Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial

Abstract

Difluoromethylornithine (DFMO), a specific, irreversible inhibitor of polyamine biosynthesis shown to be curative in animal models inoculated with various Trypanosoma spp., was evaluated in the Southern Sudan in a preliminary open clinical field trial in patients infected with Trypanosoma brucei gambiense. 20 patients were studied including 18 with late-stage disease involving the central nervous system, 16 of whom were refractory to arsenical treatment. In late-stage disease monotherapy with oral DFMO doses of about 400 mg/kg/day for five to six weeks was associated with disappearance of parasites from cerebrospinal fluid (CSF), decreased CSF WBC counts and protein concentrations and reversal of clinical signs. Side effects associated with this dose regimen included diarrhoea, abdominal discomfort and anaemia, but were seldom sufficiently severe to prompt discontinuing therapy. In early-stage patients about 200 mg/kg/day for six weeks appears adequate to eliminate parasites and reverse clinical symptoms and is well tolerated. Three cases of late-stage sleeping sickness and two of early-stage disease followed up for approximately one and a half to two years after treatment indicated that DFMO monotherapy can be curative. Additional studies are needed to define optimal posology. Inhibition of polyamine biosynthesis is a promising new approach to therapy of trypanosomiasis.