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Heart failure is characterized both by an activation of the endothelin system and an increased vasoconstrictor contractile response to the peptide. Given its pharmacological profile, it is likely that endothelin (ET-1) plays a deleterious role in the development of heart failure, and that blockers of the endothelin system are beneficial in this disease. Indeed, in rats with heart failure, ETA and dual ETA-ETB receptor antagonists reduce arterial pressure as well as left ventricular end diastolic pressure. The same antagonists also prevent the degradation of left ventricular function, as evidenced by the increased left ventricular fractional shortening and wall thickening. ETA and ETA-ETB antagonists also reduce LV dilatation and LV fibrosis, but do not affect LV hypertrophy. Moreover, comparison between selective ETA and combined ETA-ETB antagonists reveal no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. However, only combined ETA-ETB antagonists significantly decreased heart rate. ETB antagonists alone do not affect blood pressure or LV hemodynamics, but reduce LV fibrosis. With regard to survival, we have shown that long term treatment with the dual ETA-ETB antagonist bosentan increased survival to the same extent as an angiotensin converting enzyme inhibitor. However, the effect of selective ETA antagonists on survival is more controversial, since we found that the non-peptide ETA antagonists LU 135252 did not affect survival of rats with myocardial infarction, while others have shown that the peptide ETA antagonist BQ-123 increased survival in the same model. These conflicting data regarding the efficacy of selective ETA vs dual ETA-ETB blockade points out the need for controlled long term studies comparing the effects of theses two pharmacological approaches on survival. [ABSTRACT FROM AUTHOR]

The effects of nicardipine, 20 mg, three times daily, nicardipine slow release, 30 mg, twice daily and a placebo on brachial and carotid arteries diameters and flows have been investigated by the pulsed Doppler technique during a single blind and cross-over study performed in six healthy volunteers. Simultaneously, nicardipine plasma levels and relative bioavailability were determined. Nicardipine significantly increased brachial and carotid arteries diameters (by 16 and 10% respectively) and flows (by 60 and 35% respectively). These effects peaked after 4 h and lasted no longer than 6 h. Forearm vascular resistance was significantly decreased. Hence nicardipine dilated both large and small arteries. Nicardipine slow release elicited the same effects on brachial and carotid arteries diameters and flows as nicardipine. These effects peaked at 6 h and lasted up to 10 h. Although the profiles of the pharmacodynamic effects and of the kinetics of nicardipine were almost parallel in each individual after administration of both nicardipine formulations, there was no correlation between the nicardipine plasma relative bioavailability and its effects on brachial and carotid arteries blood flows when considering all subjects together. [ABSTRACT FROM AUTHOR]

1 The pharmacological effects and the pharmacokinetics of betaxolol (SL 75212), a new beta-adrenoceptor blocking agent, were compared with those of propranolol and a placebo in a double-blind trial involving six healthy volunteers. 2 Heart rate (HR), myocardial contractile force (MCF), systolic blood pressure (SBP) and peak expiratory flow rate (PEFR) were measured at rest and during vigorous exercise before and at intervals up to 25 h after oral administration of the drugs. In addition, plasma renin activity (PRA) at rest and blood levels of betaxolol and propranolol were determined. 3. Betaxolol proved to be a potent and long-lasting beta-adrenoceptor blocking drug, devoid of intrinsic beta-sympathomimetic activity. Its beta-adrenoceptor blocking action was shown to four-fold that of propranolol at the cardiac and renal levels and to last at least 25 h after drug intake. 4 The peak blood level of betaxolol was reached 2 to 4 hr after its administration, the first-pass loss is likely to be low and the half- life is 12.3 h. These pharmacokinetic data are perfectly consistent with the long duration of the pharmacological effects of betaxolol in man. [ABSTRACT FROM AUTHOR]

This study was undertaken to investigate the day-to-day pharmacokinetic variability of 5-fluorouracil (5FU) given as a continuous i.v. infusion concomitantly with cisplatin. Ten lung cancer patients were investigated during the first course of chemotherapy. All patients had advanced, previously untreated, inoperable non-small-cell lung cancer. They received continuous infusions of cisplatin given at 100 mg/m2 over 5 days and of 5FU given at 1 g/m2 daily from day 2 to day 5. Both drugs were infused i.v. for 24 h/day at a constant rate with a volumetric pump. Blood samples were drawn from day 2 to day 5, every 4 h from 8 a.m. to 8 p.m. and every 2 h during the night (8 p.m. to 8 a.m.). Plasma 5FU and FBAL concentrations were determined simultaneously by gas chromatography-mass spectrometry. Plasma 5FU concentrations varied widely over the 4-day treatment course for each patient. Despite continuous constant-rate 5FU administration, plasma 5FU concentrations were significantly lower between 8 a.m. and 8 p.m. than during the night. Mean plasma concentrations of 5FU and FBAL increased significantly from the 1st day (0.42 and 1.19 micrograms/ml for 5FU and FBAL, respectively) to the 4th day of 5FU infusion (0.67 and 1.78 micrograms/ml for 5FU and FBAL, respectively). Further study is warranted to elucidate the mechanisms of the observed increase in plasma 5FU concentrations as well as its relationship with cisplatin coadministration and to assess the clinical relevance of this plasma 5FU accumulation. [ABSTRACT FROM AUTHOR]