Randomised crossover comparison of adrenal suppressive effects of dermal creams containing glucocorticosteroids.

To compare the effect of multiple dose treatment with fatty cream 0.1% hydrocortisone-17-butyrate (LLFC) and fatty cream 0.1% mometasone furoate (EFC), under occlusion on adrenal function, we performed an open label, randomised, two-period crossover study, lasting 30 days, in 12 healthy, male volunteers (age 18-45 y). Morning plasma cortisol and ACTH concentrations were determined before, during, and after the treatments, and a Synacthen test was performed before and during the treatments. Both agents suppressed plasma cortisol concentrations, EFC significantly more than LLFC. ACTH concentrations were normal and were comparable between the two treatments throughout the studies, while the Synacthen tests showed normal rises in cortisol levels. Both treatments were well tolerated. We conclude that EFC has a stronger suppressive effect on plasma cortisol values than LLFC, although for short duration treatments both suppressive effects are transient.

Lack of pharmacokinetic interaction between vinpocetine and oxazepam.

The influence of multiple doses of vinpocetine (10 mg three times daily) on the steady state plasma concentrations of oxazepam (10 mg three times daily) was studied in 16 healthy subjects. The mean (+/- s.d.) AUC (ng ml-1h-1) of oxazepam over 24 h during combined treatment was 4716 +/- 2296 and for oxazepam treatment alone it was 4737 +/- 2448 (95% confidence intervals for ratio of means = 95.4-103.7%). The degree of plasma protein binding of oxazepam was 98.11 +/- 0.32% and was not affected by vinpocetine. Independent of vinpocentine treatment a significant diurnal change in the plasma binding of oxazepam was observed; the free drug fraction was 20% higher during the night than during the day. Cmax and AUC values based on total oxazepam in plasma were 10% lower during the night. The results indicate a lack of influence of vinpocetine on oxazepam kinetics. Diurnal changes in the plasma binding of oxazepam probably have no clinical consequences.

A comparative study of the steady-state pharmacokinetics of immediate-release and controlled-release diltiazem tablets.

We have studied the controlled-release properties and relative systemic availabilities of two dosages of the same controlled-release (CR) diltiazem tablet formulation by comparing them at steady state with those of an immediate-release formulation. We measured 24-hour plasma concentration profiles during 4-day treatments with diltiazem 90 mg CR tablet bd diltiazem 120 mg CR tablet bd, and conventional diltiazem 60 mg immediate-release (IR) tablet tid. The study had a randomized, three-way crossover design. Twelve healthy men (38-52 y) participated. Trough plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the last morning dose on day 4 of each period. The following steady-state pharmacokinetic values were calculated: the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), the time interval during which the plasma concentration exceeded 75% of Cmax (t75), the area under the plasma concentration-time curve (AUC72-96), the peak-to-trough fluctuation (PTF), and the area-under-the-curve fluctuation (AUCF). Steady state was achieved on day 3. The pharmacokinetics were comparable. For diltiazem CR 90 mg and diltiazem CR 120 mg, AUC84-96 (night) was approximately 75% of AUC72-84 (daytime). The diltiazem plasma concentration increased slowly from about 6 h after the evening dose of both CR tablets, resulting in relatively high plasma concentrations in the early morning hours. Only during treatment with diltiazem CR 120 mg were the plasma concentrations of diltiazem maintained above the minimum therapeutic plasma concentration of 50 micrograms.l-1 throughout the full 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.

The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan-phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9-hydroxyrisperidone, exhibited CYP2D6-related polymorphism. The plasma area under the concentration-time curve from time zero to infinity ratio of 9-hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half-life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) varied little among subjects (mean terminal half-life, 20 +/- 2 1/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.