Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor.
The compound 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL73811), a potent inhibitor of S-adenosylmethionine decarboxylase, was effective in mice against six of eight clinical isolates of Trypanosoma brucei rhodesiense, the causative agent of East African sleeping sickness. In combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO; Ornidyl), MDL73811 acted synergistically to cure seven of eight infections. MDL73811 was effective when given singly at 50 to 100 mg/kg of body weight per day for 7 days (osmotic pumps). In combination with subcurative DFMO levels (0.25 to 1.0% in drinking water for 7 days), the curative MDL73811 dose could be lowered to 25 or 50 mg/kg, depending on the isolate. Oral administration of the MDL73811-DFMO combination was also effective in an acute infection and in a long-term central nervous system model of Trypansoma brucei brucei infection. These data indicate that MDL73811 may be effective therapeutically in drug-refractory and late-stage East African trypanosomiasis.
Bacchi
C J
CJ
Haskins Laboratories, Pace University, New York 10038.
Nathan
H C
HC
Yarlett
N
N
Goldberg
B
B
McCann
P P
PP
Bitonti
A J
AJ
Sjoerdsma
A
A
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002493:Central Nervous System Diseases / Q000469:parasitology; D003839:Deoxyadenosines / Q000008:administration & dosage / Q000627:therapeutic use*; D000518:Eflornithine / Q000627:therapeutic use; D005260:Female; D051379:Mice; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
D000981:Antiprotozoal Agents; D003839:Deoxyadenosines; C065859:MDL 73811; D012437:Adenosylmethionine Decarboxylase; D000518:Eflornithine