Ivermectin and abamectin, members of the avermectin family of compounds, were introduced to the market in the 1980's as a veterinary antiparasitic drug and agricultural pesticide, respectively. Their acceptance and commercial success have been remarkable; both are highly effective and in worldwide use. The efficacy of ivermectin in river blindness has expanded the interest in its use in human medicine. In response to the intense scientific and industrial interest in ivermectin and abamectin and the likelihood that they will be forerunners of an expanding family of drugs, this comprehensive monograph satisfies the need for a review and synthesis of current knowledge about the use of these substances in crop protection as well as in cattle, sheep, swine, horses, dogs, cats, birds, fish, reptiles, and in man. This overview presents chemical, biochemical, and microbiological data, as well as pharmacological, safety, and environmental aspects and covers practical use of the compounds as antiparasitic and pesticide agents, as well as the available safety data that have emerged from the clinical experience with human applications.

Ivermectin and abamectin.

Modes of action of anthelmintic drugs are described. Some anthelmintic drugs act rapidly and selectively on neuromuscular transmission of nematodes. Levamisole, pyrantel and morantel are agonists at nicotinic acetylcholine receptors of nematode muscle and cause spastic paralysis. Dichlorvos and haloxon are organophosphorus cholinesterase antagonists. Piperazine is a GABA (gamma-amino-butyric acid) agonist at receptors on nematode muscles and causes flaccid paralysis. The avermectins increase the opening of glutamate-gated chloride (GluCl) channels and produce paralysis of pharyngeal pumping. Praziquantel has a selective effect on the tegument of trematodes and increases permeability of calcium. Other anthelmintics have a biochemical mode of action. The benzimidazole drugs bind selectively to beta-tubulin of nematodes, cestodes and fluke, and inhibit microtubule formation. The salicylanilides: rafoxanide, oxyclozanide, brotianide and closantel and the substituted phenol, nitroxynil, are proton ionophores. Clorsulon is a selective antagonist of fluke phosphoglycerate kinase and mutase. Diethylcarbamazine blocks host, and possibly parasite, enzymes involved in arachidonic acid metabolism, and enhances the innate, nonspecific immune system.

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Modes of Action of Anthelmintic Drugs

Structure and activity of avermectins and milbemycins in animal health

A subpopulation of collie dogs is extremely sensitive to neurotoxicity induced by ivermectin. The aim of this study was to determine the mechanistic basis for this phenomenon. The multi-drug-resistance gene (mdr1) encodes a large transmembrane protein, P-glycoprotein (P-gp), that is an integral part of the blood-brain barrier. P-gp functions as a drug-transport pump at the blood-brain barrier, transporting a variety of drugs from the brain back into the blood. Since ivermectin is a substrate for P-gp, we hypothesized that ivermectin-sensitive collies had altered mdr1 expression compared with unaffected collies. We report a deletion mutation of the mdr1 gene that is associated with ivermectin sensitivity. The 4-bp deletion results in a frame shift, generating several stop codons that prematurely terminate P-gp synthesis. Dogs that are homozygous for the deletion mutation display the ivermectin-sensitive phenotype, while those that are homozygous normal or heterozygous do not display increased sensitivity to ivermectin.

G. W. Benz

Papers

Ivermectin: a review of efficacy and safety