Benzimidazoles - Parasites Chemotherapy Drugs

Benzimidazoles

As the name benzimidazole implies, the basic structure of these antiparasitic agents consists of linked imidazole and benzene rings. Unlike their antiprotozoal cousins discussedabove, the benzimidazoles are broad-spectrum anthelmintic agents. The prototype drug, thiabendazole, acts against both adult and larval nematodes and was shown to be useful in the management of cutaneous larva migrans, trichinosis, and most intestinal nematode in-fections soon after its introduction in the early 1960s. The mechanism by which it exerts its anthelmintic action is uncertain. It is known to inhibit fumarate reductase, an impor-tant mitochondrial enzyme of helminths. The primary mode of action, however, may derive from the known capacity of all benzimidazoles to inhibit the polymerization of tubulin, the eukaryotic cytoskeletal protein, as described for mebendazole below. Side ef-fects are mild, related to the gastrointestinal tract or liver, and rapidly disappear with the discontinuation of the drug. Hypersensitivity reactions, induced either by the drug or by antigens released from the damaged parasite, may occur.

Mebendazole, a carbamate benzimidazole introduced in 1972, has a spectrum similar to that of thiabendazole, but also has been found to be effective against a number of ces-todes, including Taenia, Hymenolepsis, and Echinococcus. It irreversibly blocks glucose uptake of both adult and larval worms, resulting in glycogen depletion, cessation of ATP formation, and paralysis or death. It does not appear to affect glucose metabolism in hu-mans and is thought to exert its effect in worms by binding to tubulin, thus interfering with the assembly of cytoplasmic microtubules, structures essential to glucose uptake. Unlike thiabendazole, the drug is not well absorbed from the gastrointestinal tract and may owe part of its effectiveness against intestine-dwelling adult worms to its high con-centrations in the gut. Toxicity is uncommon. Teratogenic effects have been observed in experimental animals; its use in infants and pregnant women is contraindicated.

Albendazole is a benzimidazole carbamate that has recently been made available in the United States. It has a somewhat broader spectrum than that of its close relative, mebendazole, being more active against Strongyloides stercoralis and several tissue nematodes. In addition to the vermicidal and larvicidal properties that it shares with other benzimidazoles, it is ovicidal, enhancing its effectiveness in tissue cestode infec-tions such as echinococciasis and cysticercosis. Its activity against Giardia, one of the most common intestinal protozoa, makes it an appealing candidate for the treatment of polyparasitism. Although it shares the teratogenic potential of other benzimidazoles, it is otherwise extremely well tolerated. Single-dose therapy is effective in the management of many intestinal nematode infections.