Melatonin is increasingly used for the treatment of sleep disorders. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. However, relatively little is known about the pharmacokinetic properties of low dose (<0.5 mg) and high dose (>2 mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low (0.4 mg) and high (4.0 mg) dose melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine if melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3 hrs vs 1.5 hrs), elimination half-life (1.8 hrs vs 2.1 hrs), and apparent total clearance (379 l/hr vs 478 l/hr) did not differ significantly between the low and high dose arms, respectively. The maximum concentration was 405±93 pg/ml for the low dose arm and 3999±700 pg/ml for the high dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. In addition, subjects in the high dose arm maintained melatonin levels >50 pg/ml for an average of 10 hours, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6 weeks of treatment. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes.
Key Points
Infant acute lymphoblastic leukemia is sensitive to therapeutic targeting by apoptosis, necoptosis, and autophagy activation whether MLL is rearranged or germline. The disease-specific form of triple death mode killing by obatoclax overcomes the intrinsic resistance of MLL-rearranged infant acute lymphoblastic to cell death.
OBJECTIVETo compare the efficacy and safety of sildenafil and apomorphine in the treatment of men with erectile dysfunction (ED).
PATIENTS AND METHODSIn all, 139 men with ED who were naïve to treatment were entered into an open-label crossover trial with two treatment periods, each of 8 weeks, separated by a 2-week washout period. Men were randomized to receive either sildenafil then apomorphine or apomorphine then sildenafil, and were allowed to titrate the dose on both drugs. The primary endpoint was the erectile function (EF) domain of the International Index of Erectile Function (IIEF), and other endpoints included diary data, the other domains of the IIEF, overall assessment questions and the Erectile Dysfunction Index of Treatment Satisfaction (EDITS) questionnaire.
RESULTSThe EF domain score after treatment was 25.2 for sildenafil and 15.9 for apomorphine. The treatment difference of the adjusted means was 9.3 points (95% confidence interval 7.6-11.1; P < 0.001). After sildenafil the successful intercourse rate was 75%, vs 35% for apomorphine ( P < 0.001), and the EDITS scores were 82.5 for sildenafil and 46.8 for apomorphine ( P < 0.001). Of the men, 96% expressed a preference for sildenafil as a treatment for their ED. The side-effect profiles for both drugs were in keeping with published data.
CONCLUSIONBy all measurable endpoints sildenafil was superior to apomorphine in this open-label crossover study of men with ED who were naïve to therapy
A population PK model for custirsen was successfully developed in cancer patients and healthy subjects, including covariates contributing to variability in custirsen PK.
BackgroundLimited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC).AimTo evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC.MethodsParticipants (5–17 years of age; 18–82 kg, stratified by weight) with UC received multi-matrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model.ResultsFifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%–45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified.ConclusionChildren and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844.
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