Ivermectin

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Ivermectin
Systematic (IUPAC) name
22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b
Clinical data
Trade names Stromectol
AHFS/Drugs.com monograph
MedlinePlus a607069
Pregnancy cat. B3 (AU) C (US)
Legal status ℞-only (US)
Routes Oral
Pharmacokinetic data
Protein binding 93%
Metabolism Liver (CYP450)
Half-life 18 hours
Excretion Feces; <1% urine
Identifiers
CAS number 70288-86-7 YesY 71827-03-7
ATC code P02CF01 QP54AA01 QS02QA03
PubChem CID 9812710
DrugBank APRD01058
ChemSpider 7988461 YesY
UNII 8883YP2R6D YesY
KEGG D00804 YesY
ChEMBL CHEMBL341047 N
Chemical data
Formula C48H74O14 (22,23-dihydroavermectin B1a)
C47H72O14 (22,23-dihydroavermectin B1b) 
Mol. mass 875.10 g/mol
 N (what is this?)  (verify)

Ivermectin (22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b) is a broad-spectrum antiparasitic avermectin medicine. It is sold under brand names Heartgard, Sklice, and Stromectol in the United States, Ivomec in Europe by Merial Animal Health, Mectizan in Canada by Merck, 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.[1]

Uses

Ivermectin is a broad-spectrum antiparasitic agent, traditionally against worms.

It is mainly used in humans in the treatment of onchocerciasis, but is also effective against other worm infestations (such as strongyloidiasis, ascariasis, trichuriasis, filariasis, enterobiasis, and some epidermal parasitic skin diseases, including scabies.

Ivermectin, under the brand name Mectizan, 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.[2][3][4] Currently, large amounts of ivermectin are donated by Merck to fight river blindness in countries unable to afford the drug.[5] The disease is endemic in 30 African countries, six Latin American countries, and Yemen, according to studies conducted by the World Health Organization.[6] 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.[7]

Arthropod

More recent evidence supports its off-label use against arthropods:

  • Mites such as scabies:[8][9][10] 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).[10]
  • Lice:[11][12] Ivermectin lotion (0.5%) is FDA-approved for patients six months of age and older.[13] 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.[14] This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.[15]
  • Bed bugs:[16] 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.

Veterinary use

Ivermectin is also used in veterinary medicine. 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; affected animals are particularly sensitive to the toxic effects of ivermectin.[17] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[18] 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.

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).[19] 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,[20] although crossing may still become significant if it 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.

Toxicity and potential drug interactions

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 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.[21]

For dogs, the insecticide spinosad may have the effect of increasing the potency of ivermectin.[22]

Ecotoxicity

Field studies have demonstrated the dung of animals treated with ivermectin supports a significantly reduced diversity of invertebrates, and the dung persists longer.[23]

Contraindications

Ivermectin is contraindicated in children under the age of five, or those who weigh less than 15 kg (33 lb);[24] and those who are breastfeeding, and have a hepatic or renal disease.[25]

Discovery

The discovery of the avermectin family of compounds, from which ivermectin is chemically derived, was made by a team of scientists at Merck Institute for Therapeutic Research. A large international program of development resulted in the introduction of ivermectin as a commercial antiparasitic agent in 1981.[26]

Notes and references

  1. ↑ 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. 
  2. ↑ The Carter Center. "River Blindness (Onchocerciasis) Program". Retrieved 2008-07-17 .
  3. ↑ The Carter Center. "Lymphatic Filariasis Elimination Program". Retrieved 2008-07-17 .
  4. ↑ WHO. accessdate=2009-11-12 "African Programme for Onchocerciasis Control" .
  5. ↑ http://www.mectizan.org/about
  6. ↑ United Front Against Riverblindness. "Onchocerciasis or Riverblindness" .
  7. ↑ United Front Against Riverblindness. "Control of Riverblindness" .
  8. ↑ 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. 
  9. ↑ 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. 
  10. ↑ 10.0 10.1 Strong M, Johnstone PW (2007). "Interventions for treating scabies". In Strong, Mark. Cochrane Database of Systematic Reviews (Online) (3): CD000320. doi:10.1002/14651858.CD000320.pub2. PMID 17636630. 
  11. ↑ 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. 
  12. ↑ 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. 
  13. ↑ "Sklice lotion".
  14. ↑ 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. 
  15. ↑ Study shows ivermectin ending lice problem in one treatment, Los Angeles Times, Nov 5, 2012 
  16. ↑ DONALD G. MCNEIL JR. (2012-12-31). "Pill Could Join Arsenal Against Bedbugs". The New York Times. Retrieved 2013-04-05. 
  17. ↑ "MDR1 FAQs", Australian Shepherd Health & Genetics Institute, Inc.
  18. ↑ Frischke H, Hunt L (April 1991). "Suspected ivermectin toxicity". Canadian Veterinary Journal 32 (4): 245. PMC 1481314. PMID 17423775. 
  19. ↑ 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. 
  20. ↑ 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. 
  21. ↑ Goodman and Gilman's Pharmacological Basis of Therapeutics, 11th edition, pages 122, 1084-1087.
  22. ↑ "COMFORTIS® and ivermectin interaction Safety Warning Notification". U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM). 
  23. ↑ 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. 
  24. ↑ 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. 
  25. ↑ 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. 
  26. ↑ W. C. CAMPBELL; R. W. BURG, , M. H. FISHER, and , R. A. DYBAS (June 26, 1984). "1". The Discovery of Ivermectin and Other Avermectins. American Chemical Society. pp. 5–20. ISBN 9780841210837. 

See also

External links

Antiparasitics – Anthelmintics (P02) and Endectocides (QP54)
Antiplatyhelmintic agents
Binds tubulin
Other/unknown
Binds tubulin
Other/unknown
Antinematodal agents
(including
macrofilaricides)
Binds tubulin
Glutamate-gated chloride channel, GABA receptor
NMDA
Other/unknown

M: IFT

helm, arth (acar)

helm, arth (lice), zoon

helm, arth

Insecticide/pediculicide
Chlorine-containing products
Acaricide/miticide/scabicide
Pyrethrines
Sulfur-containing products
Chlorine-containing products
Other/ungrouped

M: IFT

helm, arth (acar)

helm, arth (lice), zoon

helm, arth

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