Sertindole
Sertindole, sold under the brand name Serdolect among others, is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company 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.
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| Trade names | Serdolect, Serlect |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 75%[1] |
| Protein binding | 99.5%[1] |
| Metabolism | Liver (mostly via CYP2D6 and CYP3A4)[2][3] |
| Elimination half-life | 3 days[2] |
| Excretion | Faecal (the majority), Kidney (4% metabolites; 1% unchanged)[2] |
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| ECHA InfoCard | 100.162.562 |
| Chemical and physical data | |
| Formula | C24H26ClFN4O |
| Molar mass | 440.95 g·mol−1 |
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Sertindole is not approved for use in the United States and was discontinued in Australia in January 2014.[citation needed]
Medical Uses edit
Sertindole appears effective as an antipsychotic in schizophrenia.[4] In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, sertindole was found to be slightly less effective than haloperidol, quetiapine, and aripiprazole, as effective as ziprasidone, approximately as effective as chlorpromazine and asenapine, and slightly more effective than lurasidone and iloperidone.[5]
Adverse effects edit
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[6]
- Weight gain (which it seems to possess a similar propensity for causing as quetiapine)[5]
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)[5]
- 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)[5]
- 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)[5]
Pharmacology edit
| 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 | Responsible for the QT interval prolongation and torsade de pointes |
| H1 | 130 | |
| NK1 | 1000 |
Sertindole is metabolized in the body to dehydrosertindole.[9]
Safety and status edit
United States edit
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[update], the drug has not been approved by the FDA for use in the USA.[15][failed verification]
European Union edit
In the European Union, 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] As of September 2020[update], sertindole is authorized in several states of the European Union.[19]
References edit
- ^ 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): 1047–62. doi:10.1517/14740338.2012.726984. PMID 22992213. S2CID 11339387.
- ^ 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.
- ^ Juruena MF, de Sena EP, de Oliveira IR (May 2011). "Sertindole in the management of schizophrenia". Journal of Central Nervous System Disease. 3: 75–85. doi:10.4137/JCNSD.S5729. PMC 3663609. PMID 23861640.
- ^ Lewis R, Bagnall AM, Leitner M (July 2005). "Sertindole for schizophrenia". The Cochrane Database of Systematic Reviews. 2005 (3): CD001715. doi:10.1002/14651858.CD001715.pub2. PMC 7025766. PMID 16034864.
- ^ a b c d e f Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. S2CID 32085212.
- ^ a b Taylor D, Paton C, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
- ^ Roth BL, Driscol J (12 January 2011). . Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 27 October 2013.
- ^ a b c d e Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
- ^ . Archived from the original on 27 April 2015. Retrieved 20 April 2015.
- ^ Zeneca's Seroquel Nears Market Approval - The Pharma Letter, 16 July 1997
- ^ Abbott Labs Withdraws Sertindole NDA Sertindole - The Pharma Letter, 12 January 1998
- ^ a b . Archived from the original on 22 June 2011.
- ^ FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia 14 July 2011 at the Wayback Machine - Lundbeck press release, 8 April 2009
- ^ Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
- ^ "Welcome to Lundbeck's global site".
- ^ EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) 2 October 2011 at the Wayback Machine - National electronic Library for Medicines, NHS
- ^ COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE - European Medicines Agency, 13 September 2002
- ^ Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) 17 November 2010 at the Wayback Machine - MHRA, 2002
- ^ Sertindole: List of nationally authorised medicinal products - PSUSA/00002695/202001 (PDF) (Report). European Medicines Agency (EMA). 3 September 2020. EMA/270645/2015.