Ivermectin is the 22,23-dihydro derivative of avermectin B1, a macrocyclic lactone produced by an actinomycete, Streptomyces avermitilis. It is active at extremely low dosage against a wide variety of nematode and arthropod parasites, apparently by virtue of its action on the mediation of neurotransmission by gamma-aminobutyric acid. It is now in commercial use in various countries for the treatment and control of parasites in cattle, horses, and sheep, and is expected to become available for use in swine and dogs. Since studies with the drug in man are in a preliminary stage, it is not yet known whether ivermectin will be useful in human medicine.

22,23-Dihydroavermectin B1, ivermectin, derived from avermectin B1 by selective hydrogenation using Wilkinson's homogenous catalyst [Ph3P)3RhCl], was shown to be a highly effective drug for the treatment of a wide variety of metazoan parasitic diseases in animals.

When given to sheep as a single oral dose at 0.1 mg/kg, the Bia component of the avermectins caused a reduction of >95% in the numbers of Haemonchus contortus, Ostertagia circumcincta (including inhibited L4 larvae), Tricho- Fermentation-derived natural products which are attributed with anthelmintic activity have been described in the literature. Hygromycin B, which has been used in treating domestic animals in practice, was described in 1958 (8). It was shown to have some effect upon adult swine ascarids when fed to infected pigs (7) but found ineffective against the migrating larvae of Ascaris suum (6). The principal utility of hygromycin B appears directed against members of the nematode order Ascaroidea. In this paper we report the anthelmintic activity of a natural product, the B18 component of the avermectins (3, 9), an a-L-oleandrosyl-a-L-oleandroside macrocyclic lactone, against nematode parasites of cattle, sheep, dogs, and chickens.MATERIALS AND METHODS Sheep. Sheep raised under "parasite-free" conditions (i.e., management conditions designed to ensure minimal exposure to helminth infection) and weighing between 14 and 25 kg at the time of treatment were experimentally infected with third-stage infective larvae of six nematode species, passaged in the laboratory as pure isolates, according to the following: day 0, 360 Oesophagostomum columbianum; day 16, 7,500 Ostertagia circumcincta and 7,500 Trichostrongylus colubriformis; day 18, 7,500 Trichostrongylus axei and 7,500 Cooperia oncophora; day 21, 2,000 Haemonchus contortus. The isolates of T. colubriformis and H. contortus used to infect sheep were tolerant to benzimidazole anthelmintic treatment, requiring more than the recommended use level of various benzimidazoles for high-order efficacy. Numbers of larvae were estimated by counting multiple samples of larval suspensions in tap water, and each animal was infected per os with 5 ml of larval suspension containing the desired number.On day 35, when the infections were patent, 15 infected sheep were randomly allotted to five treatment groups of three sheep each. The groups were randomly allotted to infected control (no treatment, two groups) or treatment with avermectin B,I at 0.

The macrocyclic lactones enjoy a position of prominence in the control of parasites, and their history may be of interest, and even of use, in an age in which the search for chemotherapeutic agents has been transformed by modern technology. Much of their history has been recorded piecemeal in a wide variety of publications. The present review provides additional detail, and offers a personal perspective on the history of ivermectin and related avermectins. Brief notes are included on the subsequent development of other macrocyclic lactones. Milbemycin preceded the avermectins as a macrocyclic lactone of agricultural importance, but was used for a different purpose. Development of the avermectins arose from the isolation, in the laboratories of the Kitasato Institute, of a novel soil-dwelling bacterium and its transmittal (in 1974) to the laboratories of Merck & Co., Inc. There it was found (in 1975) to produce a potent anthelmintic substance, which was then identified and transmuted by interdisciplinary research into an antiparasitic product. Initially the focus was on its applicability to veterinary science and animal husbandry; and after developmental research by many scientific teams, the product was introduced commercially (in 1981) for the control of endoparasitic nematodes and ectoparasitic arthropods in livestock. Subsequently, special applications in human medicine were developed, and were successfully implemented in partnership with World Health Organization and several non-governmental organizations (NGOs).

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