IN-VIVO TRYPANOCIDAL ACTIVITIES OF NEW S-ADENOSYLMETHIONINE DECARBOXYLASE INHIBITORS

A series of novel aromatic derivatives based on the structure of methy lglyoxal bis(guanylhydrazone) (MGBG) was examined for trypanocidal act ivities in human and veterinary trypanosomes of African origin, One ag ent, CGP 40215A, a bicyclic analog of MGBG which also resembles the di amidines diminazene (Berenil) and pentamidine, was curative of infecti ons by 19 isolates of Trypanosoma brucei subspecies as well as a Trypa nosoma congolense isolate, Several of these isolates were resistant to standard trypanocides, Curative doses were greater than or equal to 2 5 mg/kg of body weight/day for 3 days in these acute laboratory model infections, In addition, CGP 40215A also cured a model central nervous system infection in combination with the ornithine decarboxylase inhi bitor DL-alpha-difluoromethylornithine (DFMO; Ornidyl, eflornithine), Curative combinations were 14 days of oral 2% DFMO (similar to 5 g/kg/ day) plus 5, 10, or 25 mg/kg/day for 3 or 7 days given by intraperiton eal injection or with a miniosmotic pump, Combinations were most effec tive if CGP 40215A was given in the second half or at the end of the D FMO regimen, MGBG has modest activity as an inhibitor of trypanosome S -adenosylmethionine decarboxylase (50% inhibitory concentration [IC50] , 130 mu M), while CGP 40215A was a more active inhibitor (IC50, 20 mu M). Preincubation of trypanosomes with CGP 40215A for 1 h caused a re duction in spermidine content (36%) and an increase in putrescine cont ent (20%), indicating that one possible mechanism of its action may be inhibition of polyamine biosynthesis.