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Nematode © SLAGMULDER Christian

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

Coming to the rescue of ivermectin!

Research on the mechanisms of action of ivermectin at molecular level is opening up new avenues to better ways of slowing the onset and development of resistance to the drug.

By Pascale Mollier and Delphine Achour, translated by Inge Laino
Updated on 06/20/2017
Published on 12/07/2015

Observation of trichinella under the microscope. A team from the joint research unit (ANSES-INRA-ENVA) for molecular biology and parasitic immunology at ENVA in Maisons-Alfort serves as the national laboratory of reference for this parasite that attacks swine and horses.. © INRA, NICOLAS Bertrand
Observation of trichinella under the microscope. A team from the joint research unit (ANSES-INRA-ENVA) for molecular biology and parasitic immunology at ENVA in Maisons-Alfort serves as the national laboratory of reference for this parasite that attacks swine and horses. © INRA, NICOLAS Bertrand

Molecular structure of ivermectin, an anti-parasitic drug of the avermectins class of compounds.. © Wikipedia
Molecular structure of ivermectin, an anti-parasitic drug of the avermectins class of compounds. © Wikipedia

Ivermectin is the most effective and widely-used endectocide (cf glossary) developed in the past 30 years to combat parasitic worms. Unfortunately, parasites that attack both humans and animals have developed resistance to the drug. As of now, there is no drug as effective as ivermectin on the horizon. That is why learning the mode of action, including the loss of effectiveness, of the compound is top priority, both for human and animal health. INRA has developed several strategies to do just that.

Preserving the power of ivermectin

When parasitic worms are exposed to drugs, they develop complex mechanisms to survive. When treatment is repeated and/or poorly dosed, resistant parasites survive at doses that are supposed to kill them. Worms have an efflux pump system that protects them from toxic substances like ivermectin. If this pump system is blocked, the drug will no longer be expulsed from the parasite’s cells, and will reach its target. Thus, resistant worms will once again become vulnerable to ivermectin.

"The problem”, explains Anne Lespine, “is that these pump systems also exist in mammals. They prevent ivermectin from passing into the brain, where they could have neurotoxic effects (see box). That’s why we need to find a way to neutralise the parasite’s efflux pump system without neutralising the same system in the host”. That is why research is focusing on detailed studies of the compared structures of permeability glycoproteins, or P-gps (1), which make up these pumps. The sequencing in 2013 of the genome of a first parasitic nematode (2) brought precious information to light. There are about a dozen P-gp genes in the nematode, from which the sequence of the protein is deduced, allowing scientists to then model its three-dimensional structure. From there, a specific inhibitor can be described. “We have a candidate, a derivative of ivermectin, that inhibits preferentially the P-gp of the parasite and is not toxic for mammals (3)”, explains Anne Lespine.

(1) ABCB1, P-gp, permeability glycoprotein

(2) Haemonchus contortus. The genome of Caenorhabditis elegans (free-living non-parasitic nematode) was the first multi-cellular organism sequenced in 1998.

(3) Patent applications filed in 2011 by INRA and McGill University in Canada. (PCT/EP2012/070704; EP, US, NZ, BR, AU).

Publication : Lespine et al. 2012. P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: Prospects for reversing transport-dependent anthelmintic resistance. International journal for parasitology-drugs and drug resistance 2 : 58 - 75.

Developing a sister drug for humans: moxidectin

To slow the development of resistance to ivermectin, similar substances can also be borrowed from veterinary medicine. Moxidectin is a close relative of ivermectin, largely used in livestock animals, with a wider margin of security than ivermectin. However, moxidectin is not authorised for use in humans. Research headed by INRA has shown that moxidectin has fewer undesirable effects compared with ivermectin, which could encourage the development of the drug for use in humans.

Publication : Menez-Berlioz et al. 2012. Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (-/-) Mice and Effects on Mammalian GABA (A) Channel Activity. Plos Neglected Tropical Diseases 6 (11).

Contact(s)
Scientific contact(s):

Associated Division(s):
Nutrition, Chemical Food Safety and Consumer Behaviour, Animal Health
perro Colley. © Wikipedia

The enigma of Collie dogs sensitive to ivermectin

Although ivermectin is widely used in veterinary medicine, cases of neurotoxicity were observed in 1995 in certain Collie dogs treated with the drug. Some cases resulted in death.

Since the 1970s, studies have been carried out on reflux pumps against foreign substances (xenobiotic) consisting of permeability gylcoproteins, or P-gps, since these systems are widespread in animals. These pumps reject xenobiotics from cells, including anti-cancerous or anti-infectious drugs in man. In ordinary circumstances, they have a beneficial effect, by offering protection from the toxic effects of foreign substances. But inversely, in exceptional circumstances such as illness (for example, cancer), the pumps inadvertently prevent a body from benefitting from drugs, by inhibiting the xenobiotic from entering into contact with its target (a cancer cell, for example). The undesirable reinforcement of these reflux pumps, during chemotherapy against cancer, contributes to poly-chemo resistance.

In 1994, a report was published showing that mice mutated for permeability gylcoproteins, and that do not express these reflux pumps, died from a neurological syndrome during routine treatment with ivermectin. This incidental observation suggests that there is a cause-and-effect relationship between the natural expression of P-gps and a cerebral protective function against ivermectin.

Going a step further with the case of the Collie dogs, an INRA team of researchers showed that dogs that are sensitive to ivermectin have a natural congenital mutation (deletion of four base pairs) in the P-gp gene that prevents its expression.  In the absence of the protein, these dogs, like the model mice, are no longer protected against ivermectin, which can now cross the blood-brain barrier to reach the brain and make its now undesirable effects felt.    

Publication: Roulet A, Puel O, Gesta S, Lepage JF, Drag M, Soll M, Alvinerie M, Pineau T. 2003. 2-MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. Eur J Pharmacol. 460, 85-91.

Other alternative research on avermectins

- Research on new medicine and new molecular targets (ionic channels) in parasites.

       Contact: Cedric.Neveu@tours.inra.fr, Joint Research Unit 1282 ISP Infectiology and Public Health, Loire Valley.

- Vaccines, biological control, nutricines rich in tannins, selection of nematode-resistant races. Read the article (in French).

       Contact: Hervé Hoste, h.hoste@envt.fr, P. Jacquier, Joint Research Unit 1225 IHAP Host-pathogenic Agent Interactions, Toulouse.