Acute canine model for drug-induced torsades de pointes in drug safety evaluation - Influences of anesthesia and validation with quinidine and astemizole

被引:26
作者
Yamamoto, K [1 ]
Tamura, T [1 ]
Imai, R [1 ]
Yamamoto, M [1 ]
机构
[1] Takeda Chem Ind Ltd, Drug Safety Res Labs, Yodogawa Ku, Osaka 5328686, Japan
关键词
torsades de pointes; dog model; astemizole; quinidine; anesthesia; drug safety;
D O I
10.1093/toxsci/60.1.165
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
An acute in vivo model for drug-induced torsades de pointes (TdP) for use in safety evaluation of drugs was developed using dogs with acute complete atrioventricular (AV) block. In order to study the effects of anesthetic agents on the inducibility of TdP, arrhythmias were induced by programmed electrical stimulation (PES) before and after cumulative intravenous administration of quinidine under anesthesia with sodium pentobarbital, halothane, or isoflurane. Both prolongation of the QTc and the incidence of TdP were greatest in dogs anesthetized with halothane and were smallest in those given pentobarbital, suggesting that halothane is the most suitable anesthetic for this TdP model. To further validate this model, astemizole was administered intravenously to other dogs under halothane anesthesia. Astemizole at 0.3 mg/kg caused slight prolongation of the QT interval but did not induce any arrhythmias. At 1 mg/kg, however, TdP were induced in 5 of 10 animals and in an additional 2 animals at 3 mg/kg. Single and multiple ectopic beats preceded the induction of TdP, and the ectopic beats were observed in a dose-dependent manner. The plasma concentrations of quinidine in dogs with TdP were equivalent to or less than quinidine levels in humans with TdP, while those of astemizole were higher in dogs. In conclusion, this acute canine model of TdP with halothane anesthesia, complete AV block, PES, and simultaneous measurements of plasma drug concentration would be valuable for assessing the risk of drugs, especially I-Kr blockers, to induce TdP in humans.
引用
收藏
页码:165 / 176
页数:12
相关论文
共 60 条
[1]   MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia [J].
Abbott, GW ;
Sesti, F ;
Splawski, I ;
Buck, ME ;
Lehmann, WH ;
Timothy, KW ;
Keating, MT ;
Goldstein, SAN .
CELL, 1999, 97 (02) :175-187
[2]   Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes [J].
Antzelevitch, C ;
Sun, ZQ ;
Zhang, ZQ ;
Yan, GX .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1996, 28 (07) :1836-1848
[3]   The M cell: Its contribution to the ECG and to normal and abnormal electrical function of the heart [J].
Antzelevitch, C ;
Shimizu, W ;
Yan, GX ;
Sicouri, S ;
Weissenburger, J ;
Nesterenko, VV ;
Burashnikov, A ;
Di Diego, J ;
Saffitz, J ;
Thomas, GP .
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, 1999, 10 (08) :1124-1152
[4]   K(v)LQT1 and IsK (minK) proteins associate to form the I-Ks cardiac potassium current [J].
Barhanin, J ;
Lesage, F ;
Guillemare, E ;
Fink, M ;
Lazdunski, M ;
Romey, G .
NATURE, 1996, 384 (6604) :78-80
[5]   TORSADE DEPOINTES DUE TO QUINIDINE - OBSERVATIONS IN 31 PATIENTS [J].
BAUMAN, JL ;
BAUERNFEIND, RA ;
HOFF, JV ;
STRASBERG, B ;
SWIRYN, S ;
ROSEN, KM .
AMERICAN HEART JOURNAL, 1984, 107 (03) :425-430
[6]   ERYTHROMYCIN-INDUCED QT PROLONGATION AND POLYMORPHIC VENTRICULAR-TACHYCARDIA (TORSADES-DE-POINTES) - CASE-REPORT AND REVIEW [J].
BRANDRISS, MW ;
RICHARDSON, WS ;
BAROLD, SS .
CLINICAL INFECTIOUS DISEASES, 1994, 18 (06) :995-998
[7]   Electropharmacologic characteristics of ventricular proarrhythmia induced by ibutilide [J].
Chen, YJ ;
Hsieh, MH ;
Chiou, CW ;
Chen, SA .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1999, 34 (02) :237-247
[8]   MEXILETINE ANTAGONIZES EFFECTS OF SOTALOL ON QT INTERVAL DURATION AND ITS PROARRHYTHMIC EFFECTS IN A CANINE MODEL OF TORSADE-DE-POINTES [J].
CHEZALVIELGUILBERT, F ;
DAVY, JM ;
POIRIER, JM ;
WEISSENBURGER, J .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1995, 26 (03) :787-792
[9]   SYNCOPE AND CARDIAC-ARRHYTHMIA DUE TO AN INTERACTION BETWEEN ITRACONAZOLE AND TERFENADINE [J].
CRANE, JK ;
SHIH, HT .
AMERICAN JOURNAL OF MEDICINE, 1993, 95 (04) :445-446
[10]   A MOLECULAR-BASIS FOR CARDIAC-ARRHYTHMIA - HERG MUTATIONS CAUSE LONG QT SYNDROME [J].
CURRAN, ME ;
SPLAWSKI, I ;
TIMOTHY, KW ;
VINCENT, GM ;
GREEN, ED ;
KEATING, MT .
CELL, 1995, 80 (05) :795-803