Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ICI 204,636 (I) is an orally active antipsychotic agent under development for the treatment of schizophrenia in humans. It is partially converted in animals to an active 7-hydroxy metabolite (II). Methods were developed for the simultaneous determination of both analytes in human plasma using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The analytes were extracted from plasma using phenyl solid-phase extraction columns. Quantification by isocratic HPLC was performed in the reversed-phase mode with detection at 250 nm. Extracts were derivatized to trimethylsilyl ethers for quantification by GC-MS using selected-ion monitoring. Both assays were evaluated for consistency of response, precision, accuracy and specificity. Limits of quantification for I and II by HPLC were 15 and 20 ng/ml, respectively; limits of quantification for I and II by GC-MS were 2 and 5 ng/ml, respectively. Both methods were applied to the analysis of clinical samples from oral dosing studies with I.
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PMID:Determination of an antipsychotic agent (ICI 204,636) and its 7-hydroxy metabolite in human plasma by high-performance liquid chromatography and gas chromatography-mass spectrometry. 134 47

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)- piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles. 136 72

We evaluated the effects of ICI 204,636 in 12 hospitalized patients with schizophrenia in a double-blind, placebo-controlled, parallel-group, rising-dose study. Patients met the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria for chronic or subchronic schizophrenia and had a total score > or = 30 on the 18-item Brief Psychiatric Rating Scale (BPRS) and a score > or = 3 on the Clinical Global Impression (CGI) Severity of Illness item. Patients received 21 days of double-blind treatment with increasing doses of ICI 204,636 (25 to 250 mg/d) or placebo. Efficacy was assessed using the BPRS and CGI. Response to treatment was defined as a > or = 30% decrease in the BPRS total score from baseline. Extrapyramidal symptoms and abnormal involuntary movements were assessed using the Simpson Scale and Abnormal Involuntary Movement Scale. Changes from baseline in the BPRS and CGI were significantly greater at end point for patients who received ICI 204,636 versus placebo (BPRS, -20.9 vs -4.8; CGI, -2.9 vs -1.0; P < 0.05, analysis of covariance; P < or = 0.06, Wilcoxon rank sum test). All patients in the ICI 204,636 group responded to treatment (P < 0.10) versus only two patients in the placebo group. Mild somnolence occurred in 50% of ICI 204,636-treated patients. No treatment-emergent extrapyramidal symptoms or dystonic reactions were observed. ICI 204,636 showed efficacy in the positive and negative symptoms of schizophrenia and was well tolerated.
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PMID:ICI 204,636, a novel, atypical antipsychotic: early indication of safety and efficacy in patients with chronic and subchronic schizophrenia. 758 41

Preclinical data indicated that seroquel (ICI 204 636), a dibenzothiazepine with 5-HT2 and D2-like receptor antagonistic properties, might be an effective antipsychotic agent, causing fewer extrapyramidal side effects than typical neuroleptics. In the present study, 12 patients suffering from schizophrenia or schizophreniform disorder with predominantly positive symptomatology were treated in an open clinical trial for 4 weeks with seroquel at a maximum dosage of 750 mg/day. The drug was generally well tolerated, and virtually no adverse extrapyramidal side effects such as acute dystonia, parkinsonism or akathisia were observed. Total scores for BPRS (item score 0-6; baseline: 42.0 +/- 2.3; mean +/- SEM), SAPS (64.5 +/- 4.8) and SANS (55.0 +/- 4.3) showed a moderate decrease at the end of treatment (BPRS: 30.0 +/- 3.5; SAPS: 36.1 +/- 6.7; SANS: 42.5 +/- 5.9), when intention-to-treat analysis was applied. There were considerable interindividual differences in treatment response, with some subjects showing almost full remission of positive symptoms, in contrast to about half of the patients who showed no satisfactory clinical improvement. Interestingly, patients showing good antipsychotic response reported slight initial side effects like mild sedation. Prolactin and TSH levels were not altered during seroquel administration. As to pharmaco-EEG investigations, seroquel caused a moderate increase of the absolute power in the alpha, theta, and beta frequency bands, paralleled by a decrease of delta activity. There were no signs of paroxysmal EEG activity under seroquel.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Seroquel (ICI 204 636), a putative "atypical" antipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters. 765 71

ICI 204,636 is a new, potentially atypical antipsychotic. In early phase II trials, the antipsychotic was well tolerated and results suggested efficacy in the treatment of the positive and negative symptoms of schizophrenia. The efficacy and safety of ICI 204,636 were evaluated on a larger scale in a 6-week, multicenter, double-blind trial. Hospitalized patients who met DSM-III-R criteria for chronic or subchronic schizophrenia with acute exacerbation, as well as other criteria, were randomized to ICI 204,636 (75 to 750 mg daily) (N = 54) or placebo (N = 55). Patients were assessed weekly by use of the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression Scale (CGI) for efficacy and the Simpson Scale and Abnormal Involuntary Movement Scale for extrapyramidal side effects (EPS). Significant differences (p < or = 0.05) between treatment groups, which favored ICI 204,636, were identified throughout the trial. Endpoint differences were significant (by analysis of covariance) for BPRS factor IV (activation) and SANS scores and were marginally significant for total BPRS, BPRS factor III (thought disturbance), BPRS positive-symptom cluster, and CGI Severity of Illness item scores (p = 0.07, 0.09, 0.06, and 0.09, respectively). ICI 204,636 was well tolerated, although it was associated with mild transient increases in alanine aminotransferase and a higher incidence of somnolence and anticholinergic effects compared with placebo. In the dose range studied, treatment with ICI 204,636 did not induce EPS as determined by analysis of Simpson Scale total scores and lack of treatment-emergent acute dystonic reactions. Furthermore, ICI 204,636 did not produce sustained levels of prolactin; the mean change from baseline at endpoint (-7.2 micrograms/L) was comparable (p = 0.44) to that for placebo (-8.2 micrograms/L). These findings distinguish ICI 204,636 from standard antipsychotics and confirm preclinical predictions that ICI 204,636 is an atypical antipsychotic.
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PMID:ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. U.S. SEROQUEL Study Group. 869 Aug 31

We have recently demonstrated that specific neuroanatomical patterns of Fos-like immunoreactivity are predictive of atypical antipsychotic activity. However, the fact that neuroleptics must be administered chronically in order to generate both extrapyramidal side effects and an optimal therapeutic response calls into question the relevance of acute changes in Fos-like immunoreactivity for these slowly developing events. Fos-like immunoreactivity cannot be used to identify neurons activated by chronic neuroleptic administration because the increase in Fos-like immunoreactivity produced by an acute antipsychotic injection is dramatically reduced following repeated neuroleptic administration. In contrast, expression of the immediate-early gene product deltaFosB is persistently elevated in the striatum by chronic haloperidol administration. This suggests that deltaFosB-like immunoreactivity may be used to identify neurons activated by chronic antipsychotic administration. Since typical and atypical neuroleptics elevate Fos-like immunoreactivity in different regions of the forebrain acutely, the purpose of the present study was to determine whether typical (haloperidol) and atypical (clozapine, ICI 204,636) antipsychotics produce distinct patterns of elevated deltaFosB-like immunoreactivity in the forebrain after chronic administration. Administration of haloperidol (2 mg/kg/day) to rats for 19 days induced a homogeneous elevation of neurons which displayed deltaFosB-like immunoreactivity in the ventral, medial and dorsolateral aspects of the striatum. Chronic haloperidol administration did not enhance the deltaFos-like immunoreactivity in the prefrontal cortex and lateral septal nucleus. Repeated administration of clozapine (20 mg/kg/day) and ICI 204,636 (20 mg/kg/day) for 19 days elevated deltaFosB-like immunoreactivity not only in the ventral striatum but also in the prefrontal cortex and lateral septal nucleus. However, these compounds had weak effects on deltaFosB-like immunoreactivity in the dorsolateral striatum. These results suggest that a preferential action on limbic structures such as the prefrontal cortex, ventral striatum and lateral septal nucleus may account for the ability of chronic clozapine and ICI 204, 636 administration to reduce the symptoms of schizophrenia without generating extrapyramidal side effects.
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PMID:Contrasting effects of chronic clozapine, Seroquel(TM) (ICI 204,636) and haloperidol administration of deltaFosB-like immunoreactivity in the rodent forebrain. 874 40

Refractoriness to treatment is a common problem in management of schizophrenics. Conventional pharmacotherapy is usually effective in controlling positive symptoms of the disease, such as delusions and hallucinations. However, they have restricted ability to affect negative symptoms (flat affect, social withdrawal) and to reverse functional disability and behavioral deviance. Furthermore, typical neuroleptics produce adverse effects, such as extrapyramidal symptoms and tardive dyskinesia. A new generation of antipsychotic agents with a low profile of side-effects and good tolerance has recently been developed and actively investigated. Seroquel (ICI 204-636), a dibenzoth azepine derivative, is a novel, putative, potential, atypical neuroleptic; it is a combined dopamine/ serotonin receptor antagonist. We report a 54-year-old man suffering from chronic therapy-resistant schizophrenia, with both positive and negative symptoms, who was successfully treated with Seroquel during 1 year.
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PMID:[Seroquel in a resistant schizophrenic with negative and positive symptoms]. 879 56

The pharmacologic treatment of schizophrenia still suffers from two major problems: (1) most antipsychotic drugs still induce severe neurologic (extrapyramidal) side effects; (2) few antipsychotic drugs are effective in treating the negative symptoms of schizophrenia. In the present study, we have evaluated the effects of ICI 204,636 in the rat paw test and the amphetamine-induced social isolation in monkeys and compared them with the effects of clozapine. The paw test has been shown to be a valid model for differentiating classic and atypical neuroleptic drugs. The monkey social isolation model seems to represent one of the few animal models with validity for the negative symptoms of schizophrenia. The results show that both ICI 204,636 and clozapine had the profile of an atypical antipsychotic in the paw test, suggesting a reduced propensity to induce extrapyramidal side effects in humans. Likewise, ICI 204,636 and clozapine were found to prevent the amphetamine-induced social isolation in monkeys, suggesting a good therapeutic effect mitigating the negative symptoms in schizophrenia. Overall, the data suggest that ICI 204,636 may represent a new and interesting antipsychotic drug, closely resembling clozapine.
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PMID:Activity of "seroquel" (ICI 204,636) in animal models for atypical properties of antipsychotics: a comparison with clozapine. 888 95

Treatment with standard antipsychotic medications causes side effects such as hyperprolactinemia and extrapyramidal symptoms. Because these side effects can cause noncompliance with antipsychotic medication and consequent relapse, they add to the morbidity of schizophrenia. A compound with antipsychotic efficacy but without the side effects of standard antipsychotic agents would improve compliance and treatment outcomes and enhance quality of life. Improved compliance, reduced relapse, and decreased hospitalization would also reduce the cost of treatment of schizophrenia. Seroquel (ICI 204,636), an atypical antipsychotic compound in Phase III development, was found to be well tolerated and effective in treating subjects with DSM-III-R schizophrenia in three Phase II clinical trials. Analysis of plasma prolactin concentrations obtained during these trials revealed that ICI 204,636 did not differ from placebo in its effect on plasma prolactin after up to 6 weeks of treatment; no significant difference was found in the degree of decline of plasma prolactin levels when subjects treated with ICI 204,636 and placebo were compared. A significant difference was found, however, between ICI 204,636- and chlorpromazine-treated subjects; prolactin levels in ICI 204,636-treated subjects fell to a greater degree than they did in chlorpromazine-treated subjects, however in all three trials, ICI 204,636 did not cause sustained elevation of prolactin.
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PMID:Plasma prolactin in schizophrenia subjects treated with Seroquel (ICI 204,636). 892 58

The beta-adrenoceptor antagonist as well as serotonin 5-HT1 receptor antagonist, (-)alprenolol, was found to potentiate the disrupting effect of the noncompetitive NMDA receptor antagonist, dizocilpine, on prepulse inhibition (PPI) of the acoustic startle response (ASR) in the rat. The facilitating effect of dizocilpine on ASR amplitude was also potentiated by (-)alprenolol. (-)Alprenolol by itself did not affect either of these measures. These effects did not seem to be related to the unselective beta-adrenoceptor antagonist property of (-)alprenolol, since combined pretreatment with the beta1- and beta2-adrenoceptor antagonists, metoprolol and ICI 118551, did not alter the effects of dizocilpine on startle behaviour. However, a serotonergic influence was suggested by the fact that a facilitating effect of dizocilpine on ASR amplitude was also obtained by pretreatment with the 5-HT precursor, L-5-HTP, in benserazide-pretreated rats. Furthermore, pretreatment with the 5-HT2 selective receptor antagonist, MDL 100907, significantly reduced the (-)alprenolol-induced potentiation of the effects of dizocilpine on startle behaviour, while the 5-HT3 selective receptor antagonist, ondansetron, failed to do that. Finally, the (-)alprenolol-induced potentiation of the effects of dizocilpine was significantly reduced by pretreatment with the atypical antipsychotic, clozapine, and by the potential antipsychotic and selective dopamine D2 receptor antagonist, raclopride. This study suggests that altered 5-HT activity may influence the effects of psychotomimetic drugs such as dizocilpine on sensorimotor function, and this observation may have implications for the pharmacological treatment of schizophrenia in humans.
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PMID:(-)Alprenolol potentiates the disrupting effects of dizocilpine on sensorimotor function in the rat. 929 28


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