Hemodynamic and electrophysiological effects of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin in a halothane-anesthetized canine model.
Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. We investigated the QT-prolonging effects of mitemcinal using a halothane-anesthetized canine model. Intravenous administration of mitemcinal at doses of more than 8.3 mg/kg per 10 min significantly prolonged the QT interval corrected by Fridericia's corrections. Mitemcinal exhibited a bradycardiac effect and produced significantly greater prolongation in monophasic action potential duration (MAP(90)) at sinus rhythm compared with MAP(90) at pacing and showed reverse use-dependent prolongation of repolarization, suggesting that the negative chronotropic effect of mitemcinal potentiates the prolongation of the repolarization period. A technique using MAP/pacing electrodes allowed measurements of both MAP(90) and effective refractory period (ERP) simultaneously at the same ventricular site. Although mitemcinal slightly prolonged the MAP(90(CL400)) and ERP in comparison with the control group at the dose of 25 mg/kg per 10 min, the terminal repolarization period, the difference between MAP(90(CL400)) and ERP, did not increase suggesting the absence of a proarrhythmic effect even with a 7000-fold for the therapeutic blood concentration as free level. The electrophysiological results from mitemcinal in this study indicate that the risk of serious arrhythmia such as torsades de pointes, a major clinical concern related to QT interval prolongation, might be low.
Kimura
Kazuya
K
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kimurakzy@chugai-pharm.co.jp
Tabo
Mitsuyasu
M
Mizoguchi
Keiji
K
Kato
Atsuhiko
A
Suzuki
Masami
M
Itoh
Zen
Z
Omura
Satoshi
S
Takanashi
Hisanori
H
D000200:Action Potentials / Q000187:drug effects; D000768:Anesthesia, General; D018685:Anesthetics, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002304:Cardiac Pacing, Artificial; D020117:Cisapride / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004917:Erythromycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006221:Halothane; D006339:Heart Rate / Q000187:drug effects*; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D018570:Risk Assessment; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects