The acute effects of intravenously administered mibefradil, a new calcium antagonist, on the electrophysiologic characteristics of the human heart

Rosenquist, M.; Brembilla‐Perrot, Béatrice; Meinertz, Thomas; Neugebauer, A; Crijns, Harry J.; Smeets, J. L. R. M.; Vring, J.A.F.M. van der; Fromer, Martin; Kobrin, Isaac

doi:10.1007/s002280050241

Cited by 17 publications

(6 citation statements)

References 20 publications

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“…While mibefradil shares with verapamil and diltiazem the ability to lower HR, it is the only CA that decreases HR without concomitantly suppressing cardiac contractility at therapeutic concentrations [26,27]. Indeed, the lack of negative inotropic effect and the absence of reflex tachycardia and neurohormonal activation [6] coupled with the anti-anginal and anti-ischemic efficacy of mibefradil suggest that the compound may have a role in the treatment of patients with left-ventricular dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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“…81 At the clinical level, mibefradil was not associated with QT prolongation but was associated with bradycardia and an increase in sinus node recovery time. 87,88 Another anti‐anginal agent associated with QT prolongation, perhexiline, has been shown to inhibit heterologously expressed HERG channels. 89 The block by perhexiline is use and voltage dependent and a hyperpolarizing shift in the voltage dependence of steady state inactivation suggests that the agent may bind to the inactivated state of the channel.…”

Section: Acquired Lqts and Pharmacological Inhibition Of Ikrmentioning

confidence: 99%

Familial And Acquired Long QT Syndrome And The Cardiac Rapid Delayed Rectifier Potassium Current

Witchel

Hancox

2000

Clin Exp Pharma Physio

163

112

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SUMMARY1. Long QT syndrome (LQTS) is a cardiac disorder characterized by syncope, seizures and sudden death; it can be congenital, idiopathic, or iatrogenic.2. Long QT syndrome is so-named because of the connection observed between the distinctive polymorphic ventricular tachycardia torsade de pointes and prolongation of the QT interval of the electrocardiogram, reflecting abnormally slowed ventricular action potential (AP) repolarization. Acquired LQTS has many similar clinical features to congenital LQTS, but typically affects older individuals and is often associated with specific pharmacological agents.3. A growing number of drugs associated with QT prolongation and its concomitant risks of arrhythmia and sudden death have been shown to block the 'rapid' cardiac delayed rectifier potassium current (IKr) or cloned channels encoded by the human ether-a-go-go-related gene (HERG; the gene believed to encode native IKr). Because IKr plays an important role in ventricular AP repolarization, its inhibition would be expected to result in prolongation of both the AP and QT interval of the electrocardiogram.4. The drugs that produce acquired LQTS are structurally heterogeneous, including anti-arrhythmics, such as quinidine, non-sedating antihistamines, such as terfenadine, and psychiatric drugs, such as haloperidol. In addition to heterogeneity in their structure, the electrophysiological characteristics of HERG/IKr inhibition differ between agents.5. Here, clinical observations are associated with cellular data to correlate acquired LQTS with the IKr/HERG potassium (K ؉ ) channel. One strategy for developing improved compounds in those drug classes that are currently associated with LQTS could be to design drug structures that preserve clinical efficacy but are modified to avoid pharmacological interactions with IKr. Until such time, awareness of the QT-prolongation risk of particular agents is important for the clinician.

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“…The same decrease was observed in earlier studies with 100 mg once-daily mibefradil given long-term to healthy volunteers. Mibefradil appears to decrease heart rate by a direct effect on the SA node, as shown in a study with isolated dog sino-atrial preparations (23) and also suggested by invasive electrophysiological measurements in humans (24). An additive effect of digoxin and mibefradil in decreasing heart rate was seen, indicating that both drugs have a direct effect on the SA node.…”

Section: Discussionmentioning

confidence: 84%

Pharmacokinetic and pharmacodynamic aspects of concomitant mibefradil-digoxin therapy at therapeutic doses

Peters

Welker

Bullingham

1999

Eur. J. Drug Metab. Pharmacokinet.

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This study investigated the effect of mibefradil on digoxin pharmacokinetics an pharmacodynamics. Following a loading dose of digoxin (0.375 mg, three times, day 1), 0.375 mg was administered once daily to 40 healthy subjects (days 2-15). Mibefradil was administered daily at 50 mg, 100 mg, or 150 mg (days 9-15). With co-administration of 50 mg or 100 mg mibefradil (the recommended doses), mean digoxin Cmax values increased 1.19- and 1.32-fold, respectively; Cmin values were 0.95- and 1.04-fold, respectively; mean AUC0-24 h increased 1.05- and 1.11-fold, respectively; and the total amount of digoxin excreted in urine remained unchanged. Digoxin monotherapy produced modest but transient prolongations of PQ interval, small decreases in heart rate, and no changes in blood pressure. With the addition of mibefradil, no effects on trough blood pressure or cardiac index were observed, but there was a further increase in PQ interval and decrease in heart rate. In a previous study, mibefradil had no significant effect on trough plasma digoxin concentration in patients with congestive heart failure and ischemia. Therefore, while the vast majority of patients should not need their digoxin dosages adjusted when given mibefradil, an occasional patient may require dose reductions based on clinical response and plasma digoxin.

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The acute effects of intravenously administered mibefradil, a new calcium antagonist, on the electrophysiologic characteristics of the human heart

Cited by 17 publications

References 20 publications

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

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

Familial And Acquired Long QT Syndrome And The Cardiac Rapid Delayed Rectifier Potassium Current

Pharmacokinetic and pharmacodynamic aspects of concomitant mibefradil-digoxin therapy at therapeutic doses

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