Ivermectin

Ivermectin
Names
Trade namesStromectol, Soolantra cream
IUPAC name
  • 22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b
Clinical data
Main usesScabies, river blindness[1]
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth, topical
    Defined daily dose12 mg[2]
    External links
    AHFS/Drugs.comSystemic: Monograph
    Topical: Monograph
    MedlinePlusa607069
    Legal
    License data
    Legal status
    Pharmacokinetics
    Protein binding93%
    MetabolismLiver (CYP450)
    Elimination half-life18 hours
    ExcretionFeces; <1% urine
    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)
      SMILES
      • 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
      • 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

      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] Use in the eyes should be avoided.[3]

      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 by causing the parasite's cell membrane to increase in permeability, resulting in paralysis and death.[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] The wholesale cost in the developing world for the tablets is about US$0.12 for a course of treatment.[12] In the United States, the costs is less than US$50 and is available over the counter.[13][14] In other animals, it is used to prevent and treat heartworm and acariasis, among other indications.[5]

      Medical uses

      Pinworms

      Ivermectin is as effective as albendazole or alternative antinematode drugs for treatment of pinworm infection (enterobiasis).[15]

      River blindness

      Ivermectin is used for prevention, treatment, and control of river blindness (onchocerciasis) in populations where the disease is common. However, ivermectin is contraindicated in persons with a high burden of loiasis (e.g., >20,000 Loa loa microfilariae per mL), due to risk of ivermectin-associated severe inflammatory events.[16]

      A single dose of ivermectin reduces microfilaridermia by 98–99% after 1–2 months.[17] Ivermectin does not kill adult worms. A single oral dose of ivermectin, taken once or twice a year for the 10–15-year lifespan of the adult worms, is required to protect the individual from river blindness.[18]

      A 2012 Cochrane review found weak evidence suggesting that ivermectin could result in the reduction of chorioretinal lesions and prevent loss of vision in people with river blindness.[19] 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.[20][21]

      Loa loa

      Massive orbital myiasis, healing of lids after ivermectin.[22]

      A single dose of ivermectin gives a rapid and durable decrease in body burden of eyeworm (Loa loa). The risk of ivermectin-associated severe adverse drug events is very low in persons with less than 20,000 microfilariae per mL of blood.[23]

      Threadworm

      Ivermectin is more effective than albendazole and equally as effective as thiabendazole for treatment of threadworm (enterobiasis). Ivermectin has fewer adverse effects than does thiabendazole and is at least as well tolerated as albendazole.[24] 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.[25] 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.[26]

      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.[27]

      Lymphatic filariasis

      Combination therapy with ivermectin plus albendazole is effective for treatment of Lymphatic filariasis due to Wuchereria bancrofti,[28] Brugia malayi, or Brugia timori.[29]

      Arthropod

      Evidence supports its use against parasitic arthropods and insects:

      • Mites such as scabies:[30][31][32] 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).[32] One review found that the efficacy of permethrin is similar to that of systemic or topical ivermectin.[33] 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.[34] Another review found that oral ivermectin provided a reasonable balance between efficacy and safety.[35] Since ivermectin is more convenient than permethrin,[36] many have turned to veterinary sources of the drug to obtain assurance of a cure at an affordable price.[37]
      • Lice:[38][39] Ivermectin lotion (0.5%) is FDA-approved for patients six months of age and older.[40] 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.[41] This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.[42]
      • Bedbugs: There is tentative evidence that ivermectin kills bedbugs, as part of integrated pest management for bedbug infestations.[43][44][45] Such use however may require a prolonged course of treatment which is of unclear safety.[46]
      • 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.[47]

      Rosacea

      A review found that ivermectin was effective for treatment of rosacea.[48] 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.[49] In a clinical study, ivermectin reduced lesions by 83% over 4 months, as compared to 74% under a metronidazole standard therapy.[50]

      Dosage

      The defined daily dose is 12 mg by mouth.[2] For scabies in those who weight over 15 kg a single dose of 0.2 mg/kg is recommended with the potential to repeat this dose after one week.[1] For river blindness in those over 15 kg 0.15 mg/kg is recommended with a second dose in three months if symptoms remain.[1] Further doses may be given at 6 to 12 month intervals.[1] It is not recommended in those who weight less than 15 kg.[1]

      Side effects

      The main concern is neurotoxicity, which in most mammalian species may manifest as central nervous system depression, and consequent ataxia, as might be expected from potentiation of inhibitory GABA-ergic synapses.

      Since drugs that inhibit the enzyme CYP3A4 often also inhibit P-glycoprotein transport, the risk of increased absorption past the blood-brain barrier exists when ivermectin is administered along with other CYP3A4 inhibitors. These drugs include statins, HIV protease inhibitors, many calcium channel blockers, lidocaine, the benzodiazepines, and glucocorticoids such as dexamethasone.[51]

      Ivermectin is contraindicated in children under the age of five or those who weigh less than 15 kilograms (33 pounds),[38] and individuals with liver or kidney disease.[52]

      Pregnancy and breastfeeding

      Ivermectin is secreted in very low concentration in breast milk.[53] It may be used in pregnancy.[1]

      It remains unclear if ivermectin is safe during pregnancy and thus such use is not recommended.[54][1]

      Pharmacology

      Pharmacodynamics

      Ivermectin and other avermectins (insecticides most frequently used in home-use ant baits) are macrocyclic lactones derived from the bacterium Streptomyces avermitilis. Ivermectin kills by interfering with nervous system and muscle function, in particular by enhancing inhibitory neurotransmission.

      The drug binds to glutamate-gated chloride channels (GluCls) in the membranes of invertebrate nerve and muscle cells, causing increased permeability to chloride ions, resulting in cellular hyper-polarization, followed by paralysis and death.[3][55] GluCls are invertebrate-specific members of the Cys-loop family of ligand-gated ion channels present in neurons and myocytes.

      Pharmacokinetics

      Ivermectin can be given by mouth, topically, or via injection. It does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein,[56] (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.[57]

      History

      The discovery of the avermectin family of compounds, from which ivermectin is chemically derived, was made by Satoshi Ōmura of Kitasato University, Tokyo and William C. Campbell of the Merck Institute for Therapeutic research. Ōmura identified avermectin from the bacterium Streptomyces avermitilis.[58] Campbell purified avermectin from cultures obtained from Ōmura and led efforts leading to the discovery of ivermectin, a derivative of greater potency and lower toxicity.[59] Ivermectin was introduced in 1981.[60] 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".[61]

      Society and culture

      Cost

      The initial price, proposed by Merck in 1987, was US$6.[62] The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries.[62] Between 1995 and 2010 the program using donated ivermectin to prevent river blindness is estimated to have prevented 7 million years of disability well costing US$257 million.[63]

      As of 2019, the cost effectiveness of treating scabies and lice with ivermectin has not been studied.[64][65]

      As of 2019 ivermectin tablets in the United States were the least expensive treatment option for lice in children at about US$10.[66] The hair lotion, however, costs about US$300 for a course of treatment.[66]

      • Ivermectin costs (US)
        Ivermectin costs (US)
      • Ivermectin prescriptions (US)
        Ivermectin prescriptions (US)

      Brand names

      Ivermectin is available as a generic prescription drug in the U.S. in a 3 mg tablet formulation.[67] It is also sold under the brand names Heartgard, Sklice[68] and Stromectol[69] in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[70] 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.[71]

      Veterinary use

      Ivermectin is routinely used to control parasitic worms in the gastrointestinal tract of ruminant animals. These parasites normally enter the animal when it is grazing, pass the bowel and set and mature in the intestines, after which they produce eggs which leave the animal via its droppings and can infest new pastures. Ivermectin is effective in killing some, but not all, of these parasites.

      In dogs it is routinely used as prophylaxis against heartworm.[72]

      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.[73] 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.[74][75] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[76] A 0.01% ivermectin topical preparation for treating ear mites in cats is available.[77]

      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.[78] For dogs, the insecticide spinosad may have the effect of increasing the toxicity of ivermectin.[79]

      Research

      Ivermectin is being studied as a potential antiviral agent against chikungunya and yellow fever.[80]

      In 2013, this antiparasitic drug was demonstrated as a novel ligand of farnesoid X receptor (FXR),[81][82] a therapeutic target for Nonalcoholic Fatty Liver Disease.[83]

      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.[84][85]

      COVID19

      As of July 2021 it is unclear if ivermectin is effective or safe to treat or prevent COVID19.[86]

      Ivermectin inhibits replication of SARS-CoV-2 in monkey kidney cell culture with an IC50 of 2.2 - 2.8 µM, making it a possible candidate for COVID-19 drug repurposing research.[87][88] The doses used in cell culture would require 104 larger doses in humans based on this data, which does not look promising as an effective treatment for COVID-19.[89][90] 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,[90] specifically the inhibition of nuclear transport by importin α/β1.[91]

      On 10 April 2020, the FDA issued guidance to not use ivermectin intended for animals as treatment for COVID-19 in humans.[92]

      See also

      References

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      2. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on October 31, 2020. Retrieved August 31, 2020.
      3. 1 2 3 4 5 6 7 8 "Ivermectin". The American Society of Health-System Pharmacists. Archived from the original on January 3, 2016. Retrieved January 16, 2016.
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      5. 1 2 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.
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      35. ↑ Thadanipon K, Anothaisintawee T, Rattanasiri S, Thakkinstian A, Attia J (2019). "Efficacy and safety of antiscabietic agents: A systematic review and network meta-analysis of randomized controlled trials". J Am Acad Dermatol. 80 (5): 1435–1444. doi:10.1016/j.jaad.2019.01.004. PMID 30654070. open access
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      38. 1 2 Dourmishev AL, Dourmishev LA, Schwartz RA (December 2005). "Ivermectin: pharmacology and application in dermatology". International Journal of Dermatology. 44 (12): 981–8. doi:10.1111/j.1365-4632.2004.02253.x. PMID 16409259. Archived from the original on August 29, 2021. Retrieved April 6, 2020.
      39. ↑ Strycharz JP, Yoon KS, Clark JM (January 2008). "A new ivermectin formulation topically kills permethrin-resistant human head lice (Anoplura: Pediculidae)". Journal of Medical Entomology. 45 (1): 75–81. doi:10.1603/0022-2585(2008)45[75:ANIFTK]2.0.CO;2. PMID 18283945.
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