Allopregnanolone is a
naturally occurring neurosteroid
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 ...
which is made in the body from the
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
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 ...
.
[ As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso,] and used to treat postpartum depression.[ ] It is used by injection into a vein
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
over a 60-hour period under medical supervision.
Side effects of brexanolone may include sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...
, sleepiness
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
, dry mouth, hot flash
Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...
es, and loss of consciousness
Loss may refer to:
Arts, entertainment, and media Music
* ''Loss'' (Bass Communion album) (2006)
* ''Loss'' (Mull Historical Society album) (2001)
*"Loss", a song by God Is an Astronaut from their self-titled album (2008)
* Losses "(Lil Tjay son ...
. It is a neurosteroid
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 acts 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 ...
of the GABAA receptor, the major biological target of the inhibitory
An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a Chemical synapse, postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Inc ...
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
γ-aminobutyric acid (GABA).
Brexanolone was approved for medical use in the United States in 2019. The U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) considers it to be a first-in-class medication A first-in-class medication is a pharmaceutical that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medicat ...
. The long administration time, as well as the cost for a one-time treatment, have raised concerns about accessibility for many women.
Medical uses
Brexanolone is used to treat postpartum depression in adult women.[
]
Side effects
Side effects of brexanolone include sedation (13–21%), dry mouth (3–11%), loss of consciousness (3–5%), and flushing (2–5%). It can also produce euphoria
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...
to a degree similar to that of alprazolam (3–13% at infusion doses of 90–270 μg over a one-hour period).
Biological function
Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
, anxiolytic, stress-reducing, rewarding
The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and class ...
, prosocial
Prosocial behavior, or intent to benefit others, is a social behavior that "benefit other people or society as a whole", "such as helping, sharing, donating, co-operating, and volunteering". Obeying the rules and conforming to socially accepted beh ...
, antiaggressive A serenic, or antiaggressive agent, is a type of drug which reduces the capacity for irritability and aggression.
Examples
The recreational drug MDMA ("ecstasy") and a variety of related drugs have been described as '' empathogen-entactogens'', or ...
, prosexual, sedative, pro-sleep, cognitive
Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
, memory-impairment, 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 ...
, anesthetic, anticonvulsant
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
, neuroprotective, and neurogenic effects. Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
, premenstrual syndrome
Premenstrual syndrome (PMS) refers to emotional and physical symptoms that regularly occur in the one to two weeks before the start of each menstrual period. Symptoms resolve around the time menstrual bleeding begins. Different women experienc ...
, catamenial epilepsy
Catamenial epilepsy is a form of epilepsy in women where seizures are exacerbated during certain phases of the menstrual cycle. In rare cases, seizures occur only during certain parts of the cycle; in most cases, seizures occur more frequently (b ...
, and various other neuropsychiatric conditions.
During pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
, allopregnanolone and 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 ...
are involved in sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...
and 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), ...
of the fetus
A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
.
Mechanism of action
Molecular interactions
Allopregnanolone is an endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
inhibitory
An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a Chemical synapse, postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Inc ...
pregnane neurosteroid
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 ...
. It is made
Made or MADE may refer to:
Entertainment Film
* ''Made'' (1972 film), United Kingdom
* ''Made'' (2001 film), United States Music
* ''Made'' (Big Bang album), 2016
* ''Made'' (Hawk Nelson album), 2013
* ''Made'' (Scarface album), 2007
*'' M.A.D.E. ...
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 ...
, and is 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 ...
of the action of γ-aminobutyric acid (GABA) at GABAA receptor. Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepine
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, ...
s, including anxiolytic, sedative, and anticonvulsant activity. Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.
Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor. While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation. Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear. In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors, and also appears to act as a negative allosteric modulator of the 5-HT3 receptor. Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptor
The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current. It is one of the most widely distributed inhibitory ...
s.
Unlike progesterone, allopregnanolone is inactive at the classical nuclear
Nuclear may refer to:
Physics
Relating to the nucleus of the atom:
* Nuclear engineering
*Nuclear physics
*Nuclear power
*Nuclear reactor
*Nuclear weapon
*Nuclear medicine
*Radiation therapy
*Nuclear warfare
Mathematics
*Nuclear space
*Nuclear ...
progesterone receptor
The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone.
In humans, PR is encoded by a single ''PGR'' gene resid ...
(PR). However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone
5α-Dihydroprogesterone (5α-DHP, allopregnanedione, or 5α-pregnane-3,20-dione) is an endogenous progestogen and neurosteroid that is synthesized from progesterone. It is also an intermediate in the synthesis of allopregnanolone and isopre ...
, which does act as an 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 PR, and for this reason, allopregnanolone can produce PR-mediated progestogen
Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the body. ...
ic effects. In addition, allopregnanolone was reported in 2012 to be an agonist of the membrane progesterone receptors (mPRs) discovered shortly before, including mPRδ
Membrane progesterone receptor delta (mPRδ), or progestin and adipoQ receptor 6 (PAQR6), is a protein that in humans is encoded by the ''PAQR6'' gene.
See also
* Membrane progesterone receptor
* Progestin and adipoQ receptor
The progestin and ...
, mPRα
Membrane progesterone receptor alpha (mPRα), or progestin and adipoQ receptor 7 (PAQR7), is a protein that in humans is encoded by the ''PAQR7'' gene.
See also
* Membrane progesterone receptor
* Progestin and adipoQ receptor
The progestin and ...
, and mPRβ
Membrane progesterone receptor beta (mPRβ), or progestin and adipoQ receptor 8 (PAQR8), is a protein that in humans is encoded by the ''PAQR8'' gene.
See also
* Membrane progesterone receptor
* Progestin and adipoQ receptor
The progestin and ad ...
, with its activity at these receptors about a magnitude more potent than at the GABAA receptor. The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic
An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...
properties. Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor
In the field of molecular biology, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein that in humans is encoded by the ' ...
.
Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor
Inhibitor or inhibition may refer to:
In biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...
of L-type voltage-gated calcium channel
The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel.
"L" stands for long-lasting referring to the length of activation. This c ...
s (L-VGCCs), including α1 subtypes Cav1.2 and Cav1.3. However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain. Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone. Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor
The G protein-coupled bile acid receptor 1 (GPBAR1) also known G-protein coupled receptor 19 (GPCR19), membrane-type receptor for bile acids (M-BAR) or TGR5 as is a protein that in humans is encoded by the ''GPBAR1'' gene.
Function
This gene ...
(GPBAR1, or TGR5). However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.
Biphasic actions at the GABAA receptor
Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression
Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...
. This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nmol/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it. This seems to be a common effect of many GABAA receptor positive allosteric modulators. In accordance, acute administration of low doses of micronized progesterone
Progesterone (P4) is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used ...
(which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.
Antidepressant effects
The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown. Other GABAA receptor PAMs, such as benzodiazepines, are not thought of as antidepressants and have no proven efficacy, despite clinicians prescribing Alprazolam for depression in the past. Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and sub-populations differently than benzodiazepines. As examples, GABAA receptor-potentiating neurosteroids may preferentially target δ subunit-containing GABAA receptors, and enhance both tonic and phasic inhibition mediated by GABAA receptors. It is also possible that neurosteroids like allopregnanolone may act on other target
Target may refer to:
Physical items
* Shooting target, used in marksmanship training and various shooting sports
** Bullseye (target), the goal one for which one aims in many of these sports
** Aiming point, in field artillery, fi ...
s, including membrane progesterone receptors, T-type voltage-gated calcium channels, and others, to mediate antidepressant effects.
Pharmacology
Pharmacokinetics
Brexanolone has low oral
The word oral may refer to:
Relating to the mouth
* Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid
**Oral administration of medicines
** Oral examination (also known as an oral exam or oral ...
bioavailability of less than 5%, necessitating non-oral administration. The 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 ...
of brexanolone is approximately 3 L/kg. Its plasma protein binding
Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...
is more than 99%. Brexanolone is metabolized
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
by keto- reduction mediated via aldo-keto reductases. The compound is also conjugated by glucuronidation
Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosid ...
via glucuronosyltransferases and sulfation via sulfotransferases. It is not metabolized importantly by the 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 ...
system. The three main metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s of brexanolone are inactive. The elimination 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 ...
of brexanolone is 9 hours. Its total plasma
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
clearance is 1 L/h/kg. It is excreted
Excretion is a process in which metabolic waste
is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...
47% in feces
Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...
and 42% in 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 ...
. Less than 1% is excreted as unchanged brexanolone.
Chemistry
Allopregnanolone is a pregnane (C21) 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 is also known as 5α-pregnan-3α-ol-20-one, 5α-Pregnane-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione Pregnanedione, or pregnane-3,20-dione, may refer to:
* 5α-Dihydroprogesterone (5α-pregnane-3,20-dione)
* 5β-Dihydroprogesterone (5β-pregnane-3,20-dione)
See also
* Progesterone (pregn-4-ene-3,20-dione)
* Pregnanolone
* Pregnanediol
* Pregnan ...
(5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol
Pregnanediol, or 5β-pregnane-3α,20α-diol, is an inactive metabolic product of progesterone. A test can be done to measure the amount of pregnanediol in urine, which offers an indirect way to measure progesterone levels in the body.
From the ur ...
(5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of 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 ...
(3,5-tetrahydroprogesterone), with the other three isomers being 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 ...
(5β-pregnan-3α-ol-20-one), isopregnanolone
Isopregnanolone, also known as isoallopregnanolone and epiallopregnanolone, as well as sepranolone (), and as 3β-hydroxy-5α-pregnan-20-one or 3β,5α-tetrahydroprogesterone (3β,5α-THP), is an endogenous neurosteroid and a natural 3β-epimer of ...
(5α-pregnan-3β-ol-20-one), and epipregnanolone
Epipregnanolone, also known as 3β-hydroxy-5β-pregnan-20-one, 3β,5β-tetrahydroprogesterone, or 3β,5β-THP, is an endogenous neurosteroid. It acts as a negative allosteric modulator of the GABAA receptor and reverses the effects of potentiato ...
(5β-pregnan-3β-ol-20-one).
Biosynthesis
The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase
5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of ...
. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone. Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.
Derivatives
A variety of 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 ...
derivatives
The derivative of a function is the rate of change of the function's output relative to its input value.
Derivative may also refer to:
In mathematics and economics
* Brzozowski derivative in the theory of formal languages
* Formal derivative, an ...
and analogues of allopregnanolone with similar activity and effects exist, including alfadolone
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
* Hydroxydion ...
(3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone
Alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name Alfaxan, is a neuroactive steroid and general anesthetic which is used currently in veterinary practice as an induction agent for anesthesia and as an injectable ...
(3α-hydroxy-5α-pregnane-11,20-dione), 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 ...
(3α-hydroxy-3β-methyl-5α-pregnan-20-one), 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 ...
(21-hydroxy-5β-pregnane-3,20-dione), 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 ...
(11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), 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 ...
(3α-hydroxy-5β-pregnan-11,20-dione).
The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone
Tetrahydrodeoxycorticosterone (abbreviated as THDOC; 3α,21-dihydroxy-5α-pregnan-20-one), also referred to as ''allotetrahydrocorticosterone'', is an endogenous neurosteroid. It is synthesized from the adrenal hormone deoxycorticosterone by the ...
(THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
and other conditions, including post-traumatic stress disorder
Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on ...
(PTSD).
History
In March 2019, brexanolone was approved in the United States for the treatment of postpartum depression (PPD) in adult women, the first drug approved by the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) specifically for PPD.
The efficacy of brexanolone was shown in two clinical studies in participants who received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for four weeks. The FDA approved allopregnanolone based on evidence from three clinical trials, conducted in the United States, (Trial 1/NCT02942004, Trial 3/NCT02614541, Trial 2/ NCT02942017) of 247 women with moderate or severe postpartum depression.
The FDA granted the application for brexanolone priority review designation, breakthrough therapy
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...
designation, and granted approval of allopregnanolone to Sage Therapeutics, Inc.
Society and culture
Names
Allopregnanolone is the name of the molecule commonly used in the literature when it is discussed as an endogenous neurosteroid. Brexanolone is both the and the in the context of its use as a medication.
Zulresso is a brand name of the medication.
Legal status
In the United States, brexanolone is a Schedule IV controlled substance. Allopregnanolone is available only through a restricted program called the Zulresso REMS Program that requires the drug to be administered by a healthcare provider in a certified healthcare facility. The REMS requires that patients be enrolled in the program prior to administration of the drug.
Dose
It is given continuously by intravenous infusion
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
over a period of 60 hours (2.5 days). The dosage of brexanolone is progressively adjusted over a range of 30 to 90 μg/kg/hour during this period.
Several warnings and precautions are addressed in a boxed warning
In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because
the U.S. Food and Drug Administration specifies that it ...
in the drug's prescribing information. Because of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring (monitors oxygen levels in the blood). While receiving the infusion, women must be accompanied during interactions with children. Women should be counseled on the risks of allopregnanolone treatment and instructed that they must be monitored for these effects at a healthcare facility for the entire 60 hours of infusion. Women who have received the treatment should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely gone away.
Available forms
Brexanolone is an aqueous mixture
In chemistry, a mixture is a material made up of two or more different chemical substances which are not chemically bonded. A mixture is the physical combination of two or more substances in which the identities are retained and are mixed in the ...
of synthetic allopregnanolone and sulfobutyl ether β-cyclodextrin (betadex sulfobutyl ether sodium), a solubilizing agent. It is provided at an allopregnanolone concentration of 100 mg/20 mL (5 mg/mL) in single-dose vial
A vial (also known as a phial or flacon) is a small glass or plastic vessel or bottle, often used to store medication as liquids, powders or capsules. They can also be used as scientific sample vessels; for instance, in autosampler devices i ...
s for use by intravenous infusion. Each mL of brexanolone solution contains 5 mg allopregnanolone, 250 mg sulfobutyl ether β-cyclodextrin, 0.265 mg citric acid monohydrate, 2.57 mg sodium citrate dihydrate Sodium citrate may refer to any of the sodium salts of citric acid (though most commonly the third):
* Monosodium citrate
* Disodium citrate
* Trisodium citrate
The three forms of salt are collectively known by the E number E331.
Applications
F ...
, and water for injection. The solution is hypertonic
In chemical biology, tonicity is a measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a partially-permeable cell membrane. Tonicity depends on the relative concentration of selective membrane- ...
and must be diluted to a target concentration of 1 mg/mL with sterile water and sodium chloride
Sodium chloride , commonly known as salt (although sea salt also contains other chemical salts), is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. With molar masses of 22.99 and 35.45 g ...
prior to administration. Five infusion bags are generally required for the full infusion. More than five infusion bags are necessary for patients weighing more than 90 kg (200 lbs).
Research
Brexanolone was under development as an intravenously administered medication for the treatment of major depressive disorder
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
, super-refractory status epilepticus, and essential tremor, but development for these indications was discontinued.
Exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogeno ...
progesterone, such as oral
The word oral may refer to:
Relating to the mouth
* Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid
**Oral administration of medicines
** Oral examination (also known as an oral exam or oral ...
progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations. Due to this, it has been suggested that oral progesterone could be described as a prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
of sorts for allopregnanolone. As a result, there has been some interest in using oral progesterone to treat catamenial epilepsy, as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to oral progesterone, oral pregnenolone
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/ metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...
has also been found to act as a prodrug of allopregnanolone, though also of pregnenolone sulfate
Pregnenolone sulfate (PS, PREGS) is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects.
Biological activity
Pre ...
.
References
Further reading
*
*
External links
*
*
*
*
{{Portal bar , Medicine
Anticonvulsants
Antidepressants
Breakthrough therapy
GABAA receptor positive allosteric modulators
GABAA-rho receptor positive allosteric modulators
Glycine receptor agonists
Ketones
Neurosteroids
Nicotinic antagonists
Pregnane X receptor agonists
Pregnanes
5α-Pregnanes
Progestogens
Sterols