Abstract
Abstract Coartem (CA) artemether/lumefantrine) is a combination therapy widely used in sub-Saharan Africa in managing uncomplicated Plasmodium falciparum-induced malaria. According to manufacturer’s literature, no long-term carcinogenicity studies have been carried out on CA. Therapy with CA places a burden on hepatic metabolism, accumulation of its metabolites (dihyroartemisinin, desbutyl-lumefantrine) induces hepatotoxicity, altering hepatic functions and formation of DNA adducts that may have implication in hepatocarcinogenesis. Wistar rats (n=20) were treated with CA (1, 3 and 5mg/kg) twice daily, thrice weekly for 40 consecutive days exhibited symptoms such as sneezing, lethargy with no effects on final body weight, relative liver weight or mortality during the study. Histopathological examination of treated rats’ liver revealed mild portal cellular infiltration in the group administered 1mg/kg Coartem. There was mild Kupffer cells hyperplasia in the rats that received 3mg/kg Coartem and mild to moderate portal mononuclear cellular infiltration in the group that received 5mg/kg. In addition, there was severe portal congestion and hyperplasia of the bile duct, which made the portal triad very prominent. These observations were in contrast to the negative control group with no macro /microscopic visible lesion. Serum levels of hepatotoxicity markers (γ-glutamyl-, alanine amino-, aspartate amino- transferases and alkaline phosphatase) in CA treated group showed no significant difference (p>0.05) compared with controls. Means of urea, creatinine (in whole blood), albumin and total protein (liver homogenate) of the CA administered group were not different (p>0.05) compared with controls. CA treatment dose dependently increased the formation of micronucleated polychromatic erythrocytes (mPCEs) in rat bone marrow cells. Although this was not statistically significant (p>0.05) for the various doses of CA administered when compared with control groups. Taken together, CA treatment (1, 3 and 5mg/kg body) for a period of 40 days had no hepatotoxic and nephrotoxic effect. Although prolonged administration may likely be toxic, Kupffer cell hyperplasia mild to moderate portal cellular infiltration of hepatic sinusoid may exacerbate drug-induced hepatocarcinogenesis over a prolonged treatment period as observed in this study. Longer-term chronic studies for 80-120 are being investigated. Citation Format: Martins A. Aloba, Fisayo A. Olotu, Oyeronke A. Odunola, Michael A. Gbadegesin, Solomon E. Owumi. Chronic Coartem treatment and hepatocarcinogenesis in male Wistars rat. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A12.
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