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Wikipedia

Allopregnanolone

April 24, 2023

Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone.[9][10] As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso,[6][11] and used to treat postpartum depression.[10][12][13] It is given by injection into a vein.[10][6]

Allopregnanolone
Clinical data
Trade namesZulresso
Other namesALLO; Allo; ALLOP; AlloP; SAGE-547; SGE-102; 5α-Pregnan-3α-ol-20-one; 5α-Pregnane-3α-ol-20-one;[1][2][3][4][5] 3α-Hydroxy-5α-pregnan-20-one; 3α,5α-Tetrahydroprogesterone; 3α,5α-THP, brexanolone (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa619037
License data
Routes of
administration		Intravenous[6]
Drug classNeurosteroids; Antidepressants
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: <5%[8]
Protein binding>99%[6][8]
MetabolismNon-CYP450 (keto-reduction via aldo-keto reductases (AKR), glucuronidation via glucuronosyltransferases (UGT), sulfation via sulfotransferases (SULT))[6][8]
Elimination half-life9 hours[6][8]
ExcretionFeces: 47%[6][8]
Urine: 42%[6][8]
Identifiers
  • 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone
CAS Number
  • 516-54-1
PubChem CID
  • 92786
DrugBank
  • DB11859
ChemSpider
  • 83760
UNII
  • S39XZ5QV8Y
KEGG
  • D11149
ChEBI
  • CHEBI:50169
ChEMBL
  • ChEMBL207538
CompTox Dashboard (EPA)
  • DTXSID1046342
Chemical and physical data
FormulaC21H34O2
Molar mass318.501 g·mol−1
3D model (JSmol)
  • Interactive image
  • CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CC[C@H](C4)O)C)C
  • InChI=1S/C21H34O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h14-19,23H,4-12H2,1-3H3/t14-,15+,16-,17+,18-,19-,20-,21+/m0/s1
  • Key:AURFZBICLPNKBZ-SYBPFIFISA-N

Side effects of brexanolone may include sedation, sleepiness, dry mouth, hot flashes, and loss of consciousness.[6][10] It is a neurosteroid and acts as a positive allosteric modulator of the GABAA receptor, the major biological target of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).[6]

Brexanolone was approved for medical use in the United States in 2019.[10][14] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[15] The long administration time, as well as the cost for a one-time treatment, have raised concerns about accessibility for many women.[16]

Medical uses

Brexanolone is used to treat postpartum depression in adult women.[10]

Side effects

Side effects of brexanolone include sedation (13–21%), dry mouth (3–11%), loss of consciousness (3–5%), and flushing (2–5%).[6][10][8] It can also produce euphoria to a degree similar to that of alprazolam (3–13% at infusion doses of 90–270 μg over a one-hour period).[6]

Biological function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,[17] prosocial,[18] antiaggressive,[19] prosexual,[18] sedative, pro-sleep,[20] cognitive, memory-impairment, analgesic,[21] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.[9] Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.[22][23][24]

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.[25][26]

Mechanism of action

Molecular interactions

Allopregnanolone is an endogenous inhibitory pregnane neurosteroid.[9] It is made from progesterone, and is a positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor.[9] Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.[9][27][28] 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.[29]

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor.[9] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.[30] 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.[31][32] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,[33] and also appears to act as a negative allosteric modulator of the 5-HT3 receptor.[34] 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 receptors.[35]

Unlike progesterone, allopregnanolone is inactive at the classical nuclear progesterone receptor (PR).[35] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which does act as an agonist of the PR, and for this reason, allopregnanolone can produce PR-mediated progestogenic effects.[36][37] In addition, allopregnanolone was reported in 2012 to be an agonist of the membrane progesterone receptors (mPRs) discovered shortly before, including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[38][39] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.[38][40] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.[35][41]

Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),[42] including α1 subtypes Cav1.2 and Cav1.3.[43] 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.[43] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.[43] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).[44] 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.[44]

Biphasic actions at the GABAA receptor

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.[45][46][47] 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.[45][46] This seems to be a common effect of many GABAA receptor positive allosteric modulators.[22][47] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[48]

Antidepressant effects

The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown.[49] Other GABAA receptor PAMs, such as benzodiazepines, are not thought of as antidepressants and have no proven efficacy,[49] despite clinicians prescribing Alprazolam for depression in the past.[50][51] Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and sub-populations differently than benzodiazepines.[49] 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.[49] It is also possible that neurosteroids like allopregnanolone may act on other targets, including membrane progesterone receptors, T-type voltage-gated calcium channels, and others, to mediate antidepressant effects.[49]

Pharmacology

Pharmacokinetics

Brexanolone has low oral bioavailability of less than 5%, necessitating non-oral administration.[8] The volume of distribution of brexanolone is approximately 3 L/kg.[8] Its plasma protein binding is more than 99%.[6][8] Brexanolone is metabolized by keto-reduction mediated via aldo-keto reductases.[6][8] The compound is also conjugated by glucuronidation via glucuronosyltransferases and sulfation via sulfotransferases.[6] It is not metabolized importantly by the cytochrome P450 system.[6][8] The three main metabolites of brexanolone are inactive.[8] The elimination half-life of brexanolone is 9 hours.[6][8] Its total plasma clearance is 1 L/h/kg.[8] It is excreted 47% in feces and 42% in urine.[6][8] Less than 1% is excreted as unchanged brexanolone.[8]

Chemistry

See also: List of neurosteroids

Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 5α-Pregnane-3α-ol-20-one,[1][2][3][4][5] 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 (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 (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone (5α-pregnan-3β-ol-20-one), and epipregnanolone (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. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.[9] Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.[52]

Derivatives

A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (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 (3α-hydroxy-5β-pregnan-11,20-dione).

The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (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 and other conditions, including post-traumatic stress disorder (PTSD).[9]

History

In March 2019, brexanolone was approved in the United States for the treatment of postpartum depression (PPD) in adult women,[10][14] the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for PPD.[10]

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.[10] 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.[53]

The FDA granted the application for brexanolone priority review designation, breakthrough therapy designation, and granted approval of allopregnanolone to Sage Therapeutics, Inc.[10]

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 INN and the USAN in the context of its use as a medication.[54][55]

Zulresso is a brand name of the medication.[6]

Legal status

In the United States, brexanolone is a Schedule IV controlled substance.[7][6] 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.[10]

Available forms

Brexanolone is an aqueous mixture of synthetic allopregnanolone and sulfobutyl ether β-cyclodextrin (betadex sulfobutyl ether sodium), a solubilizing agent.[6][8] It is provided at an allopregnanolone concentration of 100 mg/20 mL (5 mg/mL) in single-dose vials for use by intravenous infusion.[6] 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, and water for injection.[6] The solution is hypertonic and must be diluted to a target concentration of 1 mg/mL with sterile water and sodium chloride prior to administration.[6] Five infusion bags are generally required for the full infusion.[6] More than five infusion bags are necessary for patients weighing more than 90 kg (200 lbs).[6]

Research

Brexanolone was under development as an intravenously administered medication for the treatment of major depressive disorder, super-refractory status epilepticus, and essential tremor, but development for these indications was discontinued.[56]

Exogenous progesterone, such as oral progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[57] Due to this, it has been suggested that oral progesterone could be described as a prodrug of sorts for allopregnanolone.[57] As a result, there has been some interest in using oral progesterone to treat catamenial epilepsy,[58] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to oral progesterone, oral pregnenolone has also been found to act as a prodrug of allopregnanolone,[59][60][61] though also of pregnenolone sulfate.[62]

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Further reading

  • Herd MB, Belelli D, Lambert JJ (October 2007). "Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors". Pharmacology & Therapeutics. 116 (1): 20–34. arXiv:1607.02870. doi:10.1016/j.pharmthera.2007.03.007. PMID 17531325.
  • Zorumski CF, Paul SM, Covey DF, Mennerick S (November 2019). "Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond". Neurobiology of Stress. 11: 100196. doi:10.1016/j.ynstr.2019.100196. PMC 6804800. PMID 31649968.

External links

  • "Brexanolone". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02942004 for "A Study to Evaluate Efficacy and Safety of SAGE-547 in Participants With Severe Postpartum Depression (547-PPD-202B)" at ClinicalTrials.gov
  • Clinical trial number NCT02614547 for "A Study to Evaluate SAGE-547 in Patients With Severe Postpartum Depression" at ClinicalTrials.gov
  • Clinical trial number NCT02942017 for "A Study to Evaluate Safety and Efficacy of SAGE-547 in Participants With Moderate Postpartum Depression (547-PPD-202C)" at ClinicalTrials.gov

April 24, 2023
allopregnanolone, naturally, occurring, neurosteroid, which, made, body, from, hormone, progesterone, medication, allopregnanolone, referred, brexanolone, sold, under, brand, name, zulresso, used, treat, postpartum, depression, given, injection, into, vein, cl. Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone 9 10 As a medication allopregnanolone is referred to as brexanolone sold under the brand name Zulresso 6 11 and used to treat postpartum depression 10 12 13 It is given by injection into a vein 10 6 AllopregnanoloneClinical dataTrade namesZulressoOther namesALLO Allo ALLOP AlloP SAGE 547 SGE 102 5a Pregnan 3a ol 20 one 5a Pregnane 3a ol 20 one 1 2 3 4 5 3a Hydroxy 5a pregnan 20 one 3a 5a Tetrahydroprogesterone 3a 5a THP brexanolone USAN US AHFS Drugs comMonographMedlinePlusa619037License dataUS DailyMed Brexanolone US FDA ZulressoRoutes ofadministrationIntravenous 6 Drug classNeurosteroids AntidepressantsATC codeN06AX29 WHO Legal statusLegal statusUS Schedule IV 7 6 Pharmacokinetic dataBioavailabilityOral lt 5 8 Protein binding gt 99 6 8 MetabolismNon CYP450 keto reduction via aldo keto reductases AKR glucuronidation via glucuronosyltransferases UGT sulfation via sulfotransferases SULT 6 8 Elimination half life9 hours 6 8 ExcretionFeces 47 6 8 Urine 42 6 8 IdentifiersIUPAC name 1 3R 5S 8R 9S 10S 13S 14S 17S 3 hydroxy 10 13 dimethyl 2 3 4 5 6 7 8 9 11 12 14 15 16 17 tetradecahydro 1H cyclopenta a phenanthren 17 yl ethanoneCAS Number516 54 1PubChem CID92786DrugBankDB11859ChemSpider83760UNIIS39XZ5QV8YKEGGD11149ChEBICHEBI 50169ChEMBLChEMBL207538CompTox Dashboard EPA DTXSID1046342Chemical and physical dataFormulaC 21H 34O 2Molar mass318 501 g mol 13D model JSmol Interactive imageSMILES CC O C H 1CC C H 2 C 1 CC C H 3 C H 2CC C H 4 C 3 CC C H C4 O C CInChI InChI 1S C21H34O2 c1 13 22 17 6 7 18 16 5 4 14 12 15 23 8 10 20 14 2 19 16 9 11 21 17 18 3 h14 19 23H 4 12H2 1 3H3 t14 15 16 17 18 19 20 21 m0 s1Key AURFZBICLPNKBZ SYBPFIFISA NSide effects of brexanolone may include sedation sleepiness dry mouth hot flashes and loss of consciousness 6 10 It is a neurosteroid and acts as a positive allosteric modulator of the GABAA receptor the major biological target of the inhibitory neurotransmitter g aminobutyric acid GABA 6 Brexanolone was approved for medical use in the United States in 2019 10 14 The U S Food and Drug Administration FDA considers it to be a first in class medication 15 The long administration time as well as the cost for a one time treatment have raised concerns about accessibility for many women 16 Contents 1 Medical uses 2 Side effects 3 Biological function 4 Mechanism of action 4 1 Molecular interactions 4 1 1 Biphasic actions at the GABAA receptor 4 2 Antidepressant effects 5 Pharmacology 5 1 Pharmacokinetics 6 Chemistry 6 1 Biosynthesis 6 2 Derivatives 7 History 8 Society and culture 8 1 Names 8 2 Legal status 8 3 Available forms 9 Research 10 References 11 Further reading 12 External linksMedical uses EditBrexanolone is used to treat postpartum depression in adult women 10 Side effects EditSide effects of brexanolone include sedation 13 21 dry mouth 3 11 loss of consciousness 3 5 and flushing 2 5 6 10 8 It can also produce euphoria to a degree similar to that of alprazolam 3 13 at infusion doses of 90 270 mg over a one hour period 6 Biological function EditAllopregnanolone possesses a wide variety of effects including in no particular order antidepressant anxiolytic stress reducing rewarding 17 prosocial 18 antiaggressive 19 prosexual 18 sedative pro sleep 20 cognitive memory impairment analgesic 21 anesthetic anticonvulsant neuroprotective and neurogenic effects 9 Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood anxiety premenstrual syndrome catamenial epilepsy and various other neuropsychiatric conditions 22 23 24 During pregnancy allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus 25 26 Mechanism of action EditMolecular interactions Edit Allopregnanolone is an endogenous inhibitory pregnane neurosteroid 9 It is made from progesterone and is a positive allosteric modulator of the action of g aminobutyric acid GABA at GABAA receptor 9 Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines including anxiolytic sedative and anticonvulsant activity 9 27 28 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 29 Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor 9 While allopregnanolone like other inhibitory neurosteroids such as THDOC positively modulates all GABAA receptor isoforms those isoforms containing d subunits exhibit the greatest potentiation 30 Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA r receptor though the implications of this action are unclear 31 32 In addition to its actions on GABA receptors allopregnanolone like progesterone is known to be a negative allosteric modulator of nACh receptors 33 and also appears to act as a negative allosteric modulator of the 5 HT3 receptor 34 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 receptors 35 Unlike progesterone allopregnanolone is inactive at the classical nuclear progesterone receptor PR 35 However allopregnanolone can be intracellularly oxidized into 5a dihydroprogesterone which does act as an agonist of the PR and for this reason allopregnanolone can produce PR mediated progestogenic effects 36 37 In addition allopregnanolone was reported in 2012 to be an agonist of the membrane progesterone receptors mPRs discovered shortly before including mPRd mPRa and mPRb with its activity at these receptors about a magnitude more potent than at the GABAA receptor 38 39 The action of allopregnanolone at these receptors may be related in part to its neuroprotective and antigonadotropic properties 38 40 Also like progesterone recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor 35 41 Similarly to many other GABAA receptor positive allosteric modulators allopregnanolone has been found to act as an inhibitor of L type voltage gated calcium channels L VGCCs 42 including a1 subtypes Cav1 2 and Cav1 3 43 However the threshold concentration of allopregnanolone to inhibit L VGCCs was determined to be 3 mM 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 43 Thus inhibition of L VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone 43 Also allopregnanolone along with several other neurosteroids has been found to activate the G protein coupled bile acid receptor GPBAR1 or TGR5 44 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 44 Biphasic actions at the GABAA receptor Edit Increased levels of allopregnanolone can produce paradoxical effects including negative mood anxiety irritability and aggression 45 46 47 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 45 46 This seems to be a common effect of many GABAA receptor positive allosteric modulators 22 47 In accordance acute administration of low doses of micronized progesterone which reliably elevates allopregnanolone levels has been found to have negative effects on mood while higher doses have a neutral effect 48 Antidepressant effects Edit The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown 49 Other GABAA receptor PAMs such as benzodiazepines are not thought of as antidepressants and have no proven efficacy 49 despite clinicians prescribing Alprazolam for depression in the past 50 51 Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and sub populations differently than benzodiazepines 49 As examples GABAA receptor potentiating neurosteroids may preferentially target d subunit containing GABAA receptors and enhance both tonic and phasic inhibition mediated by GABAA receptors 49 It is also possible that neurosteroids like allopregnanolone may act on other targets including membrane progesterone receptors T type voltage gated calcium channels and others to mediate antidepressant effects 49 Pharmacology EditPharmacokinetics Edit Brexanolone has low oral bioavailability of less than 5 necessitating non oral administration 8 The volume of distribution of brexanolone is approximately 3 L kg 8 Its plasma protein binding is more than 99 6 8 Brexanolone is metabolized by keto reduction mediated via aldo keto reductases 6 8 The compound is also conjugated by glucuronidation via glucuronosyltransferases and sulfation via sulfotransferases 6 It is not metabolized importantly by the cytochrome P450 system 6 8 The three main metabolites of brexanolone are inactive 8 The elimination half life of brexanolone is 9 hours 6 8 Its total plasma clearance is 1 L h kg 8 It is excreted 47 in feces and 42 in urine 6 8 Less than 1 is excreted as unchanged brexanolone 8 Chemistry EditSee also List of neurosteroids Allopregnanolone is a pregnane C21 steroid and is also known as 5a pregnan 3a ol 20 one 5a Pregnane 3a ol 20 one 1 2 3 4 5 3a hydroxy 5a pregnan 20 one or 3a 5a tetrahydroprogesterone 3a 5a THP It is closely related structurally to 5 pregnenolone pregn 5 en 3b ol 20 dione progesterone pregn 4 ene 3 20 dione the isomers of pregnanedione 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 5 pregnane 3 20 diol In addition allopregnanolone is one of four isomers of pregnanolone 3 5 tetrahydroprogesterone with the other three isomers being pregnanolone 5b pregnan 3a ol 20 one isopregnanolone 5a pregnan 3b ol 20 one and epipregnanolone 5b pregnan 3b ol 20 one Biosynthesis Edit The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5a dihydroprogesterone by 5a reductase After that 3a hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone 9 Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal like neurons of the basolateral amygdala 52 Derivatives Edit A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist including alfadolone 3a 21 dihydroxy 5a pregnane 11 20 dione alfaxolone 3a hydroxy 5a pregnane 11 20 dione ganaxolone 3a hydroxy 3b methyl 5a pregnan 20 one hydroxydione 21 hydroxy 5b pregnane 3 20 dione minaxolone 11a dimethylamino 2b ethoxy 3a hydroxy 5a pregnan 20 one Org 20599 21 chloro 3a hydroxy 2b morpholin 4 yl 5b pregnan 20 one Org 21465 2b 2 2 dimethyl 4 morpholinyl 3a hydroxy 11 20 dioxo 5a pregnan 21 yl methanesulfonate and renanolone 3a hydroxy 5b pregnan 11 20 dione The 21 hydroxylated derivative of this compound tetrahydrodeoxycorticosterone THDOC is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone and the 3b methyl analogue of allopregnanolone ganaxolone is under development to treat epilepsy and other conditions including post traumatic stress disorder PTSD 9 History EditIn March 2019 brexanolone was approved in the United States for the treatment of postpartum depression PPD in adult women 10 14 the first drug approved by the U S Food and Drug Administration FDA specifically for PPD 10 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 10 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 53 The FDA granted the application for brexanolone priority review designation breakthrough therapy designation and granted approval of allopregnanolone to Sage Therapeutics Inc 10 Society and culture EditNames Edit Allopregnanolone is the name of the molecule commonly used in the literature when it is discussed as an endogenous neurosteroid Brexanolone is both the INN and the USAN in the context of its use as a medication 54 55 Zulresso is a brand name of the medication 6 Legal status Edit In the United States brexanolone is a Schedule IV controlled substance 7 6 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 10 Available forms Edit Brexanolone is an aqueous mixture of synthetic allopregnanolone and sulfobutyl ether b cyclodextrin betadex sulfobutyl ether sodium a solubilizing agent 6 8 It is provided at an allopregnanolone concentration of 100 mg 20 mL 5 mg mL in single dose vials for use by intravenous infusion 6 Each mL of brexanolone solution contains 5 mg allopregnanolone 250 mg sulfobutyl ether b cyclodextrin 0 265 mg citric acid monohydrate 2 57 mg sodium citrate dihydrate and water for injection 6 The solution is hypertonic and must be diluted to a target concentration of 1 mg mL with sterile water and sodium chloride prior to administration 6 Five infusion bags are generally required for the full infusion 6 More than five infusion bags are necessary for patients weighing more than 90 kg 200 lbs 6 Research EditBrexanolone was under development as an intravenously administered medication for the treatment of major depressive disorder super refractory status epilepticus and essential tremor but development for these indications was discontinued 56 Exogenous progesterone such as oral progesterone elevates allopregnanolone levels in the body with good dose to serum level correlations 57 Due to this it has been suggested that oral progesterone could be described as a prodrug of sorts for allopregnanolone 57 As a result there has been some interest in using oral progesterone to treat catamenial epilepsy 58 as well as other menstrual cycle related and neurosteroid associated conditions In addition to oral progesterone oral pregnenolone has also been found to act as a prodrug of allopregnanolone 59 60 61 though also of pregnenolone sulfate 62 References 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explained by the paradoxical effect mediated by GABAA modulators Psychoneuroendocrinology 34 8 1121 32 doi 10 1016 j psyneuen 2009 02 003 PMID 19272715 S2CID 22259026 a b Backstrom T Bixo M Johansson M Nyberg S Ossewaarde L Ragagnin G et al February 2014 Allopregnanolone and mood disorders Progress in Neurobiology 113 88 94 doi 10 1016 j pneurobio 2013 07 005 PMID 23978486 S2CID 207407084 Andreen L Sundstrom Poromaa I Bixo M Nyberg S Backstrom T August 2006 Allopregnanolone concentration and mood a bimodal association in postmenopausal women treated with oral progesterone Psychopharmacology 187 2 209 21 doi 10 1007 s00213 006 0417 0 PMID 16724185 S2CID 1933116 a b c d e Zorumski CF Paul SM Covey DF Mennerick S November 2019 Neurosteroids as novel antidepressants and anxiolytics GABA A receptors and beyond Neurobiology of Stress 11 100196 doi 10 1016 j ynstr 2019 100196 PMC 6804800 PMID 31649968 Warner MD Peabody CA Whiteford HA Hollister LE April 1988 Alprazolam as an antidepressant The Journal of Clinical Psychiatry 49 4 148 50 PMID 3281931 Srisurapanont M Boonyanaruthee V 1997 Alprazolam and standard antidepressants in the treatment of depression a meta analysis of the antidepressant effect Journal of the Medical Association of Thailand Chotmaihet Thangphaet Centre for Reviews and Dissemination UK 80 3 183 188 PMID 9175386 Agis Balboa RC Pinna G Zhubi A Maloku E Veldic M Costa E et al September 2006 Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis Proceedings of the National Academy of Sciences of the United States of America 103 39 14602 7 Bibcode 2006PNAS 10314602A doi 10 1073 pnas 0606544103 PMC 1600006 PMID 16984997 Drug Trials Snapshots Zulresso U S Food and Drug Administration FDA 2 April 2019 Archived from the original on 28 September 2019 Retrieved 24 November 2019 INN Brexanolone Archived from the original on 4 November 2021 Retrieved 3 September 2019 KEGG DRUG Brexanolone Brexanolone Sage Therapeutics AdisInsight a b Andreen L Spigset O Andersson A Nyberg S Backstrom T June 2006 Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low dose progesterone Maturitas 54 3 238 44 doi 10 1016 j maturitas 2005 11 005 PMID 16406399 Devinsky O Schachter S Pacia S 1 January 2005 Complementary and Alternative Therapies for Epilepsy Demos Medical Publishing pp 378 ISBN 978 1 934559 08 6 Saudan C Desmarchelier A Sottas PE Mangin P Saugy M March 2005 Urinary marker of oral pregnenolone administration Steroids 70 3 179 83 doi 10 1016 j steroids 2004 12 007 PMID 15763596 S2CID 25490229 Piper T Schlug C Mareck U Schanzer W May 2011 Investigations on changes in 13C 12C ratios of endogenous urinary steroids after pregnenolone administration Drug Testing and Analysis 3 5 283 90 doi 10 1002 dta 281 PMID 21538944 Sripada RK Marx CE King AP Rampton JC Ho SS Liberzon I June 2013 Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits Biological Psychiatry 73 11 1045 53 doi 10 1016 j biopsych 2012 12 008 PMC 3648625 PMID 23348009 Ducharme N Banks WA Morley JE Robinson SM Niehoff ML Mattern C et al September 2010 Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration European Journal of Pharmacology 641 2 3 128 34 doi 10 1016 j ejphar 2010 05 033 PMC 3008321 PMID 20570588 Further reading EditHerd MB Belelli D Lambert JJ October 2007 Neurosteroid modulation of synaptic and extrasynaptic GABA A receptors Pharmacology amp Therapeutics 116 1 20 34 arXiv 1607 02870 doi 10 1016 j pharmthera 2007 03 007 PMID 17531325 Zorumski CF Paul SM Covey DF Mennerick S November 2019 Neurosteroids as novel antidepressants and anxiolytics GABA A receptors and beyond Neurobiology of Stress 11 100196 doi 10 1016 j ynstr 2019 100196 PMC 6804800 PMID 31649968 External links Edit Brexanolone Drug Information Portal U S National Library of Medicine Clinical trial number NCT02942004 for A Study to Evaluate Efficacy and Safety of SAGE 547 in Participants With Severe Postpartum Depression 547 PPD 202B at ClinicalTrials gov Clinical trial number NCT02614547 for A Study to Evaluate SAGE 547 in Patients With Severe Postpartum Depression at ClinicalTrials gov Clinical trial number NCT02942017 for A Study to Evaluate Safety and Efficacy of SAGE 547 in Participants With Moderate Postpartum Depression 547 PPD 202C at ClinicalTrials gov Portal Medicine Retrieved from https en wikipedia org w index php title Allopregnanolone amp oldid 1143517223, wikipedia, wiki, book, books, library,

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