Review
Ivermectin: From theory to clinical application

https://doi.org/10.1016/j.ijantimicag.2019.05.003Get rights and content

Highlights

  • Ivermectin (IVM) was the only macrocyclic lactone approved for human use until June 2018.

  • IVM use has increased worldwide to overcome many parasitic diseases.

  • The host immune response is required for full activity of IVM.

  • IVM resistance has emerged in small ruminants, cattle and some humans.

  • IVM nanoformulations can improve its therapeutic efficacy.

ABSTRACT

Approximately 250 million people have been using ivermectin (IVM) annually to combat many parasitic diseases including filariasis, onchocerciasis, strongyloidiasis, scabies and pediculosis. Many clinical studies have proven its efficacy against these diseases and have reported the optimum dose and duration of treatment. Moreover, its antiparasitic range has increased to cover more parasitic infections, but it still requires further exploration, e.g. for trichinosis and myiasis. Furthermore, IVM showed high efficacy in killing vectors of disease-causing parasites such as mosquitoes, sandflies and tsetse flies. The World Health Organization (WHO) has managed many control programmes involving the use of IVM to achieve elimination of onchocerciasis and lymphatic filariasis and to reduce malaria transmission. However, IVM is not exempt from the possibility of resistance and, certainly, its intensive use has led to the emergence of resistance in some parasites. Recent research is investigating the possibility of novel drug delivery systems for IVM that increase its potential to treat a new range of diseases and to overcome the possibility of drug resistance. This review highlights the most common human uses of IVM, with special reference to the new and promising properties of IVM.

Introduction

Campbell and Omura were awarded the 2015 Nobel Prize in Physiology or Medicine for their discoveries regarding avermectin [1]. The avermectins were discovered in 1967 in fermentation broth of an actinomycete culture in Japan [2]. It was then found that avermectins are produced by Streptomyces avermitilis in the soil [3], [4]. The avermectins are a class of macrocyclic lactones (MLs) with nematocidal, acaricidal and insecticidal activities [2]. MLs, including the avermectins, have gained a valuable therapeutic role since the 1980s as antiparasitic drugs for animals and humans [5].

The first avermectin drug was introduced as a veterinary drug by Merck & Co. in 1981 [6], and new formulations of ivermectin (IVM), a derivative of avermectin, were released almost every year. There was very little motivation to produce IVM for the human health market until its efficacy against filarial nematodes was shown. IVM was first registered as a human drug under the brand name Mectizan® in 1987 and was first used to treat onchocerciasis in humans in 1988 [7]. IVM was the only member of the MLs approved for human use until the recent approval of moxidectin by the US Food and Drug Administration (FDA) in June 2018 for the treatment of onchocerciasis in humans [8]. They have been labelled as ‘wonder drugs’ [9].

IVM is a derivative of naturally-produced avermectin B1, comprised of approximately 80% 22,23-dihydro-avermectin B1a (molecular weight, 875.10 g/mol) and approximately 20% 22,23-dihydro-avermectin B1b (molecular weight, 861.07 g/mol) [10]. Oral IVM is the only licensed route of administration for human use, although it has been given successfully subcutaneously and topically [11], [12].

IVM is incompletely absorbed following oral administration, with a peak plasma concentration achieved in approximately 4 h. Oral IVM is available in different forms, i.e. solution, tablets or capsules, however the solution has approximately twice the systemic availability compared with the solid forms (tablets and capsules). Owing to the high lipid solubility of IVM, its administration following a high-fat meal increases its bioavailability by approximately 2.5-folds [5]. IVM is metabolised in human liver microsomes by a cytochrome P450 (CYP) enzyme, converting the drug to at least 10 metabolites, mostly hydroxylated and demethylated derivatives [13]. IVM and its metabolites are excreted mainly in the faeces in about 12 days. Only small amounts (<1%) are excreted in urine. The plasma half-life of IVM ranges from 9.8–14.3 h and about 3 days for the metabolites [5].

IVM is an endectocide, i.e. active both against endoparasites and ectoparasites. Beside filarial nematodes, IVM is effective against a number of soil-transmitted helminths, myiasis and scabies. Since its discovery, the antiparasitic uses of IVM have increased and continue to accumulate [1].

This review highlights the most common clinical uses of IVM, with special reference to the promising impact of IVM against other parasitic infections as well as the new formulations of IVM and their progress in the field.

Section snippets

Mechanism of action

MLs affect various life stages of many nematode and arthropod species, which can be attributed to modulation of the Cys-loop family of ligand-gated ion channels including glutamate-gated chloride channels (GluCls) [14]. IVM increases chloride conductance resulting in a long-lasting hyperpolarisation and less formation of action potentials and blocking of further functions [15]. It affects the motor neurons, interneurons and pharyngeal muscle cells leading to general locomotor paralysis, and

Current clinical uses of ivermectin

IVM use has increased worldwide to overcome many parasitic diseases infecting millions of people, such as strongyloidiasis (infecting about 100 million people) and onchocerciasis (infecting about 18 million people) [28].

Safety and side effects

No serious adverse events were reported in patients treated with IVM [97]. However, headache, dizziness, muscle pain, nausea or diarrhoea may occur. Moreover, low IVM levels are detected in human breast milk after a single oral dose of 150–250 µg/kg for up to 14 days. Likewise, studies in experimental animals showed teratogenicity at 400 µg/kg given to the mother [90]. On the other hand, it was estimated that in Onchocerca-endemic areas, up to 50% of pregnant women in the first trimester are

Potential drug resistance

Many studies have reported that intensive use of MLs creates a drug pressure on parasite populations and leads to the emergence of drug resistance in small ruminants, cattle and some humans. However, exploring the mechanisms responsible for this resistance remains an important challenge today [112], [113].

Resistance to IVM had been previously found in nematodes infecting animals. Human resistance of O. volvulus to IVM was reported as a suboptimal response to IVM treatment in Sudan [114],

Future perspectives and concluding remarks

Drug delivery systems can affect drug pharmacokinetics, the duration of its therapeutic effect and toxicity. Innovative drug delivery approaches and formulations such as slow-release formulations, IVM skin patches and IVM-impregnated clothing are being developed [11].

IVM nanoformulations can prolong the microfilaricidal action, which has a great potential in endemic areas compared with conventional treatments mostly due to improvement of poor pharmacokinetics or bioavailability of the drug [127]

Funding

None.

Competing interests

None declared.

Ethical approval

Not required.

References (140)

  • E.A. Ottesen

    Lymphatic filariasis: treatment, control and elimination

    Adv Parasitol

    (2006)
  • M.M. Lloyd et al.

    Conventional parasitology and DNA-based diagnostic methods for onchocerciasis elimination programmes

    Acta Trop

    (2015)
  • T. Satou et al.

    Nematocidal activities of thiabendazole and ivermectin against the larvae of Strongyloides ratti and S. venezuelensis

    Vet Parasitol

    (2001)
  • E. Pozio

    World distribution of Trichinella spp. infections in animals and humans

    Vet Parasitol

    (2007)
  • T. Vos et al.

    Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

    Lancet

    (2012)
  • S.E. Huffam et al.

    Ivermectin for Sarcoptes scabiei hyperinfestation

    Int J Infect Dis

    (1998)
  • K.C. Kobylinski et al.

    The effect of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease vectors

    Acta Trop

    (2010)
  • M.P. Butters et al.

    Comparative evaluation of systemic drugs for their effects against Anopheles gambiae

    Acta Trop

    (2012)
  • M. Pacque et al.

    Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution

    Lancet

    (1990)
  • J.A. Lasota et al.

    Avermectins, a novel class of compounds: implications for use in arthropod pest control

    Annu Rev Entomol

    (1991)
  • D.H. Kwon et al.

    A point mutation in a glutamate-gated chloride channel confers abamectin resistance in the two-spotted spider mite, Tetranychus urticae Koch

    Insect Molec Biol

    (2010)
  • O.F. Hüter

    Use of natural products in the crop protection industry

    Phytochem Rev

    (2011)
  • A. González Canga et al.

    The pharmacokinetics and interactions of ivermectin in humans—a mini-review

    AAPS J

    (2008)
  • MOXIDECTIN tablets, for oral use Melbourne. Victoria, Australia: Medicines Development for Global Health; 2018...
  • W.C. Campbell et al.

    Ivermectin: a potent new antiparasitic agent

    Science

    (1983)
  • A. Crump

    Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations

    J Antibiot (Tokyo)

    (2017)
  • F.M. Marty et al.

    Treatment of human disseminated strongyloidiasis with a parenteral veterinary formulation of ivermectin

    Clin Infect Dis

    (2005)
  • Z. Zeng et al.

    Identification of cytochrome P4503A4 as the major enzyme responsible for the metabolism of ivermectin by human liver microsomes

    Xenobiotica

    (1998)
  • J.I. Meyers et al.

    Characterization of the target of ivermectin, the glutamate-gated chloride channel, from Anopheles gambiae

    J Exp Biol

    (2015)
  • C. Menez et al.

    Relative neurotoxicity of ivermectin and moxidectin in Mdr1ab (–/–) mice and effects on mammalian GABA(A) channel activity

    PLoS Negl Trop Dis

    (2012)
  • M.L. Fritz et al.

    Toxicity of blood meals from ivermectin-treated cattle to Anopheles gambiae s.l

    Ann Trop Med Parasitol

    (2009)
  • J.R. Lopez-Olvera et al.

    Effects of parasitic helminths and ivermectin treatment on clinical parameters in the European wild boar (Sus scrofa)

    Parasitol Res

    (2006)
  • Y. Moreno et al.

    Ivermectin disrupts the function of the excretory–secretory apparatus in microfilariae of Brugia malayi

    Proc Natl Acad Sci USA

    (2010)
  • D.S. Carithers

    Examining the role of macrolides and host immunity in combatting filarial parasites

    Parasit Vectors

    (2017)
  • J.F. Chehayeb et al.

    Proteomic analysis of adult Ascaris suum fluid compartments and secretory products

    PLoS Negl Trop Dis

    (2014)
  • A.J. Wolstenholme et al.

    How do the macrocyclic lactones kill filarial nematode larvae?

    Invert Neurosci

    (2016)
  • F.L. Njoo et al.

    Neutrophil activation in ivermectin-treated onchocerciasis patients

    Clin Exp Immunol

    (1993)
  • F.L. Njoo et al.

    C-reactive protein and interleukin-6 are elevated in onchocerciasis patients after ivermectin treatment

    J Infect Dis

    (1994)
  • T. Hirata et al.

    Impairment of host immune response against Strongyloides stercoralis by human T cell lymphotropic virus type 1 infection

    Am J Trop Med Hyg

    (2006)
  • A.R. dos Santos et al.

    Ivermectin-derived leishmanicidal compounds

    Bioorg Med Chem

    (2009)
  • P.J. Hotez et al.

    Neglected tropical diseases in sub-Saharan Africa: review of their prevalence, distribution, and disease burden

    PLoS Negl Trop Dis

    (2009)
  • Global Programme to Eliminate Lymphatic Filariasis: progress report, 2016

    Wkly Epidemiol Rec

    (2017)
  • B.F.R. Dickson et al.

    The prevalence of lymphatic filariasis infection and disease following six rounds of mass drug administration in Mandalay Region, Myanmar

    PLoS Negl Trop Dis

    (2018)
  • E.A. Ottesen et al.

    The Global Program To Eliminate Lymphatic Filariasis: health impact after 8 years

    PLoS Negl Trop Dis

    (2008)
  • J. Dupuy et al.

    Fumagillin, a new P-glycoprotein-interfering agent able to modulate moxidectin efflux in rat hepatocytes

    J Vet Pharmacol Ther

    (2006)
  • R. Sharma et al.

    Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis

    Sci Rep

    (2016)
  • D.H. Molyneux et al.

    Lymphatic filariasis elimination: progress in global programme development

    Ann Trop Med Parasitol

    (2002)
  • World Health Organization (WHO). Global Programme to Eliminate Lymphatic Filariasis. Geneva, Switzerland: WHO....
  • P.U. Fischer et al.

    Potential value of triple drug therapy with ivermectin, diethylcarbamazine, and albendazole (IDA) to accelerate elimination of lymphatic filariasis and onchocerciasis in Africa

    PLoS Negl Trop Dis

    (2017)
  • M.P. Little et al.

    Incidence of blindness during the Onchocerciasis Control Programme in western Africa, 1971–2002

    J Infect Dis

    (2004)
  • Cited by (0)

    View full text