Electropharmacology of OPC‐88117, A New Antiarrhythmic Agent

Kodama, Itsuo; Honjo, Haruo; Kamiya, Kaichiro; Toyama, Junji

doi:10.1111/j.1527-3466.1990.tb00401.x

Cited by 7 publications

(10 citation statements)

References 24 publications

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“…Regarding other drugs, the extracardiac side effects, such as hypoglycemia, hyponatremia, or hypokalemia, being reported following clinical introduction of cibenzolin, disopyramid and indapamide, respectively, may limit their clinical application [87,88]. Unwanted side effects (pulmonary fibrosis and hepatotoxicity after long term application [89,90,91]) were reported even with amiodarone, the drug seemingly lacking proarrhythmic potency, in spite of its mixed (predominantly class III) mechanism of action [92].…”

Section: Pharmacology Of I Ks Channelmentioning

confidence: 99%

Profile of IKs During the Action Potential Questions the Therapeutic Value of IKs Blockade

Bányász

Koncz

Fülöp

et al. 2004

CMC

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The goal of this paper is two fold. First, we attempt to review the reports available on the role of I(Ks) in myocardial repolarization. Based on theoretical considerations and experimental results, it seems reasonable to assume that I(Ks)blockade will lengthen the action potential. However, results obtained with I(Ks) blockers, like chromanol 293B or L-735,821, are conflicting, since from slight lengthening to marked prolongation of action potentials were equally obtained. Although these contradictory results were explained by interspecies or regional differences, the role of I(Ks) in repolarization is a matter of growing dispute. In the second part of this study, we simulated the performance of I(Ks) during cardiac action potentials. We compared the profile of the predicted current in three mathematical models in order to determine the relative role of the current in repolarization. We studied the effect of the cycle length, action potential duration and height of the plateau on the profile of I(Ks) in epicardiac, endocardiac and midmyocardiac ventricular action potentials. The results indicate that the height of the plateau is the most important parameter to control activation of I(Ks)in cardiac tissues, and accordingly, the interspecies and regional differences observed in the efficacy of I(Ks) blockers are likely due to the known differences in action potential morphology. We conclude also that I(Ks)blockade may have unpredictable effects on the length of the action potential in a diseased heart, questioning the possible therapeutic value of drugs blocking I(Ks).

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Section: Pharmacology Of I Ks Channelmentioning

confidence: 99%

Profile of IKs During the Action Potential Questions the Therapeutic Value of IKs Blockade

Bányász

Koncz

Fülöp

et al. 2004

CMC

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“…Although amiodarone blocks K + channels and in long- term therapy produces a marked QT prolongation, it is rarely associated with onset of TdP (incidence <1%) [72]. In contrast to other class III agents, amiodarone reduces EADs in isolated cardiac preparations, probably because it blocks I Ca and b-adrenergic receptors, it produces a shorter prolongation of the APD in the Purkinje and ventricular muscle cells, thus rendering ventricular refractoriness less heterogeneous [56,70,73]. Because it prolongs the APD to a similar extent in different regions of the heart, regardless of the underlying heart rate, it does not display reverse usedependency [73,74].…”

Section: • Antiarrhythmic Drugsmentioning

confidence: 97%

“…In details, from those class III agents that are currently in use or tested in clinical trials, d-sotalol, dofetilide, sematilide and almokalant selectively block I Kr in the open-activated state [16,31,32,64], ibutilide blocks I Kr , and enhances a slow inward Na + current [16,66], azimilide blocks I Kr , I Ks and I Ca [35,67], ambasilide and cibenzoline block I Kr and I Ks [16,68], tedisamil blocks I to and I Kr as well as I Ca and I Na at high concentrations [16,69], and d,l-sotalol is both a nonselective b-adrenergic receptor antagonist and blocks I Kr [14]. Amiodarone blocks Na + , Ca 2+ and K + channels and exhibits non-competitive a-and b-adrenergic blocking properties [70]. Because they prolong the APD, class III agents would be expected to induce dose-related TdP [15,16].…”

Section: • Antiarrhythmic Drugsmentioning

confidence: 99%

Molecular Predictors of Drug-induced Prolongation of the QT Interval

Dilaveris

2005

CMCCHA

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One of the most common causes of drug withdrawal from the market is the prolongation of the QT interval associated with polymorphic ventricular tachycardia or torsade de pointes (TdP) that can degenerate into ventricular fibrillation and sudden cardiac death. Cardiac and non-cardiac drugs prolong the QT interval and cause TdP by blocking cardiac K+ channels in general, and selectively blocking the rapidly activating delayed rectifier channel IKr. Co-assembly of HERG (human-ether-a-go-go-related gene) alpha-subunits and MiRP1 (MinK-related peptide 1) beta-subunits recapitulate the behavior of native human IKr, and the majority of mutations of HERG and MiRP1 decrease the repolarizing current, delay ventricular repolarization and prolong the QT. Thus, drug-induced QT prolongation and TdP might represent an iatrogenic reproduction of the congenital long-QT syndrome (LQTS). Current evidence suggests that 5 to 10% of persons in whom TdP develops on exposure to QT-interval prolonging drugs harbor mutations associated with the LQTS and can therefore be viewed as having a subclinical form of the congenital syndrome. This clinical observation is entirely consistent with the concept of reduced repolarization reserve arising from a mutation in an ion-channel gene, which predisposes the carrier to drug-induced TdP. This review centers on the possible molecular mechanisms underlying drug-induced QT prolongation and TdP, the description of specific drugs and risk factors facilitating the development of TdP, and the recommendations for preventing and treating this potentially fatal arrhythmia.

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“…147 Binding and unbinding rate constants for mexiletine and aprindine were also measured, and at the common receptor site, a competitive interaction between them was shown. 148 Recent measurement of the gating currents of canine cardiac Purkinje cell sodium channels gave support for the modulated receptor model.…”

Section: A Sodium Channel Antagonistsmentioning

confidence: 99%