Avermectin
Encyclopedia
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
.
from a soil sample collected at Kawana, Ito City
, Shizuoka Prefecture, Japan. Later that year, the isolated actinomycete was sent to Merck Sharp & 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 Sharp and Dohme 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.
administration of avermectins. They show activity against a broad range of nematode
s 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 activity.
(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.
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+.
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
derivatives with potent anthelmintic
Anthelmintic
Anthelmintics or antihelminthics are drugs that expel parasitic worms from the body, by either stunning or killing them. They may also be called vermifuges or vermicides .-Pharmaceutical classes:...
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
Selamectin
Selamectin is a topical parasiticide and antihelminthic used on dogs and cats, distributed by Pfizer. It prevents heartworms, fleas, ear mites, sarcoptic mange , and certain types of ticks in dogs, and prevents heartworms, fleas, ear mites, hookworms, and roundworms in cats...
, doramectin
Doramectin
Doramectin is a veterinary drug approved by the Food and Drug Administration for the treatment of parasites such as gastrointestinal roundworms, lungworms, eyeworms, grubs, sucking lice and mange mites in cattle....
and abamectin
Abamectin
Abamectin is a widely used insecticide and anthelmintic.-Chemistry:Abamectin is a mixture of avermectins containing more than 80% avermectin B1a and less than 20% avermectin B1b. These two components, B1a and B1b have very similar biological and toxicological properties...
.
History
In 1978, an actinomycete was isolated at The Kitasato InstituteKitasato Shibasaburō
Baron was a Japanese physician and bacteriologist. He is remembered as the co-discoverer of the infectious agent of bubonic plague in Hong Kong in 1894, almost simultaneously with Alexandre Yersin.-Biography:...
from a soil sample collected at Kawana, Ito City
Ito, Shizuoka
is a city located on the eastern shore of the Izu Peninsula in Shizuoka, Japan. As of 2010, the city had an estimated population of 71,400 and the density of 578 persons per km². The total area was...
, Shizuoka Prefecture, Japan. Later that year, the isolated actinomycete was sent to Merck Sharp & 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 Sharp and Dohme 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 parenteralParenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...
administration of avermectins. They show activity against a broad range of nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
s and arthropod
Arthropod
An arthropod is an invertebrate animal having an exoskeleton , a segmented body, and jointed appendages. Arthropods are members of the phylum Arthropoda , and include the insects, arachnids, crustaceans, and others...
parasites of domestic animals at dose rates of 300 microgram/kg or less. Unlike the macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
or polyene
Polyene
Polyenes are poly-unsaturated organic compounds that contain one or more sequences of alternating double and single carbon-carbon bonds. These double carbon-carbon bonds interact in a process known as conjugation, which results in an overall lower energy state of the molecule.Organic compounds with...
antibiotics, they lack significant antibacterial or antifungal activity.
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 acidGamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(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.
Avermectin therapy is not without its drawbacks. Resistance to avermectins has been reported, which suggests use in moderation. Research on ivermectin, piperazine
Piperazine
Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
, and dichlorvos
Dichlorvos
Dichlorvos or 2,2-dichlorovinyl dimethyl phosphate is a highly volatile organophosphate, widely used as a insecticide to control household pests, in public health, and protecting stored product from insects. It is effective against mushroom flies, aphids, spider mites, caterpillars, thrips, and...
in combinations also shows potential for toxicity. Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
, nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
E2, and increase of intracellular concentration of Ca2+.