Pharmacological Profile of the Atypical Neuroleptic Sertindole

Hyttel, John; Arnt, Jørn; Costall, B.; Domeney, A.M.; Dragsted, Nils; Hl, Lembøl; Meier, Eddi; Rj, Naylor; Nowak, Gabriel; Sanchez, Cécile

doi:10.1097/00002826-199201001-00139

Cited by 32 publications

(13 citation statements)

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“…Sertindole displays weak dopamine antagonism in vivo, while its action on central 5-HT2A receptors is potent with long duration [23]. In clinical trials, its EPS profile has been found to be similar to that of placebo [19].…”

Section: Sertindolementioning

confidence: 99%

“…The reason that this is not translated into EPS is probably due to a protective effect of high affinity 5-HT blockade [24]. Nasal congestion has been the most commonly reported side-effect and is thought to be mediated through its blockade of the α 1 receptor; this effect was reversible upon discontinuation [23]. Sertindole was launched in the UK during the summer of 1996.…”

Section: Sertindolementioning

confidence: 99%

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Future therapies for schizophrenia

Sodhi¹,

Murray²

1997

Expert Opinion on Therapeutic Patents

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Despite decades of research, the aetiology of schizophrenia remains elusive. However, the recent success of atypical antipsychotic drugs such as clozapine and risperidone has broken a 30 year trend during which pharmaceutical companies focused solely on D2 receptor antagonism in their quest for new drug treatments for schizophrenia. In the next few years, at least four other new atypical antipsychotics, olanzapine, sertindole, seroquel and ziprasidone, will be introduced throughout the developed world. It is likely that atypical compounds such as these will largely displace the typical neuroleptics, which provide only limited efficacy and produce unpleasant side-effects. The majority of the patents taken out in recent years remain focussed on the traditional notions of dopamine blockade, but there is an increasing trend in industry to select D 1 , D 3 and D 4 receptors as targets for potential drugs, rather than the D2 subtype. Greater emphasis is now being placed on the serotonergic hypothesis of schizophrenia, as more ligands selective for serotonin receptors are developed. A large number of companies have combined both theories in an effort to produce improved versions of clozapine; thus the serotonin-dopamine antagonist (SDA) class of compounds has emerged. Such drugs certainly display fewer extrapyramidal side-effects than traditional neuroleptics and there is considerable hope that they may prove more effective in the treatment of negative symptoms. Patent applications for radically different compounds have also appeared during 1995 and 1996, including some based on the glutamatergic and developmental theories of schizophrenia. These potential new therapies are reviewed. Exp. Opin. Ther. Patents (1997) 7(2):151-165

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Section: Sertindolementioning

confidence: 99%

Section: Sertindolementioning

confidence: 99%

Future therapies for schizophrenia

Sodhi¹,

Murray²

1997

Expert Opinion on Therapeutic Patents

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“…It has affinity for and functions as an antagonist at a number of receptor systems, including dopamine D2 receptors, 5-HT 2 receptors (particularly 2A and 2C subtypes), and α-1-noradrenergic receptors. 45 Antagonism of these receptor systems are hypothesized to be involved in the antipsychotic effectiveness. 46 Like other atypicals, sertindole has selective effects on the dopaminergic system, affecting the mesocorticolimbic rather than mesostriatal neurons.…”

Section: Pharmacology Mode Of Action and Pharmacokinetics Of Sertinmentioning

confidence: 99%

Emerging role of sertindole in the management of schizophrenia

Cincotta¹,

Rodefer²

2010

NDT

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The atypical antipsychotic sertindole is a phenylindole-derived compound that has affinity for and functions as an antagonist at a number of receptor systems, including dopamine D2 receptors, 5-HT 2A and 5-HT 2C receptors, and α-1-noradrenergic receptors. Although previous data suggested that sertindole was well tolerated and had good efficacy against both positive and negative symptom clusters, reports of QT prolongation with sertindole prompted its voluntary removal from the market in 1998. After further safety analyses, it recently regained approval and was reintroduced to the European market for the treatment of schizophrenia, where its role in therapy among available atypicals remains unclear. This article evaluates the preclinical and clinical data regarding sertindole's effectiveness and concludes that sertindole continues to demonstrate a number of strengths, including effective management of both positive and negative symptoms, well-tolerated side effects (including little or no sedation, weight gain, and extrapyramidal side effects), and a superior procognitive profile that is unique among atypical antipsychotics. However, minor concerns regarding its sexual side effects and the major consideration of QT prolongation suggest that additional comparative effectiveness studies are needed to determine the superiority of sertindole vs other atypical antipsychotics recently introduced.

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“…delirium) as well as negative (e.g. withdrawal) symptoms of schizophrenia [15] and it has a limited risk for causing extrapyramidal side effects at therapeutically effective doses [16,17]. It has a high HERG channel affinity with an IC 50 between 3 and 64 nm, depending on assay conditions [2,18,19] and has been shown to increase the action potential duration [20] and QT interval, in a concentration dependent manner, on isolated feline hearts [4,21].…”

Section: Introductionmentioning

confidence: 99%

Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea‐pigs

Canal-Raffin

Titier

Déridet

et al. 2006

Biopharm & Drug Disp

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Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised.

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Pharmacological Profile of the Atypical Neuroleptic Sertindole

Cited by 32 publications

References 0 publications

Future therapies for schizophrenia

Future therapies for schizophrenia

Emerging role of sertindole in the management of schizophrenia

Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea‐pigs

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