Azimilide Dihydrochloride

Azimilide dihydrochloride.[Pubmed:15889966]

Expert Rev Cardiovasc Ther. 2005 May;3(3):387-91.

Azimilide Dihydrochloride is an antiarrhythmic drug with Vaughn Williams class III properties, which blocks both fast (IKr) and slow (IKs) components of the delayed rectifier cardiac potassium channel. The drug slows the heart rate slightly and, like other class III antiarrhythmic drugs, prolongs ventricular repolarization and thus, the QT interval. Unlike sotalol, another class III antiarrhythmic drug, azimilide does not exhibit reverse-use dependence, that is, its binding characteristics and effectiveness are not related to the heart rate. Azimilide is 85% bioavailable, reaches peak blood concentrations in 6-8 h and has a long elimination half-life of 114 h. Clinical trials have utilized once-daily dosing. These trials have tested the use of the drug for patients with supraventricular and ventricular arrhythmias.

Azimilide dihydrochloride: a new class III anti-arrhythmic agent.[Pubmed:11060832]

Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15.

Azimilide Dihydrochloride (Stedicor) is a new class III anti-arrhythmic agent that is being developed by Proctor & Gamble to treat supraventricular and ventricular arrhythmias. Development of this agent is being undertaken due to the high prevalence of atrial fibrillation and the lack of satisfactory therapy for this arrhythmia, along with the desire to develop therapy to reduce the risk of life-threatening ventricular arrhythmias in patients following myocardial infarction. The mechanism of action of azimilide is to block both the slowly conducting (I(Ks)) and rapidly conducting (I(Kr)) rectifier potassium currents in cardiac cells. This differs from other class III agents that block I(Kr) exclusively or in combination with sodium, calcium, or transient outward (I(to)) potassium current channels. Azimilide is distinguished by a relative lack of reverse use-dependence, excellent oral absorption, no need for dose titration, an option for out-patient initiation, no need for adjustment associated with renal or liver failure and a lack of interaction with warfarin or digoxin. It carries some risk of torsade de pointes and rarely, neutropoenia. Azimilide has shown dose-related efficacy in prolonging the time to recurrence of atrial fibrillation. A large trial examining the impact of azimilide on mortality in high-risk patients following myocardial infarction has completed enrolment and should yield data in the next couple of years and further studies are planned. Even if this trial fails to show a survival benefit, a neutral effect on mortality will make the agent attractive for atrial arrhythmias.

Influence of coadministration on the pharmacokinetics of azimilide dihydrochloride and digoxin.[Pubmed:15951467]

J Clin Pharmacol. 2005 Jul;45(7):773-80.

The influence of coadministration on digoxin and azimilide pharmacokinetics/pharmacodynamics was assessed in a randomized, 3-way crossover study in 18 healthy men. Serial blood and urine samples were obtained for azimilide and digoxin quantitation. Treatment effects on pharmacokinetics were assessed using analysis of variance. The relationship between azimilide blood concentrations and QT(c) prolongation was characterized by an E(max) model. Effects of coadministration on pharmacodynamics were assessed using a mechanistic-based inhibition model. Azimilide pharmacokinetics was unaffected by digoxin, except for a 36% increase in CL(r) (P = .0325), with no change in CL(o). Digoxin pharmacokinetics was unaffected by azimilide, except for a 21% increase in C(max) (P = .0176) and a 10% increase in AUC(tau) (P = .0121). Digoxin coadministration increased the apparent EC(50) with no effect on E(max), consistent with competitive inhibition (K(i) = 0.899 ng/mL). The pharmacokinetic and pharmacodynamic changes observed upon coadministration were small and are not expected to be clinically important.

Azimilide dihydrochloride: a unique class III antiarrhythmic agent.[Pubmed:11720612]

Heart Dis. 1999 May-Jun;1(2):114-6.

The introduction of class III (Vaughn Williams classification) antiarrhythmic agents has improved the available drug treatment modalities for managing cardiac supraventricular and ventricular tachyarrhythmia. An appreciation of the importance of the delayed rectifier potassium current in the pathogenesis of various cardiac arrhythmias has led to the development of azimilide, an oral type III potassium channel blocker agent that blocks both the rapid activating component (I(kr), common to sotalol, amiodarone, and ibutilide) and the slow activating component (I(ks), a unique action of azimilide) of the delayed rectifier potassium current. Both preclinical and clinical studies have demonstrated the efficacy of azimilide and its safety in the management of supraventricular and ventricular tachyarrhythmia. Azimilide also is being studied in a worldwide multicenter trial for prevention of sudden cardiac death in patients after myocardial infarction. Azimilide soon will become available for clinical use as a treatment for preserving normal sinus rhythm in patients with atrial fibrillation and paroxysmal atrial tachycardia.

Azimilide Dihydrochloride (NE-10064 Dihydrochloride) is a class III antiarrhythmic compound, inhibits I(Ks) and I(Kr) in guinea-pig cardiac myocytes and I(Ks) (minK) channels expressed in Xenopus oocytes.

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