Chemotherapy of Onchocerca lienalis microfilariae in mice: a model for the evaluation of novel compounds for the treatment of onchocerciasis

Abstract

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 5x100 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 5x0.0063 mg/kg and producing a significant mf reduction (63.5%) at 5x0.008 mg/kg following subcutaneous administration. In comparison, DEC was much less active, producing a 32.4% mf reduction at 5x25 mg/kg ranging up to a maximum of 72% reduction at 5x100 mg/kg. CGI 17658 was the most active compound examined next to ivermectin, almost 100% effective against skin mf at a dose of 5x6.25 mg/kg via the oral route while being less effective via subcutaneous administration (65% reduction). The lowest effective dose examined was 5x3.13 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 5x6.25 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.

Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis

“…Traditionally pre-clinical and clinical studies of anti-filarial chemotherapies have linked drug dosage to pharmacological effect 35 36 37 . Linking dosage to pharmacological effect when comparing chemotherapies is inherently flawed as the pharmacokinetics (absorption, distribution, metabolism and excretion) of different chemotherapies within a target population can vary radically and therefore the systemic exposure of the drug at the effect site can be significantly different for the same dose of two different drugs.…”

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

“…Infectious stage (L3) larvae of O. volvulus can be implanted within micro-chambers to achieve only abbreviated development to the L4 larval stage [ 17 ]. Microfilarial infections of the skin, utilising purified cattle Onchocerca mf , can be established in inbred laboratory mouse strains and have been utilised in pre-clinical filaricidal testing [ 18 ]. However, no reliable macrofilarial Onchocerca small animal model has been described.…”

Challenges in drug discovery for novel antifilarials

“…The development and further optimisation of this assay are described in [81][82][83]86] . This assay has been used in the identification of compounds with anti-Onchocerca adult worm activity.…”

“…The Onchocerca lienalis mf mouse model for the evaluation of drugs had been previously described [86] . Clearly the preferred parasite target for chemotherapy is the adult worm; however, Onchocerca parasites cannot be cyclically maintained in laboratory hosts and the difficulties involved in procuring and transplanting adult worms from natural hosts into rodents more or less excludes this approach for routine work.…”

“…SOPs for in vitro primary screening of compounds using adult male worms of O. gutturosa as a surrogate for O. volvulus , the human pathogen, are all in place at NPIMR (see Section 2 for SOPs). In addition to in vitro compound screening, NPIMR also uses an additional in vivo O. lienalis mf model using mice [84][85][86] .…”