ganaxolone
{{Short description|Chemical compound}}
{{Refimprove science|date=May 2017}}
{{Use dmy dates|date=April 2017}}
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{{Infobox drug
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| image = Ganaxolone.svg
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| pronounce =
| tradename = Ztalmy
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| licence_EU =
| DailyMedID = Ganaxolone
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| routes_of_administration = By mouth
| class = Neurosteroid
| ATC_prefix = N03
| ATC_suffix = AX27
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| legal_US = Schedule V
| legal_EU = Rx-only
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| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 38398-32-2
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| PubChem = 6918305
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB05087
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 5293511
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 98WI44OHIQ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D04300
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| ChEMBL = 161915
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| synonyms = GNX; CCD-1042; 3β-Methyl-5α-pregnan-3α-ol-20-one; 3α-Hydroxy-3β-methyl-5α-pregnan-20-one
| IUPAC_name = 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-Hydroxy-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone
| C=22 | H=36 | O=2
| SMILES = CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CC[C@@](C4)(C)O)C)C
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C22H36O2/c1-14(23)17-7-8-18-16-6-5-15-13-20(2,24)11-12-21(15,3)19(16)9-10-22(17,18)4/h15-19,24H,5-13H2,1-4H3/t15-,16-,17+,18-,19-,20+,21-,22+/m0/s1
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = PGTVWKLGGCQMBR-FLBATMFCSA-N
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Ganaxolone, sold under the brand name Ztalmy, is a medication used to treat seizures in people with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder.{{cite journal | vauthors = Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW | title = Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 280 | issue = 3 | pages = 1284–1295 | date = March 1997 | pmid = 9067315 }} Ganaxolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator.
The most common side effects of treatment with ganaxolone include somnolence (sleepiness), fever, excessive saliva or drooling, and seasonal allergy.
Ganaxolone was approved for medical use in the United States in March 2022,{{cite journal | vauthors = Lamb YN | title = Ganaxolone: First Approval | journal = Drugs | volume = 82 | issue = 8 | pages = 933–940 | date = June 2022 | pmid = 35596878 | doi = 10.1007/s40265-022-01724-0 }} and in the European Union in July 2023. The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.{{cite web | title=Advancing Health Through Innovation: New Drug Therapy Approvals 2022 | website=U.S. Food and Drug Administration (FDA) | date=10 January 2023 | url=https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022 | access-date=22 January 2023 | archive-date=21 January 2023 | archive-url=https://web.archive.org/web/20230121035714/https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022 | url-status=live }} {{PD-notice}}{{cite report | title=New Drug Therapy Approvals 2022 | website=U.S. Food and Drug Administration (FDA) | date=January 2024 | url=https://www.fda.gov/media/164429/download | format=PDF | access-date=14 January 2024 | archive-url=https://web.archive.org/web/20240114065648/https://www.fda.gov/media/164429/download | archive-date=14 January 2024 | url-status=live }} {{PD-notice}}
Medical uses
Ganaxolone is indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder.{{cite journal | vauthors = Gould A, Amin S | title = An overview of ganaxolone as a treatment for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder | journal = Expert Review of Neurotherapeutics | volume = | issue = | pages = 1–7 | date = July 2024 | pmid = 39082513 | doi = 10.1080/14737175.2024.2385937 }}{{cite journal | vauthors = Khan P, Saini S, Hussain S, Majid H, Gupta S, Agarwal N | title = A systematic review and meta-analysis on efficacy and safety of Ganaxolone in epilepsy | journal = Expert Opinion on Pharmacotherapy | volume = 25 | issue = 5 | pages = 621–632 | date = April 2024 | pmid = 38606458 | doi = 10.1080/14656566.2024.2342413 }}
Pharmacology
=Mechanism of action=
The exact mechanism of action for ganaxolone is unknown; however, results from animal studies suggest that it acts by blocking seizure propagation and elevating seizure thresholds.
Ganaxolone is thought to modulate both synaptic and extrasynaptic GABAA receptors to normalize over-excited neurons. Ganaxolone's activation of the extrasynaptic receptor is an additional mechanism that provides stabilizing effects that potentially differentiates it from other drugs that increase GABA signaling.
Ganaxolone binds to allosteric sites of the GABAA receptor to modulate and open the chloride ion channel, resulting in a hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission, reducing the chance of a successful action potential (depolarization) from occurring.{{cite journal | vauthors = Kaminski RM, Livingood MR, Rogawski MA | title = Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice | journal = Epilepsia | volume = 45 | issue = 7 | pages = 864–867 | date = July 2004 | pmid = 15230714 | doi = 10.1111/j.0013-9580.2004.04504.x | s2cid = 21974013 }}{{cite journal | vauthors = Reddy DS, Rogawski MA | title = Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model | journal = Epilepsy Research | volume = 89 | issue = 2–3 | pages = 254–260 | date = May 2010 | pmid = 20172694 | pmc = 2854307 | doi = 10.1016/j.eplepsyres.2010.01.009 }}
It is unknown whether ganaxolone possesses significant hormonal activity in vivo, with a 2020 study finding evidence of in vitro binding to the membrane progesterone receptor.{{cite journal | vauthors = Thomas P, Pang Y | title = Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells | journal = Frontiers in Endocrinology | volume = 11 | issue = 417 | pages = 417 | date = Jun 24, 2020 | pmid = 32670200 | pmc = 7331777 | doi = 10.3389/fendo.2020.00417 | doi-access = free }}
Chemistry
{{Unreferenced section|date=March 2022}}
Ganaxolone is an analog of the neurosteroid allopregnanolone that possesses no known hormonal activity and, instead, is thought to primarily function by binding to GABAA receptors as a positive allosteric modulator.{{cite web |title=Ganaxolone |url=https://pubchem.ncbi.nlm.nih.gov/compound/6918305 | work = PubChem |publisher= U.S. National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM) |access-date=6 August 2022 |archive-date=10 December 2022 |archive-url=https://web.archive.org/web/20221210192506/https://pubchem.ncbi.nlm.nih.gov/compound/6918305 |url-status=live }}
Other pregnane neurosteroids include alfadolone, alfaxolone, hydroxydione, minaxolone, pregnanolone (eltanolone), and renanolone, among others.{{Cite patent| country = US | number = 20190160078A1 |title=Ganaxolone for use in treating genetic epileptic disorders|gdate=2019-05-30| inventor = Masuoka LK, Lappalainen J | assign = Marinus Pharmaceuticals Inc. |url=https://patents.google.com/patent/US20190160078A1/en}}
History
The FDA approved ganaxolone based on evidence from a single, double-blind, randomized, placebo-controlled study (Study 1, NCT03572933) of 101 participants with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder who were two years of age and older. The trial was conducted at 36 sites in 8 countries including Australia, France, Israel, Italy, Poland, Russian Federation, the United Kingdom, and the United States. Forty-four (40.7%) of the participants were from US sites.{{cite web | title=Drug Trials Snapshots: Ztalmy | website=U.S. Food and Drug Administration | date=18 March 2022 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-ztalmy | access-date=9 October 2023}} {{PD-notice}} Safety was assessed from a pool of two clinical studies. These include the study of participants with cyclin-dependent kinase-like 5 deficiency disorder and a clinical study that included seven additional participants from a trial of ganaxolone in children and young adults.
References
{{Reflist}}
External links
- {{ClinicalTrialsGov|NCT03572933|Study of Adjunctive Ganaxolone Treatment in Children and Young Adults With CDKL5 Deficiency Disorder (Marigold)}}
{{Anticonvulsants}}
{{GABAA receptor positive modulators}}
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