MK-208, a novel histamine H2-receptor inhibitor with prolonged antisecretory effect.

MK-208 is a guanidinothiazole derivative reported to be a potent H2 blocker devoid of antiandrogenic activity. Its potency and duration of action, in inhibiting pentagastrin-stimulated gastric secretion in man, was evaluated in this double-blind, five-way cross-over trial. Ten healthy male volunteers received single oral doses of placebo, cimetidine 300 mg, and MK-208 5, 10, and 20 mg. A continuous intravenous infusion of pentagastrin (1 microgram/kg/hr) was given 2-4 and 5-7 hr after each oral dose. Gastric contents were continuously aspirated and volumes and acid content determined every 30 min. Plasma levels for MK-208 and cimetidine were monitored over the 7 hr of the study. Cimetidine and all doses of MK-208 significantly inhibited gastric acid secretion in the initial 2-4 hr; however, 10- and 20-mg doses of MK-208 were significantly more potent than cimetidine. In the 5- to 7-hr period, cimetidine 300 mg was not different from placebo, while MK-208 in all doses studied continued to significantly suppress gastric secretion. Plasma levels for MK-208 showed dose-related increments. The results suggest that: (1) MK-208 is a potent inhibitor of gastric secretion in man, in a dose-related fashion at the doses tested; (2) under the study conditions, 5 mg MK-208 was equipotent to 300 mg cimetidine but with greater duration of action, extending at least 7 hr; and (3) these data suggest a future role for this new agent in therapy for acid-peptic disease in man.

Timolol and propranolol: bioavailability, plasma concentrations, and beta blockade.

Timolol, like propranolol, is a nonselective beta-adrenergic blocker, but it is much less lipid soluble and is formulated as a single enantiomer rather than a racemic mixture. We examined the effects of such differences on bioavailability, systemic clearance, and pharmacologic response. Ten healthy subjects received placebo, 0.2 mg/kg IV propranolol, 3.2 mg/kg oral propranolol, 0.025 mg/kg IV timolol, and 0.4 mg/kg oral timolol in double-blind, randomized crossover fashion. Plasma concentrations of total drug were monitored up to 8 hr, while responses to submaximal exercise were measured at 0, 2, and 6 hr. Timolol had greater bioavailability (F = 0.61 +/- 0.06(SEM) and 0.32 +/- 0.04) and lower systemic clearance (463 +/- 74 ml kg-1 hr-1 and 1040 +/- 120 ml kg-1 hr-1) than propranolol. Half-lifes were of the same order (2.7 and 2.9 hr). There was a marginal correlation between areas under the intravenous and oral plasma concentration-time curves for timolol (r = 0.66, P = 0.054), but none for propranolol (r = 0.48, P NS). There were also correlations of the response (percent reduction in heart rate) to oral and intravenous timolol at 2 hr (r = 0.72, P less than 0.05) and 6 hr (r = 0.84, P less than 0.01) hr, but none between responses to oral and intravenous propranolol. Finally, the response to oral timolol was related to the area under its plasma concentration-time curve, whereas that to propranolol was not. We conclude that the physicochemical properties of timolol lead to greater bioavailability. Pharmacologic response to an oral dose of timolol, unlike that to propranolol, can be predicted from the response to an intravenous dose and reflects its plasma concentration.

Effects of enalapril, a new converting enzyme inhibitor, in hypertension.

The new angiotensin converting enzyme inhibitor enalapril maleate was given in single oral doses of 2.5, 5, and 10 mg to 11 hospitalized patients with uncomplicated essential hypertension who were on a 150-mEq sodium diet. All doses of enalapril induced reduction of mean seated diastolic blood pressure (SDBP). The magnitude of the initial SDBP reduction was not dose related, but the duration of effect was longer (greater than 12 hr) after the 5 and 10 mg. After dosing, mean plasma angiotensin converting enzyme activity (ACE) and aldosterone concentration (PAC) fell, while plasma renin activity (PRA) rose. Serum concentrations of the active diacid from of enalapril increased linearly with dosage; ACE was inhibited maximally at concentrations above 10 ng/ml. During repeated dosing in the outpatient trial there was attenuation of the antihypertensive effect (12 to 24 hr after dosing) in eight of 10 patients. Despite dose increases only two patients achieved SDBP control (less than or equal to 90 mm Hg). In the five patients in whom 50 mg/day hydrochlorothiazide was added near the end of the trail mean SDBP was further reduced. Enalapril was well tolerated. Further studies of the drug, especially in combination with diuretic, are needed.

Effect of antacids on the bioavailability of diflunisal in the fasting and postprandial states.

Diflunisal is long-acting salicylate derivative. We examined the effect of single concomitant doses of three antacids on diflunisal bioavailability under fasting or fed conditions (30 min after finishing a standard meal). With the use of an open, randomized, and balanced design, one 250-mg diflunisal tablet was given to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area uiven to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area uiven to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area under the time curve (AUC), peak plasma concentrations, and 0-to 96-hr urinary excretion were determined. Food (alone) decreased peak plasma concentrations by 16% (P less than 0.05) but did not affect AUC or urinary excretion. Under fasting conditions, aluminum hydroxide reduced AUC by 26% (P less than 0.01), peak plasma concentrations by 46% (P less than 0.01), and urinary excretion by 14% (P less than 0.05). Magenisuum hydroxide suspension (in the fasting state) increased the early plasma concentrations (by 130% at 0.5 hr and 64% at 1 hr, P less than 0.05) and increased AUC by 10% (P less than 0.05) but had no effect on urinary excretion. In the fed state neither aluminum hydroxide nor the aluminum hydroxide/magnesium hydroxide mixture had any detectable effect.

Pharmacology of enantiomers and (-) p-OH metabolite of indacrinone.

Indacrinone, a racemic mixture, is a loop-blocking diuretic with effects on uric acid elimination that differ from those of furosemide. A series of studies in healthy men was undertaken to characterize the pharmacologic activity of the positive (+) and negative (-) enantiomers (E) of indacrinone and its (-) p-OH metabolite, (-) MET. All subjects were on sodium- and potassium-controlled diet; each experiment was similar in design and included placebo and positive controls. Oral (-)E and (-)MET exerted dose-related natriuretic and diuretic effects; intravenous doses of (-)E were more effective than (-)MET. The effects of (-)E and (-)MET on serum uric acid were the same as those reported with indacrinone. After (-)E, both (-)E and generated (-)MET appeared to contribute to the natriuresis. (+)E induced dose-related decreases in serum uric acid up to 24 hr after dosage; at the higher doses of (+)E, the hypouricemic effects were of the order of those after 500 mg of probenecid. Thus, indacrinone is a novel loop diuretic with enantiomers and a (-)MET, each of which has a different pharmacologic profile.

Comparison of oral indacrinone with furosemide.

The oral dose response and time course of action of indacrinone was compared with that of furosemide in six healthy men on a sodium and potassium-controlled diet. The single doses were 5, 10, 20, 40, and 80 mg indacrinone and 20, 40, and 80 mg furosemide. Diuretic, natriuretic, and kaliuretic effects revealed that indacrinone was more potent, had a longer duration of action, and induced a greater sodium for equivalent potassium loss during its period of peak activity than furosemide. During the 8 hr after drug, all doses of indacrinone decreased serum uric acid levels and increased uric acid clearance while furosemide generally increased serum uric acid and decreased uric acid clearance. After 24 hr, serum uric acid and uric acid clearance were the same for the two drugs. A rise in plasma renin activity was observed 2 hr after an 80-mg dose of furosemide but not after indacrinone.