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Ivermectin

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Ivermectin
Ivermectin skeletal.svg
Ivermectin-B1a-from-xtal-3D-bs-17.png
Clinical data
Trade namesStromectol, Soolantra, Sklice, others
Other namesMK-933
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
48
H
74
O
14
(22,23-dihydroavermectin B1a)
C
47
H
72
O
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
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Ivermectin, sold under the brand name Stromectol among others, is a medication that is used to treat parasite infestations.[6][7] In humans, this includes head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis, and lymphatic filariasis.[6][8][9][10] In veterinary medicine, it is used to prevent and treat heartworm and acariasis, among other indications.[9] It can be taken by mouth or applied to the skin for external infestations.[6][11]

Common side effects 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.[12] It is unclear if it is safe for use during pregnancy, but is probably acceptable for use during breastfeeding.[13] It belongs to the avermectin family of medications.[6] It works through many mechanisms of action that result in death of the targeted parasites.[6]

Ivermectin was discovered in 1975 and came into medical use in 1981.[14][15] It is on the World Health Organization's List of Essential Medicines.[16] Ivermectin is FDA-approved as an antiparasitic agent.[17] In 2018, it was the 420th most commonly prescribed medication in the United States, with more than one hundred thousand prescriptions.[18]

During the COVID-19 pandemic, misinformation was widely spread claiming that ivermectin is beneficial for treating and preventing COVID-19.[19][20] Such claims are not backed by trustable scientific evidence.[21][22]

Medical uses

Ivermectin is used to treat human diseases caused by roundworms and ectoparasites. It was developed, primarily, to treat parasitic infections which were difficult to treat with other anti-parasitics.[23]

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; 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, a 0.5% ivermection 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] Ivermectin is secreted in very low concentration in breast milk.[44] It remains unclear if ivermectin is safe during pregnancy.[45]

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.[46] 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.[46]

One main concern is neurotoxicity after large doses, which in most mammalian species may manifest as central nervous system depression,[47] ataxia, coma, and even death,[48][49] as might be expected from potentiation of inhibitory GABA-ergic synapses.[50]

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.[51]

During the course of a typical treatment, ivermectin can cause minor aminotransferase elevations and, rarely, mild clinically apparent liver disease.[52]

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.[53] The drug binds to glutamate-gated chloride channels that are common to invertebrate nerve and muscle cells.[54] Ivermectin binding pushes these channels open, increasing the flow of chloride ions and hyper-polarizing the cell membranes.[54][53] This hyperpolarization paralyzes the affected tissue, eventually killing the invertebrate.[54] 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.[54]

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[55] (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.[56]

Chemistry

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.[57][58][59]

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.[59] Ōmura sent the bacteria to William Campbell, who showed that the bacterial culture could cure mice infected with the roundworm Heligmosomoides polygyrus.[59] 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').[59] Of the various avermectins, Campbell's group found the compound "avermectin B1" to be the most potent when taken orally.[59] 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".[59][60]

Ivermectin was introduced in 1981.[61] 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".[62]

By 1986, ivermectin was registered for use in 46 countries and was administered massively to cattle, sheep and other animals.[63] Ivermectin was approved for human use in 1988.[64] Ivermectin earned the title of "wonder drug" for the treatment of nematodes and arthropod parasites.[65] Ivermectin has been used safely by hundreds of millions of people to treat river blindness and lymphatic filariasis.[66]

Society and culture

Economics

The initial price proposed by Merck in 1987 was US$6 per treatment, not affordable for most patients in Africa.[67] The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries.[67] 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.[68]

As of 2019, the cost effectiveness of treating scabies and lice with ivermectin has not been studied.[69][70]

As of 2019, ivermectin tablets in the United States were the least expensive treatment option for lice in children at about US$10.[71] The hair lotion, however, costs[which?] about US$300 for a course of treatment.[71]

Ivermectin is considered an inexpensive drug.[72]

Brand names

Ivermectin is available as a generic prescription drug in the U.S. in a 3 mg tablet formulation.[73] It is also sold under the brand names Heartgard, Sklice[74] and Stromectol[1] in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[75] 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.[2] While in development, it was assigned the code MK-933 by Merck.[76]

COVID-19 misinformation

During the COVID-19 pandemic, the antiparasitic drug ivermectin became a cause célèbre for right-wing figures promoting it as a supposed COVID treatment.[77]

In December 2020, Chair of the US Senate Homeland Security Committee Ron Johnson used a Senate hearing to promote fringe theories about COVID-19.[78] 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.[79] In the United Kingdom, Andrew Hill, a senior research fellow at Liverpool University, posted a video of a draft meta-analysis that went viral before it was removed.[80] An evidence-based review of Hill's paper by scientists at the Interdisciplinary Centre for Health Studies in Valparaíso, Chile found "serious methodological limitations" which cast the findings into doubt.[81]

During the pandemic, a number of misleading websites appeared purporting to show meta-analyses of clinical evidence in favor of ivermectin's use in treating COVID-19.[81][82] The sites in question had anonymous owners, multiple domains which redirected to the same content, and used many colorful, but misleading, graphics to communicate their point.[83][81] The web servers used for these sites are the same as those previously used to spread misinformation about hydroxychloroquine.[84]

While these sites gained traction among many non-scientists on social media, they also violated many of the basic norms of meta-analysis methodology. Notably, many of these sites included studies with small sample sizes, widely different dosages of the treatment, an open-label design (in which experimenters and participants both know who is in the control group), poor-quality control groups (such as another untested treatment which may worsen outcomes), or no control group at all.[82] Another issue is the inclusion of multiple ad-hoc un-published trials which did not undergo peer-review, and which had different incompatible outcome measures.[85] Such methodological problems are known to distort the findings of meta-analyses and cause spurious or false findings.[86] The misinformation communicated by these sites created confusion among the public and policy makers.[81]

A review article by Kory, Paul E. Marik, and others on the efficacy of ivermectin, which had been provisionally accepted for publication by a Frontiers Media journal, was subsequently rejected on account of what the publisher said were "a series of strong, unsupported claims based on studies with insufficient statistical significance" meaning that the article did "not offer an objective [or] balanced scientific contribution to the evaluation of ivermectin as a potential treatment for COVID-19".[87]

In the United States, the use of ivermectin for COVID-19 is championed by a group calling itself the "Frontline COVID-19 Critical Care Alliance" (FLCCC), which says it heads "the global movement to move #Ivermectin into the mainstream". The effort has gone viral on social media, where it has been adopted by COVID deniers, anti-vaccination proponents, and conspiracy theorists.[88] 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 profit.[89]

The viral social media misinformation about ivermectin has gained particular attention in South Africa where an anti-vaccination group called "South Africa Has A Right To Ivermectin" has been lobbying for the drug to be made available for prescription.[80] Another group, the "Ivermectin Interest Group" launched a court case against the South African Health Products Regulatory Authority (SAHPRA), and as a result a compassionate use exemption was granted. SAPHRA stated in April 2021 that "At present, there are no approved treatments for COVID-19 infections."[80]

In July 2021, a large randomized control trial apparently showing the effectiveness of ivermectin for COVID-19 was suspected of being fraudulent. The pre-printed paper, a mainstay of ivermectin supporters' claims, was discovered to be mash-up of press releases run through software which changed some words. The paper was withdrawn from the Research Square platform for "ethical concerns".[77]

Research

COVID-19

In vitro, ivermectin has antiviral effects against several distinct positive-sense single-strand RNA viruses, including SARS-CoV-2.[90] Subsequent studies found that ivermectin could inhibit replication of SARS-CoV-2 in monkey kidney cell culture with an IC50 of 2.2–2.8 μM.[91][92] Based on this information, however, doses much higher than the maximum approved or safely achievable for use in humans would be required for an antiviral effect.[93][94] Aside from practical difficulties, such high doses are not covered by current human-use approvals of the drug and would be toxic, as the antiviral mechanism of action is considered to operate by the suppression of a host cellular process,[93] specifically the inhibition of nuclear transport by importin α/β1.[95] Therefore, the rationale for the clinical evaluation of ivermectin in COVID-19 seems insufficient.[96] Self-medication with a highly concentrated formula intended for horses has led to numerous hospitalizations, and overdose can lead to death, possibly due to interaction with other medications.[97] To resolve uncertainties from previous small or poor-quality studies, as of June 2021, large scale trials are underway in the United States and the United Kingdom.[98][99]

Many studies on ivermectin for COVID-19 have serious methodological limitations, resulting in very low evidence certainty.[96][100][101] As a result, several organizations have publicly expressed that the evidence of effectiveness against COVID-19 is weak. In February 2021, Merck, the developer of the drug, issued a statement saying that there is no good evidence ivermectin is plausible or effective against COVID-19, and that attempting such use may be unsafe.[102][103] The U.S. National Institutes of Health COVID-19 Treatment Guidelines state that the evidence for ivermectin is too limited to allow for a recommendation for or against its use.[104] In the United Kingdom, the national COVID-19 Therapeutics Advisory Panel determined that the evidence base and plausibility of ivermectin as a COVID-19 treatment were insufficient to pursue further investigations.[105]

Ivermectin is not approved by the U.S. Food and Drug Administration (FDA) for use in treating any viral illness and is not authorized for use to treat COVID-19 within the European Union.[104][106] After reviewing the evidence on ivermectin, the EMA said that "the available data do not support its use for COVID-19 outside well-designed clinical trials".[106] In March 2021, both the FDA and the European Medicines Agency (EMA) issued guidance that ivermectin should not be used to treat or prevent COVID-19.[97][106] The WHO also said that ivermectin should not be used to treat COVID-19 except in a clinical trial.[107] The Brazilian Health Regulatory Agency, Brazilian Society of Infectious Diseases, and Brazilian Thoracic Society issued position statements advising against the use of ivermectin for prevention or treatment of early-stage COVID-19.[108][109][110]

Misinformation, lower degrees of trust, a sense of loss of control and despair over the increase in the number of cases and deaths led to an increase in the use of the drug and the emergence of a black market in Central and Eastern Europe, Latin America[111][112] and South Africa, raising concerns about self-medication, safety and feasibility of future clinical trials.[113]

Despite the absence of high-quality evidence to suggest any efficacy and advice to the contrary, some governments have allowed its off-label use for prevention and treatment of COVID-19. Countries that have granted such official approval for ivermectin include the Czech Republic,[113] Slovakia,[113] Mexico,[114] Peru (later rescinded),[115][116], India[117][118] (later rescinded),[119] the Philippines,[120] and the Colombian city of Cali.[121]

Tropical diseases

Ivermectin is being studied as a potential antiviral agent against chikungunya and yellow fever.[122]

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.[123][124] A direct effect on malaria parasites could not be shown in an experimental infection of volunteers with Plasmodium falciparum.[125] 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.[126] 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.[127]

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.[128][129]

Bedbugs: There is tentative evidence that ivermectin kills bedbugs, as part of integrated pest management for bedbug infestations.[130][131][132] Such use however may require a prolonged course of treatment which is of unclear safety.[133]

NAFLD

In 2013, this antiparasitic drug was demonstrated as a novel ligand of farnesoid X receptor (FXR),[134][135] a therapeutic target for nonalcoholic fatty liver disease.[136]

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.[137]

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.[138] 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.[139][140] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[141] A 0.01% ivermectin topical preparation for treating ear mites in cats is available.[142]

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.[143]

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.[144]

For dogs, the insecticide spinosad may have the effect of increasing the toxicity of ivermectin.[145]

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.[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]

References

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  2. ^ a b "Soolantra- ivermectin cream". DailyMed. Retrieved July 18, 2021.
  3. ^ "FDA Approves Lotion for Nonprescription Use to Treat Head Lice". U.S. Food and Drug Administration (FDA) (Press release). October 27, 2020. Retrieved October 27, 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  4. ^ https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202736Orig1s006lbl.pdf
  5. ^ "List of nationally authorised medicinal products", European Medicines Agency, 26 November 2020.
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  9. ^ a b Saunders Handbook of Veterinary Drugs: Small and Large Animal (4 ed.). Elsevier Health Sciences. 2015. p. 420. ISBN 978-0-323-24486-2. Archived from the original on January 31, 2016.
  10. ^ U.S. Centers for Disease Control and Prevention (CDC) (August 23, 2019). "Ascariasis - Resources for Health Professionals". U.S. Centers for Disease Control and Prevention (CDC). Retrieved December 28, 2019.
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  16. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
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  19. ^ Evershed N, McGowan M, Ball A. "Anatomy of a conspiracy theory: how misinformation travels on Facebook". The Guardian. Retrieved May 26, 2021.
  20. ^ "Fact-checking claim about the use of ivermectin to treat COVID-19". PolitiFact. District of Columbia 1100 Connecticut Ave NW Suite 1300B. Retrieved May 26, 2021.CS1 maint: location (link)
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