EFFECT OF CHRONOMODULATED ARTESUNATE ON RENAL AND HAEMATOLOGICAL TOXICITY IN CISPLATIN-TREATED WISTAR RATS
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ABSTRACT
Cisplatin is a non-cell-cycle dependent chemotherapeutic agent used in the treatment of several common solid tumours. However, an array of serious toxicities in various organs and systems limit its therapeutic use. Artesunate, a semisynthetic derivative of artemisinin is the recommended treatment by the WHO for severe and complicated malaria in low-transmission areas and in the second and third trimesters of pregnancy. In contrast, animal experiments show considerable toxicity upon administration of artemisinins. When malaria and cancer coexist, treatment of patients could be challenging due to the burden of disease and possible drug-drug interaction. The present study investigates the effect of 7-day chronomodulated artesunate administration on renal and haematological toxicity in cisplatin-treated rats. Four groups (n=7/group) of rats received intraperitoneal (i.p.) injection of 3 mg/kg daily dosing of cisplatin at four equispaced circadian times (00:00, 06:00, 12:00 and 18:00 h), for four days to determine the time of least renal and hematological toxicity. Another, two groups of rats (n=7/group) pre-treated with cisplatin (3 mg/kg i.p.) at 06:00 h received artesunate (60 mg/kg i.p.) at 12:00 h and 18:00 h. Parameters of the kidney function, histology of the kidneys and haematological variables were measured on day-8. Post-treatment results showed that administration of cisplatin at 06:00 h and 18:00 h appeared to produce least renal and haematological toxicity. However, kidney function as determined by urea and creatinine levels were not significantly (p>0.05) different between cisplatin-artesunate treated groups and saline control rats.. The group pre-treated with cisplatin and then artesunate at 12:00 h had higher (p<0.05) mean magnesium levels when compared to the saline control and the group pre-treated with cisplatin and then artesunate at 18:00 h. This is indicative of a less protective effect of time of artesunate administration, which is consistent with the impaired kidney histologic architecture observed. The red blood cell (RBC) and haemoglobin (HGB) vi counts were unaffected in cisplatin-artesunate treatment groups irrespective of the time of artesunate administration. However, cisplatin-treated rats that received artesunate at 12:00 h had slightly higher RBC and HGB values indicative of enhanced erythropoiesis. A reduction (p<0.05) in mean serum levels of white blood cell (WBC), platelets (PLT) and lymphocytes (LYM) was observed in both groups of rats pretreated with cisplatin and then artesunate at 12:00 h or 18:00 h. Conversely, neutrophils and monocytes (granulocytes) in these groups had higher (p<0.05) mean values indicative of time dependent immune reconstitution. The ameliorative effect of late activity span cisplatin-treatment on renal and haematological toxicity in wistar rats does not appear to be negated by 7-day chronomodulated daily administration of artesunate. However, this study illustrated the potential therapeutic value of time dependent administration of artesunate in contributing to the ameliorative effect of late activity span cisplatin dosing.
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Chapter One: Introduction
