Disease relevance of SerLect

• CONCLUSIONS: Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine [1].
• Despite side effects of tiredness, weight gain, headache, nausea, and decreased ejaculatory volume, sertindole was generally well tolerated [2].
• In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0-2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30-157 nM), QTc was prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB) [3].
• Three of the four patients apparently recovered from the movement disorders after switching to sertindole [4].
• All three drugs reduce psychosis in humans, whereas only haloperidol, but not olanzapine or sertindole, induce purposeless oral chewing movements (CMs) in rats or cause high rates of parkinsonism or tardive dyskinesia in humans [5].

Psychiatry related information on SerLect

• METHOD: Ten patients diagnosed with either schizophrenia or schizoaffective disorder were treated with sertindole for 18 months and observed for changes in Clinical Global Impression scale scores [2].
• Risperidone, clozapine and haloperidol but not sertindole decreased locomotor activity [6].
• Sertindole was the only antipsychotic drug able to produce antipsychotic effect without significant inhibition of intracranial self-stimulation behaviour at a narrow dose interval [7].
• Clozapine withdrawal symptoms after change to sertindole in a schizophrenic patient [8].
• On the 1st day sertindole induced a significant increase in deep slow-wave sleep, but only with a dose of 0.32 mg/kg [9].

High impact information on SerLect

• Pharmacokinetics of sertindole in healthy young and elderly male and female subjects [10].
• The higher Cmax and AUC values in females may be a result of a higher extent of absorption or a dependence of sertindole clearance on lean body mass [10].
• CONCLUSION: Clozapine and olanzapine caused the most weight gain, risperidone was intermediate, and sertindole had less associated weight gain than haloperidol [11].
• In vitro binding profiles have been created for the atypical antipsychotics that have been approved by the U.S. Food and Drug Administration (FDA)-clozapine, olanzapine, and risperidone and those that are under FDA review-quetiapine and sertindole [12].
• Serotonin: 5-HT2A receptor occupancy in vivo and response to the new antipsychotics olanzapine and sertindole [13].

Chemical compound and disease context of SerLect

• With the introduction of risperidone and the imminent prospect of other atypical antipsychotic drugs (olanzapine, sertindole, quetiapine, ziprasidone), clinicians may be able to improve dramatically the methods and manner in which they treat schizophrenia and related psychotic disorders [14].
• METHOD: Data were analyzed to determine differences in weight gain during treatment among patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]) [11].
• Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy [15].

Biological context of SerLect

• When currents were measured at the end of prolonged (20 sec) depolarizing pulses, the IC50 of sertindole measured 2.99 nM [16].
• The 5-HT2c receptor downregulation during repeated dosing may contribute to therapeutic efficacy and/or side effects of sertindole treatment [17].
• Action potentials in these cells prolonged in a reverse rate- and concentration-dependent manner at 10 to 300 nM sertindole [3].
• Using patch clamp electrophysiology, we found sertindole blocked HERG currents with an IC50 value of 14.0 nM when tail currents at -40 mV were measured after a 2-sec depolarization to +20 mV [16].
• RESULTS: Sertindole exhibited little or no effect on D1 and D2 binding sites in vivo [18].

Anatomical context of SerLect

• In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 21 nM [3].
• OBJECTIVE: To characterise the interaction of sertindole with the 5-HT2C receptor using rat choroid plexus as a physiological receptor source [17].
• We therefore examined the effects of sertindole on two cloned human cardiac potassium channels, the human ether-a-go-go-related gene (HERG) and Kv1.5, stably transfected into mammalian cell lines [16].
• We have investigated the adrenergic antagonist effect of the antipsychotic sertindole in rat resistance vessels and in membranes of HEK293 cells transfected with alpha1-adrenoceptors [19].
• Electrophysiological profile of the new atypical neuroleptic, sertindole, on midbrain dopamine neurones in rats: acute and repeated treatment [20].

Associations of SerLect with other chemical compounds

• Clinical trial data have so far been published for only three SDAs to date, namely, risperidone, sertindole, and olanzapine [21].
• Comparison of short-term administration of sertindole, clozapine and haloperidol on the inactivation of midbrain dopamine neurons in the rat [22].
• The antipsychotic drugs sertindole and pimozide block erg3, a human brain K(+) channel [23].
• The mean area under the concentration-time curve (AUC) value of sertindole did not change significantly in the presence of erythromycin (alone: 159 +/- 111 ng.hr/mL, in combination: 179 +/- 144 ng.hr/mL, P > 0.05) [24].
• The effect of the atypical neuroleptics clozapine and risperidone, the potential atypical neuroleptics sertindole and NNC 22-0031 as well as the prototypical neuroleptic haloperidol on Fos protein expression in the rat forebrain was examined by use of immunohistochemistry [25].

Gene context of SerLect

• Quetiapine is metabolised by CYP3A4 and sertindole by CYP2D6 [26].
• Lack of CYP3A inhibition effects of sertindole on terfenadine in healthy volunteers [27].
• The antipsychotic drugs sertindole and pimozide are known to prolong the QT interval on the electrocardiogram via a high affinity block of the cardiac K(+) channel known as HERG (human ether-a-go-go-related gene; erg1) [23].
• Block of erg3 by sertindole also displayed a positive voltage-dependence [23].
• Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone [28].

Analytical, diagnostic and therapeutic context of SerLect

• Two rapid-dose titrations of sertindole in patients with schizophrenia [29].
• Sertindole (1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone), an atypical antipsychotic drug, was separated by capillary electrophoresis from its two main metabolites norsertindole and dehydrosertindole [30].
• Clinical trials have shown antipsychotic efficacy and very few extrapyramidal symptoms (EPS) with sertindole at 20 mg/day [31].
• This patient had averaged 2.5 inpatient admissions per year for the 8 years preceding initiation of sertindole therapy, but has had no hospitalizations or psychosis in the 3.5 years since [32].
• This 40-day randomized, placebo-controlled, dose-ranging multicenter study was designed to assess the effect of sertindole on previously neuroleptic-responsive, hospitalized schizophrenic patients (n = 205) [33].

References