Nematode © Christian SLAGMULDER

Anti-parasitic drugs: humans and animals united in the same fight

What are avermectins?

Nematodes, insects, arachnids, mites (intestinal parasites, but also scabies, lice, ticks, etc.): a large range of parasites can be treated by avermectins in animals as well as in man. In the absence of alternative medicines, scientists are working to prevent and contain resistance to these drugs.

By Pascale Mollier and Delphine Achour, translated by Inge Laino
Updated on 07/04/2017
Published on 12/07/2015

Digestive strongyles, ruminant parasites. Third-stage infective larvae. © INRA, HUBERT J.
Digestive strongyles, ruminant parasites. Third-stage infective larvae © INRA, HUBERT J.

A broad-spectrum class of medicines: a little goes a long way

Avermectins are anti-parasitic compounds used in animals and man. They have revolutionised the treatment of parasitic disease, thanks to their effectiveness at low doses and broad spectrum of action, both against internal parasites - endo-parasites (1) - and external parasites - ecto-parasites (2). The term endectocide was therefore coined to speak of them. Avermectins are effective against a wide range of parasites: nematodes, insects, arachnids, mites, etc.

Avermectins belong to the class of macrocyclic lactones. Ivermectin is its most frequently used derivative, and the only one authorised for use in humans. Used in Africa to fight onchocerciasis, ivermectin also slows the spread of malaria when used as an insecticide against mosquitoes. In farm animals, ivermectin is used to treat intestinal parasites, but also ticks, scabies, etc.
Ivermectin is effective in small doses, by comparison with other drugs, and has the added benefit of being long-lasting. Indeed, it continues to be effective several weeks after treatment.
As of today, there is no satisfying alternative for treating parasitic diseases in animals.

Apart from ivermectin, the main anthelmintics derived from avermectin used in veterinary medicine are doramectin, selamectin and eprinomectin.

Neurotoxic activity

Ivermectin acts on glutamate-gated chloride channels, which are specific to invertebrates. These cellular channels regulate nerve transmission in the neuromuscular systems of parasites. By blocking the transmission of nerve impulses, ivermectin paralyses and kills the parasites. But the drug also acts on other ionic channels, so-called GABA-gated channels, which exist in some neurons of mammals. The drug is nevertheless harmless to mammals because the neurons that are sensitive to it are located in the brain, an organ that is off limits to ivermectin. Indeed, a pump system, present in the blood vessels of the brain, rejects ivermectin before the drug can reach the brain. Ivermectin stays in the bloodstream, but it cannot enter into contact with the brain since it cannot cross the so-called blood-brain barrier.  

Emerging resistance in parasites

Resistance to ivermectinin parasites that attack small ruminants (3) emerged soon after the drug went to market, and has recently been detected in human parasites (4). Today, many parasites that affect farm animals are resistant to avermectins, and the situation is particularly alarming in countries where livestock breeding is widespread: United Kingdom, South Africa, South America, New Zealand and Australia. Cases of resistance to ivermectin are starting to emerge in France.

To predict and slow the onset of resistance to these highly effective and indispensable drugs, researchers are working to better understand their mechanisms of action, define optimal conditions to boost efficiency, limit overall quantities administered, and prolong their effectiveness and use in veterinary medicine.

(1) Gastro-intestinal or pulmonary nematodes, onchocerca and other filariases

(2) Lice, scabies, hypodermis, mosquitoes that carry malaria, etc.

(3) In particular, Haemonchus contortus.

(4) In particular, Onchocerca volvulus.

Anti-parasitic drugs gain in strength

- 1940: Use of chemical treatments: phenothiazin (600mg/animal kg) against parasites in farm animals, and organo-chlorides (DDT, Lindane) against insects.

- 1960-1970: Appearance of benzimidazoles: tiabendazole (50mg/kg) followed by oxfendazole (5mg/kg). Resistance starts to develop in parasites despite a decrease in doses. Use of organophosphorous compounds (trichlorfon, fenthion etc.) against insects.

- 1978: Discovery and characterisation of avermectin, following the detection of an anti-parasitic effect of a substance produced by bacteria in soil, Streptomyces avermitilis, isolated by the Japanese Institute Kitasato, in nematode-infected mice.

- 1981: Ivermectine is marketed for use in veterinary medicine, against parasites and insects, at doses of 0.2mg/kg by sub-cutaneous application.

- 1983: First cases of resistance to ivermectin detected in parasites.

- 1987: Ivermectin is authorised for use in humans against diseases common in Africa: river blindness (onchocerciasis) and lymphatic filariasis.