Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Assessment of General and Cardiac Toxicities of Astemizole in Male Cynomolgus Monkeys: Serum Biochemistry and Action Potential Duration

  • Lee, Jong-Hwa (Research and Development Division, Korea Institute of Toxicology) ;
  • Kim, Do-Geun (Research and Development Division, Korea Institute of Toxicology) ;
  • Seo, Joung-Wook (Division of Non-clinical Studies, Korea Institute of Toxicology) ;
  • Lee, Hyang-Ae (Research and Development Division, Korea Institute of Toxicology) ;
  • Oh, Jeong-Hwa (Research and Development Division, Korea Institute of Toxicology) ;
  • Shin, Ho-Chul (Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University) ;
  • Yoon, Seok-Joo (Research and Development Division, Korea Institute of Toxicology) ;
  • Kim, Choong-Yong (Research and Development Division, Korea Institute of Toxicology)
  • Published : 2008.12.01
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Abstract

Toxicology screening following treatment with astemizole, a histamine receptor antagonist, at oral doses of 0, 10, 30 and 60 mg/kg was carried out in male cynomolgus monkeys (Macaca fascicularis). No dose-related changes in mortality, clinical signs, body weight changes, food consumption, or urine analysis occurred in any animal compared to the vehicle control. However, the high-dose group showed a decrease in BUN and ALP compared to vehicle control group. In addition, the levels of TG, AST, ALP and CK increased. Although astemizole did not produce significant toxicological changes at any dose tested, we predict that it can cause toxicological changes of the liver and heart based on the changes in the serum parameters related to the heart and liver. The Action Potential Duration (APD) was prolonged in the heart of 60 mg/kg treatment group compared to the control group. The APD increase in 60 mg/kg treatment group along the other related changes in toxicological parameters imply that astemizole has major cardiotoxic effects in the cynomolgus monkey. This study is a valuable assessment for predicting the general toxicity and cardiotoxic effects of antihistamine drugs using nonhuman primates.

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References

  1. Kim, C.-Y., Lee, H.-S., Han, S.-C., Heo, J.-D., Ha, C.-S., Kwon, M.-S. and Chung, M.-K. (2004). Haematologic and serum biochemical variables in cynomolgus monkeys. Korean J. Lab. Ani. Sci., 20, 44-48
  2. Kim, C.-Y., Han, S.-C., Heo, J.-D., Lee, H.-S. Ha, C.-S., Kang, B.-H, Kwon, M.-S. and Han, S.-S. (2004). Effect of transportation on haematological and serum biochemical values in cynomolgus monkeys. Korean J. Lab. Ani. Sci., 20, 328-332.
  3. Matsuzawa, T., Nomura, M. and Unno, T. (1993). Clinical pathology reference ranges of laboratory animals. J. Vet. Med. Sci., 55, 351-362 https://doi.org/10.1292/jvms.55.351
  4. Milberg, P., Pott, C., Fink, M., Frommeyer, G., Matsuda, T., Baba, A., Osada, N., Breithardt, G., Noble, D. and Eckardt, L. (2008). Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3. Heart Rhythm, 5, 1444-1452 https://doi.org/10.1016/j.hrthm.2008.06.017
  5. Nouchi, H., Takahara, A., Nakamura, H., Namekata, I., Sugimoto, T., Tsuneoka, Y., Takeda, K., Tanaka, T., Shigenobu, K., Sugiyama, A. and Tanaka, H. (2008). Chronic left atrial volume overload abbreviates the action potential duration of the canine pulmonary vein myocardium via activation of IK channel. Eur. J. Pharmacol. 597, 81-85 https://doi.org/10.1016/j.ejphar.2008.09.002
  6. Paakkari, I. (2002). Cardiotoxicity of new antihistamines and cisapride. Toxcol. Lett., 127, 279-284 https://doi.org/10.1016/S0378-4274(01)00510-0
  7. Rao, K.A., Adlakha, A., Verma-Ansil, B., Meloy, T.D. and Stanton, M.S. (1994). Torsades de pointes ventricular tachycardia associated with overdose of astemizole. Mayo Clin. Proc., 69, 589-593 https://doi.org/10.1016/S0025-6196(12)62252-6
  8. Schuurman, H.-J. and Smith, H.T. (2005). Reference values potential duration at 90%. for clinical chemistry and clinical haematology parameters in cynomolgus monkeys. Xenotransplantation 12, 72- 75 https://doi.org/10.1111/j.1399-3089.2004.00186.x
  9. Vorperian, V.R., Zhou, Z., Mohammad, S., Hoon, T.J., Studenik, C. and January, C.T. (1996). Torsade de pointes with an antihistamine metabolite, potassium channel blockade with desmethylastemizole. J. Am. Coll. Cardiol., 28. 1556-1561 https://doi.org/10.1016/S0735-1097(96)00352-X
  10. Walter, F.L. (1989). The Clinical Chemistry of Laboratory Animals, Pergamon Press, pp. 59-69
  11. Wolford, S.T., Schroer, R.A., Gohs, F.X., Gallo, P.P., Brodeck, M., Falk, H.B. and Ruhren, R. (1986). Reference range data base for serum chemistry and haematology values in laboratory animals. J. Toxicol. Environ. Health, 18, 161- 188 https://doi.org/10.1080/15287398609530859