Interventions for preventing cardiomyopathy due to anthracyclines: a Bayesian network meta-analysis.

Background: The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown. Methods: We conducted a systematic review of randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in adult cancer patients. We used hierarchal outcome definitions in the following order of priority: (1) composite of heart failure or decline in left ventricular ejection fraction, (2) decline in ejection fraction, or (3) heart failure. Data were analyzed using a Bayesian network meta-analysis with random effects. Results: A total of 16 trials reported cardiotoxicity as a dichotomous outcome among 1918 patients, evaluating dexrazoxane, angiotensin antagonists, beta-blockers, combination angiotensin antagonists and beta-blockers, statins, Co-enzyme Q-10, prenylamine, and N-acetylcysteine. Compared with control, dexrazoxane reduced cardiotoxicity with a pooled odds ratio (OR) of 0.26 (95% credible interval [CrI] 0.11-0.74) and had the highest probability (33%) of being most effective. No other agent was demonstrably better than placebo. Angiotensin antagonists had an 84% probability of being most effective in a sensitivity analysis excluding one outlying study (OR 0.06 [95% CrI 0.01- 0.24]). When the outcome was restricted to heart failure, dexrazoxane was associated with an OR of 0.12 (95% CrI 0.06-0.23) relative to control and had 58% probability of being most effective, while angiotensin antagonists had an OR of 0.18 (95% CrI 0.05-0.55). Available data suggested that dexrazoxane and angiotensin antagonists did not affect malignancy response rate or risk of death. Conclusion: Moderate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists, are likely to be effective for cardiotoxicity prevention.

Effects of prenylamine and AQ-A 39 on reentrant ventricular arrhythmias induced during the late myocardial infarction period in conscious dogs.

The effects of prenylamine (PNL) and AQ-A 39 on sustained ventricular tachycardia (SVT) were studied by programmed stimulation in conscious dogs 4-10 days after ligation of the left anterior descending (LAD) coronary artery. In 8 of 16 dogs developing SVT in the control, PNL (3 mg/kg intravenously, i.v.) suppressed inducibility of SVT and slowed the rate of tachycardia in 6 other animals. In a separate group of 10 dogs with inducible SVT, AQ-A 39 (4 mg/kg i.v.) abolished elicitation of tachycardia in 3 dogs and decreased its rate in 6 other dogs. Neither drug affected normal conduction significantly, but PNL impaired slow conduction in the infarct zone, as indicated by prolongation of late potential. Both agents increased the effective refractory period (ERP) of infarcted and normal ventricular myocardium and prolonged the corrected QT interval. PNL and AQ-A 39 exert notable efficacy in preventing infarcted heart from severe ventricular arrhythmias. Prolongation of ventricular refractoriness and repolarization, as well as decreased slow conduction in ischemically damaged myocardium, are major mechanisms accounting for the effectiveness of these drugs against ventricular arrhythmias.

The role of prenylamine in the prevention of adriamycin-induced cardiotoxicity. A review of experimental and clinical findings.

Experimental and clinical trials to determine the potential of prenylamine in the prevention of adriamycin-related cardiotoxicity are reviewed. In mice given 4 mg/kg body weight adriamycin, the incidence of myocardial damage after 19 days' treatment was lower than in those given adriamycin and placebo. Rabbits were given adriamycin (total dose 10.8 mg/kg body weight), adriamycin plus prenylamine (1.5 mg/kg body weight), and adriamycin plus vitamins A (250 IU) and E (40 mg) for 9-11 weeks. Adriamycin-induced electrocardiogram changes were observed to a lesser extent in animals also receiving prenylamine. Heart homogenates from adriamycin-treated animals showed enhanced hydroperoxide-initiated chemiluminescence which was not affected by the simultaneous administration of prenylamine. The extent of adriamycin-induced myocytolysis and the degree of alterations observed on electron microscopy were markedly reduced by prenylamine. In a double-blind clinical trial with 26 oncological patients, no cardiomyopathy, arrhythmia or adverse reactions were observed in the group given adriamycin plus prenylamine. In those given adriamycin plus placebo, two patients developed congestive cardiopathy and another showed severe supraventricular arrhythmias together with hypotension and dyspnoea. The mechanisms of adriamycin-related cardiotoxicity, the effects of prenylamine and the benefit from combined treatment are discussed.

Antithrombotics in view of thrombosis models.

Two highly sensitive models of arterial and venous thrombosis forming with the test of endothelial stability a complementary system with a maximum stress on the role of vascular lesion were used to test a series of four antithrombotic drugs (heparin, acetylsalicylic acid, dipyridamole, sulfinpyrazone) and four drugs with other indications but with an antithrombotic activity in experiment (prenylamine, troxerutin, ketanserin and pizotifen). All drugs, except heparin, were given orally. Whereas heparin, aspirin and prenylamine had mixed effects on both arterial thrombosis (i.e. mostly on platelet functions) as well as on endothelial stability, ketanserin and pizotifen had a predominant effect on the former while dipyridamole, troxerutin and sulfinpyrazone influenced mostly the latter function.

The effect of antithrombotics in a new model of arterial thrombosis.

A series of drugs representing several groups of antithrombotics was tested in a new model of arterial thrombosis in rats. Thrombosis was produced in the aorta by the combination of local partial obstruction and systemic administration of hypotonic saline with serotonin. High efficacy was demonstrated with heparin, acetylsalicylic acid, troxerutin, prenylamine, antiserotonin agents /pizotifen, ketanserin/ and particularly with the combinations of antiserotonins and the above mentioned antithrombotic drugs. The model showed high sensitivity to all tested drugs in the clinical dose range.

Amelioration of adriamycin-induced cardiotoxicity in rabbits by prenylamine and vitamins A and E.

The cardioprotective potentials of prenylamine (a calcium antagonist) and of a combination of vitamins A and E (a singlet oxygen quencher and a free radical scavenger, respectively) were evaluated in rabbits given chronically large doses of Adriamycin (ADM) (10.8 mg/kg body weight for 9 to 11 weeks). Among ADM-treated rabbits, 8 of 10 showed post-treatment ECG changes; in rabbits treated with ADM and prenylamine, changes were found in a smaller number (5 of 10); and in animals treated with ADM and vitamins A and E, the incidence was only one in six (p less than 0.05). Heart homogenates from ADM-treated rabbits showed an increased hydroperoxide-initiated chemiluminescence (expressed as cpm/mg protein X 10(-3)) of 77 +/- 4 compared to control animals (52 +/- 1) (p less than 0.01). Prenylamine administration did not alter hydroperoxide-initiated chemiluminescence in ADM-treated rabbits, whereas treatment with a combination of vitamins A and E showed a significant decrease in hydroperoxide-initiated chemiluminescence in control (40 +/- 2) and ADM-treated rabbits (42 +/- 1). Microscopically, myocardial fibers had mild to severe hydropic vacuolization of sarcoplasm, which led to progressive myocytolysis. A total of 103 +/- 13 damaged fibers were detected over 700 counted fibers. Myocardial damage was lowered to 47 +/- 16 by administration of prenylamine and to 28 +/- 8 by administration of vitamins A and E. It is suggested that ADM leads to myocardial lipid peroxidation (ameliorated by vitamins A and E) with membrane damage and to an increase in calcium permeability, the latter being counteracted by prenylamine.

Double-blind comparison of prenylamine and penbutolol in patients with angina pectoris.

This study was performed to re-evaluate the clinical position of prenylamine in the management of angina pectoris. After 1 week withdrawal of all anti-anginal agents, followed by another week of placebo administration, seventeen patients were allocated at random to 6 weeks treatment with either penbutolol 40 mg once a day or prenylamine 60 mg t.i.d. Clinical examination, exercise test and anginal attack rate were recorded every 2 weeks. Both drugs reduced the anginal attack rate. None of the drugs caused a significant increase in maximal workload or a significant change in ST-segment depression. Beside a substantially lower rate-pressure product at maximal comparable workload in the penbutolol group (p less than 0.001), no significant differences were observed between the two drugs. No adverse reactions were reported. From these results one can conclude that prenylamine and penbutolol do not differ in their anti-anginal effect. Therefore we are of the opinion that prenylamine has a place in the therapeutic armamentarium for the management of angina pectoris, particularly in patients where beta-blocking agents are contraindicated or in patients who have experienced side-effects of beta-blocking or calcium-entry blocking agents.

Acute coronary artery occlusion-reperfusion arrhythmias in pigs: antiarrhythmic and antifibrillatory evaluation of verapamil, nifedipine, prenylamine and propranolol.

The antiarrhythmic activity of the calcium entry blockers, verapamil, nifedipine and prenylamine, was assessed against arrhythmias occurring during 20 min of acute occlusion, or upon rapid reperfusion of the left anterior descending coronary artery (LAD) in anesthetized pigs. Propranolol, which may indirectly reduce calcium entry by blocking the facilitory action of catecholamines on slow channel conductance, was also evaluated for antiarrhythmic activity in this acute arrhythmia model. Only verapamil (0.2 mg/kg i.v.) reduced both the number of arrhythmias occurring during LAD occlusion and the incidence of ventricular fibrillation (VF) occurring after occlusion and reperfusion. Although both nifedipine (0.04-0.2 mg/kg i.v.) and propranolol (1-2 mg/kg i.v.) produced a slight but significant (P less than 0.05) dose-dependent decrease in the incidence of VF during the occlusion period only, this protection was accompanied by a significant increase in ectopic activity. The increase in ectopic activity produced by propranolol (1.0 mg/kg i.v.) persisted even in combination with verapamil (0.2 mg/kg i.v.) which given alone decreased the ectopic frequency. Prenylamine up to 5 mg/kg was without significant antiarrhythmic or antifibrillatory activity. However, unlike verapamil and nifedipine, this drug produced only slight changes in heart rate or blood pressure which suggested the presence of only minimal calcium entry blocking action on myocardial and vascular tissue at the doses we employed. Because the relative antifibrillatory efficacies of verapamil and nifedipine paralleled the relative efficacies reported for depression of atrioventricular conduction, this may implicate the slow inward current channel in the etiology of VF occurring during acute myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible female preponderance in prenylamine-induced 'torsade de pointes' tachycardia. Short communication.

Episodes of ventricular tachycardia of the 'torsade de pointes' (VTTP) types provoked by prenylamine were observed in 7 patients: 5 females and 2 males. They all received prenylamine in a dose of 120-180 mg daily for anginal pains. Syncope or syncopal equivalents occurred in all 7 patients. Q-T intervals ranged from 0.52 to 0.64 s. Review of the literature revealed 11 patients with prenylamine-induced VTTP, of whom 8 were females. The female preponderance (72.2%), hitherto not commented upon in the literature, is highlighted. Prenylamine-indiced VTTP may appear late after initiation of therapy, consequently clinical and ECG long-term follow-up is mandatory. The drug should promptly be discontinued in symptomatic patients, and particularly in females showing prolonged Q-T.

Effects of calcium antagonists, especially nifedipine, on variant angina, resting angina, and unstable angina.

The effects of drugs were evaluated in 47 cases with variant angina (VA), 19 with resting angina showing ST depression (RA), and 84 with unstable angina (UA). In VA patients, calcium antagonists were effective in 87.1% of the cases, while other drugs were effective in 56.3%. The difference was statistically significant. In RA patients, calcium antagonists were effective in 80.0% of the cases and other drugs in 44.4%. Nifedipine was effective in all 5 cases with coronary stenosis of more than 75.0%. All cases of RA had multiple vessel disease and nifedipine was effective in 80.0% of the patients. Nifedipine was effective in 83.3% of VA cases showing ST elevation during an exercise test, and was particularly effective in all patients having attacks only at rest. The effects of nifedipine were confirmed in 83.3% of UA cases. These results indicate that calcium antagonists are effective in VA, RA, and UA.

An overall review on prenylamine mechanisms of action in experimental models of myocardial damage.

In this review we present the effects of a well-known antianginal drug, prenylamine (PNL), in experimental models of acute myocardial damage induced by a beta-agonistic drug, isoproterenol (ISP), in several trials conducted in our laboratory in both rats (n = 204) and monkeys (n = 26). PNL significantly inhibited ISP-induced lesions, protecting the majority of animals studied. Studies dealing with the site of action of the drug, such as 45Ca, 3H-PNL and 3H-ISP trials, showed a clear membrane effect slowing down Ca transport. Correlation between ECG (inhibition of ST depression after ISP) and pathological findings in monkeys was also obtained in one of our experiments. These series of assays were useful in obtaining a more complete idea of activity and site of action of the drug. It seems that, in acute models, PNL acts as a calcium antagonistic drug rather than an adrenergic moderator.