The avermectins are a series 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties. These naturally occurring compounds are generated as fermentation products by Streptomyces avermitilis, a soil actinomycete. Eight different avermectins were isolated in 4 pairs of homologue compounds, with a major (a-component) and minor (b-component) component usually in ratios of 80:20 to 90:10. Other anthelmintics derived from the avermectins include ivermectin, selamectin, doramectin and abamectin.
In 1978, an actinomycete was isolated at The Kitasato Institute from a soil sample collected at Kawana, Ito City, Shizuoka Prefecture, Japan. Later that year, the isolated actinomycete was sent to Merck Sharp and Dohme Research Laboratories for testing. Various, carefully controlled broths were fermented using the isolated actinomycete. Early tests indicated that some of the whole, fermented broths were active against Nematospiroides dubius in mice over at least an eightfold range without notable toxicity. Subsequently, the anthelmintic activity was isolated and identified as a family of closely related compounds. The family of compounds were finally characterized and the novel species that produced them were described by a team at Merck in 1978.
In 2002, Yoko Takahashi and others at the Kitasato Institute for Life Sciences, Kitasato University and at The Kitasato Institute, proposed that Streptomyces avermitilis be renamed Streptomyces avermectinius.
Avermectin therapy for rodent fur mite infestation
A commonly used therapy in recent times has been based on oral or parenteral administration of avermectins. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at dose rates of 300 microgram/kg or less. Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activities.
Mechanism of action
The avermectins block the transmittance of electrical activity in nerves and muscle cells by stimulating the release and binding of gamma-aminobutyric acid (GABA) at nerve endings. This causes an influx of chloride ions into the cells leading to hyperpolarisation and subsequent paralysis of the neuromuscular systems. GABA-ergic receptors are found at the neuromuscular junctions and the central ventral cords in nematodes, whereas in mammals they are found primarily in the brain. Ivermectin does not readily cross the blood brain barrier in mammals at therapeutic doses.
Toxicity and side effects
Avermectin therapy is not without its drawbacks. Resistance to avermectins has been reported, which suggests use in moderation. Research on ivermectin, piperazine, and dichlorvos in combinations also shows potential for toxicity. Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor, nitric oxide, prostaglandin E2, and increase of intracellular concentration of Ca2+. Adverse effects are usually transient; severe effects are rare and probably occur only with substantial overdose, but include coma, hypotension, and respiratory failure, which can lead to death. No specific therapy exists, but symptomatic management usually leads to a favorable prognosis.
Abamectin is the active ingredient in some commercial ant bait traps.
- Milbemycins are a chemically closely related group of parasiticides.
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