Jump to content

Asenapine: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
MCE-CN (talk | contribs)
41 edits
No edit summary
Line 185: Line 185:
|}
|}


Asenapine shows high [[Affinity (pharmacology)|affinity]] (pKi) for numerous [[Receptor (biochemistry)|receptors]], including the [[serotonin]] [[5-HT1A|5-HT<sub>1A</sub>]] (8.6), [[5-HT1B|5-HT<sub>1B</sub>]] (8.4), [[5-HT2A|5-HT<sub>2A</sub>]] (10.2), [[5-HT2B receptor|5-HT<sub>2B</sub>]] (9.8), [[5-HT2C|5-HT<sub>2C</sub>]] (10.5), [[5-HT5A|5-HT<sub>5A</sub>]] (8.8), [[5-HT6|5-HT<sub>6</sub>]] (9.5), and [[5-HT7|5-HT<sub>7</sub>]] (9.9) receptors, the [[adrenaline|adrenergic]] [[Alpha-1 adrenergic receptor|α<sub>1</sub>]] (8.9), [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] (8.9), [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]] (9.5), and [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] (8.9) receptors, the [[dopamine]] [[Dopamine receptor D1|D<sub>1</sub>]] (8.9), [[Dopamine receptor D2|D<sub>2</sub>]] (8.9), [[Dopamine receptor D3|D<sub>3</sub>]] (9.4), and [[Dopamine receptor D4|D<sub>4</sub>]] (9.0) receptors, and the [[histamine]] [[Histamine H1 receptor|H<sub>1</sub>]] (9.0) and [[Histamine H2 receptor|H<sub>2</sub>]] (8.2) receptors. It has much lower affinity (pKi < 5) for the [[muscarinic acetylcholine receptor]]s. Asenapine behaves as a partial [[agonist]] at the 5-HT<sub>1A</sub> receptors.<ref>http://cat.inist.fr/?aModele=afficheN&cpsidt=21237275</ref> At all other targets asenapine is an [[receptor antagonist|antagonist]].<ref name="pmid18308814">{{cite journal |vauthors=Shahid M, Walker GB, Zorn SH, Wong EH | title = Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. | journal = J. Psychopharmacol. | volume = 23 | issue = 1 | pages = 65–73 | year = 2009 | pmid = 18308814 | doi = 10.1177/0269881107082944 }}</ref> As of November 2010 asenapine is also in clinical trials at UC Irvine to treat stuttering.
Asenapine shows high [[Affinity (pharmacology)|affinity]] (pKi) for numerous [[Receptor (biochemistry)|receptors]], including the [[serotonin]] [[5-HT1A|5-HT<sub>1A</sub>]] (8.6), [[5-HT1B|5-HT<sub>1B</sub>]] (8.4), [[5-HT2A|5-HT<sub>2A</sub>]] (10.2), [[5-HT2B receptor|5-HT<sub>2B</sub>]] (9.8), [[5-HT2C|5-HT<sub>2C</sub>]] (10.5), [[5-HT5A|5-HT<sub>5A</sub>]] (8.8), [[5-HT6|5-HT<sub>6</sub>]] (9.5), and [[5-HT7|5-HT<sub>7</sub>]] (9.9) receptors, the [[adrenaline|adrenergic]] [[Alpha-1 adrenergic receptor|α<sub>1</sub>]] (8.9), [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] (8.9), [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]] (9.5), and [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] (8.9) receptors, the [[dopamine]] [[Dopamine receptor D1|D<sub>1</sub>]] (8.9), [[Dopamine receptor D2|D<sub>2</sub>]] (8.9), [[Dopamine receptor D3|D<sub>3</sub>]] (9.4), and [[Dopamine receptor D4|D<sub>4</sub>]] (9.0) receptors, and the [[histamine]] [[Histamine H1 receptor|H<sub>1</sub>]] (9.0) and [[Histamine H2 receptor|H<sub>2</sub>]] (8.2) receptors. It has much lower affinity (pKi < 5) for the [[muscarinic acetylcholine receptor]]s. Asenapine behaves as a partial [[agonist]] at the 5-HT<sub>1A</sub> receptors.<ref>http://cat.inist.fr/?aModele=afficheN&cpsidt=21237275</ref> At all other targets asenapine is an [[receptor antagonist|antagonist]].<ref name="pmid18308814">{{cite journal |vauthors=Shahid M, Walker GB, Zorn SH, Wong EH | title = Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. | journal = J. Psychopharmacol. | volume = 23 | issue = 1 | pages = 65–73 | year = 2009 | pmid = 18308814 | doi = 10.1177/0269881107082944 }}</ref> As of November 2010 asenapine is also in clinical trials at UC Irvine to treat stuttering. Asenapine has a broad receptor affinity profile for most serotonergic, dopaminergic, and adrenergic receptors, with no appreciable affinity for muscarinic receptors<ref>[https://www.medchemexpress.com/Asenapine.html "Asenapine (Synonyms: Org 5222)"]''MedChemExpress''</ref>.


==History==
==History==

Revision as of 07:03, 1 July 2019

Asenapine
Skeletal formula of asenapine
Ball-and-stick model of the asenapine molecule
Clinical data
Trade namesSaphris, Sycrest
AHFS/Drugs.comMonograph
MedlinePlusa610015
License data
Pregnancy
category
  • AU: C
Routes of
administration		sublingual
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING[1]Rx-only
Pharmacokinetic data
Bioavailability35% (sublingual), <2% (Oral)[2][3][4][5]
Protein binding95%[2][3][4][5]
Metabolismhepatic (glucurinodation by UGT1A4 and oxidative metabolism by CYP1A2)[2][3][4][5]
Elimination half-life24 hours[2][3][4][5]
ExcretionRenal (50%), Faecal (40%; ~5-16% as unchanged drug in faeces)[2][3][4][5]
Identifiers
  • (3aRS,12bRS)-rel-5-Chloro-2,3,3a,12b-tetrahydro-
    2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
ECHA InfoCard100.059.828 Edit this at Wikidata
Chemical and physical data
FormulaC17H16ClNO
Molar mass285.77 g/mol g·mol−1
3D model (JSmol)
  • Clc4cc2c(Oc1c(cccc1)[C@@H]3CN(C[C@@H]23)C)cc4
  • InChI=1S/C17H16ClNO/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17)15(14)10-19/h2-8,14-15H,9-10H2,1H3/t14-,15-/m0/s1 checkY
  • Key:VSWBSWWIRNCQIJ-GJZGRUSLSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Asenapine, sold under the trade names Saphris and Sycrest among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder.

It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.[6]

Medical uses

Asenapine has been approved by the FDA for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults.[7] In Australia asenapine's approved (and also listed on the PBS) indications include the following:[8]

  • Schizophrenia
  • Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder
  • Maintenance treatment, as monotherapy, of bipolar I disorder

In the European Union and the UK asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.[4][5]

Absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed.[9]

Schizophrenia

There is only weak evidence supporting the use of Asenapine for treating schizophrenia, making it hard to recommend.[10]

Acute mania

As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs (with the exception of ziprasidone) such as risperidone and olanzapine. Drop-out rates (in clinical trials) were also unusually high with asenapine.[11] According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes.[12]

Pharmacodynamics

See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications

Based on its exceptionally high, unequaled (among antipsychotics) affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors, asenapine, given normal tolerability, should theoretically demonstrate among the highest improvements in the negative symptomology of schizophrenia among all current antipsychotics (August 2017), such as high cognitive improvements and positive, stable mood maintenance.[13]

Adverse effects

Adverse effect incidence[2][3][4][5]
Note: The discussion below these lists provides some more context into the frequency and severity of these adverse effects.

Very common (>10% incidence) adverse effects include:

Common (1-10% incidence) adverse effects include:

Uncommon (0.1-1% incidence) adverse effects include:

Rare (0.01-0.1% incidence) adverse effects include:

Unknown incidence adverse effects

  • Allergic reaction
  • Restless legs syndrome
  • Nausea
  • Oral mucosal lesions (ulcerations, blistering and inflammation)
  • Salivary hypersecretion
  • Hyperprolactinaemia


Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and according to a recent meta-analysis it produces significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22).[16] Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis.[16] This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic.[16] Being a second-generation (atypical) antipsychotic its liability for causing extrapyramidal side effect is comparatively low compared to first-generation antipsychotics such as haloperidol as is supported by the aforementioned meta-analysis (although this meta-analysis did reveal it had a relatively high EPS liability for an atypical antipsychotic drug).[16]

Pharmacology

Asenapine[13][7]
Site pKi Ki (nM) Action
5-HT1A 8.6 2.5 Partial agonist
5-HT1B 8.4 4.0 Antagonist
5-HT2A 10.2 0.06 Antagonist
5-HT2B 9.8 0.16 Antagonist
5-HT2C 10.5 0.03 Antagonist
5-HT5A 8.8 1.6 Antagonist
5-HT6 9.5 0.25 Antagonist
5-HT7 9.9 0.13 Antagonist
α1 8.9 1.2 Antagonist
α2A 8.9 1.2 Antagonist
α2B 9.5 0.32 Antagonist
α2C 8.9 1.2 Antagonist
D1 8.9 1.4 Antagonist
D2 8.9 1.3 Antagonist
D3 9.4 0.42 Antagonist
D4 9.0 1.1 Antagonist
H1 9.0 1.0 Antagonist
H2 8.2 6.2 Antagonist
mACh <5 8128 Antagonist

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors.[17] At all other targets asenapine is an antagonist.[13] As of November 2010 asenapine is also in clinical trials at UC Irvine to treat stuttering. Asenapine has a broad receptor affinity profile for most serotonergic, dopaminergic, and adrenergic receptors, with no appreciable affinity for muscarinic receptors[18].

History

It was developed by Schering-Plough after its November 19, 2007 merger with Organon International. Though Phase III trials began while Organon was still a part of Akzo Nobel.[19] Preliminary data indicate that it has minimal anticholinergic and cardiovascular side effects, as well as minimal weight gain. Over 3000 people have participated in clinical trials of asenapine, and the FDA approved the manufacturer's NDA in August 2009.[20]

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b c d e f "PRODUCT INFORMATION SAPHRIS® (asenapine maleate)" (PDF). TGA eBusiness Services. Merck Sharp & Dohme (Australia) Pty Limited. 14 January 2013. Retrieved 23 October 2013.
  3. ^ a b c d e f "SAPHRIS (asenapine maleate) tablet [Organon Pharmaceuticals USA]". DailyMed. Organon Pharmaceuticals USA. March 2013. Retrieved 23 October 2013.
  4. ^ a b c d e f g "Sycrest 5mg and 10mg sublingual tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Lundbeck Limited. 18 April 2013. Retrieved 23 October 2013.
  5. ^ a b c d e f g "Product information 21/02/2013 Sycrest -EMEA/H/C/001177 -II/0012" (PDF). European Medicines Agency. N.V. Organon. 21 February 2013. Retrieved 23 October 2013.
  6. ^ Minassian, A; Young, JW (August 2010). "Evaluation of the clinical efficacy of asenapine in schizophrenia". Expert Opinion on Pharmacology. 11 (12): 2107–2115. doi:10.1517/14656566.2010.506188. PMC 2924192. PMID 20642375.
  7. ^ a b "Saphris (asenapine) prescribing information" (PDF). Schering Corporation. 2009-08-01. Archived from the original (PDF) on 2009-11-22. Retrieved 2009-09-05. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  8. ^ Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  9. ^ Stoner, Steven (2012). "Asenapine: a clinical review of a second-generation antipsychotic". Clinical Therapeutics. 34 (5): 1023–40. doi:10.1016/j.clinthera.2012.03.002. PMID 22494521.
  10. ^ Hay, A; Byers, A; Sereno, M (2015). "Asenapine versus placebo for schizophrenia". Cochrane Database of Systematic Reviews (11): CD011458.pub2. doi:10.1002/14651858.CD011458.pub2. PMID 26599405.
  11. ^ Cipriani, A; Barbui, C; Salanti, G; Rendell, J; Brown, R; Stockton, S; Purgato, M; Spineli, LM; Goodwin, GM; Geddes, JR (October 2011). "Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis". Lancet. 378 (9799): 1306–1315. doi:10.1016/S0140-6736(11)60873-8. PMID 21851976.
  12. ^ Szegedi, A; Zhao, J; van Willigenburg, A; Nations, KR; Mackle, M; Panagides, J (June 2011). "Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials". BMC Psychiatry. 11: 101. doi:10.1186/1471-244X-11-101. PMC 3152513. PMID 21689438.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ a b c Shahid M, Walker GB, Zorn SH, Wong EH (2009). "Asenapine: a novel psychopharmacologic agent with a unique human receptor signature". J. Psychopharmacol. 23 (1): 65–73. doi:10.1177/0269881107082944. PMID 18308814.
  14. ^ Washington, Nicole B. (October 2012). "Which psychotropics carry the greatest risk of QTc prolongation?". Current Psychiatry. 11 (10): 36–39. Retrieved 14 April 2017.
  15. ^ Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
  16. ^ a b c d Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
  17. ^ http://cat.inist.fr/?aModele=afficheN&cpsidt=21237275
  18. ^ "Asenapine (Synonyms: Org 5222)"MedChemExpress
  19. ^ "Bipolar Disorder". Clinical Trials Update. Genetic Engineering & Biotechnology News. 2007-06-15. pp. 52, 55.
  20. ^ "Schering-Plough Announces Asenapine NDA Accepted for Filing by the U.S. FDA" (Press release). Schering-Plough. 2007-11-26. Retrieved 2008-12-29.[permanent dead link‍]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Asenapine&oldid=904296748"