Lack of Negative Inotropic Effects of the New Calcium Antagonist Ro 40–5967 in Patients with Stable Angina Pectoris

Portegies, M. C. M.; Schmitt, Rita; Kraaij, C. J.; Braat, Simon H.; Gaßner, A; Hagemeijer, F; Pozenel, H; Prager, Gerold; Viersma, Jw; Wall, Ernst E. van der; Kleinbloesem, C. H.; Lie, Ki

doi:10.1097/00005344-199111000-00013

Cited by 79 publications

(20 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In additon to causing vasodilation, blockade of T-type Ca 2ϩ channels slows the sinus rate and prolongs AV nodal conduction without adverse negative inotropic or positive chronotropic cardiac actions. 6,7) However, despite its excellent antihypertensive effects, mibefradil was withdrawn from the market in 1998 due to its pharmacokinetic interactions with other drugs metabolized by cytochrome P450. 8,9) Since the withdrawal of mibefradil, increased interest in T-type Ca 2ϩ channels as a therapeutic target has fueled significant efforts to discover novel T-type Ca 2ϩ channel blockers.…”

mentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of 1-Alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide Derivatives as Novel Antihypertensive Agents

Watanuki

Matsuura

Tomura

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of 1-Alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide Derivatives as Novel Antihypertensive Agents

Watanuki

Matsuura

Tomura

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

show abstract

“…Mibefradil induces coronary and peripheral vasodilation through a direct effect on smooth muscle via blockade of T-type and L-type Ca 2ϩ channels (Massie, 1997). Although mibefradil binds to a unique receptor site that overlaps with that of verapamil (Rutledge and Triggle, 1995), it does not depress myocardial contractility (Clozel et al, 1990), and it is not associated with negative inotropism (Portegies et al, 1991), which represents a therapeutic advantage for mibefradil.…”

mentioning

confidence: 99%

The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Bui

Quesada²,

Handforth³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Mibefradil (Ro 40-5967) is a calcium channel antagonist that, in experimental animals 12,13 as well as clinical studies (involving patients with angina pectoris), 14 was found to lack the substantial negative inotropic effect of verapamil. This attribute suggested that mibefradil might offer unique advantages over previous calcium channel blockers in clinical ischemic heart disease.…”

Section: See P 305mentioning

confidence: 99%

Good News for Experimental Concept but Bad News for Clinically Effective Therapy

Reimer

Califf

1999

Circulation

View full text Add to dashboard Cite

A lthough it is widely accepted from experimental studies that timely reperfusion limits myocardial infarct size, reperfusion by itself may not achieve the greatest possible effect. In a clinical setting, reperfusion, whether by thrombolytic therapy or emergency coronary angioplasty, never can be achieved instantaneously. Thus, adjunctive therapy, which could either slow ischemic metabolism and cellular injury pending successful reperfusion or protect myocytes against undesired, potentially lethal effects of reperfusion ("lethal reperfusion injury"), should have added clinical benefit for limiting infarct size. Moreover, it would be possible to treat patients at high risk of infarction prophylactically if a safe and effective cardioprotective agent could be developed. See p 305Several endogenous mechanisms or exogenous interventions are known to both slow the rate of ischemic metabolism and delay the onset of lethal myocyte injury. For example, the speed at which ischemic cell injury occurs is markedly temperature-dependent. Hypothermia substantially slows ischemic metabolism and the onset of lethal myocyte injury. 1 This approach is commonly used in cardiac surgical procedures requiring a cessation of myocardial blood flow to slow ischemic injury and thereby prolong the tolerable period of ischemia.Studies in several animal species have shown that exposing myocardium to Ն1 short (5-to 15-minute) episodes of ischemia ("ischemic preconditioning") slows energy metabolism and delays the onset of myocardial necrosis in a subsequent prolonged period of ischemia. 2,3 Although the mechanism is not completely established, there is considerable evidence that the effect requires activation of Ն1 signaling pathways, the end effect of which is enhanced opening of ATP-dependent potassium (K ATP ) channels. 3 Calcium channel blockers also generally have had cardioprotective, infarct-limiting effects in studies based on an animal model in which infarcts were induced by relatively short periods of ischemia (40 to 90 minutes) followed by reperfusion. 4 -6

show abstract

Lack of Negative Inotropic Effects of the New Calcium Antagonist Ro 40–5967 in Patients with Stable Angina Pectoris

Cited by 79 publications

References 0 publications

Synthesis and Pharmacological Evaluation of 1-Alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide Derivatives as Novel Antihypertensive Agents

Synthesis and Pharmacological Evaluation of 1-Alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide Derivatives as Novel Antihypertensive Agents

The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Good News for Experimental Concept but Bad News for Clinically Effective Therapy

Contact Info

Product

Resources

About