Ivermectin

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Ivermectin
Ivermectin skeletal.svg
250px
Systematic (IUPAC) name
22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b
Clinical data
Trade names Stromectol, Soolantra, Sklice, others
AHFS/Drugs.com
MedlinePlus a607069
Licence data EMA:Link, US Daily Med:link
Pregnancy
category
Legal status
Routes of
administration		 By mouth, topical
Pharmacokinetic data
Bioavailability –
Protein binding 93%
Metabolism Liver (CYP450)
Biological half-life 18 hours
Excretion Feces; <1% urine
Identifiers
CAS Number 70288-86-7 YesY Template:CAS
ATC code D11AX22 (WHO) , P02CF01, QP54AA01 (WHO), QS02QA03 (WHO)
PubChem CID: 6321424
DrugBank DB00602 YesY
ChemSpider 7988461 YesY
UNII 8883YP2R6D YesY
KEGG D00804 YesY
ChEBI CHEBI:6078
ChEMBL CHEMBL1200633 YesY
Synonyms MK-933
PDB ligand ID IVM (PDBe, RCSB PDB)
Chemical data
Formula C
48H
74O
14 (22,23-dihydroavermectin B1a)
C
47H
72O
14 (22,23-dihydroavermectin B1b)
Molecular mass
  • 875.106 g·mol−1 (22,23-dihydroavermectin B1a)
  • 861.079 g·mol−1 (22,23-dihydroavermectin B1b)
  • 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 YesY
  • Key:SPBDXSGPUHCETR-JFUDTMANSA-N YesY
 NYesY (what is this?)  (verify)

Ivermectin (/ˌaɪvərˈmɛktɪn/, EYE-vər-MEK-tin) is an antiparasitic medication.[6][7] Parasitic infestations in humans include head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis, and lymphatic filariasis.[6][8][9][10] In veterinary medicine, the medication is used to prevent and treat heartworm and acariasis, among other indications.[9] Ivermectin works through many mechanisms of action that result in the death of the targeted parasites;[6] it can be taken by mouth or applied to the skin for external infestations.[6][11] The drug belongs to the avermectin family of medications.[6]

Ivermectin was discovered in 1975 and first marketed as a veterinary medicine in 1981.[12] Human applications followed in the late 1980s.[13] William Campbell and Satoshi Ōmura won the 2015 Nobel Prize in Physiology or Medicine for its discovery and applications.[14] The medication is on the World Health Organization's List of Essential Medicines,[15] and is approved by the U.S. Food and Drug Administration as an antiparasitic agent.[16] In 2018, ivermectin was the 420th most commonly prescribed medication in the United States, with more than one hundred thousand prescriptions.[17] It is available as a generic medicine.[18][19]

During the COVID-19 pandemic, misinformation has been widely spread claiming that ivermectin is beneficial for treating and preventing COVID-19.[20][21] Such claims are not backed by credible scientific evidence.[22][23] Research into its use is ongoing, and multiple major health organizations, including the Food and Drug Administration, U.S. Centers for Disease Control, the European Medicines Agency, and the World Health Organization have stated that ivermectin is not authorized or approved to treat COVID-19.

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.[24] 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.[24] 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.[25] 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; and ivermectin and albendazole in places with onchocerciasis.[26][note 1]

The World Health Organization (WHO) considers ivermectin the drug of choice for strongyloidiasis.[28] 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.[24] Ivermectin is also the primary treatment for Mansonella ozzardi and cutaneous larva migrans.[29][30] The U.S. Centers for Disease Control and Prevention (CDC) recommends ivermectin, albendazole, or mebendazole as treatments for ascariasis.[31][note 2] Ivermectin is sometimes added to albendazole or mebendazole for whipworm treatment, and is considered a second-line treatment for gnathostomiasis.[30][35]

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.[36][37] For severe "crusted scabies", the U.S. Centers for Disease Control and Prevention (CDC) recommends up to seven doses of ivermectin over the course of a month, along with a topical antiparasitic.[37] Both head lice and pubic lice can be treated with oral ivermectin, an ivermectin lotion applied directly to the affected area, or various other insecticides.[38][39] Ivermectin is also used to treat rosacea and blepharitis, both of which can be caused or exacerbated by Demodex folliculorum mites.[40][41]

Contraindications

Ivermectin is contraindicated in children under the age of five or those who weigh less than 15 kilograms (33 pounds),[42] and individuals with liver or kidney disease.[43] The medication is secreted in very low concentration in breast milk.[44] It remains unclear if ivermectin is safe during pregnancy.[45]

Adverse effects

Side effects, although uncommon, include fever, itching, and skin rash when taken by mouth;[6] and red eyes, dry skin, and burning skin when used topically for head lice.[46] It is unclear if the drug is safe for use during pregnancy, but it is probably acceptable for use during breastfeeding.[47]

Ivermectin is considered relatively free of toxicity in standard doses (around 300 µg/kg).[48][49] Based on the data drug safety sheet for ivermectin,[lower-alpha 1] side effects are uncommon. However, serious adverse events following ivermectin treatment are more common in people with very high burdens of larval Loa loa worms in their blood.[50] 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.[50]

One concern is neurotoxicity after large overdoses, which in most mammalian species may manifest as central nervous system depression,[51] ataxia, coma, and even death,[52][53] as might be expected from potentiation of inhibitory chloride channels.[54]

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.[55]

During the course of a typical treatment, ivermectin can cause minor aminotransferase elevations. In rare cases it can cause mild clinically apparent liver disease.[56]

To provide context for the dosing and toxicity ranges, the LD50 of ivermectin in mice is 25 mg/kg (oral), and 80 mg/kg in dogs, corresponding to an approximated human-equivalent dose LD50 range of 2.02-43.24 mg/kg,[57] which is far in excess of its FDA-approved usage (a single dose of 0.150-0.200 mg/kg to be used for specific parasitic infections).[58] While ivermectin has also been studied for use in COVID-19, and while it has some ability to inhibit SARS-CoV-2 in vitro, achieving 50% inhibition in vitro was found to require an estimated oral dose of 7.0 mg/kg (or 35x the maximum FDA-approved dosage),[59] high enough to be considered ivermectin poisoning.[57] Despite insufficient data to show any safe and effective dosing regimen for ivermectin in COVID-19, doses have been taken far in excess of FDA-approved dosing, leading the CDC to issue a warning of overdose symptoms including nausea, vomiting, diarrhea, hypotension, decreased level of consciousness, confusion, blurred vision, visual hallucinations, loss of coordination and balance, seizures, coma, and death. The CDC advises against consuming doses intended for livestock or doses intended for external use and warns that increasing misuse of ivermectin-containing products is resulting in an increasing rate of harmful overdoses.[60]

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 only effective in killing some of these parasites, this is because of an increase in anthelmintic resistance.[61] This resistance has arisen from the persistent use of the same anthelmintic drugs for the past 40 years.[62][63]

In dogs, ivermectin is routinely used as prophylaxis against heartworm.[64] 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.[65] 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.[66][67] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[68] A 0.01% ivermectin topical preparation for treating ear mites in cats is available.[69]

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.[70]

A characteristic of the antinematodal action of ivermectin is its potency: for instance, to combat Dirofilaria immitis in dogs, ivermectin is effective at 0.001 milligram per kilogram of body weight when administered orally.[71]

For dogs, the insecticide spinosad may have the effect of increasing the toxicity of ivermectin.[72][73]

Pharmacology

File:Ivermectin mechanism of action 3RHW.png
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 the nerve and muscle functions of helminths and insects.[74] The drug binds to glutamate-gated chloride channels common to invertebrate nerve and muscle cells.[75] The binding pushes the channels open, which increases the flow of chloride ions and hyper-polarizes the cell membranes,[74] paralyzing and killing the invertebrate.[75] Ivermectin is safe for mammals (at the normal therapeutic doses used to cure parasite infections) because mammalian glutamate-gated chloride channels only occur in the brain and spinal cord: the causative avermectins usually do not cross the blood–brain barrier, and are unlikely to bind to other mammalian ligand-gated channels.[75]

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 (the MDR1 gene mutation affects the function of this protein).[76] 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.[77]

Chemistry

File:Avermectins.png
Avermectins produced 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.[78][79][7]

Ivermectin is a macrocyclical lactone.[80]

History

The avermectin family of compounds was discovered by Satoshi Ōmura of Kitasato University and William Campbell of Merck.[7] In 1970, Ōmura isolated unusual Streptomyces bacteria from the soil near a golf course along the south east coast of Honshu, Japan.[7] Ōmura sent the bacteria to William Campbell, who showed that the bacterial culture could cure mice infected with the roundworm Heligmosomoides polygyrus.[7] 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').[7] Of the various avermectins, Campbell's group found the compound "avermectin B1" to be the most potent when taken orally.[7] 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".[7][71]

The discovery of ivermectin has been described as a combination of "chance and choice." Merck was looking for a broad-spectrum anthelmintic, which ivermectin is indeed; however, Campbell noted that they "...also found a broad-spectrum agent for the control of ectoparasitic insects and mites."[81]

Merck began marketing ivermectin as a veterinary antiparasitic in 1981.[7] By 1986, ivermectin was registered for use in 46 countries and was administered massively to cattle, sheep and other animals.[82] By the late 1980s, ivermectin was the bestselling veterinary medicine in the world.[7] Following its blockbuster success as a veterinary antiparasitic, another Merck scientist, Mohamed Aziz, collaborated with the World Health Organization to test the safety and efficacy of ivermectin against onchocerciasis in humans.[13] They found it to be highly safe and effective,[83] triggering Merck to register ivermectin for human use as "Mectizan" in France in 1987.[13] A year later, Merck CEO Roy Vagelos agreed that Merck would donate all ivermectin needed to eradicate river blindness.[13] In 1998, that donation would be expanded to include ivermectin used to treat lymphatic filariasis.[13]

Ivermectin earned the title of "wonder drug" for the treatment of nematodes and arthropod parasites.[84] Ivermectin has been used safely by hundreds of millions of people to treat river blindness and lymphatic filariasis.[7]

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".[14]

Society and culture

COVID-19 misinformation

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Main article: Ivermectin during the COVID-19 pandemic
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Economics

The initial price proposed by Merck in 1987 was US$6 per treatment, which was unaffordable for patients who most needed ivermectin.[85] The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries.[85] Between 1995 and 2010, the program using donated ivermectin to prevent river blindness is estimated to have prevented seven million years of disability at a cost of US$257 million.[86]

Ivermectin is considered an inexpensive drug.[87] As of 2019, ivermectin tablets (Stromectol) in the United States were the least expensive treatment option for lice in children at approximately US$9.30, while Sklice, an ivermectin lotion, cost around US$300 for Lua error in Module:Convert at line 272: attempt to index local 'cat' (a nil value)..[88]

As of 2019, the cost effectiveness of treating scabies and lice with ivermectin has not been studied.[89][90]

Brand names

It is sold under the brand names Heartgard, Sklice[91] and Stromectol[2] in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[92] 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 under the brand name Soolantra.[3] While in development, it was assigned the code MK-933 by Merck.[93]

Research

COVID-19

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Further information: Ivermectin during the COVID-19 pandemic § Research

During the COVID-19 pandemic, ivermectin was researched for possible utility in preventing and treating COVID-19, but no good evidence of benefit was found.[94]

Parasitic disease

Ivermectin has been researched in laboratory animals, as a potential treatment for trichinosis.[95]

Tropical diseases

As of 2016 ivermectin was studied as a potential antiviral agent against chikungunya and yellow fever.[96] In chikungunya, ivermectin showed a wide in vitro safety margin as an antiviral.[96]

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.[97][98] A direct effect on malaria parasites could not be shown in an experimental infection of volunteers with Plasmodium falciparum.[99] 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 or safety of ivermectin for prophylaxis or treatment of malaria.[100] Mass drug administration of a population with ivermectin to treat and prevent nematode infestation is effective for eliminating malaria-bearing mosquitos and thereby reducing infection with residual malaria parasites.[101]

One alternative to ivermectin is moxidectin, which has been approved by the Food and Drug Administration for use in people with river blindness. Moxidectin 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.[102][103]

There is tentative evidence that ivermectin kills bedbugs, as part of integrated pest management for bedbug infestations.[104][105][106] However, such use may require a prolonged course of treatment which is of unclear safety.[107]

NAFLD

In 2013, ivermectin was demonstrated as a novel ligand of the farnesoid X receptor,[108][109] a therapeutic target for nonalcoholic fatty liver disease.[110]

See also

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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.[27]
  2. ↑ This recommendation is not universal. The World Health Organization recommends ascariasis be treated with mebendazole or pyrantel pamoate,[32] while the textbook Parasitic Diseases recommends albendazole or mebendazole.[33] A 2020 Cochrane review concluded that the three drugs are equally safe and effective for treating ascariasis.[34]
  1. ↑ New Drug Application Identifier: 50-742/S-022

References

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  80. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  81. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  82. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  83. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  84. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  85. ↑ 85.0 85.1 Lua error in package.lua at line 80: module 'strict' not found.
  86. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  87. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  88. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  89. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  90. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  91. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  92. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  93. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  94. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  95. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  96. ↑ 96.0 96.1 Lua error in package.lua at line 80: module 'strict' not found.
  97. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  98. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  99. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  100. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  101. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  102. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  103. ↑ Lua error in package.lua at line 80: module 'strict' not found. open access publication - free to read
  104. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  105. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  106. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  107. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  108. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  109. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  110. ↑ Lua error in package.lua at line 80: module 'strict' not found.

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