Toxicological profile of aimpila drug in chronic experiment on rats

Introduction. As a rule, pharmacotherapy of neoplastic diseases is associated with side effects varying degrees of severity. This is determined by the insufficient selective action of antitumor agents and, as a result, high nonspecific toxicity. One way to solve this problem is the development of the targeted drugs, delivered the active agent to the tumor cells. Over the past decades many experimental and clinical studies were undertake, but only few of them have demonstrated clinical efficacy of targeted drugs. This determines the necessity of further search in this direction. Objective: to investigate the toxicity of aimpila, its correlation with dose and reversibility. Materials and methods. Toxicological study of aimpila, developed by Pharmaceutical Scientific Center “PharmAccess” Ltd. (Moscow), was performed in male and female outbred rats. Aimpila is atractyloside alpha-fetoprotein noncovalent complex. Capsule mass of the drug in starch gel was administrated per os at the 1 and 10 therapeutic dose (30 x 0.1 mg/kg or 30 x 1 mg/kg with 24-h interval). Dynamics of body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed for all animals. 5 animals in each group were sacrificed 1 and 30 days post treatment. Results. The results of the study demonstrate that the treatment with aimpila does not produce any changes in examined clinical-labora- tory parameters. Liver, renal, cardio, pancreatic and gastrointestinal toxicity of aimpila have been documented by microscopic pathology observation only in groups of rats, treated with high dose of drug. Histopathological findings of hepatotoxicity were supported by the results of clinical chemistry. Marked elevation of aspartate aminotransferase in serum was found after high dose aimpila treatment. These abnormalities were reversible during a month. Conclusion. The overall result of this study suggests the aimpila formulation has favorable toxicological profiles. Dose dependence and reversibility of toxic effects allows us to recommend it to further advance.

аимпила, альфа-фетопротеин, атрактилозид, хроническая токсичность, крысы, aimpila, alpha-fetoprotein, atractyloside, chronic toxicity, rats

1. Biological activities of alpha-fetoprotein. Vol. 1. Ed. by G.J. Mezejewsky, H.J. Jakobson. Boca Raton, Florida: CRC Press, Inc., 1987. Pp. 3-19.

2. Абелев Г. И. 25 лет изучения а-фето-протеина. Онтогенез 1989;20(6):607-15.

3. Решетников С.С. Иммуноферментный анализ альфа-фетопротеина, использование в диагностике заболеваний человека. В сб.: Диагностическая значимость выявления маркеров фетоплацентарного комплекса в контроле развития беременности и онкозаболеваний. Кольцово, 2005. С. 9-30.

4. Эренпрейс Я.Г. Эмбриональные свойства опухолевых клеток: факты и гипотезы. Экспериментальная онкология 1982;4(6):13-8.

5. Neame P.B., Pillay V.K. Spontaneous hypoglycaemia, hepatic and renal necrosis following the intake of herbal medicines. S Afr Med J 1964;38:729-32. PMID: 14208883.

6. Klingenberg M., Grebe K., Scherer B. The binding of atractylate and carboxy-atractylate to mitochondria. Eur J Biochem 1975;52(2):351-63. PMID: 1175588.

7. Stewart M.J., Steenkamp V. The biochemistry and toxicity of atractyloside: a review. Ther Drug Monit 2000;22(6):641-9. PMID: 11128230.

8. Руководство по проведению доклинических исследований лекарственных средств. Под ред. А.Н. Миронова. М.: Гриф и К., 2012. Ч. 1. С. 13-24.

9. Черешнев В.А., Родионов С.Ю., Черкасов В.А. и др. Альфа-фетопротеин. Екатеринбург, 2004. С. 104-19.

10. Bruni A., Contessa A., Luciani S. Atractyloside as an inhibitor of energy transfer reactions in liver mitochondria. Biochim Biophys Acta 1962;60:301-11. PMID: 6552848.

11. Bruni A., Luciani S., Bortignon C. Competitive reversal by adenine nucleotides of atractyloside effect on mitochondrial energy transfer. Biochim Biophys Acta 1965;97:434-41. PMID: 14323588.

12. Obatomi D.K., Bach P.H. Atractyloside nephrotoxicity: in vitro studies with sus pensions of rat renal fragments and precision-cut cortical slices. In Vitr Mol Toxicol 2000;13(1):25-36. PMID: 10900405.

13. Obatomi D.K., Thanh N.T., Brant S., Bach P.H. The toxic mechanism and metabolic effects of atractyloside in precision-cut pig kidney and liver slices. Arch Toxicol 1998;72(8):524-30. PMID: 9765068.

14. Pocciari F., Silano V. Effect of atractyloside on glucose and pyruvate metabolism in rat diaphragm muscle. Biochem J 1968;107(2):305-9. PMID: 5641884.

15. Carpenedo F., Luciani F., Scaravilli F. et al. Nephrotoxic effect of atractyloside in rats. Arch Toxicol 1974;32(3):169-80. PMID: 4479740.

16. Koechel D.A., Krejci M.E. Extrarenal and direct renal actions of atractyloside contribute to its acute nephrotoxicity in pentobarbital-anesthetized dogs. Toxicology 1993;79(1):45-66. PMID: 8475499.

17. Hedili A., Warnet J., Thevenin M. et al. Biochemical investigation of Atractylis gummifera L. hepatotoxicyty in the rat. Arch Toxicol Suppl 1989;13:312-5. PMID: 2774952.

18. Wang Y., Han T., Xue L.M. et al. Hepatotoxicity of kaurene glycosides from Xanthium strumarium L. fruits in mice. Pharmazie 2011;66(6):445-9. PMID: 21699085.

19. Bhoola K.A. Clinico-pathologic and biochemical study of the toxicity of Callilepis laureola (Impila) [M. D.]. Durban: University of Natal, 1983. Pp. 28-33.

20. Hamouda C., Hedhili A., Ben Salah N. et al. A review of acute poisoning from Atractylis gummifera L. Vet Hum Toxicol 2004;46(3):144-6. PMID: 15171492.

21. Wainwright J., Schonland M.M. Toxic hepatitis in black patients in natal. S Afr Med J 1977;51(17):571-3. PMID: 867172.

22. Watson A.R., Coovadia H.M., Bhoola K.D. The clinical syndrome of Impila (Callilepis laureola) poisoning in children. S Afr Med J 1979;55(8):290-2. PMID: 441880.

23. Obatomi D.K., Bach P.H. Biochemistry and toxicology of the diterpenoid glycoside atractyloside. Food Chem Toxicol 1998;36(4):335-46. PMID: 9651051.

24. Seedat Y.K., Hitchcock P.J. Acute renal failure from Callilepis laureola. S Afr Med J 1971;45(30):832-3. PMID: 5128528.

25. Song R., Bian H., Huang X., Zhao K.S. Atractyloside induces low contractile reaction of arteriolar smooth muscle through mitochondrial damage. J Appl Toxicol 2012;32(6):402-8. DOI: 10.1002/jat.1688. PMID: 21598287.