【作者】 聂颖兰；

【导师】 王唯红； 胡欣；

【作者基本信息】 山东大学 ， 药物分析学， 2008， 硕士

【摘要】 精神分裂症是以基本个性改变,思维、情感、行为的分裂,精神活动与环境的不协调为主要特征的一类常见精神病。其发病率在15‰,随着社会的发展,竞争压力的增大,其发病率有明显的上升。氯丙嗪（chlorpromazine）等典型抗精神病药可以有效控制精神分裂症阳性症状,但其并非对所有病人都有效,且对阴性症状无能为力,特别是存在严重的锥体外系不良反应（60%）。与典型抗精神病药物相比,非典型抗精神病药物（Atypicalantipsychotic drugs,APDs）在临床上具有以下的优点:①没有传统的抗精神病药物所具有的副作用或较之轻微得多;②对阴性症状有效;③可改善患者的认知功能缺陷。目前在美国已有50%以上的患者接受APDs的治疗。1965年,Christensen等首先报道美哌隆是一个新型的丁酰苯类抗精神药。临床实践证明:美哌隆可改善精神分裂症阳性、阴性症状,对难治性精神分裂症有效,并可提高患者认知功能;锥体外系不良反应（EPS）及迟发型运动障碍（TD）较少,且不会持久地引起催乳素升高。由于其药理作用不同于传统的丁酰苯类药物,如氟哌啶醇,近几年有人也认为其药理机制属于APDs,重新对其进行研究。APDs对不同脑区神经核作用具有相对特异性,如更明显地影响边缘叶和额叶皮质区神经化学活动。研究表明,精神分裂症的阴性症状和认知缺陷是由前额叶的多巴胺（DA）下降引起;中脑边缘DA系统中,伏核作为该通路的功能中心,可能是精神病治疗的重要靶点。精神分裂症病人的认知缺陷与皮质乙酰胆碱转移酶活性相关。本论文以大鼠脑内特定区域的DA和乙酰胆碱（ACh）水平作为药效学考察的指标,利用脑微透析采样技术,结合HPLC-ECD,HPLC-MS/MS检测技术测定内侧额叶前皮质（Medial prefrontal cortex,mPFC）和伏核（Nucleusaccumbens,NAC）内DA和ACh的含量,通过对脑内神经递质给药前后一段时间的动态监测和给药后脑内药物浓度的测定,考察药物对大鼠脑内多巴胺和乙酰胆碱释放的影响。结果表明,盐酸美哌隆剂量相关性的增加大鼠mPFC和NAC内DA释放;并可剂量相关性的增加mPFC内ACh释放,但对NAC内ACh不明显。盐酸美哌隆对mPFC内多巴胺水平较NAC影响大,与氯氮平等APDs作用一致。本论文建立了大鼠血浆内盐酸美哌隆固相萃取HPLC-UV测定方法,进行大鼠静脉和灌胃给药体内药代动力学研究。本方法灵敏度高、准确、简便,提取回收率达75%以上。盐酸美哌隆在血浆内的药代动力学呈剂量依赖型,静脉给药药物的药时曲线呈双峰现象,表明药物在体内存在肝肠循环。本论文建立了脑透析液中盐酸美哌隆的HPLC-UV测定方法。利用脑微透析技术取样,测定皮下给药后脑内盐酸美哌隆的浓度,通过考察药物浓度对脑内神经递质释放的影响,更直观地反映药物的作用机制和药效。研究表明,盐酸美哌隆皮下给药后可迅速透过血脑屏障,30min时即可检测。5和10 mg·kg^-1给药后药物在脑内分布呈剂量相关性,表明药物对神经递质的影响与药物浓度相关,但两者达峰时并不一致,表明药物浓度并非神经递质变化的唯一决定因素,还应考虑受体分布、受体浓度和受体结合力等因素。同时测定灌胃给药后脑区内药物的药动学变化。血药浓度不能完全反映药物的脑内的浓度,药物在通过血脑屏障时可能存在饱和。更多还原

【Abstract】 Schizophrenia is a serious and challenging medical illness that often interferes with a person’s ability to think clearly,to distinguish reality from fantasy,to manage emotions,make decisions,and relate to others.It affects about 1.5 percent of the population age 18 and older.The disease incidence is increased for the competition pressure.Typical neuroleptic drugs,e.g.chlorpromazine,produce extrapyramidal side effects（EPS）at doses which are effective in AChieving control of positive symptoms in schizophrenia,and they have nothing to do to improve negative symptoms and cognitive function.The newer antipsychotic drugs,e.g.clozapine,are designated as atypical antipsychotic drugs（APDs）because they produce fewer EPS at clinically effective doses than do typical agents.Additionally,they improve negative symptoms and cognitive function.Nowadays,about 50%of patients with schizophrenia are treated with APDs in USA.Melperone is a butyrophenone used in Western Europe and other countries for treatment of patients with schizophrenia first reported in 1965.It can improve positive and negative symptoms equally,and enhance some types of cognitive function in schizophrenia,but it produces low EPS and tardive dyskinesia（TD）with no increase in plasma prolactin（pPRL）levels at clinically effective doses.Meltzer suggested that Melperone has clozapine-like antipsychotic properties.Thus,Melperone fulfils criteria for APDs.It was previously postulated that APDs preferentially increase Dopamine（DA） release in the medial prefrontal cortex（mPFC）compared to the limbic system,e.g., the nucleus accumbens（NAC）.DAminergic hypofunction in the mPFC has been suggested to be related to the etiology of negative symptoms and cognitive dysfunction of schizophrenia;The nucleus accumbens（NAC）,the main target of the mesotelencephalic DA system,has been the focus of many theories exploring the chemoarchitectural substrates of schizophrenia and affective disorders as well as theories of reward and motivation;Acetylcholine（ACh）may be important to either the cognitive dysfunction of schizophrenia or the ability of APDs to improve some or all aspects of that cognitive deficit.The present study was designed to monitor drug-induced changes in extracellular DA and ACh levels in the mPFC and the NAC,using in vivo microdialysate with dual probe implantation in awake,freely moving rats.DA was detectde by HPLC-ECD and ACh was detected by HPLC-MS/MS.The present microdialysate study first demonstrated that,Melperone（1-10 mg/kg）dose- dependently increases DA release in the mPFC and NAC to the same extent.Melperone also increased ACh release in the mPFC,but not the NAC.Like clozapine,it produced greater increases in DA release in rat mPFC compared to the NAC,which is suggested to be related to its ability to treat negative symptoms and to improve cognitive function.A rapid,sensitive HPLC-UV method was developed to determine Melperone in rat blood.Samples was extracted with Oasis^?HLB solid phase extraction. Pharmacokinetics in the blood was studied after Melperone iv and po to rats,and the pharmacokinetic parameters was obtainded.With the results of Melperone concerntrations in mPFC and NAC after po to rats,the ability of Melperone to pass through the blood brain barrier（BBB）was evaluated.Melperone concerntrations increased in a dose- dependently manner.There was obvious double phenomena in C-T graph,and it maybe explained by hepato-enteric circulation.Melperone concerntrations in blood can not reflect the changes in brain,and saturate may hanppen when it passed through the BBB.A rapid,sensitive HPLC-UV method was developed to determine Melperone in dialysate.Coupled with sc drug administration,and the determine of drug concentrations,the informative correlations between neurotransmitters levels and Melperone concerntration were studied.Melperone can be determined in 30min in the brain.AUC_0-t,AUC_0-∞increased in a dose- dependently manner(5 and 10 mg·kg^-1), and this tendency is correlated with neurotransmitters changes in the brain.But the t_max of Melperone was later than neurotransmitters.The concentration of Melperone was not the only influencing factor for the neurotransmitters levels changes,and something like receptor conceentration and disposition,and the bonding of Melperone to receptors should also be concluded.Melperone concerntrations in brain after po to rats was also determined to study the brain pharmacokinetics.更多还原