Ivermectin
Ivermectin is a medication used to treat many types of parasite infestations. This includes head lice, scabies, river blindness, strongyloidiasis, trichuriasis, ascariasis, and lymphatic filariasis. It can be taken by mouth or applied to the skin for external infestations. Use in the eyes should be avoided.
Common side effects include red eyes, dry skin, and burning skin. It is unclear if it is safe for use during pregnancy, but is probably acceptable for use during breastfeeding. It belongs to the avermectin family of medications. It works by causing the parasite's cell membrane to increase in permeability, resulting in paralysis and death.
Ivermectin was discovered in 1975 and came into medical use in 1981. It is on the World Health Organization's List of Essential Medicines.
In other animals, it is used to prevent and treat heartworm and acariasis, among other indications.
Medical uses
Pinworms
Ivermectin is as effective as albendazole or alternative antinematode drugs for treatment of pinworm infection.River blindness
Ivermectin is used for prevention, treatment, and control of river blindness in populations where the disease is common. However, ivermectin is contraindicated in persons with a high burden of loiasis, due to risk of ivermectin-associated severe inflammatory events.A single dose of ivermectin reduces microfilaridermia by 98–99% after 1–2 months. Ivermectin does not kill adult worms. A single oral dose of ivermectin, taken once or twice a year for the 1015-year lifespan of the adult worms, is required to protect the individual from river blindness.
A 2012 Cochrane review found weak evidence suggesting that ivermectin could result in the reduction of chorioretinal lesions and prevent loss of vision in people with river blindness. Moxidectin has been approved by the FDA for use in people with river blindness, has a longer half-life than ivermectin, and may eventually supplant ivermectin, as it is a more potent microfilaricide, but there is a need for additional clinical trials, with long-term follow-up, to assess whether moxidectin is safe and effective for treatment of nematode infection in children and women of childbearing potential.
Loa loa filariasis
A single dose of ivermectin gives a rapid and durable decrease in body burden of eyeworm. The risk of ivermectin-associated severe adverse drug events is very low in persons with less than 20,000 microfilariae per mL of blood.Threadworm
Ivermectin is more effective than albendazole and equally as effective as thiabendazole for treatment of threadworm. Ivermectin has fewer adverse effects than does thiabendazole and is at least as well tolerated as albendazole. An analysis based on an economic model suggests that it is cost effective for people moving to Europe from areas where threadworm is common to be given a single-dose of ivermectin on arrival so as to cure presumptive infection with threadworm. Persons who are immunocompromised or who will receive immunosuppressive treatment and who have confirmed or presumptive threadworm infestation are likely to benefit from treatment with ivermectin.Whipworm
Combination therapy with ivermectin plus albendazole is effective for treatment of whipworm and the rate of Mazzotti reaction is no higher than for albendazole alone.Lymphatic filariasis
Combination therapy with ivermectin plus albendazole is effective for treatment of Lymphatic filariasis due to Wuchereria bancrofti, Brugia malayi, or Brugia timori.Arthropod
Evidence supports its use against parasitic arthropods and insects:- Mites such as scabies: It is usually limited to cases that prove to be resistant to topical treatments or that present in an advanced state. One review found that the efficacy of permethrin is similar to that of systemic or topical ivermectin. A separate review found that although oral ivermectin is usually effective for treatment of scabies, it does have a higher treatment failure rate than topical permethrin. Another review found that oral ivermectin provided a reasonable balance between efficacy and safety. Since ivermectin is more convenient than permethrin, many have turned to veterinary sources of the drug to obtain assurance of a cure at an affordable price.
- Lice: Ivermectin lotion is FDA-approved for patients six months of age and older. After a single, 10-minute application of this formulation on dry hair, 78% of subjects were found to be free of lice after two weeks. This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.
- Bedbugs: There is tentative evidence that ivermectin kills bedbugs, as part of integrated pest management for bedbug infestations. Such use however may require a prolonged course of treatment which is of unclear safety.
- Malaria-bearing mosquitos, such as Anopheles gambiae: Mass drug administration of a population with ivermectin for purposes of treating/preventing nematode infestation is effective for eliminating malaria-bearing mosquitos and thereby reducing infection with residual malaria parasites.
Rosacea
Contraindications
Ivermectin is contraindicated in children under the age of five or those who weigh less than, and individuals with liver or kidney disease. Ivermectin is secreted in very low concentration in breast milk. It remains unclear if ivermectin is safe during pregnancy.Adverse effects
The main concern is neurotoxicity, which in most mammalian species may manifest as central nervous system depression, and consequent ataxia, as might be expected from potentiation of inhibitory GABA-ergic synapses.Since drugs that inhibit the enzyme CYP3A4 often also inhibit P-glycoprotein transport, the risk of increased absorption past the blood-brain barrier exists when ivermectin is administered along with other CYP3A4 inhibitors. These drugs include statins, HIV protease inhibitors, many calcium channel blockers, lidocaine, the benzodiazepines, and glucocorticoids such as dexamethasone.
For dogs, the insecticide spinosad may have the effect of increasing the toxicity of ivermectin.
Pharmacology
Pharmacodynamics
Ivermectin and other avermectins are macrocyclic lactones derived from the bacterium Streptomyces avermitilis. Ivermectin kills by interfering with nervous system and muscle function, in particular by enhancing inhibitory neurotransmission.The drug binds to glutamate-gated chloride channels in the membranes of invertebrate nerve and muscle cells, causing increased permeability to chloride ions, resulting in cellular hyper-polarization, followed by paralysis and death. GluCls are invertebrate-specific members of the Cys-loop family of ligand-gated ion channels present in neurons and myocytes.
Pharmacokinetics
Ivermectin can be given by mouth, topically, or via injection. It does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein,. Crossing may still become significant if ivermectin is given at high doses.In contrast to mammals, ivermectin can cross the blood–brain barrier in tortoises, often with fatal consequences.
Ecotoxicity
Field studies have demonstrated the dung of animals treated with ivermectin supports a significantly reduced diversity of invertebrates, and the dung persists longer.History
The discovery of the avermectin family of compounds, from which ivermectin is chemically derived, was made by Satoshi Ōmura of Kitasato University, Tokyo and William C. Campbell of the Merck Institute for Therapeutic research. Ōmura identified avermectin from the bacterium Streptomyces avermitilis. Campbell purified avermectin from cultures obtained from Ōmura and led efforts leading to the discovery of ivermectin, a derivative of greater potency and lower toxicity. Ivermectin was introduced in 1981. Half of the 2015 Nobel Prize in Physiology or Medicine was awarded jointly to Campbell and Ōmura for discovering avermectin, "the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases".Society and culture
Cost
The initial price, proposed by Merck in 1987, was US$6. The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries. Between 1995 and 2010 the program using donated ivermectin to prevent river blindness is estimated to have prevented 7 million years of disability well costing US$257 million., the cost effectiveness of treating scabies and lice with ivermectin has not been studied.
As of 2019 ivermectin tablets in the United States were the least expensive treatment option for lice in children at about US$10. The hair lotion, however, costs about US$300 for a course of treatment.
Brand names
Ivermectin is available as a generic prescription drug in the U.S. in a 3 mg tablet formulation. It is also sold under the brand names Heartgard, Sklice and Stromectol in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT in Nepal by Alive Pharmaceutical and Ivexterm in Mexico by Valeant Pharmaceuticals International. In Southeast Asian countries, it is marketed by Delta Pharma Ltd. under the trade name Scabo 6. The formulation for rosacea treatment is sold as Soolantra. While in development, it was assigned the code MK-933 by Merck.Veterinary use
Ivermectin is routinely used to control parasitic worms in the gastrointestinal tract of ruminant animals. These parasites normally enter the animal when it is grazing, pass the bowel and set and mature in the intestines, after which they produce eggs which leave the animal via its droppings and can infest new pastures. Ivermectin is effective in killing some, but not all, of these parasites.In dogs it is routinely used as prophylaxis against heartworm.
Dogs with defects in the P-glycoprotein gene, often collie-like herding dogs, can be severely poisoned by ivermectin. The mnemonic "white feet, don't treat" refers to Scotch collies that are vulnerable to ivermectin. Some other dog breeds, also have a high incidence of mutation within the MDR1 gene and are sensitive to the toxic effects of ivermectin. Clinical evidence suggests kittens are susceptible to ivermectin toxicity. A 0.01% ivermectin topical preparation for treating ear mites in cats is available.
Ivermectin is sometimes used as an acaricide in reptiles, both by injection and as a diluted spray. While this works well in some cases, care must be taken, as several species of reptiles are very sensitive to ivermectin. Use in turtles is particularly contraindicated.
Research
Ivermectin is being studied as a potential antiviral agent against chikungunya and yellow fever.In 2013, this antiparasitic drug was demonstrated as a novel ligand of farnesoid X receptor, a therapeutic target for Nonalcoholic Fatty Liver Disease.
Ivermectin is also of interest in the prevention of malaria, as it is toxic to both the malaria plasmodium itself, and the mosquitos that carry it.
SARS-CoV-2
Ivermectin has antiviral effects against several distinct positive-sense single-strand RNA viruses, including SARS-CoV-2. Ivermectin inhibits replication of SARS-CoV-2 in monkey kidney cell culture with an IC50 of 2.2 - 2.8 µM, making it a possible candidate for COVID-19 drug repurposing research. The doses used in cell culture would require 10 larger doses in humans based on this data, which does not look promising as an effective treatment for COVID-19. Such high doses of ivermectin are not covered by the current human-use approvals of the drug and could be dangerous, as the likely antiviral mechanism of action is the suppression of a host cellular process, specifically the inhibition of nuclear transport by importin α/β1. Moreover, cell culture experiments also showed promise for ivermectin treating Dengue, but later failed in animal models.On 10 April 2020, the FDA issued guidance to not use ivermectin intended for animals as treatment for COVID-19 in humans.
A preprint published in early April 2020 claimed benefits of ivermectin in the treatment of COVID-19, but it was a retrospective study based on questionable hospital data from Surgisphere and was withdrawn at the end of May. The preprint led to several government agencies in Latin America recommending ivermectin as a COVID-19 treatment; these recommendations were later denounced by the regional WHO office.
As of June 4, ivermectin was being studied in 10 ongoing and 14 planned clinical trials.
A preprint published on 10 June 2020 reported on an observational retrospective study of COVID-19 patients at four Florida hospitals and found a significantly lower mortality in those who had received ivermectin.