Trends in Parasitology
Ivermectin 20 years on: maturation of a wonder drug
Section snippets
Origin of ivermectin
Ivermectin, the first commercially available macrocyclic lactone endectocide, was discovered in a screening program at Merck (http://www.merck.com/) in the mid-1970s [1]. The origin of the drug perhaps foretold its remarkable impact on both veterinary and human medical practice. Historically, drugs derived from bacterial or fungal fermentations had found application as anticancer or antibacterial agents. The only reason for screening fermentations for antiparasitic activity was the belief of
Veterinary antiparasitic chemotherapy
Anthelmintic drugs such as the benzimidazoles, levamisole, pyrantel and morantel had changed management strategies for optimizing nematode control in livestock and companion-animal veterinary practice since the 1960s. The introduction of ivermectin in 1981 elevated worm control to new levels. The unprecedented combination of potency, spectrum (which included nematodes and ectoparasites such as fleas, ticks, lice, mites and flies) and persistence opened new markets and new management options for
Human antiparasitic chemotherapy
Ivermectin had not been introduced into human medicine in 1985. After its use for preventing the development of symptoms of infection with Onchocerca volvulus became apparent, Merck initiated a remarkable give-away program to deliver ivermectin to Africa and South America. This act spurred other international pharmaceutical companies to follow suit, as evidenced by the donation of albendazole (along with ivermectin) for control of lymphatic filariasis. Based on the undeniable benefits of these
Advances in pharmacology
Initial work on the mechanism of action of ivermectin focused on its ability to open γ-aminobutyric acid (GABA)-gated Cl− channels [4]. The drug has potent activity at GABA receptors in both invertebrates and mammals, and GABA was known to be the primary inhibitory neurotransmitter in the nematode somatic neuromuscular system. However, subsequent work by Merck scientists identified glutamate-gated Cl− channels as the more likely physiological targets of ivermectin and related drugs 8, 9. This
Threats of resistance
In 1985, resistance to ivermectin in parasites was an unrealized threat. Since then, the inevitable appearance of ivermectin-resistant parasites has occurred. It has been a particular bane in small ruminants, arising in regions that rely on intensive anthelmintic treatment to optimize animal productivity and then, essentially, spreading globally [20]. Of more concern is that resistance has appeared in parasites of cattle, particularly Cooperia spp. [20], with productivity consequences. Very
The next 20 years
Much remains to be learned about ivermectin and related drugs. Priorities for research include developing a thorough understanding of the basis of resistance to ivermectin in the field. A molecular marker for resistance to this drug (if, indeed, a single genotype is found to underlie the phenotype in all species) will be of inestimable help in monitoring the spread of the phenotype and will aid the understanding of why it occurs differentially in various species of parasite in different hosts.
Acknowledgements
It is an honour to dedicate this article to William C. Campbell, who authored the review of ivermectin that graced the first issue of Parasitology Today in 1985 [4]. Bill Campbell is an outstanding parasitologist, a tremendous intellect and a grand gentleman of science who made essential contributions to the discovery and development of ivermectin.
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