The comparative steady-state bioavailability of asiatic acid was studied in 12 healthy male and female volunteers following oral administration of approximately equimolar doses of either asiatic acid (12 mg) or the glycoside derivative of asiatic acid, asiaticoside (24 mg). Both asiatic acid and asiaticoside are constituents of the marketed dermatological product Madecassol. Asiaticoside is converted in vivo to asiatic acid by hydrolytic cleavage of the sugar moiety. Steady-state AUC0-12h values for asiatic acid on either regimen were similar (614 +/- 250 ng.h/ml following asiatic acid compared to 606 +/- 316 ng.h/ml following asiaticoside) indicating comparable bioavailability for asiatic acid with the two ingredients at approximately equimolar doses. Since asiatic acid is considered to be the most therapeutically active ingredient of Madecassol, the current data suggest that the therapeutic effects of asiaticoside may be mediated through conversion to asiatic acid.

1 Studies have been carried out to investigate the disposition of nicardipine hydrochloride following intravenous and oral administration to male volunteers. 2 Following oral administration of a radiolabelled dose, nicardipine was shown to be rapidly and extensively metabolised and to be rapidly eliminated from plasma. 3 After intravenous infusion of nicardipine at 5 mg-' for 3 h, plasma levels declined biexponentially, and clearance values were of the same order as hepatic blood flow. 4 With repeated oral administration, 20 mg three times daily for 28 days, plasma levels rose over the first 3 days of administration and then declined to some extent. Possible reasons for this decline are discussed. 5 Steady-state plasma levels and bioavailability show a nonlinear relationship with doses over the range 10-40 mg three times daily. 6 Food consumption has been shown to reduce the bioavailability of nicardipine when the food is taken before or at the same time as nicardipine administration.

1. The metabolism of imiloxan hydrochloride [(+-)-2-(1-ethyl-2-imidazoyl)methyl-1,4-benzodioxane hydrochloride], an alpha 2-adrenoceptor antagonist, was studied in four male volunteers given a 500 mg oral dose containing 0.48 MBq of the 14C-labelled material. Compound-related radioactivity was rapidly excreted chiefly in the urine within 24 h of dosing. 2. Metabolites derived by initial oxidation on either or both the benzodioxane and imidazoyl moieties followed by glucuronic acid and sulphate conjugation, and an N-glucuronide of imiloxan were tentatively identified in urine. 3. The major urinary metabolites, comprising some 37-41% of the dose, appeared to be +-2-(1-ethyl-2-imidazoyl)methyl-1,4-benzodioxane-6/7-sulphonic acid (19% of dose), [+-2-(1-ethyl-2-imidazoyl)methyl-1,4-benzodioxane- 6/7-ylium D-glucopyranoside]uronate (10-14% of dose), and a glucuronide conjugate of +-2-(1-ethyl-2-imidazoyl-4/5-hydroxy)methyl-1,4-benzodioxane (8% of dose).

1. The biotransformation of nafimidone, an imidazole-substituted anticonvulsant, has been studied by characterization of urinary metabolites in dogs, cynomolgus monkeys, baboons and man. 2. The biotransformation of nafimidone in these laboratory animals and man is initially very similar, in each case proceeding by reduction to the aliphatic alcohol metabolite, nafimidone alcohol or 1-[2-hydroxy-2-(2-naphthyl)ethyl]imidazole. 3. Further transformation of this metabolite involves oxidation in the naphthyl and imidazole functions, and/or conjugation. 4. The dog differs from the higher primates in that no metabolic modification of the naphthyl group takes place, the major metabolite in the dog being the O-beta-glucuronide of nafimidone alcohol. 5. In higher primates and man two isomers involving dihydroxylation in the naphthyl ring--1-[2-hydroxy-2-(5,6- or 7,8-dihydroxydihydro-2-naphthyl)ethyl]imidazole--were tentatively identified. These species alone showed evidence of an imidazole linked N-glucuronide of nafimidone alcohol. 6. The possible occurrence of stereoselective metabolism by the introduction of a chiral centre at C-9 in nafimidone alcohol was indicated in human urine by the presence of both epimers of the O-beta-glucuronide of nafimidone alcohol in a 2:1 ratio.

Pharmacokinetic, haemodynamic and radionuclide studies explored the acute pharmacokinetic and pharmacodynamic actions of nicardipine in patients with coronary heart disease. Nicardipine infusion resulted in dose-related reductions in systolic and diastolic blood pressure and an increased heart rate. Pharmacodynamic activity was evident between 12 and 24 min following 5 and 10 mg i.v. nicardipine but by 3-6 min following the higher doses of 15 and 20 mg; hypotensive activity persisted for up to 2 h. Post-infusion nicardipine concentrations declined biexponentially; however the limited data precluded formal compartmental analysis. Plasma clearance ranged from 5-12 ml/min/kg, and appeared lower than previously reported volunteer data. The haemodynamic actions of nicardipine (10 mg infusion over 10 min) in 6 patients undergoing diagnostic catheterization were reductions in systolic, diastolic and mean systemic arterial pressure and systemic vascular resistance index. Heart rate and stroke volume index increased, and there was a small but statistically significant increase in pulmonary artery occluded pressure. Radionuclide parameters were measured in 20 patients with stable angina, at rest and during supine bicycle exercise, before and 3-5 min after nicardipine 10 mg intravenously. The left ventricular ejection fraction increased by 4% at rest but not during exercise. The left ventricular rest and exercise ejection and filling rates both increased with a concurrently reduced left ventricular ejection time. There was a highly significant inverse relationship between baseline exercise ejection fraction and the response to nicardipine; ejection fraction increased with low initial values but was either unchanged or fell with higher initial values.(ABSTRACT TRUNCATED AT 250 WORDS)