EFFECT OF MEGAZOL ON TRYPANOSOMA-BRUCEI-BRUCEI ACUTE AND SUBACUTE INFECTIONS IN SWISS MICE

Human African trypanosomiasis (HAT) or sleeping sickness is a major pu blic health problem in 36 sub-Saharan African countries and is caused by Trypanosoma brucei gambiense and T. b. rhodesiense. About 25 000 ne w cases of the disease are reported annually, and around 50 million pe ople are classed as at risk of contracting the disease. Until now, the only effective drug available for treatment of advanced HAT was the t rypanocide melarsoprol. The mortality rate of melarsoprol treated pati ents is 1-5%. Megazol is a nitroimidazole derivative shown to be effec tive in vitro against T. b. brucei with an EC(50) of 0.01 mu g . ml(-1 ). When this compound was tested for its in vivo activity in T. b. bru cei infected Swiss mice, it was shown to cure the acute disease. Howev er, megazol alone did not cause cure of mice carrying a subacute infec tion with involvement of the central nervous system (CNS). Combined su ramin and megazol treatment did prove effective and the mice were show n to have remission without further relapse from the CNS. The study of three megazol derivatives is also described here. Substitution of a b romine, methyl or trifluoromethyl moeity at the 4 position of the imid azole ring abolished trypanocidal activity both in vivo and in vitro. Intermediates of megazol synthesis (imidazole sulfoxide and imidazole sulfone) were also tested, but were shown not to be active. It is thou ght that megazol trypanocidal effect may be due to the triggering of r adical production by the compound, which have toxic effects on the try panosomes metabolism. In depth study of megazol is needed to fully elu cidate its pharmacokinetics and to precisely pin down its mode of acti on.