Bosentan and the endothelin system in congestive heart failure.

The endothelin system appears to play an important role in the pathophysiology of congestive heart failure (CHF). Endothelin receptor antagonists represent a novel class of agents that are being evaluated for their potential benefits in treating various cardiovascular disorders. Bosentan is an orally active endothelin receptor antagonist that has been studied for the treatment of CHF. Early clinical experience with bosentan has confirmed some benefits on hemodynamic parameters in patients with CHF. Its role in slowing the progression of the disease and improving survival remains to be elucidated.

The efficacy and safety of mibefradil in subgroups of patients with chronic stable angina pectoris.

The pool of controlled clinical studies on mibefradil, a new selective T-type calcium channel blocker, for the treatment of chronic stable angina pectoris was analysed to determine the effects in subgroups of patients defined by age, gender, body weight and common co-existing conditions. Total exercise tolerance test duration increased similarity in all subgroups, both at 50 mg (range 8.9-17.3%; n = 383) and 100 mg mibefradil (range 23.6-30.8%; n = 235). The increases in time to onset of angina and 1 mm ST-segment depression were similarly comparable. Safety and tolerability was similar to placebo for subgroups at 50 mg, but the incidence of adverse events was slightly higher in females, older, and lower weight patients at the 100 mg dose, particularly in reported leg oedema (7.9% in females vs 1.0% in males and 5.1% in older vs 0% in younger patients). Mibefradil proved a safe, well tolerated, and effective antianginal agent that can be used regardless of demographic factors or of frequently coexisting clinical conditions.

Anti-anginal and anti-ischemic effects of mibefradil, a new T-type calcium channel antagonist.

Mibefradil is the first of a new class of calcium antagonists (CAs), the tetralol derivatives, that selectively blocks the T-type calcium channel. The anti-anginal and anti-ischemic efficacy of mibefradil in patients with chronic stable angina pectoris was established in five placebo-controlled trials (2 monotherapy trials, 3 trials with background beta-blocker or long-acting nitrate therapy). At the recommended doses of 50 and 100 mg, mibefradil treatment was associated with a significant dose-related increase in exercise test variables regardless of demographic subpopulation or background therapy. Significant reductions in weekly anginal attacks, silent ischemic parameters, heart rate (HR) and rate-pressure product were also observed. Two active-controlled trials compared mibefradil 100 mg with amlodipine 10 mg or diltiazem SR 120 mg b.i.d., respectively. Patients receiving mibefradil showed significantly larger improvements than did those treated with amlodipine and similar improvements as those treated with diltiazem SR in all variables measured. In both studies, treatment with mibefradil was associated with a greater decrease in HR and rate-pressure product. Mibefradil was found to be well tolerated and safe; this held true for patients on chronic anti-anginal background therapy. The overall incidences of adverse events and premature withdrawals were only slightly higher than those of placebo-treated patients. Asymptomatic sinus bradycardia and first-degree atrioventricular block were the most frequently occurring mibefradil dose-related ECG changes. Mibefradil was better tolerated than amlodipine (mainly with regard to leg edema) and similarly well tolerated as diltiazem CD.

The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators.

BACKGROUND: Endothelin is a powerful vasoconstrictor peptide derived from the endothelium. We evaluated the contribution of endothelin to blood-pressure regulation in patients with essential hypertension by studying the effect of an endothelin-receptor antagonist, bosentan. METHODS: We studied 293 patients with mild-to-moderate essential hypertension. After a placebo run-in period of four to six weeks, patients were randomly assigned to receive one of four oral doses of bosentan (100, 500, or 1000 mg once daily or 1000 mg twice daily), placebo, or the angiotensin-converting-enzyme inhibitor enalapril (20 mg once daily) for four weeks. Blood pressure was measured before and after treatment. RESULTS: As compared with placebo, bosentan resulted in a significant reduction in diastolic pressure with a daily dose of 500 or 2000 mg (an absolute reduction of 5.7 mm Hg at each dose), which was similar to the reduction with enalapril (5.8 mm Hg). There were no significant changes in heart rate. Bosentan did not result in activation of the sympathetic nervous system (as determined by measurement of the plasma norepinephrine level) or the renin-angiotensin system (as determined by measurements of plasma renin activity and angiotensin II levels). CONCLUSIONS: An endothelin-receptor antagonist, bosentan, significantly lowered blood pressure in patients with essential hypertension, suggesting that endothelin may contribute to elevated blood pressure in such patients. The favorable effect of treatment with bosentan on blood pressure occurred without reflexive neurohormonal activation.

Adding the new calcium antagonist mibefradil to patients receiving long-term beta-blocker therapy results in improved antianginal and antiischemic efficacy.

OBJECTIVE: The objective of this study was to evaluate the efficacy, tolerability, and safety of mibefradil, a new selective T-type calcium channel blocker, in patients with chronic stable angina pectoris receiving concomitant beta-blocker therapy. DESIGN: This was a multicenter, double-blind, placebo-controlled study. METHODS: Ninety-five patients receiving a stable dose of beta-blockers, which was not changed for the purpose of the study, were administered either 50 mg mibefradil once daily for 2 weeks, then 100 mg once daily for 2 weeks, or matching placebo. Efficacy was evaluated by treadmill exercise tolerance testing 24 hours after dose and by diary registration of anginal episodes and nitroglycerin consumption. RESULTS: Two weeks of treatment with 50 mg mibefradil resulted in a significant increase in symptom-limited exercise duration and a significant delay in the onset of persistent 1 mm ST-segment depression (placebo-corrected treatment effect: 23.2 and 51.7 seconds, respectively). Treatment with the 100 mg dose for 2 additional weeks resulted in a larger improvement in treadmill exercise tolerance testing duration and onset of ischemia (placebo-corrected treatment effect: 52.7 and 75.8 seconds, respectively). In addition, a significant decrease in weekly anginal episodes was observed with the 100 mg dose of mibefradil compared with the effect in the placebo group (-53% vs - 12%, p = 0.037). CONCLUSIONS: The combined treatment of mibefradil and beta-blockers was well tolerated, and the overall incidence of adverse events was no different from that with beta-blockers alone. The results indicate that adding mibefradil to chronic beta-blocker treatment is associated with significant improvement in efficacy, which is not achieved at the expense of tolerability.

New developments in drug therapy of hypertension.

The explosion of new knowledge about the complex mechanisms mediating high blood pressure is providing new targets for drug therapy of hypertension and other cardiovascular disorders. This article reviews the current status of several new approaches in the management of hypertension, including vasopressin antagonists, natriuretic peptide clearance inhibitors, endothelin antagonists, renin inhibitors, angiotensin receptor antagonists, and selective T-type calcium ion channel antagonists.

Safety of mibefradil, a new once-a-day, selective T-type calcium channel antagonist.

The safety and tolerability of mibefradil, a selective T-type calcium channel antagonist, were evaluated in 3,430 patients with essential hypertension and chronic stable angina pectoris treated in 15 double-blind placebo and active-controlled clinical trials and 2 open-label, long-term safety studies. Of these patients, 2,636 were treated with the recommended doses of mibefradil (50 and 100 mg) and form the basis of this report. With the 50-mg dose of mibefradil, the incidence of each adverse event was similar to, or lower than, that observed in the placebo-treated patients. Treatment with the 100-mg dose was associated with a slightly higher incidence compared to placebo of dizziness (2.1% vs 1.8%), leg edema (3.5% vs 1.4%), fatigue (2.1% vs 1.4%), and lightheadedness (2.1% vs 0.4%). The incidence of headache (4.6%) and angina pectoris (1.1%) was more frequent in patients treated with placebo. In active-controlled trials, a lower incidence of pedal edema (5.1%) was observed with mibefradil compared to amlodipine (25.7%), diltiazem SR/CD (9.4%), or nifedipine SR/GITS (17.4%). Overall, mibefradil was better tolerated than amlodipine and nifedipine SR/GITS and was as well tolerated as diltiazem SR/CD. Rates of premature discontinuation due to clinically adverse experiences with the 50- and 100-mg doses were 2.5% and 3.5%, respectively, compared with placebo (3.5%). No consistent pattern of laboratory adverse experiences were observed for mibefradil. Sinus bradycardia (heart rate <45 beats/minute) and first-degree atrioventricular block were the only relevant treatment-emergent electrocardiographic changes that occurred more frequently with mibefradil than with placebo. No evidence of first-dose effects was observed in mibefradil-treated patients, and withdrawal effects were not observed in clinical trials. There were no clinically important differences in safety profiles in the demographic subgroups for age, gender, or race. The results of this comprehensive safety analysis indicate that treatment with the recommended doses of mibefradil is well tolerated and safe.

Reproducibility of angiotensin converting enzyme inhibitor induced cough: a double-blind randomised study.

1. The reproducibility of angiotensin converting enzyme inhibitor induced cough was examined in a double-blind cross over study in patients previously shown to have exhibited this side effect. 2. Ninety-seven patients who had experienced angiotensin converting enzyme inhibitor cough within the last 2 years were challenged with enalapril 20 mg daily for 4 weeks to establish eligibility. Eighty-eight of 97 (91%) patients experienced a repeat of their cough symptoms. Sixty-four patients entered the double-blind part of the study where they were treated with enalapril 20 mg and a renin inhibitor for up to 4 weeks in random order. These periods were separated by a minimum 4 week placebo wash out. 3. Of 59 evaluable patients who received enalapril a second time, 37 (62.7%) experienced cough again. Of 62 patients on the renin inhibitor 16 (25.8%) experienced cough, however as it was not equi-efficacious to enalapril no valid comparison could be made. 4. Angiotensin converting enzyme inhibitor cough is not reproducible within patients, as other factors are involved in the aetiology. Objective testing with blinded assessment together with symptom reporting, would give a more accurate measure of the incidence, and mechanism of this side effect.

Time dependency of the antihypertensive efficacy of the new renin inhibitor Ro 42-5892.

The objective of this study was to assess the antihypertensive efficacy of the new renin inhibitor Ro 42-5892 in patients with essential hypertension treated with 100 mg once daily orally. This was a double-blind, placebo-controlled, parallel group trial. After three weeks of wash-out and one week of single-blind placebo run-in periods, 25 patients with mild to moderate essential hypertension (sitting DBP between 95 and 114 mmHg) were randomised to receive either placebo (n = 12) or 100 mg of Ro 42-5892 (n = 13) once daily for eight days. On the eighth day, four hours after the oral administration, patients were randomised to receive intravenously either placebo or 10 mg of Ro 42-5892. BP and heart rate were measured repeatedly (hourly for eight hours and at the 24th hour post-dose) on the first and last days of active treatment. Compared with the placebo group, a slight decrease in sitting DBP was observed after the first dose in the Ro 42-5892 group. The decrease in sitting DBP reached significant levels only at six to eight hours post-dosing. In contrast, on the last day of active treatment, a larger, faster and longer decrease in sitting DBP was observed in the Ro 42-5892 group. Thus, the peak effect (-8.9 +/- 1.9 vs. -2.9 +/- 1.3 mmHg, P < 0.01) was reached 1.5 hours post-dosing and the trough effect (24 hours post-dosing) was slightly but significantly lower when compared with the placebo group (-3.0 +/- 1.0 vs -0.3 +/- 0.8 mmHg, P < 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of zinc deficiency on lipid peroxidation status and infarct size in rat hearts.

The objective of this study was to investigate the effect of dietary zinc on endogenous production of lipid peroxides, and on myocardial infarct size in rats. Male rats were fed a zinc-deficient diet containing 4 ppm zinc, or a standard diet containing 60 ppm zinc. After 3 weeks of diet, half of the animals underwent occlusion of the left coronary artery. The remaining animals underwent sham operation without occlusion. Forty-eight hours later, the hearts were sampled and lipid peroxide levels and infarct size were evaluated. Coronary occlusion was associated with an increase in cardiac lipid peroxide levels which were more pronounced in the zinc deficient group. However, infarct size appeared to be independent from zinc deficiency, despite the free radical-mediated lipid peroxide augmentation reported here. The pharmacological limitation of infarct size in rats with permanent coronary occlusion is discussed.

Effects of an orally active renin inhibitor, Ro 42-5892, in patients with essential hypertension.

Ro 42-5892 (Ro) is a new renin inhibitor that has been shown to be an orally effective compound in primates and in the first exploratory studies in humans. However, no firm conclusions could be drawn from the human trials and therefore the present study was designed to evaluate the antihypertensive efficacy of the compound in a double-blind, placebo-controlled trial. After a 3 week wash-out period and a 1 week single-blind placebo period, 24 patients were randomized to receive once daily orally either placebo or 600 mg Ro 42-5892 (N = 12/group) for 8 days. On the last day of treatment, an intravenous infusion of placebo or 100 mg Ro was given in a double-blind fashion, 4 h after the oral administration. Blood pressure (BP), heart rate (HR), plasma renin activity (PRA), immunoreactive renin (IRR), and plasma Ro levels were measured repeatedly on the first and last days of treatment. After the first oral intake of Ro, sitting diastolic BP dropped significantly from 30 min to 24 h post-dose when compared to placebo (-10.2 +/- 1.2 mm Hg v - 0.4 +/- 2.0 mm Hg at peak and -6.9 +/- 1.8 mm Hg v 1.7 +/- 0.9 mm Hg at trough; P < .01 respectively). The trough effects of Ro and placebo after the 7th and 8th doses were -5.1 +/- 1.6 mm Hg v -0.2 +/- 1.0 mm Hg; P < .05 and -5.4 +/- 1.3 mm Hg v 2.3 +/- 1.2 mm Hg; P < .01, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertrophy induced alteration of action potential and effects of the inhibition of angiotensin converting enzyme by perindopril in infarcted rat hearts.

Not much is known about alterations in electrical activity in the healthy part of a heart made hypertrophic as a result of local ischaemia, yet such an investigation might allow us to predict the stages leading to cardiac failure and so aid its prevention. We therefore studied the electrophysiological changes which occurred in rats in which ligation of the left coronary artery had produced hypertrophy of the non-infarcted myocardium. One month after the intervention the overall degree of hypertrophy of the ventricles reached 15.3%. This was accompanied in the healthy part of the left ventricle (septum) by altered electrical activity consisting of a lengthening of the action potentials at 25, 50, 75 and 90% of repolarisation. Myocardial hypertrophy was absent after chronic treatment of the animals with perindopril, an angiotensin converting enzyme inhibitor, given orally at 2 mg.kg-1 body weight, and the electrophysiological alterations induced by the infarct were partially eliminated: phase 2 of the myocardial action potential was shortened and phase 3 completely restored. We postulate that angiotensin may have a direct effect on the cardiac cell.

[Toxicity of oxygen free radicals in reperfusion. Myth or reality?]. / Toxicité des radicaux libres de l'oxygène au cours de la reperfusion. Mythe ou réalité?

It would appear from numerous experimental data that an overproduction of oxygen free radicals may occur during reperfusion of an ischaemic myocardium. However, this has not yet been confirmed experimentally owing to the lack of a method for direct measurement of these radicals. In this paper, the topic is reviewed, with emphasis on the problems associated with the study of oxygen free radicals in biological tissues. In a second part, spin-trapping studies conducted on the isolated rat heart are reported. They tend to confirm the presence of disturbances in oxygen-derived free radicals occurring as early as the first minute of reperfusion.

Ability of N-tert-butyl alpha phenylnitrone (PBN) to be used in isolated perfused heart spin trapping experiments: preliminary studies.

The aim of this study was to investigate the possibility of oxygen-free radical spin trapping with PBN, in models of isolated perfused hearts. Preliminary studies reported here demonstrate that (i) PBN may be precisely measured with UV spectroscopy, (ii) commercially available PBN does not show any ESR signal, (iii) PBN does not trap significant amounts of free radicals in a perfusion medium oxygenated for at least 3 h, and (iv) when added at 15 or 56 mM in the perfusion medium, PBN is a highly toxic compound, whereas no toxic effect was observed with 3mM-containing perfusate.

[Metabolic disorders generated by myocardial ischemia: implication of oxygen free radicals]. / Perturbations métaboliques engendrées par l'ischémie myocardique: implication des radicaux libres de l'oxygène.

A process of myocardial ischemia is developed when there is an imbalance between the tissues needs and the supply in coronary arterial blood. This imbalance causes rapidly a cascade of biochemical and metabolic events which, when the ischemia is particularly severe and extended, may lead, at the end, to tissue necrosis. However, the factors responsible for cellular death are still not precisely known and it seems, from the recent experimental results, that the exacerbated production of free radicals derived from oxygen could be one of the elements implicated in the initiation of the necrotic process. This article proposes to describe the various disturbances of the myocardial metabolism induced by the ischemic process and to consider the eventual role of the oxygen free radicals in the development of these alterations.

[Perspectives of in-situ measuring of oxygen free radicals]. / Perspectives de mesure in situ des radicaux libres de l'oxygène.

It has been proposed that the oxygen free radicals (superoxide and hydroxyl radicals), could be partially responsible for the appearance of cellular alterations in the course of various pathological situations. It has not been possible to measure these kinds of radicals because of their very short life span and the very low concentrations present in the tissues. The paramagnetic electronic resonance (PER), of which the principle lies on the specific detection of free radicals, proves, however, to be ill suited for the measurement of the oxygen free radicals, because of an insufficient sensitivity. This sensitivity may be increased with the "spin trapping" technique, the principle of which is to use a trapping component able to be associated to the unstable radical to form a stable product, which accumulates then in the tissues up to a concentration higher than the detection threshold in PER.