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=== Brand names ===
=== Brand names ===
Ivermectin is available as a generic prescription drug in the U.S. in a 3&nbsp;mg tablet formulation.<ref>{{cite web |last1=U.S. FDA |title=Abbreviated New Drug Application (ANDA): 204154 |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=204154 |website=Drugs@FDA: FDA Approved Drug Products |publisher=U.S. Food and Drug Administration |access-date=18 August 2018}}</ref> It is also sold under the brand names Heartgard, Sklice<ref>{{cite web | title=Sklice- ivermectin lotion | website=DailyMed | date=9 November 2017 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c74905e6-fc04-4244-880b-98ab0551df21 | access-date=28 October 2020}}</ref> and Stromectol<ref>{{cite web | title=Stromectol- ivermectin tablet | website=DailyMed | date=15 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=681888c9-af79-4b7d-ae80-c3f4f6f1effd | access-date=28 October 2020}}</ref> in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by [[Merck & Co.|Merck]], Iver-DT<ref>{{cite web|title = Alive Pharmaceutical (P) LTD.: Iver-DT|url = http://alivepharmaceutical.blogspot.com/2014/05/iver-dt.html|website = Alive Pharmaceutical (P) LTD.|date = May 27, 2014|access-date = October 7, 2015|first = Santosh|last = Adhikari | name-list-style = vanc |url-status = dead |archive-url = https://web.archive.org/web/20160304223410/http://alivepharmaceutical.blogspot.com/2014/05/iver-dt.html |archive-date = March 4, 2016 |df = mdy-all}}</ref> 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.<ref>{{cite journal | vauthors = Pampiglione S, Majori G, Petrangeli G, Romi R | title = Avermectins, MK-933 and MK-936, for mosquito control | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 79 | issue = 6 | pages = 797–9 | year = 1985 | pmid = 3832491 | doi = 10.1016/0035-9203(85)90121-X }}</ref>
Ivermectin is available as a generic prescription drug in the U.S. in a 3&nbsp;mg tablet formulation.<ref>{{cite web |last1=U.S. FDA |title=Abbreviated New Drug Application (ANDA): 204154 |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=204154 |website=Drugs@FDA: FDA Approved Drug Products |publisher=U.S. Food and Drug Administration |access-date=18 August 2018}}</ref> It is also sold under the brand names Heartgard, Sklice<ref>{{cite web | title=Sklice- ivermectin lotion | website=DailyMed | date=9 November 2017 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c74905e6-fc04-4244-880b-98ab0551df21 | access-date=28 October 2020}}</ref> and Stromectol<ref>{{cite web | title=Stromectol- ivermectin tablet | website=DailyMed | date=15 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=681888c9-af79-4b7d-ae80-c3f4f6f1effd | access-date=28 October 2020}}</ref> in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by [[Merck & Co.|Merck]], Iver-DT<ref>{{cite web|title = Alive Pharmaceutical (P) LTD.: Iver-DT|url = http://alivepharmaceutical.blogspot.com/2014/05/iver-dt.html|website = Alive Pharmaceutical (P) LTD.|date = May 27, 2014|access-date = October 7, 2015|first = Santosh|last = Adhikari | name-list-style = vanc |url-status = dead |archive-url = https://web.archive.org/web/20160304223410/http://alivepharmaceutical.blogspot.com/2014/05/iver-dt.html |archive-date = March 4, 2016 |df = mdy-all}}</ref> 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.<ref>{{cite journal | vauthors = Pampiglione S, Majori G, Petrangeli G, Romi R | title = Avermectins, MK-933 and MK-936, for mosquito control | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 79 | issue = 6 | pages = 797–9 | year = 1985 | pmid = 3832491 | doi = 10.1016/0035-9203(85)90121-X }}</ref>

===Misinformation===
⚫
{{Main|Misinformation related to the COVID-19 pandemic}}

In December 2020, American politician [[Ron Johnson (Wisconsin politician)|Ron Johnson]] used a Senate hearing to promote [[Misinformation related to the COVID-19 pandemic|fringe theories about COVID-19]].<ref>{{Cite news|last=Qiu|first=Linda|date=2020-12-17|title=The election is over, but Ron Johnson keeps promoting false claims of fraud.|language=en-US|work=The New York Times|url=https://www.nytimes.com/2020/12/16/technology/the-election-is-over-but-ron-johnson-keeps-promoting-false-claims-of-fraud.html|access-date=2020-12-18|issn=0362-4331}}</ref> 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.<ref>{{cite web |author=Beatrice Dupuy |date=11 December 2020 |publisher=AP News |type=Fact check |title=No evidence ivermectin is a miracle drug against COVID-19 |url=https://apnews.com/article/fact-checking-afs:Content:9768999400}}</ref>

[[David Gorski]] has written that the narrative of ivermectin as a "miracle cure" for COVID-19 is a "[[metastasized]]" version of a similar conspiracy theory around the drug [[hydroxychloroquine]], in which unspecified powers are thought to be suppressing news of the drug's effectiveness for their own malign purposes.<ref>{{cite web |vauthors=Gorski DH |publisher=[[Science-Based Medicine]] |title=2020 and the pandemic: A year of (some) physicians behaving badly |url=https://sciencebasedmedicine.org/2020-and-the-pandemic-a-year-of-physicians-behaving-badly/ |date=28 December 2020}}</ref>


== Research ==
== Research ==
Line 185: Line 178:
===COVID-19===
===COVID-19===


⚫
{{further|COVID-19 drug repurposing research#Ivermectin|Misinformation related to the COVID-19 pandemic#Ivermectin}}
''[[In vitro]]'', ivermectin had [[Antiviral drug|antiviral]] effects against several distinct [[Positive-sense single-stranded RNA virus|positive-sense single-strand RNA viruses]], including [[Severe acute respiratory syndrome coronavirus 2|SARS-CoV-2]].<ref>{{cite journal | vauthors = Heidary F, Gharebaghi R | title = Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen | journal = The Journal of Antibiotics | date = June 2020 | volume = 73 | issue = 9 | pages = 593–602 | pmid = 32533071 | pmc = 7290143 | doi = 10.1038/s41429-020-0336-z }}</ref> Although such a routine laboratory finding does not mean that the drug has any [[clinical significance|clinical effect]] against COVID-19, reports of it prompted public interest in [[self-medicating]] using veterinary supplies of the drug.<ref name=fda-warn/> On 10 April 2020, the FDA issued guidance to not use veterinary-grade ivermectin as treatment for COVID-19 in humans, as it could be seriously harmful.<ref name=fda-warn>{{cite web | title=Do Not Use Ivermectin for Animals as Treatment for COVID-19 in Humans | website=U.S. [[Food and Drug Administration]] (FDA) | date=10 April 2020 | url=https://www.fda.gov/animal-veterinary/product-safety-information/fda-letter-stakeholders-do-not-use-ivermectin-intended-animals-treatment-covid-19-humans | access-date=10 April 2020}}</ref><ref name="martin20">{{cite journal |doi=10.1016/j.pt.2020.10.005|title=Ivermectin: An Anthelmintic, an Insecticide, and Much More|year=2020|last1=Martin|first1=Richard J.|last2=Robertson|first2=Alan P.|last3=Choudhary|first3=Shivani|journal=Trends in Parasitology|volume=37|issue=1|pages=48–64|pmid=33189582|s2cid=226972704|doi-access=free}}</ref>

Ivermectin inhibits replication of SARS-CoV-2 in monkey kidney cell culture with an [[IC50|IC<sub>50</sub>]] of 2.2 - 2.8 µM, making it a possible candidate for [[COVID-19 drug repurposing research]].<ref>{{cite journal | vauthors = Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM | title = The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro | journal = Antiviral Research | volume = 178 | pages = 104787 | date = April 2020 | pmid = 32251768 | doi = 10.1016/j.antiviral.2020.104787 | pmc = 7129059 | doi-access = free }} {{open access}}</ref><ref>{{cite journal | vauthors = Şimşek Yavuz S, Ünal S | title = Antiviral treatment of COVID-19 | journal = Turkish Journal of Medical Sciences| volume = 50 | issue = SI-1 | pages = 611–619 | date = April 2020 | pmid = 32293834 | doi = 10.3906/sag-2004-145 | pmc = 7195979 | doi-access = free }}</ref> The doses used in cell culture would require 10{{sup|4}} larger doses in humans based on this data, which does not look promising as an effective treatment for COVID-19.<ref name="TW2020">{{cite web |title=TWiV 599: Coronavirus update - we need a plan {{!}} This Week in Virology |url=https://www.microbe.tv/twiv/twiv-599/ |access-date=21 April 2020}}</ref><ref name=":0">{{Cite journal|last1=Bray|first1=Mike|last2=Rayner|first2=Craig|last3=Noël|first3=François|last4=Jans|first4=David|last5=Wagstaff|first5=Kylie|date=2020-06-01|title=Ivermectin and COVID-19: A report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors' responses |url=http://www.sciencedirect.com/science/article/pii/S0166354220302199| journal=Antiviral Research|volume=178|pages=104805|doi=10.1016/j.antiviral.2020.104805|pmid=32330482|pmc=7172803|issn=0166-3542}}</ref> 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,<ref name=":0" /> specifically the inhibition of [[nuclear transport]] by [[Importin|importin α/β1]].<ref>{{Cite journal|last1=Yang|first1=Sundy N. Y.|last2=Atkinson|first2=Sarah C.|last3=Wang|first3=Chunxiao|last4=Lee|first4=Alexander|last5=Bogoyevitch|first5=Marie A.|last6=Borg|first6=Natalie A.|last7=Jans|first7=David A.|date=2020-05-01|title=The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer|url=http://dicyt.uto.edu.bo/observatorio/wp-content/uploads/2020/05/importin-alfa.pdf|journal=Antiviral Research|volume=177|pages=104760|doi=10.1016/j.antiviral.2020.104760|pmid=32135219}}</ref>

A [[preprint]] published in 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.<ref name=surgisphere>{{Cite web|title=Surgisphere Sows Confusion About Another Unproven COVID-19 Drug|url=https://www.the-scientist.com/news-opinion/surgisphere-sows-confusion-about-another-unproven-covid19-drug-67635|date=2020-06-16|access-date=2020-07-08|website=The Scientist Magazine}}</ref> On October 12, 2020 Peru withdrew its authorization to use ivermectin and hydroxychloroquine as COVID-19 treatments.<ref name=peruvian>{{Cite web|title=Resolución ministerial 839-2020/MINSA|url=https://cdn.www.gob.pe/uploads/document/file/1365531/R.M.%20839-2020.pdf.pdf|date=2020-10-12|access-date=2020-12-09|website=Plataforma digital única del Estado Peruano}}</ref>

There is only very weak evidence of ivermectin's benefit when used as an [[adjuvant therapy|add-on therapy]] for people with non-severe COVID-19.<ref name=padhy20>{{cite journal |vauthors=Padhy BM, Mohanty RR, Das S, Meher BR |title=Therapeutic potential of ivermectin as add on treatment in COVID 19: A systematic review and meta-analysis |journal=J Pharm Pharm Sci |volume=23 |pages=462–469 |date=2020 |pmid=33227231 |doi=10.18433/jpps31457|quote=the complication rate and mortality amongst patients with severe disease have been reported to be very high. In such patients the effectiveness of add on ivermectin has not yet been explored|doi-access=free }}</ref>


Ivermectin is being studied for its potential efficacy against [[Severe acute respiratory syndrome coronavirus 2|SARS-CoV-2]]. ''[[In vitro]]'', ivermectin had [[Antiviral drug|antiviral]] effects against several distinct [[Positive-sense single-stranded RNA virus|positive-sense single-strand RNA viruses]], including SARS-CoV-2.<ref>{{cite journal | vauthors = Heidary F, Gharebaghi R | title = Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen | journal = The Journal of Antibiotics | date = June 2020 | volume = 73 | issue = 9 | pages = 593–602 | pmid = 32533071 | pmc = 7290143 | doi = 10.1038/s41429-020-0336-z }}</ref>
The [[National Institutes of Health]] recommend against the use ivermectin for COVID-19.<ref name=nihcvrec>{{cite web |publisher=National Institutes of Health |url=https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/ivermectin/ |date=27 August 2020 |title=COVID-19 Treatment Guidelines |type=Clinical guideline}}</ref> The [[FDA]] advises people not to take ivermectin to prevent or treat COVID-19, and that it is not approved for that purpose.<ref>{{cite web |publisher=Food and Drug Administration |date=16 December 2020 |title=FAQ: COVID-19 and Ivermectin Intended for Animals |url=https://www.fda.gov/animal-veterinary/product-safety-information/faq-covid-19-and-ivermectin-intended-animals}}</ref>


===Tropical diseases===
===Tropical diseases===

Revision as of 07:56, 14 January 2021

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)

Ivermectin is a medication used to treat many types of parasite infestations.[3] This includes head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis, and lymphatic filariasis.[3][4][5][6] It can be taken by mouth or applied to the skin for external infestations.[3][7]

Common side effects include red eyes, dry skin, and burning skin.[3] It is unclear if it is safe for use during pregnancy, but is probably acceptable for use during breastfeeding.[8] 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.[9][10] It is on the World Health Organization's List of Essential Medicines.[11] Ivermectin is an FDA-approved anti-parasitic agent.[12]

In veterinary medicine, it is used to prevent and treat heartworm and acariasis, among other indications.[5]

Medical uses

Ivermectin is widely used to treat human diseases caused by roundworms and ectoparasites. For river blindness (onchocerciasis), 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.[13] 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.[14] 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.[15][note 1]

Pinworms

Ivermectin is as effective as albendazole or alternative antinematode drugs for treatment of pinworm infection (enterobiasis).[17]

Threadworm

Ivermectin is more effective than albendazole and equally as effective as thiabendazole for treatment of threadworm (strongyloidiasis). Ivermectin has fewer adverse effects than does thiabendazole and is at least as well tolerated as albendazole.[18] 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.[19] 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.[20]

Whipworm

Combination therapy with ivermectin plus albendazole is effective for treatment of whipworm (Trichuris trichiura) and the rate of Mazzotti reaction is no higher than for albendazole alone.[21]

Arthropod

Evidence supports its use against parasitic arthropods and insects:

  • Mites such as scabies:[22][23][24] It is usually limited to cases that prove to be resistant to topical treatments or that present in an advanced state (such as Norwegian scabies).[24] One review found that the efficacy of permethrin is similar to that of systemic or topical ivermectin.[25] 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.[26] Another review found that oral ivermectin provided a reasonable balance between efficacy and safety.[27] Since ivermectin is more convenient than permethrin,[28] many have turned to veterinary sources of the drug to obtain assurance of a cure at an affordable price.[29]
  • Lice:[30][31] Ivermectin lotion (0.5%) is FDA-approved for patients six months of age and older.[32] 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.[33] This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.[34]
  • Bedbugs: There is tentative evidence that ivermectin kills bedbugs, as part of integrated pest management for bedbug infestations.[35][36][37] Such use however may require a prolonged course of treatment which is of unclear safety.[38]
  • 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.[39]

Rosacea

A review found that ivermectin was more effective than alternatives for treatment of papulopustular acne rosacea.[40][41] An ivermectin cream has been approved by the FDA, as well as in Europe, for the treatment of inflammatory lesions of rosacea. The treatment is based upon the hypothesis that parasitic mites of the genus Demodex play a role in rosacea.[42] In a clinical study, ivermectin reduced lesions by 83% over 4 months, as compared to 74% under a metronidazole standard therapy.[43]

Blepharitis

Demodex folliculorum mites have been found to be a contributing cause for blepharitis (eyelid inflammation) and a review of treatments have showed ivermectin to be an effective for treatment for reducing or eliminating mite populations and reducing symptoms.[44]

Contraindications

Ivermectin is contraindicated in children under the age of five or those who weigh less than 15 kilograms (33 pounds),[30] and individuals with liver or kidney disease.[45] Ivermectin is secreted in very low concentration in breast milk.[46] It remains unclear if ivermectin is safe during pregnancy.[47]

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.[48] 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.[48]

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.[49]

For dogs, the insecticide spinosad may have the effect of increasing the toxicity of ivermectin.[50]

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.[51] The drug binds to glutamate-gated chloride channels that are common to invertebrate nerve and muscle cells.[52] Ivermectin binding pushes these channels open, increasing the flow of chloride ions and hyper-polarizing the cell membranes.[52][51] This hyperpolarization paralyzes the affected tissue, eventually killing the invertebrate.[52] 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.[52]

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,[53] (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.[54]

Chemistry

Ivermectin is an approximately 80:20 mixture of two avermectin B1 derivatives, called 22,23-dihydroavermectin B1a and B1b.[55]

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.[55] Ōmura sent the bacteria to William Campbell, who showed that the bacterial culture could cure mice infected with the roundworm Heligmosomoides polygyrus.[55] 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).[55] Of the various avermectins, Campbell's group found the compound "avermectin B1" to be the most potent when taken orally.[55] 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".[55][56]

Ivermectin was introduced in 1981.[57] 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".[58]

Society and culture

Cost

The initial price, proposed by Merck in 1987, was US$6.[59] The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries.[59] Between 1995 and 2010 the program using donated ivermectin to prevent river blindness is estimated to have prevented 7 million years of disability whilst costing US$257 million.[60]

As of 2019, the cost effectiveness of treating scabies and lice with ivermectin has not been studied.[61][62]

As of 2019, ivermectin tablets in the United States were the least expensive treatment option for lice in children at about US$10.[63] The hair lotion, however, costs[which?] about US$300 for a course of treatment.[63]

Brand names

Ivermectin is available as a generic prescription drug in the U.S. in a 3 mg tablet formulation.[64] It is also sold under the brand names Heartgard, Sklice[65] and Stromectol[66] in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[67] 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.[68]

Research

COVID-19

Further information: COVID-19 drug repurposing research § Ivermectin, and Misinformation related to the COVID-19 pandemic § Ivermectin

Ivermectin is being studied for its potential efficacy against SARS-CoV-2. In vitro, ivermectin had antiviral effects against several distinct positive-sense single-strand RNA viruses, including SARS-CoV-2.[69]

Tropical diseases

Ivermectin is being studied as a potential antiviral agent against chikungunya and yellow fever.[70]

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.[71][72] 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.[73]

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.[74][75]

NAFLD

In 2013, this antiparasitic drug was demonstrated as a novel ligand of farnesoid X receptor (FXR),[76][77] a therapeutic target for nonalcoholic fatty liver disease.[78]

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.[citation needed]

In dogs it is routinely used as prophylaxis against heartworm.[79]

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.[80] 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.[81][82] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[83] A 0.01% ivermectin topical preparation for treating ear mites in cats is available.[84]

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.[85]

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.[16]

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External links

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