Abstract
The use of a microfilaricidal drug for the control of onchocerciasis and lymphatic filariasis necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmintic, is an appealing candidate macrofilaricide. FLBZ has demonstrated profound and potent macrofilaricidal effects in a number of experimental filarial rodent models and one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration (MDA) campaigns due to its markedly limited oral bioavailability. However, a new formulation that provided sufficient bioavailability following oral administration could render FLBZ an effective treatment for onchocerciasis and LF. This study characterized the effects of FLBZ and its reduced metabolite (FLBZ-R) on filarial nematodes in vitro to determine the exposure profile which results in demonstrable damage. Adult female Brugia malayi were exposed to varying concentrations of FLBZ or FLBZ-R (100 nM–10 μM) for up to five days, after which worms were fixed for histology. Morphological damage following exposure to FLBZ was observed prominently in the hypodermis and developing embryos at concentrations as low as 100 nM following 24 h exposure. The results indicate that damage to tissues required for reproduction and survival can be achieved at pharmacologically relevant concentrations.
Highlights
The debilitating diseases onchocerciasis and lymphatic filariasis (LF) are major causes of long term disability and impede socioeconomic development in endemic countries (WHO, 1995; WHO, 2010)
A macrofilaricide would have the benefit of reducing pathology in LF, in which the characteristic sequelae of elephantiasis and hydrocele are initiated by adult worms residing in lymphatic vessels
Previous studies of ultrastructural changes associated with BZ exposure focused on events occurring in parasite intestinal cells all used electron microscopy, rather than the light microscopic approach used in this study
Summary
The debilitating diseases onchocerciasis and lymphatic filariasis (LF) are major causes of long term disability and impede socioeconomic development in endemic countries (WHO, 1995; WHO, 2010). To increase the likelihood that this goal will be achieved, it is important to address the challenges inherent to current chemotherapeutic strategies used in these programs. The drugs employed in mass drug administration programmes are principally microfilaricidal agents, and limit reproduction; this strategy reduces transmission and the development of pathology in onchocerciasis but necessitates annual or twice-yearly dosing for many years. An effective and safe macrofilaricide would clearly shorten the time required to reach program goals. A macrofilaricide would have the benefit of reducing pathology in LF, in which the characteristic sequelae of elephantiasis and hydrocele are initiated by adult worms residing in lymphatic vessels
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