Alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name Alfaxan, is a
neuroactive steroid
Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coin ...
and
general anesthetic
General anaesthetics (or anesthetics, see spelling differences) are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma ...
which is used currently in
veterinary practice as an
induction agent for
anesthesia
Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...
and as an
injectable
An injection (often and usually referred to as a "shot" in US English, a "jab" in UK English, or a "jag" in Scottish English and Scots) is the act of administering a liquid, especially a drug, into a person's body using a needle (usually a hypo ...
anesthetic.
Though it is more expensive than other induction agents,
it often preferred due to the lack of depressive effects on the
cardiovascular system
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
. The most common side effect seen in current veterinary practice is
respiratory
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
depression when Alfaxan is administered concurrently with other sedative and anesthetic drugs; when
premedications aren't given, veterinary patients also become agitated and hypersensitive when waking up.
Alfaxalone works as a
positive allosteric modulator
In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...
on
GABAA receptors and, at high concentrations, as a direct
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the GABA
A receptor. It is cleared quickly by the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
, giving it a relatively short
terminal half-life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
and preventing it from accumulating in the body, lowering the chance of overdose.
Veterinary use
Alfaxalone is used as an
induction agent, an injectable anesthetic, and a
sedative
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but t ...
in animals.
While it is commonly used in
cats
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 t ...
and
dogs
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 ...
, it has also been successfully used in
rabbits
Rabbits, also known as bunnies or bunny rabbits, are small mammals in the family Leporidae (which also contains the hares) of the order Lagomorpha (which also contains the pikas). ''Oryctolagus cuniculus'' includes the European rabbit specie ...
,
horses
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 yea ...
,
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 ...
,
pigs
The pig (''Sus domesticus''), often called swine, hog, or domestic pig when distinguishing from other members of the genus '' Sus'', is an omnivorous, domesticated, even-toed, hoofed mammal. It is variously considered a subspecies of ''Sus s ...
, and exotics such as
red-eared turtles,
axolotl
The axolotl (; from nci, āxōlōtl ), ''Ambystoma mexicanum'', is a paedomorphic salamander closely related to the tiger salamander. Axolotls are unusual among amphibians in that they reach adulthood without undergoing metamorphosis. Instea ...
,
green iguanas,
marmosets
The marmosets (), also known as zaris or sagoin, are 22 New World monkey species of the genera ''Callithrix'', ''Cebuella'', ''Callibella'', and ''Mico''. All four genera are part of the biological family Callitrichidae. The term "marmoset" is ...
,
and
koi fish
or more specifically , are colored varieties of the Amur carp ('' Cyprinus rubrofuscus'') that are kept for decorative purposes in outdoor koi ponds or water gardens.
Koi is an informal name for the colored variants of ''C. rubrofuscus'' kep ...
.
As an induction agent, alfaxalone causes the animal to relax enough to be
intubated
Intubation (sometimes entubation) is a medical procedure involving the insertion of a tube into the body. Patients are generally anesthetized beforehand. Examples include tracheal intubation, and the balloon tamponade with a Sengstaken-Blakemo ...
, which then allows the administration of
inhalational anesthesia. Premedication (administering
sedative drugs
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but th ...
prior to induction) increases the potency of alfaxalone as an induction agent.
Alfaxalone can be used instead of gas anesthetics in surgeries that are under 30 minutes, where it is given at a constant rate via IV (constant rate infusion); this is especially useful in procedures such as
bronchoscopies or repairing
tracheal tears, as there is no
endotracheal tube
A tracheal tube is a catheter that is inserted into the trachea for the primary purpose of establishing and maintaining a patent airway and to ensure the adequate exchange of oxygen and carbon dioxide.
Many different types of tracheal tubes are a ...
in the way.
Once the administration of alfaxalone stops, the animal quickly recovers from anesthesia.
Alfaxalone can be used as a sedative when given
intramuscularly
Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...
(IM), though this requires a larger volume (and not all countries allow alfaxalone to be administered IM).
Despite its use as an anesthetic, alfaxalone itself has no
analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
properties.
Available forms
Though alfaxalone is not licensed for IM or
subcutaneous use in the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
(as both cause longer recoveries with greater agitation and hypersensitivity to stimuli), it is routinely used IM in cats, and is licensed as such in other countries.
Alfaxalone is dissolved in
2-hydroxylpropyl-β cyclodextrin.
The cyclodextrin is a large,
starch-derived molecule with a
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
core where alfaxalone stays, allowing the mixture to be dissolved in water and sold as an aqueous solution. They act as one unit, and only dissociate once ''in vivo''.
Specific populations
Alfaxalone has been used to perform
C-sections
Caesarean section, also known as C-section or caesarean delivery, is the surgical procedure by which one or more babies are delivered through an incision in the mother's abdomen, often performed because vaginal delivery would put the baby or m ...
in pregnant cats; though it crosses the
placental barrier
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate matern ...
and had some effects on the kittens, there is no respiratory depression and no lasting effect. Alfaxalone has also been found to be safe in young puppies and kittens.
Alfaxalone has been noted to be a good anesthetic agent for dogs with
ventricular arrhythmias
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
and for
sighthounds
Sighthounds, also called gazehounds, are a type of dog, hounds that hunt primarily by sight and speed, rather than by scent and endurance as scent hounds do.
Appearance
These dogs specialize in pursuing prey, keeping it in sight, and overpow ...
.
Side effects
Alfaxalone has relatively few side effects compared to other anesthetics; most notable is its lack of
cardiovascular
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
depression at clinical doses, which makes it unique among anesthetics.
The most common side effect is respiratory depression: in addition to
apnea
Apnea, BrE: apnoea, is the temporal cessation of breathing. During apnea, there is no movement of the muscles of inhalation, and the volume of the lungs initially remains unchanged. Depending on how blocked the airways are ( patency), there ...
, the most prevalent, alfaxalone can also decrease the
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 ...
,
minute volume
Minute ventilation (or respiratory minute volume or minute volume) is the volume of gas inhaled (inhaled minute volume) or exhaled (exhaled minute volume) from a person's lungs per minute. It is an important parameter in respiratory medicine due ...
, and
oxygen saturation
Oxygen saturation (symbol SO2) is a relative measure of the concentration of oxygen that is dissolved or carried in a given medium as a proportion of the maximal concentration that can be dissolved in that medium at the given temperature. It ca ...
in the blood.
Alfaxalone should be administered slowly over a period of at least 60 seconds or until anesthesia is induced, as quick administration increases the risk of apnea.
Alfaxalone has some depressive effects on 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 ...
, including a reduction in
cerebral blood flow
Cerebral circulation is the movement of blood through a network of cerebral arteries and veins supplying the brain. The rate of cerebral blood flow in an adult human is typically 750 milliliters per minute, or about 15% of cardiac output. Arterie ...
,
intracranial pressure
Intracranial pressure (ICP) is the pressure exerted by fluids such as cerebrospinal fluid (CSF) inside the skull and on the brain tissue. ICP is measured in millimeters of mercury (mmHg) and at rest, is normally 7–15 Millimeter of mercury, mmHg ...
, and
body temperature
Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...
.
Greyhound
The English Greyhound, or simply the Greyhound, is a breed of dog, a sighthound which has been bred for coursing, greyhound racing and hunting. Since the rise in large-scale adoption of retired racing Greyhounds, the breed has seen a resurge ...
s, who are particularly susceptible to anesthetic side effects, can have decreased blood flow and oxygen supply to the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
.
When no premedications are used, alfaxalone causes animals (especially cats) to be agitated when recovering.
Dogs and cats will paddle in the air, vocalize excessively, may remain rigid or twitch, and have exaggerated reactions to external stimuli such as light and noise. For this reason, it is recommended that animals recovering from anesthesia by alfaxalone stay in a quiet, dark area.
Overdose
The quick metabolism and elimination of alfaxalone from the body decreases the chance of overdose.
It would take over 28 times the normal dose to cause toxicity in cats.
Such doses, however, can cause
low blood pressure
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
, apnea,
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
, and arrhythmia (caused by the apnea and hypoxia).
Pharmacology
Pharmacodynamics
Alfaxalone is a
neuroactive steroid
Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coin ...
derived from
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
, though it has no
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
or
mineralocorticoid
Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mi ...
action.
Instead, it works by acting on
GABAA receptors. It binds to the M3/M4 domains of the α subunit and
allosterically
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric sit ...
modifies the receptor to facilitate the movement of
chloride ions
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
into the cell, resulting in
hyperpolarization of the post-synaptic nerve (which inhibits
actions potentials). At concentrations over 1 micromolar,
alfaxalone binds to a site at the interface between the α and β subunits (near the actual GABA binding site) and acts as a GABA agonist, similar to
benzodiazepines
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, i ...
.
Alfaxalone, however, does not share the benzodiazepine binding site,
and actually prefers different GABA
A receptors than benzodiazepenes do. It works best on the
α1-β2-γ2-L isoform.
Research suggests that neuroactive steroids increase the expression of GABA
A receptors, making it more difficult to build
tolerance
Tolerance or toleration is the state of tolerating, or putting up with, conditionally.
Economics, business, and politics
* Toleration Party, a historic political party active in Connecticut
* Tolerant Systems, the former name of Veritas Software ...
.
Pharmacokinetics
Alfaxalone is metabolized quickly and does not accumulate in the body; its use as an induction agent thus doesn't increase the time needed to recover from anesthesia.
If it administered more slowly by diluting it in sterile water, less actual alfaxalone is needed.
Alfaxalone binds to 30–50% of plasma proteins,
and has a terminal half-life of 25 minutes in dogs and 45 minutes in cats when given at clinical doses (2 mg/kg and 5 mg/kg respectively). The pharmacokinetics are nonlinear in cats and dogs.
Most alfaxalone metabolism takes place in the liver, though some takes place in the
lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of th ...
and
kidneys
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
as well.
In the liver, it undergoes both
phase I (
cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
-dependent) and
phase II (conjugation-dependent) metabolism. The phase I products are the same in cats and dogs: allopregnatrione, 3β-alfaxalone, 20-hydroxy-3β-alfaxalone, 2-hydroxyalfaxalone, and 2α-hydroxyalfaxalone.
In dogs, the phase II metabolites are alfaxalone glucuronide (the major metabolite), 20-hydroxyalfaxalone sulfate, and 2α-hydroxyalfaxalone glucuronide. In cats, there is a greater production of 20-hydroxyalfaxalone sulfate than alfaxalone glucuronide; cats also have 3β-alfaxalone-sulfate, which is not present in dogs.
Alfaxalone is mostly excreted in the
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
, though some is excreted in the
bile
Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
as well.
Chemistry
Alfaxalone, also known as ''11-oxo-3α,5α-tetrahydroprogesterone'', ''5α-pregnan-3α-ol-11,20-dione'', or ''3α-hydroxy-5α-pregnane-11,20-dione'', is a
synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to:
Science
* Synthetic chemical or compound, produced by the process of chemical synthesis
* Synthetic o ...
pregnane
Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally allop ...
steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
and a
derivative
In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. F ...
of
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
.
It is specifically a
modification
Modification may refer to:
* Modifications of school work for students with special educational needs
* Modifications (genetics), changes in appearance arising from changes in the environment
* Posttranslational modifications, changes to protein ...
of progesterone in which the C3
ketone
In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
has been
reduced to a
hydroxyl group
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...
, the
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
between the C4 and C5 positions has been reduced and is now a
single bond
In chemistry, a single bond is a chemical bond between two atoms involving two valence electrons. That is, the atoms share one pair of electrons where the bond forms. Therefore, a single bond is a type of covalent bond. When shared, each of th ...
, and a ketone has been
substituted
A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...
at the C11 position.
Alfaxalone is also a derivative of
allopregnanolone
Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum d ...
, differing from it only by the addition of the C11 ketone.
Other closely related steroids include
ganaxolone
Ganaxolone, sold under the brand name Ztalmy, is a medication used to treat seizures in people with cyclin-dependent kinase-like 5 deficiency disorder, cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD).
Ganaxolone was approved ...
,
hydroxydione
Hydroxydione, as hydroxydione sodium succinate (, , ) (brand names Viadril, Predion, and Presuren), also known as 21-Hydroxy-5β-pregnane-3,20-dione, is a neuroactive steroid which was formerly used as a general anesthetic, but was discontinued ...
,
minaxolone
Minaxolone (CCI-12923) is a neuroactive steroid which was developed as a general anesthetic but was withdrawn before registration due to toxicity seen with long-term administration in rats, and hence was never marketed. It is a positive alloster ...
,
pregnanolone
Pregnanolone, also known as eltanolone, is an endogenous inhibitory neurosteroid which is produced in the body from progesterone. It is closely related to allopregnanolone, which has similar properties.
Biological activity
Pregnanolone is a ...
, and
renanolone
Renanolone ( INN), or 11-ketopregnanolone, also known as 5β-pregnan-3α-ol-11,20-dione, is a synthetic neuroactive steroid which is described as a general anesthetic but was never introduced for clinical use. Its isomers, alfaxolone and alfadolon ...
.
History
In 1941,
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
and
5β-pregnanedione were discovered to have
CNS depressant
A depressant, or central depressant, is a drug that lowers neurotransmission levels, which is to depress or reduce arousal or stimulation, in various areas of the brain. Depressants are also colloquially referred to as downers as they lower the l ...
effects in rodents. This began a search to make a synthetic steroid that could be used as an anesthetic. Most of these efforts were aimed at making alfaxalone more water-soluble.
In 1971, a combination of alfaxalone and
alfadolone acetate
Alfadolone (INN), or alphadolone is a neuroactive steroid and general anesthetic. Along with alfaxolone, as alfadolone acetate, it is one of the components of the anesthetic drug mixture althesin.
Chemistry
See also
* Ganaxolone
* Hydroxyd ...
was released as the anesthetics
Althesin
Alfaxolone/alfadolone (brand names Althesin (human), Saffan (veterinary) is a short acting intravenous anaesthetic agent. It was withdrawn from the market due to severe drug reactions. It is composed of a 3:1 mixture of alfaxalone and alfadolone ...
(for human use) and Saffan (for veterinary use).
The two were dissolved in
Cremophor EL Kolliphor EL, formerly known as Cremophor EL, is the registered trademark of BASF Corp. for its version of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. The resulting product is a mi ...
: a polyoxyelthylated
castor oil
Castor oil is a vegetable oil pressed from castor beans.
It is a colourless or pale yellow liquid with a distinct taste and odor. Its boiling point is and its density is 0.961 g/cm3. It includes a mixture of triglycerides in which about ...
surfactant
Surfactants are chemical compounds that decrease the surface tension between two liquids, between a gas and a liquid, or interfacial tension between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming ...
.
Althesin was removed from the market in 1984 for causing
anaphylaxis
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
; it was later found that this was due to Cremphor EL, which caused the body to release
histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
, rather than alfaxolone or alfadolone.
Saffan was removed from use for dogs only, but stayed on for other animals, none of which histamine release to the same extant that dogs did.
It was still especially valued in cats for its lack of depressant effects on the cardiovascular system, which made it three times less fatal than any other anesthetic on the market at the time.
The release of histamine caused most cats (70%) to have
edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
and
hyperemia
Hyperaemia (also hyperemia) is the increase of blood flow to different tissues in the body. It can have medical implications but is also a regulatory response, allowing change in blood supply to different tissues through vasodilation. Clinically, ...
in their ears and paws;
only some also got
laryngeal or
pulmonary edema
Pulmonary edema, also known as pulmonary congestion, is excessive edema, liquid accumulation in the parenchyma, tissue and pulmonary alveolus, air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia an ...
.
In 1999, a
lyophilized
Freeze drying, also known as lyophilization or cryodesiccation, is a low temperature dehydration process that involves freezing the product and lowering pressure, removing the ice by sublimation. This is in contrast to dehydration by most conve ...
form of alfaxalone was released for cats.
The new drug, Alfaxan, used a
cyclodextrin
Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. They are used in food, pharmaceutical, ...
as a carrier agent to make alfaxalone more water-soluble rather than Camphor EL.
Alfadolone was not included in the mixture, as its hypnotic effects were quite weak.
An
aqueous
An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, or sodium chloride (NaCl), in water would be rep ...
form of Alfaxan was released in Australia in 2000–2001, and Saffan was finally removed from the market in 2002. Alfaxan was released in the UK in 2007, central Europe in 2008, Canada in 2011, and the United States in 2012.
Currently, a human form of alfaxalone is in development under the name "Phaxan": alfaxalone will be dissolved in 7-sulfo-butyl-ether-β-cyclodextrin, which, unlike the cyclodextrin used in Alfaxan, is not toxic to people.
Society and culture
Generic names
''Alfaxalone'' is the , , , and of alfaxolone. ''Alphaxalone'' was the former of the drug,
but this was eventually changed. ''Alphaxolone'' and ''alfaxolone'' are additional alternative spellings.
Brand names
Alfaxalone was marketed in 1971 in combination with alfadolone acetate under the brand name ''Althesin'' for human use and ''Saffan'' for veterinary use.
Althesin was withdrawn from the market in 1984, whereas Saffan remained marketed.
A new formulation containing alfaxalone only was introduced for veterinary use in 1999 under the brand name ''Alfaxan''.
Following the introduction of Alfaxan, Saffan was gradually discontinued and is now no longer marketed.
Another new formulation containing alfaxalone alone is currently under development for use in humans with the tentative brand name ''Phaxan''.
Availability
Alfaxalone is marketed for veterinary use under the brand name Alfaxan in a number of countries, including
Australia
Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...
,
Belgium
Belgium, ; french: Belgique ; german: Belgien officially the Kingdom of Belgium, is a country in Northwestern Europe. The country is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeast, France to th ...
,
Canada
Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...
,
France
France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...
,
Germany
Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...
,
Ireland
Ireland ( ; ga, Éire ; Ulster Scots dialect, Ulster-Scots: ) is an island in the Atlantic Ocean, North Atlantic Ocean, in Northwestern Europe, north-western Europe. It is separated from Great Britain to its east by the North Channel (Grea ...
,
Japan
Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...
, the
Netherlands
)
, anthem = ( en, "William of Nassau")
, image_map =
, map_caption =
, subdivision_type = Sovereign state
, subdivision_name = Kingdom of the Netherlands
, established_title = Before independence
, established_date = Spanish Netherl ...
,
New Zealand
New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island count ...
,
South Africa
South Africa, officially the Republic of South Africa (RSA), is the southernmost country in Africa. It is bounded to the south by of coastline that stretch along the South Atlantic and Indian Oceans; to the north by the neighbouring countri ...
,
South Korea
South Korea, officially the Republic of Korea (ROK), is a country in East Asia, constituting the southern part of the Korea, Korean Peninsula and sharing a Korean Demilitarized Zone, land border with North Korea. Its western border is formed ...
,
Spain
, image_flag = Bandera de España.svg
, image_coat = Escudo de España (mazonado).svg
, national_motto = ''Plus ultra'' (Latin)(English: "Further Beyond")
, national_anthem = (English: "Royal March")
, i ...
,
Taiwan
Taiwan, officially the Republic of China (ROC), is a country in East Asia, at the junction of the East and South China Seas in the northwestern Pacific Ocean, with the People's Republic of China (PRC) to the northwest, Japan to the nort ...
, the
United Kingdom
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the continental mainland. It comprises England, Scotland, Wales and North ...
, and the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
.
References
{{Glycine receptor modulators
Sterols
GABAA receptor positive allosteric modulators
GABAA-rho receptor positive allosteric modulators
General anesthetics
Glycine receptor agonists
Ketones
Neurosteroids
Pregnanes
Veterinary drugs