Flubendazole: a candidate macrofilaricide for lymphatic filariasis and onchocerciasis field programs.

A safe, f ield-usable chemotherapeutic agent that will rapidly kill adult filarial worms is urgently needed in tropical medicine. Ivermectin, distributed as Mectizan by Merck & Co. Inc., has had an enormous impact on two major human filarial infections of developing countries, onchocerciasis and lymphatic filariasis [1]. However, this agent works primarily against the microfilarial stage and lacks the ability to rapidly kill the adult parasites. Since the adult worms can survive for many years producing offspring, it has been necessary for control programs to continue drug distribution for more than a decade, for instance, until the adult worms eventually die; a labor-intensive and expensive proposition. Other agents used in filarial control programs, such as diethylcarbamazine and albendazole, may be more effective macrofilaricides than ivermectin, but for various reasons are not suitable, or are unable, to fill the role of a being rapidly acting macrofilaricide. Thus, a drug administered once, or at least in multiple doses over a very short period, that safely kills adult filarial worms would be a major contributor to the current efforts to rid the world of filarial infections and the diseases they cause. A useful field agent has typically been required to be administered in an oral dosage form, but a truly safe agent administered by another route, including parenteral approaches, could be acceptable and may even be advantageous. Given the challenges of discovery and development of agents for human use, a drug as described previously is arguably most likely, at least at present, to come from the benzimidazole group of anthelmintics. Although several benzimidazoles are currently employed in human chemotherapy, there are other potential candidate macrofilaricides in other drug classes. However, time is of the essence in finding a new drug for use in ongoing filarial control programs, and the first priority is to consider the benzimidazoles as the most likely source of a macrofilaricide. This group has provided many important effective agents for both veterinary and human medicine over the past 50 years, beginning with thiabendazole and now most prominently including albendazole and mebendazole for human parasites and a whole range of agents in veterinary medicine [2]. Benzimidazoles work by interfering with the equilibrium among tubulin subunits, tubulin and microtubules. Not surprisingly, benzimidazoles can affect host tubulin as well as that of the parasites, are typically positive in mammalian cell cytotoxicity assays and cause chromosomal nondisjunction during mitosis [3]. However, the benzimidazole anthelmintics show a differential preference for binding to nematode tubulin compared with mammalian tubulin [4], an important factor for the development of a drug against nematodes in mammals. Benzimidazoles