Ivermectin Stromectol

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery: Late 1970s (Merck); Year of introduction: 1981 (for animal use), 1987 (for human use); Drug category: Broad-spectrum antiparasitic, especially effective against nematodes and ectoparasites; Main uses: For the treatment of onchocerciasis (river blindness) and strongyloidiasis. Also used in combination with abendazole and diethylcarbamazine against lymphatic filariasis. Related drugs: Moxidectin, Milbemycin oxime, Doramectin, Selamectin, Abamectin, Eprinomectin.

Ivermectin, a macrocyclic ester (macrolac-tone) derived semisynthetically from avermec-tins, is currently the most effective broad-spectrum, antiparasitic drug for the treatment of human (or animal) infections. Ivermectin is used to prevent the tropical disease river blindness (onchocerciasis).

Onchocerciasis is a serious global health problem which results from infestation by the nematode Onchocerca volvulus,1 The parasite is spread by the bite of the blackfly Simulium spp., which injects immature larval forms of the worms into a human host. Maturation of the larvae usually takes one year. Adult female worms live for up to 15 years and daily produce approximately 1000 larvae (microfilariae), which migrate through the skin causing rash and itching. Microfilariae can migrate over a period of months to the eye where they cause visual impairment and eventually blindness. More than 18 million people become infected annually in Africa and Latin America, and approximately 270,000 lose their eyesight.

In the 1970s, a number of microorganisms were screened for antiparasitic activity by a joint venture of Merck and the Kitasato Institute in Japan.2 3 One of the microbes, Strepto-myces avermectinius demonstrated potent activity against a wide range of nematodes and insects and had low mammalian toxicity. Eight structurally similar macrocyclic lactones, the avermectins were responsible for this remarkable activity. The two most potent compounds, avermectin B1a and B1b were 25 times more potent than the most active previously known antiparasitic agents.

The addition of two hydrogens to the C(22)-C(23) double bond (highlighted in a yellow box) yielded dihydro compounds (a mixture of 80% B1a and 20% B1b), which had improved oral potency and minimal mammalian toxicity. The mixture, now called ivermectin, was introduced into veterinary practice in 1981. Ivermectin now has annual sales over $1 billion. Based on its efficacy in animals, ivermectin was also screened for activity against human parasites. Human clinical trials, conducted in Africa, revealed that a single annual oral dose of 0.2 mg per kg eradicated microfilaria! worms from the eyes and skin after 4 weeks. Ivermectin has been widely used in Africa (Mectizan™) since 1988 for the treatment of river blindness; up to three doses per year of 0.15 mg per kg is recommended. Adverse effects are rare and mild.

Ivermectin acts by opening invertebrate-specific glutamate-gated chloride ion channels found in the nerve and muscle cells of the parasite. This leads to paralysis and death of microfilariae. Although ivermectin does not kill adult worms, it suppresses the production of microfilariae and reduces the worm's lifespan.

1. Clin. Dermatol 2006, 24. 176-180; 2. Nat. Rev. Microbiol. 2004, 2, 984-989. 3. Comp. Mot. Ins. Sci. 2005, 5, 25-52; Refs. p. 180

Avermectin B1a (R = CH2CH3) Avermectin B1b (R = CH3)
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