Foetal hepatorenal toxicity and intrauterine growth retardation in pregnant Wistar rats treated with artemether

Abstract

Objectives: Foetal hepatorenal toxicity and foetal morphology were evaluated following artemether administration to pregnant

Wistar albino rats.

Methods: Twenty pregnant Wistar rats weighing between 180–200 g were divided into four groups (n=5, each) with Group 1

serving as the control. Groups 2, 3 and 4 received 1.1 mg, 2.2 mg and 3.3 mg per kilogram body weight artemether, respectively

orally, twice daily for three days on day 7, 8 and 9 of pregnancy. The animals were sacrificed on day 20 of pregnancy and foetuses

were harvested and evaluated for morphological changes. Foetal body weight and crown-rump length (CRL) were measured;

alpha-fetoprotein (AFP) was assayed using amniotic fluid, and foetal kidney and liver were evaluated histologically for toxicity.

Results: There was a significant decrease in body weight, CRL and AFP of the treated groups compared to the control. The foetal

liver of the treated groups revealed distorted cytoarchitecture, marked hepatocyte inflammation and hepatic necrosis. The foetal

kidney of artemether-treated groups also showed disorganised renal structure, atrophic and degenerated glomeruli with acute

tubular necrosis.

Conclusion: Artemether administration to pregnant albino rats causes intrauterine growth retardation or stunted growth,

as well as foetal hepatorenal toxicity.

Keywords

• alpha-fetoprotein; artemether; foetal hepatorenal toxicity; pregnancy

References

1. 1. World Health Organisation. WHO global malaria programme: World Malaria Report 2014. Geneva: WHO Press; 2014.
2. 2. World Health Organisation. The WHO prequalification project. The global portfolio of new antimalarial medicines under development. Clin Pharmacol Ther 2009;85:584–95.
3. 3. Burke E, Deasy J. Hasson R, McCormack R, Randhawa V, Walsh P. Antimalarial drugs from nature. Trinity Student Medical Journal 2003;4:19.
4. 4. Mayxay M, Thongpraseuth V, Khanthavong M, Lindegardh N, Barends M, Keola S, Pongvongsa T, Phompida S, Phetsouvanh R, Stepniewska K, White NJ, Newton PN. An open, randomised comparison of artesunate plus mefloquine vs dihydroartemisininpiperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People’s Democratic Republic (Laos). Trop Med Int Health 2006;11:1157–65.
5. 5. Faye B, Ndiaye JL, Tine R, Sylla K, Gueye AH, Colle LA, Gaye OA. Randomised trial of artesunate/mefloquine vs artemether/lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Senegalese children. Am J Trop Med Hyg 2010;82:140–4.
6. 6. Frey SG, Chelo D, Kinkela MN, Djouknone F, Tietche F, Hatz C, Weber P. Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety. Malar J 2010;9: 291–9.
7. 7. Akpanyung EO, Bassey UE, Usoh I, Iba IU. Effect of combined administration of artequin and pefloxacin on some indices of liver and renal functions of male Wistar albino rats. PharmacologyOnLine 2015;3:84–90.
8. 8. Etim OE, Bassey UE, Charles GE, Sambo EE, Akpan EJ. Toxicological evaluation of some artemisinin combination therapies (acts) on the kidney and liver of Wistar albino rats. International Journal of Biochemistry Research and Review 2016;9:1–5.

9. 9. Bhabagrahi R, Jyotirmoyee J, Satyajit S, Bandana R. Reproductive profile of artemisinins in albino rats. Indian J Pharmacol 2010;42: 192–3.
10. 10. El-Dakdoky MH. Evaluation of the developmental toxicity of artemether during different phases of rat pregnancy. Food Chem Toxicol 2009;47:1437–41.
11. 11. Li Q, Weina PJ. Severe embryotoxicity of artemisinin derivatives in experimental animals, but possibly safe in pregnant women. Molecules 2009;15:40–57.
12. 12. Clarke RL, Lerman SA, Cox EM, Gristwood WE, White TE. Developmental toxicity of artesunate in the rat: comparison to other artemisinins, comparison of embryotoxicity and kinetics by oral and intravenous routes, and relationship to maternal reticulocyte count. Birth Defects Res (Part B) 2008;83:397–406.
13. 13. Longo M, Zanoncelli S, Torre PD, Riflettuto M, Cocco F. Effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos in vitro. Reprod Toxicol 2006;21:83–93.
14. 14. Harpey JP, Darbois Y, Lefebvre G. Teratogenicity of pyrimethamine. Lancet 1983:2:399.
15. 15. Mesembe OE, Inyang AE, Udoaffah G, Igiri AO, Fischer VA, Akpaso M, Eluwa MA. Akpa OA. A morphometric study of the teratogenic effect of artesunate on the central nervous system of the Wistar rat fetuses. Nigerian Journal of Physiological Sciences 2004; 19:1–12.
16. 16. Eluwa MA, Otung GO, UDo-afah G, Ekanem TB, Mesembe OE, Aligweke AU. Teratogenic effect of maternal administration of aloe vera extract on fetal morphology and the histology of the fetal kidney. Global Journal of Medical Sciences 2006;5:41–4.
17. 17. Akpan TB, Ekanemesang UM, Ebong PE, Singh ED. Teratogenic induction of skeletal anomalies by pyrimetamine (Daraprin) in Wistar rats fetuses (Rattus Norvegicus): a morphological study. West African Journal of Anatomy 1992;1:90–3.
18. 18. Ekanem TB, Ekanemesang UM, Ekanem P. Teratogenic effect of pyrimethamine in epiphysial rats fetuses. West African Journal of Anatomy 1999;6:9–12.
19. 19. Moore KL, Persuad TV. The Developing human. Clinically oriented embryology. 7th ed. Philadelphia, PA: W. B. Saunders; 2003. p. 547–62.
20. 20. Peter PW, Verhoef A, Hagenaars AM. Amniotic and maternal serum alpha fetoprotein of rats with induced neural tube defect. Scandinavian Acta of Morphology 1981;19:205–16.
21. 21. Abd-Elmagid BF, Al-Gharudiz FB. Effect of administration of haloperidol on the developing fetus of the chick embryo. Saudi J Biol Sci 2005;15:297–306.
22. 22. Zehra U, Tahir M, Jafferry FH, Lone KP. Ginkgo biloba effects of mice fetal liver. Int J Morphol 2010;28:765–70.
23. 23. Eluwa M, Ekere E, Ekanem T, Akpantah A, Igiri A. Teratogenic effect of beer and palmwine on the histology of the fetal kidney of Wistar rats. The Internet Journal of Toxicology 2009;6:1–5.