Efficacy of experimental trypanocidal compounds against a multiple drug-resistantTrypanosoma brucei brucei stock in mice

Abstract

Several experimental trypanocidal compounds, 6-amidino-2-(4-amidinophenyl)indole dilactate (DAPI), DL-alpha-difluoromethylornithine (DFMO), 2-(dimethylamino)-4'-[(1-methyl-2-nitroimidazole-5-yl) methoxy] aceto-anilide (Ro 15-0216), sinefungin, and triacetylbenzene-tris(guanylhydrazone)trimethanesulfonate hydrate (TBG-MS) were tested to evaluate their ability to cure mouse infections with a multiple drug-resistant Trypanosoma brucei brucei stock (CP 547). This stock proved to be drug-resistant against diminazene aceturate, homidium chloride, isometamidium, quinapyramine sulfate, Mel B, and pentamidine isethionate but fully sensitive to suramin. Compared with the sensitive stock CP 462, the drug-resistant stock CP 547 was completely resistant to 16-fold the curative dose of sinefungin and partially resistant to 4-fold the curative dose of DAPI and to 13-fold the curative dose of TBG-MS, a dose that killed 25% of the animals due to its toxicity. Ro 15-0216 cured all mice when 18 times the usual curative dose level was given. DFMO was equally effective against both stocks.

Differential susceptibility to DL-alpha-difluoromethylornithine in clinical isolates of Trypanosoma brucei rhodesiense

“…However, an examination of Tables 2 and 3 shows that the differences in drug susceptibility were (15,24) and the laboratory (28). In addition to KETRI 243, three other isolates were resistant to arsenical compounds.…”

Natural Products Active Against African Trypanosomes: A Step Towards New Drugs

“…85 In vivo 120 cures mice infected with T. b. brucei, T. congolense and T. vivax when administered intraperitoneally and is well tolerated in mice. 86, 87 However, unexpectedly, 120 proved to be very nephrotoxic at subcurative levels in goats blocking any further development. 88 …”

Rapid identification of isometamidium-resistant stocks of Trypanosoma b. brucei by PCR–RFLP

“…If Sfa NI-RFLP is found to be sensitive enough for the detection of mutated TbAT1, it might be developed into a good epidemiological tool for the early detection of drug-resistant strains of T. brucei, which would be valuable for successful chemotherapy and control of the diseases. Despite reports of significant mortality of cattle after infections with T. b. brucei from Western Kenya and Uganda (Wellde et al 1989), only a few attempts were made to study the spread of isometamidium-resistant T. b. brucei infections in the tsetse-infected areas of sub-Saharan Africa (Joshua 1988;Zweygarth and Röttcher 1989;Chitambo and Arakawa, 1991). T. b. brucei may become more pathogenic under stress conditions and in areas where other trypanosome species have been effectively reduced by chemotherapy (Kalu 1995).…”

“…b. brucei reference stocks CP 547 was isolated from a naturally infected cow in Jilib, Somalia in 1985 (Table 1). The isolate is resistant to diminazene, isometamidium, quinapyramine, melarsoprol, homidium and pentamidine (Zweygarth and Röttcher 1989). The clone CP 2469 was derived from a T. brucei stock isolated from a naturally infected cow in Hakaka, Soakow District, Somalia in 1985.…”