Abstract
BackgroundHuman onchocerciasis or river blindness, caused by the filarial nematode Onchocerca volvulus, is currently controlled using the microfilaricidal drug, ivermectin. However, ivermectin does not kill adult O. volvulus, and in areas with less than 65% ivermectin coverage of the population, there is no effect on transmission. Therefore, there is still a need for a macrofilaricidal drug. Using the bovine filarial nematode O. ochengi (found naturally in African cattle), the macrofilaricidal efficacy of the modified flubendazole, UMF-078, was investigated.MethodsGroups of 3 cows were treated with one of the following regimens: (a) a single dose of UMF-078 at 150 mg/kg intramuscularly (im), (b) 50 mg/kg im, (c) 150 mg/kg intraabomasally (ia), (d) 50 mg/kg ia, or (e) not treated (controls).ResultsAfter treatment at 150 mg/kg im, nodule diameter, worm motility and worm viability (as measured by metabolic reduction of tetrazolium to formazan) declined significantly compared with pre-treatment values and concurrent controls. There was abrogation of embryogenesis and death of all adult worms by 24 weeks post-treatment (pt). Animals treated at 50 mg/kg im showed a decline in nodule diameter together with abrogated reproduction, reduced motility, and lower metabolic activity in isolated worms, culminating in approximately 50% worm mortality by 52 weeks pt. Worms removed from animals treated ia were not killed, but exhibited a temporary embryotoxic effect which had waned by 12 weeks pt in the 50 mg/kg ia group and by 24 weeks pt in the 150 mg/kg ia group. These differences could be explained by the different absorption rates and elimination half-lives for each dose and route of administration.ConclusionAlthough we did not observe any signs of mammalian toxicity in this trial with a single dose, other studies have raised concerns regarding neuro- and genotoxicity. Consequently, further evaluation of this compound has been suspended. Nonetheless, these results validate the molecular target of the benzimidazoles as a promising lead for rational design of macrofilaricidal drugs.
Highlights
Human onchocerciasis or river blindness, caused by the filarial nematode Onchocerca volvulus, is currently controlled using the microfilaricidal drug, ivermectin
Human onchocerciasis or river blindness, caused by the filarial nematode Onchocerca volvulus, is endemic in 34 countries in Africa, the Americas and the Yemen, infecting approximately 37 million people with a further 90 million people considered to be at risk of infection in Africa [1]
Animals Fifteen 4–6 year old Gudali cows (Bos indicus), each with more than 20 palpable O. ochengi nodules in the ventral abdominal skin, were purchased from local markets in the Adamawa Province of Cameroon. They were kept on pasture at the Institut de Recherche Agricole pour le Développement (IRAD), formerly the Institut de Recherche Zootechniques et Vétérinaires (IRZV), Wakwa, 10 km SW of Ngaoundéré
Summary
Human onchocerciasis or river blindness, caused by the filarial nematode Onchocerca volvulus, is currently controlled using the microfilaricidal drug, ivermectin. Human onchocerciasis or river blindness, caused by the filarial nematode Onchocerca volvulus, is endemic in 34 countries in Africa, the Americas and the Yemen, infecting approximately 37 million people with a further 90 million people considered to be at risk of infection in Africa [1]. The OCP was phased-out in 2002 and has been superseded by the African Programme for Onchocerciasis Control (APOC), which applies community-directed treatment with ivermectin as an almost exclusive control method in a further 19 endemic African countries. Which can be removed under local anaesthetic It was adopted as a tertiary drug screen for macrofilaricides by WHO [22,23,24]
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