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Isaac Kobrin - One of the best experts on this subject based on the ideXlab platform.
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adding the new calcium antagonist Mibefradil to patients receiving long term β blocker therapy results in improved antianginal and antiischemic efficacy
American Heart Journal, 1998Co-Authors: Adam Schneeweiss, Isaac Kobrin, Vincent Charlon, Abraham Caspi, Leonardo Reisin, Alon Marmor, Samuel Sclarovsky, Zvi ZchlesingerAbstract:Abstract 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 β-blocker therapy. Design This was a multicenter, double-blind, placebo-controlled study. Methods Ninety-five patients receiving a stable dose of β-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 β-blockers was well tolerated, and the overall incidence of adverse events was no different from that with β-blockers alone. The results indicate that adding Mibefradil to chronic β-blocker treatment is associated with significant improvement in efficacy, which is not achieved at the expense of tolerability. (Am Heart J 1998;135:272-80.)
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efficacy of Mibefradil compared with amlodipine in suppressing exercise induced and daily silent ischemia results of a multicenter placebo controlled trial
Circulation, 1997Co-Authors: Dan Tzivoni, Honer Kadr, Simon H Braat, Wolfgang Rutsch, Jose Antonio Franchini Ramires, Isaac KobrinAbstract:Background Mibefradil is a new benzimidazolyl-substituted tetraline-derivative calcium antagonist. Its vasodilatory activity combined with an ability to lower heart rate without negative inotropic effects as well as its long duration of action make it a promising anti-ischemic agent. Methods and Results Three hundred nine patients with coronary artery disease, stable angina pectoris, and positive exercise tests were randomized to receive Mibefradil (50, 100, or 150 mg), amlodipine (10 mg), or placebo. The anti-ischemic effects of Mibefradil on exercise test and silent ischemia parameters were assessed. At doses of 100 and 150 mg, Mibefradil increased exercise duration (by 55.5 and 51.0 seconds, respectively; P<.001 for both), increased time to onset of angina (by 98.3 and 82.7 seconds, respectively; P<.001), and increased time to 1-mm ST depression (by 81.7 and 94.3 seconds, respectively; P<.001). By comparison, a 10 mg/d dose of amlodipine significantly improved only time to onset of angina (treatment ef...
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Mibefradil in the treatment of systemic hypertension comparative studies with other calcium antagonists
American Journal of Cardiology, 1997Co-Authors: Barry M Massie, Yves Lacourciere, Reuven Viskoper, Arend Woittiez, Isaac KobrinAbstract:This paper summarizes the results of 4 double-blind studies of antihypertensive therapy in which Mibefradil was compared with other commonly used calcium antagonists (diltiazem CD, amlodipine, nifedipine SR, and nifedipine GITS) at the recommended dose range. A total of 640 patients were included, with 361 randomized to Mibefradil, 98 to diltiazem CD, 119 to amlodipine, 71 to nifedipine SR, and 36 to nifedipine GITS. Trials included an active treatment phase of 6 or 12 weeks in duration. Compared with diltiazem CD or nifedipine SR, Mibefradil demonstrated statistically significant greater efficacy. Decreases in sitting diastolic blood pressure (SDBP) after treatment with Mibefradil 100 mg once daily were 14.0 +/- 7.8 mm Hg compared with 9.5 +/- 7.5 mm Hg with diltiazem CD 360 mg once daily (p = 0.001), and 12.8 +/- 8.4 mm Hg compared with 8.1 +/- 19.2 mm Hg with nifedipine SR 40 mg twice daily (p = 0.014). Patients on Mibefradil also had higher normalization (SDBP reduced to or = 10 mm Hg or normalization) rates than did those on diltiazem CD or nifedipine SR. The overall incidence of adverse events was similar among these 3 compounds, but the number of premature withdrawals due to adverse events was greater with both comparators than with Mibefradil. Treatment with 100 mg Mibefradil or 10 mg amlodipine once daily resulted in statistically significant decreases from baseline in SDBP of 11.5 +/- 8.2 mm Hg and 13.2 +/- 7.9 mm Hg, respectively, which were statistically equivalent. However, patients treated with amlodipine had a considerably greater incidence of leg edema than did those treated with Mibefradil (33.6% vs 4.2%, respectively). Similarly, 100 mg Mibefradil was equivalent in efficacy to 60 mg nifedipine GITS once daily, but patients on Mibefradil experienced fewer vasodilatory related adverse events. In summary, Mibefradil demonstrated superior efficacy to diltiazem CD and nifedipine SR and equivalent efficacy to amlodipine and nifedipine GITS in the treatment of hypertension.
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safety of Mibefradil a new once a day selective t type calcium channel antagonist
American Journal of Cardiology, 1997Co-Authors: Isaac Kobrin, Vincent Charlon, Elisabeth Lindberg, Robert PordyAbstract: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.
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antianginal and anti ischemic effects of Mibefradil in the treatment of patients with chronic stable angina pectoris
American Journal of Cardiology, 1997Co-Authors: Joseph S Alpert, Ad L.m. Bakx, Shimon Braun, Adam Schneeweiss, Dan Tzivoni, William H Frishman, Isaac KobrinAbstract:Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, Mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either β blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 Mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of Mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of Mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of Mibefradil. The 25-mg dose of Mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of Mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic β-blocker or long-acting nitrate therapy. Taken together, these studies indicate that Mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.
Jean-paul Clozel - One of the best experts on this subject based on the ideXlab platform.
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nonlinear kinetics and pharmacologic response to Mibefradil
Clinical Pharmacology & Therapeutics, 2000Co-Authors: Jean-paul Clozel, Patrick Du Souich, Jeanguy Besner, Horst Welker, Marc LefebvreAbstract:Background Increasing oral doses of Mibefradil (10 to 320 mg) decrease its apparent oral clearance; however, intravenous doses up to 80 mg do not reduce its systemic clearance. This study aimed to understand the mechanisms underlying the zero-order kinetics of Mibefradil. Methods A group of 10 normotensive volunteers received 50 mg/day oral Mibefradil for 8 days and, on days 1 and 8, 5 mg deuterated Mibefradil by infusion. Ten additional volunteers observed the same protocol with a daily oral dose of 100 mg Mibefradil. Serial blood samples were withdrawn, and Mibefradil plasma concentrations were assayed by liquid chromatography–mass spectrometry. Blood pressure and heart rate were measured for 4 hours, and an ECG was performed 2 hours after drug administration. Results Repeated oral administration of 50 mg Mibefradil generated zero-order kinetics secondary to a decrease in Mibefradil systemic clearance. Compared with the 50-mg dose, single and repeated oral doses of 100 mg further decreased Mibefradil clearance. Mibefradil bioavailability was not affected by increasing Mibefradil doses. Mean diastolic blood pressure was decreased by single and repeated doses of 100 mg to the same extent. Repeated doses of 100 mg reduced heart rate and prolonged the PR and QTc, changes that were associated with Mibefradil plasma concentrations. Conclusions Repeated doses of 50 mg or doses of 100 mg Mibefradil generated zero-order kinetics secondary to a decrease in hepatic extraction of the drug. Zero-order kinetics did not affect the response-concentration relationship of Mibefradil. (Clin Pharmacol Ther 2000;67:249–57.) Clinical Pharmacology & Therapeutics (2000) 67, 249–257; doi: 10.1067/mcp.2000.104616
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Mibefradil ro 40 5967 the first selective t type ca2 channel blocker
Expert Opinion on Investigational Drugs, 1997Co-Authors: Sylvie I Ertel, Jean-paul ClozelAbstract:Mibefradil is a novel Ca2+ antagonist acting on both L- and T-type Ca2+ channels, with a ten-fold selectivity for T-type Ca2+ channels. It belongs to a chemical class different from other Ca2+ antagonists (tetralol derivative), and binds to a new receptor site on the L-type Ca2+ channel, where it does not affect dihydropyridine (DHP) binding but appears to overlap the verapamil and fantofarone sites. In vitro and in vivo studies indicate that Mibefradil has a high selectivity for the coronary vasculature over the peripheral vasculature and the myocardium. It has no relevant negative inotropic effects in various animal models, in normotensive patients, and patients with hypertension or angina pectoris. Instead, treatment with Mibefradil slightly decreases heart rate and improves cardiac function. Clinical studies confirm that Mibefradil is an effective antihypertensive and anti-ischaemic drug, which may be beneficial in the treatment of heart failure. Its excellent pharmacological and safety profile combin...
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Mibefradil a selective calcium t channel blocker in stroke prone spontaneously hypertensive rats
Journal of Cardiovascular Pharmacology, 1996Co-Authors: Elisabeth Vacher, Jean-paul Clozel, Christine Richer, Paul Fornes, Jeanfrancois GiudicelliAbstract:Several types of antihypertensive agents, including calcium antagonists, have been reported to prevent stroke and prolong survival in stroke-prone spontaneously hypertensive rats (SHR-SP). We investigated whether Mibefradil, a new calcium antagonist acting selectively at the level of T-type calcium channels, would be able to (a) limit or prevent the structural and functional alterations that develop in the cerebral arteries of SHR-SP before stroke and (b) suppress stroke and prolong survival. Mibefradil (30 mg/kg/day) was given orally to young salt-loaded SHR-SP from age 5 weeks to age 20 weeks. Blood pressure (BP) (in conscious animals), diuresis, and proteinuria were determined weekly. After 1012 weeks of treatment, middle cerebral arteries and aortas were removed from randomly selected control and treated SHR-SP. Aortic media thickness and collagen density were evaluated by histomorphometry. Middle cerebral arteries were mounted in a myograph for wall thickness determination and isometric tension recordings. Mibefradil completely prevented stroke and mortality, significantly limited the increase in BP, and opposed the increases in diuresis and proteinuria observed in controls. Simultaneously, Mibefradil abolished vascular fibrinoid necrosis formation in the brain and reduced arterial thickening in the cerebral artery as well as in the aorta. The maximal contractile responses of the cerebral arteries to potassium chloride and serotonin were greater in Mibefradil-treated animals than in controls, as were the endothelium-dependent relaxant responses. Mibefradil, chronically administered to young SHRSP in a dose that limits the development of hypertension not only prevents stroke and mortality but also affords protection against the vascular structural alterations which develop with age in these animals and preserves or improves the cerebral artery's smooth muscle and endothelial cell functions.
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Mechanism of the antiischemic effect of Mibefradil, a selective T calcium channel blocker in dogs: comparison with amlodipine.
Journal of cardiovascular pharmacology, 1996Co-Authors: Sébastien Roux, Manfred Bühler, Jean-paul ClozelAbstract:Calcium channel blockers are active in variant angina principally by preventing coronary vasospasm. However, a direct antiischemic effect may also occur. In open-chest dogs, an attack of variant angina was mimicked by a 2-min critical coronary stenosis, and the following reversible myocardial ischemia was assessed by measuring the decrease of segmental shortening. We compared the antiischemic mechanism of Mibefradil, a T and L calcium channel blocker, with that of amlodipine, a pure L channel blocker. Both drugs showed a similar relationship between the decrease of the rate-pressure product and the antiischemic effect, but only Mibefradil reduced heart rate. Amlodipine and Mibefradil at the highest doses tested (20 and 70 micrograms/kg/min, respectively) restored 68 +/- 8 and 76 +/- 5% of segmental shortening in the ischemic area, respectively, as compared with preischemic values. Matching blood pressure (by intraaortic balloon) or heart rate (by atrial pacing) to predrug values showed that the antiischemic effect was mainly afterload-dependent for amlodipine and heart rate-dependent for Mibefradil. We conclude that in variant angina, in addition to their antivasospastic effects, calcium channel blockers may be antiischemic by a direct myocardial effect associated with a decrease of the rate pressure product. Blockade of the T channel does not seem to participate in the direct antiischemic effect of Mibefradil but could explain the decrease of heart rate.
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differential effects of the calcium antagonist Mibefradil in epicardial and intramyocardial coronary arteries
Journal of Cardiovascular Pharmacology, 1995Co-Authors: Christoph F Kung, Jean-paul Clozel, M Tschudi, Georg Noll, Thomas F LuscherAbstract:The efficacy of vasodilation depends on the drug and the contractile agonist involved. Furthermore, vasodilation also may be detrimental (i.e., coronary steal), possibly depending on the anatomic site and/or action of the vasodilator. We investigated the effects of Ca 2+ antagonism in porcine epicardial and intramyocardial coronary arteries suspended in organ chambers filled with physiological salt solution (95% O 2 /5% CO 2 , 37°C) ; isometric tension was measured. In epicardial vessels contracted with KCI, the thromboxane analogue U 46619, or endothelin-1 (ET-1), relaxations to the Ca 2+ antagonist Mibefradil were most effective after precontraction with KCI, followed by U 46619 and ET-1. In intramyocardial vessels, the contraction to KCI, U 46619, and particularly ET-1, was much more effectively inhibited by Mibefradil than in epicardial arteries. In vessels preincubated with Mibefradil, the drug was moderately effective in preventing the initiation of contractions. Preincubation with the inhibitor of nitric oxide production (NO), L ω -nitro arginine methyl ester (L-NAME) or endothelium removal, did not increase relaxations to Mibefradil. However, epicardial but not intramyocardial vessels incubated with Mibefradil exhibited enhanced relaxations to bradykinin (BK) and sodium nitroprusside (SNP) as compared with control. Thus, Ca 2+ antagonism is particularly effective in intramyocardial coronary arteries. In addition to its inhibitory effects on contractility, calcium antagonism facilitates the effects of endothelium-derived NO in epicardial coronaries at the level of vascular smooth muscle (VSM).
Shimon Braun - One of the best experts on this subject based on the ideXlab platform.
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antianginal and anti ischemic effects of Mibefradil in the treatment of patients with chronic stable angina pectoris
American Journal of Cardiology, 1997Co-Authors: Joseph S Alpert, Ad L.m. Bakx, Shimon Braun, Adam Schneeweiss, Dan Tzivoni, William H Frishman, Isaac KobrinAbstract:Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, Mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either β blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 Mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of Mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of Mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of Mibefradil. The 25-mg dose of Mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of Mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic β-blocker or long-acting nitrate therapy. Taken together, these studies indicate that Mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.
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effects of a new calcium antagonist Mibefradil ro 40 5967 on silent ischemia in patients with stable chronic angina pectoris a multicenter placebo controlled study
Journal of the American College of Cardiology, 1996Co-Authors: Shimon Braun, Ernst E. Van Der Wall, Håkan Emanuelsson, Isaac KobrinAbstract:Objectives. The purpose of this study was to evaluate the effects of Mibefradil (Ro 40–5967) on the frequency and duration of episodes of asymptomatic ischemia in patients with stable angina pectoris and to determine the most efficient single therapeutic dose of this drug. Background. Mibefradil is a novel calcium channel antagonist that shows a high bioavailability, induces no reflex tachycardia and has no negative inotropic effects. Methods. In a multicenter, double-blind, placebo-controlled, parallel-design trial, 126 patients with chronic stable angina pectoris were studied. After 1 week of a placebo run-in period, patients were randomized to receive 25, 50, 100, 150 mg of Mibefradil or placebo for 2 weeks. Ambulatory 48-h electrocardiographic (ECG) monitoring was performed at the end of both the placebo run-in period and the active treatment period. Results. Compared with placebo, Mibefradil was associated with significantly less ischemia as manifested during ambulatory ECG monitoring. In the 150- and 100-mg groups, respectively, the drug resulted in a 73% and 63% reduction in the frequency of episodes of ST segment depression and a 78% and 58% reduction in the total duration of ST segment depression. Highly significant linear dose-response relations were present across all treatment groups for ischemic episodes and ischemia duration (p < 0.001). Electrocardiographic abnormalities related to treatment were first-degree atrioventricular block, sinus bradycardia and short Wenckebach episodes, observed during sleep on Holter monitoring. All ECG events were dose related. Conclusions. Mibefradil is a new, safe, well tolerated and very effective dose-dependent anti-ischemic calcium channel antagonist.
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Effects of the new calcium antagonist Mibefradil (Ro 40-5967) on exercise duration in patients with chronic stable angina pectoris: A multicenter, placebo-controlled study
American heart journal, 1995Co-Authors: Ad L.m. Bakx, Ernst E. Van Der Wall, Shimon Braun, Håkan Emanuelsson, Albert V.g. Bruschke, Isaac KobrinAbstract:Abstract Mibefradil (Ro 40-5967) is a novel calcium antagonist from a new chemical class and is the first that selectively blocks the T-type calcium channel. In this multicenter, double-blind, placebo-controlled, parallel designed study, its antianginal and antiischemic effects were evaluated in 126 patients with chronic stable angina pectoris. Exercise tests were performed after 1 week of placebo (baseline) and 2 weeks after randomization to 25, 50, 100, and 150 mg (once daily) or placebo. Highly significant dose-response relations were present across all treatment groups for exercise duration, time to angina, and time to ST-segment depression. They were associated with a dose-dependent decrease in heart rate and blood pressure and plasma concentrations >300 ng/ml. Mibefradil was well tolerated. First-degree atrioventricular block (8%) and dizziness (7%) were the most frequently reported adverse events; however, the first-degree atrioventricular block was dose-related, and only one patient discontinued the trial because of dizziness. The excellent efficacy and adequate safety profile of Mibefradil may be a consequence of T-type calcium-channel selectivity.
Stanley Nattel - One of the best experts on this subject based on the ideXlab platform.
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the t type ca2 channel blocker Mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia induced atrial remodeling in dogs
Circulation, 1999Co-Authors: Samir Fareh, Agnes Benardeau, Bernard Thibault, Stanley NattelAbstract:Background —Ca2+ overload is believed to play a role in tachycardia-induced atrial electrophysiological remodeling. L-type Ca2+ channel blockers attenuate effective refractory period (ERP) changes caused by 24 hours of atrial tachycardia but may not substantially alter atrial fibrillation (AF) inducibility. This study assessed the effects of the T-type Ca2+ channel blocker Mibefradil on tachycardia-induced atrial remodeling. Methods and Results —Dogs subjected to rapid atrial pacing (400 bpm) for 7 days were treated with Mibefradil (100 mg/d, n=8) or matching placebo (n=10) in blinded fashion. Radiofrequency ablation of atrioventricular conduction and ventricular pacing were used to control ventricular rate. Placebo dogs showed significant decreases in atrial ERP (76±5 ms at a cycle length of 300 ms) and increases in ERP heterogeneity (27.7±2.4%), AF duration (414±232 seconds), and AF inducibility by single extrastimuli (41±10% of sites) compared with 10 unpaced control dogs (ERP 114±3 ms, ERP heterogeneity 13.8±0.9%, AF duration 7±3 seconds, AF inducibility 1.9±1.0% of sites). The changes caused by atrial tachycardia were strongly attenuated in Mibefradil dogs, with ERPs averaging 102±7 ms, ERP heterogeneity 18.8±1.4%, AF duration 3±1 seconds, and AF inducibility 9.6±4.0% of sites. Among Mibefradil-treated dogs, ERP, AF duration, and inducibility correlated with plasma drug concentration. Acute Mibefradil administration did not alter ERP or AF. Conclusions —Mibefradil, a drug with strong T-type Ca2+ channel blocking properties, prevents AF-promoting electrophysiological remodeling by atrial tachycardia. These findings have important potential implications for the mechanisms of tachycardia-induced atrial remodeling and demonstrate the feasibility of preventing electrical remodeling caused by several days of atrial tachycardia.
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the t type ca 2 channel blocker Mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia induced atrial remodeling in dogs
Circulation, 1999Co-Authors: Samir Fareh, Agnes Benardeau, Bernard Thibault, Stanley NattelAbstract:Background —Ca2+ overload is believed to play a role in tachycardia-induced atrial electrophysiological remodeling. L-type Ca2+ channel blockers attenuate effective refractory period (ERP) changes caused by 24 hours of atrial tachycardia but may not substantially alter atrial fibrillation (AF) inducibility. This study assessed the effects of the T-type Ca2+ channel blocker Mibefradil on tachycardia-induced atrial remodeling. Methods and Results —Dogs subjected to rapid atrial pacing (400 bpm) for 7 days were treated with Mibefradil (100 mg/d, n=8) or matching placebo (n=10) in blinded fashion. Radiofrequency ablation of atrioventricular conduction and ventricular pacing were used to control ventricular rate. Placebo dogs showed significant decreases in atrial ERP (76±5 ms at a cycle length of 300 ms) and increases in ERP heterogeneity (27.7±2.4%), AF duration (414±232 seconds), and AF inducibility by single extrastimuli (41±10% of sites) compared with 10 unpaced control dogs (ERP 114±3 ms, ERP heterogeneity 13.8±0.9%, AF duration 7±3 seconds, AF inducibility 1.9±1.0% of sites). The changes caused by atrial tachycardia were strongly attenuated in Mibefradil dogs, with ERPs averaging 102±7 ms, ERP heterogeneity 18.8±1.4%, AF duration 3±1 seconds, and AF inducibility 9.6±4.0% of sites. Among Mibefradil-treated dogs, ERP, AF duration, and inducibility correlated with plasma drug concentration. Acute Mibefradil administration did not alter ERP or AF. Conclusions —Mibefradil, a drug with strong T-type Ca2+ channel blocking properties, prevents AF-promoting electrophysiological remodeling by atrial tachycardia. These findings have important potential implications for the mechanisms of tachycardia-induced atrial remodeling and demonstrate the feasibility of preventing electrical remodeling caused by several days of atrial tachycardia.
Ad L.m. Bakx - One of the best experts on this subject based on the ideXlab platform.
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antianginal and anti ischemic effects of Mibefradil in the treatment of patients with chronic stable angina pectoris
American Journal of Cardiology, 1997Co-Authors: Joseph S Alpert, Ad L.m. Bakx, Shimon Braun, Adam Schneeweiss, Dan Tzivoni, William H Frishman, Isaac KobrinAbstract:Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, Mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either β blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 Mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of Mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of Mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of Mibefradil. The 25-mg dose of Mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of Mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic β-blocker or long-acting nitrate therapy. Taken together, these studies indicate that Mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.
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Effects of the new calcium antagonist Mibefradil (Ro 40-5967) on exercise duration in patients with chronic stable angina pectoris: A multicenter, placebo-controlled study
American heart journal, 1995Co-Authors: Ad L.m. Bakx, Ernst E. Van Der Wall, Shimon Braun, Håkan Emanuelsson, Albert V.g. Bruschke, Isaac KobrinAbstract:Abstract Mibefradil (Ro 40-5967) is a novel calcium antagonist from a new chemical class and is the first that selectively blocks the T-type calcium channel. In this multicenter, double-blind, placebo-controlled, parallel designed study, its antianginal and antiischemic effects were evaluated in 126 patients with chronic stable angina pectoris. Exercise tests were performed after 1 week of placebo (baseline) and 2 weeks after randomization to 25, 50, 100, and 150 mg (once daily) or placebo. Highly significant dose-response relations were present across all treatment groups for exercise duration, time to angina, and time to ST-segment depression. They were associated with a dose-dependent decrease in heart rate and blood pressure and plasma concentrations >300 ng/ml. Mibefradil was well tolerated. First-degree atrioventricular block (8%) and dizziness (7%) were the most frequently reported adverse events; however, the first-degree atrioventricular block was dose-related, and only one patient discontinued the trial because of dizziness. The excellent efficacy and adequate safety profile of Mibefradil may be a consequence of T-type calcium-channel selectivity.
