6-beta-hydroxycortisol and Headache

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluoro-carbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24-hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open-label, 2-way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 mug twice a day or fluticasone propionate chlorofluorocarbon 88 mug twice a day. In study 2, 63 subjects received 13.5 days of placebo followed by 27.5 days of fluticasone propionate hydrofluoroalkane 88 mug twice a day. The main outcome measure for study 1 was the difference between fluticasone propionate hydrofluoroalkane and fluticasone propionate chlorofluorocarbon in fluticasone propionate AUC(last) (area under the plasma fluticasone propionate concentration-time curve from zero up to the last quantifiable plasma concentration), and for study 2, 24-hour overnight urinary cortisol excretion. In study 1, fluticasone propionate systemic exposure was significantly lower (55%) with hydrofluoroalkane metered dose inhaler compared with chlorofluorocarbon metered dose inhaler. Study 2 showed no statistically significant changes in 24-hour overnight urinary cortisol excretion and no relationship to fluticasone propionate systemic exposure at this dose. The results of these 2 studies showed that in children aged 4 to 11 years with asthma, fluticasone propionate hydrofluoroalkane has lower systemic exposure compared with chlorofluorocarbon and no hypothalamic-pituitary-adrenal axis effects as measured by 24-hour urinary cortisol excretion.

Topics: Administration, Inhalation; Aerosol Propellants; Androstadienes; Anti-Asthmatic Agents; Area Under Curve; Asthma; Child; Child, Preschool; Chlorofluorocarbons; Cough; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fever; Fluticasone; Half-Life; Headache; Humans; Hydrocarbons, Fluorinated; Hydrocortisone; Male; Metered Dose Inhalers; Nausea; Respiratory Tract Infections

Bevirimat [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of bevirimat during repeated dosing in healthy volunteers.. The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Plasma bevirimat levels were measured from blood samples collected pre-dose on days 1-10 and then at approximately 48-hour intervals until 21 days after dosing started. On days 1 and 10, further blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after dosing. Urine samples were collected in the morning on days 1, 5 and 11 and at the end of the study for the measurement of cortisol and 6beta-hydroxycortisol. The pharmacokinetic parameters of bevirimat were estimated using non-compartmental methods.. Dose proportionality of exposure to bevirimat, assessed by the maximum plasma concentration and the area under the plasma concentration-time curve.. The mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour. Bevirimat showed approximately 4-fold greater accumulation on day 10 compared with day 1, and the degree of accumulation was similar with all doses. Maximum plasma concentrations ranged from 8 to 58 microg/mL at day 10. Testing for dose-proportionality showed that exposure to bevirimat was proportional to the dose, both after a single dose and after repeat dosing for 10 days. Measurement of the urinary 6beta-hydroxycortisol/cortisol ratio indicated that bevirimat did not affect cytochrome P450 3A activity. Repeated dosing with bevirimat for 10 days was well tolerated. There was no increase in adverse events observed for bevirimat compared with placebo, and no serious adverse events occurred. No clinically relevant changes in vital signs, physical examination or clinical laboratory evaluations were observed.. Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with bevirimat is well tolerated. These properties make bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.

Topics: Administration, Oral; Adult; Anti-HIV Agents; Area Under Curve; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Half-Life; Headache; HIV-1; Humans; Hydrocortisone; Male; Middle Aged; Nausea; Succinates; Time Factors; Triterpenes

The effects of the CYP3A4 inducer, Hypericum perforatum, on the pharmacokinetics of a single oral dose of ivabradine were assessed. An open-label, 2-period, nonrandomized, phase-I, pharmacokinetic interaction design was used. Twelve healthy volunteers received a single oral dose of ivabradine (10 mg) followed by H perforatum (300 mg orally, 3 times a day) for 14 days, combining the last dose with another single dose of ivabradine. Pharmacokinetic data for ivabradine (S16257) and its main active metabolite (S18982) prior to and after the administration of H perforatum were analyzed. After repeated administration of H perforatum, highest observed concentration in plasma (C(max)) and area under the concentration-time curve (AUC) were significantly decreased for ivabradine (32.7 +/- 16.6 vs 15.4 +/- 7.0 ng/mL, P < .01; 114 +/- 39.1 vs 43.7 +/- 12.0 ng x h/mL, P < .01, respectively), and for S18982 (C(max), 6.8 +/- 3.7 vs 5.1 +/- 2.0 ng/mL, P < .05; AUC, 56.2 +/- 23.4 vs 38.3 +/- 25.1 ng x h/mL, P < .01). Tendencies toward shorter time to C(max) and lower apparent terminal half-life values were found. Pharmacokinetic results are consistent with an induction of ivabradine metabolism by H perforatum.

Topics: Administration, Oral; Adult; Anthracenes; Area Under Curve; Benzazepines; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Electrocardiography; Female; Gastrointestinal Tract; Half-Life; Headache; Heart Rate; Herb-Drug Interactions; Humans; Hydrocortisone; Hypericum; Ivabradine; Male; Metabolic Clearance Rate; Perylene; Plant Preparations; Tablets