmed.ncbi.nlm.nih.gov/25677201/","species":"rodent","speciesRaw":"rodent","design":"other (animal intervention)","n":"NR","status":"not absorption-related","statusNote":"Rat chronobiology study: effect of oral grape seed proanthocyanidin extract (GSPE) on endogenous plasma melatonin levels (NMR metabolomics) and hypothalamic clock-gene expression; no melatonin supplement administered, no absorption/PK of melatonin.","conclusion":"PAs could have chronobiological properties, although their activity depends largely on the time of administration.","limitations":"not absorption-related"},"25851638":{"pmid":"25851638","title":"Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.","authors":"Ogilvie BW, Torres R, Dressman MA, Kramer WG, Baroldi P","journal":"Journal of clinical pharmacology","year":"2015","volume":"55","issue":"9","pages":"1004-11","doi":"10.1002/jcph.507","url":"https://pubmed.ncbi.nlm.nih.gov/25851638/","species":"human","speciesRaw":"human","design":"drug-drug interaction studies","n":"NR","status":"off-target analyte","statusNote":"Drug-drug interaction PK of tasimelteon (synthetic melatonin receptor agonist drug) with fluvoxamine, ketoconazole, rifampin, smoking; not melatonin supplement. Data sections skipped.","conclusion":"NR (off-target analyte)","limitations":"off-target analyte"},"26008214":{"pmid":"26008214","title":"Clinical pharmacokinetics of melatonin: a systematic review.","authors":"Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J","journal":"European journal of clinical pharmacology","year":"2015","volume":"71","issue":"8","pages":"901-9","doi":"10.1007/s00228-015-1873-4","url":"https://pubmed.ncbi.nlm.nih.gov/26008214/","species":"human","speciesRaw":"human","design":"other (systematic review)","n":"NR","status":"review/non-primary","statusNote":"Systematic review (PRISMA) of 22 human melatonin PK studies; secondary source, no primary data.","conclusion":"Despite methodological differences between the included studies, Tmax was approximately 50 min following oral immediate-release formulations of melatonin. T1/2 was 45 min in both administration routes.","limitations":"review"},"26300641":{"pmid":"26300641","title":"Caenorhabditis elegans as an alternative in vivo model to determine oral uptake, nanotoxicity, and efficacy of melatonin-loaded lipid-core nanocapsules on paraquat damage.","authors":"Charão MF, Souto C, Brucker N, Barth A, Jornada DS, Fagundez D, Ávila DS, Eifler-Lima VL, Guterres SS, Pohlmann AR, Garcia SC","journal":"International journal of nanomedicine","year":"2015","volume":"10","issue":"","pages":"5093-106","doi":"10.2147/IJN.S84909","url":"https://pubmed.ncbi.nlm.nih.gov/26300641/","species":"other_animal","speciesRaw":"other animal (Caenorhabditis elegans, N2 wild type, L1 larvae)","design":"other (in vivo nematode model)","n":"20 worms analyzed per uptake time point; three independent experiments","status":"partial","statusNote":"C. elegans model; oral uptake/distribution of rhodamine B-labeled melatonin-loaded lipid-core nanocapsules shown qualitatively by fluorescence microscopy only (figure-only, no numeric absorption/PK data). Remaining outcomes are toxicity/efficacy against paraquat (skipped).","conclusion":"In this study, we demonstrated the oral absorption of LNC in an in vivo alternative model based on C. elegans. Fluorescence microscopic analysis confirmed the oral uptake of LNC by nematodes and that it was distributed in the body of the worm.","limitations":"values figure-only; qualitative uptake only; non-mammalian model; label tracks nanocapsule polymer, not melatonin"},"26440286":{"pmid":"26440286","title":"A novel LC-MS/MS assay for the simultaneous determination of melatonin and its two major metabolites, 6-hydroxymelatonin and 6-sulfatoxymelatonin in dog plasma: Application to a pharmacokinetic study.","authors":"Zhao H, Wang Y, Yuan B, Liu S, Man S, Xu H, Lu X","journal":"Journal of pharmaceutical and biomedical analysis","year":"2016","volume":"117","issue":"","pages":"390-7","doi":"10.1016/j.jpba.2015.09.028","url":"https://pubmed.ncbi.nlm.nih.gov/26440286/","species":"other_animal","speciesRaw":"other animal (Beagle dog)","design":"single-arm","n":"6","status":"complete","statusNote":"Primary focus is LC-MS/MS assay validation; PK in 6 Beagle dogs after single 2.0 mg prolonged-release melatonin tablet.","conclusion":"S-O-MEL was the predominant component circulating in blood after ingestion of MEL. 6-O-MEL and MEL exhibited similar pharmacokinetic characteristics.","limitations":"small n (6); single dose, single prolonged-release product; no control/reference formulation; variance type not stated"},"26440713":{"pmid":"26440713","title":"Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans.","authors":"Garaulet M, Gómez-Abellán P, Rubio-Sastre P, Madrid JA, Saxena R, Scheer FA","journal":"Metabolism: clinical and experimental","year":"2015","volume":"64","issue":"12","pages":"1650-7","doi":"10.1016/j.metabol.2015.08.003","url":"https://pubmed.ncbi.nlm.nih.gov/26440713/","species":"human","speciesRaw":"human","design":"randomized crossover","n":"17","status":"not absorption-related","statusNote":"Pharmacodynamic/genetic study: effect of 5 mg oral melatonin vs placebo on glucose tolerance (OGTT) by MTNR1B rs10830963 genotype in 17 women. No melatonin absorption/PK measured (Cmax values in the paper are glucose/insulin responses). Only endogenous 09:00 salivary melatonin baseline reported in Table 1.","conclusion":"MTNR1B rs10830963 risk variant worsens the effect of melatonin on glucose tolerance, suggesting the importance of genotyping and personalized recommendations, especially in people consuming food when melatonin levels are elevated.","limitations":"not absorption-related"},"26445481":{"pmid":"26445481","title":"The Effect of Melatonin Adsorbed to Polyethylene Glycol Microspheres on the Survival of MCF-7 Cells.","authors":"França EL, Honorio-França AC, Fernandes RT, Marins CM, Pereira CC, Varotti Fde P","journal":"Neuroimmunomodulation","year":"2016","volume":"23","issue":"1","pages":"27-32","doi":"10.1159/000439277","url":"https://pubmed.ncbi.nlm.nih.gov/26445481/","species":"in_vitro","speciesRaw":"in vitro","design":"other (in vitro)","n":"3 (release assay, Fig. 1); 5 (cell assays)","status":"partial","statusNote":"In vitro MCF-7 cytotoxicity/apoptosis study of melatonin adsorbed to PEG microspheres. Only absorption-adjacent data: in vitro melatonin release from microspheres into RPMI medium over 24 h (no absorption/PK). Cell viability, Ca2+ and apoptosis outcomes skipped.","conclusion":"In conclusion, melatonin neurohormone adsorbed to PEG microspheres has antitumor effects against human MCF-7 breast cancer cells and is therefore a possible therapeutic alternative for treating this disease.","limitations":"in vitro only; no absorption/PK measured; release values figure-only except 24 h"},"26731571":{"pmid":"26731571","title":"Sex differences in the circadian profiles of melatonin and cortisol in plasma and urine matrices under constant routine conditions.","authors":"Gunn PJ, Middleton B, Davies SK, Revell VL, Skene DJ","journal":"Chronobiology international","year":"2016","volume":"33","issue":"1","pages":"39-50","doi":"10.3109/07420528.2015.1112396","url":"https://pubmed.ncbi.nlm.nih.gov/26731571/","species":"human","speciesRaw":"human","design":"observational","n":"32 enrolled, 28 analysed","status":"not absorption-related","statusNote":"Chronobiology study of endogenous melatonin/cortisol circadian profiles (plasma and urinary aMT6s) in males vs females under constant routine; no exogenous melatonin administered, no absorption/PK.","conclusion":"It was not possible to distinguish whether the elevated plasma melatonin and cortisol levels observed in females resulted from innate sex differences or the OCP affecting the synthetic and metabolic pathways of these hormones.","limitations":"not absorption-related"},"27000757":{"pmid":"27000757","title":"Pharmacokinetics of Melatonin: The Missing Link in Clinical Efficacy?","authors":"Andersen LP, Gögenur I, Rosenberg J, Reiter RJ","journal":"Clinical pharmacokinetics","year":"2016","volume":"55","issue":"9","pages":"1027-30","doi":"10.1007/s40262-016-0386-3","url":"https://pubmed.ncbi.nlm.nih.gov/27000757/","species":"human","speciesRaw":"human","design":"other (opinion/review)","n":"NR","status":"review/non-primary","statusNote":"Current Opinion article (Clin Pharmacokinet 2016) discussing melatonin PK literature; no original PK data. Cites secondary values (tmax 30-45 min, t1/2 45 min, oral f 3-33%) from other studies.","conclusion":"Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug.","limitations":"review/opinion article, no primary data"},"27566320":{"pmid":"27566320","title":"Pharmacokinetics of Repeated Melatonin Drug Administrations Prior to and After Surgery.","authors":"Harpsøe NG, Andersen LP, Mielke LV, Jønsson B, Jenstrup MT, Gögenur I, Rosenberg J","journal":"Clinical drug investigation","year":"2016","volume":"36","issue":"12","pages":"1045-1050","doi":"10.1007/s40261-016-0452-5","url":"https://pubmed.ncbi.nlm.nih.gov/27566320/","species":"human","speciesRaw":"human","design":"other (prospective two-phase cohort, same patients dosed twice)","n":"12","status":"complete","statusNote":"","conclusion":"These preliminary results indicate that postoperative melatonin dose should be augmented compared with preoperative administration if corresponding melatonin plasma levels are intended.","limitations":"small n (12), all female; exploratory, no sample size calculation; no control of caffeine/smoking/contraceptive confounders; different surgery times / circadian endogenous melatonin; 420 min sampling did not fully cover elimination; extrapolated AUC 2.0% (peri) and 9.8% (post); postoperative phase confounded by surgery, anesthesia, analgesics, food; values median (IQR), no baseline subtraction"},"27644893":{"pmid":"27644893","title":"Melatonin pharmacokinetics after transdermal administration changes according to the time of the day.","authors":"Flo A, Cambras T, Díez-Noguera A, Calpena A","journal":"European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences","year":"2017","volume":"96","issue":"","pages":"164-170","doi":"10.1016/j.ejps.2016.09.020","url":"https://pubmed.ncbi.nlm.nih.gov/27644893/","species":"rodent","speciesRaw":"rodent","design":"other (within-animal repeated-measures at two Zeitgeber times; not described as randomized)","n":"5","status":"complete","statusNote":"","conclusion":"Results indicate that time of day is a variable that should be taken into account when melatonin is transdermally administered.","limitations":"n=5 rats (4 oral); hairless rat skin not directly extrapolable to humans; only unbound melatonin measured; studies done at different ages, not concurrent; oral only at one ZT; skin retention variance type unlabelled"},"27697139":{"pmid":"27697139","title":"The analgesic effects of exogenous melatonin in humans.","authors":"Andersen LP","journal":"Danish medical journal","year":"2016","volume":"63","issue":"10","pages":"","doi":"NR","url":"https://pubmed.ncbi.nlm.nih.gov/27697139/","species":"human","speciesRaw":"human","design":"other (dissertation abstract)","n":"NR","status":"review/non-primary","statusNote":"PhD dissertation abstract (Acta Anaesthesiol Scand 2016;60:1024-5) summarising five studies; summary values (oral tmax 41 min, bioavailability 3%, t1/2 about 45 min) come from the separate primary papers (Studies III and IV), not reported as a data table here. Abstract-only, 2 pages.","conclusion":"Exogenous melatonin may offer an effective and safe analgesic drug. At this moment, however, the results of human studies have been contradictory.","limitations":"abstract-only dissertation summary, no primary PK data tables"},"27865856":{"pmid":"27865856","title":"Melatonin-loaded silica coated with hydroxypropyl methylcellulose phthalate for enhanced oral bioavailability: Preparation, and in vitro-in vivo evaluation.","authors":"Li Y, Zhao X, Zu Y, Wang L, Wu W, Deng Y, Zu C, Liu Y","journal":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V","year":"2017","volume":"112","issue":"","pages":"58-66","doi":"10.1016/j.ejpb.2016.11.003","url":"https://pubmed.ncbi.nlm.nih.gov/27865856/","species":"rodent","speciesRaw":"rodent","design":"other (parallel groups, randomised per Methods; preclinical formulation comparison)","n":"9 (Methods text) / '3 groups of six' (inconsistent)","status":"complete","statusNote":"Preclinical (rat) formulation study with in vitro release; no human data","conclusion":"Our in vitro release and in vivo absorption studies indicated that the proposed preparation of MLT-SiO2-HP55 is an effective method to facilitate the controlled and sustained release of MLT with enhanced bioavailability.","limitations":"rat study, per-group n unclear and inconsistent; no SD/variance or statistical tests for PK parameters; absolute AUC values not printed (only ratios); no human data; in vitro release in dialysis cassette"},"28368352":{"pmid":"28368352","title":"Melatonin Pharmacological Blood Levels Increase Total Antioxidant Capacity in Critically Ill Patients.","authors":"Mistraletti G, Paroni R, Umbrello M, D'Amato L, Sabbatini G, Taverna M, Formenti P, Finati E, Favero G, Bonomini F, Rezzani R, Reiter RJ, Iapichino G","journal":"International journal of molecular sciences","year":"2017","volume":"18","issue":"4","pages":"","doi":"10.3390/ijms18040759","url":"https://pubmed.ncbi.nlm.nih.gov/28368352/","species":"human","speciesRaw":"human","design":"RCT","n":"64 enrolled (placebo 29, melatonin 35 per Table 1)","status":"complete","statusNote":"Randomized trial primarily on antioxidant effect; serum melatonin levels after enteral 3 mg tablets reported as sparse-sample concentrations (no Cmax/Tmax). Supplementary tables S1/S2 with full melatonin values are not in the PDF.","conclusion":"Enteral administration of melatonin was adequate to obtain pharmacological levels even in the early phase of critically-illnesses, with a favourable pharmacokinetic profile.","limitations":"low number of patients; heterogeneous ICU cohort; only one dose regimen; sparse sampling (no Cmax/Tmax/t1/2); some samples excluded for insufficient serum; supplementary tables not in PDF; no sample size calculation"},"29099102":{"pmid":"29099102","title":"[Effect of melatonin administration on cyclooxygenase-2 activity, serum levels of nitric oxide metabolites, lipoperoxides and glutathione peroxidase activity in patients with Parkinson’s disease].","authors":"Ortiz GG, Moráles-Sánchez EW, Pacheco-Moisés FP, Jiménez-Gil FJ, Macías-Islas MA, Mireles-Ramírez MA, González-Usigli H","journal":"Gaceta medica de Mexico","year":"2017","volume":"153","issue":"Supl. 2","pages":"S72-S81","doi":"10.24875/GMM.M000008","url":"https://pubmed.ncbi.nlm.nih.gov/29099102/","species":"human","speciesRaw":"human","design":"RCT","n":"13","status":"not absorption-related","statusNote":"Spanish-language pilot RCT (Gac Med Mex 2017) of melatonin 25 mg every 12 h for 12 months in 13 Parkinson's disease patients; outcomes are serum COX-2 activity, nitrate/nitrite, lipoperoxides (MDA, 4-OHA), GPx activity and UPDRS. No melatonin concentration, PK or absorption data reported (checked all 10 pages by text search).","conclusion":"Resultados: la actividad de la COX-2 disminuyó, igual que los nitratos/nitritos (3, 6 y 9 meses) y los lipoperóxidos (9 y 12 meses); la GPx no mostró diferencias significativas. (English abstract: COX-2 activity decreased as did nitrates/nitrites (3, 6 and 9 months) and lipoperoxides (9 and 12 months); GPx exhibited no significant differences.)","limitations":"no absorption/PK data; pilot, n=13; text states 50 mg MEL as 25 mg every 12 h"},"29109369":{"pmid":"29109369","title":"Effects of Melatonin on Glucose Homeostasis, Antioxidant Ability, and Adipokine Secretion in ICR Mice with NA/STZ-Induced Hyperglycemia.","authors":"Lo CC, Lin SH, Chang JS, Chien YW","journal":"Nutrients","year":"2017","volume":"9","issue":"11","pages":"","doi":"10.3390/nu9111187","url":"https://pubmed.ncbi.nlm.nih.gov/29109369/","species":"rodent","speciesRaw":"rodent","design":"other (randomized parallel groups for efficacy; same-animal two-dose PK sub-study)","n":"40 (efficacy); 6 (PK)","status":"partial","statusNote":"Primary study is a glucose/antioxidant/adipokine efficacy study in NA/STZ diabetic ICR mice; extracted only the plasma/serum melatonin results (Table 7) and the small oral PK sub-study (Table 8, n=6). Non-absorption outcomes (glucose, insulin, lipids, MDA, SOD, GPx, adipokines) intentionally not extracted.","conclusion":"In conclusion, in this study, six-week oral melatonin administration at 10 mg/kg of BW was able to decrease plasma and liver cholesterol and plasma MDA levels, and increase the adiponectin level.","limitations":"mouse study; PK sub-study n=6, only 4 time points, no Cmax/Tmax reported; AUC window not stated; Ke computed from two points; plasma melatonin in Table 7 sampled at unspecified time after dose; units differ between Table 8 (µg/mL) and Table 7 (pg/mL)"},"29194416":{"pmid":"29194416","title":"Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates.","authors":"Carloni S, Proietti F, Rocchi M, Longini M, Marseglia L, D'Angelo G, Balduini W, Gitto E, Buonocore G","journal":"Molecules (Basel, Switzerland)","year":"2017","volume":"22","issue":"12","pages":"","doi":"10.3390/molecules22122115","url":"https://pubmed.ncbi.nlm.nih.gov/29194416/","species":"human","speciesRaw":"human","design":"RCT","n":"15","status":"complete","statusNote":"","conclusion":"Results point out the possibility to obtain and maintain neuroprotective concentrations of melatonin in blood using a single oral administration of the indoleamine repeated every 12/24 h.","limitations":"small n (6, 4, 5); no urinary or metabolite measurement; no adult comparator in the study; Group 1 outlier (patient C) excluded from means; dose-linearity not statistically tested; ± in text not labelled (tables give SE)"},"29702366":{"pmid":"29702366","title":"Effects of melatonin administration on seminal plasma metabolites and sperm fertilization competence during the non-reproductive season in ram.","authors":"Satta V, Manca ME, Torres-Rovira L, Succu S, Mereu P, Nehme M, Epifani G, Gallus M, Berlinguer F, Naitana S, Leoni GG","journal":"Theriogenology","year":"2018","volume":"115","issue":"","pages":"16-22","doi":"10.1016/j.theriogenology.2018.04.018","url":"https://pubmed.ncbi.nlm.nih.gov/29702366/","species":"other_animal","speciesRaw":"other animal (sheep, Sarda breed rams)","design":"other (randomized two-group parallel; treated vs untreated)","n":"8","status":"partial","statusNote":"Study of melatonin implants (rams, non-breeding season) with primary outcomes seminal plasma metabolites (amino acids, carnitines) and in vitro fertilization; only melatonin concentration in seminal plasma (arbitrary peak-area units, not absolute concentration) is an absorption-related measure and was extracted. Not a formal PK study; no serum/plasma melatonin reported in this paper.","conclusion":"In conclusion, melatonin treatment during the non-breeding season improves the concentration of several metabolites in seminal plasma and sperm fertilization competence in Sarda breed ram.","limitations":"n=4 per group; melatonin in seminal plasma expressed in arbitrary units (peak area), not calibrated concentration; no serum melatonin measured; not a PK study; SEMs inconsistent between Table 2 and Results text"},"29746721":{"pmid":"29746721","title":"Melatonin for the promotion of sleep in adults in the intensive care unit.","authors":"Lewis SR, Pritchard MW, Schofield-Robinson OJ, Alderson P, Smith AF","journal":"The Cochrane database of systematic reviews","year":"2018","volume":"5","issue":"5","pages":"CD012455","doi":"10.1002/14651858.CD012455.pub2","url":"https://pubmed.ncbi.nlm.nih.gov/29746721/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"review/non-primary","statusNote":"Cochrane systematic review of melatonin for sleep promotion in ICU adults; no primary absorption/PK data.","conclusion":"NR","limitations":""},"30089436":{"pmid":"30089436","title":"Melatonin receptor 1B gene rs10830963 polymorphism, depressive symptoms and glycaemic traits.","authors":"Haljas K, Lahti J, Tuomi T, Isomaa B, Eriksson JG, Groop L, Räikkönen K","journal":"Annals of medicine","year":"2018","volume":"50","issue":"8","pages":"704-712","doi":"10.1080/07853890.2018.1509118","url":"https://pubmed.ncbi.nlm.nih.gov/30089436/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Population genetic association study (MTNR1B rs10830963, depressive symptoms, OGTT glycaemic traits, n=4,455); no melatonin absorption/PK data.","conclusion":"NR","limitations":""},"30286985":{"pmid":"30286985","title":"Preparation, characterization and in vitro evaluation of melatonin-loaded porous starch for enhanced bioavailability.","authors":"Li Y, Zhao X, Wang L, Liu Y, Wu W, Zhong C, Zhang Q, Yang J","journal":"Carbohydrate polymers","year":"2018","volume":"202","issue":"","pages":"125-133","doi":"10.1016/j.carbpol.2018.08.127","url":"https://pubmed.ncbi.nlm.nih.gov/30286985/","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"12 rats (as printed)","status":"complete","statusNote":"Rat PK of melatonin-loaded porous starch vs raw melatonin vs Circadin; plus in vitro solubility/release. PK values for AUC and time-course are figure-only (Fig. 6).","conclusion":"The AUC0–360min of the group treated with formulation MPS was approximately 2.34-fold higher than that of raw MLT. Therefore, this study offers a new and simple approach to improve the solubility and bioavailability of MLT.","limitations":"rat study; no variance or SD reported for PK values; AUC absolute values and curves figure-only; statistical test for PK not stated; n inconsistent (12 rats vs 3 groups of n=6)"},"30595364":{"pmid":"30595364","title":"Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis.","authors":"Sánchez-López AL, Ortiz GG, Pacheco-Moises FP, Mireles-Ramírez MA, Bitzer-Quintero OK, Delgado-Lara DLC, Ramírez-Jirano LJ, Velázquez-Brizuela IE","journal":"Archives of medical research","year":"2018","volume":"49","issue":"6","pages":"391-398","doi":"10.1016/j.arcmed.2018.12.004","url":"https://pubmed.ncbi.nlm.nih.gov/30595364/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Double-blind RCT of melatonin 25 mg/d for 6 months in RRMS patients (n=36); outcomes are serum cytokines/oxidative stress markers and clinical scores; melatonin concentrations not measured, no PK/absorption data.","conclusion":"NR","limitations":""},"30625289":{"pmid":"30625289","title":"PK-PD based optimal dose and time for orally administered supra-pharmacological dose of melatonin to prevent radiation induced mortality in mice.","authors":"Choudhary S, Kumar A, Saha N, Chaudhury NK","journal":"Life sciences","year":"2019","volume":"219","issue":"","pages":"31-39","doi":"10.1016/j.lfs.2019.01.007","url":"https://pubmed.ncbi.nlm.nih.gov/30625289/","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"NR","status":"complete","statusNote":"Mouse PK of oral melatonin 250 mg/kg (suspension and PEG-400 solution) vs IV 62.5 mg/kg; tissue distribution; PK-PD (TAC) and radioprotection survival (survival not extracted).","conclusion":"PK parameters at 250 mg/kg dose were qualitatively similar to low dose of melatonin, thus preventing chances of unexpected toxicity.","limitations":"supra-pharmacological doses in mice; bioavailability compares different doses (IV 62.5 vs oral 250 mg/kg), dose-normalized in formula; clearance in mL/min not weight-normalized; text/table inconsistencies; concentration-time data figure-only; fed/fasted status NR"},"30731257":{"pmid":"30731257","title":"Melatonin loaded with bacterial cellulose nanofiber by Pickering-emulsion solvent evaporation for enhanced dissolution and bioavailability.","authors":"Li Y, Zhao X, Liu Y, Yang J, Zhang Q, Wang L, Wu W, Yang Q, Liu B","journal":"International journal of pharmaceutics","year":"2019","volume":"559","issue":"","pages":"393-401","doi":"10.1016/j.ijpharm.2019.01.059","url":"https://pubmed.ncbi.nlm.nih.gov/30731257/","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"18","status":"complete","statusNote":"Rat oral PK of melatonin-loaded bacterial cellulose nanofiber (MLT-BCNs) vs commercial melatonin (Circadin) vs physical mixture; plus in vitro solubility/release. AUC absolute values and curves figure-only (Fig. 9).","conclusion":"The bioavailability of MLT-BCNs in rat was much higher than the commercially available MLT. In conclusion, melatonin loaded with BC could be considered as a promising system for improving water solubility and bioavailability of it.","limitations":"rat study; no variance reported for PK values in text; AUC absolute values and curves figure-only; in vitro dialysis bag release may confound; tested single dose"},"30734962":{"pmid":"30734962","title":"Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia.","authors":"Balduini W, Weiss MD, Carloni S, Rocchi M, Sura L, Rossignol C, Longini M, Bazzini F, Perrone S, Ott D, Wadhawan R, Buonocore G","journal":"Journal of pineal research","year":"2019","volume":"66","issue":"4","pages":"e12565","doi":"10.1111/jpi.12565","url":"https://pubmed.ncbi.nlm.nih.gov/30734962/","species":"human","speciesRaw":"human","design":"single-arm","n":"5","status":"complete","statusNote":"Open-label single-dose enteral melatonin PK in 5 neonates with HIE under therapeutic hypothermia.","conclusion":"Melatonin half‐life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK.","limitations":"n=5; no comparison group; inter-individual variability high (patient M001 outlier); hypothermia effect inferred from historical comparison; values partly model-derived; text/table inconsistencies"},"31381847":{"pmid":"31381847","title":"A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation.","authors":"Seiden DJ, Shah SM","journal":"The primary care companion for CNS disorders","year":"2019","volume":"21","issue":"4","pages":"","doi":"10.4088/PCC.19m02450","url":"https://pubmed.ncbi.nlm.nih.gov/31381847/","species":"human","speciesRaw":"human","design":"randomized crossover","n":"10","status":"complete","statusNote":"Randomized open-label 2-way crossover single-dose PK of 5 mg CRA-melatonin vs 5 mg IR-melatonin in 10 healthy adults; only median Cmax and time above threshold given as numbers, curves figure-only.","conclusion":"The novel, well-tolerated CRA-melatonin was shown to achieve quick release and then continuous release and absorption of melatonin for up to 7 hours, making it a significant advancement in the pharmacokinetic release profile of exogenous melatonin delivery and, therefore, an important potential consideration as a baseline therapy for sleep.","limitations":"n=10; open-label; sponsor-funded; authors are sponsor consultants; no AUC, Tmax, t1/2 reported; no variance or statistical tests; not a sleep outcomes trial; curves figure-only"},"31795260":{"pmid":"31795260","title":"Higher Serum Melatonin Levels during the First Week of Malignant Middle Cerebral Artery Infarction in Non-Surviving Patients.","authors":"Lorente L, Martín MM, Abreu-González P, Sabatel R, Ramos L, Argueso M, Solé-Violán J, Cáceres JJ, Jiménez A, García-Marín V","journal":"Brain sciences","year":"2019","volume":"9","issue":"12","pages":"","doi":"10.3390/brainsci9120346","url":"https://pubmed.ncbi.nlm.nih.gov/31795260/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Prospective observational study of endogenous serum melatonin (days 1, 4, 8) as a mortality predictor in malignant MCA infarction (34 non-survivors vs 34 survivors); no melatonin supplementation, no absorption/PK data.","conclusion":"NR","limitations":""},"31852511":{"pmid":"31852511","title":"Melatonin-loaded lipid-core nanocapsules protect against lipid peroxidation caused by paraquat through increased SOD expression in Caenorhabditis elegans.","authors":"Charão MF, Goethel G, Brucker N, Paese K, Eifler-Lima VL, Pohlmann AR, Guterres SS, Garcia SC","journal":"BMC pharmacology & toxicology","year":"2019","volume":"20","issue":"Suppl 1","pages":"80","doi":"10.1186/s40360-019-0352-4","url":"https://pubmed.ncbi.nlm.nih.gov/31852511/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"C. elegans study of melatonin-loaded lipid-core nanocapsules: formulation characterization (size, zeta potential, content 0.967 mg/mL) and antioxidant effects (TBARS, SOD-3 expression) against paraquat; no absorption/PK data.","conclusion":"NR","limitations":""},"32178261":{"pmid":"32178261","title":"Bioavailability of Melatonin from Lentil Sprouts and Its Role in the Plasmatic Antioxidant Status in Rats.","authors":"Rebollo-Hernanz M, Aguilera Y, Herrera T, Cayuelas LT, Dueñas M, Rodríguez-Rodríguez P, Ramiro-Cortijo D, Arribas SM, Martín-Cabrejas MA","journal":"Foods (Basel, Switzerland)","year":"2020","volume":"9","issue":"3","pages":"","doi":"10.3390/foods9030330","url":"https://pubmed.ncbi.nlm.nih.gov/32178261/","species":"rodent","speciesRaw":"rodent","design":"other (single-arm PK study in group 1; parallel groups 2-5 for 90-min bioavailability/bioactivity study)","n":"8 (PK) + 10 per group x 4 groups (bioavailability)","status":"complete","statusNote":"Rat study; melatonin from lentil sprout extract vs synthetic melatonin. Several group values are figure-only (Fig. 4).","conclusion":"In view of the results, lentil sprouts can be considered as a source of bioavailable melatonin, whose intake could modulate plasmatic oxidative stress and defend the organism from aging and related diseases, among other potential health benefits.","limitations":"rat study, ELISA immunoassay for melatonin; bioavailability groups sampled at a single timepoint (90 min); no AUC for MEL or other groups; group absolute values figure-only (Fig. 4); PK for lentil sprouts only; no synthetic melatonin PK; each group tested on a different day; Table 4 and text disagree on Vd/F and Cl/F units/values; no absolute bioavailability reported"},"32439308":{"pmid":"32439308","title":"In vitro and in vivo evaluation of organic solvent-free injectable melatonin nanoformulations.","authors":"Molska A, Nyman AKG, Sofias AM, Kristiansen KA, Hak S, Widerøe M","journal":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V","year":"2020","volume":"152","issue":"","pages":"248-256","doi":"10.1016/j.ejpb.2020.05.003","url":"https://pubmed.ncbi.nlm.nih.gov/32439308/","species":"rodent","speciesRaw":"rodent","design":"other (IV formulation comparison, repeated-measures microdialysis in same animals on days 7, 14, 21)","n":"NR","status":"partial","statusNote":"Intravenous injectable melatonin nanoformulations in adult rats (plasma and brain microdialysis PK) plus in vitro release. Not an oral absorption study; plasma/brain Cmax, AUC, Tmax, T1/2 are figure-only (Fig. 5, 6).","conclusion":"In this study we have demonstrated a successful production of an injectable melatonin nanoformulation, which consists solely of clinically approved lipids, is stable over time, improves melatonin solubilization, and prolongs in vitro melatonin release in comparison to conventional formulations with organic solvents.","limitations":"intravenous route, not oral absorption; plasma and brain PK parameters figure-only; n per group not stated for in vivo experiments; microdialysis concentrations are lower limits (melatonin-d4 calibration failed); female rats only, no formal power calculation reported"},"32673769":{"pmid":"32673769","title":"Design of multi-particulate \"Dome matrix\" with sustained-release melatonin and delayed-release caffeine for jet lag treatment.","authors":"Razali S, Bose A, Chong PW, Benetti C, Colombo P, Wong TW","journal":"International journal of pharmaceutics","year":"2020","volume":"587","issue":"","pages":"119618","doi":"10.1016/j.ijpharm.2020.119618","url":"https://pubmed.ncbi.nlm.nih.gov/32673769/","species":"other_animal","speciesRaw":"other animal (rabbit)","design":"parallel (2 groups, n=3/group)","n":"6","status":"complete","statusNote":"Formulation design paper; in vivo PK in rabbits (n=3/group) is one section (Fig. 4II). Mostly in vitro release work.","conclusion":"A Dome matrix with dual drug release kinetics and controlled pharmacokinetics responses can be produced through appropriate choice of polymer and formulation designs. The Dome matrix of melatonin and caffeine is envisaged to introduce melatonin-induced sleep phase followed by caffeine-stimulated wake phase in jet lag cases.","limitations":"rabbit study, n=3 per group; no statistical comparison reported for PK; PK parameters in Fig. 4II table image; melatonin and caffeine co-administered; 3 mg melatonin dose in rabbits"},"32937627":{"pmid":"32937627","title":"Pharmacokinetics and Safety of Intravenous, Intravesical, Rectal, Transdermal, and Vaginal Melatonin in Healthy Female Volunteers: A Cross-Over Study.","authors":"Zetner D, Andersen LPK, Alder R, Jessen ML, Tolstrup A, Rosenberg J","journal":"Pharmacology","year":"2021","volume":"106","issue":"3-4","pages":"169-176","doi":"10.1159/000510252","url":"https://pubmed.ncbi.nlm.nih.gov/32937627/","species":"human","speciesRaw":"human","design":"randomized crossover (route order not stated in extracted text; 5 sessions)","n":"10","status":"complete","statusNote":"Crossover PK of melatonin by non-oral routes; IV is the reference; no oral arm.","conclusion":"Rectally and vaginally administered melatonin may serve as relevant alternatives to standard oral melatonin therapy. Transdermal delivery of melatonin displayed an extended absorption and can be applied if prolonged effects are intended. Intravesical administration displayed, as expected, a very limited bioavailability. Melatonin administered by these routes of administration was safe.","limitations":"n=10 women only; IV given as 10-min infusion; may overestimate bioavailability of other routes; vaginal bioavailability >100% in 3 participants; DMSO included in several formulations; no oral arm; sampling times may not describe full curves; missing data in 2 participants"},"33540815":{"pmid":"33540815","title":"Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.","authors":"Lalanne S, Fougerou-Leurent C, Anderson GM, Schroder CM, Nir T, Chokron S, Delorme R, Claustrat B, Bellissant E, Kermarrec S, Franco P, Denis L, Tordjman S","journal":"International journal of molecular sciences","year":"2021","volume":"22","issue":"3","pages":"","doi":"10.3390/ijms22031490","url":"https://pubmed.ncbi.nlm.nih.gov/33540815/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"review/non-primary","statusNote":"Narrative review (Int J Mol Sci, 2021): melatonin pharmacokinetics and clinical use in autism spectrum disorder; not a primary PK study. Data sections skipped per rules.","conclusion":"()","limitations":""},"33549911":{"pmid":"33549911","title":"Pharmacokinetics of exogenous melatonin in relation to formulation, and effects on sleep: A systematic review.","authors":"Moroni I, Garcia-Bennett A, Chapman J, Grunstein RR, Gordon CJ, Comas M","journal":"Sleep medicine reviews","year":"2021","volume":"57","issue":"","pages":"101431","doi":"10.1016/j.smrv.2021.101431","url":"https://pubmed.ncbi.nlm.nih.gov/33549911/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"review/non-primary","statusNote":"Systematic review (Sleep Med Rev 2021) of 19 human melatonin PK studies by formulation; secondary data, not a primary study. Data sections skipped per rules.","conclusion":"()","limitations":""},"35007949":{"pmid":"35007949","title":"Melatonin and dopamine mediate the regulation of nitrogen uptake and metabolism at low ammonium levels in Malus hupehensis.","authors":"Du P, Yin B, Zhou S, Li Z, Zhang X, Cao Y, Han R, Shi C, Liang B, Xu J","journal":"Plant physiology and biochemistry : PPB","year":"2022","volume":"171","issue":"","pages":"182-190","doi":"10.1016/j.plaphy.2022.01.004","url":"https://pubmed.ncbi.nlm.nih.gov/35007949/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Plant physiology study (Malus hupehensis apple seedlings): effects of exogenous melatonin/dopamine on 15NH4+ uptake and nitrogen metabolism. Not a supplement absorption/PK study in humans or animals.","conclusion":"()","limitations":""},"35350746":{"pmid":"35350746","title":"Physiologically-based pharmacokinetic simulations in pharmacotherapy: selection of the optimal administration route for exogenous melatonin.","authors":"Savoca A, Manca D","journal":"ADMET & DMPK","year":"2019","volume":"7","issue":"1","pages":"44-59","doi":"10.5599/admet.625","url":"https://pubmed.ncbi.nlm.nih.gov/35350746/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"review/non-primary","statusNote":"In silico PBPK modelling/simulation of melatonin (IV, oral, transdermal) in a virtual subject, validated against previously published PK data; no new experimental absorption data. Printed tables are model-performance indices (%dAUC, %dCmax, MeSE), not measured PK values; simulated values appear only in figures.","conclusion":"()","limitations":""},"36046952":{"pmid":"36046952","title":"Dose assessment of melatonin in sepsis (DAMSEL2) study: Pharmacokinetics of two doses of oral melatonin in patients with sepsis.","authors":"Galley HF, Allen L, Colin PJ, Galt SP, Webster NR","journal":"Journal of pineal research","year":"2022","volume":"73","issue":"4","pages":"e12830","doi":"10.1111/jpi.12830","url":"https://pubmed.ncbi.nlm.nih.gov/36046952/","species":"human","speciesRaw":"human","design":"open-label","n":"10","status":"complete","statusNote":"Open-label two-cohort PK study in septic ICU patients with population PK modelling versus previously published healthy-subject capsule data.","conclusion":"We conclude that 20 mg seems a suitable dose of liquid melatonin in patients with sepsis.","limitations":"small open-label, single-centre (n=5 per cohort); sepsis patients older than healthy comparators; healthy subjects all male; different formulation (liquid vs capsule) and population confounded; wide CIs for ka, CLint, Km; healthy comparator data from earlier study"},"36565889":{"pmid":"36565889","title":"Combined effects of zinc oxide nanoparticles and melatonin on wheat growth, chlorophyll contents, cadmium (Cd) and zinc uptake under Cd stress.","authors":"Chen F, Li Y, Zia-Ur-Rehman M, Hussain SM, Qayyum MF, Rizwan M, Alharby HF, Alabdallah NM, Alharbi BM, Ali S","journal":"The Science of the total environment","year":"2023","volume":"864","issue":"","pages":"161061","doi":"10.1016/j.scitotenv.2022.161061","url":"https://pubmed.ncbi.nlm.nih.gov/36565889/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Plant study (wheat): effects of ZnO nanoparticles and melatonin on growth, chlorophyll and Cd/Zn uptake under Cd stress. Not a supplement absorption/PK study in humans or animals.","conclusion":"()","limitations":""},"37150895":{"pmid":"37150895","title":"A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.","authors":"Mun JG, Wang D, Doerflein Fulk DL, Fakhary M, Gualco SJ, Grant RW, Mitmesser SH","journal":"Journal of dietary supplements","year":"2024","volume":"21","issue":"2","pages":"182-194","doi":"10.1080/19390211.2023.2206475","url":"https://pubmed.ncbi.nlm.nih.gov/37150895/","species":"human","speciesRaw":"human","design":"randomized crossover (double-blind, comparator-controlled)","n":"18 randomized; 17 per-protocol","status":"complete","statusNote":"","conclusion":"In conclusion, this extended-release melatonin formulation quickly raised plasma melatonin levels and sustained levels above 300 pg/mL for 6 h before falling below 50 pg/mL by 9 h.","limitations":"industry funded (Pharmavite employees); small n (17 PP); healthy adults 18-65 y only; daytime dosing; large SDs relative to means; ka and ta1/2 values implausible/inconsistent as printed; figure-only concentration-time data"},"37176896":{"pmid":"37176896","title":"Soil Amendments and Foliar Melatonin Reduced Pb Uptake, and Oxidative Stress, and Improved Spinach Quality in Pb-Contaminated Soil.","authors":"Iqbal N, Tanzeem-Ul-Haq HS, Gull-E-Faran, Turan V, Iqbal M","journal":"Plants (Basel, Switzerland)","year":"2023","volume":"12","issue":"9","pages":"","doi":"10.3390/plants12091829","url":"https://pubmed.ncbi.nlm.nih.gov/37176896/","species":"other_animal","speciesRaw":"other animal (specify)","design":"other (specify)","n":"NR","status":"not absorption-related","statusNote":"Plant pot study (spinach in Pb-contaminated soil) testing biochar/MKC soil amendment and foliar melatonin/proline on Pb uptake and oxidative stress; no human or animal melatonin absorption/PK data. Read abstract and introduction (pp.1-2).","conclusion":"()","limitations":""},"37438493":{"pmid":"37438493","title":"Bioavailability of Melatonin after Administration of an Oral Prolonged-Release Tablet and an Immediate-Release Sublingual Spray in Healthy Male Volunteers.","authors":"Ait Abdellah S, Raverot V, Gal C, Guinobert I, Bardot V, Blondeau C, Claustrat B","journal":"Drugs in R&D","year":"2023","volume":"23","issue":"3","pages":"257-265","doi":"10.1007/s40268-023-00431-9","url":"https://pubmed.ncbi.nlm.nih.gov/37438493/","species":"human","speciesRaw":"human","design":"randomized crossover (single-center, open-label)","n":"14 included; PK in 13 per form (text); Table 1 states 12 volunteers","status":"complete","statusNote":"","conclusion":"Overall, our results suggest that the galenic forms containing melatonin assessed in this study are suitable for the management of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form.","limitations":"industry funded (PiLeJe); open-label; small n (12-13); men only; doses differ between forms (1.9 mg vs 1 mg); fed state only; inconsistent n and Cmax values across text and Table 1; figure-only concentration-time data"},"37562466":{"pmid":"37562466","title":"Fucoidan/chitosan layered PLGA nanoparticles with melatonin loading for inducing intestinal absorption and addressing triple-negative breast cancer progression.","authors":"Yen YW, Lee YL, Yu LY, Li CE, Shueng PW, Chiu HC, Lo CL","journal":"International journal of biological macromolecules","year":"2023","volume":"250","issue":"","pages":"126211","doi":"10.1016/j.ijbiomac.2023.126211","url":"https://pubmed.ncbi.nlm.nih.gov/37562466/","species":"rodent","speciesRaw":"rodent","design":"other (specify)","n":"NR","status":"not absorption-related","statusNote":"Preclinical cancer drug-delivery paper (mouse 4T1 TNBC model, cell assays): melatonin/fucoidan chitosan-PLGA nanoparticles (MNPs@C@F). No melatonin plasma/tissue PK. Only a Cy5.5-labelled carrier fluorescence biodistribution (IVIS, relative intensity, Fig. 3; text says approx 12.7% tumor accumulation vs whole harvested organs) and in vitro melatonin release/leakage percentages (Fig. 2H) were reported; these measure the nanoparticle carrier or in vitro release, not melatonin absorption. Read pages 1-8 (methods, results).","conclusion":"()","limitations":""},"37652870":{"pmid":"37652870","title":"Protective Effects of Melatonin in High-Fat Diet-Induced Hepatic Steatosis via Decreased Intestinal Lipid Absorption and Hepatic Cholesterol Synthesis.","authors":"Ku H, Kim Y, Kim AL, Lee G, Choi Y, Kim B","journal":"Endocrinology and metabolism (Seoul, Korea)","year":"2023","volume":"38","issue":"5","pages":"557-567","doi":"10.3803/EnM.2023.1672","url":"https://pubmed.ncbi.nlm.nih.gov/37652870/","species":"rodent","speciesRaw":"rodent","design":"other (specify)","n":"15","status":"not absorption-related","statusNote":"Mouse pharmacology study (HFD mice, melatonin 50 mg/kg i.p., plus HepG2 cells) of melatonin's effect on intestinal nutrient transporter expression, hepatic cholesterol synthesis and serum lipids. Not absorption/PK of melatonin itself (intraperitoneal dosing, no melatonin concentrations measured). Read abstract and methods (pp.1-2); text search found no melatonin PK/serum-level data.","conclusion":"()","limitations":""},"37736919":{"pmid":"37736919","title":"Community Pharmacists' Knowledge, Attitudes and the Perceived Safety and Effectiveness of Melatonin Supplements: A Cross-Sectional Survey.","authors":"Tobaiqy M, AlZahrani FA, Hassan AS, Alirbidi AH, Alraddadi OA, AlSadah OA, Yamani MB, Alqutub ST","journal":"Pharmacy (Basel, Switzerland)","year":"2023","volume":"11","issue":"5","pages":"","doi":"10.3390/pharmacy11050147","url":"https://pubmed.ncbi.nlm.nih.gov/37736919/","species":"human","speciesRaw":"human","design":"observational","n":"300","status":"not absorption-related","statusNote":"Cross-sectional questionnaire survey of community pharmacists in Jeddah (n=300) on knowledge, attitudes and perceived safety/effectiveness of melatonin; no pharmacokinetic or absorption measurements. Read abstract (p.1).","conclusion":"()","limitations":""},"37969335":{"pmid":"37969335","title":"Dietary effects of melatonin on growth performance by modulation of protein bioavailability and behavior in early weaned rats and pigs.","authors":"Kwak MJ, Chae KS, Kim JN, Whang KY, Kim Y","journal":"Journal of animal science and technology","year":"2023","volume":"65","issue":"5","pages":"1053-1064","doi":"10.5187/jast.2023.e44","url":"https://pubmed.ncbi.nlm.nih.gov/37969335/","species":"pig","speciesRaw":"pig","design":"parallel","n":"Pigs 120; rats: 24 in Methods (abstract says 42)","status":"partial","statusNote":"Growth/antioxidant/behavior feeding study in weaned rats and piglets with dietary melatonin; not a PK/absorption study. Only absorption-relevant item is serum melatonin in pigs (Fig. 3A, figure only; text states no difference between diets). Rat experiment did not report serum melatonin.","conclusion":"Collectively, early weaned animals given dietary melatonin supplementation showed improved growth through upregulation of hepatic antioxidant capacity and minimization of energy-wasting behavior, including roaming and fight states, after pigs' social hierarchy establishment.","limitations":"not a PK study; serum melatonin figure-only; rat n inconsistent between abstract (42) and methods (24); no dose-response or timed sampling; industry co-support (Pathway Intermediates Inc.)"},"38769992":{"pmid":"38769992","title":"Designing an effective dissolution test for bilayer tablets tailored for optimal melatonin release in sleep disorder management.","authors":"Bassetto R, Amadio E, Ciampanelli F, Perin S, Ilari P, Gaballo P, Callegari M, Feltrin S, Gobbo J, Zanatta S, Bertin W","journal":"Frontiers in nutrition","year":"2024","volume":"11","issue":"","pages":"1394330","doi":"10.3389/fnut.2024.1394330","url":"https://pubmed.ncbi.nlm.nih.gov/38769992/","species":"in_vitro","speciesRaw":"in vitro","design":"other (specify)","n":"NR","status":"partial","statusNote":"In vitro formulation/dissolution and biomimetic-membrane permeability study of melatonin bilayer vs monolayer tablets; no in vivo absorption data. Dissolution curves and ML-Tablet permeability are figure-only; only text-printed values extracted.","conclusion":"the inclusion of retarding agents in the BL-Tablet's formulation does not have an adverse impact on melatonin absorption.","limitations":"in vitro only; no in vivo PK; industry authors (Labomar SpA, tablet manufacturer); permeability and dissolution data figure-only; membrane permeability does not equal human bioavailability; t-test interpretation stated backwards in Methods"},"38797355":{"pmid":"38797355","title":"Melatonin improves nitric oxide bioavailability in isoproterenol induced myocardial injury.","authors":"Santos R, Turck P, de Mello Palma V, Visioli F, Ortiz VD, Proença ICT, Fernandes TRG, Fernandes E, Tasca S, Carraro CC, Belló-Klein A, da Rosa Araujo AS, Khaper N, de Castro AL","journal":"Molecular and cellular endocrinology","year":"2024","volume":"591","issue":"","pages":"112279","doi":"10.1016/j.mce.2024.112279","url":"https://pubmed.ncbi.nlm.nih.gov/38797355/","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"NR","status":"not absorption-related","statusNote":"Rat isoproterenol-induced myocardial injury study of melatonin cardioprotection; 'bioavailability' refers to nitric oxide, not melatonin. No melatonin concentrations or PK reported (text search found no serum/plasma melatonin or pharmacokinetic content). Read abstract and introduction (p.1).","conclusion":"()","limitations":""},"39044710":{"pmid":"39044710","title":"Co-delivery of Siape1 and Melatonin by (125)I-loaded PSMA-targeted Nanoparticles for the Treatment of Prostate Cancer.","authors":"Liu Y, Hao L, Dong Y, Dong BZ, Wang XL, Liu X, Hu ZX, Fang GC, Wang GY, Qin JX, Shi ZD, Pang K","journal":"Recent patents on anti-cancer drug discovery","year":"2024","volume":"19","issue":"4","pages":"503-515","doi":"10.2174/1574892818666230419081414","url":"https://pubmed.ncbi.nlm.nih.gov/39044710/","species":"rodent","speciesRaw":"rodent","design":"other (specify)","n":"NR","status":"not absorption-related","statusNote":"Preclinical prostate-cancer nanocarrier paper (PSMA-R12 nanoparticles loaded with melatonin, siAPE1 and 125I). PK/biodistribution after tail-vein (intravenous) injection tracks the 125I radiolabel (%ID/g) of the nanoparticle, not melatonin concentrations, and is not oral absorption. Read abstract, methods and PK section (pp.1, 5-8).","conclusion":"()","limitations":""},"39065568":{"pmid":"39065568","title":"Development, Characterization, and Evaluation of Potential Systemic Toxicity of a Novel Oral Melatonin Formulation.","authors":"Cheaburu-Yilmaz CN, Atmaca K, Yilmaz O, Orhan H","journal":"Pharmaceutics","year":"2024","volume":"16","issue":"7","pages":"","doi":"10.3390/pharmaceutics16070871","url":"https://pubmed.ncbi.nlm.nih.gov/39065568/","species":"rodent","speciesRaw":"rodent","design":"single-dose animal PK / in vitro release study","n":"Control n:3 and MEL n:3 (as printed)","status":"complete","statusNote":"Novel chitosan-coated polymeric melatonin formulation; mouse PK (n=3) plus in vitro release; main focus is formulation and acute toxicity. Only PK/release values extracted.","conclusion":"Encapsulation in a polymeric carrier can significantly reduce many disadvantages, both by stabilizing the molecule and by providing a sustained release.","limitations":"n=3 mice, no reference/free melatonin PK arm; no variance reported for PK parameters in table; unit inconsistencies (µg/mL vs ng/L); dose basis of in vitro 10 mg unclear; focus on formulation/toxicity"},"39174857":{"pmid":"39174857","title":"Melatonin Bioavailability After Oral Administration of a New Delayed-Release Form in Healthy Male Volunteers.","authors":"Ait Abdellah S, Gal C, Guinobert I, Bardot V, Raverot V, Vitacca A, Blondeau C, Claustrat B","journal":"Drugs in R&D","year":"2024","volume":"24","issue":"3","pages":"415-423","doi":"10.1007/s40268-024-00482-6","url":"https://pubmed.ncbi.nlm.nih.gov/39174857/","species":"human","speciesRaw":"human","design":"open-label, single-arm, single-centre bioavailability study (compared with historical prolonged-release data from a previous study)","n":"14 included; 12 in PK analysis","status":"complete","statusNote":"","conclusion":"The melatonin release profile of the newly developed delayed-release form is in line with what was anticipated for this formulation, with a peak observed 3 h after intake and significant release up to 7 h after intake.","limitations":"only male volunteers; no concurrent control; comparison with prolonged-release form is across separate studies; industry funded; employees as authors; fed state (breakfast and snack) not varied; PK values highly variable (SD > mean for Cmax)"},"39441486":{"pmid":"39441486","title":"Administration of melatonin nanoparticles improves testicular blood flow, echotexture of testicular parenchyma, scrotal circumference, and levels of estradiol and nitric oxide in prepubertal ossimi rams under summer heat stress.","authors":"Fayez E, Samir H, Youssef FS, Salama A, ElSayed MA","journal":"Veterinary research communications","year":"2024","volume":"48","issue":"6","pages":"3953-3965","doi":"10.1007/s11259-024-10563-1","url":"https://pubmed.ncbi.nlm.nih.gov/39441486/","species":"other_animal","speciesRaw":"other animal (sheep, Ossimi ram lambs)","design":"parallel controlled","n":"15","status":"not absorption-related","statusNote":"Pharmacodynamic study in heat-stressed prepubertal Ossimi ram lambs (single s.c. melatonin vs nano-melatonin vs corn oil): testicular Doppler indices, echotexture, scrotal circumference, testosterone, estradiol, NO and TAC. Melatonin concentrations were not measured; no PK/absorption data.","conclusion":"A single s.c dose of melatonin and nano melatonin improves TBF (as measured by color-pulsed Doppler ultrasonography), testicular echotexture, testicular volume, and scrotal circumference.","limitations":"no melatonin PK measured"},"39458580":{"pmid":"39458580","title":"Comparative Pharmacokinetics of Sustained-Release versus Immediate-Release Melatonin Capsules in Fasting Healthy Adults: A Randomized, Open-Label, Cross-Over Study.","authors":"Thanawala S, Abiraamasundari R, Shah R","journal":"Pharmaceutics","year":"2024","volume":"16","issue":"10","pages":"","doi":"10.3390/pharmaceutics16101248","url":"https://pubmed.ncbi.nlm.nih.gov/39458580/","species":"human","speciesRaw":"human","design":"randomized crossover (open-label, balanced, two-treatment, two-sequence, two-period)","n":"16","status":"complete","statusNote":"","conclusion":"Melatonin-SR capsules, on a single oral dose administration, elevated plasma melatonin levels and sustained them over an extended period (up to 8 h) as compared to immediate release products.","limitations":"small sample size (16); single dose; open-label; sponsor-funded; AUC0-inf and t1/2 exclude 5 SR and 1 IR participants for poor terminal fit; fasting only"},"39722474":{"pmid":"39722474","title":"Preclinical Evidence for a Drug-Drug Interaction Between Cannabinol and Melatonin.","authors":"Anderson LL, Hawkins NA, Yip KL, Udoh M, Kearney JA, Arnold JC","journal":"Basic & clinical pharmacology & toxicology","year":"2025","volume":"136","issue":"1","pages":"e14120","doi":"10.1111/bcpt.14120","url":"https://pubmed.ncbi.nlm.nih.gov/39722474/","species":"rodent","speciesRaw":"rodent","design":"parallel, randomized (terminal sampling, separate mice per time point)","n":"48 mice (in total, both experiments)","status":"complete","statusNote":"Short communication; in vitro CYP1A2 inhibition plus mouse oral PK of melatonin with/without cannabinol (drug-drug interaction).","conclusion":"We found CBN potently inhibited CYP1A2-mediated metabolism of melatonin and increased the apparent oral bioavailability of melatonin in mice with a four-fold increase in the plasma melatonin exposure.","limitations":"mouse study with doses above those used in the community; sparse sampling (separate animals per time point), no variance for AUC; no statistical tests reported for PK parameters; variance type not stated in Table 1"},"39771491":{"pmid":"39771491","title":"LC-MS/MS-Based Concurrent Quantification of Cannabidiol and Melatonin in Mouse Plasma to Elucidate Complex PK Interactions.","authors":"Wang M, Zhang W, Wu X, Wang L, Li C, Liu C, Zhuang X","journal":"Pharmaceutics","year":"2024","volume":"16","issue":"12","pages":"","doi":"10.3390/pharmaceutics16121511","url":"https://pubmed.ncbi.nlm.nih.gov/39771491/","species":"rodent","speciesRaw":"rodent","design":"parallel, randomized (5 groups)","n":"30","status":"complete","statusNote":"Mouse PK of melatonin (i.v. and oral) with CBD co-administration; LC-MS/MS method validation tables not extracted. CBD PK (Table 6) recorded as interacting compound.","conclusion":"High oral doses of CBD inhibit both the intestinal absorption and metabolic clearance of MT, resulting in a more smooth PK profile.","limitations":"mouse study; human relevance uncertain; n=6 per group; metabolites not measured; mechanism not tested directly; sparse design with i.v. and oral groups at different doses"},"39884559":{"pmid":"39884559","title":"Effects of melatonin on the pharmacokinetics and amino acid metabolism profile of vigabatrin in rats.","authors":"Zheng Q, Xu SL, Guo XL, Wang CY, Ma MD, Ge JF","journal":"Toxicology and applied pharmacology","year":"2025","volume":"496","issue":"","pages":"117247","doi":"10.1016/j.taap.2025.117247","url":"https://pubmed.ncbi.nlm.nih.gov/39884559/","species":"rodent","speciesRaw":"rodent","design":"parallel","n":"NR","status":"off-target analyte","statusNote":"PK study of vigabatrin (R- and S-enantiomers) in rats with melatonin (20 mg/kg) as the co-administered interacting agent; plasma/tissue melatonin concentrations were not measured, so no melatonin absorption data. Data sections skipped.","conclusion":"MLT affected the pharmacokinetics and tissue distribution of VGB in rats, prolonging its elimination time and improving the tissue distribution.","limitations":"melatonin not measured"},"40231558":{"pmid":"40231558","title":"Melatonin and the nervous system: nanomedicine perspectives.","authors":"Luo F, Deng Y, Angelov B, Angelova A","journal":"Biomaterials science","year":"2025","volume":"13","issue":"13","pages":"3421-3446","doi":"10.1039/d4bm01609b","url":"https://pubmed.ncbi.nlm.nih.gov/40231558/","species":"other_animal","speciesRaw":"other animal","design":"other (narrative review)","n":"NR","status":"review/non-primary","statusNote":"Narrative review (Biomaterials Science 2025, 13, 3421-3446) of melatonin nanocarriers for the nervous system; no original PK/absorption data. Pages 1-4 read; remaining pages are review of literature.","conclusion":"Not extracted (review).","limitations":"review article"},"40426828":{"pmid":"40426828","title":"The Pharmacokinetics, Dosage, Preparation Forms, and Efficacy of Orally Administered Melatonin for Non-Organic Sleep Disorders in Autism Spectrum Disorder During Childhood and Adolescence: A Systematic Review.","authors":"Paditz E, Renner B, Koch R, Schneider BM, Schlarb AA, Ipsiroglu OS","journal":"Children (Basel, Switzerland)","year":"2025","volume":"12","issue":"5","pages":"","doi":"10.3390/children12050648","url":"https://pubmed.ncbi.nlm.nih.gov/40426828/","species":"human","speciesRaw":"human","design":"other (systematic review)","n":"NR","status":"review/non-primary","statusNote":"Systematic review (Children 2025, 12, 648) of oral melatonin for sleep disorders in children and adolescents with ASD; synthesizes RCTs and a case series (N=9) of blood melatonin; no new primary PK data. Pages 1-4 read.","conclusion":"From a clinical, pharmacokinetic, and physiological point of view, the RCTs available to date and the data on melatonin concentrations in the blood of children with ASD, measured several times over 24 h, suggest that a low oral melatonin dose and a non-delayed preparation with rapid onset should be started in children and adolescents with non-organic sleep disorders in ASD.","limitations":"review article"},"40608082":{"pmid":"40608082","title":"Melatonin for prevention of delirium in patients receiving mechanical ventilation in the intensive care unit: a multiarm multistage adaptive randomized controlled clinical trial (DEMEL).","authors":"Mekontso Dessap A, Ricard JD, Contou D, Desnos C, Decavèle M, Sonneville R, Vivier E, Terzi N, Callahan JC, Jochmans S, Leon R, Carreira S, Nseir S, Chemouni F, Castelain V, Paul M, Benoist JF, Audureau E, Razazi K","journal":"Intensive care medicine","year":"2025","volume":"51","issue":"7","pages":"1292-1305","doi":"10.1007/s00134-025-08002-z","url":"https://pubmed.ncbi.nlm.nih.gov/40608082/","species":"human","speciesRaw":"human","design":"RCT (multiarm multistage adaptive phase 2b/3, placebo-controlled, double-blind)","n":"355 randomized; 334 ITT; 75 in activity-stage PK analysis","status":"partial","statusNote":"Phase 2b/3 delirium RCT in ventilated ICU patients; melatonin PK reported only as proportion of patients with optimal profile (text) and median/IQR concentrations in Fig. 2A (figure only). No numeric Cmax/AUC/Tmax.","conclusion":"This randomized clinical trial found that the low-dose of melatonin (0.3 mg nightly) achieved a better pharmacokinetic profile than the high-dose (3 mg nightly), but did not change the incidence of delirium compared to placebo in mechanically ventilated critically-ill patients.","limitations":"PK values for concentrations are figure-only; only two doses tested; critically ill ventilated population (altered absorption/elimination); 22 of 102 activity-stage patients excluded for incomplete PK profiles; high-dose arm small and discontinued; sparse sampling (baseline, peak, next morning)"},"40948465":{"pmid":"40948465","title":"Development and estimation of lipid hybrid nanocarriers co-loaded oxaliplatin and melatonin for breast cancer.","authors":"Topal GR, Adatepe S, Secerli J, Gudul Bacanli M","journal":"Drug development and industrial pharmacy","year":"2025","volume":"51","issue":"12","pages":"1779-1791","doi":"10.1080/03639045.2025.2562182","url":"https://pubmed.ncbi.nlm.nih.gov/40948465/","species":"in_vitro","speciesRaw":"in vitro","design":"other (in vitro formulation study)","n":"NR","status":"not absorption-related","statusNote":"In vitro formulation/characterization of oxaliplatin-melatonin lipid-polymer hybrid nanoparticles (size, encapsulation efficiency, in vitro dialysis release, MCF-7 cytotoxicity). No absorption or PK data in humans or animals.","conclusion":"The findings suggest that LPNs offer a promising platform for combination therapy, potentially improving treatment outcomes in breast cancer.","limitations":"in vitro only"},"41599679":{"pmid":"41599679","title":"Unraveling Cannabidiol's Bidirectional Regulation of Melatonin Pharmacokinetics via PEPT1/CYP1A2: Mechanistic Insights and Quantitative Projections.","authors":"Zheng B, Wang M, Zhang Q, Li C, Wang L, Zhang W, Liu C, Zhuang X","journal":"Pharmaceuticals (Basel, Switzerland)","year":"2025","volume":"19","issue":"1","pages":"","doi":"10.3390/ph19010080","url":"https://pubmed.ncbi.nlm.nih.gov/41599679/","species":"in_vitro","speciesRaw":"other animal (beagle dog, Sprague-Dawley rat) and in vitro","design":"other (animal PK drug-interaction study; randomized groups, parallel)","n":"beagles 12; rats 24 (methods) + 12 (ABT)","status":"complete","statusNote":"Animal (beagle, rat) PK of melatonin with/without cannabidiol, plus in vitro PEPT1 uptake and CYP inhibition; no human PK. In vitro enzyme kinetics (Km, Vmax, phenotyping %, protein binding, Rb/p) not extracted except IC50/KI from the abstract.","conclusion":"This study identifies the critical role of PEPT1 in MT absorption and elucidates the dual mechanisms of CBD; namely, absorption inhibition and metabolic delay in regulating MT pharmacokinetics, which exhibits interspecies differences.","limitations":"animal and in vitro data only; no human PK; CBD doses may not match clinical range (authors); PEPT1 role in human MT absorption not verified (authors); dog IC50 and other in vitro values inconsistent across text/table; Table 3 arms not described in Methods"},"41706381":{"pmid":"41706381","title":"Hepatic Safety of Adjunctive High-Dose Melatonin in Participants Receiving Ocrelizumab for Primary Progressive Multiple Sclerosis: Liver Toxicity Findings from a Phase I/II Randomised Clinical Trial (MELATOMS-1).","authors":"Bejarano I, Jiménez-Jorge S, Lobo-Acosta MÁ, Álvarez-López AI, Rosso-Fernández CM, López-Ruiz R, Eichau S, Ruiz-Peña JL, Géniz MÁ, Ampuero J, Ponce-España E, Merino-Bohorquez V, Cameán M, García-Sánchez MI, Izquierdo G, Guerrero JM, Romero-Gómez M, Lardone PJ, Carrillo-Vico A","journal":"CNS drugs","year":"2026","volume":"40","issue":"4","pages":"579-596","doi":"10.1007/s40263-025-01261-w","url":"https://pubmed.ncbi.nlm.nih.gov/41706381/","species":"human","speciesRaw":"human","design":"RCT (phase I/II, double-blind, placebo-controlled; safety report)","n":"NR","status":"not absorption-related","statusNote":"Hepatic safety (transaminase elevations) report from the MELATOMS-1 RCT of 300 mg/day melatonin in PP-MS patients on ocrelizumab (8 patients); no melatonin PK/absorption measurements in this paper (only literature mentions of serum melatonin in other studies).","conclusion":"these findings raise concerns regarding the hepatotoxic potential of high doses of melatonin in polymedicated patients.","limitations":"no PK data; 8 patients"},"41842581":{"pmid":"41842581","title":"Brain-Targeted RVG-Liposomal Melatonin Ameliorates Manganese Neurotoxicity by Enhancing Neurogenesis and Modulating Systemic Amino Acid Profiles.","authors":"Wang X, Chen J, Xia J, Ma T, Yang W, Shan T, He W, Zhang G, Xia Z, Wang W, Liu Z, Zheng Y, Nong K, Niu P, Chen T","journal":"Journal of pineal research","year":"2026","volume":"78","issue":"2","pages":"e70137","doi":"10.1111/jpi.70137","url":"https://pubmed.ncbi.nlm.nih.gov/41842581/","species":"rodent","speciesRaw":"rodent","design":"other (animal efficacy study)","n":"NR","status":"not absorption-related","statusNote":"Mouse efficacy/mechanism study of intranasal RVG-liposomal melatonin in manganese neurotoxicity (behaviour, neurogenesis, transcriptomics, serum amino acids, microbiome). Only in vitro release (~72.6% at 12 h, ~82% at 24 h in text) and particle characterisation; no melatonin PK, tissue or plasma melatonin concentrations measured.","conclusion":"The RVG-modified liposomal formulation conferred sustained release and improved brain-targeting capability, prolonging MT bioavailability and enhancing therapeutic outcomes.","limitations":"no PK measurements; bioavailability claim not supported by measured concentrations in text"},"41843085":{"pmid":"41843085","title":"Melatonin alleviates diabetic-induced vascular dysfunction by modulating endothelin-1 receptors (ETA and ETB) reactivity in rat aortic rings.","authors":"Khdhir CJ, Hussein RH, Maulood IM","journal":"Acta diabetologica","year":"2026","volume":"63","issue":"6","pages":"1011-1023","doi":"10.1007/s00592-026-02677-6","url":"https://pubmed.ncbi.nlm.nih.gov/41843085/","species":"rodent","speciesRaw":"rodent","design":"other (animal pharmacodynamic study)","n":"NR","status":"not absorption-related","statusNote":"Rat aortic ring pharmacodynamic study of melatonin (30 mg/kg oral for 14 d; 10 uM ex vivo) on endothelin-1 vasoreactivity in diabetic rats; no melatonin absorption or concentration measurements.","conclusion":"melatonin improves ET-1-induced vascular dysfunction in experimental diabetes by attenuating exaggerated vasoconstrictor responses and modulating ETA- and ETB-dependent functional pathways.","limitations":"no PK data"},"42306921":{"pmid":"42306921","title":"Dissolving Microneedles for Transdermal Delivery of Melatonin: Fabrication, Characterization, and In Vivo Pharmacokinetic Evaluation in Mice.","authors":"Nimni H, Nesterenko V, Bader N, Sheeni Y, Shekh-Ahmad T, Abu Ammar A","journal":"ACS applied bio materials","year":"2026","volume":"9","issue":"13","pages":"5722-5733","doi":"10.1021/acsabm.6c00235","url":"https://pubmed.ncbi.nlm.nih.gov/42306921/","species":"rodent","speciesRaw":"rodent","design":"single-arm","n":"NR","status":"complete","statusNote":"Mouse plasma and brain PK of melatonin delivered by dissolving HPMC-PVP microneedle patch; summary parameters only (Table 2), concentration-time curves figure-only (Fig. 11). Microneedle mechanical/FTIR/DSC data not extracted.","conclusion":"Taken together, MEL MNs hold promise as a viable transdermal delivery modality. However, further investigation is warranted to comprehensively evaluate their therapeutic efficacy.","limitations":"single formulation, no oral or IV comparator, so bioavailability not determined; 3 mice per time point (composite sampling); mouse dose not stated; Vz/F and CL/F units (L, L/min) implausible for mice; no dermal safety testing (authors)"},"42325096":{"pmid":"42325096","title":"Pharmacokinetics of Intravenous Melatonin in Preschool-Aged Pediatric Surgical Patients.","authors":"Garioud ALB, Afshari A, Halgreen LR, Nielsen KØ, Andersen LPK","journal":"Paediatric anaesthesia","year":"2026","volume":"36","issue":"10","pages":"1308-1315","doi":"10.1002/pan.70248","url":"https://pubmed.ncbi.nlm.nih.gov/42325096/","species":"human","speciesRaw":"human","design":"single-arm","n":"20","status":"complete","statusNote":"Intravenous melatonin PK sub-study (no oral/absorption arm); IV Cmax, t1/2, AUC, CL, Vd in children. Individual concentration-time profiles are figure-only (Fig. 1). Clinical outcomes/adverse events not extracted.","conclusion":"Administering intravenous melatonin in a dose of 0.15 mg·kg−1 in 1–6-year-olds yielded pharmacokinetic characteristics comparable to those reported in adults.","limitations":"small n (20), mostly male; sparse sampling to 90 min only, about 14.5% AUC extrapolated; IV route only, no absorption data; anaesthesia may alter PK; baseline samples below LLOQ"},"42589559":{"pmid":"42589559","title":"Effects of Melatonin Formulations on Caffeine-Evoked Cortical Activity and Pentobarbital-Induced Sleep in Mice.","authors":"Sahin N, Yabas M, Er B, Erten F, Kursun OED, Cikim IG, Kaplan B, Erek G, Ozmen B, Orhan C, Kilic E, Sahin K","journal":"International journal of molecular sciences","year":"2026","volume":"27","issue":"15","pages":"","doi":"10.3390/ijms27156906","url":"https://pubmed.ncbi.nlm.nih.gov/42589559/","species":"rodent","speciesRaw":"rodent","design":"parallel (randomized groups, two experiments)","n":"84 (both experiments)","status":"partial","statusNote":"Mouse pharmacodynamic study comparing standard vs lipid-multiparticulate oral melatonin (ECoG, pentobarbital sleep, biomarkers). Only absorption-related data are serum melatonin levels at one terminal time point, figure-only (Fig. 3A) with p-values in text; authors state PK exposure was not assessed.","conclusion":"LMP-melatonin produced greater formulation-dependent effects than conventional melatonin on caffeine-evoked cortical electrical activity, pentobarbital-induced sedative-hypnotic responses, and selected biochemical and molecular outcomes. However, pharmacokinetic exposure, physiological sleep stages, sleep architecture, sleep quality, and direct measures of neuronal injury were not assessed. Therefore, the findings do not directly establish enhanced bioavailability, physiological sleep promotion, or neuroprotection.","limitations":"no pharmacokinetic profile or brain melatonin measured (authors); serum melatonin by direct ELISA in melatonin-deficient strain, light phase; relative differences only (authors); single time point; no empty-LMP control; male mice only; values figure-only"},"42771218":{"pmid":"42771218","title":"Melatonin beyond chronobiology: integrating pharmacokinetics, dose-exposure forecasting, and clinical evidence.","authors":"Pandolfi S, Paone FM, Metalla M, Ghezzi C, Bjørlund G, Chirumbolo S","journal":"Molecular biology reports","year":"2026","volume":"53","issue":"1","pages":"","doi":"10.1007/s11033-026-12765-z","url":"https://pubmed.ncbi.nlm.nih.gov/42771218/","species":"human","speciesRaw":"human","design":"other (narrative review)","n":"NR","status":"review/non-primary","statusNote":"Narrative review with scientometric analysis and ODE dose-exposure forecasting of oral and IV melatonin; no primary PK data collected.","conclusion":"Future studies should prospectively link administered dose, timing, formulation, achieved concentration, target engagement, and clinically meaningful outcomes.","limitations":"review, secondary data"},"42813838":{"pmid":"42813838","title":"Influence of Intravenous Norepinephrine Administration on Melatonin Plasma Concentration in Awake and Anaesthetised Healthy Adult Volunteers.","authors":"Sahinovic MM, de Keijzer IN, Stern M, Vermeulen KM, Struys MMRF, Absalom AR, van den Berg JP, Vos JJ","journal":"Journal of pineal research","year":"2026","volume":"78","issue":"6","pages":"e70188","doi":"10.1111/jpi.70188","url":"https://pubmed.ncbi.nlm.nih.gov/42813838/","species":"unclear","speciesRaw":"NR","design":"NR","n":"NR","status":"not absorption-related","statusNote":"Secondary analysis of IV norepinephrine infusion effect on endogenous plasma melatonin in awake vs anaesthetised volunteers. No melatonin supplement/exogenous melatonin was administered, so no absorption/PK of supplemented melatonin is reported.","conclusion":"In conclusion, intravenous NE increases plasma MEL concentrations in both awake and anaesthetised individuals.","limitations":""}},"rejected":[{"pmid":"10459702","status":"not absorption-related","note":"Single-subject case report of endogenous plasma melatonin rhythm amplitude/AUC in non-24-h sleep-wake syndrome; exogenous melatonin (1 or 3 mg) was given for 5 weeks but not sampled on dosing days, so no absorption/PK of the supplement is reported."},{"pmid":"10877005","status":"not absorption-related","note":"Randomized blinded crossover in 7 healthy subjects of placebo, citalopram 40 mg or fluvoxamine 50 mg on endogenous nocturnal serum melatonin (MT-AUC0-20, urinary MT); no exogenous melatonin given. Plasma citalopram/fluvoxamine levels are PK of other drugs, not the listed supplement. Data sections skipped."},{"pmid":"11168905","status":"not absorption-related","note":"Open pilot clinical safety/efficacy study of 3 mg melatonin nightly for 6 months in 22 insomniac patients (serum prolactin, FSH, TSH, estradiol, blood chemistry, sleep scores). Only pre-treatment urinary aMT6s (endogenous) was measured; no melatonin PK/absorption data."},{"pmid":"12644393","status":"not absorption-related","note":"Rat pharmacology study: melatonin 0.8 mg/kg/day i.p. for 15 days; effects on uterine estrogen/progesterone receptor staining and oxytocin-induced uterine contraction. No melatonin PK or absorption data."},{"pmid":"12661062","status":"off-target analyte","note":"Absorption/PK study of BMS-214778, a synthetic melatonin receptor agonist drug (rats, monkeys, in vitro), not melatonin supplement. Listed supplement: Melatonin; list species/form (human, IV) do not match paper. Data sections skipped."},{"pmid":"15302228","status":"off-target analyte","note":"Human PK/safety study of beta-methyl-6-chloromelatonin, a synthetic melatonin analog/agonist (20, 35, 50, 100 mg oral), not melatonin itself. Data sections skipped."},{"pmid":"16432265","status":"off-target analyte","note":"Human PK/tolerance study of ramelteon (MT1/MT2 melatonin receptor agonist drug), not melatonin. Identified from title and PubMed metadata; data sections skipped."},{"pmid":"16914418","status":"not absorption-related","note":"Rat study of melatonin effects on blood pressure and ischemia/reperfusion infarct size after NOS inhibition; no melatonin concentration, absorption or PK data found (text searched for plasma/serum/concentration/absorption/PK terms)."},{"pmid":"17389558","status":"off-target analyte","note":"Human age/gender PK and PD study of ramelteon (MT1/MT2 melatonin receptor agonist drug), not melatonin. Identified from title and PubMed metadata; data sections skipped."},{"pmid":"18277460","status":"not absorption-related","note":"Rat study of pinealectomy and ip melatonin on plasma leptin and zinc; no melatonin absorption/PK data. PDF contains only first 2 pages (335-336) of the 335-343 article; abstract and intro readable."},{"pmid":"20140668","status":"not absorption-related","note":"Pharmacodynamic/antioxidant study in ovariectomized rats (intraperitoneal melatonin 10 mg/kg/day for 30 days; oxidative stress markers, vitamins, GSH, NMDA receptor subunits). No melatonin concentrations or PK/absorption parameters measured; entire text including pages 5-8 searched for absorption/PK content."},{"pmid":"21709095","status":"off-target analyte","note":"Nephroprotection study in rats (IV melatonin 5 mg/kg twice daily with IV colistin for 7 days). PK reported is of colistin (effect of melatonin on colistin clearance), not melatonin absorption; melatonin concentrations not measured. IV route."},{"pmid":"22642804","status":"off-target analyte","note":"Absorption/PK study of IS0042, a novel synthetic isoquinolinone MT2 melatonin-receptor agonist in rats (IV 10 or 25 mg/kg, oral 100 mg/kg), not melatonin itself. Melatonin not administered or measured; melatonin only mentioned in the introduction."},{"pmid":"2300680","status":"not absorption-related","note":"Pharmacodynamic study of moclobemide (100/200/300 mg) and deprenyl (10 mg) on endogenous daytime plasma melatonin; no melatonin was administered, so no melatonin absorption/PK data."},{"pmid":"23352467","status":"not absorption-related","note":"Rat study of oral melatonin (10 mg/kg/d in drinking water, 6 wk) on plasma Cu, Zn, Fe, Mn, Se in ZDF and lean rats; no melatonin absorption/PK measured. Paper only mentions an earlier report that melatonin increases Zn absorption, not supported by present plasma Zn results."},{"pmid":"24120727","status":"review/non-primary","note":"PBPK modeling study (MATLAB Simulink) of endogenous and exogenous melatonin (IV, oral IR/CR, transdermal); compares model simulations with PK data re-used or re-calculated from previously published studies (Demuro 2000, Mallo 1990, Hughes 1998, Benes 1997, Gooneratne 2012, Aeschbach 2009 etc.). No new human PK data; Table 4 gives model-predicted vs literature-observed PK parameters (data not extracted)."},{"pmid":"24441643","status":"not absorption-related","note":"Rat study of oral melatonin (10 mg/kg/d in drinking water, 6 wk) on plasma Cr, V and Mg in ZDF and lean rats; melatonin was not measured and no absorption/PK of any supplement was assessed."},{"pmid":"24756186","status":"not absorption-related","note":"RCT of 6 mg oral melatonin daily vs placebo for depressive symptoms in breast cancer surgery patients; no melatonin concentrations or PK/absorption data reported (searched pages 5-13 for plasma/serum/concentration/absorption terms: none)."},{"pmid":"25197811","status":"not absorption-related","note":"Pharmacodynamic study of 5 mg oral melatonin (liquid) on glucose tolerance (OGTT) in the morning and evening; plasma melatonin was not measured (only the dosing solution was assayed: 5.5 mg/mL). Reported Cmax/AUC refer to plasma glucose and insulin."},{"pmid":"25243731","status":"off-target analyte","note":"Population PK/PD study of propofol (plasma propofol concentrations) in patients premedicated with oral melatonin (5 mg night before + 5 mg 60 min pre-op) or clonidine; melatonin concentrations/absorption not measured. Analyte of PK is propofol, not melatonin."},{"pmid":"25450415","status":"off-target analyte","note":"PK of tasimelteon (synthetic dual melatonin receptor agonist drug), not melatonin supplement; hepatic and renal impairment studies, single 20 mg oral dose. Data sections skipped."},{"pmid":"25579320","status":"review/non-primary","note":"Patent review (2012-2014) of therapeutic uses of melatonin and derivatives; no primary PK data."},{"pmid":"25677201","status":"not absorption-related","note":"Rat chronobiology study: effect of oral grape seed proanthocyanidin extract (GSPE) on endogenous plasma melatonin levels (NMR metabolomics) and hypothalamic clock-gene expression; no melatonin supplement administered, no absorption/PK of melatonin."},{"pmid":"25851638","status":"off-target analyte","note":"Drug-drug interaction PK of tasimelteon (synthetic melatonin receptor agonist drug) with fluvoxamine, ketoconazole, rifampin, smoking; not melatonin supplement. Data sections skipped."},{"pmid":"26008214","status":"review/non-primary","note":"Systematic review (PRISMA) of 22 human melatonin PK studies; secondary source, no primary data."},{"pmid":"26440713","status":"not absorption-related","note":"Pharmacodynamic/genetic study: effect of 5 mg oral melatonin vs placebo on glucose tolerance (OGTT) by MTNR1B rs10830963 genotype in 17 women. No melatonin absorption/PK measured (Cmax values in the paper are glucose/insulin responses). Only endogenous 09:00 salivary melatonin baseline reported in Table 1."},{"pmid":"26731571","status":"not absorption-related","note":"Chronobiology study of endogenous melatonin/cortisol circadian profiles (plasma and urinary aMT6s) in males vs females under constant routine; no exogenous melatonin administered, no absorption/PK."},{"pmid":"27000757","status":"review/non-primary","note":"Current Opinion article (Clin Pharmacokinet 2016) discussing melatonin PK literature; no original PK data. Cites secondary values (tmax 30-45 min, t1/2 45 min, oral f 3-33%) from other studies."},{"pmid":"27697139","status":"review/non-primary","note":"PhD dissertation abstract (Acta Anaesthesiol Scand 2016;60:1024-5) summarising five studies; summary values (oral tmax 41 min, bioavailability 3%, t1/2 about 45 min) come from the separate primary papers (Studies III and IV), not reported as a data table here. Abstract-only, 2 pages."},{"pmid":"29099102","status":"not absorption-related","note":"Spanish-language pilot RCT (Gac Med Mex 2017) of melatonin 25 mg every 12 h for 12 months in 13 Parkinson's disease patients; outcomes are serum COX-2 activity, nitrate/nitrite, lipoperoxides (MDA, 4-OHA), GPx activity and UPDRS. No melatonin concentration, PK or absorption data reported (checked all 10 pages by text search)."},{"pmid":"29746721","status":"review/non-primary","note":"Cochrane systematic review of melatonin for sleep promotion in ICU adults; no primary absorption/PK data."},{"pmid":"30089436","status":"not absorption-related","note":"Population genetic association study (MTNR1B rs10830963, depressive symptoms, OGTT glycaemic traits, n=4,455); no melatonin absorption/PK data."},{"pmid":"30595364","status":"not absorption-related","note":"Double-blind RCT of melatonin 25 mg/d for 6 months in RRMS patients (n=36); outcomes are serum cytokines/oxidative stress markers and clinical scores; melatonin concentrations not measured, no PK/absorption data."},{"pmid":"31795260","status":"not absorption-related","note":"Prospective observational study of endogenous serum melatonin (days 1, 4, 8) as a mortality predictor in malignant MCA infarction (34 non-survivors vs 34 survivors); no melatonin supplementation, no absorption/PK data."},{"pmid":"31852511","status":"not absorption-related","note":"C. elegans study of melatonin-loaded lipid-core nanocapsules: formulation characterization (size, zeta potential, content 0.967 mg/mL) and antioxidant effects (TBARS, SOD-3 expression) against paraquat; no absorption/PK data."},{"pmid":"33540815","status":"review/non-primary","note":"Narrative review (Int J Mol Sci, 2021): melatonin pharmacokinetics and clinical use in autism spectrum disorder; not a primary PK study. Data sections skipped per rules."},{"pmid":"33549911","status":"review/non-primary","note":"Systematic review (Sleep Med Rev 2021) of 19 human melatonin PK studies by formulation; secondary data, not a primary study. Data sections skipped per rules."},{"pmid":"35007949","status":"not absorption-related","note":"Plant physiology study (Malus hupehensis apple seedlings): effects of exogenous melatonin/dopamine on 15NH4+ uptake and nitrogen metabolism. Not a supplement absorption/PK study in humans or animals."},{"pmid":"35350746","status":"review/non-primary","note":"In silico PBPK modelling/simulation of melatonin (IV, oral, transdermal) in a virtual subject, validated against previously published PK data; no new experimental absorption data. Printed tables are model-performance indices (%dAUC, %dCmax, MeSE), not measured PK values; simulated values appear only in figures."},{"pmid":"36565889","status":"not absorption-related","note":"Plant study (wheat): effects of ZnO nanoparticles and melatonin on growth, chlorophyll and Cd/Zn uptake under Cd stress. Not a supplement absorption/PK study in humans or animals."},{"pmid":"37176896","status":"not absorption-related","note":"Plant pot study (spinach in Pb-contaminated soil) testing biochar/MKC soil amendment and foliar melatonin/proline on Pb uptake and oxidative stress; no human or animal melatonin absorption/PK data. Read abstract and introduction (pp.1-2)."},{"pmid":"37562466","status":"not absorption-related","note":"Preclinical cancer drug-delivery paper (mouse 4T1 TNBC model, cell assays): melatonin/fucoidan chitosan-PLGA nanoparticles (MNPs@C@F). No melatonin plasma/tissue PK. Only a Cy5.5-labelled carrier fluorescence biodistribution (IVIS, relative intensity, Fig. 3; text says approx 12.7% tumor accumulation vs whole harvested organs) and in vitro melatonin release/leakage percentages (Fig. 2H) were reported; these measure the nanoparticle carrier or in vitro release, not melatonin absorption. Read pages 1-8 (methods, results)."},{"pmid":"37652870","status":"not absorption-related","note":"Mouse pharmacology study (HFD mice, melatonin 50 mg/kg i.p., plus HepG2 cells) of melatonin's effect on intestinal nutrient transporter expression, hepatic cholesterol synthesis and serum lipids. Not absorption/PK of melatonin itself (intraperitoneal dosing, no melatonin concentrations measured). Read abstract and methods (pp.1-2); text search found no melatonin PK/serum-level data."},{"pmid":"37736919","status":"not absorption-related","note":"Cross-sectional questionnaire survey of community pharmacists in Jeddah (n=300) on knowledge, attitudes and perceived safety/effectiveness of melatonin; no pharmacokinetic or absorption measurements. Read abstract (p.1)."},{"pmid":"38797355","status":"not absorption-related","note":"Rat isoproterenol-induced myocardial injury study of melatonin cardioprotection; 'bioavailability' refers to nitric oxide, not melatonin. No melatonin concentrations or PK reported (text search found no serum/plasma melatonin or pharmacokinetic content). Read abstract and introduction (p.1)."},{"pmid":"39044710","status":"not absorption-related","note":"Preclinical prostate-cancer nanocarrier paper (PSMA-R12 nanoparticles loaded with melatonin, siAPE1 and 125I). PK/biodistribution after tail-vein (intravenous) injection tracks the 125I radiolabel (%ID/g) of the nanoparticle, not melatonin concentrations, and is not oral absorption. Read abstract, methods and PK section (pp.1, 5-8)."},{"pmid":"39441486","status":"not absorption-related","note":"Pharmacodynamic study in heat-stressed prepubertal Ossimi ram lambs (single s.c. melatonin vs nano-melatonin vs corn oil): testicular Doppler indices, echotexture, scrotal circumference, testosterone, estradiol, NO and TAC. Melatonin concentrations were not measured; no PK/absorption data."},{"pmid":"39884559","status":"off-target analyte","note":"PK study of vigabatrin (R- and S-enantiomers) in rats with melatonin (20 mg/kg) as the co-administered interacting agent; plasma/tissue melatonin concentrations were not measured, so no melatonin absorption data. Data sections skipped."},{"pmid":"40231558","status":"review/non-primary","note":"Narrative review (Biomaterials Science 2025, 13, 3421-3446) of melatonin nanocarriers for the nervous system; no original PK/absorption data. Pages 1-4 read; remaining pages are review of literature."},{"pmid":"40426828","status":"review/non-primary","note":"Systematic review (Children 2025, 12, 648) of oral melatonin for sleep disorders in children and adolescents with ASD; synthesizes RCTs and a case series (N=9) of blood melatonin; no new primary PK data. Pages 1-4 read."},{"pmid":"40948465","status":"not absorption-related","note":"In vitro formulation/characterization of oxaliplatin-melatonin lipid-polymer hybrid nanoparticles (size, encapsulation efficiency, in vitro dialysis release, MCF-7 cytotoxicity). No absorption or PK data in humans or animals."},{"pmid":"41706381","status":"not absorption-related","note":"Hepatic safety (transaminase elevations) report from the MELATOMS-1 RCT of 300 mg/day melatonin in PP-MS patients on ocrelizumab (8 patients); no melatonin PK/absorption measurements in this paper (only literature mentions of serum melatonin in other studies)."},{"pmid":"41842581","status":"not absorption-related","note":"Mouse efficacy/mechanism study of intranasal RVG-liposomal melatonin in manganese neurotoxicity (behaviour, neurogenesis, transcriptomics, serum amino acids, microbiome). Only in vitro release (~72.6% at 12 h, ~82% at 24 h in text) and particle characterisation; no melatonin PK, tissue or plasma melatonin concentrations measured."},{"pmid":"41843085","status":"not absorption-related","note":"Rat aortic ring pharmacodynamic study of melatonin (30 mg/kg oral for 14 d; 10 uM ex vivo) on endothelin-1 vasoreactivity in diabetic rats; no melatonin absorption or concentration measurements."},{"pmid":"42771218","status":"review/non-primary","note":"Narrative review with scientometric analysis and ODE dose-exposure forecasting of oral and IV melatonin; no primary PK data collected."},{"pmid":"42813838","status":"not absorption-related","note":"Secondary analysis of IV norepinephrine infusion effect on endogenous plasma melatonin in awake vs anaesthetised volunteers. No melatonin supplement/exogenous melatonin was administered, so no absorption/PK of supplemented melatonin is reported."},{"pmid":"7800718","status":"not absorption-related","note":"Oral 8-methoxypsoralen (0.6 mg/kg) given to 15 PUVA patients; endogenous plasma melatonin, 6-sulfatoxymelatonin and 8-MOP were measured. No melatonin supplement administered. Melatonin/8-MOP/aMT6s time-courses are shown only in Fig. 1 (means with 95% CI); no tabulated PK values. Could alternatively be classed off-target analyte (8-MOP)."},{"pmid":"8791041","status":"not absorption-related","note":"Effect of IV flunitrazepam (1 mg) vs placebo on endogenous nocturnal plasma melatonin in 10 healthy men. No melatonin supplement administered; no absorption/PK of exogenous melatonin."}],"indirect":[{"anchor":"indirect-immediate-release-vs-extended-release","a":"immediate-release","b":"extended-release","aLabel":"Immediate-release tablet / capsule","bLabel":"Prolonged / extended-release","label":"Indirect comparison","baseline_nr":true,"grade":"D","grade_basis":"non-overlapping ranges but <2 studies per form (single-study ranges); uses value(s) with baseline correction not reported (capped at C under rubric v2)","head_to_head_grade":"C","note":"Head-to-head evidence exists and takes precedence over this indirect comparison.","status":"draft — pending reviewer (Dr. Colin Reily)","comparisons":[{"parameter":"Cmax","analyte":"melatonin","matrix":"serum/plasma","fed":"fed","dosing":"single","auc_interval":"","baseline_corrected":"no","units":"pg/ml","baseline_nr":true,"label":"baseline correction not reported","basis":"values as printed (doses not normalized)","a":{"n_studies":2,"n_values":2,"total_n":23,"range":[4701,11039.84],"per_mg_range":null,"values":[{"pmid":"10690873","value":"4,701","units":"pg/ml","dose":"3 mg","dose_basis":"active compound","n":"17","arm":"","location":"Table 2 (Exp 2)","per_mg":null},{"pmid":"20070489","value":"11039.84","units":"pg/ml","dose":"3 mg","dose_basis":"active compound","n":"6","arm":"","location":"Table 3","per_mg":null}]},"b":{"n_studies":3,"n_values":5,"total_n":35,"range":[52,1151],"per_mg_range":null,"values":[{"pmid":"22348451","value":"52","units":"pg/ml","dose":"0.4 mg","dose_basis":"active compound","n":"9","arm":"","location":"Table 2","per_mg":null},{"pmid":"22348451","value":"61","units":"pg/ml","dose":"4.0 mg","dose_basis":"active compound","n":"10","arm":"","location":"Table 2","per_mg":null},{"pmid":"37438493","value":"1151","units":"pg/ml","dose":"1.9 mg","dose_basis":"active compound","n":"13","arm":"","location":"Table 1; Abstract; Results 3.3","per_mg":null},{"pmid":"39174857","value":"740","units":"pg/ml","dose":"1.9 mg","dose_basis":"active compound","n":"12","arm":"","location":"Abstract; Results 3.2","per_mg":null},{"pmid":"39174857","value":"1151","units":"pg/ml","dose":"1.9 mg","dose_basis":"active compound","n":"12","arm":"","location":"Introduction p.416; Discussion p.420","per_mg":null}]},"higher":"immediate-release","separated":true,"pmids":["10690873","20070489","22348451","37438493","39174857"]},{"parameter":"Cmax","analyte":"melatonin","matrix":"serum/plasma","fed":"fed","dosing":"single","auc_interval":"","baseline_corrected":"not reported","units":"pg/ml","baseline_nr":true,"label":"baseline correction not reported","basis":"values as printed (doses not normalized)","a":{"n_studies":2,"n_values":2,"total_n":23,"range":[4701,11039.84],"per_mg_range":null,"values":[{"pmid":"10690873","value":"4,701","units":"pg/ml","dose":"3 mg","dose_basis":"active compound","n":"17","arm":"","location":"Table 2 (Exp 2)","per_mg":null},{"pmid":"20070489","value":"11039.84","units":"pg/ml","dose":"3 mg","dose_basis":"active compound","n":"6","arm":"","location":"Table 3","per_mg":null}]},"b":{"n_studies":2,"n_values":3,"total_n":25,"range":[740,1151],"per_mg_range":null,"values":[{"pmid":"37438493","value":"1151","units":"pg/ml","dose":"1.9 mg","dose_basis":"active compound","n":"13","arm":"","location":"Table 1; Abstract; Results 3.3","per_mg":null},{"pmid":"39174857","value":"740","units":"pg/ml","dose":"1.9 mg","dose_basis":"active compound","n":"12","arm":"","location":"Abstract; Results 3.2","per_mg":null},{"pmid":"39174857","value":"1151","units":"pg/ml","dose":"1.9 mg","dose_basis":"active compound","n":"12","arm":"","location":"Introduction p.416; Discussion p.420","per_mg":null}]},"higher":"immediate-release","separated":true,"pmids":["10690873","20070489","37438493","39174857"]},{"parameter":"Tmax","analyte":"melatonin","matrix":"serum/plasma","fed":"fed","dosing":"single","auc_interval":"","baseline_corrected":"no","units":"h","baseline_nr":true,"label":"baseline correction not reported","basis":"values as printed (doses not normalized)","a":{"n_studies":2,"n_values":2,"total_n":11,"range":[0.27,0.46],"per_mg_range":null,"values":[{"pmid":"20070489","value":"0.27","units":"h","dose":"3 mg","dose_basis":"active compound","n":"6","arm":"","location":"Table 3","per_mg":null},{"pmid":"3994899","value":"0.46","units":"h","dose":"2 mg","dose_basis":"active compound","n":"5","arm":"","location":"Results p.519","per_mg":null}]},"b":{"n_studies":1,"n_values":2,"total_n":10,"range":[4.7,5.1],"per_mg_range":null,"values":[{"pmid":"22348451","value":"4.7","units":"h","dose":"0.4 mg","dose_basis":"active compound","n":"9","arm":"","location":"Table 2","per_mg":null},{"pmid":"22348451","value":"5.1","units":"h","dose":"4.0 mg","dose_basis":"active compound","n":"10","arm":"","location":"Table 2","per_mg":null}]},"higher":"immediate-release","separated":true,"pmids":["20070489","22348451","3994899"]},{"parameter":"Tmax","analyte":"melatonin","matrix":"serum/plasma","fed":"fed","dosing":"single","auc_interval":"","baseline_corrected":"not reported","units":"min","baseline_nr":true,"label":"baseline correction not reported","basis":"values as printed (doses not normalized)","a":{"n_studies":1,"n_values":1,"total_n":17,"range":[60,60],"per_mg_range":null,"values":[{"pmid":"10690873","value":"60","units":"min","dose":"3 mg","dose_basis":"active compound","n":"17","arm":"","location":"Results, Study 2","per_mg":null}]},"b":{"n_studies":2,"n_values":3,"total_n":25,"range":[64,179],"per_mg_range":null,"values":[{"pmid":"37438493","value":"64.2","units":"min","dose":"1.9 mg","dose_basis":"active compound","n":"13","arm":"","location":"Table 1; Abstract","per_mg":null},{"pmid":"39174857","value":"179","units":"min","dose":"1.9 mg","dose_basis":"active compound","n":"12","arm":"","location":"Abstract; Results 3.2","per_mg":null},{"pmid":"39174857","value":"64","units":"min","dose":"1.9 mg","dose_basis":"active compound","n":"12","arm":"","location":"Introduction p.416; Discussion p.420","per_mg":null}]},"higher":"immediate-release","separated":true,"pmids":["10690873","37438493","39174857"]}],"pmids":["10690873","20070489","22348451","37438493","39174857","3994899"]},{"anchor":"indirect-immediate-release-vs-sublingual","a":"immediate-release","b":"sublingual","aLabel":"Immediate-release tablet / capsule","bLabel":"Sublingual / oral spray","label":"Indirect comparison","baseline_nr":true,"grade":"D","grade_basis":"non-overlapping ranges but <2 studies per form (single-study ranges); uses value(s) with baseline correction not reported (capped at C under rubric v2)","head_to_head_grade":null,"note":"No head-to-head grade; indirect only.","status":"draft — pending reviewer (Dr. Colin Reily)","comparisons":[{"parameter":"Cmax","analyte":"melatonin","matrix":"serum/plasma","fed":"fed","dosing":"single","auc_interval":"","baseline_corrected":"not reported","units":"pg/ml","baseline_nr":true,"label":"baseline correction not reported","basis":"values as printed (doses not normalized)","a":{"n_studies":3,"n_values":3,"total_n":40,"range":[4701,13120],"per_mg_range":null,"values":[{"pmid":"10690873","value":"4,701","units":"pg/ml","dose":"3 mg","dose_basis":"active compound","n":"17","arm":"","location":"Table 2 (Exp 2)","per_mg":null},{"pmid":"20070489","value":"11039.84","units":"pg/ml","dose":"3 mg","dose_basis":"active compound","n":"6","arm":"","location":"Table 3","per_mg":null},{"pmid":"37150895","value":"13120","units":"pg/ml","dose":"4 mg","dose_basis":"active compound","n":"17","arm":"","location":"Table 2; Abstract","per_mg":null}]},"b":{"n_studies":1,"n_values":1,"total_n":13,"range":[2380,2380],"per_mg_range":null,"values":[{"pmid":"37438493","value":"2380","units":"pg/ml","dose":"1 mg","dose_basis":"active compound","n":"13","arm":"","location":"Table 1; Discussion","per_mg":null}]},"higher":"immediate-release","separated":true,"pmids":["10690873","20070489","37150895","37438493"]},{"parameter":"Tmax","analyte":"melatonin","matrix":"serum/plasma","fed":"fed","dosing":"single","auc_interval":"","baseline_corrected":"not reported","units":"min","baseline_nr":true,"label":"baseline correction not reported","basis":"values as printed (doses not normalized)","a":{"n_studies":1,"n_values":1,"total_n":17,"range":[60,60],"per_mg_range":null,"values":[{"pmid":"10690873","value":"60","units":"min","dose":"3 mg","dose_basis":"active compound","n":"17","arm":"","location":"Results, Study 2","per_mg":null}]},"b":{"n_studies":1,"n_values":1,"total_n":13,"range":[23.3,23.3],"per_mg_range":null,"values":[{"pmid":"37438493","value":"23.3","units":"min","dose":"1 mg","dose_basis":"active compound","n":"13","arm":"","location":"Table 1; Abstract","per_mg":null}]},"higher":"sublingual","separated":true,"pmids":["10690873","37438493"]}],"pmids":["10690873","20070489","37150895","37438493"]}],"indirectUnavailable":[{"a":"immediate-release","b":"liquid","aLabel":"Immediate-release tablet / capsule","bLabel":"Liquid / oral solution","reason":"no matched condition set: arms differ on dosing"},{"a":"extended-release","b":"liquid","aLabel":"Prolonged / extended-release","bLabel":"Liquid / oral solution","reason":"no matched condition set: arms differ on dosing"},{"a":"extended-release","b":"sublingual","aLabel":"Prolonged / extended-release","bLabel":"Sublingual / oral spray","reason":"all arms come from the same studies (head-to-head only, see above)"},{"a":"liquid","b":"sublingual","aLabel":"Liquid / oral solution","bLabel":"Sublingual / oral spray","reason":"no matched condition set: arms differ on dosing"}],"indirectMethod":"Indirect (cross-study) PK comparisons from bundle_v2 single-form human arms.\nValues are copied as printed. Matching key: parameter, analyte, matrix, fed/fasted, single vs repeated,\nAUC interval (from parameter_detail), baseline correction, units (exact). No pooling/averaging: per-form\nranges are min–max of printed values. Analyte for minerals/B12 is classed as total element vs isotope/radiotracer; units compared after removing spaces/separators only; IV arms excluded; serum and plasma treated as the same matrix; curated magnesium v1 rows (mapped from stated conditions only, NR otherwise, deduped against the bundle) are included; baseline correction NR is treated as unknown (may match corrected or uncorrected sets; labeled and capped at C); for % absorption endpoints an unreported baseline correction is treated as not applicable. Normalization: value / elemental dose (mg) ONLY when dose_basis is\n'elemental', dose unit is mg, single dose, baseline-corrected=yes, parameter Cmax/AUC. Grade capped at C.\nRun after merge_bundle.py.","formGrades":{"immediate-release":{"label":"Immediate-release tablet / capsule","grade":"A","basis":"11 human studies, total n=124, 6 randomized/crossover; median CV 41.5% across 4 matched set(s) (consistent)","studies":11,"total_n":124,"randomized":6,"median_cv":41.5,"cv_sets":[{"set":"Cmax / melatonin / serum/plasma / fasted / single /  / pg/ml","studies":["10883420","18982259","31381847","39458580"],"cv":97.5},{"set":"Cmax / melatonin / serum/plasma / fed / single /  / pg/ml","studies":["10690873","20070489","37150895"],"cv":45.6},{"set":"Tmax / melatonin / serum/plasma / fasted / single /  / h","studies":["10085470","18490497","18982259","39458580"],"cv":27.3},{"set":"Tmax / melatonin / serum/plasma / fed / single /  / h","studies":["20070489","37150895","3994899"],"cv":37.4}],"pmids":["10085470","10690873","10883420","18490497","18982259","20070489","27566320","31381847","37150895","39458580","3994899"]},"extended-release":{"label":"Prolonged / extended-release","grade":"B","basis":"7 human studies, total n=93, 6 randomized/crossover; median CV 59.2% across 7 matched set(s) (consistent)","studies":7,"total_n":93,"randomized":6,"median_cv":59.2,"cv_sets":[{"set":"Cmax / 6-sulfatoxymelatonin / serum/plasma / fed / single /  / pg/ml","studies":["37438493","39174857"],"cv":14.6},{"set":"Cmax / melatonin / serum/plasma / fasted / single /  / pg/ml","studies":["31381847","39458580"],"cv":59.2},{"set":"Cmax / melatonin / serum/plasma / fed / single /  / pg/ml","studies":["22348451","37150895","37438493","39174857"],"cv":142.4},{"set":"Tmax / 6-sulfatoxymelatonin / serum/plasma / fed / single /  / min","studies":["37438493","39174857"],"cv":43.8},{"set":"Tmax / melatonin / serum/plasma / fasted / single /  / h","studies":["10085470","39458580"],"cv":66.6},{"set":"Tmax / melatonin / serum/plasma / fed / single /  / h","studies":["22348451","37150895"],"cv":73.1},{"set":"Tmax / melatonin / serum/plasma / fed / single /  / min","studies":["37438493","39174857"],"cv":43.6}],"pmids":["10085470","22348451","31381847","37150895","37438493","39174857","39458580"]},"liquid":{"label":"Liquid / oral solution","grade":"B","basis":"3 human studies, total n=21, 1 randomized/crossover; consistency not evaluable (no matched set with ≥2 studies)","studies":3,"total_n":21,"randomized":1,"median_cv":null,"cv_sets":[],"pmids":["11038434","18423009","29194416"]},"sublingual":{"label":"Sublingual / oral spray","grade":"C","basis":"1 human study, total n=13, 1 randomized/crossover; consistency not evaluable (no matched set with ≥2 studies)","studies":1,"total_n":13,"randomized":1,"median_cv":null,"cv_sets":[],"pmids":["37438493"]}},"headlineGrade":"A","rubric":"Rubric v2 (draft, pending reviewer): single-form human studies count.\n(1) Per-form 'absorption evidence' grade from human PK/absorption values of single-form arms:\n    studies, total n, design (randomized/crossover share), consistency = CV of per-study medians within\n    matched condition sets (same parameter, analyte, matrix [serum=plasma], fed, dosing, AUC interval, units; >=2 studies).\n    A: >=5 studies, total n >=100, >=2 randomized/crossover, and no evidence of inconsistency\n       (median CV <=100% across matched sets, or not evaluable because no matched set has >=2 studies; this is reported).\n    B: >=3 studies (or 2 studies with consistent matched values). C: 1-2 studies. D: animal/in vitro only.\n    Median CV <=50% = consistent; 50-100% = heterogeneous (reported, not penalized: dose, iron status and\n    population differ between studies); >100% = inconsistent, grade lowered one step.\n(2) Per pair: combine head-to-head (H2H) grade with matched single-form (indirect) evidence.\n    Indirect direction = form favored in matched sets whose ranges do not overlap (Tmax excluded).\n    Strong indirect: separated set(s) with >=3 studies per form (A-capable) or >=2 (B-capable), no contradicting set.\n    A: strong indirect (>=3/form) agreeing with H2H or no H2H, or H2H A not contradicted.\n    Conflict between H2H and indirect direction: one step below the better of the two (min D).\n    Comparisons using values with baseline correction not reported are capped at C.\nValues are never computed into new estimates: CV is used only as a consistency check and is shown with its inputs.","headlineBasis":"best grade across this page's form absorption grades and 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