No abstract

Several series of heterocyclic carboxylic esters were found to be active in the benzodiazepine receptor binding assay, a typical example being ethyl 7-ethyl-5-methoxyimidazo[1,2-a]quinoline-2-carboxylate (4b) with an IC50 of 150 nM. The corresponding phenylmethanone 5d was more potent with an IC50 of 14 nM and was orally active in animal models thought to predict anxiolytic effects. The synthesis of a large number of compounds resulted in the optimization of this activity in a series of (imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones of which compounds 7e, 8b, 8h, 8j, and 8k were equipotent with chlordiazepoxide while exhibiting reduced anticonvulsant activity, little or no muscle relaxation, and negligible sedative effects.

The effects of the potassium channel opener levcromakalim (BRL 38227) 7.5 micrograms kg‐1 were examined on urodynamic variables and blood pressure during inflow and voiding cystometry in six high spinal cord lesion patients. Levcromakalim administration significantly increased the duration of bladder contraction (197 +/‐ 128 s to 267 +/‐ 167 s, P < 0.05) and also reduced blood pressure (126 +/‐ 13/67 +/‐ 9 mm Hg to 104 +/‐ 25/52 +/‐ 12 mm Hg) but was without effect on other urodynamic parameters. Because of concerns about hypotensive responses, further studies involving higher doses of levcromakalim should be considered only if the drug was administered intravesically.

Omeprazole has been shown in previous studies to inhibit the hepatic metabolism of selected drugs. Quinidine is an antiarrhythmic and antimalarial agent with a low therapeutic index. We therefore examined the effect of 40 mg omeprazole daily for one week or placebo on the pharmacokinetics and pharmacodynamics of a single 400 mg dose of quinidine in 8 healthy volunteers in a double-blind crossover study.During placebo and omeprazole treatment, there was no significant difference in area under the time-plasma quinidine concentration curve, (17.0 f 4.83 p g . h/ml, 18.6 k 4.43 pg . h/ml, respectively; P > 0.2) or renal clearance of quinidine (56.2 respectively; P > 0.5). Quinidine unbound fraction in plasma (0.170f0.041 US. 0.166k0.041 in the presence of omeprazole; P > 0.5) was not altered by omeprazole. Peak plasma quinidine concentration and the time this occurred did not differ. Omeprazole also had no effect on these parameters for the metabolite 3-hydroxyquinidine. There was no significant difference in the change in the corrected Q-T interval on the electrocardiogram due to quinidine (mean area under the time versus 26.0 ml/min, 55.6 -t 12.7 ml/min,