Pharmacokinetic and pharmacodynamic interaction of single doses of valsartan and atenolol.

OBJECTIVE: Valsartan (V), a specific inhibitor of the angiotensin II receptor subtype, AT1, has been developed for treatment of hypertension. Combination therapy with a beta-adrenoceptor blocking agent might be considered in cases with insufficient efficacy of V alone. Therefore, an interaction trial was performed to evaluate the effects of co-administration of V on the pharmacokinetics of atenolol (A), and vice versa, and to monitor the pharmacodynamic response of plasma angiotensin II (ANG II) concentrations and plasma renin activity (PRA), as well as of heart rate and blood pressure, under resting and exercise conditions. METHODS: Twelve healthy, normotensive, male volunteers aged 23-46 years were treated with single doses of either 160 mg V or 100 mg A alone, or with both drugs in combination (V + A) according to a three-period crossover design. Plasma concentrations of V and A were determined using HPLC with fluorimetric and UV detection, respectively, and concentration-time profiles were established over 24 h. Plasma ANG II concentrations and PRA were monitored using specific radioimmunoassays. Heart rate and blood pressure were measured at rest and during exercise on a cycle ergometer at a workload of 2.5 W/kg-1. RESULTS: For V, mean AUC and Cmax were slightly higher when A was co-administered, the ratios of log transformed values being 1.13 and 1.22 for AUC(0-inf) and Cmax, respectively. For A, mean AUC and Cmax were slightly lower when the drug was given in combination with V. The ratios of log-transformed values in this case were 0.90 and 0.92, respectively. The sharp increase in plasma ANG II concentrations and PRA, induced by administration of V, was significantly attenuated when the drug was combined with A. In the first 12 h after drug intake, heart rate and systolic blood pressure at rest were significantly decreased when V and A were co-administered compared with treatment with V alone. V given alone did not influence heart rate or systolic blood pressure during exercise, whereas A alone and V + A led to a significant reduction in those variables. Adverse experiences reported after A and V + A could be explained by the high degree of beta-adrenoceptor blockade resulting from the administration of A. CONCLUSIONS: Co-administration of single doses of V and A does not modify the pharmacokinetics of the two drugs to a clinically relevant degree. With respect to pharmacodynamics, a single dose of A attenuates the increase in plasma ANG II and PRA in response to a single dose of V, and V has no effect on the hemodynamic response to exercise. The combined treatment with single doses of 160 mg V and 100 mg A has some additive effects on resting blood pressure in healthy, normotensive subjects.

Pharmacokinetic and pharmacodynamic interaction of single oral doses of valsartan and furosemide.

OBJECTIVE: Pharmacokinetic and pharmacodynamic interactions between single oral doses of valsartan (160 mg) and furosemide (40 mg) were investigated in an open, randomized, three-period crossover study in twelve healthy male subjects. METHODS: A washout period of one week was observed between treatments. Pharmacokinetic measurements included plasma concentrations of valsartan and furosemide, and urinary excretion of the latter. Plasma renin activity (PRA), plasma angiotensin II, blood pressure, heart rate, as well as urinary water and electrolyte excretion were determined as pharmacodynamic variables. Efficiency of furosemide for sodium and water excretion was calculated as the ratio of the measured pharmacodynamic effect and the urinary excretion of furosemide. RESULTS: Simultaneous administration of valsartan and furosemide did not modify the pharmacokinetics of valsartan. In contrast, Cmax, AUC, and urinary excretion of furosemide were significantly reduced following simultaneous treatment with valsartan. Inter- and intra-individual variability of the pharmacokinetic variables was high for both furosemide and valsartan. PRA and angiotensin II increased, and blood pressure decreased after all treatments. These effects were most pronounced after the combined treatment. The decrease in blood pressure was additive, at most, while the increase in PRA and angiotensin II appeared to exceed simple addition. No relevant effects on heart rate were observed. The diuretic effect of furosemide, as assessed by urinary water and electrolyte excretion, was unchanged after co-administration of valsartan, despite the lower bioavailability of furosemide after the combined treatment.

CGP 36742: the first orally active GABAB blocker improves the cognitive performance of mice, rats, and rhesus monkeys.

The learning capacity of experimental animals in cognitive tests can be improved by blockade of the GABAB receptors. After treatment with the GABAB antagonist CGP 36742, mice performed better in a passive-avoidance test; rats did likewise in a partner-recognition test, and rhesus monkeys also in a "conditional spatial color" task. The effects demonstrated in these three different species and covering diverse manifestations of learning and memory give reason to hope that this new active principle may prove therapeutically useful.

Antialdosterones: incidence and prevention of sexual side effects.

The use of spironolactone in the treatment of hypertension has been limited by the occurrence of sexual side effects, mainly menstrual disturbances in women and gynaecomastia in men. In order to minimize this limitation on the use of an effective potassium-sparing antihypertensive agent, two strategies can be proposed: (1) A decrease in the daily dose of spironolactone. In 182 patients with essential hypertension treated with spironolactone alone for a mean follow-up period of 23 months, daily doses of 75-100 mg were as effective on blood pressure as doses of 150-300 mg. In contrast, the development of gynaecomastia--91 cases among 699 men--was dose-related in 6.9% (50 mg/day) to 52.2% (150 mg or more/day) of the cases. (2) An improvement in the receptor-binding specificity of spironolactone. Three 9 alpha, 11 alpha-epoxy derivatives have been characterized in vitro in rats and in rabbits. They exhibited a 3- to 10-fold decrease of the antiandrogenic and progestagenic effect, compared with spironolactone. In humans, one of these derivatives counteracted the fall in urinary Na/K ratio induced by 9 alpha-fluorohydrocortisone at a 25 mg dose.

Spontaneous motor activity in healthy volunteers after single doses of haloperidol.

Video recordings of the spontaneous motor activity of 6 healthy volunteers after treatment with 0.75 mg haloperidol i.v., or placebo, were transcribed into a time-series protocol of motor behaviour. Characteristic changes seen after the injection of haloperidol consisted in a reduction of the motility of the extremities and prolongation of the phases of both movement and immobility of the head. The tested dose of haloperidol induced a distinct rise in serum prolactin and sedation, but had no effects on the pharmaco-EEG or on the critical flicker-fusion frequency. Analysis of the motor phenomena evoked by neuroleptics in healthy persons and in patients may help, on the other hand, to establish correlations with the motor effects observable in preclinical investigations in animals and might also contribute towards the elucidation of the extrapyramidal side-effects of these drugs.

Examination of the fundus of the eye of renal hypertensive dogs.

Only 1 of 7 dogs with long-standing renovascular hypertension showed clear changes in the fundus. No distinct retinopathy was seen in the others. Ophthalmoscopy alone is thus of limited value in assessing the progress of benign hypertension in the dog.