Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지

Intravenous Single Dose and Four-week Repented Dose Toxicity Study of YHB216, a Recombinant Human Erythropoietin, in Beagle Dogs

YHB216의 비글개에서 정맥내 단회 및 4주 반복투여독성시험

  • 노용우 (충북대학교 수의과대학) ;
  • 장호송 (충북대학교 수의과대학) ;
  • 지형진 (충북대학교 수의과대학) ;
  • 정은용 (충북대학교 수의과대학) ;
  • 신지순 (충북대학교 수의과대학) ;
  • 강민정 ((주)유한양행 중앙연구소) ;
  • 안경규 ((주)유한양행 중앙연구소) ;
  • 최연식 ((주)유한양행 중앙연구소) ;
  • 이종욱 ((주)유한양행 중앙연구소)
  • Published : 2002.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Recently, recombinant human erythropoietin (rHu-EPO) has been used to treat various types of anemia. YHB216 is a new rHu-EPO developed by Yuhan Research Institute. In this study, we investigated the single dose and 4-week repeated dose toxicity of YHB216 in Beagle dogs. In the single dose toxicity study, YHB216 was administered intravenously at single dose levels of 0 and 25,000 IU/kg to dogs (2 dogs/sex/group). There were no treament-related changes in survivals, clinical signs, body weight gain, hematological values, blood chemical values, and necropsy finding during experimental period. In the repeated dose toxicity study, YHB216 was administered intravenously to dogs for 4 weeks at the dose levels of 0, 100, 500, and 2,500IU／kg (3 dogs/sex／group). There were no toxicologically significant changes in clinical signs, body weights, food and water consumptions, ophthalmoscopy, urinalysis and blood chemistry. There were increased values of red blood cell, hemoglobin, and hematocrit at all treated groups. Spleen revealed increased weight and extramedullary hematopoiesis at 500 IU/kg or more. These changes are all considered to be Pharmacology-related effects and were recovered after 4-week recovery period. From these results, it is concluded that LD50 value was above 25,000 IU/kg in the single dose toxicity study of YHB216 in dogs and the no observed adverse effect level (NOAEL) was 100 IU/kg day in the repeated dose toxicity study of YHB216 in dogs.

Keywords

References

  1. Cho, M. H, Kim, D. H., Kang, K. K., Baik, N. G. and Kim, W. B. (1998). Single and 4-week repeated dose toxicity studies of DA-3585, a recombinant human erythropoietin, in rabbits. J. AppI. Pharmacol. 6, 171-181
  2. Cho, M. H., Seong, H. H. J., Kim, H. S., Kwack, S. J., Chun, S. A., Lim, S. Y., Kim, W. B., Kim, B. M., Ahn, B. 0. and Lee, B. M. (1996). Acute toxicity of recombinant human erythropoietin (rHu-EPO) in Beagle dogs. Korean J. Toxicol. 12, 305-308
  3. Cho., M. H., Seong, H. J., Kim, H. S., Kwack, S. J., Lim, S. Y., Chun, S. A., Kim, W. B., Kim, B. M., Ahn, B. 0. and Lee, B. M. (1996). Subacute toxicity of rccombinant human erythropoietin (rHu-EPO) in Beagle dogs. J. Appl. Pharmacol. 4, 323-329
  4. Eric, J. F., Spicer and John A., Wksler. (1990). Acute subcutaneous and intravenous toxicity studies in rats and monkeys with TYB-5220: A recombinant human eryhropoietin. 藥理と治齋18, 45-106
  5. Eric, J. F. Spicer and John A. Wisler. (1990). Twenty eight days intravenous toxicity studies of TYB-5220 in rats and monkeys with a 28 day rccovery period: A recombinant human ethropoietin. 藥理と治齋18, 107-206
  6. Erslev, A. J., Caro, J., Kansu, E. and Silver, R. (1980). Renal and extrarenal erythropoietin production in anemic rats, Brit. J. Hematol. 45, 65-72 https://doi.org/10.1111/j.1365-2141.1980.tb03811.x
  7. Eschbach, J. W. and Adamson, J. W. (1989). Guidelines for recombinant human. erythropoietin therapy. Am. J. Kidney Dis. 14, 2-8 https://doi.org/10.1016/S0272-6386(89)80086-1
  8. Fisher, J. W. (1993). Recent advances in erythropoietin research. pp. 293-311. in: Progeress in Drug Research. Vo1. 41. eds. Emst Juckcr, Birkhauser Verlag Basel, Switzerland. pp. 293-331
  9. Jacobs, K., Shoemaker, C., Rudersdorf, R. Neill S. D. et al. (1985). Isolation and charactehzation of genomic and cDNA clones of human erythropoietin, Nature 313, 806 -810 https://doi.org/10.1038/313806a0
  10. Jacobson, L. 0., Goldwasser, E., Fied, W. and Plzak, L. (1957). Role of the kidney in erythropoiesis, Nature 179, 633-634 https://doi.org/10.1038/179633a0
  11. Koury, S. T., Bondurant, M. C. and Koury, M. ,J. (1988). Localization of eiyttiropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood 71, 524-527
  12. Krantz, S. B. (1991). Erythropoietin. Blood 77, 2497-2503
  13. Lin, F. K., Suggs, S., Lin, C. H., Browne, J. K., Smalling, R,, Egrie, J. C., Cjen, K. K., Fox, G. M., Martin, F., Stabinsky, Z., Bdrawi, S., Lin, P. H. and Goldwasser, E. (1985). Cloning and expression of human erythropoietin gene. Proc. NatiI. Acad. Sci. 49, 807-815
  14. Maxwell, A. P., Lappin, T. R. J., Johnston, C. F., Bridges, J. M. and McGeown, M. G. (1990). Erythropoietin production in kidney tubular cells. Brit J Hematol. 74, 535-539 https://doi.org/10.1111/j.1365-2141.1990.tb06347.x
  15. Mikito Kikumori et al. (1988). A four-week intravenous subacule toxicity study of KRN5702 in Beagle dogs. The Clinical Report$\circledR$ 15, 123-153
  16. Mino, T., Ohmura, T., Hiraoka, Y., Sugino, T. and Hayashi, H. (1990). General pharmacological studies of erythropoietin (TYB-5220). 藥理と治齋18, 953-971
  17. Miyake, T., Kung, C. K. H. and Goldwasser, E. (1977). Purification of human erythropoietin, J. Biol. Chem. 252, 55-58
  18. Noguchi, G., Matsuoka, A., Shinkura, H., Hiromichi, K., Suzuki, S., Kataoka, S., Noguchi, G. and Usami, M. (1990). Four-week intravenous toxicity study of EPOCH in dogs. 臨床醫藥 6, 117-142
  19. Noguchi, G., Takahashi, T., Komatsu, H., Suzuki, S. and Usami, M. (1990). Single-dose intravenous toxicity study of EPOCH in dogs. 臨床醫藥6, 82-88
  20. Okumura, K., Aoki, S., Sugino, T., Ono, T., Nagano, N. and Iba, Y. (1990). Metabolic fatc of erythropoietin (TYB-5220). 藥理と治齋18, 2009-2019
  21. Ridley, D. M., Dawkins, F. and Perlin, E. (1994). Erythropoietin: A review. J. Natl. Med. Assoc. 86, 129-135
  22. Sandra, E., Juul, Anthony, T., Yachnis, Robert, D. and Chhstensen (1998). Tissue disthbution of erythropoietin and erytbropoietin receptor in the developing human fetus, Early Human Development 52, 235-249 https://doi.org/10.1016/S0378-3782(98)00030-9
  23. Siren, A. L. and Ehrenreich, H. (2001). Erythropoietin - a novel concept for neuroprotection, European Archives of Psychiatry and Clinical Neuroscience 251, 179-184 https://doi.org/10.1007/s004060170038
  24. Vreundenhil, G., Frenken, L. A. M. and Koene, R. A. P. (1993). Erythropoietin; mechanisims of action and indications for treatment. Netherlands J. Med. 42, 187-202
  25. 식품의약안전청(1999). '의약품등의 독성 시험기준', 식품의약품안전청고시 제 1999-61호
  26. 식품의약품안전청(2000). 비임상시험관리기준 , 식품의약품안전청 고시 제 2000-63호