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PubMed1998

Effect of the novel T-selective calcium channel antagonist mibefradil on kidney function in comparison with amlodipine.

In the present study, the renal effects of mibefradil (CAS 116666-63-8), a novel calcium channel antagonist which more selectively blocks T-type than L-type calcium channels, was tested by applying clearance techniques to anaesthetized rats. The effects of mibefradil on kidney function and on arterial blood pressure were compared with those of the long acting dihydropyridine-type calcium antagonist amlodipine (CAS 88150-42-9). The results show that, within a dosage range of 0.1 to 1.0 mg/kg i.v., mibefradil induced a dose-dependent decrease of arterial blood pressure. Kidney function was not significantly affected at a dose of 0.1 mg/kg. By increasing the dose to 0.3 mg/kg, mibefradil induced a significant increase in urine flow, renal sodium, chloride and potassium excretion. Also fractional sodium and chloride excretions were significantly enhanced at this dose. The diuretic and saluretic effects of mibefradil were accompanied by a significant increase in the glomerular filtration rate. At the highest dose of 1 mg/kg used, the blood pressure lowering effect of mibefradil was most pronounced and glomerular filtration rate rose only slightly and not significantly. At this dose, the enhancement of urine flow and urinary electrolyte excretion was smaller than at the dose of 0.3 mg/kg. The actions of mibefradil were qualitatively similar to those of the dihydropyridine derivate amlodipine which at a dose of 0.3 mg/kg produced nearly identical renal effects to mibefradil, but exerted stronger antihypertensive effects. This study demonstrates that mibefradil shares with amlidopine the property to induce, at appropriate doses, diuretic and saluretic effects with a concomitant increase in glomerular filtration rate.

Amlodipine↗
PubMed1996

Prevention of neointima formation by mibefradil after vascular injury in rats: comparison with ACE inhibition.

Cilazapril, an angiotensin-converting enzyme inhibitor, and mibefradil, a selective T-type voltage-operated calcium channel blocker, have been shown to prevent neointima formation after vascular injury. The goal of the present study was to evaluate the mechanism of action of both drugs. For this purpose, the influence of the renin angiotensin system on the effects of mibefradil (30 mg/kg po) and cilazapril (10 mg/kg po) on neointima formation after carotid injury were evaluated in normotensive rats (normal renin angiotensin system) and DOCA hypertensive rats (suppressed renin angiotensin system). In addition, in order to differentiate an effect on cell migration or cell proliferation, both drugs were given either before or after the smooth muscle migration phase. Finally, cilazapril and mibefradil were given in combination. In normotensive rats, mibefradil and cilazapril decreased neointima formation, resulting in neointima/media ratios of 38% (p < 0.05) and 53% (p < 0.01), respectively. However, in DOCA hypertensive rats, mibefradil was active, with a reduction of the neointima/media ratio by 63% (p < 0.001), whereas cilazapril reduced it only slightly (19%) and not significantly. In addition, cilazapril was active only when treatment started before the migration phase (63%, reduction in neointima/media ratio, p < 0.001) but not when started thereafter (13% reduction in neointima/media ratio, n.s.). In contrast, treatment with mibefradil was also active when started after the migration phase (51% reduction in neointima/ media ratio, p < 0.001 when treatment started 1 day before balloon injury and 41%, p < 0.01 when treatment started 5 days after balloon injury). The combination of both drugs was additive (67% reduction in neointima/media ratio, p < 0.001 vs. control). These experiments clearly show that mibefradil and cilazapril have a different mechanism of action after vascular injury. Mibefradil most likely prevents the proliferation of smooth muscle cells. In contrast, cilazapril most likely inhibits the migration of smooth muscle cells. These two different mechanisms of action explain why the effects of both drugs are additive.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Antioxidative action of the novel calcium channel antagonist mibefradil on low-density lipoproteins.

OBJECTIVE: Mibefradil is a novel calcium channel antagonist that selectively blocks T-channels. It acts to reduce hypertension, is cardioprotective and reduces ischemic episodes. Oxidative modification of low-density lipoproteins (LDL) is well known to contribute to coronary atherosclerosis and we therefore investigated to see whether mibefradil had antioxidative action on LDL. METHODS: Human LDL were isolated by ultracentrifugation. In vitro oxidation of LDL (0.1 micromol x l(-1) protein) in the presence of various concentrations of mibefradil was initiated by 3.2 micromol x l(-1) copper ions. The kinetics of formation of conjugated dienes was followed photometrically. Malondialdehyde and lipoperoxides were determined at maximum oxidation. LDL (0.3 micromol x l(-1)) were also pre-incubated with mibefradil (120 micromol x l(-1)). Excessive mibefradil was separated by column technique. The resultant LDL were oxidized using copper ions or (AAPH) 2,2'-azobis(2-amidinopropane) hydrochloride. RESULTS: The presence of mibefradil in the concentration range from 10 to 200 micromol x l(-1) had dose-dependent effects. These were protection of LDL against oxidation measured as prolongation of the lagtime up to 250%, and reduction in the formation of malondialdehyde down to 65% and of lipoperoxides to 20%. Pre-incubation of LDL with mibefradil prolonged the lagtime of Cu-mediated oxidation up to 132% and of AAPH-mediated oxidation up to 138%. CONCLUSION: In addition to the T-channel blocking and antiproliferative effects, our results provide arguments for a protective role of mibefradil (10-200 micromol x l(-1)) on LDL against in vitro oxidation. This was shown with three independent parameters (lagtime, malondialdehyde and lipoperoxides) and in different oxidation models.

Amidines↗
PubMed2004

The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon.

OBJECTIVES: The aim of the study was to assess the angiographic and clinical benefits of the calcium T-channel blocker, mibefradil, in the coronary slow flow phenomenon (CSFP). BACKGROUND: The CSFP is characterized by delayed vessel opacification on angiography (Thrombolysis In Myocardial Infarction [TIMI]-2 flow) in the absence of obstructive epicardial coronary disease and is often associated with recurrent chest pain. METHODS: A total of 10 CSFP patients (46 +/- 9 years) underwent angiography before and 30 min after 50 mg mibefradil; off-line blinded analysis of angiographic data included comparisons of epicardial vessel diameter, TIMI flow grade and TIMI frame count. We also performed a randomized, double-blind, placebo-controlled, cross-over study to examine the long-term efficacy of mibefradil 100 mg/day on the frequency of total angina, prolonged angina (i.e., persisting >20 min) episodes, and sublingual nitrate consumption, during consecutive one-month treatment periods in 20 patients (age 51 +/- 12 years) with the CSFP. RESULTS: Without changing epicardial vessel diameter or rate-pressure product, mibefradil reduced the number of vessels exhibiting TIMI-2 flow from 18 to 5; furthermore, mibefradil significantly improved the TIMI frame count only in those vessels exhibiting TIMI-2 flow (28 +/- 18%, p < 0.005). Compared with placebo, mibefradil significantly reduced total angina frequency by 56% (p < 0.001), prolonged episodes of angina by 74% (p < 0.001), and sublingual nitrate consumption by 59% (p < 0.01); furthermore, mibefradil improved physical quality of life as assessed by the Health Outcome Study Short Form-36. CONCLUSIONS: These angiographic and clinical improvements produced by mibefradil support a microspastic pathogenesis of the CSFP.

Adult↗
PubMed1997

Antianginal and anti-ischemic effects of mibefradil in the treatment of patients with chronic stable angina pectoris.

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 beta 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 beta-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.

Aged↗
PubMed1998

Effects of the calcium channel antagonist mibefradil on haemodynamic and morphological parameters in myocardial infarction-induced cardiac failure in rats.

OBJECTIVE: Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Mibefradil is a CCA featuring a selective blockade of T-type Ca2(+)-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and morphological parameters in a model of postMI chronic heart failure and to establish the "therapeutic window" for the start of therapy. METHODS: MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were assigned to placebo- or mibefradil-treated (10 mg/kg/day p.o.) groups as follows: (1) sham operation; (2) MI placebo treatment; (3) 7 days preMI start of treatment; (4) 3 h postMI start of treatment; (5) 24 h postMI start of treatment; (6) 3 days postMI start of treatment; (7) 7 days postMI start of treatment. Treatment was continued for 6 weeks postMI. At this time point, mean arterial blood pressure (MAP), heart rate, left ventricular enddiastolic pressure (LVEDP) and contraction force (dP/dtmax) were measured in conscious rats at baseline and after methoxamine (MEX; 0.5-1.0 mg/h i.v.) stimulation to increase afterload. The hearts were subjected to histological determination of infarct size (IS), infarct length (IL), noninfarcted length (NL), left ventricular circumference (LVC), inner LV-diameter (LVD) and septal thickness (ST). RESULTS: Six weeks after MI, MAP was lowered, LVEDP increased and dP/dtmax reduced. Mibefradil treatment increased basal MAP in groups 3-5 compared to the placebo-treated MI group. Under mibefradil, LVEDP was reduced at baseline in groups 3-6 and, after MEX, in all groups. dP/dtmax was increased in groups 3-4 at baseline and after MEX. In the placebo-treated MI group, the infarcted area was 39% of the LV and heart weight, LVD and LVC were increased. Heart weights of mibefradil-treated rats (groups 3-6) did not differ from those of the placebo-treated group. Early onset of treatment with mibefradil reduced IS and IL and increased NL in groups 3-4. LVD and LVC were decreased in group 3 only. ST was increased in groups 3-5. CONCLUSION: Chronic treatment with mibefradil exerts beneficial actions on cardiac structure and performance in postMI cardiac failure in rats, especially when the onset of treatment is either prior to or within hours after the acute ischemic event.

Analysis of Variance↗
PubMed1998

Effects of mibefradil, a novel calcium channel blocking agent with T-type activity, in acute experimental myocardial ischemia: maintenance of ventricular fibrillation threshold without inotropic compromise.

OBJECTIVES: We tested whether mibefradil, a selective T-type calcium channel blocking agent, could differentially inhibit experimental ventricular arrhythmogenesis more than contractility during acute regional ischemia and reperfusion compared with that during L-channel blockade by verapamil. BACKGROUND: T-type calcium channels are found in nodal and conduction tissue and in vascular smooth muscle, but in much lower density in contractile myocardium. The potential role of mibefradil in ventricular arrhythmogenesis remains unclear. METHODS: Mibefradil (Ro 40-5967, 1 mg/kg body weight intravenously [i.v.]) was given as a bolus 30 min before anterior descending coronary artery ligation, followed by 2 mg/kg per h i.v. during 20 min of ischemia and 25 min of reperfusion in open chest pigs. In a second group, mibefradil was given in a dose twice as high. A third group received verapamil (0.3 mg/kg i.v.), followed by an infusion of 0.6 mg/kg per h. RESULTS: During the ischemic period, the low (clinically relevant) dose of mibefradil prevented the fall of the ventricular fibrillation threshold, without depressing the maximal rate of pressure development of the left ventricle (LVmax dP/dt). This low dose increased left ventricular blood flow, whereas peripheral arterial pressure remained unchanged. The higher dose of both mibefradil and verapamil was antiarrhythmic during ischemia, at the cost of depressed contractile activity. During reperfusion, only the higher dose of mibefradil and verapamil was antiarrhythmic but both depressed contractile activity. CONCLUSIONS: Mibefradil is antiarrhythmic, without inotropic compromise. Speculatively, both T-type and L-type calcium channel blockade are involved in these effects.

Animals↗
PubMed1998

Mibefradil, a T-type channel-selective calcium antagonist: clinical trials in chronic stable angina pectoris.

Pharmacotherapy with nitrates, beta-blockers, and calcium antagonists is the cornerstone of management of patients with chronic stable angina pectoris. While these agents are all effective, their use may be limited by pharmacologic tolerance, side effects, and drug interactions. Mibefradil is a recently developed calcium antagonist with a unique chemical structure, pharmacologic profile, and mode of action. Unlike all previously available calcium antagonists, mibefradil acts primarily by selective blockade of T-type calcium channels, rather than L-type channels, at clinically relevant concentrations. It has been evaluated as a treatment for angina in placebo-controlled and active-controlled clinical trials. Treatment with 50 mg mibefradil resulted in a significant improvement in exercise tolerance test duration in three of the five placebo-controlled trials, and a significant improvement in time to onset of angina in two of the five trials. Time to onset of ischemia as evaluated by 0.1 mV ST-segment depression was increased in all five placebo-controlled trials. Treatment with 100 mg mibefradil resulted in significant improvement in all three exercise tolerance test parameters in all studies. Mibefradil further improved exercise tolerance test duration and other efficacy parameters when administered concomitantly to patients on background beta-blocker or nitrate therapy. In addition, treatment with mibefradil was associated with a dose-dependent decrease in heart rate, double product, frequency of anginal attacks, nitroglycerin consumption, and both frequency and duration of silent ischemic episodes. In comparative trials, 100 mg mibefradil once daily was superior in efficacy to 10 mg amlodipine once daily and was at least equivalent to diltiazem in both efficacy and tolerability. Mibefradil was safe and well tolerated in all studies.

Amlodipine↗
PubMed2001

Effects of mibefradil, a T- and L-type calcium channel blocker, on cardiac remodeling in the UM-X7.1 cardiomyopathic hamster.

Abnormalities of T-type calcium channel function reported to occur in the transition phase to heart failure in the hamster cardiomyopathy may contribute to progression of the disease. We tested the hypothesis that chronic exposure to mibefradil, a selective T-type calcium channel blocker, improves the deleterious cardiac remodeling observed in this condition. In the present study, 40 normal (N) and 40 UM-X7.1 cardiomyopathic hamsters (CMH), aged 180 days, were treated daily by gavage for 21 days with mibefradil (30 mg/Kg). Eight to 10 animals from each group were sacrificed at the end of the treatment period while the remainder were followed for an additional 30 days without treatment (washout period). Hearts were harvested, fixed with 10%-buffered paraformaldehyde and then cut in half down the middle. Several slices were dehydrated, embedded in paraffin and stained with Masson Trichrome. Wall thickness and dilatation index of the left ventricle were estimated by planimetry. Myocardial capillary density was also computed. The greater heart weight/body weight ratio seen in untreated CMH (7.7 +/- 0.4 vs 5.5 +/- 0.2 in N, p < 0.05) was improved with mibefradil. The dilatation index averaged 0.504 +/- 0.04 in N was increased in untreated CMH (0.566 +/- 0.03) and ameliorated in mibefradil-treated CMH. The 1-month washout period led to further deterioration of the dilatation index in untreated and mibefradil-treated CMH. Capillary density averaged 10,000 +/- 781 per mm2 in hearts from untreated N hamsters and 8,830 +/- 795 per mm2 in untreated CMH (p = NS). Chronic exposure to mibefradil resulted in a significant reduction of capillary density in both N and CMH hearts. Following the 1-month washout period, the change in myocardial capillary density associated with mibefradil was no longer detectable. In conclusion, chronic exposure to mibefradil, a T- and L-type calcium channel blocker, exerts opposite effects during the transition phase to heart failure in CMH, improving the deleterious left ventricular remodeling in UM-X7.1 hamsters and reducting myocardial capillary density independently of the disease process.

Animals↗
PubMed2000

Effects of mibefradil and nifedipine on arteriolar myogenic responsiveness and intracellular Ca(2+).

1. Ca(2+) entry mechanisms underlying spontaneous arteriolar tone and acute myogenic reactivity remain uncertain. These studies aimed to compare the effects of nifedipine and the putative T-channel blocker, mibefradil, on arteriolar myogenic responsiveness and intracellular Ca(2+) (Ca(2+)(i)). 2. First order cremaster muscle arterioles (1A) were isolated from rats, cannulated, pressurized to 70 mmHg in the absence of intraluminal flow, and mechanical responses studied by video microscopy. The Ca(2+)(i) was measured using fluorescence imaging of Fura 2 loaded arterioles. 3. Both nifedipine and mibefradil showed dose-dependent inhibition of spontaneous myogenic tone (at 70 mmHg; pEC(50) 7.04+/-0.17 vs 6.65+/-0.20 respectively, n=6 for both, n.s.) and KCl-induced vasoconstriction (at 70 mmHg; pEC(50) 6.93+/-0. 38 vs 6.45+/-0.27 respectively, n=6 for both, n.s.). 4. In arterioles maintained at 50 mmHg, nifedipine (10(-7) and 10(-5) M) caused a concentration dependent reduction in Ca(2+)(i), however, mibefradil (10(-7) and 10(-5) M) had no effect. Furthermore nifedipine significantly attenuated the increase in Ca(2+)(i) associated with an acute pressure step (50 - 120 mmHg) whereas mibefradil was considerably less effective. 5. Mibefradil (10(-7) M) significantly attenuated contractile responses to 60 mM KCl without altering the KCl-induced increase in Ca(2+)(i), in contrast to nifedipine (10(-7) M) which reduced both Ca(2+)(i) and contraction. 6. Membrane potential of arterioles with spontaneous myogenic tone (70 mmHg) was -41.5+/-1. 0 mV. Nifedipine (10(-7) or 10(-5) M) had no effect on membrane potential, however mibefradil (10(-5) M) caused significant depolarization. 7. In summary, both mibefradil and nifedipine inhibit arteriolar spontaneous tone and acute myogenic reactivity. While there may be overlap in the mechanisms by which these agents inhibit tone, differences in effects on membrane potential and intracellular Ca(2+) levels suggest mibefradil exhibits actions other than blockade of Ca(2+) entry in skeletal muscle arterioles.

Animals↗
PubMed1997

The addition of mibefradil to chronic hydrochlorothiazide therapy in hypertensive patients is associated with a significant antihypertensive effect.

OBJECTIVE: To evaluate the antihypertensive efficacy, tolerability, safety, and dose-response characteristics of the novel calcium antagonist, mibefradil, in combination with a diuretic regimen. DESIGN: A multinational, double-blind, randomised, placebo-controlled, parallel-design trial. METHODS: Three hundred and seven patients whose mild-to-moderate essential hypertension remained uncontrolled after 4 weeks of treatment with hydrochlorothiazide (HCTZ) 25 mg/day and placebo were randomised to receive combined treatment with HCTZ and once-daily doses of 12.5, 25, 50, or 100 mg of mibefradil or placebo. After 8 weeks of combined treatment, HCTZ was withdrawn and the mibefradil groups continued on their respective doses for an additional 6 weeks. RESULTS: After 8 weeks, the addition of once-daily doses of mibefradil to the initial HCTZ regimen resulted in clinically relevant, dose-related reductions in sitting diastolic blood pressure (SDBP) and sitting systolic blood pressure (SSBP) at trough, which were significantly greater in the 50 and 100 mg dose groups compared to the placebo group (P < or = 0.003). Placebo-corrected treatment effects on SDBP and SSBP at the end of the combined treatment period relative to baseline were, respectively, -4.1 and -8.0 mm Hg in the 50 mg mibefradil group and -9.5 and -8.0 mm Hg in the 100 mg mibefradil group. Therapeutic response rates to combination mibefradil and HCTZ therapy were high and dose related, reaching 82% for SDBP in the 100 mg group. CONCLUSIONS: The addition of once-daily doses of 50 or 100 mg of mibefradil to patients whose hypertension is not controlled by HCTZ alone is well tolerated and effective in improving BP control.

Adult↗
PubMed2000

Beneficial effects of the T- and L-type calcium channel antagonist, mibefradil, against exercise-induced myocardial stunning in dogs.

Abnormalities in calcium homeostasis such as calcium overload have been shown to participate in the pathogenesis of myocardial stunning. The goal of this study was to investigate the effects of mibefradil, a mixed T- and L-type calcium channels antagonist on exercise-induced ischemia (i.e., high-flow ischemia). Nine dogs were permanently instrumented to measure left ventricular wall thickening (Wth) and coronary blood flow (Doppler). Infusion of saline or mibefradil (30 and 40 microg/kg/min, i.v., for 20 min) was started 10 min before exercise (10 min, 14 km/h; slope, 13%) and stopped at its end. Circumflex coronary artery stenosis (pneumatic occluders) was set up 5 min before exercise to suppress exercise-induced increase in mean coronary blood flow without simultaneously affecting Wth at rest. Mibefradil (30 microg/kg/min) was also administered at the beginning of the recovery period in a subset of four dogs. During exercise with saline, Wth was dramatically reduced (-77 +/- 7%; p < 0.05) and recovered only after 24 h. Mibefradil at both doses significantly limited tachycardia during exercise (211 +/- 7 and 210 +/- 5 beats/min vs. 240 +/- 8 beats/min for mibefradil, 30 microg/kg/min, mibefradil, 40 microg/kg/min, and saline, respectively) but exerted no negative inotropic effects. Mibefradil at both doses significantly reduced the intensity of myocardial stunning and the time to recovery in Wth (3 h). Administration of mibefradil at the beginning of the recovery period did not protect against myocardial stunning. Administration of a mixed T- and L-type calcium channel antagonists before ischemia confers cardioprotection against exercise-induced myocardial stunning. This may potentially be related to the limitation of exercise-induced tachycardia and/or the prevention of calcium overload.

Animals↗
PubMed2003

Cellular mechanism for mibefradil-induced vasodilation of renal microcirculation: studies in the isolated perfused hydronephrotic kidney.

Although nifedipine and other conventional calcium antagonists elicit preferential vasodilation of renal afferent arterioles, we demonstrate that mibefradil and nickel, T-type calcium channel blockers, reverse the angiotensin II-induced constriction of both afferent and efferent arterioles. Since the angiotensin II-induced vasoconstriction involves inositol trisphosphate (IP3)-induced calcium release from the sarcoplasmic reticulum in the afferent arteriole, and both IP3- and protein kinase C (PKC)-mediated pathways in the efferent arteriole, we investigated the cellular mechanism for the mibefradil-induced dilation of angiotensin II-constricted renal arterioles, using the isolated perfused hydronephrotic rat kidney. Mibefradil caused a dose-dependent dilation of angiotensin II-constricted afferent and efferent arterioles, with 88 +/- 9% and 74 +/- 10% reversal observed at 1 micromol/L, respectively. The blockade of PKC by staurosporine did not alter the mibefradil-induced vasodilator responses of either arterioles (P > 0.5). In contrast, the pretreatment with thapsigargin, which predominantly blocked the IP3-mediated intracellular calcium release, prevented the afferent arteriolar constrictor response to angiotensin II, but caused a significant constriction of efferent arterioles. The subsequent addition of mibefradil had no effect on the efferent arteriolar diameter. Furthermore, the efferent arteriolar constriction induced by direct PKC activation by phorbol myristate acetate was refractory to mibefradil, but completely reversed by LOE908, a nonselective cation channel blocker. In summary, mibefradil markedly dilates the angiotensin II-induced renal arteriolar constriction; the action of mibefradil is most likely mediated by the inhibition of the IP3-mediated pathway, but the inhibitory action on the PKC pathway appears modest.

Analysis of Variance↗
PubMed1998

Single- and multiple-dose mibefradil pharmacokinetics in normal and hypertensive subjects.

Mibefradil is a single-enantiomer calcium antagonist belonging to a new class, the tetralol derivatives. The recommended doses for treatment of hypertension and chronic stable angina pectoris are 50 or 100 mg. Mibefradil is metabolized via parallel pathways of esterase-catalysed hydrolysis and cytochrome P450 3A4-mediated oxidation. Mibefradil also inhibits cytochrome P450 3A4 and consequently inhibits its own metabolism, a property illustrated by three studies performed early in the drug's development. After single intravenous doses of 2.5 to 80 mg to healthy male subjects, pharmacokinetics are linear. At the representative 40 mg intravenous dose mean pharmacokinetic parameters were clearance 241 +/- 76 mL min(-1), terminal exponential half-life 15.0 h and volume of distribution at steady state 213 L. After single oral doses of 10 to 320 mg, reduced first-pass metabolism occurs with increasing dose. This effect is accompanied by increasing absolute bioavailability as the dose is increased. In an oral multiple-dose study of healthy male volunteers mibefradil doses of 100, 150 or 250 mg (from tablets) were administered once daily for 28 days. Reduction of the first-pass effect was noted, although the data suggested that a maximum was reached for doses of 150 mg or more. In a study of the effect of hypertension on mibefradil pharmacokinetics, 12 patients received oral mibefradil once daily at doses of 50, 100, 150, or 200 mg in 100 mL orange juice for 8 days. Steady state was reached within 3 days and accumulation generally ranged from three- to sevenfold. Single-dose non-linearity was observed in the first-pass effect, although for multiple dosing oral clearance values were dose-independent and lower than for single doses. After multiple dosing at the recommended dosage of 50 and 100 mg once daily, oral clearance of mibefradil stabilizes to approximately the same value for both doses. Hence, the single-dose non-linearity has little clinical relevance but demonstrates the self-inhibition of metabolism seen with mibefradil. Studies so far suggest that self-inhibition of its oxidative metabolic pathway leads to a low clearance and long half-life, enabling once-daily dosing and conferring low intra- and inter-patient variability in pharmacokinetics.

Administration, Oral↗
PubMed2006

An inner pore residue (Asn406) in the Nav1.5 channel controls slow inactivation and enhances mibefradil block to T-type Ca2+ channel levels.

Mibefradil is a tetralol derivative once marketed to treat hyper-tension. Its primary target is the T-type Ca(2+) channel (IC(50), approximately 0.1-0.2 microM), but it also blocks Na(+),K(+),Cl(-), and other Ca(2+) channels at higher concentrations. We have recently reported state-dependent mibefradil block of Na(+) channels in which apparent affinity was enhanced when channels were recruited to slow-inactivated conformations. The structural determinants controlling mibefradil block have not been identified, although evidence suggests involvement of regions near or within the inner pore. We tested whether mibefradil interacts with the local anesthetic (LA) binding site, which includes residues in the S6 segments of domains (D) I, III, and IV. Mutagenesis of DIII S6 and DIVS6 did not reveal critical binding determinants. Substitution of Asn406 in DI S6 of cardiac Na(v)1.5, however, altered affinity in a manner dependent on the identity of the substituting residue. Replacing Asn406 with a phenylalanine or a cysteine increased affinity by 4- and 7-fold, respectively, thus conferring T-type Ca(2+) channel-like mibefradil sensitivity to the Na(+) channel. A series of other substitutions that varied in size, charge, and hydrophobicity had minimal effects on mibefradil block, but all mutations dramatically altered the magnitude and voltage-dependence of slow inactivation, consistent with data in other isoforms. Channels did not slow-inactivate, however, at the voltages used to assay mibefradil block, supporting the idea that Asn406 lies within or near the mibefradil binding site.

Amino Acid Sequence↗
PubMed1998

A comparison of the effects of mibefradil and atenolol on regression of left ventricular hypertrophy in hypertensive patients.

OBJECTIVE: This study was designed to compare the effect of mibefradil, a selective T-type calcium channel antagonist, with the beta-blocker atenolol on regression of left ventricular (LV) hypertrophy in hypertensive patients. METHODS: In this multicenter, double-blind, active-controlled, randomized, parallel-group comparison, 66 patients with mild-to-moderate hypertension (sitting diastolic blood pressure, SDBP, 95-114 mm Hg) and LV mass index > 102 g/m2 for males and > 88 g/m2 for females were randomized to an initial treatment with 50 mg of either mibefradil or atenolol for 4 weeks. Doses were increased to 100 mg/day if blood pressure was not normalized to < or = 90 mm Hg, and, if needed, 25 mg of hydrochlorothiazide was added. Treatment continued for a total of 24 weeks. LV hypertrophy was assessed by echocardiography, and trough SDBP and adverse events were recorded. RESULTS: Treatment with mibefradil or atenolol resulted in decreases from baseline in LV mass index of 11.1% (p < 0.001) and 9.1% (p < 0.001), respectively. The treatment difference (mibefradil vs. atenolol) was not statistically significant. Reductions in SDBP with mibefradil and atenolol were 14.3 and 10.7 mm Hg, respectively, again not statistically significant. Both drugs were well tolerated; however, overall there were more potentially drug-related adverse events reported with atenolol (48.5%) than with mibefradil (24.2%). CONCLUSIONS: The reductions in LV hypertrophy and blood pressure achieved with mibefradil were larger but statistically equivalent to those with atenolol, but a lower overall incidence of treatment-related adverse events was seen in the mibefradil-treated patients.

Adrenergic beta-Antagonists↗
PubMed1998

Mibefradil: a new class of calcium-channel antagonists.

OBJECTIVE: To describe the pharmacology, pharmacokinetics, and clinical efficacy of mibefradil compared with other agents used for hypertension and angina. DATA SOURCES: A MEDLINE search was performed for the period of January 1980 through September 1997 using the key terms mibefradil or Ro 40-5967. All articles written in English were considered for review. STUDY SELECTION AND DATA EXTRACTION: All clinical studies involving mibefradil were evaluated. Preclinical data were included if these data were not adequately represented in clinical (human) studies. DATA SYNTHESIS: Mibefradil is the first member of a new class of calcium-channel antagonists (CCAs) that block the T-type calcium channels. A long elimination half-life makes once-daily dosing feasible, and the drug's lack of negative inotropy and reflex tachycardia distinguishes it from other available CCAs. When administered at recommended dosages (50 or 100 mg once daily), mibefradil reduces blood pressure over 24 hours in patients with hypertension, improves exercise capacity, and relieves anginal symptoms in patients with chronic stable angina pectoris. CONCLUSIONS: Clinical studies have found that the antihypertensive effects of mibefradil are comparable with those of nifedipine, verapamil, and amlodipine, and more effective than those of diltiazem. These effects result from peripheral vasodilation and a slight reduction in heart rate. Selective vasodilation of the coronary vasculature makes it an effective antianginal agent when used alone or added to beta-blocker therapy. Mibefradil demonstrates no significant effects on cardiac contractility, and no adrenergic stimulation resulting in reflex tachycardia. Therefore, it may have some advantages over currently available CCAs, especially in patients with congestive heart failure, although such advantages are unproven in published clinical trials. Ongoing clinical studies, including the Mortality Assessment in Congestive Heart Failure Trial (MACH-1) currently in progress, are needed to clarify mibefradil's place in cardiovascular therapy.

Aged↗
PubMed2002

A post-marketing observational study to assess the safety of mibefradil in the community in England.

OBJECTIVES: To conduct a post-marketing observational cohort study to assess the safety of mibefradil in the community, using Prescription-Event Monitoring (PEM). METHOD: Data were collected and analyzed on patients prescribed mibefradil by 1,996 General Practitioners (GPs) throughout England. Incidence densities were calculated for all reported events and selected events were followed-up by means of further questionnaires. RESULTS: The study was terminated early due to the voluntary withdrawal of mibefradil from the market because of potential drug interactions. A cohort of 3,085 patients was recruited, with a mean age of 64.5 years. The major indication for use was hypertension (55% of the cohort), the indication was not specified in 33% of patients. 80% of GPs expressing an opinion rated mibefradil as effective. The major reason for stopping was withdrawal from the market (2,342 patients). The commonest reported adverse events and reasons for stopping were malaise/lassitude, dizziness, edema and headache. Seven clinically serious reports of bradycardia/collapse were considered to be possible adverse drug reactions (ADRs) to mibefradil. All were in the elderly (> 65 years), 6 were considered to be a result of possible drug interactions. In total, 11 possible drug interactions occurred. Nine (8 reports of bradycardia and 1 of syncope) involved beta-blockers. Another, a report of collapse and severe bradycardia, occurred in a patient who had started a dihydropyridine calcium channel blocker within 24 hours of stopping mibefradil and the other was a report of palpitations and dyspnea in a patient on concomitant digoxin and sotalol. None of the 53 deaths occurring during the study was attributed to mibefradil. CONCLUSION: Mibefradil was only available on the UK market for 6 months before it was withdrawn from the market because of potential drug interactions. With respect to the reasons leading to its withdrawal, in this cohort of 3,085 patients, 11 possible drug interactions were detected (6 clinically significant) involving beta-blockers, a dihydropyridine calcium channel blocker and digoxin and/or sotalol. PEM can contribute to the understanding of ADRs caused by drug interactions occurring in real-life settings.

Adolescent↗