Afoxolaner (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

) is an insecticide and

acaricide Acaricides are pesticides that kill members of the arachnid subclass ''Acari'', which includes ticks and mites. Acaricides are used both in medicine and agriculture, although the desired selective toxicity differs between the two fields. Termino ...

that belongs to the isoxazoline chemical compound group. It acts as an antagonist at ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid ( GABA-receptors). Isoxazolines, among the chloride channel modulators, bind to a distinct and unique target site within the insect GABA-gated chloride channels, thereby blocking pre-and post- synaptic transfer of chloride ions across

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

s. Prolonged afoxolaner-induced hyperexcitation results in uncontrolled activity of 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 p ...

and death of

insect Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three ...

s and

acari Mites are small arachnids (eight-legged arthropods). Mites span two large orders of arachnids, the Acariformes and the Parasitiformes, which were historically grouped together in the subclass Acari, but genetic analysis does not show clear evid ...

nes.

Marketing

Afoxolaner is the

active principle An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. The ...

of the veterinary medicinal products NexGard (alone), Frontpro (alone) and Nexgard Spectra (in combination with milbemycin oxime). They are indicated for the treatment and prevention of

flea Flea, the common name for the order Siphonaptera, includes 2,500 species of small flightless insects that live as external parasites of mammals and birds. Fleas live by ingesting the blood of their hosts. Adult fleas grow to about long, a ...

infestations, and the treatment and control of

tick Ticks (order Ixodida) are parasitic arachnids that are part of the mite superorder Parasitiformes. Adult ticks are approximately 3 to 5 mm in length depending on age, sex, species, and "fullness". Ticks are external parasites, living by ...

infestations 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 ...

s and

puppies A puppy is a juvenile dog. Some puppies can weigh , while larger ones can weigh up to . All healthy puppies grow quickly after birth. A puppy's coat color may change as the puppy grows older, as is commonly seen in breeds such as the York ...

(8 weeks of age and older, weighing 4 pounds (~1.8 kilograms) of body weight or greater) for one month. These products are administered orally and poisons

s once they start feeding. The marketing authorization was granted by the European Medicines Agency in February 2014, for NexGard and January 2015, for Nexgard Spectra, after only 14 and 12 months of quality, safety and efficacy assessment performed by the

Committee for Medicinal Products for Veterinary Use The Committee for Medicinal Products for Veterinary Use (CVMP) is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding veterinary medicines. Text was copied from this source which is © ...

(CVMP). Therefore, long-term effects are not known.

List of
excipient An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...
s

In NexGard and NexGard Spectra: * Maize starch *

Soy protein Soy protein is a protein that is isolated from soybean. It is made from soybean meal that has been dehulled and defatted. Dehulled and defatted soybeans are processed into three kinds of high protein commercial products: soy flour, concentrates, ...

fines * Beef braised

flavouring A flavoring (or flavouring), also known as flavor (or flavour) or flavorant, is a food additive used to improve the taste or smell of food. It changes the perceptual impression of food as determined primarily by the chemoreceptors of the gus ...

* Povidone ( E1201) *

Macrogol Macrogol, also known as polyethylene glycol (PEG), is used as a medication to treat constipation in children and adults. It is also used to empty the bowels before a colonoscopy. It is taken by mouth. Benefits usually occur within three days. ...

400 (reputed laxatives) *

4000 (reputed laxatives) *

15 hydroxystearate (reputed laxatives) * Glycerol ( E422) *

Triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other ...

s, medium-chain Additionally in NexGard Spectra: * Citric acid monohydrate ( E330) * Butylated hydroxytoluene ( E321)

Safety

Dosage

Afoxolaner is recommended to be administered at a dose of 2.7–7 mg/kg dog's body weight.

Toxicity for mammals

According to clinical studies performed prior marketing: * The oral toxicity profile of afoxolaner consists of a

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...

effect (rats only), effects secondary to a reduction in food consumption (rats and rabbits only) and occasional

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

and/or

diarrhoea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

(dogs, 120 and 200 mg/kg bodyweight (bw)) following high oral doses. No treatment-related effects on vomiting or diarrhoea were noted following oral doses of up to 31.5 mg/kg bw in the pivotal target animal safety study, nor in the EU field trial. * mild

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

effects (

pruritus Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...

lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

, and

neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...

signs ( convulsions,

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 ...

and muscle tremors) have been reported in less than 0.1% of 10,000 animals treated, including isolated reports, most reported adverse reactions being self-limiting and of short duration, * (in combination with milbemycin oxime): vomiting,

, and

were observed in 0.2 to 1% of 10,000 animals treated and were generally self-limiting and of short duration, * ''In vitro'' studies reported that afoxolaner can bind to dopamine and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...

cellular transport receptor systems and the

CB1 receptor Cannabinoid receptor type 1 (CB1), also known as cannabinoid receptor 1, is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. The human CB1 receptor is expressed in the peripheral nervous system and centr ...

; inhibition of these

catecholaminergic Catecholaminergic means "related to catecholamines". The catecholamine neurotransmitters include dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline). A catecholaminergic agent (or drug) is a chemical which functions to direc ...

systems and certain types of

competitive binding Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...

at CB1 receptors may mediate pharmacodynamic effects of

diuresis Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pr ...

, decreased food consumption, and decreased body weight in animals. According to post-marketing safety experience: * (in combination with milbemycin oxime):

erythema Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not asso ...

and

signs ( convulsions,

and muscle tremors) have been reported in less than 0.1% of 10,000 animals treated, including isolated reports, * The

US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

reports that some drugs in this class ( isoxazolines), including afoxolaner, can have adverse

neurologic Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...

effects on some dogs, such as muscle tremors,

, and

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

. *Extralabel use of afoxolaner in a pet pig has been described without any adverse effects. Experimental use in commercial pigs also did not result in any adverse effects.

Selectivity in insects over mammalians

''In vivo'' studies (repeat-dose

toxicology Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating e ...

laboratory animals Animals used by laboratories for testing purposes are largely supplied by dealers who specialize in selling them to universities, medical and veterinary schools, and companies that provide contract animal-testing services. It is comparatively rare ...

, target animal safety, field studies) provided by

MERIAL Boehringer Ingelheim Animal Health is a multinational animal health company, formed in January 2017 when Merial was acquired by Boehringer Ingelheim and merged with Boehringer Ingelheim's existing animal health assets. Overview In August 1997, ...

, the company that produces afoxolaner-derivative medicines, did not show evidence of neurological or behavioural effects suggestive of GABA-mediated perturbations in mammals. The

(CVMP) therefore concluded that binding to

, rat or human

GABA receptor The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...

s is expected to be low for afoxolaner. Selectivity for

over mammalian GABA-receptors has been demonstrated for other isoxazolines. The selectivity might be explained by the number of pharmacological differences that exist between GABA-gated chloride channels of

s and

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...

References

{{insecticides Acaricides Chloroarenes Insecticides Isoxazolines Naphthalenes Trifluoromethyl compounds Carboxamides

Marketing

List of excipient An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...s

Safety

Dosage

Toxicity for mammals

Selectivity in insects over mammalians

See also

References

List of
excipient An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...
s