The influence of hepatic cirrhosis on the pharmacokinetics of benazepril hydrochloride.

The influence of hepatic disease on the pharmacokinetics of the new ACE inhibitor, benazepril hydrochloride, was evaluated in 12 male patients suffering from liver cirrhosis. The patients received a single oral 20 mg dose. The plasma concentrations and urinary excretion of unchanged benazepril and its active metabolite benazeprilat were determined. Compared with a historical control group of healthy volunteers treated with the same benazepril. HC1 dose, the plasma concentrations of benazepril were doubled in the cirrhotic patients. However, the time to reach maximum concentration (0.5 h) was not affected. The plasma kinetics and the urinary excretion of the metabolite benazeprilat were not significantly altered: Area under the curve and maximum concentration as well as time to maximum concentration (1.5 h) were comparable with those in the healthy subjects. There was also no significant difference between the two populations for the total urinary excretion and the renal clearance of benazeprilat. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 94 per cent, respectively). In conclusion, the rate and the amount of bioactivation of the inactive prodrug benazepril to the active benazeprilat were virtually unaffected by hepatic cirrhosis. Thus, there seems to be no need for dosage adjustment of benazepril hydrochloride in patients suffering from cirrhosis of the liver.

Pharmacokinetics and pharmacodynamics of the ace inhibitor benazepril hydrochloride in the elderly.

The pharmacokinetics and pharmacodynamics of a single oral dose benazepril.HCl 10 mg have been studied in 15 healthy volunteers aged 65 to 80 y. The kinetics of unchanged benazepril and its active metabolite benazeprilat did not differ significantly in males and females, so the combined kinetic data from all 15 elderly subjects were compared with a historical control group of 19-32 year-old healthy men treated in the same way. The disposition of benazepril was not affected by age. The time to maximum plasma concentration, tmax (0.5 h) and elimination half-life (0.6 h) in the elderly were the same as in young subjects. The kinetics of benazeprilat was slightly changed in the elderly; although its tmax (1.5 h) was not affected, Cmax and the AUC were 20-40% greater. The elimination half-life of benazeprilat during the first 24 h after dosing in the elderly was increased by about 20% to 3.2 h. The renal plasma clearance of benazeprilat (18.1 ml.min-1) was about 20% smaller than in the young subjects. An average of 18.5% of the dose was recovered as benazeprilat in the 24 h urine from the elderly subjects, which was similar to the recovery in the young subjects. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 95%, respectively). Mean systolic and diastolic blood pressures in the elderly were reduced by a maximum of 37/16 mm Hg at 6 h, in association with a small rise in pulse rate. Treatment was generally well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

L-643.441: an H2-receptor antagonist with potent and long-lasting effects in man.

Submaximal dose pentagastrin tests conducted in normal male volunteers with L-643.441, a novel histamine H2-receptor antagonist, indicate that it is a potent and long-acting inhibitor of gastric acid secretion. The effect appears dose-dependent and single doses of 50 mg are sufficient to reduce secretory potential by at least 50% when examined 24 h after drug administration. No adverse effects attributable to treatment were observed.

Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase, in healthy volunteers.

Mevinolin reduces cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The safety and effectiveness of this agent was evaluated in a double-blind, placebo-controlled study in 59 healthy men (serum cholesterol 3.88--7.76 mmol/liter) in five centers. Subjects maintained their usual diet and activities. Doses of 6.25, 12.5, 25, or 50 mg twice daily for 4 wk produced mean reductions of total serum cholesterol fo 23--27% [vs. placebo (4%), P less than 0.01]. Mean low density lipoprotein cholesterol fell 35--45%, while high density lipoprotein and very low density lipoprotein cholesterol, and triglycerides were not significantly affected. Mean apolipoprotein B fell 27--34%. 50 mg was not significantly more effective than 6.25 mg. Mevinolin was generally well tolerated, and no serious clinical or laboratory abnormalities occurred. One subject (12.5 mg) was withdrawn because of abdominal pain and diarrhea. These results suggest that if long-term safety can be demonstrated, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase are likely to prove useful in the treatment of hypercholesterolemia.

Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase.

Mevinolin (MK-803) is a potent inhibitor of HMG-CoA reductase. After a placebo run-in period, mevinolin 5,15 or 50 mg, or placebo was given twice daily for 7-11 days under double -blind conditions ot 4 groups of 6 normocholesterolemic male volunteers. After 7 days, mean serum cholesterol fell 14%, 25% and 24% on 5, 15 and 50 mg, respectively, which was significantly greater than the fall on placebo (4%) in the case of the two higher doses (P less than 0.01). Serum triglycerides did not change significantly. Mevinolin was generally well-tolerated and there were no serious adverse effects.

Enhancement of uricosuric properties of indacrinone by manipulation of the enantiomer ratio.

Racemic indacrinone is a high-ceiling, relatively long-acting diuretic. Both enantiomers have uricosuric activity, but the diuretic activity resides predominantly in the (-) enantiomer. Usual therapeutic doses of racemic indacrinone have only transient uricosuric activity, so that, as with other diuretics, hyperuricemia occurs. Sixty-five healthy men participated in a multicenter, double-blind, randomized, balanced, incomplete-block study comparing the effects on plasma urate and urate clearance of indacrinone (-) enantiomer 10 mg given concomitantly with 0, 10, 20, 40, and 80 mg (+) enantiomer (10/0, 10/10, 10/20, 10/40, 10/80), as single daily doses for 7 days. Hydrochlorothiazide (HCTZ) 50 mg daily and ticrynafen (T) 250 mg daily were controls. Each subject received two of the seven treatments, so that there were 18 subjects per treatment. On days 7 to 8, morning (mean of 0-hr values on days 7 and 8), HCTZ, 10/0, 10/10, and 10/20 elevated plasma urate by 8% to 16%. 10/40 was approximately isouricemic, and 10/80 and T lowered plasma urate by 13% and 41%. There were corresponding changes in urate clearance.

Potentiating effect of adrenaline on adenosine diphosphate-induced reduction in rabbit circulating platelet count: inhibition by dihydroergotoxine.

The number of circulating platelets was monitored in anaesthetized rabbits by a continuous flow technique, using a Technicon Autocounter. Transient reductions in circulating platelet count induced by a submaximal dose of adenosine diphosphate (ADP) were potentiated by concomitant infusion of adrenaline at doses (1-25 microgram/kg) i.v.) which did not influence platelet count when infused alone. The adrenaline effect was dose-dependent. Repeated infusions of adrenaline at 15 min intervals resulted in reproducible reductions in circulating platelet count during an observation period of at least 105 min. Dihydroergotoxine (DHET), administered either i.v. (2.5-10 microgram/kg) or intraduodenally (i.d.; 25-100 microgram/kg), inhibited adrenaline-induced potentiation dose-dependently; ADP-induced effects were not influenced. Duration of action was relatively long, and significant inhibitory activity was still apparent 50 (i.v.) and 115 (i.d.) min after drug administration. DHET doses inhibiting adrenaline-induced potentiation of platelet aggregation in the rabbit are similar to doses used in the treatment of impaired human cerebral function. It is conceivable that DHET could prevent activation of human platelets by catecholamines released into the blood stream in clinical stress situations.

The effect of intravenous adenosine diphosphate on the number of circulating platelets in experimental animals: inhibition by prostaglandin E1, dipyridamole, SH-869 and VK-774.

The number of circulating platelets was monitored in anaesthetized animals by a continuous flow technique, using a Technicon Autocounter. Intravenous infusions of adenosine diphosphate (ADP) produced transient, dose-dependent falls in circulating platelet numbers in rabbits, dogs, rats, pigs and squirrel monkeys. The rat was the most sensitive of the species investigated. In the rabbit, the effect of a submaximal dose of ADP was inhibited in a dose-dependent manner by intravenous infusions of prostaglandin E1 (PGE1), dipyridamole, and two derivatives of dipyridamole (SH-869 and VK-774). The dose-response curves for PGE1, SH-869 and VK-774 were approximately parallel, whereas that for dipyridamole was considerably less steep. PGE1 was the most potent inhibitor, but the duration of action was very short. Dipyridamole and SH-869 produced inhibition of long duration. The duration of action of VK-774 was intermediate. All inhibitors produced marked and often long-lasting hypotension. The fact no inhibition of ADP effects could be demonstrated with dibenzyline and hexamethonium, which also produced marked hypotension of long duration, indicated that inhibition of the ADP effect by the four antagonists studied was not due to changes in blood pressure.

Effect of rifampin, clofazimine, and B1912 on the viability of Mycobacterium leprae in established mouse footpad infection.

Continuous dietary administration of rifampin to mice with an established Mycobacterium leprae footpad infection reduced the bacillary solid ratio, with an estimated survival half-life of 5-6 days. In rifampin-treated immunosuppressed animals the survival half-life of solid bacilli, in the absence of host immunity, was 12-13 days. Clofazimine and B1912 produced a significant effect on solid ratio only after a lag period of apparently 100 days. The rate of action was considerably slower than that of rifampin. Intermittent (once monthly) administration of both drugs produced effects similar to those of continuous administration.

Effect of rifampin, clofazimine, and B1912 on the viability of Mycobacterium leprae in established mouse footpad infection

Continuous dietary administration of rifampin to mice with an established Mycobacterium leprae footpad infection reduced the bacillary solid ratio, with an estimated survival half-life of 5-6 days. In rifampin-treated immunosuppressed animals the survival half-life of solid bacilli, in the absence of host immunity, was 12-13 days. Clofazimine and B1912 produced a significant effect on solid ratio only after a lag period of apparently 100 days. The rate of action was considerably slower than that of rifampin. Intermittent (once monthly) administration of both drugs produced effects similar to those of continuous administration.

In vitro and in vivo studies of the action of rifampicin, clofazimine and B1912 on Mycobacterium marinum.

Rifampicin (RMP) and two riminophenazine compounds (B663 and B1912) suppressed the growth of Mycobacterium marinum in vitro and in a mouse footpad infection. At appropriate concentrations and dietary dosage, all three drugs showed bactericidal activity in vitro and in vivo. On the basis of minimum inhibitory concentration, RMP was considerably more active than the other two substances in vitro. However, the rate of bactericidal effect was similar for all three drugs. In vivo, the minimum bactericidal dietary dosages of RMP, B663 and B1912 were 0.03, 0.03 and less than or equal to 0.01%, respectively. Results suggest that these drugs may be of value for the treatment of clinical M. marinum infections.