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Sujane Wang - One of the best experts on this subject based on the ideXlab platform.
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inhibition of glutamate release by Fluspirilene in cerebrocortical nerve terminals synaptosomes
Synapse, 2002Co-Authors: Sujane WangAbstract:Fluspirilene, a neuroleptic drug which is used clinically to treat schizophrenic patients, is a dopamine D2 receptor antagonist. Besides its well-known actions on the dopamine receptors, Fluspirilene also displays calcium channel-blocking activity. The aim of this study was to investigate the effect of Fluspirilene on the 4-aminopyridine (4AP)-evoked glutamate release in the cerebrocortical nerve terminals (synaptosomes). Fluspirilene reduced 4AP-evoked glutamate release in a concentration-dependent manner. This inhibitory effect was associated with a decrease in the depolarization-evoked increase in the cytoplasmic free Ca2+ concentration ([Ca2+]C), which could be completely abolished by the Ca2+ channel blocker ω-CgTX GVIA. Furthermore, Fluspirilene did not produce any effect on ionomycin-evoked glutamate release. These results suggest that Fluspirilene inhibits glutamate release primarily by reducing presynaptic Ca2+ influx via N-type Ca2+ channels in rat cerebrocortical nerve terminals. This finding implies that presynaptic Ca2+ channel blockade concomitant with inhibition of glutamate release and possibly other neurotransmitters release may contribute to the antischizophrenic action of Fluspirilene. Synapse 44:36–41, 2002. © 2002 Wiley-Liss, Inc.
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Inhibition of glutamate release by Fluspirilene in cerebrocortical nerve terminals (synaptosomes).
Synapse, 2002Co-Authors: Sujane WangAbstract:Fluspirilene, a neuroleptic drug which is used clinically to treat schizophrenic patients, is a dopamine D2 receptor antagonist. Besides its well-known actions on the dopamine receptors, Fluspirilene also displays calcium channel-blocking activity. The aim of this study was to investigate the effect of Fluspirilene on the 4-aminopyridine (4AP)-evoked glutamate release in the cerebrocortical nerve terminals (synaptosomes). Fluspirilene reduced 4AP-evoked glutamate release in a concentration-dependent manner. This inhibitory effect was associated with a decrease in the depolarization-evoked increase in the cytoplasmic free Ca2+ concentration ([Ca2+]C), which could be completely abolished by the Ca2+ channel blocker omega-CgTX GVIA. Furthermore, Fluspirilene did not produce any effect on ionomycin-evoked glutamate release. These results suggest that Fluspirilene inhibits glutamate release primarily by reducing presynaptic Ca2+ influx via N-type Ca2+ channels in rat cerebrocortical nerve terminals. This finding implies that presynaptic Ca2+ channel blockade concomitant with inhibition of glutamate release and possibly other neurotransmitters release may contribute to the antischizophrenic action of Fluspirilene.
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inhibition of synaptic transmission and epileptiform activity in central neurones by Fluspirilene
British Journal of Pharmacology, 1997Co-Authors: Sujane Wang, Kwok Tung Lu, Powu GeanAbstract:Recent studies have shown that Fluspirilene, a dopamine D2 receptor antagonist which is a long-acting neuroleptic useful in the maintenance therapy of schizophrenic patients, also displays Ca2+ channel blocking activity. In the present study, we have investigated the effect of Fluspirilene on synaptic transmission and epileptiform activity induced in slices of hippocampus and amygdala. Fluspirilene reversibly suppressed the field excitatory postsynaptic potential (f-e.p.s.p) in a concentration-dependent manner in the area CAl of the hippocampus without affecting the size and shape of fibre volley. Fluspirilene also inhibited the intracellularly recorded e.p.s.p. in amygdala neurones without affecting the resting membrane potential or neuronal input resistance. Fluspirilene increased the ratio of paired-pulse facilitation suggesting a presynaptic mode of action. Epileptiform activity induced in the disinhibited slices was suppessed by Fluspirilene in a concentration-dependent manner. This antiepileptic effect was occluded in slices pretreated with the adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA). It is concluded that Fluspirilene-induced synaptic inhibition is probably due to a reduction in presynaptic Ca2+ currents. In clinical trials, the low incidence of seizures provoked by Fluspirilene might be related to its intrinsic ability to inhibit synaptic transmission and epileptiform activity. British Journal of Pharmacology (1997) 120, 1114–1118; doi:10.1038/sj.bjp.0701008
J. E. Leysen - One of the best experts on this subject based on the ideXlab platform.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding.
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. Gommeren, W. H. M. L. Luyten, P. Gompel, A. S. Lesage, K. Loore, J. E. LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, Fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and Fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, Fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except Fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. Gommeren, W. H. M. L. Luyten, P. Gompel, A. S. Lesage, K. Loore, J. E. LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, Fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT_2A receptors and D_2-type receptors. Predominant 5HT_2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D_2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D_3 and in particular D_4 receptors has been proposed. In vitro, all compounds, except the ‘typical’ antipsychotics haloperidol and Fluspirilene, showed higher affinity for 5HT_2A than for D_2 receptors. Subnanomolar affinity for human 5HT_2A receptors was observed for ORG-5222, sertindole, resperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D_2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D_2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D_4 than for D_2 receptors. For most other compounds, D_4 affinity was only slightly lower than their D_2 affinity. Seroquel was totally devoid of D_4 affinity. None of the compounds had nanomolar affinity for D_1 receptors; their affinity for D_3 receptors was usually slightly lower than for D_2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT_2A than D_2 receptors. Risperidone and ORG-5222 had 5HT_2A versus D_2 potency ratio of about 20. Highest potency for 5HT_2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT_2A receptors. ORG-5222, haloperidol, Fluspirilene and olanzapine showed the highest potency for occupying D_2 receptors. No regional selectivity for D_2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D_2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic α_1 receptors, except Fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more α_1 than D_2 receptors. Clozapine showed predominant occupancy of H_1 receptors and occupied cholinergic receptors with equivalent potency to D_2 receptors. A stronger predominance of 5HT_2A versus D_2 receptor occupancy combined with a more gradual occupancy of D_2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT_2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D_2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT_2A and D_2 occupancy and the avoidance of D_2 receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. Gommeren, W. H. M. L. Luyten, P. Gompel, A. S. Lesage, K. Loore, J. E. LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, Fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed.
Michael Spedding - One of the best experts on this subject based on the ideXlab platform.
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New drug binding sites in Ca2+ channels
Trends in Pharmacological Sciences, 1995Co-Authors: Michael Spedding, B. Kenny, P. ChatelainAbstract:New classes of drugs modifying Ca2+ channel activity have become available, this may enlarge the clinical utilities that have been associated with established Ca2+ channel antagonists such as the dihydropyridines (for example, nifedipine). Two such classes are reviewed by Michael Spedding, Barry Kenny and Pierre Chatelain. Fantofarone is a non-dihydropyridine with a novel site of action in the L-type Ca2+ channel that appears to yield a distinct cardiovascular profile. In contrast, Fluspirilene and related Na+ and Ca2+ channel inhibitors have a distinct site of action in Ca2+ channels, which is not specific for one channel type. The utility of Na+ and Ca2+ channel inhibitors in ischaemic stroke is compared with new and more selective Na+ channel inhibitors.
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selective antagonism of calcium channel activators by Fluspirilene
British Journal of Pharmacology, 1990Co-Authors: B A Kenny, Stuart Fraser, Andrew T Kilpatrick, Michael SpeddingAbstract:Abstract 1. Fluspirilene has been claimed to bind to a high affinity site in the calcium channel in skeletal muscle. We have investigated its calcium-antagonistic effects in smooth muscle and affinity for the channel in radioligand binding assays. 2. Fluspirilene was weakly active as an antagonist of Ca2(+)-induced contractions in K(+)-depolarized taenia preparations from the guinea-pig caecum, with threshold antagonism starting from concentrations of 30 nM. Nitrendipine, nicardipine and nimodipine were very potent antagonists in this model (threshold antagonism, greater than 1 nM). 3. In contrast, Fluspirilene (10-1000 nM) was a potent non-competitive antagonist of the effects of Bay K 8644 (1-3000 nM) on Ca2(+)-induced contractions and, at 10 nM, selectively antagonised the effects of Bay K 8644, abolished the Ca2(+)-channel activator effects of CGP 28392, without changing the calcium antagonist effects of nitrendipine, or modifying the sensitivity of the tissues to Ca2+. In contrast, the dihydropyridines were more effective as antagonists of Ca2+ than of Bay K 8644. Fluspirilene therefore selectively antagonised the effects of dihydropyridine Ca2+ channel activators without affecting the antagonist potency. 4. In radioligand binding experiments, Fluspirilene was a potent displacer of [3H]-PN-200-110 binding to rat cerebral cortical membranes (EC50 30 nM), albeit with a low Hill slope (0.66), and was more potent than other lipophilic diphenylalkylamines such as flunarizine and lidoflazine. Fluspirilene interacted non-competitively with [3H]-PN-200-110 and increased dissociation of the radioligand.
A. Schotte - One of the best experts on this subject based on the ideXlab platform.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding.
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. Gommeren, W. H. M. L. Luyten, P. Gompel, A. S. Lesage, K. Loore, J. E. LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, Fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and Fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, Fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except Fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. Gommeren, W. H. M. L. Luyten, P. Gompel, A. S. Lesage, K. Loore, J. E. LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, Fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT_2A receptors and D_2-type receptors. Predominant 5HT_2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D_2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D_3 and in particular D_4 receptors has been proposed. In vitro, all compounds, except the ‘typical’ antipsychotics haloperidol and Fluspirilene, showed higher affinity for 5HT_2A than for D_2 receptors. Subnanomolar affinity for human 5HT_2A receptors was observed for ORG-5222, sertindole, resperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D_2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D_2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D_4 than for D_2 receptors. For most other compounds, D_4 affinity was only slightly lower than their D_2 affinity. Seroquel was totally devoid of D_4 affinity. None of the compounds had nanomolar affinity for D_1 receptors; their affinity for D_3 receptors was usually slightly lower than for D_2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT_2A than D_2 receptors. Risperidone and ORG-5222 had 5HT_2A versus D_2 potency ratio of about 20. Highest potency for 5HT_2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT_2A receptors. ORG-5222, haloperidol, Fluspirilene and olanzapine showed the highest potency for occupying D_2 receptors. No regional selectivity for D_2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D_2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic α_1 receptors, except Fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more α_1 than D_2 receptors. Clozapine showed predominant occupancy of H_1 receptors and occupied cholinergic receptors with equivalent potency to D_2 receptors. A stronger predominance of 5HT_2A versus D_2 receptor occupancy combined with a more gradual occupancy of D_2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT_2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D_2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT_2A and D_2 occupancy and the avoidance of D_2 receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. Gommeren, W. H. M. L. Luyten, P. Gompel, A. S. Lesage, K. Loore, J. E. LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, Fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed.
Cornelius Wurthmann - One of the best experts on this subject based on the ideXlab platform.
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Side effects of low dose neuroleptics and their impact on clinical outcome in generalized anxiety disorder
Progress in Neuro-psychopharmacology & Biological Psychiatry, 1997Co-Authors: Cornelius Wurthmann, E Klieser, E LehmannAbstract:Abstract 1. 1. The present study was designed to determine the impact of neuroleptic side effects on clinical outcome in generalized anxiety disorder. 2. 2. 205 outpatients entered the study. In an open label design Fluspirilene 1.5mg per week was administered for a period of 6 weeks. 3. 3. Consistent with previous studies Fluspirilene demonstrated again anxiolytic properties and was in general tolerated well. 4. 4. However, in responders significantly less side effects were observed than in nonresponders. The interaction between tolerability and clinical outcome is the main finding of the present study. 5. 5. In conclusion, the data suggest, that neuroleptic treatment of generalized anxiety disorder should be guided by paying more attention to potential side effects. If under neuroleptic treatment of generalized anxiety disorders side effects are observed, pharmacotherapy should be discontinued, because this fact predicts an unfavourable clinical outcome.
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test therapy in the treatment of generalized anxiety disorders with low dose Fluspirilene
Progress in Neuro-psychopharmacology & Biological Psychiatry, 1995Co-Authors: Cornelius Wurthmann, E Lehmann, E Klieser, Uwe PesterAbstract:Abstract 1. 1. The present double-blind study was designed to determine under three different conditions (0.5 mg, 1.0 mg, 1.5 mg per week) whether response or non-response within a two-week test-therapy predicts clinical outcome after 6 weeks of Fluspirilene treatment in generalized anxiety disorders. 2. 2. 106 outpatients entered the study. The period of observation was 6 weeks. 3. 3. Confirming previous reports of their study group the authors found a significant reduction of anxiety in all treatment groups. However, this effect was mainly observed with the highest dose administered. The main finding of the study is that there is a significant correlation between initial response after 2 weeks of test therapy and therapeutic success after 6 weeks in Fluspirilene treatment of generalized anxiety disorders. 4. 4. Decreases in somatic anxiety, psychic anxiety and Hamilton —total — score within the first 2 weeks correlate with the baseline — to — week 6 decreases of the corresponding item and with the global clinical assessment of efficacy after 6 weeks. 5. 5. By means of test therapy patients with an unfavourable outcome are identified and, if medication is discontinued, are prevented from an ineffective longterm treatment.
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interaction of therapeutic effects and side effects in drug therapy of generalized anxiety disorders with low dosage Fluspirilene
Fortschritte Der Neurologie Psychiatrie, 1995Co-Authors: Cornelius Wurthmann, E Klieser, E LehmannAbstract:: The present study was designed to investigate the interaction between therapeutic effects and side-effects in Fluspirilene treatment of generalised anxiety disorders (GAD). 205 outpatients received in an open trial 1.5 mg Fluspirilene per week for 6 weeks. Confirming previous reports of our study group Fluspirilene demonstrated marked efficacy and was generally well tolerated. However, the main finding of our study is that side effects, although rare in Fluspirilene treatment, predict an unfavourable clinical outcome. This phenomenon is integrated in a psychological model implying that when GAD patients are aware of side-effects this induces anxiety. Again anxiety gives rise to somatic symptoms, both interacting in a forward loop. In conclusion, our data suggest that in the sense of Heinrich (1988) Fluspirilene treatment of GAD should be guided by paying attention to possible side effects.