MS-551: Pharmacological profile of a novel class III antiarrhythmic agent

Autor: Hitoshi Banno, Tstutomu Katakami, Kanji Yoshihara, Akihiro Oyabe, Masaaki Ishii, Joji Kamiya
Rok vydání: 1993
Předmět:
Zdroj: Drug Development Research. 30:37-44
ISSN: 1098-2299
0272-4391
DOI: 10.1002/ddr.430300106
Popis: The class II antiarrhythmic agent properties of the novel compound MS-551 (1,3-dimethyl-6-{(2-[N-(2-hydroxyethyl-3-(4-nitrophenyl)propylamino]ethylamino} ) 2,4 (1H3H)-pyrimidinedione hydrochloride) have been characterized in vitro and in vivo. Using isolated canine Purkinje fibers, the effect of MS551 on the action potentials was studied. MS-551 (0.1-10μg/ml) caused a uniform and concentration-dependent increase in action potential duration without changing parameters of action potential depolarization. IN anesthetized open-chested dogs. MS-551 (0.1-10 mg/kg i,v.) produced a dose-dependent increase in both atrial and ventricular effective refractory periods 9ERP) with QTc prolongation. At 0.3 mg/kg i.v., atrial and ventricular ERP were significantly increased 28 ± 4 mec and 12 ± 2 msec, respectively, and the minimum e4ffective plasma concentration of MS-551 for atrial ERP prolongation was approximately 0.1 μg/ml. However, MS-551 did not slow intracardiac conduction time (A-H, H-V) even at the highest dose studied (30 mg/kg i.v.). These data suggest that MS-551 has a “pure” class III electrophysioloigcal property in dogs. Furthermore, we compared the effects of MS-551 on the hemodynamics in anesthetized dogs with those of d-sotalol. MS-551 (0.1-3 mg/kg) produced dose-dependent decrease in heart rate with QTc prolongation and slight increase in LVdP/dtmax. In contrast d-sotalol (0.1-10 mg/kg i.v.) depcreased heart rate, mean arterial pressure, LVdP/dtmax and aortic flow in a dose-dependent manner. Moreover, we reassessed in anesthetized dogs the cardiovascular toxicity of continuously infused MS-551 (2 mg/kg/min for 50 min). Ath the end of the infusion (total dose: MS-551 100 mg/kg), LVdP/dtmax was decreased 23%, but QTc prolongation never exceeded 30%. Thus, arrhythmias, such as torsade de pointes, were not seen. In conclusion, MS-551 appears to be a pure and potent class III antiarrhythmic agent with a favourable hemodhynamic profile. © 1993 wiley-Liss, Inc.
Databáze: OpenAIRE
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