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 and without causing significant damage to the host. They may a ...

drug used in animals to prevent or control

parasitic Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson has c ...

worms (

helminths Parasitic worms, also known as helminths, are 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 parasitic worms such as schi ...

), such as

heartworm ''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, that causes dirofilariasis. It is spread from host to host through the bites of mosquitoe ...

and intestinal worms, in

dog The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is derived from the extinct Pleistocene wolf, and the modern wolf is the dog's nearest living relative. Do ...

cat The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members of ...

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 million y ...

cattle Cattle (''Bos taurus'') are large, domesticated, cloven-hooved, herbivores. They are a prominent modern member of the subfamily Bovinae and the most widespread species of the genus ''Bos''. Adult females are referred to as cows and adult mal ...

and

sheep Sheep or domestic sheep (''Ovis aries'') are domesticated, ruminant mammals 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 domesticated 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 a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...

and

muscle cell A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

s; when moxidectin binds to the channels, it disrupts

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

, resulting in

paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...

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

. 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 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 ...

. * Horses: Treatment of parasites including '' Strongylus vulgaris'', and stomach

bot 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 **a Spambot, an internet bot des ...

s such as ''

Gasterophilus intestinalis ''Gasterophilus intestinalis'', also known as horse bot fly, is a species of insect of the family Oestridae, and is found worldwide. The adults, which have a bumblebee-like appearance, are prominently active in the summer. ''G. intestinalis'' is ...

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

nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...

Ostertagia ostertagi ''Ostertagia ostertagi'', commonly known as the medium stomach worm or brown stomach worm, is a parasitic nematode (round worm) of cattle. ''O. ostertagi'' can also be found to a lesser extent in sheep, goats, wild ruminants, and horses. It cau ...

'', and the lungworm ''

Dictyocaulus ''Dictyocaulus'' is a genus of nematode parasites of the bronchial tree of horses, sheep, goats, deer, and cattle. ''Dictyocaulus arnfieldi'' is the lungworm of horses, and ''Dictyocaulus viviparus'' is the lungworm affecting ruminants. ''Dict ...

viviparus''. * Sheep: Treatment of the nematodes ''

Teladorsagia circumcincta ''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, tempera ...

'' 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 anemia ...

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

ivermectin Ivermectin (, '' EYE-vər-MEK-tin'') 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, today it is used to treat inf ...

doramectin Doramectin (Dectomax) is a veterinary drug approved by the Food and Drug Administration (FDA) for the treatment of parasites such as gastrointestinal roundworms, lungworms, eyeworms, grubs, sucking lice and mange mites in cattle. It is used for ...

and

abamectin Abamectin 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 (also called Avermectin B1), differ ...

. Moxidectin is being evaluated as a treatment to eradicate

scabies Scabies (; also sometimes known as the seven-year itch) is a contagious skin infestation by the mite ''Sarcoptes scabiei''. The most common symptoms are severe itchiness and a pimple-like rash. Occasionally, tiny burrows may appear on the skin ...

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. An overdose of moxidectin enhances the effect of ''gamma''-aminobutyric acid ( GABA) in the

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

. 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 oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...

, lack of coordination when moving (

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

), 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, inse ...

and

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

. 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. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...

. Some

Collie Collies form a distinctive type of herding dogs, including many related landraces and standardized breeds. The type originated in Scotland and Northern England. Collies are medium-sized, fairly lightly-built dogs, with pointed snouts. Many ...

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 λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...

, 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, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...

, 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 The milbemycins are a group of macrolides chemically related to the avermectins and were first isolated in 1972 from '' Streptomyces hygroscopicus''. They are used in veterinary medicine as antiparasitic agents against worms, ticks and fleas.

class, is a semisynthetic derivative of nemadectin, which is a fermentation product of the

bacterium Bacteria (; singular: 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 ...

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

History

In the late 1980s, an

American Cyanamid Company American Cyanamid Company was a leading American conglomerate which became one of the nation's top 100 manufacturing companies during the 1970s and 1980s, according to the Fortune 500 listings at the time. It started in fertilizer, but added ...

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 ...

discovered the ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...

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

Glaxo Group GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the tent ...

and the

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

Argentina Argentina (), officially the Argentine Republic ( es, link=no, República Argentina), is a country in the southern half of South America. Argentina covers an area of , making it the second-largest country in South America after Brazil, th ...

. 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

External links

* {{Portal bar , Medicine Anthelmintics Veterinary drugs Orphan drugs