UMF-078: A modified flubendazole with potent macrofilaricidal activity against Onchocerca ochengi in African cattle

Bronsvoort, Barend M. deC.; Makepeace, Benjamin L.; Renz, Alfons; Tanya, Vincent N.; Fleckenstein, Lawrence; Ekale, David; Trees, A. J.

doi:10.1186/1756-3305-1-18

Cited by 10 publications

(11 citation statements)

References 37 publications

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“…By applying the efficacious FBZ regimen demonstrable to exert macrofilaricidal effects against Bm adults, we could reproduce the profound effect of this drug against implanted adult male Onchocerca macrofilariae within SCID mice. This tallies with the reported macrofilaricidal effect of the modified FBZ, UMF078, against O. ochengi in the natural cattle host [ 48 ]. Thus, our experiment demonstrates ‘proof of principle’ that the SCID mouse Onchocerca macrofilariae implant model is sufficiently robust to test macrofilaricide activity over a 5 week time frame.…”

Section: Discussionsupporting

confidence: 82%

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

et al. 2014

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BackgroundNew drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model.MethodsThe filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brugia malayi (Bm)-parasitized BALB/c SCID mice vs vehicle control (VC). Responses were compared to BALB/c wild type (WT). Onchocerca ochengi male worms or onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or Meriones gerbils. Survival was evaluated at 7–15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ and rifapentine (RIFAP) against male Onchocerca.ResultsWT and SCID responded with >95% efficacy following ABZ or DEC treatments against Bm larvae (P < 0.0001). IVM was partially filaricidal against Bm larvae in WT and SCID (WT; 39.8%, P = 0.0356 and SCID; 56.7%, P = 0.026). SCID responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, P = 0.0194. SCID; 76%, P = 0.0473). FBZ induced a total macrofilaricidal response against adult Bm in WT and SCID (WT; P = 0.0067, SCID; P = 0.0071). MIN induced a >90% reduction in Bm Wolbachia burdens (P < 0.0001) and a blockade of microfilarial release (P = 0.0215) in SCID. Male Onchocerca survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% vs 22% vs 39% P = 0.0475). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7 days and yielded viable macro/microfilariae ex vivo. FBZ induced a macrofilaricidal effect in Onchocerca male implanted SCID at +5 weeks (FBZ; 1.67% vs VC; 43.81%, P = 0.0089). Wolbachia loads within male Onchocerca were reduced by 99% in implanted SCID receiving RIFAP for +2 weeks.ConclusionsWe have developed a ‘pan-filarial’ small animal research model that is sufficiently robust, with adequate capacity and throughput, to screen existing and future pre-clinical candidate macrofilaricides. Pilot data suggests a murine onchocercoma xenograft model is achievable.

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Section: Discussionsupporting

confidence: 82%

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

et al. 2014

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“…FLBZ nevertheless appears to have significant effects on adult filariae, and in all likelihood considerably more than IVM does. Thus, its ability to eliminate adult worms [ 20 – 23 , 47 ] without a potentially dangerous direct effect on mf makes it a good candidate for use in the global elimination/eradication programs for filarial infections.…”

Section: Discussionmentioning

confidence: 99%

“…The benzimidazoles are broad spectrum anthelmintics that bind preferentially to parasite β-tubulin leading to the disruption of microtubules and, ultimately, to the death of the parasite. FLBZ exhibits macrofilaricidal activity against Brugia pahangi [ 20 , 21 ], Breinlia booliati [ 22 ], and, as a pro-drug of FLBZ (UMF-078), on Onchocerca ochengi [ 23 ]. In addition, several studies in other filarial species have indicated that FLBZ lacks or has only very little activity against mf stages.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity in the in vitro susceptibility of Loa loa microfilariae to drugs commonly used in parasitological infections

et al. 2018

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BackgroundCo-infection with loiasis remains a potential problem in control programs targeting filarial infections. The effects of many anti-parasitic drugs often administered to Loa loa infected people are not well documented. This study compared the in vitro activity of several of these drugs on the viability of L. loa microfilariae (mf).MethodsHuman strain L. loa mf were isolated from baboon blood using iso-osmotic Percoll gradient, and cultured in RPMI 1640/10% FBS with antimalarial drugs (mefloquine, amodiaquine, artesunate, chloroquine and quinine), anthelmintics (ivermectin, praziquantel, flubendazole and its reduced and hydrolyzed metabolites), two potential trypanocidal agents (fexinidazole and Scynexis-7158) and the anticancer drug imatinib. The drug concentrations used varied between 0.156 μg/ml and 10 μg/ml. Mf motility (CR50 = 50% immotility) and a metabolic viability assay (MTT) were used to assess the effects of these drugs on the parasites.ResultsMf in control cultures showed only a slight reduction in motility after 5 days of culture. Active inhibition of Loa loa motility was seen with mefloquine and amodiaquine (CR50 values of 3.87 and 4.05 μg/ml, respectively), immobilizing > 90% mf within the first 24 hours: mefloquine killed the mf after 24 hours of culture at concentrations ≥ 5 μg/ml. SCYX-7158 also induced a concentration-dependent reduction in mf motility, with > 50% reduction in mf motility seen after 5 days at 10 μg/ml. The anticancer drug imatinib reduced mf motility at 10 μg/ml from the first day of incubation to 55% by day 5, and the reduction in motility was concentration-dependent. Praziquantel and fexinidazole were inactive, and FLBZ and its metabolites, as well as ivermectin at concentrations > 5 μg/ml, had very minimal effects on mf motility over the first 4 days of culture.ConclusionsThe considerable action of the anti-malarial drugs mefloquine and amodiaquine on Loa mf in vitro highlights the possibility of repurposing the existing anti-infectious agents for the development of drugs against loiasis. The heterogeneity in the activity of anti-parasitic agents on Loa loa mf supports the need for further investigation using animal models of loiasis.Electronic supplementary materialThe online version of this article (10.1186/s13071-018-2799-3) contains supplementary material, which is available to authorized users.

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“…The O. lienalis mf mouse model has been validated with ivermectin and other filaricides [ 10 , 13 ]. However, O. ochengi in cattle is the closest in phylogeny to O. volvulus [ 14 ] and many onchocerciasis drug tests in vitro [ 15 – 18 ] and in naturally infected cows [ 19 – 21 ] have been done based on O. ochengi . However, the cow is too big, requires huge quantities of drugs, thereby rendering it too expensive for routine screening.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of an Onchocerca ochengi microfilarial hamster model for onchocerciasis drug screens

2016

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BackgroundOnchocerciasis, caused by the parasitic nematode, Onchocerca volvulus afflicts some 37 million people worldwide, and is the second leading infectious cause of blindness globally. The only currently recommended drug for treatment of the disease, ivermectin, is only microfilaricidal and has serious adverse effects in individuals co-infected with high loads of Loa loa microfilariae (mf), prompting the search for new and better drugs. Onchocerciasis drug discovery studies have so far been based on in vivo models using Onchocerca species which are not the closest to O. volvulus, and which may therefore, not adequately mimic the natural infection in humans. Therefore, this study was carried out to develop a better drug screening model for onchocerciasis, based on the use of cow-derived O. ochengi, the closest known relative of O. volvulus.MethodsMf of O. ochengi were injected subcutaneously at the nape of Syrian hamsters (Mesocricetus auratus) and BALB/c mice. The skin, and especially the earlobes of the animals were examined for mf 15–31 days after infection. For selected model validation, the hamsters were treated with ivermectin at 150 or 600 μg/kg body weight and examined 30 days after infection for mf. For L. loa studies in hamsters, isolated mf were injected intraperitoneally and animal organs were examined on day 26 for mf.ResultsThe Syrian hamsters were found to be the more permissive to O. ochengi mf as fully viable mf were recovered from them on day 30, compared to BALB/c mice where such mf were recovered on day 15, but not 30. However, both animals were not permissive to L. loa mf even by day 15. Interestingly, more than 50 % of the total O. ochengi mf recovered were from the earlobes. The number of mf injected was directly proportional to the number recovered. Ivermectin at both concentrations tested completely eliminated the O. ochengi mf from the hamsters.ConclusionThis study reveals the Syrian hamster as an appropriate small animal model for screening of novel compounds against O. ochengi, the closest known relative of O. volvulus.

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UMF-078: A modified flubendazole with potent macrofilaricidal activity against Onchocerca ochengi in African cattle

Cited by 10 publications

References 37 publications

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

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

Heterogeneity in the in vitro susceptibility of Loa loa microfilariae to drugs commonly used in parasitological infections

Development and validation of an Onchocerca ochengi microfilarial hamster model for onchocerciasis drug screens

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