Benzimidazole anthelmintic drugs

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. 

Eight methyl AT-(l/f-benzimidazol-2-yl)carbamates 78 with various 5-substituents have been labelled with 13C at carbon-2, and at the carbonyl and methoxy carbons according to the synthetic scheme of equation 25 using commercially available 13C-enriched (91-92 atom%) carbon tetrachloride, methanol and thiourea63. The three labelled positions indicated with asterisks are at or near the site involved in binding to tubulin (which performs a variety of vital functions in the cell). A correlation has been found between anthelmintic potency of the benzimidazole carbamate group of anthelmintic drugs widely used to control nematode parasites in sheep and their ability to bind tubulin. 

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. 

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 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]. 

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). 

In a broader perspective, the relationship between the development of immunological disorders and immunostimulant therapy must also be debated with respect to levamisole and to a lesser extent, to the benzimidazole anthelmintics, although in normal anthelmintic therapy the immunologically based side effects of these drugs are not apparent. 

Some antiparasitic drugs, notably the macrocyclic lactones, have already been addressed in Chapter 6. This chapter will examine the toxic effects of other compounds that are widely used, or have been used, as antiparasitic drugs in animals. In Europe and elsewhere, the main anthelmintic drugs are the benzimidazoles and levamisole. The major benzimidazole drugs are thiabendazole, albendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxiben-dazole, triclabendazole and albendazole sulphoxide (ricobendazole, albendazole oxide). Febantel and netobimin are two prodrugs that in vivo are converted to fenbendazole and albendazole, respectively. Levamisole is the levo ( ) isomer of (dextro isomers. Tetramisole has been superseded by levamisole. These and some other antiparasitic drugs are discussed in this chapter. 

S. Sharma and S. Abuzar, The benzimidazole anthelmintics - chemistry and biological activity. Prog. Drug Res., 1983, 27, 85-161. 

There is a need for development of new anthelmintics, as resistance in livestock has been recorded against benzimidazoles, imidothiazoles and the avermectin/macrocyclic lactones, in addition to older drugs... 

Binding to P-tubulin. The anthelmintic benzimidazoles, such as thiabendazole and albendazole, are drugs that bind selectively to nematode... 

It is a synthetic benzimidazole having a wide spectrum of anthelmintic activity. After administration it is poorly absorbed and approximately 90 percent of the drug is passed in faeces. Complete clearance of the parasites from the GIT may take up to three days. 

Several related analogues of the benzimidazoles are also anthelmintics including the imidazopyridine (5), tioxidazole (6), and the prodrugs, thiophanate (7) and febantel (8). However, although the benzimidazoles and related anthelmintics have proved a rich source of drugs, there is now evidence of widespread resistance to them, particularly in sheep parasites. Moreover, some benzimidazole carbamates are suspect in respect of teratogenicity and mutagenicity. 

In 1966 the second modern broad spectrum anthelmintic, tetramisole (9), was introduced by Jannsen. The discovery of this drug followed the observation that the thiazothienol (10) was metabolized to an active compound in chickens. This was shown to be the thiazothielite (11) which led ultimately to the discovery of tetramisole (9). Later investigations showed that most of the activity of tetramisole (9) was due to the L-isomer, levamisole, which was more potent and less toxic than the D-isomer. Since their introduction, tetramisole (9) and levamisole have probably become the most widely used anthelmintics against a broad range of nematodes in pigs, sheep and poultry. Furthermore, unlike most benzimidazole carbamates, which are rather insoluble and must be given as an oral drench, levamisole may be given by the more convenient injectable route at a dose of 7.5 mg kg-1. 

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