Chemotherapy of Onchocerca lienalis microfilariae in mice: a model for the evaluation of novel compounds for the treatment of onchocerciasis.
The model of Onchocerca lienalis microfilariae (mf) injected into inbred CBA/Ca mice was studied for its usefulness as an additional primary/secondary drug screen for onchocerciasis. Invermectin, DEC, suramin, flubendazole, mebendazole, levamisole, Mel W, furapyrimidone, metrifonate, amoscanate and the new Ciba-Geigy compounds CGP 6140, CGP 20'376 and CGI 17658 all significantly reduced levels of mf at a dose of 5 X 100 mg/kg or less. An early dosing protocol, on days 3-7 after infection, was found to be generally more effective than dosing on days 11-15, followed by necropsy on day 18. In some cases there were important differences in levels of drug activity depending on whether the drug was administered by the subcutaneous or oral route, indicating that new compounds should be tested via both routes. Ivermectin was by far the most active compound examined, virtually clearing mf from the skin at a dose of 5 X 0.0063 mg/kg and producing a significant mf reduction (63.5%) at 5 X 0.0008 mg/kg following subcutaneous administration. In comparison, DEC was much less active, producing a 32.4% mf reduction at 5 X 25 mg/kg ranging up to a maximum of 72% reduction at 5 X 100 mg/kg. CGI 17658 was the most active compound examined next to ivermectin, almost 100% effective against skin mf at a dose of 5 X 6.25 mg/kg via the oral route while being less effective via subcutaneous administration (65% reduction). The lowest effective dose examined was 5 X 3.13 mg/kg (per os) which reduced mf levels by 64%. CGP 20'376 was also very active, resulting in a 46% (subcutaneous) and 62% (per os) reduction at a dose of 5 X 6.25 mg/kg. This mouse model has clearly identified all the known microfilaricides examined and also, to a lesser extent, those compounds considered to be principally macrofilaricides. We believe it has value as an additional drug screen for onchocerciasis, which will enable the evaluation of novel compounds against skin-dwelling Onchocerca mf at the primary/secondary level, providing complementary information to new in vitro screens using adult Onchocerca.
Townson
S
S
CAB International Institute of Parasitology, St. Albans, Herts., UK.
Dobinson
A
A
Connelly
C
C
Muller
R
R
D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005369:Filaricides / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008842:Microfilariae / Q000187:drug effects; D009855:Onchocerciasis / Q000188:drug therapy*
D000871:Anthelmintics; D005369:Filaricides