World Library  
Flag as Inappropriate
Email this Article

Sertindole

Article Id: WHEBN0000336870
Reproduction Date:

Title: Sertindole  
Author: World Heritage Encyclopedia
Language: English
Subject: Atypical antipsychotic, Lurasidone, Asenapine, Amisulpride, Quetiapine
Collection: Atypical Antipsychotics, Chloroarenes, Imidazolidinones, Indoles, Organochlorides, Organofluorides, Piperidines, Ureas, Withdrawn Drugs
Publisher: World Heritage Encyclopedia
Publication
Date:
 

Sertindole

Sertindole
Systematic (IUPAC) name
1-[2-[4-[5-chloro-1-(4-fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
Clinical data
AHFS/Drugs.com
Pregnancy
category
  • AU: C
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 75%[1]
Protein binding 99.5%[1]
Metabolism Hepatic (mostly via CYP2D6 and CYP3A4)[2][3]
Biological half-life 3 days[2]
Excretion Faecal (the majority), Renal (4% metabolites; 1% unchanged)[2]
Identifiers
CAS Registry Number  Y
ATC code N05
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
Chemical data
Formula C24H26ClFN4O
Molecular mass 440.941
 Y   

Sertindole (brand names: Serdolect, and Serlect) is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company H. Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.

Sertindole is not approved for use in the United States.

Contents

  • Medical Uses 1
  • Adverse effects 2
  • Pharmacology 3
  • Safety and status 4
    • USA 4.1
    • Europe 4.2
  • Synthesis 5
  • References 6

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia.[4]

Adverse effects

Very common (>10% incidence) adverse effects include:[2]

  • Headache
  • Ejaculation failure
  • Insomnia
  • Dizziness

Common (1-10% incidence) adverse effects include:[2]

  • Urine that tests positive for red and/or white blood cells
  • Sedation (causes less sedation than most antipsychotic drugs according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs. Causes only slightly [and non-significantly] more sedation than amisulpride and paliperidone[5][6])
  • Ejaculation disorder
  • Erectile dysfunction
  • Orthostatic hypotension[5]
  • Weight gain (which it seems to possess a similar propensity for causing as quetiapine[6])

Uncommon (0.1-1% incidence) adverse effects include:[2]

  • Substernal chest pain
  • Face oedema
  • Influenza-like illness
  • Neck rigidity
  • Pallor
  • Peripheral vascular disorder
  • syncope
  • Torsades de Pointes
  • Vasodilation
  • Suicide attempt
  • Amnesia
  • Anxiety
  • Ataxia
  • Confusion
  • Incoordination
  • Libido decreased
  • Libido increased
  • Miosis
  • Nystagmus
  • Personality disorder
  • Psychosis
  • Reflexes decreased
  • Reflexes increased
  • Stupor
  • Suicidal tendency
  • Urinary retention
  • Vertigo
  • Diabetes mellitus
  • Abnormal stools
  • Gastritis
  • Gingivitis
  • Glossitis
  • Increased appetite
  • Mouth ulceration
  • Rectal disorder
  • Rectal haemorrhage
  • Stomatitis
  • Tongue disorder
  • Ulcerative stomatitis
  • Anaemia
  • Ecchymosis
  • Hypochromic anaemia
  • Leukopenia
  • Hyperglycaemia
  • Hyperlipemia
  • Oedema
  • Bone pain
  • Myasthenia
  • Twitching
  • Bronchitis
  • Hyperventilation
  • Pneumonia
  • Sinusitis
  • Furunculosis
  • Herpes simplex
  • Nail disorder
  • Psoriasis
  • Pustular Rash
  • Skin discolouration
  • Skin hypertrophy
  • Skin ulcer
  • Abnormal vision
  • Keratoconjunctivitis
  • Lacrimation disorder
  • Otitis externa
  • Pupillary disorder
  • Taste perversion
  • Anorgasmia
  • Penis disorder (gs)
  • Urinary urgency
  • Hyperprolactinaemia (which it seems to cause with a higher propensity than most other atypical antipsychotics do[6])
  • Seizures
  • Galactorrhoea

Rare (<0.1% incidence) adverse effects include:[2]

Unknown frequency adverse events include:[2]

  • Extrapyramidal side effects (EPSE; e.g. dystonia, akathisia, muscle rigidity, parkinsonism, etc. These adverse effects are probably uncommon/rare according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs which found it had the 2nd lowest effect size for causing EPSE[6])
  • Venous thromboembolism
  • QT interval prolongation (probably common; in a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to be the most prone to causing QT interval prolongation[6])

Pharmacology

Biologic protein Binding affinity (Ki[nM])[7] Notes
5-HT1A 280
5-HT1B 60
5-HT1D 96
5-HT1E 430
5-HT1F 360
5-HT2A 0.39 The receptor believed to mediate the atypicality of atypical antipsychotics.[8]
5-HT2C 0.9 Likely responsible for its propensity for causing weight gain.[8]
5-HT6 5.4
5-HT7 28
α1A 1.8 Likely responsible for the orthostatic hypotension seen in patients on sertindole.[8]
α2A 640
α2B 450
α2C 450
β1 5000
β2 5000
M1 >10000 [8]
M3 2692
D2 2.35 Believed to be responsible for the drug's efficacy against positive symptoms.[8]
D3 2.30
D4 4.92
HERG 3
H1 130
NK1 1000

Sertindole is metabolised in the body to dehydrosertindole.[9]

Safety and status

USA

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,[10] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.[11] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.[12] Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone.[13] Nevertheless in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe.[14] As of October 2010, the drug has not been approved by the FDA for use in the USA.[15]

Europe

In Europe, sertindole was approved and marketed in 19 countries from 1996,[12] but its marketing authorization was suspended by the European Medicines Agency in 1998[16] and the drug was withdrawn from the market. In 2002, based on new data, the EMA's CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.[17][18]

Synthesis

Sertindole synthesis:[19]

References

  1. ^ a b Karamatskos, E; Lambert, M; Mulert, C; Naber, D (November 2012). "Drug safety and efficacy evaluation of sertindole for schizophrenia". Expert Opinion on Drug Safety 11 (6): 1047–1062.  
  2. ^ a b c d e f g h "PRODUCT INFORMATION SERDOLECT® TABLETS" (PDF). TGA eBusiness Services. Lundbeck Australia Pty Ltd. 16 January 2013. Retrieved 27 October 2013. 
  3. ^ Juruena, MF; de Sena, EP; de Oliveira, IR (May 2011). "Sertindole in the Management of Schizophrenia" (PDF). Journal of Central Nervous System Disease 3: 75–85.  
  4. ^ Lewis, R; Bagnall, AM; Leitner, M (Jul 20, 2005). "Sertindole for schizophrenia.". Cochrane database of systematic reviews (Online) (3): CD001715.  
  5. ^ a b Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell.  
  6. ^ a b c d e 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.  
  7. ^ Roth, BL; Driscol, J (12 January 2011). Database"i"PDSP K. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 27 October 2013. 
  8. ^ a b c d e Brunton, L; Chabner, B; Knollman, B (2010).  
  9. ^ http://www.trc-canada.com/detail.php?CatNum=D230095&CAS=173294-84-3&Chemical_Name=Dehydrosertindole&Mol_Formula=C24H24ClFN4O&Synonym=1-%5B2-%5B4-%5B5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl%5D-1-piperidinyl%5Dethyl%5D-1,3-dihydro-2H-Imidazol-2-one;%20Lu%2028-092
  10. ^ Zeneca's Seroquel Nears Market Approval - The Pharma Letter, 16 July 1997
  11. ^ Abbott Labs Withdraws Sertindole NDA Sertindole - The Pharma Letter, 12 Jan 1998
  12. ^ a b "WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole - approval application withdrawn". 
  13. ^ FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia - Lundbeck press release, 8 Apr 2009
  14. ^ Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
  15. ^ [2]
  16. ^ EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) - National electronic Library for Medicines, NHS
  17. ^ COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE - European Medicines Agency, 13 Sep 2002
  18. ^ Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) - MHRA, 2002
  19. ^ Perregaard, J.; Arnt, J.; Boegesoe, K. P.; Hyttel, J.; Sanchez, C. (1992). "Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles". Journal of Medicinal Chemistry 35 (6): 1092.  
This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 



Copyright © World Library Foundation. All rights reserved. eBooks from World eBook Library are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.