THE ROLE OF OXIDATIVE STRESS IN BIOCHEMICAL, SEMINOLOGICAL AND HISTOLOGICAL CHANGES DURING ACUTE ADMINISTRATION OF ARTEMETHER

Abstract

Artemether is an antimalarial drug which is effective in the treatment of multidrug resistant malaria but also induces oxidative stress in tissues. Limited information is available on role of oxidative stress in tissue toxicity during administration of artemether. Therefore biochemical, seminological and histological changes following acute administration of artemether were evaluated. One hundred and sixty male albino mice weighing 35-37g were divided into six groups and used for the animal study. Groups 1, 2 and 3 consisted of 30 uninfected mice each given 1.2mg/kg, 24mg/kg and 4.8mg/kg artemether respectively. Group 4 consisted of 20 Plasmodium yoelli infected mice, treated with 1.2mg/kg artemether: group 5 consisted of 20 P. yoelli infected and untreated mice, while group 6 (control) consisted of 30 uninfected and untreated mice. Artemether was administered to groups 1-4 for five consecutive days after which the mice were sacrificed on day 6. Hepatotoxicity was assessed by assay of liver enzymes, lipids and lipoproteins, total proteins, catalase, superoxide dismutase, reduced glutathione activities, malondialdehyde and histological examination of liver. Effects on brain and kidney were assessed by histological examinations of the organs. Tissue homogenates of brain, liver, kidney and testes were used for the assay of malondialdehycle and antioxidants. Effect of artemether on male fertility was assessed by sperm analysis, testicular weight, testicular testosterone and histological examination of testes. In the human study, effects of artemether on liver in 20 male patients suffering from malaria disease and 20 apparently healthy male individuals (age matched) were determined by measuring changes in serum gamma glutamyl transferase, alkaline phosphatase, alanine aminotransferase, albumin, total proteins, total cholesterol, triglyceride and lipoproteins. The dosage was 200mg on day 1 and 100mg on days 2-5. Testosterone was analysed by ELISA while other biochemical parameters were analysed using spectrophotometric methods. Sperm analyses were done using the improved Neubeur's counter. Student's t- test and ANOVA were used for data analysis. There was increased lipid peroxidation in the four organs as indicated by increased malondialdehyde and antioxidants (reduced gIutathione catalase and superoxide dismutase) in groups given artemether when compared with control. In artemether treated groups, there were dose-dependent histopathological effects which include degeneration of interstitial tissues in testes and significant reductions in sperm counts, motility and viability. Activities of alkaline phosphatase in groups 1 (658.63±81.1iu/l) and 4 (666.80 ±83.2iu/l) were significantly higher than control (407.60±63.7iu/l) (p<0.05). In group 4, there were significant differences in total cholesterol (81.53±18.9mg/dI vs 49.80±3.2mg/dl), triglyceride (95.58±21.1mg/dl vs 50.00±3.5mg/dl), total proteins (7.10±0.3mg/dl vs 6.00±0.3mg/dl), catalase (2.48±1.1 vs 4.00±1.2unit/g) and superoxide dismutase (1.20±0.5 vs 1.57±1.2unit/g) when compared with control (p<0.05). There was no significant difference in the biochemical parameters in patients suffering from malaria after administration of artemether when compared with baseline. Apparently healthy volunteers showed significant changes in total protein (6.77 ±1.5 vs 7.00±1.73g/dl), albumin (3.24±0.71 vs 3.85±1.32g/dl), and gamma glutamyl transferase (51.17±2.13 vs 42.53±1.70iu/l) after administration of artemether when compared with baseline (p<0.05). Artemether induced oxidative stress which resulted in reduced sperm quality and defective histology of the animal tissues. Artemether did not cause any significant adverse effects in humans.