Sertindole
From Wikipedia, the free encyclopedia
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| Systematic (IUPAC) name | |
| 1-[2-[4-[5-chloro-1-(4-fluorophenyl)- indol-3-yl]-1-piperidyl]ethyl] imidazolidin-2-one |
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| Clinical data | |
| AHFS/Drugs.com | International Drug Names |
| Pregnancy cat. | B3 not recommended |
| Legal status | approved for marketing in approx 20 countries |
| Routes | ? |
| Pharmacokinetic data | |
| Bioavailability | volume of distribution 20 l/kg Well absorbed orally |
| Metabolism | largely liver |
| Half-life | 3 days |
| Excretion | via liver metabolism ? |
| Identifiers | |
| CAS number | 106516-24-9  |
| ATC code | N05AE03 |
| PubChem | CID 60149 |
| IUPHAR ligand | 98 |
| DrugBank | DB06144 |
| ChemSpider | 54229 |
| UNII | GVV4Z879SP |
| KEGG | D00561 |
| ChEBI | CHEBI:9122 |
| ChEMBL | CHEMBL12713 |
| Chemical data | |
| Formula | C24H26ClFN4O |
| Mol. mass | 440.941 |
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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.
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[edit] Pharmacology
Sertindole has restricted receptor and brain site activity. It mainly affects dopamine D2, serotonin 5-HT2 and α1-adrenergic receptors. The effect on D2 receptors is more pronounced in the limbic dopamine system compared with the nigrostriatal system. This is supported by findings from clinical trials that provide evidence for significantly fewer extra pyramidal side effects than haloperidol and olanzapine.[1] Weight gain is moderate, there is no diabetogenic effect, or effects on cholesterol and triglycerides, or prolactin blood levels reported. Sertindole has been shown to block hERG in the low nanomolar range.[2]
In contrast to other antipsychotics, sertindole is not associated with sedative effects; sedation may add to the cognitive problems inherent in schizophrenia. Further to that, studies show that sertindole effectively normalizes laboratory induced cognitive impairment in animals, and that sertindole treatment has shown long lasting improvements in elementary cognitive processes in humans. This advantage may be linked to the high 5HT6a receptor affinity.[citation needed]
[edit] Safety and status
[edit] USA
Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,[3] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.[4] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.[5] 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.[6] 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.[7] As of October 2010[update], the drug has not been approved by the FDA for use in the USA.[8]
[edit] Europe
In Europe, sertindole was approved and marketed in 19 countries from 1996,[5] but its marketing authorization was suspended by the European Medicines Agency in 1998[9] 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.[10][11]
[edit] References
- ^ Cost-effectiveness of sertindole vs olanzapine or haloperidol: a comprehensive model - Internal Journal of Psychiatry in Clinical Practice, 1998
- ^ http://www.sciencedirect.com/science/article/pii/S0014299902020745
- ^ Zeneca's Seroquel Nears Market Approval - The Pharma Letter, 16 July 1997
- ^ Abbott Labs Withdraws Sertindole NDA Sertindole - The Pharma Letter, 12 Jan 1998
- ^ a b "WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole - approval application withdrawn".
- ^ FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia - Lundbeck press release, 8 Apr 2009
- ^ Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
- ^ [www.serdolect.com]
- ^ EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) - National electronic Library for Medicines, NHS
- ^ COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE - European Medicines Agency, 13 Sep 2002
- ^ Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) - MHRA, 2002
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