약학회지 (YAKHAK HOEJI)

  • 제50권2호
  • /
  • Pages.129-135
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  • 2006
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  • 0377-9556(pISSN)
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  • 2383-9457(eISSN)
대한약학회 (The Pharmaceutical Society of Korea)
권호 표지

원격무선측정장치를 이용한 항히스타민제의 심혈관계 영향평가

Effects of Antihistamines on the Cardiovascular System in Telemetered Conscious Dogs

  • 이윤희 (식품의약품안전청 국립독성연구원 일반약리팀) ;
  • 나한광 (식품의약품안전청 국립독성연구원 일반약리팀) ;
  • 윤재석 (식품의약품안전청 국립독성연구원 일반약리팀) ;
  • 정수연 (식품의약품안전청 국립독성연구원 일반약리팀) ;
  • 김주일 (식품의약품안전청 국립독성연구원 일반약리팀) ;
  • 최기환 (식품의약품안전청 국립독성연구원 일반약리팀)
  • Lee Yun-Hee (General Pharmacology Team, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Na Han-Kwang (General Pharmacology Team, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Yun Jae-Suk (General Pharmacology Team, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Chung Soo-Youn (General Pharmacology Team, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Kim Joo-Il (General Pharmacology Team, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Choi Ki-Hwan (General Pharmacology Team, National Institute of Toxicological Research, Korea Food and Drug Administration)
  • 발행 : 2006.04.01
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초록

Two Antihistamines, terfenadine and astemizole have been withdrawn from major markets for the reason that these durgs have been reported to induce QT interval prolongation associated with the onset of Torsades do Pointes (TdP), resulting in a life-threatening ventricular arrhythmia. In this study, we investigated effects of diphenhydramine on electrocardiograms and hemodynamic parameters in conscious telemetered dogs. We validated and defined the sensitivity of the test system by monitoring basal parameters and using positive control substance, terfenadine. Single administration effects were tested during 24 hours for each test drug at dose 1 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg. We monitored QT, QTc, heart rate, blood pressure and body temperature after administering test drugs. In conscious telemetered dogs, diphenhydramine significantly prolonged $QT\;(6.8\%\;of\;basal)\;and\;QTc\;(7.8\%\;of\;basal)$ at 100 mg/kg. Other parameters were not affected significantly. These findings suggest that antihistamines could induce important clinical relevance for patients taking excessive dosages of conventional antihistamines and those at risk of developing cardiac arrhythmias. Future studies that include other antihistamines and other classes will be necessary to predict the torsadogenic risk of drugs in humans.

키워드

참고문헌

  1. Brown, A. M. : Drugs, hERG and sudden death. Cell Calcium 35, 543 (2004) https://doi.org/10.1016/j.ceca.2004.01.008
  2. Topol, E. J. : Failing the public health - Rofecoxib, Merck, and the FDA. New Eng. J. Med. 351, 1707 (2004) https://doi.org/10.1056/NEJMp048286
  3. Fermini, B. and Fossa, A. A. : The impact of drug-induced QT interval prolongation on drug discovery and development. Nature Rev. 2, 439 (2003) https://doi.org/10.1038/nrd1108
  4. Redfern, W. S., et al. : Relationship between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58, 32 (2003) https://doi.org/10.1016/S0008-6363(02)00846-5
  5. ICH Harmonized Tripartite Guideline (S7B revised). The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals, step 3 (2004)
  6. ICH Harmonized Tripartite Guideline (E14). The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs, step 3 (2004)
  7. Guth, B. D., et al. : Developing a strategy for the nonclinical assessment of proarrhythmic risk of pharmaceuticals due to prolonged ventricular repolarization. J. Pharmacol. Toxicol. Methods 49, 159 (2004) https://doi.org/10.1016/j.vascn.2004.02.006
  8. Antzelevitch, C. and Shimizu, W. : Cellular mechanisms underlying the long QT syndrome. Curr. Opin. Cardiol. 17, 43 (2002) https://doi.org/10.1097/00001573-200201000-00007
  9. Finlayson, K., et al. : Acquired QT interval prolongation and hERG : implications for drug discovery and development. Eur. J. Pharmacol. 500, 129 (2004) https://doi.org/10.1016/j.ejphar.2004.07.019
  10. ICH Harmonized Tripartite Guideline (S7A). Safety pharmacology studies for human pharmaceuticals (2001)
  11. Abhash, C., et al. : QT interval prolongation in diphenhydramine toxicity. International Journal of Cardiology 98, 341 (2005) https://doi.org/10.1016/j.ijcard.2003.10.051
  12. Sype, J. W., et al. : Prolonged QT interval with markedly abnormal ventricular repolarization in diphenhydramine overdose. International Journal of Cardiology 99(2), 333 (2005) https://doi.org/10.1016/j.ijcard.2003.11.035
  13. Truett, A. A. and West, D. B. : Validation of a radiotelemetry system for continuous blood pressure and heart rate monitoring in dogs. Lab. Animal. Sci. 45, 299 (1995)
  14. Gelzer, A. R. M. and Ball, H. A. : Validation of a radiotelemetry system for measurement of blood pressure, electrocardiogram and locomotor activity in beagle dogs. Clin. Exp. Hypertens 19, 1135 (1997) https://doi.org/10.3109/10641969709083209
  15. Radovanovic, D., et al. : Dose-dependent toxicity of diphenhydramine overdose. Hum. Exp. Toxicol. Sep. 19(9), 489 (2000) https://doi.org/10.1191/096032700671040438
  16. Joshi, A. K., et al. : Case of polymorphic ventricular tachycardia in diphenhydramine poisoning. J. Cardiovasc. Electrophysiol. 15(5), 591 (2004) https://doi.org/10.1046/j.1540-8167.2004.03173.x
  17. Merk, H. F. : Standard treatment : the role of antihistamines. J. Investig Dermatol. Symp. Proc. 6(2), 153 (2001)
  18. Yee, G. Y. : Drug induced QT prolongation and torsades de pointes. Heart 89, 1363 (2003) https://doi.org/10.1136/heart.89.11.1363
  19. Guth, B. B., et al. : Developing a strategy for the nonclinical assessement of proarrhythmic risk of pharmaceuticlas due to prolonged ventricular repolarization. Journal of Pharmacological Toxicological Methods 49, 159 (2004) https://doi.org/10.1016/j.vascn.2004.02.006
  20. Ajay Joshi, et al. : Preclinical strategies to assess QT liability and torsadogenic potential of new Drugs : the role of experimental models. Journal of Electrocardiology 37, 7 (2004) https://doi.org/10.1016/j.jelectrocard.2004.08.003