Ivermectin

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Ivermectin
Systematic (IUPAC) name
Ivermetcin (22,23-dihydroavermectin B_1a + 22,23-dihydroavermectin B_1b)
Identifiers
CAS number	70288-86-7 71827-03-7
ATC code	P02CF01
PubChem	6443957
DrugBank	APRD01058
Chemical data
Formula	C₄₈H₇₂O_{14 (22,23-dihydroavermectin B=1b)}
Mol. mass	875.10 g/mol
Pharmacokinetic data
Bioavailability	?
Protein binding	93%
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	?

Ivermectin (22,23-dihydroavermectin B_1a + 22,23-dihydroavermectin B_1b) is an anti-parasite medication and is effective against most common intestinal worms (except tapeworms), most mites, and some lice. While normally used to treat animals, it is also prescribed to humans to treat infections of Strongyloides stercoralis and onchocerciasis (river blindness). It is sold under brand names Stromectol® in the United States and Mectizan® in Canada by Merck.

Ivermectin is chemically related to the insecticide avermectin, the active ingredient in some home-use ant baits. Both ivermectin and avermectin are derived from the bacterium Streptomyces avermitilis and kill by interfering with the target animal's nervous system.

In General Use Pesticide (GUP) formulations, these compounds are classified by the United States' Environmental Protection Agency as toxicity category IV, or very low. This means that although highly poisonous to insects, mammals should not generally be adversely affected by normal use of avermectin pesticide formulations. As an example, one such formulation was determined to have an oral LD50 (semi-lethal dose) of 650 mg/kg in rats (qualifies as toxicity category III—low toxicity) [1]. Extrapolated to an 80 kg (180 lb) human, the semi-lethal dose is 52 g (1.9 oz), roughly the weight and volume of an iPod nano, which is considered by the EPA to be a low toxicity amount.

However, pure (as opposed to the diluted GUP formulations) avermectin formulations are both highly toxic to insects and mammals (as well as aquatic life, such as fish). One study reports an oral LD50 of 10 mg/kg in rats (qualifies as toxicity category I—high toxicity) [2].

Some dog breeds, most notably the collie, exhibit signs of ivermectin related central nervous system toxicity at ivermectin doses exceeding 150 to 200 µg/kg. [3] The cause of CNS toxicity in succeptible dogs has been traced to a mutation in a gene responsible for the MDR1 pump protein. [4] This has led some people to conclude that collies should not be treated with ivermectin or any other avermectin. Commonly prescribed veterinary formulations of ivermectin used for heartworm prophyllaxis limit dosages to the range of 6 to 12 µg/kg [5]and are generally considered safe. A severe overdosage of ivermectin is required to produce ivermectin toxicosis. [6] A test is available that checks dogs for sensitivity to ivermectin as well as several other drugs.[7] (See P-glycoprotein)

1 Use in humans
2 Use in rodents
3 Use in birds
4 References

[edit] Use in humans

Ivermectin is an antihelmintic used mainly in the treatment of onchocerciasis in humans, and also for strongyloidiasis, ascariasis, trichuriasis and enterobiasis. It is being used in mass treatment of programmes in endemic regions.

Ivermectin is an antiparasitic agent with a broad spectrum of activity against nematode worms and ectoparasites in animals, and has been in use for nearly a decade. It can also be used off-label for the treatment of topical cream resistant mites (certain scabies, lice, etc.)

Therapeutic dosage

Adults

Oral: 3 to 12 mg as a single dose per os (about 150 to 200 µg/kg bodyweight) for onchocerciasis and other parasitic infections. (Ex. 45 kg would be about 6.75 mg to 9 mg)

Children

Ivermectin is not given to children weighing less than 15 kg. The dose is 150 µg/kg bodyweight (in children weighing more).

Contraindications

Ivermectin is contraindicated in persons with an immediate hypersensitivity to the drug. It should not be given to mothers who are breast-feeding until the infant is at least three months old (Reynolds, 1993).

Mode of action

Ivermectin acts on insects by potentiation of GABA-ergic neural and neuromuscular transmission but since mammals have only central GABA-ergic synapses which are to a large extent protected by the blood-brain barrier they are relatively resistant to ivermectin. Some penetration of the blood-brain barrier does occur at relatively high doses, with brain levels peaking between two and five hours after administration. Symptoms seen in a range of mammalian species are CNS depression, and consequent ataxia, as might be expected from potentiation of inhibitory GABA-ergic synapses (Hayes & Laws, 1991).

Ivermectin inactivates parasitic nematodes, arachnids, and insects. It binds to gama-aminobutyric acid gated chloride channels (GABA mediated, present in nerves and muscle cells). This binding promotes increased membrane permeability to chloride ions which cases hyperpolarization of the nerve or muscle cell. This results in neuro-muscular paralysis which may lead to death.

At recommended doses, ivermectin does not readily penetrate the CNS of mammals, where GABA functions as a neurotransmitter. The principal peripheral neurotransmitter, acetylcholine, is unaffected by ivermectin (MSD, 1988).

[edit] Use in rodents

A commonly used therapy for rodent fur mite infestations in recent times has been based on oral or parenteral administration of avermectin, a family of macrocyclic lactones produced by fermentation of the soil micro-organism Streptomyces avermitilis. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at dose rates of 300 µg/kg or less. Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activity (Hotson, 1982).

Avermectin therapy is not without its drawbacks. Resistance to avermectins has been reported, which suggests use in moderation (Clark, 1995). Research on ivermectin, piperazine, and dichlorvos in combination also shows potential for toxicity (Toth, 2000). Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor, NO, prostaglandin E2, and increase of intracellular concentration of Ca²⁺ (Victorov, 2003). A proven ectoparasite mitigation method that stresses lab animals less than avermectin oral administration is definitely desirable.

[edit] Use in birds

Ivermectin is commonly used by avian veterinarians to treat mites in birds, usually for scaly face and scaly leg conditions resulting from the parasite Cnemidocoptes. Although this is not an approved use of the drug in all countries, it is a common and effective treatment.

[edit] References

U.S. National Library of Medicine. Hazardous Substances Databank. Bethesda, MD, 1995.10-9
Lankas, G. R and Gordon, L. R. Toxicology. In Ivermectin and Abamectin. Campbell, W. C., Ed. Springer Verlag, New York, NY, 1989.10-142
U.S. Environmental Protection Agency. Pesticide Fact Sheet Number 89.2: Avermectin B1. Office of Pesticides and Toxic Substances, Washington, DC, 1990.10-143
Hotson IK, 1982, The avermectins: A new family of antiparasitic agents, J S Afr Vet Assoc., Jun;53(2):87-90.
Clark JM, 1995, with Scott JG, Campos F, Bloomquist JR, Resistance to avermectins: extent, mechanisms, and management implications, Annu Rev Entomol, 40:1-30.
Toth LA, 2000, with Oberbeck C, Straign CM, Frazier S, Rehg JE, Toxicity evaluation of prophylactic treatments for mites and pinworms in mice, Contemp Top Lab Anim Sci., Mar;39(2):18-21.
Viktorov AV, 2003, with Yurkiv VA, Effect of ivermectin on function of liver macrophages, Bull Exp Biol Med., Dec;136(6):569-71.

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Categories: Antiparasitic agents | Merck