ToxSci Advance Access published online on June 1, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl025
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1 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210
* To whom correspondence should be addressed. Humans with underlying cardiovascular disease are at greater risk than humans with normal hearts for developing torsade de pointes (TdP) following exposure to some drugs that prolong ventricular repolarization. This study was designed to test the hypothesis that rabbits with ischemic myocardial failure are at similarly increased risk of developing QTc prolongation and torsade de pointes following exposure to escalating doses of drugs whose capacity to induce TdP is known in humans. Coronary artery ligation was performed in 28 rabbits, causing significant (p<0.05) reduction in left ventricular shortening fraction and systolic myocardial dysfunction 4 weeks after ligation in all operated animals compared to 38 normal, non-operated controls. All studies were performed on rabbits anesthetized with ketamine (35 mg/kg) and xylazine (5 mg/kg). Rabbits were exposed to escalating doses of amiodarone (3, 10, 30 mg/kg/10min), cisapride (0.10, 0.25, 0.50 mg/kg/10min), clofilium (0.1, 0.2, 0.4 mg/kg/10min), dofetilide (0.005, 0.01, 0.02, 0.04 mg/kg/10min), quinidine (3, 10, 30 mg/kg/10 min), and verapamil (0.25, 0.5, 1.0 mg/kg/10min), A greater percentage of rabbits with failing hearts developed TdP following intravenous infusion of escalating doses of dofetilide (85%), clofilium (100%), or cisapride (50%) than did normal rabbits exposed to the same drug protocol (20%, 33% and 0%, respectively). None of the rabbits in either group developed TdP when exposed to escalating doses of amiodarone, verapamil, or quinidine. Two out of 4 test articles lengthened QTc more in rabbits with myocardial failure than in normals, and TdP occurred in 13 out of 28 rabbits with myocardial failure as opposed to only 4 out of 38 rabbits with normal myocardial function.
Received April 4, 2006
Accepted September 5, 2006
Safety Evaluation
Use of a Failing Rabbit Heart as a Model to Predict Torsadogenicity
Anusak Kijtawornrat DVM 1,
Yoshinori Nishijima DVM, PhD 2,
Brian M. Roche PhD 3,
Bruce W. Keene DVM, MSc, DACVIM 4,
and
Robert L. Hamlin DVM, PhD, DACVIM 1 *
2 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210; QTest Labs, Inc. 6456 Fiesta Drive, Columbus, OH 43235
3 QTest Labs, Inc. 6456 Fiesta Drive, Columbus, OH 43235
4 QTest Labs, Inc. 6456 Fiesta Drive, Columbus, OH 43235; Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27606
Robert L. Hamlin, E-mail: hamlin.1{at}osu.edu
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