Benzimidazole anthelmintics

Thiabendazole (Mintezol) inhibits fumarate reductase and electron transport-associated phosphorylation in helminths. Interference with ATP generation decreases glucose uptake and affects the energy available for metabolism. Benzimidazole anthelmintics as a class (e.g., thiabendazole, mebendazole, and albendazole), bind selectively to (3-tubulin of nematodes (roundworms), ces-todes (tapeworms), and trematodes (flukes). This inhibits microtubule assembly, which is important in a number of helminth cellular processes, such as mitosis, transport, and motihty. 

The mode of action of benzimidazole anthelmintics has proved the subject of much debate. Although they were first thought to inhibit the fumarate-reductase enzyme system of helminths, it now seems likely that their mode of action is the inhibition of tubulin polymerization which leads to a number of degenerative processes. This is consistent with their somewhat slower mode of action than most other anthelmintics which generally cause rapid paralysis of the helminths followed by expulsion. 

RT Wilson, JM Groneck, AC Henry, LR Rowe. Multiresidue assay for benzimidazole anthelmintics by liquid chromatography and confirmation by gas chromatography/selected-ion monitoring electron impact mass spectrometry. J Assoc Off Anal Chem 74 56-57, 1991. 

S Barker, T McDowell, B Charkhian, LC Hsieh, CS Short. Methodology for the analysis of benzimidazole anthelmintics as drug residues in animal tissues. J Assoc Off Anal Chem 73 22-25, 1990. 

DL Brandon, RG Binder, AH Bates, WC Montague Jr. Monoclonal antibody for multiresidue ELISA of benzimidazole anthelmintics in liver. J Agric Food Chem 42 1588-1594, 1994. 

Ancheta PB, Dumilon RA, Venuturina VM et al (2004) Efficacy of benzimidazole anthelmintics in goats and sheep in the Philippines using a larval development assay. Vet Parasitol 120 107-121... 

Benzimidazole anthelmintics Urine, tissue, miUc Note Abbreviations as in Table 12.3. SLM HPLC, LC-MS [179]... 

Msagati T and Nindi MN. Determination of benzimidazole anthelmintics compounds by supported Uquid membrane extraction and liquid chromatography. J. Sep. Sci. 2001 24 606-614. 

The nitroimidazole metronidazole 5 mg/kg orally three times a day for 10 days is effective in the treatment of equine giardiasis. The benzimidazole anthelmintic fenbendazole is used in the treatment of giardiasis in dogs and cats. 

When absorption takes place rapidly, which is usual for conventional dosage forms, fca > kd, but when absorption takes place slowly and ka < k(j the flip-flop phenomenon occurs, whereby the rate of absorption controls the rate of elimination of the drug. This situation applies not only to sustained-release oral dosage forms administered to dogs, but also to phenylbutazone and meclofe-namic acid in horses, salicylate administered as an aspirin bolus to cattle and oral suspensions of benzimidazole anthelmintics in ruminant species. 

Albendazole and fenbendazole, prochiral sulphide benzimidazole anthelmintics, are metabolically converted (sulphoxidation) to the corresponding active sulphoxide metabolites, each of which exists in the plasma as two enantiomers. Sulphoxide benzimidazoles have a chiral centre around the sulphur atom in their molecules. The sulphoxide metabolites (enantiomers) are irreversibly metabolized (sulphonation) to inactive sulphones. This pathway of hepatic biotransformation has been shown to occur both in ruminant (sheep, goats, cattle) and monogastric (man, dogs, rats) species (Delatour et al., 1991b,... 

Benzimidazoles were the first anthelmintics which were shown to bind with tubulin and inhibit formation of microtubules in various helminths [61]. Later Bergers and De Nollin [62] showed disintegration of microtubules in the intestinal cells of Ascaris after mebendazole (6) treatment Further, it was also demonstrated that the benzimidazole anthelmintics possess high selectivity to bind 250-400 times faster to parasitic tubulin than the mammalian tubulin [63,64]. 

The discovery of parbendazole stimulated a vigorous search for better benzimidazole anthelmintics in different pharmaceutical companies of the world. Soon a number of drugs (14-22) were introduced in veterinary and humans medicine. All these benzimidazole anthelmintics may be regarded as the 5(6)-derivatives of car-bendazim (10) which per se is an effective pesticide rather than an anthelmintic [12]. A novel non-carbamate benzimidazole fasciolicide, triclabendazole (23) [13] and a benzimidazole-2-carbamate anthelmintic, ricobendazole (24) [14] have been introduced recently (Table 1). 

The benzimidazole anthelmintics have been extensively used to eradicate roundworms (nematodes) parasitizing the gastrointestinal tract, lungs, blood circulation, lymphatic system, body cavity, heart and subcutaneous tissues of cattle, sheep, goats, horses, pigs, cats, dogs and poultry [14,173-176]. The important drugs which have been used to treat domestic animals, are summarised below ... 

The benzimidazoles possess weaker activity against animal cestode parasites than the nematodes. Cambendazole (5) was the first which was claimed to be effective against cestodes in sheep. This was later replaced by more effective benzimidazole anthelmintics such as mebendazole (14), fenbendazole (18), oxfendazole (19) and albendazole (20), because of their high activity and low toxicity [176]. 

The work carried out on the mode of action of benzimidazole anthelmintics indicate that drugs of this class may exert their action either by inhibiting the energy metabolism and affecting glucose uptake or by inhibiting the polymerisation of tubulins to microtubules [5,232-235]. 

Thiabendazole, cambendazole, fenbendazole and oxfendazole have been found to inhibit fumarate-reductase in isolated mitochondria of A. siiunt and H. coti-tortus. The above drugs also cause complete inhibition of the oxidation of NADH in the presence of fumarate at low concentrations (10 " M for thiabendazole) in H. cori-tortus homogenate, thereby suggesting a common mode of action of various benzimidazole anthelmintics. The inhibition of fumarate-reductase in larvae of Trichinella spiralis treated with thiabendazole has also been demonstrated both in vivo and in vitro systems [236]. 

Benzimidazole anthelmintics exhibit in vitro and in vivo binding ability to tubulin, an important component of the cytoskeleton of all living cells, and inhibit its... 

Thiabendazole. This benzimidazole derivative (12) is an effective oral drug used in the treatment of intestinal roundworms and selected tissue parasites. Infections with S. stercorahs are commonly treated with thiabendazole for two days. Disseminated strongyloidiasis is treated for at least five days. Satisfactory results have been reported when used for T. spirahs infections however, its effectiveness on encapsulated muscle larvae has not been clinically demonstrated. Extensively used in veterinary medicine, thiabendazole was the first broad-spectrum benzimidazole anthelmintic. It is widely used in the United States. The mechanism of action is not clearly understood, but it has been shown that thiabendazole inhibits the enzyme fiima.ra.te reductase, which is found specifically in the mitochondria of helminths (31). 

Some caution is, however, required when making comparisons of pharmacokinetic data. The benzimidazole anthelmintics triclabendazole and albendazole respectively show a similar spectrum of metabolites across a range of animal species including humans (21,21). However, in rats and other species, absorption of albendazole after oral administration was in excess of 30% whereas in human it was of the order of 1% (21). With triclabendazole. 

The major nematode parasites of humans include the soil-transmitted helminths (STHs) and the filarial nematodes. The STH infections, which include ascariasis, trichuriasis, and hookworm infection, are among the most prevalent infections in developing countries. Eradication programs use schools to administer broad-spectrum anthelmintics on a periodic and frequent basis. The most widely used agents for reducing morbidity are the benzimidazole anthelmintics (BZAs), either albendazole (albenza and zentel) or mebendazole (VEEtMOX) (see Table 41-1). 

Benzimidazole Carbamates An extensive survey of mebendazole and related 5-substituted benzimidazole anthelmintics is available. The biochemical characterisation of a helminth (Ascaridia galli) tubulin, the proposed binding site of the benzimidazole carbamates, has been achieved following purification by column chromatography on DEAE-Sephadex. A single peak was responsible for both colchicine and parbendazole binding activity. 

Gottschall DW, Theodorides EJ, Wang R. The metabolism of benzimidazole anthelmintics. Parasitol Today 1990 6 115-124. 

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