Ivermectin

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Ivermectin
Ivermectin skeletal.svg
Clinical data
Trade namesStromectol, Soolantra cream
AHFS/Drugs.comMonograph (antiparasitic)
FDA Professional Drug Information (rosacea)
MedlinePlusa607069
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
ECHA InfoCard100.067.738 Edit this at Wikidata
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 mass875.10 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

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, a 50ml bottle with about 25 doses, costs $25–50.[10][11] In other animals it is used to prevent and treat heartworm among other diseases.[3]

Medical uses[edit]

Nematode[edit]

Pinworm[edit]

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

River blindness[edit]

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[edit]

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[edit]

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 on arrival so as to cure presumptive infection with threadworm.[20] 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.[21]

Whipworm[edit]

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[edit]

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[edit]

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 permethrin.[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[edit]

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[edit]

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

Adverse effects[edit]

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[edit]

Pharmacodynamics[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

Notes and references[edit]

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