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PubMed2000

The effect of mibefradil on ischemic episodes with and without increase in heart rate.

Myocardial ischemia during daily life can be induced by increased demand and by increased coronary tone. The purpose of this study was to assess the mechanism of action of mibefradil, a new T-channel calcium blocker that is a vasodilator with negative chronotropic properties. Included in this study were 114 patients with chronic stable angina pectoris and ischemic episodes during baseline 48-hour ambulatory ECG monitoring (AEM). After a placebo run-in period patients received 50 mg, 100 mg, or 150 mg of mibefradil per day and repeat 48 hours AEM was performed. Ischemic episodes were divided into 2 categories: Type I is those in which an increase in heart rate > 10% preceded the development of 1 mm ST depression; Type II is those with < or = 10% increase in heart rate. Of the 625 ischemic episodes recorded at baseline, 83% were Type I and 17% were Type II. At 50 mg mibefradil dose, there was a significant decrease in the number of Type I ischemic episodes but not of Type II. At doses of 100 mg and 150 mg/day, there was a significant decrease in frequency of both types of ischemic episodes. At a low dose of 50 mg/day, mibefradil reduces ischemia predominantly by preventing an increase in heart rate, while at higher doses of 100 mg and 150 mg/day, it also acted as a vasodilator suppressing episodes associated with increased coronary tone.

Angina Pectoris↗
PubMed1997

Effects of the novel T-type calcium channel antagonist mibefradil on human myocardial contractility in comparison with nifedipine and verapamil.

Mibefradil (Ro 40-5967) is a novel nondihydropyridine calcium antagonist. The aim of our study was to compare the negative inotropic effects of the well-known 1,4-dihydropyridine nifedipine and the phenylalkylamine verapamil with those of mibefradil. Isometric force of contraction in response to these substances was determined in isolated, electrically driven left ventricular papillary muscle strips from failing human hearts (1 Hz, 37 degrees C). The hearts were obtained during cardiac transplantation (n = 9) and mitral valve-replacement operations (n = 9). The calcium antagonists studied significantly (p < 0.05) depressed basal force of contraction in a concentration-dependent manner. The effect started at concentrations > 0.001 microM for nifedipine and > 0.01 microM for verapamil, but only at concentrations > 10 microM for mibefradil. Only in the presence of nifedipine and verapamil was a significant rightward shift of the inotropic concentration--response curves to calcium and a depression of the maximal effects of calcium observed. With respect of the relation between the therapeutic active plasma concentration in vivo and the negative intropic potency in vitro, it became evident that the difference between therapeutically beneficial concentrations and potentially hazardous cardiodepressant activity increases from nifedipine to mibefradil. We conclude that this new generation of calcium antagonists, almost lacking cardiodepressant effects, could lead to a greater therapeutic index and greater safety in the treatment of cardiovascular diseases.

Benzimidazoles↗
PubMed2002

Single-channel pharmacology of mibefradil in human native T-type and recombinant Ca(v)3.2 calcium channels.

To study the molecular pharmacology of low-voltage-activated calcium channels in biophysical detail, human medullary thyroid carcinoma (hMTC) cells were investigated using the single-channel technique. These cells had been reported to express T-type whole-cell currents and a Ca(v)3.2 (or alpha 1H) channel subunit. We observed two types of single-channel activity that were easily distinguished based on single-channel conductance, voltage dependence of activation, time course of inactivation, rapid gating kinetics, and the response to the calcium agonist (S)-Bay K 8644. Type II channels had biophysical properties (activation, inactivation, conductance) typical for high-voltage-activated calcium channels. They were markedly stimulated by 1 microM (S)-Bay K 8644, allowing to identify them as L-type channels. The channel termed type I is a low-voltage-activated, small-conductance (7.2 pS) channel that inactivates rapidly and is not modulated by (S)-Bay K 8644. Type I channels are therefore classified as T-type channels. They were strongly inhibited by 10 microM mibefradil. Mibefradil block was caused by changes in two gating parameters: a pronounced reduction in fraction of active sweeps and a slight shortening of the open-state duration. Single recombinant low-voltage-activated T-type calcium channels were studied in comparison, using human embryonic kidney 293 cells overexpressing the pore-forming Ca(v)3.2 subunit. Along all criteria examined (mechanisms of block, extent of block), recombinant Ca(v)3.2 interact with mibefradil in the same way as their native counterparts expressed in hMTC cells. In conclusion, the pharmacologic phenotype of these native human T-type channels--as probed by mibefradil--is similar to recombinant human Ca(v)3.2.

Calcium Channel Blockers↗
PubMed1998

Pharmacokinetics and pharmacodynamics of mibefradil in hypertensive patients with varying degrees of renal insufficiency.

Mibefradil, the first member of the tetralol derivatives, a new class of calcium antagonists, is used for the treatment of hypertension and angina pectoris. This study was designed to investigate the effect of varying degrees of chronic renal impairment on mibefradil pharmacokinetics and pharmacodynamics. Neither pharmacokinetic nor pharmacodynamic parameters varied as a function of renal status. Additionally, hemodialysis removed only a relatively small fraction of drug from the body. It was concluded that the majority of renal-failure patients will not require a change in mibefradil dosage relative to patients with normal renal function. Following hemodialysis, supplemental mibefradil treatment should not be necessary.

Adolescent↗
PubMed1998

Potential cardioprotective effect of mibefradil in the long-term treatment of hypertension.

During the last 2 decades, remarkable progress has been made in the treatment of hypertension with the discovery of new drugs lowering blood pressure by various mechanisms, e.g. calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin II antagonists. These antihypertensive agents are now widely used as first-line therapy although there is still no definite proof that they have a cardioprotective effect and reduce the mortality rate in patients with coronary heart disease. Mibefradil is a new calcium antagonist with a novel mechanism of action since it is the only drug available so far able to block T channels. This compound might be particularly effective in preventing cardiac morbidity and mortality. It reduces heart rate when lowering blood pressure, has no negative inotropic effect, allows regression of cardiac hypertrophy and is effective in the treatment of angina. Mibefradil produces a sustained blood pressure reduction with a close to optimal trough:peak ratio. A major advantage of this novel compound is its excellent tolerability over the dose range recommended (50-100 mg/day). In particular, leg edema is seen clearly less often during mibefradil treatment than during therapy with dihydropyridines. Mibefradil has therefore an attractive profile in terms of both efficacy and safety and represents a promising first-line option to treat hypertensive patients.

Benzimidazoles↗
PubMed2004

Michaelis-Menten kinetics under spatially constrained conditions: application to mibefradil pharmacokinetics.

Two different approaches were used to study the kinetics of the enzymatic reaction under heterogeneous conditions to interpret the unusual nonlinear pharmacokinetics of mibefradil. Firstly, a detailed model based on the kinetic differential equations is proposed to study the enzymatic reaction under spatial constraints and in vivo conditions. Secondly, Monte Carlo simulations of the enzyme reaction in a two-dimensional square lattice, placing special emphasis on the input and output of the substrate were applied to mimic in vivo conditions. Both the mathematical model and the Monte Carlo simulations for the enzymatic reaction reproduced the classical Michaelis-Menten (MM) kinetics in homogeneous media and unusual kinetics in fractal media. Based on these findings, a time-dependent version of the classic MM equation was developed for the rate of change of the substrate concentration in disordered media and was successfully used to describe the experimental plasma concentration-time data of mibefradil and derive estimates for the model parameters. The unusual nonlinear pharmacokinetics of mibefradil originates from the heterogeneous conditions in the reaction space of the enzymatic reaction. The modified MM equation can describe the pharmacokinetics of mibefradil as it is able to capture the heterogeneity of the enzymatic reaction in disordered media.

Biophysical Phenomena↗
PubMed1998

Clinical pharmacokinetics of mibefradil.

Mibefradil, a tetralol derivative, is a new long-acting calcium antagonist used for the treatment of patients with hypertension and chronic stable angina pectoris. The drug is virtually completely metabolised, with less than 3% of an oral dose excreted unchanged in urine. Its metabolism occurs via parallel pathways, which fall into 2 broad categories: esterase-catalysed hydrolysis (producing the major plasma metabolite) and cytochrome P450 (CYP) 3A4-mediated oxidation. Plasma protein binding is greater than 99.5%, predominantly to alpha 1-acid glycoprotein. Oral multiple dose administration of mibefradil 50 or 100 mg once daily is associated with inhibition of the CYP3A4 pathway of metabolism, increasing the half-life and bioavailability of the parent compound. The intensity of the inhibition of CYP similarly results in numerous clinically relevant drug interactions which ultimately motivated the voluntary withdrawal of mibefradil from the market. With multiple oral doses of 50 to 100 mg once daily, the time to maximum plasma concentration was approximately 2.4 hours, absolute bioavailability was around 80%, clearance was 5.7 to 7.5 L/h, oral terminal exponential volume of distribution was 180 L, and terminal exponential half-life was 22 hours (ranging between 17 and 25 hours). A NONMEM sparse data analysis indicated that apparent clearance is not affected by race, gender, age or bodyweight. Renal function does not affect the pharmacokinetics of mibefradil.

Benzimidazoles↗
PubMed1999

Tacrolimus toxicity due to drug interaction with mibefradil in a patient after liver transplantation.

A 54-year-old male liver transplant patient received mibefradil, a novel T-type calcium channel blocker, as antihypertensive treatment while he was on tacrolimus. He subsequently developed dizziness and fatigue of gradual onset as well as shoulder muscle ache. In addition, reversible impairment of renal function occurred with an increase in creatinine and potassium levels. Monitoring of tacrolimus levels, which had been in the desired range (5-8 ng/ml) until recently, revealed an increase to toxic level of 54 ng/ml. After discontinuation of mibefradil, tacrolimus levels returned to the normal range and all symptoms and clinical changes were reversible. Mibefradil and tacrolimus both are metabolized through the cytochrome--P-450 pathway. We suspect that drug interaction due to competitive inhibition of tacrolimus metabolism by mibefradil was responsible for these toxic effects. Therefore, special caution is recommended when administering tacrolimus with other drugs that carry the potential for pharmakokinetic interaction.

Antihypertensive Agents↗
PubMed2000

Effects of mibefradil and verapamil on ischemic-reperfusion in the hearts of guinea pigs with acute renal failure.

Two parameters indicating the ischemic-reperfusion myocardial injury, coronary flow and lactate dehydrogenase (LDH) release rate, were evaluated in guinea pigs with gentamicine-induced acute renal failure (ARF) and compared with those of healthy animals. Isolated Langendorffs hearts were exposed to 50 min of zero-flow global ischemia and 60 min of reperfusion. The influences of calcium channel antagonists (of T- and L-type antagonist mibefradil and of L-type antagonist verapamil) in reperfusion solution were evaluated. Our results showed coronary dilatation and higher LDH release rate in ARF than in control hearts before ischemia. Recovery of coronary flow during reperfusion was better and LDH release rate lower in ARF vs. control hearts. Perfusion with mibefradil and verapamil did not additionally increase coronary flow, however 0.1 microM mibefradil and verapamil decreased LDH release rate during reperfusion in ARF hearts in comparison to control hearts. Our results showed some protective effects of 0.1 microM mibefradil and verapamil on LDH release rate during reperfusion, but not on coronary flow in guinea pigs hearts with ARF.

Acute Kidney Injury↗
PubMedDate not supplied

Effects of the T-type calcium channel blockade with oral mibefradil on the electrophysiologic properties of the human heart.

BACKGROUND: As the calcium T-channel blockade is a new pharmacological category with presumably unique electrophysiological effects, the influence of its only representative yet mibefradil was tested after the single oral dose. MATERIAL AND METHODS: 10 patients underwent the electrophysiologic examination. Normal baseline values in sinus node cycle length (SNCL), sinus node recovery time (SNRT), corrected sinus node recovery time (CSNRT), PA interval, atrial effective refractory period, AH interval, Wenckebach point (WP), atrioventricular nodal refractory period, and HV interval were measured using standard techniques. After that a single dose of 100 mg mibefradil was given and the testing repeated in 90 minutes. RESULTS: Though non-significantly in a study-group limited in size due to global withdrawal of mibefradil, sinus node automaticity was suppressed (prolongation of SNRT by 5.1% and CSNRT by 11.5%) and heart rate lowered (SNCL prolonged by 2.8%) comparatively more than was the negative dromotropic effect on the atrioventricular node (negligible prolongation of AH interval by 1.1% and WP cycle by 0.4%). CONCLUSIONS: Demonstrated electrophysiological effects of oral mibefradil with more pronounced influence on the automaticity of the sinus node seem to be in agreement with the preclinical data on the predominant role of T-channels in the pacemaker activity of the sinus node. According to the Framingham data on the risk of heart rate for the cardiovascular as well as all-cause mortality, calcium T-channel blockade offers a desirable profile for antihypertensive treatment. From this point of view development of new representatives of calcium T-channel blockers could be a useful contribution to clinical practice.

Adult↗
PubMed1995

Voltage-dependent blockade of diverse types of voltage-gated Ca2+ channels expressed in Xenopus oocytes by the Ca2+ channel antagonist mibefradil (Ro 40-5967).

Four different types of Ca2+ channel alpha 1 subunits, representing the major classes of voltage-gated Ca2+ channels, were individually coexpressed along with alpha 2/delta and beta 2b subunits in Xenopus oocytes. These subunits (and the encoded channel types and major tissues of origin) included alpha 1C (L-type, cardiac), alpha 1B (N-type, central nervous system), alpha 1A (P/Q-type, central nervous system), and alpha 1E (most likely R-type, central nervous system). Divalent cation currents through these channels (5 mM Ba2+) were evaluated with the two-microelectrode voltage-clamp technique. The expressed channels were compared with regard to their responses to a structurally novel, nondihydropyridine compound, mibefradil (Ro 40-5967). In the micromolar concentration range, this drug exerted clear inhibitory effects on each of the four channel types, reducing divalent cation current at all test potentials, with the non-L-type channels being more sensitive to inhibition than the L-type channels under fixed experimental conditions. For all channel types, mibefradil was a much more effective inhibitor at more depolarized holding potentials, suggesting tighter binding of the drug to the inactivated state than to the resting state. The difference in apparent affinities of resting and inactivated states of the channels, calculated based on a modulated receptor hypothesis, was 30-70-fold. In addition, the time course of decay of Ca2+ channel current was accelerated in the presence of drug, consistent with open channel block. The effect of increasing stimulation frequency was tested for L-type channels and was found to greatly enhance the degree of inhibition by mibefradil, consistent with promotion of block by channel opening and inactivation. Allowing for state-dependent interactions, the drug concentrations found to block L-, N-, Q-, and R-type channels by 50% are at least 10-fold higher than half-blocking levels previously reported for T-type channels in vascular smooth muscle cells under similar experimental conditions. This may help explain the ability of the drug to spare working myocardium (strongly negative resting potential, dominance of L-type channels in their resting state) while reducing contraction in blood vessels (presumably involving T-type channels or partially inactivated L-type channels). Thus, mibefradil is a new addition to the family of nonselective organic Ca2+ channel inhibitors, as exemplified by bepridil and fluspirilene, and may prove useful as an experimental tool for studying diverse physiological events initiated by Ca2+ influx. It complements classes of drugs with relatively selective effects on L-type channels, as exemplified by nifedipine and diltiazem.

Animals↗
PubMed1998

A comparison of the safety and efficacy of mibefradil and nifedipine SR in patients with renal disease and hypertension.

The antihypertensive efficacy and safety of mibefradil and nifedipine SR were compared in 143 patients with chronic renal failure and mild-to-moderate hypertension in a multicenter, double-blind, randomized, parallel-design study. At treatment week 12, a significantly greater decrease in sitting diastolic blood pressure (SDBP) was seen with mibefradil than with nifedipine SR (12.8 mmHg vs 8.1 mmHg, respectively; p = 0.014). A significantly greater number of mibefradil-treated patients achieved normalization of SDBP by week 12 (62% vs 37%; p < 0.01). The changes in renal function parameters and the incidence of adverse events were similar in both groups. In this population, 12 weeks of treatment with mibefradil were more effective than nifedipine SR for lowering blood pressure and had similar effects on renal function parameters.

Adult↗
PubMed1998

The relevance of T-type calcium antagonists: a profile of mibefradil.

L- and T-type voltage-dependent transmembrane calcium channels are important for normal functioning of the cardiovascular system. T-type channels are a heterogeneous group, and have physiologic and pathophysiologic relevance in a number of organ systems, including the heart and central nervous system. They appear to be involved in the control of blood pressure in patients with essential hypertension and in protection from ischemic damage. Alterations of both L- and T-type calcium channels are involved in the development of hypertension. Pharmacologic modulation of T-type calcium channels appears to reduce membrane calcium flux and ameliorate hypertension. During early ischemic damage, T-type calcium channels appear to remain functional whereas L-type channels are already inactivated. T-type calcium channels also appear to be involved in the development of supraventricular arrhythmias, some forms of arrhythmias in cardiomyopathy, and cardiac hypertrophy. The heterogeneity of T-type calcium channels should make it possible to target drugs to specific subgroups of T-type calcium channels. A new class of calcium antagonist, the benzimidazolyl-substituted tetraline derivatives, has been shown to block both L- and T-type calcium channels. The first member of this class approved for clinical use is mibefradil. Clinical studies have demonstrated the efficacy of mibefradil in lowering blood pressure and as an antianginal and antiischemic agent. At clinically recommended doses, mibefradil has a heart rate lowering effect without a negative inotropic effect, and a favorable side effect profile. Because it is metabolized by the cytochrome P450 pathway, it should be used cautiously with other agents similarly metabolized.

Animals↗
PubMed1999

Drug-drug interactions of new active substances: mibefradil example.

INTRODUCTION: Mibefradil was approved as a novel calcium antagonist in Switzerland in 1996. Following its launch as an antihypertensive and anti-anginal agent, there were reports about serious pharmacokinetic and pharmacodynamic interactions occurring with other drugs frequently administered to patients with cardiovascular diseases. Despite appropriate modifications of the prescribing information, such interactions continued to occur. The drug was finally withdrawn after a study in patients with congestive heart failure showed a trend to higher mortality with mibefradil. This increase in mortality could again be due to multiple interactions between mibefradil and other drugs. In retrospect, it can be concluded that several of the interactions, including the theoretical risk of severe toxicity in some patients, could have been and in fact were predicted on the basis of the data available before introduction to the market. Depending on the benefits, these problems would however not necessarily represent an unacceptable risk for a new active compound. RESULTS AND CONCLUSION: The most important points revealed by this analysis were: (1) when interpreting the results of interaction studies, it is important to consider not only the mean of the interaction effect but also the observed and the theoretically conceivable extreme effects in individual subjects and (2) a drug with a high interaction potential may represent a high risk even if an adequate warning is included in the product information. The need for specific pharmacokinetic and pharmacodynamic interaction studies with new drugs and the limitations of the pivotal clinical efficacy and safety studies during phase III in order to reveal such interactions are discussed.

Calcium Channel Blockers↗
PubMed1995

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. Ro 40-5967 International Study Group.

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.

Adult↗
PubMed2004

Mibefradil is more effective than verapamil for restoring post-ischemic function of isolated hearts of guinea pigs with acute renal failure.

The deleterious intracellular Ca(2+) overload in the ischemic-reperfusion injury of the heart can be even more expressed in subjects with acute renal failure in whom maintenance of intracellular Ca(2+) has already been disturbed in normoxia. To study the influence of acute renal failure in ischemic-reperfusion injury on the heart, we used isolated Langendorff's hearts of guinea pigs with gentamicin-induced acute renal failure. We examined arrhythmias, heart contractility and myocardial cell damage during reperfusion. Two specific Ca(2+) channel antagonists, mibefradil (0.1 and 1 microM) and verapamil (0.1 microM), were used to test the possible involvement of T-type and L-type Ca(2+) channels in these processes. We exposed hearts to 50 min of zero-flow global ischemia and 60 min of reperfusion. During reperfusion, unrecoverable ventricular fibrillation appeared more often in hearts of animals with acute renal failure than in control hearts (80% vs. 0%, respectively). Mibefradil, but not verapamil, applied either pre- or post-ischemically, terminated ventricular fibrillation in all hearts of animals with acute renal failure. Mibefradil (0.1 microM only) improved contractility in hearts of animals with acute renal failure during reperfusion by 30%. During reperfusion, lactate dehydrogenase (LDH) release rate increased less in hearts of guinea pigs with acute renal failure than in control hearts and only verapamil decreased it additionally. Thus, our results suggest a more important role of T- than of L-type Ca(2+) channels in ischemic-reperfusion injury in isolated guinea pig hearts with acute renal failure.

Acute Kidney Injury↗
PubMed1997

Mibefradil, a novel calcium antagonist, in elderly patients with hypertension: favorable hemodynamics and pharmacokinetics.

A multicenter, double-blind, placebo-controlled study of 310 elderly patients with mild-to-moderate essential hypertension was conducted in 20 sites throughout Europe, Brazil, and Israel to assess the antihypertensive efficacy, tolerability, safety, and dose-response characteristics of the novel calcium antagonist mibefradil in the elderly. Patients were randomly assigned to receive once-daily doses of 6.25, 12.5, 25, 50, or 100 mg of mibefradil or placebo for 4 weeks. Statistically significant and clinically relevant reductions in sitting diastolic blood pressure (SDBP) and sitting systolic blood pressure (SSBP) were observed with the 50 and 100 mg doses. Therapeutic responses reached 88.5% for SDBP and 76.5% for SSBP in the 100 mg group. Trough/peak ratios were > 75% in SDBP and SSBP with the 50 mg and 100 mg doses. At doses of 50 to 100 mg once daily, mibefradil was well tolerated and effective with a high antihypertensive response rate and consistent 24-hour blood pressure control in elderly patients.

Aged↗
PubMed1997

Pharmacologic and pharmacokinetic profile of mibefradil, a T- and L-type calcium channel antagonist.

Mibefradil is a recently introduced calcium antagonist that, as a tetralol derivative, is chemically distinct from previous calcium antagonists. This article will review pertinent results from in vitro, animal, and clinical investigations to report the pharmacologic properties that distinguish mibefradil from all of the calcium channel antagonists in use today, all of which operate on the "L-type" calcium channel. Mibefradil's pharmacokinetic profile indicates it can be used as a once-daily oral treatment for hypertension and chronic stable angina pectoris.

Animals↗