A B S T R A C T 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and effectiveness of this agent was evaluated in a double-blind, placebo-controlled study in One subject (12.5 mg) was withdrawn because of abdominal pain and diarrhea.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. INTRODUCTION Elevated serum cholesterol is a major factor in the development of atherosclerosis and coronary heart disease (1, 2). There is a substantial and currently unsatisfied need for safe, well tolerated therapy capable of effecting large reductions in serum cholesterol.

To elucidate the role of leukotrienes (LT) in allergic asthma in humans the effect of MK-886, an LT biosynthesis inhibitor, was evaluated on antigen-induced early (EAR) and late (LAR) asthmatic reactions and bronchial responsiveness to histamine. Eight atopic men participated in a two-part, double-blind, placebo-controlled, crossover trial. MK-886 was administered in two oral doses of 500 mg and 250 mg, 1 h before and 2 h after allergen inhalation, respectively. Biochemical effects of MK-886 were evaluated by the inhibition of urinary LTE4 excretion and calcium ionophore-stimulated LTB4 biosynthesis in whole blood ex vivo. MK-886 significantly inhibited the EAR by 58.4% (AUC0-3 h) and the LAR by 43.6% (AUC3-7 h) when compared with placebo (p < 0.01). There was no difference in PC20 histamine 30 h post allergen challenge between MK-886 and placebo (0.33 and 0.27 doubling doses, p > 0.1). MK-886 inhibited calcium ionophore-stimulated LTB4 production in whole blood (54.2 +/- 25.6%) for up to 6 h post allergen challenge. LTE4 excretion in urine was inhibited by 51.5% during the EAR by as much as 80% during the LAR. This indicates that LT play a role in allergen-induced asthmatic reactions in humans in vivo and that LT synthesis inhibitors such as MK-886 should be further explored for the treatment of asthma.

The objective of this study was to estimate the minimum in vivo effective oral dose and duration of action of the competitive 5 alpha-reductase inhibitor MK-906, a 4-azasteroid, in humans. Plasma dihydrotesterone (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (AD), and its glucuronide (ADG), as well as urinary androsterone (A) and 5 alpha-pregnane-3 alpha,11 beta, 17 alpha,21-tetrol-20-one (aH4F) were determined in 54 healthy young men before and up to 7 days after a single morning dose of the compound. Twenty-four hours after a single 5- to 40-mg dose (n = 24), plasma DHT levels decreased by a mean of +/- 65%, with slow recovery of DHT levels. Seven days later, DHT remained decreased by +/- 15%. Plasma AD levels decreased to a similar degree, whereas ADG levels decreased by about 75%, indicating inhibition of target tissue 5 alpha-reductase. Testosterone levels did not show any significant variations. The A as well as aH4F excretion in the 24-hour urine test following drug administration decreased by 65%, indicating inhibition of the hepatic 5 alpha-reductase. After a single dose of 1.5 or 0.5 mg, DHT levels decreased by 50% 24 hours after administration, returning to normal within 5-7 days; at this dose, urinary A and aH4F excretion decreased by 50%. A single dose of 0.2 mg appeared to be slightly active as a 5 alpha-reductase inhibitor, but no statistically significant effect on DHT levels was observed after administration of a single 0.04-mg dose. It is concluded that MK-906 is a highly effective 5 alpha-reductase inhibitor in vivo. The effect on plasma DHT lasts for several days after administration of a single oral dose. The data suggest that both hepatic and extrasplanchnic 5 alpha-reductases are inhibited.

1 The antibiotic imipenum (thienamycin-formamidine) is partially hydrolyzed during excretion by a renal brush border dehydropeptidase. The co-administration of imipenum with the renal dehydropeptidase inhibitor cilastatin results in an increase of the urinary recovery of the antibiotic, both in animals and humans. 2 To study the pharmacokinetics of imipenem and cilastatin, subjects with normal renal function and patients with different degrees of renal insufficiency received intravenously 250 mg imipenum alone and 250 mg imipenem with 250 mg cilastatin. 3 The mean plasma half-life of imipenem varied from 52 min in subjects with normal renal function to 173 min in subjects with end-stage renal failure studied while off-dialysis. The plasma half-life of imipenem was not affected by the co-administration of cilastatin. 4 The mean plasma half-life of cilastatin varied from 54 min in normals to 798 min in patients with end-stage renal failure. 5 The co-administration of cilastatin resulted in an increase of the urinary concentration and in the urinary recovery of imipenem, the effect being more pronounced in the subjects with normal or only mildly impaired renal function. 6 The plasma clearance of imipenem was decreased when cilastatin was co-administered, possibly due to inhibition of tubular secretion of imipenem. 7 Elimination studies performed during haemodialysis indicated efficient removal of both imipenem and cilastatin during a 4 h session. 8 In view of the important increase in half-life of cilastatin as a function of increasing renal failure, a dosage reduction is proposed in patients with severe renal failure. It is recommended that the maximum dose of imipenem/cilastatin would be limited to either 1000/1000 mg twice daily or 500/500 mg four times daily in patients with a creatinine clearance of less than 15 ml/min. Also, a supplementary dose of imipenem and cilastatin after dialysis is recommended.

MK-571 is a novel leukotriene D4/E4 (LTD4/E4) receptor antagonist. The ability of MK-571 to inhibit LTD4-induced bronchoconstriction was examined both in six healthy volunteers and in six asthmatic subjects in a double-blind, placebo-controlled, randomized crossover study design. LTD4 challenges were performed during a constant infusion with placebo or the active compound. The provocative concentration of LTD4 causing a 35% decrease in SGaw (PC35 SGaw) was 4.8 +/- 0.6 x 10(-5) M (mean +/- SEM) in healthy volunteers and 1.8 +/- 0.7 x 10(-6) M in asthmatic subjects during placebo treatment. Intravenous MK-571 (1,500, 86, or 28 mg) inhibited the LTD4-induced bronchoconstriction completely in healthy volunteers, up to an inhaled concentration of 10(-4) M LTD4. In asthmatic subjects, 28 mg MK-571 caused a significant, at least 44-fold, rightward shift of the dose-response curve to LTD4, whereas 277 mg shifted the dose-response curve at least 84-fold to the right. MK-571 is therefore a potent antagonist of LTD4-induced bronchoconstriction in both normal volunteers and asthmatic patients. MK-571 also caused a small but significant increase in baseline airway caliber in asthmatic patients, suggesting the presence of LTD4 in asthmatic airways and thus providing further support to a role for sulfidopeptide leukotrienes in the pathogenesis of asthma.