Moxidectin

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Moxidectin
Moxidectin.png
Moxidectin 3D ball.png
Clinical data
Trade names Cydectin, Equest, ProHeart, Quest. [1]
Other namesCL 301,423; [2] milbemycin B. [2]
AHFS/Drugs.com International Drug Names
Routes of
administration 		By mouth, topical, subcutaneous
ATC code
Legal status
Legal status
Identifiers
  • (10E,14E,16E,22Z)-(1R,4S,5′S,6R,6′S,8R,13R,20R,21R,24S)-6′-
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.163.046 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C37H53NO8
Molar mass 639.830 g·mol−1
3D model (JSmol)
  • CC(C)\C=C(/C)[C@H]5O[C@@]2(C[C@H]1OC(=O)[C@@H]3/C=C(/C)[C@@H](O)[C@H]4OC/C(=C\C=C\[C@H](C)CC(\C)=C\C[C@H](C1)O2)[C@@]34O)C\C(=N\OC)[C@@H]5C
  • InChI=1S/C37H53NO8/c1-21(2)14-25(6)33-26(7)31(38-42-8)19-36(46-33)18-29-17-28(45-36)13-12-23(4)15-22(3)10-9-11-27-20-43-34-32(39)24(5)16-30(35(40)44-29)37(27,34)41/h9-12,14,16,21-22,26,28-30,32-34,39,41H,13,15,17-20H2,1-8H3/b10-9+,23-12+,25-14+,27-11+,38-31-/t22-,26-,28+,29-,30-,32+,33+,34+,36-,37+/m0/s1 Yes check.svgY
  • Key:YZBLFMPOMVTDJY-CBYMMZEQSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Moxidectin is an anthelmintic drug used in animals to prevent or control parasitic worms (helminths), such as heartworm and intestinal worms, in dogs, cats, horses, cattle, sheep and wombats [4] . Moxidectin kills some of the most common internal and external parasites by selectively binding to a parasite's glutamate-gated chloride ion channels. These channels are vital to the function of invertebrate nerve and muscle cells; when moxidectin binds to the channels, it disrupts neurotransmission, resulting in paralysis and death of the parasite.

Contents

Medical uses

Moxidectin was approved for onchocerciasis (river-blindness) in 2018 for people over the age of 11 in the United States based on two studies. [5] There is a need for additional 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. [6] Moxidectin is predicted to be helpful to achieve elimination goals of this disease. [7]

Nematodes can develop cross-resistance between moxidectin and other similar parasiticides, such as ivermectin, doramectin and abamectin. [11] The ways in which the parasites evolve resistance to this drug include mutations in glutamate-gated chloride channel genes, GABA-R genes, [12] or increased expression of p-glycoprotein, which is a transmembrane drug efflux pump. [13] Allele frequency changes corresponding to resistance to moxidectin and/or other macrocyclic lactone-class drugs have been observed in the glutamate-gated chloride channel α-subunit gene of Haemonchus contortus and Cooperia oncophora , as well as in the H. contortus genes coding for p-glycoprotein and the GABA-R gene. [13]

Moxidectin is being evaluated as a treatment to eradicate scabies in humans, especially when resistant to other treatments. [14]

Adverse effects

Studies of moxidectin show the side effects vary by animal and may be affected by the product's formulation, application method and dosage.[ citation needed ]. It is however regarded as relatively safe [15] .

An overdose of moxidectin enhances the effect of gamma-aminobutyric acid (GABA) in the central nervous system. [16] In horses, overdose may lead to depression, drooping of the lower lip, tremor, lack of coordination when moving (ataxia), decreased rate of breathing (respiratory rate), stupor and coma. [16]

If a dog licks moxidectin from the skin which was applied as a "spot-on" (topical) treatment, this has the same effect as an overdose, and may cause vomiting, salivation and neurological signs such as ataxia, tremor, and nystagmus. [8] Some Collie dogs can tolerate moxidectin, but other individuals are sensitive and upon ingestion, experience vomiting, salivation or transient neurological signs. [8]

Pharmacology

Moxidectin is very lipophilic, which causes it to have a high volume of distribution. [17] Moxidectin concentrates in the animal's adipose tissue, from where it is released for up to two months following administration. [17]

In goats, the oral bioavailability of moxidectin is 2.7 times lower, and the half-life is 1.8 times shorter than in sheep. [18]

Chemistry

Moxidectin, a macrocyclic lactone of the milbemycin class, [8] is a semisynthetic derivative of nemadectin, which is a fermentation product of the bacterium Streptomyces cyanogriseus subsp. noncyanogenus. [19]

History

In the late 1980s, an American Cyanamid Company agronomist discovered the Streptomyces bacteria from which moxidectin is derived in a soil sample from Australia. Two companies filed patents for moxidectin: Glaxo Group and the American Cyanamid Company; [1] in 1988, all patents were transferred to American Cyanamid. [1] In 1990, the first moxidectin product was sold in Argentina. [1]

For human use, moxidectin was approved by the United States Food and Drug Administration in June 2018 for the treatment of onchocerciasis in adults and adolescents aged 12 and older. This is the first human approval worldwide. The license holder is the nonprofit biopharmaceutical company Medicines Development for Global Health. [20]

Related Research Articles

<span class="mw-page-title-main">Onchocerciasis</span> Human helminthiasis (infection by parasite)

Onchocerciasis, also known as river blindness, is a disease caused by infection with the parasitic worm Onchocerca volvulus. Symptoms include severe itching, bumps under the skin, and blindness. It is the second-most common cause of blindness due to infection, after trachoma.

<span class="mw-page-title-main">Mange</span> Type of skin disease caused by parasitic mites

Mange is a type of skin disease caused by parasitic mites. Because various species of mites also infect plants, birds and reptiles, the term "mange", or colloquially "the mange", suggesting poor condition of the skin and fur due to the infection, is sometimes reserved for pathological mite-infestation of nonhuman mammals. Thus, mange includes mite-associated skin disease in domestic mammals, in livestock, and in wild mammals. Severe mange caused by mites has been observed in wild bears. Since mites belong to the arachnid subclass Acari, another term for mite infestation is acariasis.

<span class="mw-page-title-main">Abamectin</span> Insecticide and anti-parasitic worm chemical

Abamectin (also called avermectin B1) is a widely used insecticide and anthelmintic. Abamectin, is a member of the avermectin family and is a natural fermentation product of soil dwelling actinomycete Streptomyces avermitilis. Abamectin differs from ivermectin, the popular member of the avermectin family, by a double bond between carbons 22 and 25. Fermentation of Streptomyces avermitilis yields eight closely related avermectin homologs, with the B1a and B1b forms comprising the majority of the fermentation. The non-proprietary name, abamectin, refers to a mixture of B1a (~80%) and B1b (~20%). Out of all the avermectins, abamectin is the only one that is used both in agriculture and pharmaceuticals.

<span class="mw-page-title-main">Ivermectin</span> Medication for parasite infestations

Ivermectin is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1987, it is used to treat infestations including head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis and lymphatic filariasis. It works through many mechanisms to kill the targeted parasites, and can be taken by mouth, or applied to the skin for external infestations. It belongs to the avermectin family of medications.

<i>Haemonchus contortus</i> Species of roundworm

Haemonchus contortus, also known as the barber's pole worm, is a very common parasite and one of the most pathogenic nematodes of ruminants. Adult worms attach to abomasal mucosa and feed on the blood. This parasite is responsible for anemia, oedema, and death of infected sheep and goats, mainly during summer in warm, humid climates.

<i>Dirofilaria immitis</i> Species of worm that causes parasitic disease in animals

Dirofilaria immitis, also known as heartworm or dog heartworm, is a parasitic roundworm that is a type of filarial worm, a small thread-like worm, and which causes dirofilariasis. It is spread from host to host through the bites of mosquitoes. Four genera of mosquitoes transmit dirofilariasis, Aedes, Culex, Anopheles, and Mansonia. The definitive host is the dog, but it can also infect cats, wolves, coyotes, jackals, foxes, ferrets, bears, seals, sea lions and, under rare circumstances, humans.

<span class="mw-page-title-main">Selamectin</span> Topical parasiticide for dogs and cats

Selamectin, sold under the brand name Revolution, among others, is a topical parasiticide and anthelminthic used on dogs and cats. It treats and prevents infections of heartworms, fleas, ear mites, sarcoptic mange (scabies), and certain types of ticks in dogs, and prevents heartworms, fleas, ear mites, hookworms, and roundworms in cats. It is structurally related to ivermectin and milbemycin. Selamectin is not approved for human use.

<span class="mw-page-title-main">Avermectin</span> Drugs to treat parasitic worms and insect pests

The avermectins are a series of drugs and pesticides used to treat parasitic worm infestations and to reduce insect pests. They are a group of 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties. These naturally occurring compounds are generated as fermentation products by Streptomyces avermitilis, a soil actinomycete. Eight different avermectins were isolated in four pairs of homologue compounds, with a major (a-component) and minor (b-component) component usually in ratios of 80:20 to 90:10. Avermectin B1, a mixture of B1a and B1b, is the drug and pesticide abamectin. Other anthelmintics derived from the avermectins include ivermectin, selamectin, doramectin, eprinomectin.

<span class="mw-page-title-main">Milbemycin oxime</span> Chemical compound

Milbemycin oxime, sold under the brand name Interceptor among others, is a veterinary medication from the group of milbemycins, used as a broad spectrum antiparasitic. It is active against worms (anthelmintic) and mites (miticide).

<span class="mw-page-title-main">Anthelmintic</span> Antiparasitic drugs that expel parasitic worms (helminths) from the body

Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. They may also be called vermifuges or vermicides. Anthelmintics are used to treat people who are infected by helminths, a condition called helminthiasis. These drugs are also used to treat infected animals, particularly small ruminants such as goats and sheep.

<span class="mw-page-title-main">Emamectin</span> Chemical compound

Emamectin is the 4″-deoxy-4″-methylamino derivative of abamectin, a 16-membered macrocyclic lactone produced by the fermentation of the soil actinomycete Streptomyces avermitilis. It is generally prepared as the salt with benzoic acid, emamectin benzoate, which is a white or faintly yellow powder. Emamectin is widely used in the US and Canada as an insecticide because of its chloride channel activation properties.

<span class="mw-page-title-main">Oxfendazole</span> Chemical compound

Oxfendazole is a broad spectrum benzimidazole anthelmintic. Its main use is for protecting livestock against roundworm, strongyles and pinworms. Oxfendazole is the sulfoxide metabolite of fenbendazole.

<i>Teladorsagia circumcincta</i> Species of roundworm

Teladorsagia circumcincta is a nematode that is one of the most important parasites of sheep and goats. It was previously known as Ostertagia circumcincta and is colloquially known as the brown stomach worm. It is common in cool, temperate areas, such as south-eastern and south-western Australia and the United Kingdom. There is considerable variation among lambs and kids in susceptibility to infection. Much of the variation is genetic and influences the immune response. The parasite induces a type I hypersensitivity response which is responsible for the relative protein deficiency which is characteristic of severely infected animals. There are mechanistic mathematical models which can predict the course of infection. There are a variety of ways to control the infection and a combination of control measures is likely to provide the most effective and sustainable control.

<span class="mw-page-title-main">Mites of domestic animals</span> Type of parasite of domestic animals

Mites that infest and parasitize domestic animals cause disease and loss of production. Mites are small invertebrates, most of which are free living but some are parasitic. Mites are similar to ticks and both comprise the order Acari in the phylum Arthropoda. Mites are highly varied and their classification is complex; a simple grouping is used in this introductory article. Vernacular terms to describe diseases caused by mites include scab, mange, and scabies. Mites and ticks have substantially different biology from, and are classed separately from, insects. Mites of domestic animals cause important types of skin disease, and some mites infest other organs. Diagnosis of mite infestations can be difficult because of the small size of most mites, but understanding how mites are adapted to feed within the structure of the skin is useful.

<span class="mw-page-title-main">Fluralaner</span> Chemical compound

Fluralaner (INN) is a systemic insecticide and acaricide that is administered orally or topically. The U.S. Food and Drug Administration (FDA) approved it under the trade name Bravecto for flea treatment in dogs in May 2014 and Bravecto Plus as a topical treatment for cats in November 2019, with warnings about possible side effects in both species. The EU approved the drug in February 2014. Australia approved it for the treatment and prevention of ticks and fleas on dogs in January 2015. For treating mites in chickens, a solution for use in drinking water is available under the name Exzolt; it was introduced by the EU in 2017.

<i>Cooperia oncophora</i> Species of roundworm

Cooperia oncophora is one of the most common intestinal parasitic nematodes in cattle in temperate regions. Infections with C. oncophora may result in mild clinical symptoms, but can lead to weight loss and damage of the small intestine, especially when co-infections with other nematodes such as O. ostertagi occur. Infections are usually treated with broad-spectrum anthelmintics such as benzimidazole, but resistance to these drugs has developed in the last decades and is now very common. C. oncophora has a direct life cycle. Infective larvae are ingested by the host. The larvae grow to adults, which reproduce in the small intestines. Eggs are shed onto the pasture with the faeces, which leads to new infections. Co-infections with other gastro-intestinal nematodes such as O. ostertagi and H. contortus are common.

<i>Cooperia</i> (nematode) Genus of roundworms

Cooperia is a genus of nematode from the Cooperiidae family that is one of the most common intestinal parasitic nematodes in cattle in temperate regions. Infections with Cooperia may result in mild clinical symptoms, but can lead to weight loss and damage of the small intestine, especially when co-infections with other nematodes such as Ostertagia ostertagi occur. Infections are usually treated with broad-spectrum anthelmintics such as benzimidazole, but resistance to these drugs has developed in the last decades and is now very common. Cooperia has a direct life cycle. Infective larvae are ingested by the host. The larvae grow to adults, which reproduce in the small intestines. Eggs are shed onto the pasture with the faeces, which leads to new infections. Co-infections with other gastro-intestinal nematodes such as O. ostertagi and Haemonchus contortus are common.

<span class="mw-page-title-main">Cattle drenching</span> Administration of anti-parasite drugs to cattle

Cattle drenching is the process of administering chemical solutions (anthelmintics) to cattle or Bos taurus with the purpose of protecting livestock from various parasites including worms, fluke, cattle ticks, lice and flies. Parasites hinder the production of cattle through living off their host and carrying diseases that can be transmitted to cattle. Cattle drenches can be applied through a solution poured on the back, throat or an injection. Cattle drenches are predominately necessary for young cattle with weaker immune systems that are susceptible to parasite infestation. Drenching is a common method for controlling parasites in the meat and dairy industries. Drenching cattle improves the health, condition and fertility of cattle leading to increased calving rates, weight gain, hide condition and milk production.

<span class="mw-page-title-main">Carlos Lanusse</span> Argentinean pharmacology researcher

Carlos E. Lanusse is an Argentine scientist and a professor of Pharmacology. He is the Director of the Veterinary Research Center and the Science and Technology Center of the Argentina National Council of Research in Tandil.

<span class="mw-page-title-main">Monepantel</span> Antiparasitic drug for sheep and cattle

Monepantel is an anthelmintic approved for use in sheep and cattle to control gastrointestinal nematodes. It belongs to a new class of anthelmintics called aminoacetonitrile derivatives (AAD). It is marketed by Elanco as Zolvix as a single active, or Zolvix Plus in combination with the macrocyclic lactone abamectin.

References

  1. 1 2 3 4 5 Awasthi A, Razzak M, Al-Kassas R, Harvey J, Garg S (2013). "Chapter 7: Analytical profile of moxidectin". In Brittain H (ed.). Profiles of drug substances, excipients and related methodology: Volume 38. Amsterdam: Academic Press. pp. 315–366. ISBN   9780124078284.
  2. 1 2 "milbemycin". MeSH - NCBI. Retrieved 21 July 2017.
  3. ↑ "Cydectin Product information". Health Canada. 25 April 2012. Retrieved 29 May 2022.
  4. ↑ Old JM, Skelton C, Stannard HJ (2021). "The use of Cydectin® by wildlife carers to treat sarcoptic mange in free-ranging bare-nosed wombats (Vombatus ursinus)". Parasitology Research. 120: 1077–1090. doi:10.1007/s00436-020-07012-8.
  5. ↑ Awadzi K, Opoku NO, Attah SK, Lazdins-Helds J, Kuesel AC (June 2014). "A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection". PLOS Neglected Tropical Diseases. 8 (6): e2953. doi: 10.1371/journal.pntd.0002953 . PMC   4072596 . PMID   24968000.
  6. ↑ 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. S2CID   46921091.
  7. ↑ Turner HC, Walker M, Attah SK, Opoku NO, Awadzi K, Kuesel AC, Basáñez MG (March 2015). "The potential impact of moxidectin on onchocerciasis elimination in Africa: an economic evaluation based on the Phase II clinical trial data". Parasites & Vectors. 8: 167. doi: 10.1186/s13071-015-0779-4 . PMC   4381491 . PMID   25889256.
  8. 1 2 3 4 Patel A, Forsythe P (2008). Small animal dermatology . Edinburgh: Elsevier/Saunders. p.  26. ISBN   9780702028700.
  9. ↑ Papich MG (2011). "Moxidectin". Saunders handbook of veterinary drugs small and large animal (3rd ed.). Philadelphia, PA: Elsevier/Saunders. pp. 525–526. ISBN   9781437701920.
  10. ↑ Sargison N (2008). "Moxidectin". Sheep flock health a planned approach. Oxford: Blackwell Publishing. pp. 180–181. ISBN   9781444302608.
  11. ↑ Rugg D, Buckingham SD, Sattelle DB, Jansson RK (2010). "The insecticidal macrocyclic lactones". In Gilbert GI, Gill SS (eds.). Insect pharmacology channels, receptors, toxins and enzymes. London: Academic Press. ISBN   9780123814487.
  12. ↑ Wolstenholme, Adrian J.; Fairweather, Ian; Prichard, Roger; von Samson-Himmelstjerna, Georg; Sangster, Nicholas C. (October 2004). "Drug resistance in veterinary helminths". Trends in Parasitology. 20 (10): 469–476. doi:10.1016/j.pt.2004.07.010. ISSN   1471-4922. PMID   15363440.
  13. 1 2 Blackhall, William J.; Prichard, Roger K.; Beech, Robin N. (25 March 2008). "P-glycoprotein selection in strains of Haemonchus contortus resistant to benzimidazoles". Veterinary Parasitology. 152 (1–2): 101–107. doi:10.1016/j.vetpar.2007.12.001. ISSN   0304-4017. PMID   18241994.
  14. ↑ Mounsey KE, Bernigaud C, Chosidow O, McCarthy JS (March 2016). "Prospects for Moxidectin as a New Oral Treatment for Human Scabies". PLOS Neglected Tropical Diseases. 10 (3): e0004389. doi: 10.1371/journal.pntd.0004389 . PMC   4795782 . PMID   26985995.
  15. ↑ Schraven AL, Stannard HJ, Old JM (2021). "A systematic review of moxidectin as a treatment for parasitic infections in mammalian species". Parasitology Research. 120: 1167–1181. doi:10.1007/s00436-021-07092-0.
  16. 1 2 Dowling PM (2012). "Ivermectin and moxidectin toxicosis". In Wilson DA (ed.). Clinical veterinary advisor: The horse. St. Louis, MO: Elsevier Saunders. pp. 307–308. ISBN   9781437714494.
  17. 1 2 Lanusse CE, Lifschitz AL, Imperiale FA (2013). "Chapter 42: Macrocyclic lactones: Endectocide compounds". In Riviere JE, Papich MG (eds.). Veterinary Pharmacology and Therapeutics (9th ed.). John Wiley & Sons. p. 1126. ISBN   978-1118685907.
  18. ↑ Baynes RE, Payne M, Martin-Jimenez T, Abdullah AR, Anderson KL, Webb AI, et al. (September 2000). "Extralabel use of ivermectin and moxidectin in food animals". Journal of the American Veterinary Medical Association. 217 (5): 668–671. doi: 10.2460/javma.2000.217.668 . PMID   10976297.
  19. ↑ Lumaret JP, Errouissi F, Floate K, Römbke J, Wardhaugh K (May 2012). "A review on the toxicity and non-target effects of macrocyclic lactones in terrestrial and aquatic environments". Current Pharmaceutical Biotechnology. 13 (6): 1004–1060. doi:10.2174/138920112800399257. PMC   3409360 . PMID   22039795.
  20. ↑ "MOXIDECTIN tablet". Dailymed. U.S. National Library of Medicine.
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