不同浓度氯氮平对小鼠空腹血糖和骨骼肌葡萄糖转运蛋白4基因表达的影响

目的探讨氯氮平对雄性C57BL/6小鼠空腹血糖和骨骼肌葡萄糖转运蛋白4(GLUT4)基因表达的影响。方法将63只雄性C57BL/6小鼠随机分为3组,每组21只,分别灌胃给予蒸馏水、氯氮平4mg/kg及氯氮平20mg/kg,于给药后3h、1周、4周以试纸法测定各组空腹血糖,用逆转录-聚合酶链反应测定GLUT4mRNA表达。结果(1)灌药后3h、1周氯氮平4mg/kg组和氯氮平20mg/kg组空腹血糖和GLUT4mRNA的表达与空白对照组相比,差异无统计学意义(P>0.05);(2)灌药后4周氯氮平4mg/kg组和20mg/kg组的空腹血糖值[(5.6±0.5)mmol/L和(5.8±0.5)mmol/L]高于空白对照组[(4.6±0.6)mmol/L],而GLUT4mRNA的表达(0.50±0.14和0.48±0.12)却低于空白对照组(0.85±0.27),差异均有统计学意义(P<0.01)。结论氯氮平可以慢性升高空腹血糖,降低GLUT4mRNA的表达,可能是抗精神病药长期应用后血糖升高的发生机制之一。     

阿立哌唑治疗难治性精神分裂症的疗效观察

目的观察阿立哌唑治疗难治性精神分裂症的疗效及不良反应。方法48例难治性精神分裂症患者,随机分为两组,分别给予阿立哌唑与氯氮平治疗,疗程8周。采用阳性与阴性症状量表(PANSS)、副反应量表(TESS)评定疗效及不良反应。结果阿立哌唑组显效率为65．4%,氯氮平组显效率为68．2%。氯氮平药物副反应明显高于阿立哌唑组。结论对难治性精神分裂症阿立哌唑疗效与氯氮平相似,但副反应少。     

阿立哌唑与氯氮平对精神分裂症患者生活质量影响的对照研究

目的探讨阿立哌唑对精神分裂症患者生活质量的影响。方法对90例精神分裂症患者随机分为两组，分别给予阿立哌唑、氯氮平治疗6个月。用阳性症状与阴性症状量表（PANSS）评定精神症状，用世界卫生组织编制的生活质量量表（WHO QOL-100）评定生活质量，用TESS评定药物不良反应。结果治疗6个月后，两组对患者的生活质量均有改善。阿立哌唑组对WHO QOL-100各领域中，除精神支柱领域外，在生理、心理、独立性、社会关系和环境等领域的改善均明显优于氯氮平组；而氯氮平组仅明显改善心理领域。两组PANSS总分较疗前均有极显著性差异（P〈0．01），两组间比较无显著性差异，但阿立哌唑对阴性症状的改善优于氯氮平。阿立哌唑比氯氮平的不良反应少且轻。结论阿立哌唑对精神分裂症患者生活质量的改善优于氯氮平，有利于患者重返社会。     

氯丙嗪和氯氮平对小鼠生殖细胞和人淋巴细胞的诱变效应

为探讨氯丙嗪和氯氮平在使用临床治疗剂量时的遗传毒理效应，研究了两药对小鼠生殖细胞和小鼠子代体细胞的影响，以及对人体淋巴细胞姊妹染色单体互换（ＳＣＥ）频率及微核率的影响。结果显示：（１）连续给药５天后第１周两药高、中、低三个剂量组均能引起小鼠精子头部畸形率明显增高，但停药４周后对精子的致畸作用基本消失；（２）两药对小鼠睾丸细胞及子代体细胞的染色体结构畸变率均无明显影响；（３）两药在治疗剂量时对人淋巴细胞的ＳＣＥ频率及微核率无明显影响，治疗前后的自身对照研究亦未见两频率有明显改变；（４）两药的血药浓度与ＳＣＥ频率及微核率之间无量效关系。研究结果提示，两药在临床治疗剂量时对小鼠生殖细胞染色体结构以及对人体遗传物质均无明显损伤作用。     

Repeated treatment with ascorbate or haloperidol,but not clozapine,elevates extracellular ascorbate in the neostriatum of freely moving rats

Acute administration of neuroleptic drugs alters the extracellular level of ascorbate in the neostriatum, and increasing evidence suggests a role for this vitamin in the behavioral, and possibly therapeutic, effects of these drugs. To shed further light on this issue, extracellular ascorbate was recorded in the neostriatum and nucleus accumbens of awake, behaving rats following chronic treatment with either classical (haloperidol) or atypical (clozapine) neuroleptics or ascorbate itself. Electrochemically modified, carbon-fiber microelectrodes were lowered in place the day after the last of 21 daily injections of either haloperidol (0.5 mg/kg, SC), clozapine (20 mg/kg, IP), sodium ascorbate (500 mg/kg, IP) or vehicle. Voltammetric measurements were obtained during quiet rest and following administration ofd-amphetamine (2.5 mg/kg). Repeated treatment with either haloperidol or ascorbate elevated basal extracellular ascorbate and potentiated the amphetamine-induced increase in ascorbate release in neostriatum but not nucleus accumbens. Both treatment groups also showed a significant increase in amphetamine-induced sniffing and repetitive head movements compared to vehicle-treated animals. In contrast, repeated clozapine had no effect on extracellular ascorbate in either neostriatum or nucleus accumbens, but increased the locomotor response to an amphetamine challenge. Thus, to the extent that increases in neostriatal ascorbate exert neuroleptic-like effects, such effects are likely to parallel haloperidol rather than clozapine.     

利培酮、氯氮平治疗精神分裂症患者生活质量的长期随访对照研究

目的　探讨长期服用利培酮对精神分裂症患者生活质量的影响作用。方法　对 1997年 7月～ 2 0 0 0年 6月住院服用利培酮或氯氮平治疗达痊愈或显著进步、出院后回归社会达 18个月及以上的 174例精神分裂症患者 (利培酮 89例、氯氮平 75例 )的生活质量进行了分别于 2 0 0 0年 7月和 2 0 0 1年 7月进行了两次追踪随访对照研究。结果　第二次随访利培酮组患者的随访成功率高于氯氮平组 (χ2 =34.11,P <0 .0 0 0 1) ;利培酮组患者的生活质量两次随访结果均极显著高于氯氮平组 ,且利培酮组患者的生活质量较之一年前随访又有新的提高 ,多元逐步回归分析表明 :出院时服用药物剂量和种类是影响患者生活质量的较强因素。结论　利培酮能够提高精神分裂症患者的生活质量 ,远期疗效更突出     

Decreased R-R variation: A criterium for overdosage of tricyclic psychotropic drugs

Objective Since intoxication with tricyclic antidepressants is common, a supplementary screening method for differentiation between therapeutic and supratherapeutic ranges would be a valuable diagnositc tool, particularly in delirious and unconscious patientsSetting 109 patients treated with amitriptyline, 8 patients treated with doxepin, 10 patients treated with clozapine, and 72 normal control subjects matched for age and sex were tested for heart rate variability while resting.Results Considering time and frequency derived measures, which are rather independent of heart rate, the patients showed significantly decreased heart rate variability parameters (p<0.0001), as compared with the normal subjects. Of the patients presenting delirious symptoms 6 showed coefficients of variation more than 4 standard deviations below the mean control value.Conclusions As heart rate variability can be easily calculated, this measurement is suggested as a useful tool to quickly exclude or support the diagnosis of chronic intoxication with tricyclic antidepressants or clozapine.     

Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine

Prepulse inhibition (PPI) of the startle reflex provides an operational measure of sensorimotor gating. Deficits in PPI are observed in schizophrenia patients and can be modelled in animals by administration of noncompetitive NMDA antagonists such as phencyclidine (PCP) or dizocilpine (MK-801). Previous studies indicate that the atypical antipsychotic clozapine restores PPI in PCP-treated animals while the typical antipsychotic haloperidol does not. Olanzapine (LY170053) is a novel putative atypical antipsychotic that shares many pharmacological and behavioral properties with clozapine. The present study assessed the ability of olanzapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg) to antagonize deficits in PPI produced by PCP (1.5 mg/kg) and dizocilpine (0.1 mg/kg). At the two highest doses, olanzapine significantly increased PPI in PCP- and dizocilpine-treated animals without affecting PPI or baseline startle reactivity by itself. These results support the notion that olanzapine is functionally similar to clozapine and may have utility as an atypical antipsychotic agent.     

精神分裂症服用氯氮平能降低其甲状腺素水平的对照分析

目的探索氯氮平治疗是否影响T3、T4和TSH水平.方法对17例精神分裂症患者,给予氯氮平治疗第4天和第4周末分别测定T3、T4和TSH水平.结果治疗第4周末的T3(3.309±0.689)、T4(9.449±1.941)水平比第4天的T3(3.915±0.850)、T4(11.178±2.180)水平明显降低(P均＜0.05).结论氯氮平治疗能降低甲状腺素水平.     

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET)

By means of positron emission tomography the uptake and kinetics of N-(methyl-¹¹C)clozapine in different brain regions have been studied in Rhesus monkeys. ¹¹C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of ¹¹C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for ¹¹C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.