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Brexanolone

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Product Description

Basic Characteristics

Product Name Brexanolone
CAS Number 516-54-1
Molecular Formula C21H34O2
Formula Weight 318.501
Synonyms Allopregnanolone

Brexanolone

516-54-1

Allotetrahydroprogesterone

Allopregnan-3alpha-ol-20-one

Appearance White powder
Storage and Handling Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years)..

 

Brexanolone Description

Brexanolone is a unique, intravenously administered, neuroactive steroidal antidepressant used in the therapy of moderate-to-severe postpartum depression. In prelicensure clinical trials, brexanolone therapy was not associated with an increased rate of serum aminotransferase elevations, and it has not been linked to instances of clinically apparent acute liver injury.

Brexanolone also is a 3-hydroxy-5alpha-pregnan-20-one in which the hydroxy group at position 3 has alpha-configuration. It is a metabolite of the sex hormone progesterone and used for the treatment of postpartum depression in women. It has a role as a human metabolite, an antidepressant, a GABA modulator, an intravenous anaesthetic and a sedative.

 

Brexanolone Mechanism of Action

Mechanism of action of brexanolone is not fully known. Brexanolone is an aqueous formulation of allopregnanolone. Allopregnanolone is a major metabolite of progesterone. Levels of allopregnanolone continue to rise with progesterone during pregnancy with the highest in the third trimester. Allopregnanolone is a potent, endogenous neuroactive steroid that modulates neuronal excitability through positive allosteric modulation on the synaptic and extrasynaptic gamma-aminobutyric acid (GABA) type A receptors. The extrasynaptic GABA type A receptors mediate tonic inhibition which makes allopregnanolone’s mechanism unique when compared to benzodiazepines which mediate the phasic inhibition at GABA type A receptors.

 

Brexanolone Application

Brexanolone is the first drug to have ever been approved by the US FDA specifically for the treatment of postpartum depression (PPD) in adult females. Since PPD, like various other types of depression, is characterized by feelings of sadness, worthlessness or guilt, cognitive impairment, and/or possibly suicidal ideation, it is considered a life-threatening condition. Studies have consequently found that PPD can genuinely have profound negative effects on the maternal-infant bond and later infant development. The development and availability of brexanolone for the treatment of PPD in adult females subsequently provides a new and promising therapy where few existed before. In particular, the use of brexanolone in treating PPD is surrounded with promise because it acts in part as a synthetic supplement for possible deficiencies in endogenous brexanolone (allopregnanolone) in postpartum women susceptible to PPD whereas many commonly used anti-depressive medications elicit actions that may modulate the presence and activity of substances like serotonin, norepinephrine, and/or monoamine oxidase but do not mediate activities directly associated with PPD like natural fluctuations in the levels of endogenous neuroactive steroids like allopregnanolone. And finally, although brexanolone may also be undergoing clinical trials to investigate its abilities to treat super-refractory status epilepticus, it appears that some such studies have failed to meet primary endpoints that compare success in the weaning of third-line agents and resolution of potentially life-threatening status epilepticus with brexanolone vs. placebo when added to standard-of-care.

 

Brexanolone Side Effects & Warning

Brexanolone is extensively metabolized by many pathways and thus unlikely to have significant drug-drug interactions. CYP2C9 is the only cytochrome P450 enzyme that has shown to be inhibited by brexanolone in in vitro studies. A clinical interaction study failed to show any alterations in pharmacokinetics when brexanolone was coadministered with phenytoin, a CYP2C9 substrate. Abuse potential has also been demonstrated to be low, as evidenced by no differences in subjective reports compared with placebo. In terms of the impact of hepatic and renal impairment on pharmacokinetics, there were no changes in tolerability in patients with moderate to severe liver disease, and no dose adjustments were necessary for severe kidney disease . However, the solubilizing agent SBECD may accumulate in patients with severe renal impairment, and thus brexanolone should not be given to patients with end-stage renal disease.

 

Reference

[1] Meltzer-Brody S, Colquhoun H, Riesenberg R, et al.: Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 2018; 392:1058–1070 Crossref, Google Scholar.

[2] Luke DR, Tomaszewski K, Damle B, et al.: Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD). J Pharm Sci 2010; 99:3291–3301 Crossref, Google Scholar.

[3] Brexanolone Injection, for Intravenous Use: Sponsor Briefing Document. Cambridge, Mass, Sage Therapeutics, Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting, Nov 2, 2018. Google Scholar.

[4] Luisi S, Petraglia F, Benedetto C, Nappi RE, Bernardi F, Fadalti M, Reis FM, Luisi M, Genazzani AR. Serum allopregnanolone levels in pregnant women: changes during pregnancy, at delivery, and in hypertensive patients. J Clin Endocrinol Metab. 2000 Jul;85(7):2429-33. [PubMed].

[5]  Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992 Mar;6(6):2311-22. [PubMed].

[6] Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 2005 Mar;6(3):215-29. [PubMed].

[7] Johannsen BM, Larsen JT, Laursen TM, Bergink V, Meltzer-Brody S, Munk-Olsen T. All-Cause Mortality in Women With Severe Postpartum Psychiatric Disorders. Am J Psychiatry. 2016 Jun 01;173(6):635-42. [PMC free article] [PubMed].

[8] Noorlander Y, Bergink V, van den Berg MP. Perceived and observed mother-child interaction at time of hospitalization and release in postpartum depression and psychosis. Arch Womens Ment Health. 2008;11(1):49-56. [PubMed].