Mode of action of common anthelmintics

Abstract

The primary physiological mode of action of nearly all drugs used to control helminth parasites is not well understood. Examination of the general modes of action in terms of parasite requirements for survival may, however, provide guidelines to continue our present investigations and direct us for future research. Two general areas of drug activity are (1) interference with energy‐generating metabolism, and (2) interference with proper neuromuscular coordination. Few exceptions are found to these areas because the target organisms require little else for survival. The target of most previously effective and many presently effective anthelmintics is an adult parasite. Adult helminth parasites must maintain an advantageous feeding site and must transport and metabolize substrates (primarily glucose) to generate life‐maintaining energy. Adult worms have almost no other short‐term requirements for survival because they have little or no metabolic activity in either lipid synthesis or oxidation, nucleic acid synthesis, or protein synthesis (except egg‐laying). Examination of specifics of energy‐generating metabolism and putative neurochemical transmitters allows us certain predictions in relating a given drug activity to an individual species. These examinations indicate that such diversity exists among helminth metabolic or nervous systems that a broad‐spectrum anthelmintic would most likely inhibit at several sensitive points. Published information on drug action and differences in data interpretation are discussed. Two novel areas for future anthelmintic investigations may be (1) juvenile hormone or ecdysone analogs, and (2) pheromones. A combined empirical and rational approach to the development of new drugs may be the most efficient avenue of future research.

Pharmacological evaluation of contractile activity of the dog heartworm Dirofilaria immitis

“…Inhibition of glycolysis by thiacetarsamide may have contributed to these effects of this organoarsenical (Rew 1978).…”

Antiprotozoals effective in vitro against the scuticociliate fish pathogen Philasterides dicentrarchi

“…Bithionol sulfoxide is another anthelmintic that, like the salicylanilides, uncouples electron transport (Rew 1978). This compound has been shown to be effective against other fish ciliates, such as Tetrahymena pyriformis (in vitro: Griffin 1989) and Trichodina jadranica (in eel culture: Madsen et al 2000).…”

“…The recommended dosages for the treatment of cestodes, including the turbot cestode Bothriocephalus scorpii, range between 5 and 40 mg kg -1 d -1 (Sanmartín et al 1989, Schmahl et al 1989). The lack of activity of closantel, another salicylanilide that acts as proton ionophore, may indicate either (1) that niclosamide and oxyclonazide have a specific mechanism of action (other than the blockade of electron transport), or (2) that Philasterides dicentrarchi is resistant to closantel.Bithionol sulfoxide is another anthelmintic that, like the salicylanilides, uncouples electron transport (Rew 1978). This compound has been shown to be effective against other fish ciliates, such as Tetrahymena pyriformis (in vitro: Griffin 1989) and Trichodina jadranica (in eel culture: Madsen et al 2000).…”

In vitro toxicity of bithionol and bithionol sulphoxide to Neoparamoeba spp., the causative agent of amoebic gill disease (AGD)

“…Bithionol, 2, 2'-thiobis (4, 6-dichlorophenol), and bithionol sulphoxide, bis (2-hydroxy-3, 5-dichlorophenyl) sulphoxide, are anthelmintics that are known to uncouple electron transport (Rew 1978), act on the mitochondrial respiratory chain (Iglesias et al 2002) and aid in the suppression of adenosine-5'-triphosphate (ATP) synthesis via uncoupling of oxidative phosphorylation (Harder 2002). They are also reported to be halogenated anti-infective agents that are used against trematode and cestode infestations in humans (Harder 2002).…”

“…or whether they are capable of stimulating a therapeutic effect similar to that of freshwater by sloughing off affected gill tissue by effectively poisoning the epithelial tissue or if these chemicals are directly toxic to the amoeba. Bithionol is also known to interfere with oxidative metabolism and inhibition of NADH-fumerate reductase (Hamajima 1973, Reid et al 2001; therefore, the potential to poison epithelia exists in addition to its effects on mitochondrial respiratory chain (Rew 1978, Harder 2002, Iglesias et al 2002. Such treatments are beneficial if they are directly toxic to Neoparamoeba spp.…”