Wikipedia

Ivermectin

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Ivermectin is a medication used to treat many types of parasite infestations.[3] In humans, this includes head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis, and lymphatic filariasis.[3][4][5][6] In veterinary medicine, it is used to prevent and treat heartworm and acariasis, among other indications.[5] It can be taken by mouth or applied to the skin for external infestations.[3][7]

Ivermectin
Clinical data
Trade namesStromectol, Soolantra, Sklice, others
AHFS/Drugs.comSystemic Monograph
Topical Monograph
MedlinePlusa607069
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability–
Protein binding93%
MetabolismLiver (CYP450)
Elimination half-life18 hours
ExcretionFeces; <1% urine
Identifiers
  • 22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.067.738 Edit this at Wikidata
Chemical and physical data
FormulaC
48H
74O
14 (22,23-dihydroavermectin B1a)
C
47H
72O
14 (22,23-dihydroavermectin B1b)
Molar mass875.106 g·mol−1 (22,23-dihydroavermectin B1a)
861.079 g·mol−1 (22,23-dihydroavermectin B1b)
3D model (JSmol)
  • CC[C@H](C)[C@@H]1[C@H](CC[C@@]2(O1)C[C@@H]3C[C@H](O2)C/C=C(/[C@H]([C@H](/C=C/C=C/4\CO[C@H]5[C@@]4([C@@H](C=C([C@H]5O)C)C(=O)O3)O)C)O[C@H]6C[C@@H]([C@H]([C@@H](O6)C)O[C@H]7C[C@@H]([C@H]([C@@H](O7)C)O)OC)OC)\C)C.C[C@H]1CC[C@]2(C[C@@H]3C[C@H](O2)C/C=C(/[C@H]([C@H](/C=C/C=C/4\CO[C@H]5[C@@]4([C@@H](C=C([C@H]5O)C)C(=O)O3)O)C)O[C@H]6C[C@@H]([C@H]([C@@H](O6)C)O[C@H]7C[C@@H]([C@H]([C@@H](O7)C)O)OC)OC)\C)O[C@@H]1C(C)C
  • InChI=1S/C48H74O14.C47H72O14/c1-11-25(2)43-28(5)17-18-47(62-43)23-34-20-33(61-47)16-15-27(4)42(26(3)13-12-14-32-24-55-45-40(49)29(6)19-35(46(51)58-34)48(32,45)52)59-39-22-37(54-10)44(31(8)57-39)60-38-21-36(53-9)41(50)30(7)56-38;1-24(2)41-27(5)16-17-46(61-41)22-33-19-32(60-46)15-14-26(4)42(25(3)12-11-13-31-23-54-44-39(48)28(6)18-34(45(50)57-33)47(31,44)51)58-38-21-36(53-10)43(30(8)56-38)59-37-20-35(52-9)40(49)29(7)55-37/h12-15,19,25-26,28,30-31,33-45,49-50,52H,11,16-18,20-24H2,1-10H3;11-14,18,24-25,27,29-30,32-44,48-49,51H,15-17,19-23H2,1-10H3/b13-12+,27-15+,32-14+;12-11+,26-14+,31-13+/t25-,26-,28-,30-,31-,33+,34-,35-,36-,37-,38-,39-,40+,41-,42-,43+,44-,45+,47+,48+;25-,27-,29-,30-,32+,33-,34-,35-,36-,37-,38-,39+,40-,41+,42-,43-,44+,46+,47+/m00/s1 checkY
  • Key:SPBDXSGPUHCETR-JFUDTMANSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Common side effects include fever, itching, and skin rash when taken by mouth,[3] and red eyes, dry skin, and burning skin when used topically for head lice.[8] It is unclear if it is safe for use during pregnancy, but is probably acceptable for use during breastfeeding.[9] It belongs to the avermectin family of medications.[3] It works through many mechanisms of action that result in death of the targeted parasites.[3]

Ivermectin was discovered in 1975 and came into medical use in 1981.[10][11] It is on the World Health Organization's List of Essential Medicines.[12] Ivermectin is FDA-approved as an antiparasitic agent.[13]

During the 2020 COVID-19 pandemic, misinformation was widely spread claiming that ivermectin was not beneficial for treating and preventing COVID-19.[14][15] No reliable evidence exists to back up such claims.[16][17][18]

Medical uses

Ivermectin is used to treat human diseases caused by roundworms and ectoparasites.

Worm infections

For river blindness (onchocerciasis) and lymphatic filariasis, ivermectin is typically given as part of mass drug administration campaigns that distribute the drug to all members of a community affected by the disease.[19] For river blindness, a single oral dose of ivermectin (150 micrograms per kilogram of body weight) clears the body of larval Onchocerca volvulus worms for several months, preventing transmission and disease progression.[19] Adult worms survive in the skin and eventually recover to produce larval worms again. To keep the worms at bay, ivermectin is given at least once per year for the 10–15-year lifespan of the adult worms.[20] For lymphatic filariasis, oral ivermectin (200 micrograms per kilogram body weight) is part of a combination treatment given annually: ivermectin, diethylcarbamazine citrate and albendazole in places without onchocerciasis; ivermectin and albendazole in places with onchocerciasis.[21][note 1]

The World Health Organization considers ivermectin the "drug of choice" for strongyloidiasis.[23] Most cases are treated with two daily doses of oral ivermectin (200 μg per kg body weight), while severe infections are treated with five to seven days of ivermectin.[19] Ivermectin is also the primary treatment for Mansonella ozzardi and cutaneous larva migrans.[24][25] The U.S. Centers for Disease Control recommends ivermectin, albendazole, or mebendazole as treatments for ascariasis.[26][note 2] Ivermectin is sometimes added to albendazole or mebendazole for whipworm treatment, and is considered a second-line treatment for gnathostomiasis.[25][30]

Mites and insects

Ivermectin is also used to treat infection with parasitic arthropods. Scabies – infestation with the mite Sarcoptes scabiei – is most commonly treated with topical permethrin or oral ivermectin. For most scabies cases, ivermectin is used in a two dose regimen: a first dose kills the active mites, but not their eggs. Over the next week, the eggs hatch, and a second dose kills the newly hatched mites.[31][32] For severe "crusted scabies", the Centers for Disease Control recommends up to seven doses of ivermectin over the course of a month, along with a topical antiparasitic.[32] Both head lice and pubic lice can be treated with oral ivermectin, a 0.5% ivermection lotion applied directly to the affected area, or various other insecticides.[33][34] Ivermectin is also used to treat rosacea and blepharitis, both of which can be caused or exacerbated by Demodex folliculorum mites.[35][36]

Contraindications

Ivermectin is contraindicated in children under the age of five or those who weigh less than 15 kilograms (33 pounds),[37] and individuals with liver or kidney disease.[38] Ivermectin is secreted in very low concentration in breast milk.[39] It remains unclear if ivermectin is safe during pregnancy.[40]

Adverse effects

Serious adverse events following ivermectin treatment are more common in people with very high burdens of larval Loa loa worms in their blood.[41] Those who have over 30,000 microfilaria per milliliter of blood risk inflammation and capillary blockage due to the rapid death of the microfilaria following ivermectin treatment.[41]

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.[42]

For dogs, the insecticide spinosad may have the effect of increasing the toxicity of ivermectin.[43]

Pharmacology

 
Ivermectin (IVM) bound to a C. elegans GluClR. IVM molecules interact with a binding pocket formed by the transmembrane domains of adjacent GluClR subunits, “locking” the receptor in an activated (open) conformation that allows unrestricted passage of chloride (Cl−) ions into the cell. (The plasma membrane is represented as a blue–pink gradient.) From PDB: 3RHW​.

Mechanism of action

Ivermectin and its related drugs act by interfering with nerve and muscle function of helminths and insects.[44] The drug binds to glutamate-gated chloride channels that are common to invertebrate nerve and muscle cells.[45] Ivermectin binding pushes these channels open, increasing the flow of chloride ions and hyper-polarizing the cell membranes.[45][44] This hyperpolarization paralyzes the affected tissue, eventually killing the invertebrate.[45] In mammals (including humans) glutamate-gated chloride channels are restricted to the brain and spinal cord; ivermectin cannot cross the blood-brain barrier and so it does not make it to the brain to affect mammalian channels.[45]

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[46] (the MDR1 gene mutation affects function of this protein). Crossing may still become significant if ivermectin is given at high doses (in which case, brain levels peak 2–5 hours after administration). 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.[47]

Chemistry

 
Avermectins producted by fermentation are the chemical starting point for Ivermectin

Fermentation of Streptomyces avermitilis yields eight closely related avermectin homologues, of which B1a and B1b form the bulk of the products isolated. In a separate chemical step, the mixture is hydrogenated to give ivermectin, which is an approximately 80:20 mixture of the two 22,23-dihydroavermectin compounds.[48][49][50]

History

The avermectin family of compounds was discovered by Satoshi Ōmura of Kitasato University and William Campbell of Merck. In 1970, Ōmura isolated unusual Streptomyces bacteria from the soil near a golf course along the south east coast of Honshu, Japan.[50] Ōmura sent the bacteria to William Campbell, who showed that the bacterial culture could cure mice infected with the roundworm Heligmosomoides polygyrus.[50] Campbell isolated the active compounds from the bacterial culture, naming them "avermectins" and the bacterium Streptomyces avermitilis for the compounds' ability to clear mice of worms (in Latin: a 'without', vermis 'worms').[50] Of the various avermectins, Campbell's group found the compound "avermectin B1" to be the most potent when taken orally.[50] They synthesized modified forms of avermectin B1 to improve its pharmaceutical properties, eventually choosing a mixture of at least 80% 22,23-dihydroavermectin B1a and up to 20% 22,23-dihydroavermectin B1b, a combination they called "ivermectin".[50][51]

Ivermectin was introduced in 1981.[52] 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".[53]

Society and culture

Cost

The initial price proposed by Merck in 1987 was US$6 per treatment, not affordable for most patients in Africa.[54] The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries.[54] Between 1995 and 2010 the program using donated ivermectin to prevent river blindness is estimated to have prevented seven million years of disability whilst costing US$257 million.[55]

As of 2019, the cost effectiveness of treating scabies and lice with ivermectin has not been studied.[56][57]

As of 2019, ivermectin tablets in the United States were the least expensive treatment option for lice in children at about US$10.[58] The hair lotion, however, costs[which?] about US$300 for a course of treatment.[58]

Brand names

Ivermectin is available as a generic prescription drug in the U.S. in a 3 mg tablet formulation.[59] It is also sold under the brand names Heartgard, Sklice[60] and Stromectol[61] in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[62] 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.[63]

COVID-19 misinformation

Further information: COVID-19 misinformation § Ivermectin

In December 2020, Chair of the US Senate Homeland Security Committee Ron Johnson used a Senate hearing to promote fringe theories about COVID-19.[64] Among the witnesses was Pierre Kory, a pulmonary and critical care doctor, who erroneously described ivermectin as "miraculous" and as a "wonder drug" to be used against COVID-19. Video footage of his statements went viral on social media, receiving over one million views as of 11 December 2020.[65]

During the pandemic, a number of misleading websites appeared purporting to show meta-analyses of clinical evidence in favour of ivermectin and sporting colorful graphics. While these gained traction in social media they violated the necessary norms of scientific practice, and the misinformation they contained created confusion among the public and policy makers.[66]

Research

COVID-19

This section is an excerpt from COVID-19 drug repurposing research § Ivermectin.[edit]
Template loop detected: Template:Excerpt

Tropical diseases

Ivermectin is being studied as a potential antiviral agent against chikungunya and yellow fever.[67]

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.[68][69] A direct effect on malaria parasites could not be shown in an experimental infection of volunteers with Plasmodium falciparum.[70] Use of ivermectin at higher doses necessary to control malaria is probably safe, though large clinical trials have not yet been done to definitively establish the efficacy and safety of ivermectin for prophylaxis or treatment of malaria.[71] 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.[72]

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.[73][74]

Bedbugs: There is tentative evidence that ivermectin kills bedbugs, as part of integrated pest management for bedbug infestations.[75][76][77] Such use however may require a prolonged course of treatment which is of unclear safety.[78]

NAFLD

In 2013, this antiparasitic drug was demonstrated as a novel ligand of farnesoid X receptor (FXR),[79][80] a therapeutic target for nonalcoholic fatty liver disease.[81]

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 that leave the animal via its droppings and can infest new pastures. Ivermectin is effective in killing some, but not all, of these parasites.[citation needed]

In dogs it is routinely used as prophylaxis against heartworm.[82]

Dogs with defects in the P-glycoprotein gene (MDR1), 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.[83] Some other dog breeds (especially the Rough Collie, the Smooth Collie, the Shetland Sheepdog, and the Australian Shepherd), also have a high incidence of mutation within the MDR1 gene (coding for P-glycoprotein) and are sensitive to the toxic effects of ivermectin.[84][85] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[86] A 0.01% ivermectin topical preparation for treating ear mites in cats is available.[87]

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.[88]

See also

Notes

  1. ^ In people with onchocerciasis, diethylcarbamazine citrate can cause a dangerous set of side effects called Mazzotti reaction. Due to this, diethylcarbamazine citrate is avoided in places where onchocerciasis is common.[22]
  2. ^ This recommendation is not universal. The World Health Organization recommends ascariasis be treated with mebendazole or pyrantel pamoate,[27] while the textbook Parasitic Diseases recommends albendazole or mebendazole.[28] A 2020 Cochrane review concluded that the three drugs are equally safe and effective for treating ascariasis.[29]

References

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