Kinetics and pharmacologic effects of three formulations of nifedipine were examined in six healthy young men in a crossover design. Each subject received intravenous nifedipine, 0.015 mg/kg body weight, 20 mg in a capsule, and 20 mg in a slow-release tablet. Changes in heart rate (HR), blood pressure, heart dimensions, and plasma norepinephrine levels (PNE) were examined serially. Plasma concentrations of nifedipine (Cp) and urinary metabolite concentrations were measured by liquid chromatography. After intravenous injection the elimination t1/2 was 1.7 +/- 0.4 hr, systemic clearance was 26.7 +/- 5.4 l/hr, and volume of distribution was 0.8 +/- 0.2 l/kg. After the capsule, Cp rose rapidly, to a maximum concentration (Cmax) of 117 +/- 15 ng/ml at a maximum time (tmax) of 1.4 +/- 0.5 hr. After the sustained release tablet tmax was 4.2 +/- 0.7 hr and Cmax was 26 +/- 10 ng/ml. Nifedipine bioavailability was 56% +/- 25% for the capsule and 52% +/- 13% for the tablet, but there were large interindividual differences. Urinary excretion was 58% +/- 13% 24 hr after intravenous injection, and after 32 hr was 55% +/- 13% after capsules and 32% +/- 8% after tablets. HR increased briefly after intravenous injection and after capsules (15 to 20 bpm), but not significantly after tablets. Diastolic blood pressure (DBP) fell briefly after capsules (8 to 10 mm Hg), but there was a sustained effect after tablets. Cardiac dimensions were unchanged. PNE levels paralleled plasma drug levels in the three experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

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The relevance of the rate of increase in the plasma concentration of nifedipine for the drug's hemodynamic effect was investigated in healthy volunteers. Nifedipine was given intravenously according to two regimens, each designed to produce the same steady-state concentration, but attained gradually (within 5 to 7 hours) with one regimen and rapidly (within 3 minutes) with the other. The mean steady-state concentrations obtained were 31.7 +/- 5.2 (SD) ng/ml and 29.4 +/- 9.8 ng/ml, respectively (not significant). With the gradual regimen, heart rate was unchanged and diastolic blood pressure was lowered gradually by approximately 10 mm Hg. With the rapid regimen, heart rate increased immediately and remained elevated for the duration of the infusion, whereas diastolic blood pressure did not change significantly. At the end of the gradual-rise regimen, the infusion rate was increased tenfold for 10 minutes, promptly resulting in tachycardia and a paradoxical rise in diastolic blood pressure. These divergent hemodynamic responses of the gradual- and rapid-rise regimens could well be related to differences in baroreceptor activation. It is concluded that the hemodynamic response to nifedipine is influenced by the rate of increase of its concentration in plasma.

The pharmacokinetics and hemodynamic effects of nifedipine were studied in patients with liver cirrhosis and in age-matched healthy control subjects. In a randomized order each subject received nifedipine by intravenous infusion (4.5 mg in 45 minutes) and as a tablet (20 mg). After intravenous nifedipine patients had a longer elimination t1/2 (420 +/- 254 vs. 111 +/- 22 minutes; P less than 0.01), a greater volume of distribution (1.29 +/- 0.60 vs. 0.97 +/- 0.42 L/kg), and a lower systemic clearance (233 +/- 109 vs. 588 +/- 140 ml/min; P less than 0.001). Plasma protein binding of nifedipine was lower in the patients (P less than 0.001). After oral nifedipine systemic availability was much higher in patients (90.5% +/- 26.2% vs. 51.1% +/- 17.1%; P less than 0.01) and maximal in patients with a portacaval shunt. Blood pressure decreased and heart rate increased after intravenous nifedipine and these effects could be fitted to plasma concentrations by a sigmoidal model. Maximal effects on heart rate and diastolic blood pressure were not different in liver cirrhosis. When free drug levels were considered, the concentrations corresponding to half the maximal effect were also not different. Blood pressure changes with oral nifedipine were comparable with those after intravenous infusion. We conclude that in patients with liver cirrhosis the pharmacokinetics of nifedipine are considerably altered; dose reduction is recommended when such patients need oral nifedipine.

Key Words: Ro 40-5967--calcium antagonists-hypertension-coronary heart diseaseCalcium antagonists are now widely used for the treatment of angina pectoris and hypertension (for review, see ref. 25). Despite different chemical structures, they all inhibit the slow Ca2+ inward current (7,15). Three main classes of calcium antagonists have been described: dihydropyridines, represented by nifedipine; phenylalkylamines, represented by verapamil; and benzothiazepines, represented by diltiazem. Each of these compounds has its own advantages and disadvantages. Dihydropyridine-type calcium antagonists are very potent peripheral vasodilators and can therefore produce headache, ankle edema, and reflex tachycardia (24). Verapamil has a very potent negative inotropic effect (29) that makes this compound dangerous in patients with a compromised myocardium (8,27). Diltiazem is also negatively inotropic, can produce severe bradycardia, and has also been shown to increase the mortality of patients with prior myocardial infarction and clinical signs of heart failure (30).Finally, all existing calcium antagonists (except the novel dihydropyridine, amlodipine) have a poor bioavailability due to a large first-pass effect and a rather short half-life requiring slow-release formulation for once-a-day dosing. Therefore, the purpose of the calcium antagonist program at F. Hoffmann-La Roche Ltd, Basel was to find a compound with the following properties: (a) high bioavailability; (b) long half-life, allowing once-a-day dosing; (c) lack of biologically relevant negative inotropism; and (d) no strong peripheral vasodilation in normotensive subjects.Ro 40-5967, a novel calcium antagonist, which was selected in animal experiments, fulfilled these criteria. The first clinical studies confirmed the preclinical findings. CHEMISTRYThe chemical name of Ro 40-5967 (see Fig. 1) is (lS,2S)-2-(2-[[3-(2-benzimidazolyl)propyl]methylamino]ethyl)-6-fluoro-1,2,3 ,Ctetrahydro-1 -isopropy1-2-naphthylAddress conespondence and reprint requests to Dr.

The tolerability and hemodynamic and humoral effects of the structurally novel calcium antagonist Ro 40-5967 were investigated in 64 patients with hypertension. In a double-blind, placebo-controlled study, ascending oral doses of 50, 100, 150, or 200 mg were administered once daily for 8 days in a solution. Ro 40-5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia. Blood pressure was dose-dependently reduced over the full 24-hour dosing period with more pronounced effects on day 8 than on day 1. The maximum blood pressure reduction was obtained after 150 mg (supine blood pressure, -34/-25 mm Hg, p less than 0.001). Despite a slight decrease in supine heart rate, cardiac output increased. PQ time was dose-dependently increased and concentration-effect analysis showed that relevant atrioventricular conduction disturbances occur only at concentrations much higher than those required to reduce blood pressure. Changes in catecholamines, plasma renin activity, and aldosterone were small and inconsistent. In conclusion, Ro 40-5967 has a long-lasting antihypertensive effect after once-daily administration.

Under the conditions of this study, food increases the rate and the extent of mefloquine absorption. It is reasonable to recommend that mefloquine be administered with food in travellers receiving chemoprophylaxis and in patients on recovery receiving curative treatment. In acutely ill patients, mefloquine should be taken as soon as possible and administration with or shortly after meals should be attempted as soon as feasible.

The hemodynamic effects and kinetics of nifedipine were examined in four groups of five subjects with different degrees of impaired renal function. In a randomized order, each subject received nifedipine by an intravenous infusion (4.5 mg in 45 minutes) and by mouth as a sustained-release tablet (20 mg). Plasma concentrations of nifedipine and urinary metabolite excretion were measured by liquid chromatography. Heart rate, blood pressure, forearm blood flow, and plasma norepinephrine levels were examined serially. After intravenous nifedipine infusion, the elimination t1/2 was 106 +/- 24 minutes in controls and increased gradually across the groups to 230 +/- 94 minutes in the group with severe renal impairment. In these same groups, the volume of distribution at steady state was 0.78 +/- 0.23 and 1.47 +/- 0.24 L/kg, but total systemic clearance did not differ. Plasma protein binding decreased from 96.0% +/- 0.5% in controls to 93.5% +/- 0.4% in severe renal insufficiency. Except for systemic clearance, kinetics were closely related to creatinine clearance, as was the urinary excretion of the main nifedipine metabolite. Except for systemic availability, which tended to decrease, the kinetics of nifedipine tablets were not influenced by the degree of renal failure. Hemodynamic effects after intravenous nifedipine could be fit to plasma concentrations under a sigmoidal model. When compared with control values, the maximal effect on diastolic blood pressure was more than doubled in severe renal failure. The inverse correlation between maximal effect on diastolic blood pressure and creatinine clearance (r = -0.68) was independent of pretreatment values. Neither free drug levels corresponding to 50% of the maximal effect on diastolic blood pressure nor the slope of the concentration-effect curve was influenced by the degree of renal impairment. The maximal effect on forearm blood flow tended to increase in renal failure, whereas the effect on heart rate was unchanged. Blood pressure changes after oral nifedipine were of the order of those after intravenous infusion. We conclude that, although nifedipine kinetics differ in patients with renal failure, these changes do not explain the greater blood pressure lowering effect.