Ivermectin

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Ivermectin
Ivermectin skeletal.svg
Systematic (IUPAC) name
22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b
Clinical data
Trade names Stromectol
AHFS/Drugs.com monograph
MedlinePlus a607069
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral, topical
Pharmacokinetic data
Protein binding 93%
Metabolism Liver (CYP450)
Biological half-life 18 hours
Excretion Feces; <1% urine
Identifiers
CAS Number 70288-86-7 YesY Template:CAS
ATC code D11AX22 (WHO) P02CF01 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)
Chemical data
Formula C
48
H
74
O
14
(22,23-dihydroavermectin B1a)
C
47
H
72
O
14
(22,23-dihydroavermectin B1b)
Molecular mass 875.10 g/mol
 NYesY (what is this?)  (verify)

Ivermectin (22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b) is a broad-spectrum antiparasitic drug in the avermectin family. It is taken internally or used topically, depending on the treated condition.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[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.[2][3][4] The disease is endemic in 30 African countries, six Latin American countries, and Yemen, according to studies conducted by the World Health Organization.[5] 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.[6]

An Ivermectin cream called Soolantra has been approved by the FDA for treatment of rosacea.[7][8]

Arthropod

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

  • Lice:[12][13] Ivermectin lotion (0.5%) is FDA-approved for patients six months of age and older.[14] 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.[15] This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.[16]
  • Bed bugs:[17] Early research shows that the drug kills bed bugs when taken by humans at normal doses. The drug enters the human bloodstream and if the bedbugs bite during that time, they will die in a few days.

Contraindications

Ivermectin is contraindicated in children under the age of five, or those who weigh less than 15 kg (33 lb);[18] and those who are breastfeeding, and have a hepatic or renal disease.[19]

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.[20]

For dogs, the insecticide spinosad may have the effect of increasing the potency of ivermectin.[21]

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 and activates glutamate-gated chloride channels (GluCls).[22] 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,[23] (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.[24]

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.[25] Ivermectin was introduced in 1981.[26] 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".[27]

Brand names

It is sold under brand names Heartgard, Sklice[28] and Stromectol[29] in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[30] 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.[31]

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.[32][33] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[34] 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.

See also

Notes and references

  1. "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. The Carter Center. "River Blindness (Onchocerciasis) Program". Retrieved 2008-07-17.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>.
  3. The Carter Center. "Lymphatic Filariasis Elimination Program". Retrieved 2008-07-17.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>.
  4. WHO. "African Programme for Onchocerciasis Control". Retrieved 2009-11-12.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>.
  5. United Front Against Riverblindness. "Onchocerciasis or Riverblindness".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>.
  6. United Front Against Riverblindness. "Control of Riverblindness".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>.
  7. Galderma Receives FDA Approval of Soolantra (Ivermectin) Cream for Rosacea"
  8. "SOOLANTRA- ivermectin cream (NDC Code(s): 0299-3823-30, 0299-3823-45, 0299-3823-60)". DailyMed. December 2014. Retrieved 2015-09-09.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  10. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  11. 11.0 11.1 Strong M, Johnstone PW (2007). Strong, Mark (ed.). "Interventions for treating scabies". Cochrane Database of Systematic Reviews (Online) (3): CD000320. doi:10.1002/14651858.CD000320.pub2. PMID 17636630.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  12. 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.CS1 maint: multiple names: authors list (link)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  13. 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.CS1 maint: multiple names: authors list (link)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  14. "Sklice lotion".
  15. 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.CS1 maint: multiple names: authors list (link)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  16. Study shows ivermectin ending lice problem in one treatment, Los Angeles Times, Nov 5, 2012<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  17. DONALD G. MCNEIL JR. (2012-12-31). "Pill Could Join Arsenal Against Bedbugs". The New York Times. Retrieved 2013-04-05.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  18. 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.CS1 maint: multiple names: authors list (link)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  19. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  20. Goodman and Gilman's Pharmacological Basis of Therapeutics, 11th edition, pages 122, 1084-1087.
  21. "COMFORTIS® and ivermectin interaction Safety Warning Notification". U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM).<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  22. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  23. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  24. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  25. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  26. W. C. CAMPBELL (June 26, 1984). "The Discovery of Ivermectin and Other Avermectins". American Chemical Society. pp. 5–20. ISBN 9780841210837. Unknown parameter |coauthors= ignored (help); |chapter= ignored (help)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  27. "The Nobel Prize in Physiology or Medicine 2015" (PDF). Nobel Foundation. Retrieved 7 October 2015.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  28. "SKLICE- ivermectin lotion (NDC Code(s): 49281-183-71)". DailyMed. February 2012. Retrieved 2015-09-09.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  29. "STROMECTOL- ivermectin tablet (NDC Code(s): 0006-0032-20)". DailyMed. May 2010. Retrieved 2015-09-09.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  30. Adhikari, Santosh (2014-05-27). "ALIVE PHARMACEUTICAL (P) LTD.: Iver-DT". ALIVE PHARMACEUTICAL (P) LTD. Retrieved 2015-10-07.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  31. 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.CS1 maint: multiple names: authors list (link)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  32. "MDR1 FAQs", Australian Shepherd Health & Genetics Institute, Inc.
  33. "Multidrug Sensitivity in Dogs", Washington State University's College of Veterinary Medicine
  34. Frischke H, Hunt L (April 1991). "Suspected ivermectin toxicity". Canadian Veterinary Journal. 32 (4): 245. PMC 1481314. PMID 17423775.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

External links