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Ivermectin

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Ivermectin
Clinical data
Trade namesStromectol, Soolantra cream
AHFS/Drugs.comMonograph (antiparasitic)
FDA Professional Drug Information (rosacea)
MedlinePlusa607069
Pregnancy
category
  • AU: B3
Routes of
administration		by mouth, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
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
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 mass875.10 g/mol
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
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Ivermectin is a medication used to treat many types of parasite infestations.[1] This includes head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, and lymphatic filariasis.[1][2][3] It can be taken by mouth or applied to the skin for external infestations.[1][4] Use in the eyes should be avoided.[1]

Common side effects include red eyes, dry skin, and burning skin.[1] It is unclear if it is safe for use during pregnancy, but is likely acceptable for use during breastfeeding.[5] It belongs to the avermectin family of medications.[1] It works by causing the parasite's cell membrane to increase in permeability, resulting in paralysis and death.[1]

Ivermectin was discovered in 1975 and came into medical use in 1981.[6][7] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[8] The wholesale cost in the developing world is about US$0.12 for a course of treatment.[9] In the United States it costs $25–50 for a 50ml bottle suitable for about 25 doses.[10][11] In other animals it is used to prevent and treat heartworm among other diseases.[3]

Medical uses

Nematode

Pinworm

Ivermectin is as effective as albendazole or alternative antinematode drugs for treatment of pinworm infection (enterobiasis).[12]

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.[13]

A single dose of ivermectin reduces microfilaridermia by 98–99% after 1–2 months.[14] 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.[15]

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.[16][17]

Loa loa filariasis

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.[18]

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.[19] 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 so as to cure presumptive infection with threadworm.[20] Persons who are immunocompromised or who will receive immunosuppresive treatment and who have confirmed or presumptive threadworm infestation are likely to benefit from treatment with ivermectin.[21]

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.[22]

Lymphatic filariasis

Combination therapy with ivermectin plus albendazole is effective for treatment of Lymphatic filariasis due to Wuchereria bancrofti,[23] Brugia malayi, or Brugia timori.[24]

Arthropod

Evidence supports its use against parasitic arthropods and insects:

  • Mites such as scabies:[25][26][27] 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).[27] One review found that the efficacy of permethrin is similar to that of systemic or topical ivermectin.[28] 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 permithrin.[29] Another review found that oral ivermectin provided a reasonable balance between efficacy and safety.[30] Since ivermectin is more convenient than permethrin,[31] many have turned to veterinary sources of the drug to obtain assurance of a cure at an affordable price.[32]
  • Lice:[33][34] Ivermectin lotion (0.5%) is FDA-approved for patients six months of age and older.[35] 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.[36] This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.[37]
  • Bedbugs: There is tentative evidence that ivermectin kills bedbugs, as part of integrated pest management for bedbug infestations.[38][39][40] Such use however may required a prolonged course of treatment which is of unclear safety.[41]
  • 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.[42]

Rosacea

A review found that ivermectin was effective for treatment of rosacea.[43] 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. In a clinical study, ivermectin reduced lesions by 83% over 4 months, as compared to 74% under a metronidazole standard therapy.[44][45]

Contraindications

Ivermectin is contraindicated in children under the age of five, or those who weigh less than 15 kilograms (33 pounds)[33] and those who are breastfeeding, and have a liver or kidney disease.[46]

Adverse 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.

Dogs with defects in the P-glycoprotein gene (MDR1), often collie-like herding dogs, can be severely poisoned by ivermectin, leading to the adage, "white feet, don't treat", in reference to Scotch collies that are vulnerable to ivermectin.[47]

Since drugs that inhibit CYP3A4 enzymes 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.[48]

For dogs, the insecticide spinosad may have the effect of increasing the potency of ivermectin.[49]

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.[1][50] 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,[51] (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.[52]

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. 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.[53] Ivermectin was introduced in 1981.[54] 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".[55]

Brand names

Ivermectin is available as a generic prescription drug in the U.S. in a 3 mg tablet formulation.[56] It is also sold under the brand names Heartgard, Sklice[57] and Stromectol[58] in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[59] 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.[60]

Veterinary use

Some dog breeds (especially the Rough Collie, the Smooth Collie, the Shetland Sheepdog, and the Australian Shepherd), though, have a high incidence of a certain mutation within the MDR1 gene (coding for P-glycoprotein); affected animals are particularly sensitive to the toxic effects of ivermectin.[61][62] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[63] A 0.01% ivermectin topical preparation for treating ear mites in cats (Acarexx) is available.[64]

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.[65]

Research

Ivermectin is also being studied as a potential antiviral agent against the viruses chikungunya and yellow fever.[66]

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 onchocerciasis.[67]

In 2013, this antiparasitic drug was demonstrated as a novel ligand of farnesoid X receptor (FXR),[68][69] a therapeutic target for Nonalcoholic Fatty Liver Disease.[70]

See also

Notes and references

  1. ^ a b c d e f g h "Ivermectin". The American Society of Health-System Pharmacists. Archived from the original on January 3, 2016. Retrieved January 16, 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  2. ^ Sneader, Walter (2005). Drug Discovery a History. Chichester: John Wiley & Sons. p. 333. ISBN 978-0-470-01552-0.
  3. ^ 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. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  4. ^ Panahi Y, Poursaleh Z, Goldust M (2015). "The efficacy of topical and oral ivermectin in the treatment of human scabies". Annals of Parasitology. 61 (1): 11–6. PMID 25911032.
  5. ^ "Ivermectin Levels and Effects while Breastfeeding". Archived from the original on January 1, 2016. Retrieved January 16, 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  6. ^ Mehlhorn, Heinz (2008). Encyclopedia of parasitology (3rd ed.). Berlin: Springer. p. 646. ISBN 978-3-540-48994-8. Archived from the original on January 31, 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  7. ^ Vercruysse J, Rew RS, eds. (2002). Macrocyclic lactones in antiparasitic therapy. Oxon, UK: CABI Pub. p. Preface. ISBN 978-0-85199-840-4. Archived from the original on January 31, 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  8. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived from the original (PDF) on December 13, 2016. Retrieved December 8, 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  9. ^ "Ivermectin". International Drug Price Indicator Guide. Retrieved January 16, 2016.
  10. ^ "Amazon.com: Ivomec Injection 1% 50ml Btl".
  11. ^ Hamilton, Richard J. (2014). Tarascon pocket pharmacopoeia : 2014 deluxe lab-pocket edition (15th ed.). Sudbury: Jones & Bartlett Learning. p. 422. ISBN 978-1-284-05399-9. Archived from the original on January 31, 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  12. ^ Ottesen EA, Campbell WC (August 1994). "Ivermectin in human medicine". The Journal of Antimicrobial Chemotherapy. 34 (2): 195–203. PMID 7814280.
  13. ^ Keating J, Yukich JO, Mollenkopf S, Tediosi F (July 2014). "Lymphatic filariasis and onchocerciasis prevention, treatment, and control costs across diverse settings: a systematic review". Acta Tropica. 135: 86–95. doi:10.1016/j.actatropica.2014.03.017. PMID 24699086.
  14. ^ Basáñez MG, Pion SD, Boakes E, Filipe JA, Churcher TS, Boussinesq M (May 2008). "Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis". The Lancet. Infectious Diseases. 8 (5): 310–22. doi:10.1016/S1473-3099(08)70099-9. PMID 18471776.
  15. ^ United Front Against Riverblindness. "Control of Riverblindness". Archived from the original on August 27, 2007. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  16. ^ Maheu-Giroux M, Joseph SA (August 2018). "Moxidectin for deworming: from trials to implementation". The Lancet. Infectious Diseases. 18 (8): 817–819. doi:10.1016/S1473-3099(18)30270-6. PMID 29858152.
  17. ^ Boussinesq M (October 2018). "A new powerful drug to combat river blindness". Lancet. 392 (10154): 1170–1172. doi:10.1016/S0140-6736(18)30101-6. PMID 29361336.
  18. ^ Pion, Sébastien D; Tchatchueng-Mbougua, Jules Brice; Chesnais, Cédric B; Kamgno, Joseph; Gardon, Jacques; Chippaux, Jean-Philippe; Ranque, Stéphane; Ernould, Jean-Christophe; Garcia, André; Boussinesq, Michel (January 11, 2019). "Effect of a single standard dose (150–200 μg/kg) of ivermectin on microfilaremia: systematic review and meta-analysis". Open Forum Infectious Diseases. doi:10.1093/ofid/ofz019.
  19. ^ Henriquez-Camacho C, Gotuzzo E, Echevarria J, White AC, Terashima A, Samalvides F, Pérez-Molina JA, Plana MN (January 2016). "Ivermectin versus albendazole or thiabendazole for Strongyloides stercoralis infection". The Cochrane Database of Systematic Reviews (1): CD007745. doi:10.1002/14651858.CD007745.pub3. PMC 4916931. PMID 26778150.
  20. ^ Agbata EN, Morton RL, Bisoffi Z, Bottieau E, Greenaway C, Biggs BA, Montero N, Tran A, Rowbotham N, Arevalo-Rodriguez I, Myran DT, Noori T, Alonso-Coello P, Pottie K, Requena-Méndez A (December 2018). "Effectiveness of Screening and Treatment Approaches for Schistosomiasis and Strongyloidiasis in Newly-Arrived Migrants from Endemic Countries in the EU/EEA: A Systematic Review". Int J Environ Res Public Health. 16 (1). doi:10.3390/ijerph16010011. PMID 30577567.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Kotton, Camille; Mileno, Maria; Keystone, J. (2019). "The Immunocompromised Traveler". Travel medicine. Edinburgh: Elsevier. pp. 269–277. ISBN 978-0-323-54696-6.
  22. ^ Palmeirim MS, Hürlimann E, Knopp S, Speich B, Belizario V, Joseph SA, Vaillant M, Olliaro P, Keiser J (April 2018). "Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-transmitted helminths: A systematic review, meta-analysis and individual patient data analysis". PLoS Neglected Tropical Diseases. 12 (4): e0006458. doi:10.1371/journal.pntd.0006458. PMC 5942849. PMID 29702653.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ de Kraker ME, Stolk WA, van Oortmarssen GJ, Habbema JD (May 2006). "Model-based analysis of trial data: microfilaria and worm-productivity loss after diethylcarbamazine-albendazole or ivermectin-albendazole combination therapy against Wuchereria bancrofti". Tropical Medicine & International Health. 11 (5): 718–28. doi:10.1111/j.1365-3156.2006.01606.x. PMID 16640625.
  24. ^ Taylor MJ, Hoerauf A, Bockarie M (October 2010). "Lymphatic filariasis and onchocerciasis". Lancet. 376 (9747): 1175–85. doi:10.1016/S0140-6736(10)60586-7. PMID 20739055.
  25. ^ Brooks PA, Grace RF (August 2002). "Ivermectin is better than benzyl benzoate for childhood scabies in developing countries". Journal of Paediatrics and Child Health. 38 (4): 401–4. doi:10.1046/j.1440-1754.2002.00015.x. PMID 12174005.
  26. ^ Victoria J, Trujillo R (2001). "Topical ivermectin: a new successful treatment for scabies". Pediatric Dermatology. 18 (1): 63–5. doi:10.1046/j.1525-1470.2001.018001063.x. PMID 11207977.
  27. ^ a b Strong M, Johnstone P (July 2007). Strong M (ed.). "Interventions for treating scabies". The Cochrane Database of Systematic Reviews (3): CD000320. doi:10.1002/14651858.CD000320.pub2. PMID 17636630.
  28. ^ Rosumeck S, Nast A, Dressler C (April 2018). "Ivermectin and permethrin for treating scabies". Cochrane Database Syst Rev. 4: CD012994. doi:10.1002/14651858.CD012994. PMID 29608022.
  29. ^ Dhana A, Yen H, Okhovat JP, Cho E, Keum N, Khumalo NP (January 2018). "Ivermectin versus permethrin in the treatment of scabies: A systematic review and meta-analysis of randomized controlled trials". Journal of the American Academy of Dermatology. 78 (1): 194–198. doi:10.1016/j.jaad.2017.09.006. PMID 29241784.
  30. ^ 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. doi:10.1016/j.jaad.2019.01.004. PMID 30654070.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ Crump A, Ōmura S (February 10, 2011). "Ivermectin, 'wonder drug' from Japan: the human use perspective". Proceedings of the Japan Academy. Series B, Physical and Biological Sciences. 87 (2): 13–28. doi:10.2183/pjab.87.13. PMC 3043740. PMID 21321478.
  32. ^ Laing R, Gillan V, Devaney E (June 2017). "Ivermectin - Old Drug, New Tricks?". Trends in Parasitology. 33 (6): 463–472. doi:10.1016/j.pt.2017.02.004. PMC 3043740. PMID 28285851.
  33. ^ a b 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.
  34. ^ 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.
  35. ^ "Sklice lotion". Archived from the original on May 12, 2012.
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  37. ^ Study shows ivermectin ending lice problem in one treatment, Los Angeles Times, November 5, 2012
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  40. ^ James, William D.; Elston, Dirk; Berger, Timothy; Neuhaus, Isaac (2015). Andrews' Diseases of the Skin: Clinical Dermatology. Elsevier Health Sciences. p. 439. ISBN 9780323319690. Ivermectin treatment is emerging as a potential ancillary measure.
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  44. ^ Galderma Receives FDA Approval of Soolantra (Ivermectin) Cream for Rosacea Archived January 22, 2015, at the Wayback Machine"
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