The binding interactions of Ro 40-5967 at the L-type Ca2+ channel in cardiac tissue

Rutledge, A.; Triggle, David J.

doi:10.1016/0014-2999(95)00194-p

Cited by 58 publications

(22 citation statements)

References 15 publications

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“…1) fig. 2) [27,28]. Hence, mibefradil appears to bind to a binding site different from that described for phenylalkylamines, dihydropyridines or benzothiazepines.…”

Section: Binding To Calcium Channelsmentioning

confidence: 99%

Comparative Pharmacological Properties among Calcium Channel Blockers: T-Channel versus L-Channel Blockade

Noll¹,

Lüscher²

1998

Cardiology

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Calcium antagonists are potent vasodilators and are widely used in the treatment of hypertension and angina pectoris. The currently available compounds belong to three classes: (1) dihydropyridines (e.g. nifedipine, amlodipine and felodipine), (2) phenylalkylamines (e.g. verapamil) and (3) benzothiazepines (e.g. diltiazem). The three classes differ in their pharmacological profile and safety. For example, verapamil and diltiazem lower heart rate, while dihydropyridines increase it or leave it unchanged. With most of the latter compounds, a marked activation of the sympathetic nervous system has been noted. Most compounds exhibit negative inotropic effects, particularly the first-generation molecules, which is disadvantageous in patients with impaired left-ventricular function. The most common side effects of these drugs are flushing, headache and edema. With verapamil, constipation may represent a problem in certain patients. Hence, in spite of a large number of calcium antagonists available, there remains a need for new compounds with enhanced efficacy and improved tolerability. A new compound should lack any negative inotropism, avoid any increase in sympathetic outflow or heart rate and exhibit a high degree of vascular selectivity. Furthermore, a low incidence of side effects, particularly ankle edema and optimal pharmacokinetics allowing once-daily dosing would be desirable. Mibefradil is a new calcium antagonist with promising pharmacological and clinical properties. The compound has a high bioavailability, lacks negative inotropic effects at therapeutic concentrations, does not exhibit reflex tachycardia during vasodilation and actually slightly decreases heart rate. It is a potent direct vasodilator efficacious in hypertension and chronic angina pectoris, elicits endothelium-dependent relaxations and facilitates the effects of nitric oxide in vascular smooth muscle. The drug is a particularly efficacious vasodilator in intramyocardial coronary arteries which may be important for its anti-ischemic effects and the lack of steal in the coronary circulation. Furthermore, mibefradil has antiproliferative properties in human vascular smooth muscle cells in culture. As a unique property, mibefradil blocks T-type calcium channels and hence represents a new class of calcium channel blockers. In patients with hypertension, mibefradil has a high efficacy in controlling blood pressure. The drug does not cause constipation and has a low incidence of ankle edema. A large trial is under way to further delineate the properties of this new calcium antagonist in patients with heart failure.

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“…1) fig. 2) [27,28]. Hence, mibefradil appears to bind to a binding site different from that described for phenylalkylamines, dihydropyridines or benzothiazepines.…”

Section: Binding To Calcium Channelsmentioning

confidence: 99%

Comparative Pharmacological Properties among Calcium Channel Blockers: T-Channel versus L-Channel Blockade

Noll¹,

Lüscher²

1998

Cardiology

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“…verapaniil, diltiazem, the dihydropyridines) that block L-type calcium channels, mibefradil blocks both L-and T-type calciumchannels with a higher selectivity for T-type calcium channels. 16. l7 As mibefiadil is the first available compound with this mechanism of action, the complex relationships between the blockade of T-type calcium channels and the resultant clinical effects have not yet been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Additional antianginal and anti‐ischemic efficacy of mibefradil in patients concomitantly treated with long‐acting nitrates for chronic stable angina pectoris

Frishman

Bittar

Glasser

et al. 1998

Clinical Cardiology

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SummaryHrrc~kgmw7cl: Mibefradil, a newly approved antihypertensive and antianginal drug, is the first member of a new class of calcium antagonists (CAs), the tetralol derivatives, that selectively blocks T-type Ca2+ channels in contrast to classical CAs which. at therapeutic concentrations. block only L-type Ca2+ channels. Since patients with chronic stable angina pectoris typically may be treated with the combination of a long-acting nitrate and a CA, the additive efficacy and safety ofmibefradil in combination with nitrate therapy needs to be determined.Hypotliosis: This study was designed to assess the efficacy, tolerability, and safety of mibefradil when added to longacting nitrate therapy in patients with chronic stable anginaMctllod~s: Following a 1 -week placebo i-un-in period, patients were randomized to receive either mibefradil 50 mg ( n = 96) or placebo (n = 93) once daily in addition to their nitrate therapy. After 2 weeks of active treatment, patients receiving the mibefradil were force titrated to I50 mg once daily for an additional 2 weeks. Exercise tolerance tests ( E n s ) were perpectoris.formed at the end of Weeks 2 and 4; patients also maintained an anginal diary during the 4-week treatment period.Results: After 2 weeks of treatment with 50 mg mibefradil (within the current recommended dose range), a statistically significant but modest increase in total exercise duration was observed (treatment effect 16.4 s, p = 0.04). Similarly, there WiiS a significant increase in time to onset of ischemia (treatment effect 26 s, p = 0.008). The adverse event profile ofthe 50 mg dose was indistinguishable from placebo, indicating that this dose was extremely well tolerated. At Week 4, the mibefradil-treated patients were taking 150 mg, which is above the current recommended dose range. The increase in total exercise duration was larger for the mibefradil 1 SO mg group than for the placebo goup. For the intent-to-treat population, this difference did not reach statistical significance, whereas in the standard population it did (treatment effect 2 1 s, p = 0.05). The other two ETT variables, time to onset ofangina and time to onset of I mm ST-segment depression, demonstrated significantly greater effect with mibefradil IS0 mg (treatment effects 40 s, p = 0.002, and 55 s, p < 0.00 1, respectively, for the intent-to-treat population). Mibefradil I50 mg was associated with more adverse events than placebo, specifically, dizziness, leg edema, and postural hypotension.Conclusiotis: This study demonstrates that mibefradil 50 mg once daily in the setting ofthe background long-acting nitrate therapy produces additive antianginal and anti-ischemic effects and is extremely well tolerated.

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“…11 This effect is associated with a slight decrease in heart rate. 14,23,24 In preclinical models, mibefradil was found to have no relevant depressant effect on myocardial contractility. 13,25,26 The lack of negative inotropic effect has been confirmed in studies of patients with hypertension, 12,[15][16][17][18] angina pectoris, 14 and impaired cardiac function secondary to chronic 15 ; B: broad-range, dose-finding study 16 ; C: dose-finding study in elderly subjects 17 ; D: dose-finding study in subjects with background HCTZ 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…10 It also interacts with the L-type channel in a manner that is different from dihydropyridine-, phenylalkylamine-, and benzothiazepinebased CA. 23 Mibefradil causes coronary and peripheral vasodilation through a direct effect on vascular smooth muscle. 11 This effect is associated with a slight decrease in heart rate.…”

Section: Discussionmentioning

confidence: 99%

Mibefradil, a T-Channel?Selective Calcium AntagonistClinical Trials in Hypertension

Oparil

1998

American Journal of Hypertension

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Mibefradil, a tetralol derivative, is the first representative of a new class of calcium antagonists. It selectively blocks entry of calcium into cells through T-type channels. The efficacy and tolerability of mibefradil in the treatment of mild-to-moderate essential hypertension were evaluated in four placebo-controlled, double-blind, dose-finding studies involving over 1000 patients. Two trials involved patients from the general population, one examined a subpopulation of elderly patients, and one evaluated patients receiving chronic hydrochlorothiazide (HCTZ) treatment. Based on these studies, the recommended doses of mibefradil are 50 mg and 100 mg. Doses >100 mg/day were associated with small gains in efficacy and an increased incidence of adverse effects. Response (sitting diastolic blood pressure normalization to <90 mm Hg or reduction by >10 mm Hg) rates to mibefradil ranged from 46.0% to 68.6% with 50 mg, and from 60.0% to 93.2% with 100 mg. Normalization rates paralleled the response rates, ranging from 34.0% to 62.9% with 50 mg, and from 42.5% to 81.8% with 100 mg.The effects on sitting systolic blood pressure were similar. Treatment was associated with a slight, potentially beneficial reduction in heart rate. Results were similar across all populations, indicating that no dose adjustment is required for elderly and for HCTZ-treated patients. The frequency of adverse events was similar to that reported for placebo groups, with headache being the most common complaint. In comparative trials, mibefradil was more effective than nifedipine SR and diltiazem CD, and at least as effective as amlodipine and nifedipine GITS. Overall, mibefradil was better tolerated than the comparison drugs. Mibefradil, at the recommended doses of 50 to 100 mg/day, is safe and effective for the treatment of mild-to-moderate hypertension. Am J Hypertens 1998;11:88S-94S

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The binding interactions of Ro 40-5967 at the L-type Ca2+ channel in cardiac tissue

Cited by 58 publications

References 15 publications

Comparative Pharmacological Properties among Calcium Channel Blockers: T-Channel versus L-Channel Blockade

Comparative Pharmacological Properties among Calcium Channel Blockers: T-Channel versus L-Channel Blockade

Additional antianginal and anti‐ischemic efficacy of mibefradil in patients concomitantly treated with long‐acting nitrates for chronic stable angina pectoris

Mibefradil, a T-Channel?Selective Calcium AntagonistClinical Trials in Hypertension

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