Research

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

Barend M deC Bronsvoort^1,5 , Benjamin L Makepeace¹ , Alfons Renz^2,6 , Vincent N Tanya^3,7 , Lawrence Fleckenstein⁴ , David Ekale¹ and Alexander J Trees¹

¹  Veterinary Parasitology, Liverpool School of Tropical Medicine/Faculty of Veterinary Science, University of Liverpool, Pembroke Place, Liverpool, UK

²  Fachgebiet Parasitologie, Universität Hohenhiem, Germany

³  Institut de Recherche Agricole pour le Développement, Wakwa, Cameroon

⁴  College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA

⁵  The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Veterinary Centre, Roslin, Midlothian, EH25 9RG, UK

⁶  Universität Tübingen, Friedhofstrasse 73, 72074 Tübingen, Germany

⁷  Technical Adviser No.1, Ministry of Scientific Research and Innovation, P.O. Box 1457, Yaoundé, Cameroon

author email corresponding author email

Parasites & Vectors 2008, 1:18doi:10.1186/1756-3305-1-18

Published:	20 June 2008

Abstract

Background

Human 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.

Methods

Groups 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).

Results

After 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.

Conclusion

Although 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.