Author: Chorvat, Robert J. ; Stout, David M. ; Barcelon-Yang, Cynthia ; Brown, Barry S. ; Ranade, Vasant V. ; Black, Lawrence A. ; Quon, Check Y. ; Stampfli, Herman F.

The synthesis, antiarrhythmic activity, and blood hydrolysis properties of a series of mono- and bis(aminomethyl)phenylacetic acid esters related to a previously reported class Ic antiarrhythmic agent (ACC-9358) are described. Of the various oxa-, aza-, thia-, and carbacyclic esters initially prepared in the bis(pyrrolidinomethyl)-4-hydroxyphenylacetic acid series, the 1,4-benzodioxanyl-2-methyl(3q) and the thienyl-2-methyl(31) esters were evaluated in vivo for antiarrhythmic efficacy. In addition, a number of monoappended phenylacetic esters of 3q with or without the 4-hydroxy group were also prepared for evaluation of antiarrhythmic, lipophilic, and metabolic properties. Of these compounds, 3q possessed the most desirable pharmacological and pharmacokinetic profile.

01 Mar 1991·Clinical Pharmacology and TherapeuticsQ2 · MEDICINE

Prospective pharmacokinetically based development of effective infusion regimens for ACC–9358, a new antiarrhythmic drug

Q2 · MEDICINE

Article

Author: Raymond L Woosley ; Mark D Lineberry ; Harris N Pavlou ; Christian Funck-Brentano ; Dan M Roden

In this study we evaluated the clinical pharmacology of intravenous ACC-9358, a new antiarrhythmic drug derived from a Chinese herbal remedy. In a first-study phase, 0.125 to 1.0 mg/kg during 10 minutes was administered to six patients with chronic nonsustained ventricular arrhythmias. These data were then used to design 3-hour infusions to maintain stable plasma concentrations: these infusions suppressed arrhythmias by 90% or greater for 2 1/2 hours or more at plasma concentrations of 114 to 1010 ng/ml (mean, 400 +/- 421 ng/ml [SD]), and with QRS interval increases of 2.5% to 8.8% (5.1% +/- 2.9%). Mean clearance was 478 +/- 151 ml/min, and elimination half-life was 19.1 +/- 6.1 hours. ACC-9358 did not produce adverse effects in this study. ACC-9358 shows antiarrhythmic activity in humans at concentrations that prolong QRS only slightly and do not alter rate-corrected QT; further studies in other patient populations, at dosages and plasma concentrations defined here, are required to establish a clinical role for ACC-9358. The pharmacokinetically based dose-ranging approach allowed the safe initial evaluation of ACC-9358 in patients.

01 Apr 1990·The American Journal of CardiologyQ3 · MEDICINE

Efficacy and safety of ACC-9358, a new antiarrhythmic agent

Q3 · MEDICINE

Article

Author: Raymond L. Woosley ; Liping Feng ; Steven N. Singh ; Margaret Shand ; Ross D. Fletcher ; Yiwang Chen

1. Falk RH, Knowlton AA, Bernard SA, Gotlieb NE, Battinelli NJ. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. Ann Inrem Med 1978;106:503-506. 2. Weiner P, Bassan MM, Jarchovsky J, Iusim S, Plavnick L. Clinical course of acute atria1 fibrillation treated with rapid digitalization. Am Hearr J 1983; 105223-227. 3. Mallis GI, Schmidt DH, Lindebaum J. Superior bioavailability of digoxin solution in capsules. Clin Pharmacol Ther 1976;18:761-768. 4. Rosen MR. Wu AL, Hoffman BF. Electrophysiology and pharmacology of cardiac arrhythmias: IV. Cardiac antiarrhythmic and toxic effects of digitalis. Am Heart J 1975;89:391-399. 5. Meijler FL. An “account” of digitalis and atrial fibrillation. JACC 1985; S(suppl A):60A-68A. 6. Allesie M, Lammers W, Smeets J, Bonke F, Hollen J. Total mapping of atrial excitation during acetylcholine-induced atria1 flutter and fibrillation in the iwlated canine heart. In: Kulbertus HE, Olsson SB, Schlepper M, eds. Atrial Fibrillation. Moltl41:981-988.

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Indication	Highest Phase	Country/Location	Organization	Date
Arrhythmias, Cardiac	Phase 2	US	Bristol Myers Squibb Co.	-

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