Moxidectin is an

anthelmintic 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 without causing significant damage to the host. They may also ...

drug used in animals to prevent or control parasitic worms (

helminths Parasitic worms, also known as helminths, are a polyphyletic group of large macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms that are soil-transmitted and infect the gastrointestinal tract. Other par ...

), such as heartworm and intestinal worms, in

dog The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the gray wolf. Also called the domestic dog, it was selectively bred from a population of wolves during the Late Pleistocene by hunter-gatherers. ...

cat The cat (''Felis catus''), also referred to as the domestic cat or house cat, is a small domesticated carnivorous mammal. It is the only domesticated species of the family Felidae. Advances in archaeology and genetics have shown that the ...

horse The horse (''Equus ferus caballus'') is a domesticated, one-toed, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two extant subspecies of ''Equus ferus''. The horse has evolved over the past 45 to 55 mi ...

cattle Cattle (''Bos taurus'') are large, domesticated, bovid ungulates widely kept as livestock. They are prominent modern members of the subfamily Bovinae and the most widespread species of the genus '' Bos''. Mature female cattle are calle ...

sheep Sheep (: sheep) or domestic sheep (''Ovis aries'') are a domesticated, ruminant mammal typically kept as livestock. Although the term ''sheep'' can apply to other species in the genus '' Ovis'', in everyday usage it almost always refers to d ...

and

wombat Wombats are short-legged, muscular quadrupedal marsupials of the family Vombatidae that are native to Australia. Living species are about in length with small, stubby tails and weigh between . They are adaptable and habitat tolerant, and are ...

s. 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 Invertebrates are animals that neither develop nor retain a vertebral column (commonly known as a ''spine'' or ''backbone''), which evolved from the notochord. It is a paraphyletic grouping including all animals excluding the chordata, chordate s ...

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons). Nerves have historically been considered the basic units of the peripheral nervous system. A nerve provides a common pathway for the Electrochemistry, electrochemical nerv ...

and

muscle cell A muscle cell, also known as a myocyte, is a mature contractile Cell (biology), cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal muscle, skeletal, smooth muscle, smooth, and Cardiac muscle, cardiac ...

s; when moxidectin binds to the channels, it disrupts neurotransmission, resulting in

paralysis Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...

and death of the parasite.

Medical uses

Moxidectin was approved for

onchocerciasis 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 blindne ...

(river-blindness) in 2018 for people over the age of 11 in the United States based on two studies. 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. Moxidectin is predicted to be helpful to achieve elimination goals of this disease. * Dogs: Prevention of heartworm. In combination with

imidacloprid Imidacloprid is a systemic insecticide belonging to a class of chemicals called the neonicotinoids which act on the central nervous system of insects. The chemical works by interfering with the transmission of stimuli in the insect nervous system. ...

to treat sarcoptic mange. * Horses: Treatment of parasites including '' Strongylus vulgaris'', and stomach

bot Bot or BOT may refer to: Sciences Computing and technology * Chatbot, a computer program that converses in natural language * Internet bot, a software application that runs automated tasks (scripts) over the Internet **Spambot, an internet bot ...

s such as '' Gasterophilus intestinalis''. * Cattle: Treatment of parasites such as the gastrointestinal

nematode The nematodes ( or ; ; ), roundworms or eelworms constitute the phylum Nematoda. Species in the phylum inhabit a broad range of environments. Most species are free-living, feeding on microorganisms, but many are parasitic. Parasitic worms (h ...

'' Ostertagia ostertagi'', and the lungworm '' Dictyocaulus viviparus''. * Sheep: Treatment of the nematodes '' Teladorsagia circumcincta'' and ''

Haemonchus contortus ''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 anemi ...

''. Nematodes can develop cross-resistance between moxidectin and other similar parasiticides, such as

ivermectin 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 ...

doramectin Doramectin, sold under the brand name Dectomax among others, is a veterinary medication approved by the US Food and Drug Administration (FDA) for the treatment of parasites such as gastrointestinal roundworms, lungworms, eyeworms, Larva, grubs, s ...

and abamectin. The ways in which the parasites evolve resistance to this drug include mutations in glutamate-gated chloride channel genes, GABA-R genes, or increased expression of p-glycoprotein, which is a transmembrane drug efflux pump. 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 ''

'' and '' Cooperia oncophora'', as well as in the ''H. contortus'' genes coding for p-glycoprotein and the GABA-R gene. Moxidectin is being evaluated as a treatment to eradicate

scabies Scabies (; also sometimes known as the seven-year itch) is a contagious human skin infestation by the tiny (0.2–0.45 mm) mite ''Sarcoptes scabiei'', variety ''hominis''. The word is from . The most common symptoms are severe itchiness a ...

in humans, especially when resistant to other treatments.

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.. It is however regarded as relatively safe. An overdose of moxidectin enhances the effect of ''gamma''-aminobutyric acid (

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

) in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. In horses, overdose may lead to depression, drooping of the lower lip,

tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

, lack of coordination when moving (

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

), decreased rate of breathing (

respiratory rate The respiratory rate is the rate at which breathing occurs; it is set and controlled by the respiratory center of the brain. A person's respiratory rate is usually measured in breaths per minute. Measurement The respiratory rate in humans is mea ...

stupor Stupor is the lack of critical mental function and a level of consciousness, in which an affected person is almost entirely unresponsive and responds only to intense stimuli such as pain. The word derives from the Latin '' stupor'' ("numbness, in ...

and

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...

. If a dog licks moxidectin from the skin which was applied as a "spot-on" (

topical A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

) treatment, this has the same effect as an overdose, and may cause vomiting, salivation and neurological signs such as

, tremor, and

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) Eye movement (sensory), eye movement. People can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in visual impairment, re ...

. Some Collie dogs can tolerate moxidectin, but other individuals are sensitive and upon ingestion, experience vomiting, salivation or transient neurological signs.

Pharmacology

Moxidectin is very

lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...

, which causes it to have a high

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

. Moxidectin concentrates in the animal's

adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

, from where it is released for up to two months following administration. In goats, the oral bioavailability of moxidectin is 2.7 times lower, and the half-life is 1.8 times shorter than in sheep.

Chemistry

Moxidectin, a macrocyclic lactone of the milbemycin class, is a semisynthetic derivative of nemadectin, which is a fermentation product of the

bacterium Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among the ...

'' Streptomyces cyanogriseus'' subsp. ''noncyanogenus''.

History

In the late 1980s, an American Cyanamid Company

agronomist An agriculturist, agriculturalist, agrologist, or agronomist (abbreviated as agr.) is a professional in the science, practice, and management of agriculture and agribusiness. It is a regulated profession in Canada, India, the Philippines, the Uni ...

discovered the '' Streptomyces'' bacteria from which moxidectin is derived in a soil sample from Australia. Two companies filed patents for moxidectin:

Glaxo Group GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British multinational pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham, w ...

and the American Cyanamid Company; in 1988, all patents were transferred to American Cyanamid. In 1990, the first moxidectin product was sold in

Argentina Argentina, officially the Argentine Republic, is a country in the southern half of South America. It covers an area of , making it the List of South American countries by area, second-largest country in South America after Brazil, the fourt ...

. 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.

References

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