Anti-Anginal and Anti-Ischemic Effects of Mibefradil, a New T-Type Calcium Channel Antagonist

Abstract

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 β-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 Efficacy and Safety of Mibefradil in Subgroups of Patients With Chronic Stable Angina Pectoris

“…When patients of African descent from all clinical studies on mibefradil were analysed, no difference in either efficacy or tolerability was observed compared with non-black patients. 21 These observations are consistent with other reports confirming that black patients respond as well to calcium antagonists as Caucasian patients. 22 • 24 Female patients taking 100 • mg mibefradil also demonstrated a considerably greater percent change from baseline in time to onset of ST-segment depression than males.…”

Voltage-gated calcium channel blockers deregulate macroautophagy in cardiomyocytes

“…Clinical trials have proved the effectiveness of dihydropyridine and non-dihydropyridine VGCC blockers as anti-anginal and antiischemic agents (Chouairi et al, 1995;Leitch et al, 1998;Kobrin et al, 1998).…”

T‐channel‐like pharmacological properties of highvoltage‐activated, nifedipine‐insensitive Ca2+ currents inthe rat terminal mesenteric artery

“…Mibefradil was developed as a new generation of VDCC blocker having a distinct structure from the other types of calcium channel antagonists such as dihydropyridines, phenylalkylamines and bezothiazepines (Osterrieder & Holck, 1989: for review; Bernink et al ., 1996). This drug was soon shown to potently inhibit low voltage activated‐Ca 2+ currents in cultured vascular smooth muscle cells (Mishra & Hermsmeyer, 1994) and to have strong anti‐hypertensive and anti‐anginal effects (Bernink et al ., 1996; Li & Schiffrin, 1997; Massie, 1997; Frishman, 1997; Kobrin, 1998). However, subsequent electrophysiological analyses have unraveled that the selectivity of this drug for T‐type over other types of VDCC would not be so superior as anticipated (Bezprovanny & Tsien, 1995; Molderings et al ., 2000; Jimenez et al ., 2000; Angus and Wright, 2000).…”