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991.
A Schotte PF Janssen W Gommeren WH Luyten P Van Gompel AS Lesage K De Loore JE Leysen 《Canadian Metallurgical Quarterly》1996,124(1-2):57-73
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 相似文献
992.
JE Franklin 《Canadian Metallurgical Quarterly》1995,273(21):1656-1657
Diagnoses for substance dependence and abuse have been modified in the latest edition of the Diagnostic and Statistical Manual of Mental Disorders. The Food and Drug Administration approved marketing of naltrexone as a medication for alcohol-dependence treatment. 相似文献
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AD Rae-Grant N Eckert PJ Barbour JE Castaldo W Gee CJ Wohlberg ZS Lin JF Reed 《Canadian Metallurgical Quarterly》1996,40(3):40l-407
We screened all head-injured trauma patients admitted to Lehigh Valley Hospital during a 2-year period. From 725 screened patients, 69 patients in a coma on the second day after trauma were entered into this study. During the first week, these patients underwent electroencephalography (EEG), evoked potentials, ocular pneumoplethysmography, and transcranial Doppler (TCD) sonography. Clinical examinations were undertaken 2 and 7 days after trauma. Test results were correlated with functional clinical outcome at 6 months. In a multiple regression analysis, EEG was the major independent variable that significantly predicted 6-month outcome based on Glasgow Outcome Scale score. Transcranial Doppler sonography contributed a small additional component. Though EEG was the most significant predictive factor in this neurophysiological battery, it did not add significantly to the predictive power of Glasgow Coma Scale score determined at day 7. These findings suggest that in neurophysiologic testing in this type of patient is not useful in improving predictive outcome data. 相似文献
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GE Meredith A Pattiselanno HJ Groenewegen SN Haber 《Canadian Metallurgical Quarterly》1996,365(4):628-639
The neurochemical division of the rodent nucleus accumbens into shell and core is now a widely accepted concept. However, such divisions in the primate nucleus accumbens have yet to be fully clarified and described. In the present study, the forebrains of three primates--marmoset, rhesus monkey, and human--and a Wistar rat, were immunoreacted with antibodies directed against calbindin-D28k. The patterns of immunoreactivity in the primates' ventral striatum were mapped and compared to that of rat. Calbindin staining was uneven in all species and there was no evidence of a bicompartmental organization, i.e., striosome/patch and matrix, in central parts of the nucleus. Nucleus accumbens in primates, as in rat, could be divided immunohistochemically into a crescent-shaped outer shell--medially, ventrally and laterally--and an inner core. In general, medial parts of the shell stained less intensely for calbindin than did lateral parts. However, interspecific variation in the intensity of the immunoreactive staining and the mediolateral extent of the shell was obvious. The core, which immunostained unevenly, was consistently more intensely immunoreactive than either medial or lateral shell in all species except the marmoset. These results suggest that the neurochemical subdivisions of shell and core established for nucleus accumbens of rodents are also present in primates. However, further work is needed to establish whether these territories are homologous and, if so, the full extent of that homology. 相似文献