Ivermectin

Ivermectin
Systematic (IUPAC) name
22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b
Clinical data
Trade names Stromectol, Soolantra cream
AHFS/Drugs.com monograph (antiparasitic)
FDA Professional Drug Information (rosacea)
MedlinePlus a607069
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral, topical
Legal status
Legal status
Pharmacokinetic data
Protein binding 93%
Metabolism Liver (CYP450)
Biological half-life 18 hours
Excretion Feces; <1% urine
Identifiers
CAS Number 70288-86-7 YesY 71827-03-7
ATC code D11AX22 (WHO) P02CF01 (WHO) QP54AA01 (WHO) QS02QA03 (WHO)
PubChem CID 9812710
DrugBank DB00602 YesY
ChemSpider 7988461 YesY
UNII 8883YP2R6D YesY
KEGG D00804 YesY
ChEMBL CHEMBL341047 N
PDB ligand ID IVM (PDBe, RCSB PDB)
 NYesY (what is this?)  (verify)

Definition and medical uses

Ivermectin is a medication that is effective against many types of parasites.[1] It is used to treat head lice,[2] scabies,[3] river blindness,[4] strongyloidiasis,[5] and lymphatic filariasis, among others.[6] It can be either applied to the skin or taken by mouth. The eyes should be avoided.[2]

Side effects and mechanism

Common side effects include red eyes, dry skin, and burning skin.[2] It is unclear if it is safe for use during pregnancy but is likely okay during breastfeeding.[7] It is in the avermectin family of medications, which work by causing the membrane of invertebrate nerve and muscle cells to become more permeable to chloride ions, resulting in paralysis and death.[2]

Society and culture

Ivermectin was discovered in 1975 and came into medical use in 1981.[6][8] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[9] The wholesale cost is about US$0.12 for a course of treatment.[10] In the United States it costs $25–50.[5] In other animals it is used to prevent and treat heartworm among other diseases.[1]

Medical uses

Ivermectin is a broad-spectrum antiparasitic agent, traditionally against parasitic worms. It is mainly used in humans in the treatment of onchocerciasis (river blindness), but is also effective against other worm infestations (such as strongyloidiasis, ascariasis, trichuriasis, filariasis and enterobiasis), and some epidermal parasitic skin diseases, including scabies.

Ivermectin is currently being used to help eliminate river blindness (onchocerciasis) in the Americas, and to stop transmission of lymphatic filariasis and onchocerciasis around the world in programs sponsored by the Carter Center using ivermectin donated by Merck.[11][12][13] The disease is common in 30 African countries, six Latin American countries, and Yemen.[14] The drug rapidly kills microfilariae, but not the adult worms. A single oral dose of ivermectin, taken annually for the 10- to 15-year lifespan of the adult worms, is all that is needed to protect the individual from onchocerciasis.[15]

Arthropod

More recent evidence supports its use against parasitic arthropods and insects:

Rosacea

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.[25][26][27]

Contraindications

Ivermectin is contraindicated in children under the age of five, or those who weigh less than 15 kg (33 lb);[28] and those who are breastfeeding, and have a hepatic or renal disease.[29]

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.

Dogs with defects in the P-glycoprotein gene (MDR1), often collie-like herding dogs, can be severely poisoned by ivermectin.

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, and glucocorticoids such as dexamethasone, lidocaine, and the benzodiazepines.[30]

For dogs, the insecticide spinosad may have the effect of increasing the potency of ivermectin.[31]

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.[2][32] 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 either by mouth or injection. It does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein,[33] (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 hr 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.[34]

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.[35] Ivermectin was introduced in 1981.[36] 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".[37]

Brand names

It is sold under brand names Heartgard, Sklice[38] and Stromectol[39] in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[40] 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. While in development, it was assigned the code MK-933 by Merck.[41]

Veterinary use

In veterinary medicine ivermectin is used against many intestinal worms (but not tapeworms), most mites, and some lice. Despite this, it is not effective for eliminating ticks, flies, flukes, or fleas. It is effective against larval heartworms, but not against adult heartworms, though it may shorten their lives. The dose of the medicine must be very accurately measured as it is very toxic in over-dosage. It is sometimes administered in combination with other medications to treat a broad spectrum of animal parasites. 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.[42][43] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[44] A 0.01% ivermectin topical preparation for treating ear mites in cats (Acarexx) is available.

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.

Research

Ivermectin is also being studied as a potential antiviral agent against the viruses chikungunya and yellow fever.[45]

See also

Notes and references

  1. 1 2 Saunders Handbook of Veterinary Drugs: Small and Large Animal (4 ed.). Elsevier Health Sciences. 2015. p. 420. ISBN 9780323244862.
  2. 1 2 3 4 5 "Ivermectin". The American Society of Health-System Pharmacists. Retrieved Jan 2016.
  3. ↑ 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.
  4. ↑ Sneader, Walter (2005). Drug Discovery a History. Chichester: John Wiley & Sons. p. 333. ISBN 9780470015520.
  5. 1 2 Hamilton, Richard J. (2014). Tarascon pocket pharmacopoeia : 2014 deluxe lab-pocket edition (15th ed.). Sudbury: Jones & Bartlett Learning. p. 422. ISBN 9781284053999.
  6. 1 2 Mehlhorn, Heinz (2008). Encyclopedia of parasitology (3rd ed.). Berlin: Springer. p. 646. ISBN 9783540489948.
  7. ↑ "Ivermectin Levels and Effects while Breastfeeding". Retrieved 16 January 2016.
  8. ↑ Vercruysse, edited by J.; Rew, R.S. (2002). Macrocyclic lactones in antiparasitic therapy. Oxon, UK: CABI Pub. p. Preface. ISBN 9780851998404.
  9. ↑ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  10. ↑ "Ivermectin". International Drug Price Indicator Guide. Retrieved 16 January 2016.
  11. ↑ The Carter Center. "River Blindness (Onchocerciasis) Program". Retrieved 2008-07-17..
  12. ↑ The Carter Center. "Lymphatic Filariasis Elimination Program". Retrieved 2008-07-17..
  13. ↑ WHO. "African Programme for Onchocerciasis Control". Retrieved 2009-11-12..
  14. ↑ United Front Against Riverblindness. "Onchocerciasis or Riverblindness"..
  15. ↑ United Front Against Riverblindness. "Control of Riverblindness"..
  16. ↑ Brooks PA, Grace RF (August 2002). "Ivermectin is better than benzyl benzoate for childhood scabies in developing countries". J Paediatr Child Health 38 (4): 401–4. doi:10.1046/j.1440-1754.2002.00015.x. PMID 12174005.
  17. ↑ Victoria J, Trujillo R (2001). "Topical ivermectin: a new successful treatment for scabies". Pediatr Dermatol 18 (1): 63–5. doi:10.1046/j.1525-1470.2001.018001063.x. PMID 11207977.
  18. 1 2 Strong M, Johnstone PW (2007). Strong, Mark, ed. "Interventions for treating scabies". Cochrane Database of Systematic Reviews (3): CD000320. doi:10.1002/14651858.CD000320.pub2. PMID 17636630.
  19. ↑ 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.
  20. ↑ 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. ISSN 0022-2585. PMID 18283945.
  21. ↑ "Sklice lotion".
  22. ↑ David M. Pariser, M.D., Terri Lynn Meinking, Ph.D., Margie Bell, M.S., and William G. Ryan, B.V.Sc. (November 1, 2012). "Topical 0.5% Ivermectin Lotion for Treatment of Head Lice". New England Journal of Medicine 367: 1687–1693. doi:10.1056/NEJMoa1200107.
  23. ↑ Study shows ivermectin ending lice problem in one treatment, Los Angeles Times, Nov 5, 2012
  24. ↑ DONALD G. MCNEIL JR. (2012-12-31). "Pill Could Join Arsenal Against Bedbugs". The New York Times. Retrieved 2013-04-05.
  25. ↑ Galderma Receives FDA Approval of Soolantra (Ivermectin) Cream for Rosacea"
  26. ↑ "SOOLANTRA- ivermectin cream (NDC Code(s): 0299-3823-30, 0299-3823-45, 0299-3823-60)". DailyMed. December 2014. Retrieved 2015-09-09.
  27. ↑ "Galderma Announces Positive Outcome of European Decentralised Procedure for Approval of Soolantra (ivermectin) Cream 10mg/g for Rosacea Patients". Galderma. 27 March 2015.
  28. ↑ Dourmishev AL, Dourmishev LA, Schwartz RA (December 2005). "Ivermectin: pharmacology and application in dermatology". International Journal of Dermatology 44 (12): 981–988. doi:10.1111/j.1365-4632.2004.02253.x. PMID 16409259.
  29. ↑ Huukelbach J, Winter B, Wilcke T, et al. (August 2004). "Tratmient masivo selectivo con ivermectina contra las helmintiasis intestinales y parasitos cutáneas en una población gravemente afectada". Bull World Health Organ 82 (7): 563–571. doi:10.1590/S0042-96862004000800005.
  30. ↑ Goodman and Gilman's Pharmacological Basis of Therapeutics, 11th edition, pages 122, 1084-1087.
  31. ↑ "COMFORTIS® and ivermectin interaction Safety Warning Notification". U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM).
  32. ↑ Yates DM, Wolstenholme AJ (August 2004). "An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis". Int. J. Parasitol. 34 (9): 1075–81. doi:10.1016/j.ijpara.2004.04.010. PMID 15313134.
  33. ↑ Borst P, Schinkel AH (June 1996). "What have we learnt thus far from mice with disrupted P-glycoprotein genes?". European Journal of Cancer 32 (6): 985–990. doi:10.1016/0959-8049(96)00063-9.
  34. ↑ Iglesias LE, Saumell CA, Fernández AS, et al. (December 2006). "Environmental impact of ivermectin excreted by cattle treated in autumn on dung fauna and degradation of faeces on pasture". Parasitology Research 100 (1): 93–102. doi:10.1007/s00436-006-0240-x. PMID 16821034.
  35. ↑ Fisher MH, Mrozik H (1992). "The chemistry and pharmacology of avermectins". Annu. Rev. Pharmacol. Toxicol. 32: 537–53. doi:10.1146/annurev.pa.32.040192.002541. PMID 1605577.
  36. ↑ W. C. CAMPBELL; R. W. BURG, , M. H. FISHER, and , R. A. DYBAS (June 26, 1984). "The Discovery of Ivermectin and Other Avermectins". American Chemical Society. pp. 5–20. ISBN 9780841210837. Cite uses deprecated parameter |coauthors= (help); |chapter= ignored (help)
  37. ↑ "The Nobel Prize in Physiology or Medicine 2015" (PDF). Nobel Foundation. Retrieved 7 October 2015.
  38. ↑ "SKLICE- ivermectin lotion (NDC Code(s): 49281-183-71)". DailyMed. February 2012. Retrieved 2015-09-09.
  39. ↑ "STROMECTOL- ivermectin tablet (NDC Code(s): 0006-0032-20)". DailyMed. May 2010. Retrieved 2015-09-09.
  40. ↑ Adhikari, Santosh (2014-05-27). "ALIVE PHARMACEUTICAL (P) LTD.: Iver-DT". ALIVE PHARMACEUTICAL (P) LTD. Retrieved 2015-10-07.
  41. ↑ Pampiglione S, Majori G, Petrangeli G, Romi R (1985). "Avermectins, MK-933 and MK-936, for mosquito control". Trans R Soc Trop Med Hyg 79 (6): 797–9. doi:10.1016/0035-9203(85)90121-X. PMID 3832491.
  42. ↑ "MDR1 FAQs", Australian Shepherd Health & Genetics Institute, Inc.
  43. ↑ "Multidrug Sensitivity in Dogs", Washington State University's College of Veterinary Medicine
  44. ↑ Frischke H, Hunt L (April 1991). "Suspected ivermectin toxicity". Canadian Veterinary Journal 32 (4): 245. PMC 1481314. PMID 17423775.
  45. ↑ Varghese FS; et al. (Feb 2016). "Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses". Antiviral Res 126: 117–24. doi:10.1016/j.antiviral.2015.12.012. PMID 26752081.

External links

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