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PubMed2000

High affinity interaction of mibefradil with voltage-gated calcium and sodium channels.

Mibefradil is a novel Ca(2+) antagonist which blocks both high-voltage activated and low voltage-activated Ca(2+) channels. Although L-type Ca(2+) channel block was demonstrated in functional experiments its molecular interaction with the channel has not yet been studied. We therefore investigated the binding of [(3)H]-mibefradil and a series of mibefradil analogues to L-type Ca(2+) channels in different tissues. [(3)H]-Mibefradil labelled a single class of high affinity sites on skeletal muscle L-type Ca(2+) channels (K(D) of 2.5+/-0.4 nM, B(max)=56.4+/-2.3 pmol mg(-1) of protein). Mibefradil (and a series of analogues) partially inhibited (+)-[(3)H]-isradipine binding to skeletal muscle membranes but stimulated binding to brain L-type Ca(2+) channels and alpha1C-subunits expressed in tsA201 cells indicating a tissue-specific, non-competitive interaction between the dihydropyridine and mibefradil binding domain. [(3)H]-Mibefradil also labelled a heterogenous population of high affinity sites in rabbit brain which was inhibited by a series of nonspecific Ca(2+) and Na(+)-channel blockers. Mibefradil and its analogue RO40-6040 had high affinity for neuronal voltage-gated Na(+)-channels as confirmed in binding (apparent K(i) values of 17 and 1.0 nM, respectively) and functional experiments (40% use-dependent inhibition of Na(+)-channel current by 1 microM mibefradil in GH3 cells). Our data demonstrate that mibefradil binds to voltage-gated L-type Ca(2+) channels with very high affinity and is also a potent blocker of voltage-gated neuronal Na(+)-channels. More lipophilic mibefradil analogues may possess neuroprotective properties like other nonselective Ca(2+)-/Na(+)-channel blockers.

Animals↗
PubMed1999

Mibefradil potently blocks ATP-activated K(+) channels in adrenal cells.

Mibefradil is a novel Ca(2+) channel antagonist that preferentially blocks T-type Ca(2+) channels in many cells. Using whole-cell and single-channel patch-clamp recording, we found that mibefradil also potently blocked an ATP-activated K(+) channel (I(AC)) expressed by adrenal zona fasciculata cells. I(AC) channels were inhibited by mibefradil with an IC(50) value of 0.50 microM, a concentration 2-fold lower than that required to inhibit T-type Ca(2+) channels under similar conditions in the same cells. The inhibition of I(AC) by mibefradil was independent of the membrane potential. Mibefradil also reversibly blocked, with similar potency, unitary I(AC) currents recorded in outside-out membrane patches. An analysis of dwell time histograms indicated the presence of two closed and one open state. Mibefradil (1 microM) increased the duration of the two closed time constants (tau(c1) and tau(c2)) from 2.30 +/- 0.18 and 27.9 +/- 4.7 ms to 4.32 +/- 0.61 and 62.5 +/- 13.8 ms, respectively, but did not alter the open time constant (tau(o)). Mibefradil also failed to reduce the size of the unitary I(AC) current. A voltage-gated A-type K(+) current was also inhibited by mibefradil at concentrations approximately 10-fold higher than those required to block I(AC) (IC(50) = 4.65 microM). These results identify mibefradil as a potent inhibitor of ATP-activated K(+) channels in adrenal zona fasciculata cells. It appears to function by stabilizing closed states of these channels. In contrast to its selective block of T-type Ca(2+) channels, mibefradil may be a potent but less-selective K(+) channel blocker. In this regard, the block of K(+) channels may produce some of the toxicity associated with mibefradil in cardiovascular pharmacology.

Adenosine Triphosphate↗
PubMed1997

Mibefradil: a selective T-type calcium antagonist.

Mibefradil is the first of a new class of calcium antagonists with a unique structure and pharmacology. Its novel mechanism of action is characterized by L-type and selective T-type calcium channel blockade. Mibefradil is selective for smooth muscle over cardiac muscle and selectively dilates the coronary vasculature over the peripheral vasculature. In animal studies, mibefradil increases coronary blood flow during induced ischemia. In addition, in vitro studies demonstrated that mibefradil decreases smooth muscle proliferation in response to vascular injury. The most intriguing effects of mibefradil include a lack of negative inotropy and reflex tachycardia, as well as inhibition of pathologic hypertrophy and remodeling in response to vascular injury. In clinical trials, mibefradil (100 mg) was more effective than diltiazem dual-release capsules (360 mg) and as effective as amlodipine (10 mg) in treating mild-to-moderate hypertension; mibefradil (100 mg) also resulted in a greater reduction in sitting diastolic blood pressure than did nifedipine GITS (60 mg) in patients with moderate-to-severe hypertension. In patients with chronic stable angina, mibefradil (100 mg) was as effective as diltiazem SR capsules (120 mg) twice daily and more effective than amlodipine (10 mg) in improving exercise tolerance and reducing ischemic episodes. Mibefradil improved survival in a rat model of heart failure as effectively as the angiotensin-converting enzyme (ACE) inhibitor, cilazapril. The apparent lack of negative inotropic activity and neurohormonal activity with mibefradil, as well as its favorable effects on cardiac remodeling in experimental models, suggest that this agent may be beneficial in congestive heart failure. This hypothesis is being tested in the ongoing Mortality Assessment in Congestive Heart Failure (MACH-1) trial.

Angina Pectoris↗
PubMed2000

Effect of mibefradil on voltage-dependent gating and kinetics of T-type Ca(2+) channels in cortisol-secreting cells.

We have studied the effect of the Ca(2+) antagonist mibefradil on low voltage-activated T-type Ca(2+) channels in whole-cell patch clamp recordings from bovine adrenal zona fasciculata (AZF) cells. AZF cells are distinctive in expressing only T-type Ca(2+) channels, allowing the mechanism of pharmacological agents to be explored without interference from other Ca(2+) channels. The inhibition of T-type Ca(2+) channels by mibefradil was voltage- and use-dependent. When Ca(2+) currents were activated from holding potentials of -80 and -60 mV, mibefradil inhibited currents with IC(50) values of 1.0 and 0.17 microM, respectively. When T-type Ca(2+) current (I(T)) was activated from a holding potential of -90 mV in the presence of 2 microM mibefradil, a single voltage step to -10 mV inhibited I(T) by 16.2% +/- 2.9% (n = 10). With subsequent voltage steps, applied at 10-s intervals, block reached a steady-state value of 51.9% +/- 5.0% (n = 5). Mibefradil (1 microM) produced a leftward shift of 5.7 mV (n = 4) in the voltage-dependent steady-state availability curve such that T-type Ca(2+) channels inactivated at more negative potentials, but this drug did not change the voltage-dependence of T channel opening. Mibefradil failed to alter the kinetics of T channel activation, inactivation, or deactivation, but markedly slowed T channel recovery following an inactivating prepulse. Mibefradil inhibited adrenocorticotropin-stimulated cortisol secretion from AZF cells with an IC(50) value of 3.5 microM. These results show that mibefradil is a relatively potent antagonist of T-type Ca(2+) channels in cortisol-secreting cells. The enhanced potency of mibefradil with sustained or repetitive depolarizations, its shifting of the steady-state inactivation curve, and its slowing of recovery all indicate that this drug preferentially interacts with Ca(2+) channels in the open or inactivated state. The inhibition of cortisol secretion by mibefradil at concentrations similar to those that block I(T) is consistent with a requirement for these channels in corticosteroidogenesis.

Adrenocorticotropic Hormone↗
PubMed2000

Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro.

Mibefradil, a calcium T- and L-channel blocker developed for use in hypertension, was recently removed from the market after reports of severe drug-drug interactions. Mibefradil is known to inhibit various cytochrome P450 enzymes involved in drug metabolism, particularly CYP3A. However, the extent and the severity of the observed drug interactions in humans suggest that inhibition of additional systems important to drug disposition, such as the drug transporter P-glycoprotein (P-gp), may also have contributed to the severity of the mibefradil interactions. A polarized epithelial cell line, LLC-PK1, which does not express P-gp, and the derived L-MDR1 cell line, which overexpresses human P-gp, were used to study the effects of mibefradil on drug transport. A markedly greater basal-to-apical versus apical-to-basal transport of [H3]mibefradil was seen in the L-MDR1, but not in the LLC-PK1 cells, suggesting that the drug is a substrate of P-gp. Using a human intestinal cancer-derived cell line Caco-2, which constitutively expresses P-gp, mibefradil was shown to be a potent inhibitor of P-gp-mediated digoxin transport, with an IC50 of 1.6 microM. Additionally, the effect of mibefradil on CYP3A was assessed using human liver microsomes. Mibefradil inhibited CYP3A-mediated nifedipine oxidase activity with an IC50 of 0.8 microM, and a Ki of 0.6 microM. Thus, mibefradil is not only a P-gp substrate, but also a potent inhibitor of both P-gp and CYP3A. These data suggest that the severity of drug interactions seen with mibefradil use is due to the dual inhibition of both P-gp and CYP3A.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Haemodynamics, cardiac conduction and pharmacokinetics of mibefradil (Ro 40-5967), a novel calcium antagonist.

OBJECTIVES: Mibefradil (Ro40-5967) is a chemically novel non-dihydropyridine calcium antagonist. In this phase II study we compared its acute and chronic effects on blood pressure, heart rate and atrioventricular conduction (electrocardiographic PQ interval) with those of verapamil and diltiazem. PATIENTS AND METHODS: After a 4-week placebo run-in, 18 patients with mild to moderate essential hypertension were given single doses of mibefradil (150 mg), slow-release (SR) verapamil (240 mg), diltiazem (240 mg) and placebo at weekly intervals; pharmacokinetics and the effects on blood pressure, heart rate and PQ interval were studied on four 10-h study days. Seventeen of the same patients subsequently underwent 4 weeks of treatment with either mibefradil (100 mg daily; n = 10) or verapamil SR (240 mg daily; n = 7), and on the last day, they attended a further 10-h study day. Two studies were conducted: an acute, single-dose, double-blind, randomly allocated, placebo-controlled, crossover study and a chronic, open-label, randomly allocated, parallel-group study. RESULTS: Mibefradil was well tolerated. In the acute study, the antihypertensive effect (difference from placebo) of mibefradil 150 mg was of slower onset than that of verapamil or diltiazem, but comparable blood pressure reductions had been achieved by 6 h. The mean +/- SD maximal PQ prolongation (difference from placebo) was 15.6 +/- 16.1 ms, compared with 44.0 +/- 22.6 ms for verapamil and 56.0 +/- 48.9 ms for diltiazem (P<0.05 mibefradil versus verapamil; P<0.01 mibefradil versus diltiazem). In the chronic study there were no significant differences during steady-state conditions between mibefradil at 100 mg and verapamil SR at 240 mg in their effects on blood pressure, PQ and heart rate. The mean +/- SD elimination half-life (t1/2) of mibefradil under steady-state conditions was 26.8 +/- 5.5 h (versus an apparent t1/2 of 16.9 +/- 11.1 h for verapamil SR, P<0.05). CONCLUSIONS: Mibefradil is a well-tolerated and efficacious antihypertensive agent well suited to single daily dosing because of its intrinsic long plasma half-life. The effects on both blood pressure and PQ interval are of more gradual onset than those of unmodified verapamil and diltiazem after single doses.

Adolescent↗
PubMed1997

Additional antianginal and anti-ischemic efficacy of mibefradil in patients pretreated with a beta blocker for chronic stable angina pectoris.

This study assessed the safety, tolerability, and efficacy of mibefradil when added to beta-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive double-blind treatment with either placebo (n = 70), mibefradil 25 mg (n = 67), or mibefradil 50 mg (n = 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 +/- 51 seconds; p = 0.036), time to onset of angina (48 +/- 65 seconds; p = 0.002), and time to persistent 1-mm ST-segment depression (47 +/- 77 seconds; p = 0.004). Greater reductions in heart rate, blood pressure, and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (-2.1 +/- 4.0, p = 0.020) compared with placebo. The addition of mibefradil to existing beta-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable beta-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated.

Adrenergic beta-Antagonists↗
PubMed1997

Safety of mibefradil, a new once-a-day, selective T-type calcium channel antagonist.

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.

Aged↗
PubMed1998

Antioxidant and cytoprotective activities of the calcium channel blocker mibefradil.

Mibefradil is a new calcium channel antagonist (CCA) that acts on both L- and T-type channels, with 10-fold selectivity for T-type channels. In this study, the structural interactions of mibefradil with cardiac membrane lipid bilayers were directly examined with small-angle x-ray diffraction approaches and correlated with lipid peroxidation and bovine aortic endothelial cell viability assays. Electron density profiles (A vs electrons/A3) calculated from the diffraction data (37 degrees C) demonstrated that mibefradil had an equilibrium location in the hydrocarbon core/headgroup region of the cardiac bilayer, 12-27 A from the center of the membrane. Mibefradil also effected a pronounced reduction in electron density 0-11 A from the center of the cardiac membrane concomitant with a 7.5% (3 A) decrease in membrane hydrocarbon core thickness; these changes in membrane structure were not observed with the phenylalkylamine verapamil, a CCA with some structural similarity to mibefradil. As a result of membrane physico-chemical interactions, mibefradil inhibited (10-500 nM) lipid peroxide formation in liposomes enriched in polyunsaturated fatty acids. In aortic endothelial cells, mibefradil also inhibited loss of cell viability (IC50 of 2 microM) following acute oxy-radical generation by dihydroxyfumarate and Fe-ADP; the order of potency was mibefradil > verapamil > diltiazem. These findings indicate that the chemical structure of mibefradil contributes to biophysical interactions with the cell membrane that underlie antioxidant and cytoprotective activities in models of oxidative stress.

Animals↗
PubMed1997

Increased survival after long-term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure.

OBJECTIVES: We sought to investigate the effects of mibefradil on survival, hemodynamic variables and cardiac remodeling in a rat model of chronic heart failure (HF) and to compare these effects with those of the angiotensin-converting enzyme (ACE) inhibitor cilazapril. BACKGROUND: The use of calcium channel blocking agents in chronic HF has been disappointing. Most studies have shown that these drugs have either no or even detrimental effects due in part to the negative inotropic effects they induce. Mibefradil is a calcium channel blocker that selectively blocks T channels and displays moderately negative inotropic properties only at high doses. Because T channels are upregulated in the hypertrophied heart and could mediate hypertrophic signals and increase arrhythmogenicity, blockade of these channels might be beneficial in chronic HF. METHODS: Rats were subjected to coronary artery ligation and 9 months of treatment with mibefradil (15 mg/kg body weight per day) or cilazapril (10 mg/kg per day) or no treatment. Survival and systolic blood pressure were assessed over the 9-month treatment period, after which cardiac hemodynamic variables and structure were determined. RESULTS: Mibefradil increased survival rate to the same extent as cilazapril (71% for mibefradil vs. 75% for cilazapril and 44% for no treatment). Mibefradil decreased systolic blood pressure, although to a lesser extent than cilazapril. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures, without any change in the first derivative of LV pressure over time or heart rate. Mibefradil decreased LV weight (although less than cilazapril) without affecting right ventricular weight. Finally, both drugs normalized LV collagen density. CONCLUSIONS: Mibefradil in a rat model improved survival to the same extent as an ACE inhibitor, without impairing LV function, and was associated with a reduction in LV weight and fibrosis. Thus, mibefradil might be beneficial in the treatment of chronic HF.

Animals↗
PubMed1997

Inhibition by mibefradil, a novel calcium channel antagonist, of Ca(2+)- and volume-activated Cl- channels in macrovascular endothelial cells.

1. We have studied the effects of mibefradil, a novel calcium antagonist, on the resting potential and ion channel activity of macrovascular endothelial cells (calf pulmonary artery endothelial cells, CPAE). The patch clamp technique was used to measure ionic currents and the Fura-II microfluorescence technique to monitor changes in the intracellular Ca2+ concentration, [Ca2+]i. 2. Mibefradil (10 microM) hyperpolarized the membrane potential of CPAE cells from its mean control value of -26.6 +/- 0.6 mV (n = 7) to -59.8 +/- 1.7 mV (n = 6). A depolarizing effect was observed at higher concentrations (-13.7 +/- 0.6 mV, n = 4, 30 microM mibefradil). 3. Mibefradil inhibited Ca(2+)-activated Cl- currents, ICl,Ca, activated by loading CPAE cells via the patch pipette with 500 nM free Ca2+ (Ki = 4.7 +/- 0.18 microM, n = 8). 4. Mibefradil also inhibited volume-sensitive Cl- currents, ICl,vol, activated by challenging CPAE cells with a 27% hypotonic solution (Ki = 5.4 +/- 0.22 microM, n = 6). 5. The inwardly rectifying K+ channel, IRK, was not affected by mibefradil at concentrations up to 30 microM. 6. Ca2+ entry activated by store depletion, as assessed by the rate of [Ca2+]i-increase upon reapplication of 10 mM extracellular Ca2+ to store-depleted cells, was inhibited by 17.6 +/- 6.5% (n = 8) in the presence of 10 microM mibefradil. 7. Mibefradil inhibited proliferation of CPAE cells. Half-maximal inhibition was found at 1.7 +/- 0.12 microM (n = 3), which is similar to the concentration for half-maximal block of Cl- channels. 8. These actions of mibefradil on Cl- channels and the concomitant changes in resting potential might, in addition to its effect on T-type Ca2+ channels, be an important target for modulation of cardiovascular function under normal and pathological conditions.

Animals↗
PubMed1999

Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam.

BACKGROUND: The calcium channel blockers mibefradil and isradipine inhibit CYP3A4 in vitro. However, their in vivo inhibitory effects on CYP3A4 are not known in detail, although mibefradil was recently withdrawn from the market because of serious drug interactions. METHODS: The effects of mibefradil and isradipine on the pharmacokinetics and pharmacodynamics of oral triazolam, a model substrate of CYP3A4, were studied in a randomized, double-blind crossover study with three phases. Nine healthy subjects took 50 mg mibefradil, 5 mg isradipine, or placebo orally once a day for 3 days. On day 3, each subject received a single 0.25 mg oral dose of triazolam. Thereafter, blood samples were collected up to 18 hours, and pharmacodynamic effects of triazolam were measured up to 8 hours. RESULTS: Mibefradil increased the total area under the plasma triazolam concentration-time curve [AUC(0 - infinity)] 9-fold compared with placebo (P < .001). The peak plasma concentration of triazolam was increased 1.8-fold (3.4+/-0.1 ng/mL versus 1.8+/-0.2 ng/mL [mean +/- SEM]; P < .001), and the elimination half-life (t 1/2) was increased 4.9-fold (18.5+/-1.9 hours versus 4.0+/-0.5 hours; P < .001) by mibefradil. In addition, mibefradil was associated with increased pharmacodynamic effects of triazolam. In contrast to mibefradil, isradipine reduced the AUC(0 - infinity) and t 1/2 of triazolam by about 20% (P < .05) and had no significant effects on the pharmacodynamics of triazolam. CONCLUSION: Mibefradil but not isradipine markedly increases the plasma concentrations of triazolam and thereby enhances and prolongs its pharmacodynamic effects, consistent with potent inhibition of CYP3A4.

Administration, Oral↗
PubMed1998

Pharmacokinetic interaction between oral cyclosporin and mibefradil in stabilized post-renal-transplant patients.

BACKGROUND: The potential for interaction between oral cyclosporin (Sandimmun) and the new calcium antagonist mibefradil was assessed as part of the clinical development of the new compound. METHODS: Six stable renal transplant patients on long-term, oral, twice-daily (Q 12 H) cyclosporin (CsA) therapy received 25 mg mibefradil on Day 1, followed by 50 mg once daily for 5 or 6 days. At baseline, as well as on the last day of mibefradil dosing, complete steady-state CsA blood concentration-time profiles were characterized over a dosing interval. RESULTS: Mibefradil led to mean increases in minimum and maximum CsA blood concentrations and area under the curve of CsA by 2.7-, 2.1-, and 2.3-fold, respectively (all significantly different from CsA alone, P < 0.02). Mibefradil is therefore associated with a clinically relevant increase in CsA blood concentrations. The mechanism of elevation of CsA blood concentrations is probably mibefradil and/or metabolite inhibition of the cytochrome P-450 isoenzyme 3A4. CsA had no clinically significant effect on mibefradil plasma concentrations. CONCLUSIONS: These results confirm previous findings of cytochrome P-450 3A4 inhibition by mibefradil and suggest that, for patients receiving CsA, its dose must be adjusted and its plasma concentration must be monitored when adding or stopping mibefradil.

Administration, Oral↗
PubMed1999

Mibefradil prevents L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats.

OBJECTIVE: To determine the potential renal protective effects of a novel calcium channel blocker mibefradil in chronic renal failure. METHOD: We compared the long-term effects of mibefradil with an angiotensin-converting enzyme inhibitor cilazapril on blood pressure, proteinuria, renal function and histological alterations in N-nitro-L-arginine methylester (L-NAME)-treated spontaneously hypertensive rats (SHR). Three groups of SHR were studied for 45 days: group 1 (n = 14), treated with L-NAME only (50 mg/l in the drinking water); group 2 (n = 15) L-NAME plus co-treatment with mibefradil (30 mg/kg per day); group 3 (n = 15), L-NAME plus co-treatment with cilazapril (10 mg/kg per day). RESULTS: Both mibefradil and cilazapril attenuated the increased systolic blood pressure, and prevented the development of proteinuria and the decreased creatinine clearance (Ccr) seen at day 42 in the group treated with L-NAME alone. Notably, mibefradil had similar effects to cilazapril on proteinuria and Ccr, despite a reduced antihypertensive effect All animals receiving mibefradil co-treatment remained alive throughout the experiment, whereas the mortality rate was 43% in SHR treated with L-NAME alone. Both mibefradil and cilazapril completely prevented renal structural damage as assessed by scoring glomerular, tubulo-interstitial and vascular lesions. CONCLUSIONS: Our data show that mibefradil prevented the development of hypertension and proteinuria, renal functional impairment and nephrosclerosis, and also improved animal survival. The renal protective effects of mibefradil were at least equivalent to those of an ACE inhibitor in this animal model of chronic renal failure.

Animals↗
PubMed1999

Mibefradil, a potent CYP3A inhibitor, does not alter pravastatin pharmacokinetics.

Dramatic drug-drug interactions have been observed between several HMG-CoA reductase inhibitors and cytochrome P450 3A (CYP3A) inhibitors. The aim of the present study was to investigate the effects of mibefradil, a potent CYP3A inhibitor, on pravastatin pharmacokinetics. 12 healthy volunteers were included in this open-label one-period study. Pravastatin pharmacokinetics (following a single oral dose of 40 mg) was studied in the absence of mibefradil (day 1) and after repeated doses (100 mg/day) of mibefradil (day 8). Pravastatin pharmacokinetics after repeated doses of 40 mg/day was also studied in association with repeated doses (100 mg/day) of mibefradil (day 16). Pravastatin area under the plasma concentration vs. time curve (AUC0-infinity) and Cmax in the absence of mibefradil on day 1 (170 [117 to 395] ng h/mL and 91 [72 to 200] ng/mL respectively, geometric mean [95% confidence intervals]) were not significantly altered in the presence of mibefradil on day 8 (224 [174 to 381] ng h/mL and 124 [72 to 200] ng/mL) and on day 16 (200 [137 to 555] ng h/mL and 91 [74 to 184] ng/mL). Tmax of pravastatin in the absence of mibefradil (0.9 +/- 0.1 h, arithmetic mean +/- SD) was slightly delayed in the presence of mibefradil on day 8 and 16 (1.1 +/- 0.3 and 1.2 +/- 0.3 h respectively, p < 0.01 for both comparisons). The results of the present study confirm the lack of pharmacokinetic interactions between mibefradil and pravastatin and indicate that pravastatin may be safely prescribed in the presence of potent CYP3A inhibitors.

Adult↗
PubMedDate not supplied

Comparison of the efficacy and safety of losartan (50-100 mg) with the T-type calcium channel blocker mibefradil (50-100 mg) in mild to moderate hypertension.

The objective of this study was to compare the antihypertensive efficacy and safety of losartan and mibefradil. 324 outpatients (57 +/- 9.2 years) with mild to moderate hypertension were randomly allocated in a double-blind fashion to receive 50 mg of losartan or mibefradil once daily p.o. for 6 weeks after 2 weeks of placebo run-in. Titration was then forced to 100 mg of losartan or mibefradil for an additional 6 weeks. Patients were assessed at baseline, 6 and 12 weeks. The primary efficacy variable was change in predose sitting diastolic (SDBP) and systolic (SSBP) blood pressure at 12 weeks. Secondary variables included change in mean 24-hour ambulatory blood pressure and comparison of safety and tolerability. Both treatments lowered SSBP and SDBP at 6 and 12 weeks (week 6: mibefradil -14/-9 mm Hg; losartan -12/-7 mm Hg) (P <0.001). The primary objective, a difference between treatments in reduction of SSBP and SDBP at week 12 could be demonstrated (mibefradil -22/-16 mm Hg; losartan -16/-10 mm Hg) (P=0.003 and P=0.001, respectively). Twenty-four-hour SBP and 24-hour DBP were reduced (P<0.001) within each treatment group at weeks 6 and 12. The secondary objective, a difference between treatments in reduction of 24-hour blood pressure at week 12 could be demonstrated (P<0.001). Twenty-four-hour heart rate was lowered in the mibefradil group at weeks 6 and 12 (P < 0.001). Responder rates at 6 and 12 weeks were 56.2% and 78.5% for mibefradil versus 56.1% and 55.3% for losartan (P = 0.001). Both treatments were equally well tolerated. This study demonstrates that 50 mg losartan is comparably effective to 50 mg mibefradil in the treatment of mild to moderate hypertension with 100 mg mibefradil being more potent than losartan.

Adolescent↗
PubMed2004

State-dependent mibefradil block of Na+ channels.

Mibefradil is a T-type Ca2+ channel antagonist with reported cross-reactivity with other classes of ion channels, including K+, Cl-, and Na+ channels. Using whole-cell voltage clamp, we examined mibefradil block of four Na+ channel isoforms expressed in human embryonic kidney cells: Nav1.5 (cardiac), Nav1.4 (skeletal muscle), Nav1.2 (brain), and Nav1.7 (peripheral nerve). Mibefradil blocked Nav1.5 in a use/frequency-dependent manner, indicating preferential binding to states visited during depolarization. Mibefradil blocked currents of all Na+ channel isoforms with similar affinity and a dependence on holding potential, and drug off-rate was slowed at depolarized potentials (k(off) was 0.024/s at -130 mV and 0.007/s at -100 mV for Nav1.5). We further probed the interaction of mibefradil with inactivated Nav1.5 channels. Neither the degree nor the time course of block was dependent on the stimulus duration, which dramatically changed the residency time of channels in the fast-inactivated state. In addition, inhibiting the binding of the fast inactivation lid (Nav1.5 ICM + MTSET) did not alter mibefradil block, confirming that the drug does not preferentially interact with the fast-inactivated state. We also tested whether mibefradil interacted with slow-inactivated state(s). When selectively applied to channels after inducing slow inactivation with a 60-s pulse to -10 mV, mibefradil (1 microM) produced 45% fractional block in Nav1.5 and greater block (88%) in an isoform (Nav1.4) that slow-inactivates more completely. Our results suggest that mibefradil blocks Na+ channels in a state-dependent manner that does not depend on fast inactivation but probably involves interaction with one or more slow-inactivated state(s).

Calcium Channel Blockers↗
PubMed1998

Anti-anginal and anti-ischemic effects of mibefradil, a new T-type calcium channel antagonist.

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 beta-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.

Adolescent↗