盐酸美哌隆的脑内作用机制和药代动力学初步研究
|
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。
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.
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。
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.
引文
[1]曾凡新,傅洁民,董志.非典型抗精神病药的受体药理学研究进展[J].中国临床药理学杂志,2003,19(5):393-396.
[2]Christensen JA,Hermestam S,Buus-Lassen J,et al.Pharmacological and toxicological studies on γ-(4-methylpiperidino)-ρ-fluorobutyrophenone(FG5111)-a new neuroleptic agent[J].Acta Pharmacol Toxicol,1965,23:109-132
[3]Meltzer HY,Koenig JI,Nash JF,et al.Melperone and clozapine:neuroendocrine effects of atypical neuroleptic drugs[J].Acta Psychiatr Scand Suppl,1989;80(s352):24-30
[4]Christensson E G.Pharmacological data of the atypical neuroleptic compound melperone(Buronil~@),Actapsychiatr.scand.Suppl.1989,352.:7-15
[5]http://www.ncbi.nlm.nih.gov/sites/entrez.Melperone-PubChem Substance Results.
[6]Neuroleptic action of metyleperone.Dissert.Pharm.Pharmacol,1970,ⅩⅫ,2/3
[7]Richelson E,Souder T.Binding of antipsychotic drugs to human brain receptors:Focus on newer generation compounds[J].Life Scienses,2000,68(1):29-39
[8]Roth B L,Craigo S C,Choudhary M S,et al.Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-and 5-hydroxytryptaminereceptors [J].J.Pharmacol.Exp.Ther,1994,268(3):1403-1410
[9]Ichikawa J,Meltzer HY.The effect of chronic atypical antipsychotic drugs and haloperidol on amphetamine-induced dopamine release in vivo[J].Brain Res.1992,574(1-2):98-104
[10]Distribution in mice of ~(14)C-γ-(4-methylpiperidino)-ρ-fluorobutyrophenone hydrochloride(FG 511),a butyrophenone derivative with tranquillizing propertiey,Acta pharmacol.et toxicol.,1965(23),65-72
[11]Uhr M,NamendorfC,Grauer MT,et al.P-glycoprotein is a factor in the uptake of dextromethorphan,but not ofmelperone,into the mouse brain:evidence for an overlap in substrate specificity between P-gp and CYP2D6.J Psychopharmacol.2004,18(4):509-515
[12]Bjerkenstedt L.Melperone in the treatment of schizophrenia[J].Acta Psychiatrica Scandinavica,1989,80(s352):35-39
[13]Bjerkenstedt L,Harnryd C,Grimm V.A double-blind comparison of melperone and thiothixene in psychotic women using a new rating scale,the CPRS[J].Arch Psychiatr Nervenkr, 1978, 226(3): 157-172
[14]Harnryd C, Bjerkenstedt L, Gullberg B .A clinical comparison of melperone and placebo in schizophrenic women on a milieu therapeutic ward[J].Acta Psychiatrica Scandinavica, 1989, 80(s352):40-47
[15]Sumiyoshi T, Jayathilake K , Meltzer H Y. A comparison of two doses of melperone, an atypical antipsychotic drug, in the treatment of schizophrenia[J]. Schizophrenia Research , 2003 , 62 (1-2) : 65- 72
[16]Haldun Soygu¨r , O¨ zden Palaog(?)lu , Nur Alt(?)no¨rsa, Melperone treatment in an organic delusional syndrome induced by hyperprolactinemia: a case report[J] .European Neuropsychopharmacology, 1997, 7 (2) 161 -163
[17] Meltzer HY, Sumiyoshi T, Jayathilake K . Melperone in the treatment of neuroleptic-resistant schizophrenia[J].Psychiatry Research , 2001, 105 (3) : 201-209
[18] Sumiyoshi T, Jayathilake K, Meltzer H Y . The effect of melperone, an atypical antipsychotic drug , on cognitive function in schizophrenia[J]. Schizophrenia Research , 2002 , 59 (1) : 7-16
[19] Barbato L, Monge A, Stocchi F, et al. Melperone in the treatment of iatrogenic psychosis in Parkinson's disease[J]. Funct Neurol, 1996 , 11(4):201-207
[20] http://clinicaltrialsfeeds.org/clinical-trials/show/NCTOO 125138.Melperone (an Anti-Psychotic) in Patients With Psychosis Associated With Parkinson's Disease.Ovation Pharmaceuticals, Date First Received: July 29, 2005, Last Updated: June 4, 2007
[21]Poldinger WJ. Melperone in low doses in anxious neurotic patients.A double-blind placebo -controlled clinical study[J]. Neuropsychobiology, 1984,11(3):181-186
[22]Carlsson C, Gullberg B.A double blind study with melperone and placebo in the treatment of chronic alcoholics[J]. Int J Clin Pharmacol Biopharm, 1978, 16 (7):331-332
[23] Gunne L M, Johansson P. Chronic melperone administration does not enhance oral movements in rats[J]. Acta Psychiatrica Scandinavica, 1989, 80 (s352) : 48-50
[24]Kirkegaard A, Kirkegaard G, Geismar L, et al. Additional studies on side effects of melperone in long-term therapy for 1 to 15 years in psychiatric patients[J]. Arzneimittelforschung,1981:31(4):737-740
[25]Christensen I,Geismar L,Kirkegaard A,et al.Additional studies on side effects of melperone in long-term therapy for 1 to 20 years in psychiatric patients[J].Arzneimittelforschung,1986,36(5):855-860
[26]Grozinger M,Dragicevic A,Hiemke C.Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation ofvenlafaxine[J].Pharmacopsychiatry,2003,36(1):3-6
[27]Kohnke MD,Lutz U,Wiatr G,Schwarzler,et al.Cytochrome P450 2D6dependent metabolization of risperidone is inhibited by melperone[J].Eur J Clin Pharmacol,2006,62(4):333-334
[28]Venton B J,Robinson T E,Kennedy RT.In vivo measurements of neurotransmitters by microdialysate sampling[J].Analytical Chemistry,2006,78(5),1391-1399
[29]Delgado JM,Defeudis FV,Roth RH,et al.Dialytrode for long term intracerebral perfusion in awake monkeys[J].Arch Int Pharmacodyn Ther,1972,198(1):9-21
[30]Ungerstedt U,Pycock C.Functional correlates ofdopamine neurotransmission [J].Bull Schweiz Akad Med Wiss,1974,30(1-3):44-55
[31]Bourne JA.Intracerebral microdialysate:30 years as a tool for the neuroscientist [J].Clin Exp Pharmacol Physiol,2003,30(1-2):16-24
[32]Khan SH,Shuaib A.The technique of intracerebral microdialysate[J].Methods,2001,23(1):3-9
[33]韩慧婉,舒鸿钧,刘国诠.微透析技术及其应用[J].化学通报,2000,(12):52-56
[34]张金兰,刘颖,周同惠.微透析取样技术在药物代谢研究中的应用及前景[J].药学学报,2001,36(7):555-558
[35]韩冬,班春林,崔黎丽等.微透析技术及在药学中的应用进展[J].药学实践杂志,2005,23(3):139-142
[36]张英丰.微透析法进行青藤碱贴剂透皮特性及药物动力学的研究.广州中医药大学博士学位论文,2006
[37]李智平,施孝金,李中东等.在体微透析技术应用于神经药动学研究进展[J].中国医院药学杂志,2003,23(6):362-364
[38]Benveniste H.Brain microdialysate[J].J.Neurochem,1989,52(6):1667-1679
[39]Alexander GM,Grothusen JR,Schwartzman RJ.Flow dependent changes in the effective surface area of microdialysate probes[J].Life Sci,1988,43(7):595-601
[40]Levine JE,Powell KD.Microdialysate for measurement of neuroendocrine peptides[J].Methods Enzymol,1989,168:166-181
[41]李范珠,冯健.脑微透析技术及其在脑内药动学中的应用[J].中国药学杂志,2006,41(6):405-407
[42]Horn T,Bauce L,Landgraf R,et al.Microdialysate with high NAC1 causes central release of amino acids and dopamine[J].JNeurochem,1995,64(4):1632-1644
[43]Westeink BH,Hofsteede HM,Damsma G,et al.The significance of extracellular calcium for the release of dopamine,acetylcholine and amino acids in conscious rats,evaluated by brain microdialysate[J].Naunyn Schmiedebergs Arch Pharmacol,1988,337(4):373-378
[44]Osborne P G,O'Connor WT,Ungersted TU.Effect of varying the ionic concentration of a microdialysate perfusate on basal striatal dopamine levels in awake rats[J].J Neurochem,1991,56(2):452-456
[45]Bungay PM,Morrison PF,Dedrick RL.Steady-state theory for quantitative microdialysate of solutes and water in vivo and in vitro.Life Sci,1990,46(2),105-119
[46]Malonne I,Davies.A review of microdialysate sampling for pharmacokinetic application[J].Analytica Chimica Acta,1999,379(3):227-249
[47]Pepeu G,Giovannini MG.Changes in acetylcholine extracellular levels during cognitive processes.Learn Mem.2004;11(1):21-27
[48]Zhang M Y,Beyer C E.Measurement of neurotransmitters from extracellular fluid in brain by in vivo microdialysate and chromatography-mass spectrometry [J].Journal of Pharmaceutical and Biomedical Analysis.2006,40(3)492-499
[49]Stavinoha WB,Weintraub ST.Estimation of choline and acetylcholine in tissue by pyrolysis gas chromatography[J].Anal.Chem,1974,46(6):757-760
[50]Fidone SJ,Weintraub ST,Stavinoha WB,Acetylcholine content of normal and denervated cat carotid bodies measured by pyrolysis gas chromatography/mass fragmentometry[J].J.Neurochem,1976,26(5):1047-1049
[51]郑红,石力夫,胡晋红.微透析与现代分析技术联用的研究进展[J].国外医学药学分册,2005,(32)4:275-278
[52]王俏.脑乙酰胆碱分析技术研究进展[J].西北药学杂志,2007,22(1):43-45
[53]Ichikawa J , Dai J , Meltzer H Y .Acetylcholinesterase Inhibitors Are Neither Necessary nor necessary nor desirable for microdialysate studies of brain acetylcholine[J].Current seperations, 2000. 19(2):37-43
[54]De Boer P , Westerinck BHC , Horn A S.The effect of acetylcholinesterase inhibition on the release of acetylcholine from the striatum in vivo: interaction with autoreceptor responses[J]. Neurosci. Lett, 1990, 116:357-360
[55]Acquas E, Fibiger HC.Dopaminergic Regulation of Striatal Acetylcholine Release: The Critical Role of Acetylcholinesterase Inhibition[J].J. Neurochem. , 1998, 70(3): 1088-1093
[56]Parada MA, Hernandez L, De Parada MP. Selective Action of Acute Systemic Clozapine on Acetylcholine Release in the Rat Prefrontal Cortex by Reference to the Nucleus Accumbens and Striatum[J]. J Pharmacol ExpTher ,1997, 281(1): 582-588
[57]Ichikawa J, O'Laughlin IA, Dai J , et al. Clozapine increased extracellular acetylcholine (ACh-ext) levels in rat medial prefrontal cortex (mPFC) but not striatum (STR) or nucleus accumbens (NAC) in the absence of AChesterase (AChE) inhibition[J]. Society for Neuroscience Abstracts , 1999, 25( pt1): 452
[58]DeBoer P, Abercrombie ED. Physiological release of striatal acetylcholine in vivo: modulation by D1 and D2 dopamine receptor subtypes[J]. J Pharmacol Exp Ther, 1996, 277(2):775-783
[59]Huang T, Yang L, Gitzen J, et, al. Detection of basal acetylcholine in rat brain microdialysate[J].J. Chromatogr. B, 1995, 670 (2) :323-327
[60]KatoT, Liu JK, Yamamoto K, et al .Detection of basal acetylcholine release in the microdialysate of rat frontal cortex by high-performance liquid chromatography using a horseradish peroxidase-osmium redox polymer electrode with pre-enzyme reactor[J]. J. Chromatogr.B , 1996, 682 (1) :162-166
[61] Hows MEP, Andrew JO, Murray S, et al. High-performance liquid chromatography/ tandem mass spectrometry assay for the rapid high sensitivity measurement of basal acetylcholine from microdialysates [J].J. Neurosci.Methods , 2002, 121(1):33-39
[62]Zhang MY, Li P, Lin Q, et al.52nd ASMS, Nashville, TN, 2004 May , 24-27
[63]ZhuY, Wong PSH, Cregor M, et , al. In vivo microdialysate and reverse phase ion pair liquid chromatography/tandem mass spectrometry for the determination and identification of acetylcholine and related compounds in rat brain[J].Rapid Comrnun.Mass Spectrom,2000,14(18):1695-1700
[64]景富春,刘小莉,陈虹.HPLC-ECD法测定大鼠脑微透析液中的多巴胺及其代谢产物[J].中国临床药理学与治疗学,2006,11(9):1003-1005
[65]Zhang W,Xie YF,Ai SY.Liquid chromatography with amperometric detection using functionized multi-wall carbon nanotube modified electrode for the determination of monoamine neurotransmitters and their metabolites[J].J Chromatogr B,2003,791:217-225
[66]Xu F,Gao MN,Shi GY.Simultaneous detection of monoamines in rat striatal microdialysate at poly(para2aminobenzoic acid)modified electrode by highperformance liquid chromatography[J].Analytica Chirnica Acta,2001;439:239-246
[67]王巍,赵德忠,王卫霞.应用HPLC-ED同时测定脑匀浆8种生物胺及其代谢产物含量[J].中国药理学通报,2004;20:119-120
[68]Virag L,Whittington RA.Highly sensitive chromatographic assay for dopamine determination during in vivo cerebral micro dialysate in the rat[J].J Chromatogr B,2002;772:267-272
[69]马爱梅,赵永波,陈英辉.苯妥英钠在大鼠血液和脑细胞外液药动学研究[J].中国临床神经科学,2005,13(2):118-122
[70]Borgstrom L.Pharmacokinetics of parenteral and oral melperone in man[J].Eur J Clin Pharmacol,1982,23(2):173-176
[71]Chan KY,Okerholm RA.Quantitative analysis of melperone in human plasma by gas chromatography-mass spectrometry-selected ion monitoring[J].J Chromatogr.1983,274:121-127
[72]Koppel C,Tenczer J,Ibe K.Gas chromatographic-mass spectrometric study of urinary metabolism of melperone[J].J Chromatogr.1988,427(1):144-150
[73]Carsten Kratzsch,Frank T.Peters,Thomas Kraemer.Screening,library-assisted identification and validated quantification of fifteen neuroleptics and three of their metabolites in plasma by liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization[J].J.Mass Spectrom.2003;38:283-295
[74]Winkeler H D,Szigan J,Gerhards P.Development Of A Robust And Sensitive Analytical Method For The Measurement Of Pharmaceutical Compounds In Serum Using LC/MS[J].Consumable Products Application Note A02100,2004,8.
[75]赵靖平,杨德森.精神分裂症单胺病理假说的药理学研究进展[J].国外医学精神病学分册,1999,26(3):140-143
[76]黄继忠,张明园.非典型抗精神病药治疗精神分裂症的评价(一)[J].上海精神医学2005,17(4):230-232
[77]Cai JX,Arnsten AFT.Dose dependent effects of the doparaine Dl receptor agonistsA77636 or SKF 81297 on spatial working memory in aged monkeys[J].J Pharmacol Exp Ther,1997,283:183-189
[78]Okubo Y,Suhara T,Suzuki K,et al.Decreased prefrontal dopamine Dl receptor in schizophrenia revealed by PET[J].Nature,1997,385:634-636
[79]张秀娟,徐满英.伏隔核功能的研究进展[J].哈尔滨医科大学学报,2002,36(4):334-335
[80]Rupniak NM,Tye S J,FieldMJ.Enhanced performance of spatial and visual recognition memory tasks,by the selective acetylcholinesterase inhibitor E2020in rhesus monkeys[J].Psychopharmacology,1997,131:406-410
[81]牛雅娟,吉中孚.精神分裂症认知功能障碍的烟碱机制.国外医学·精神病学分册,2001,28(2):79
[82]王向兵,顾钧,周文华.中枢毒蕈碱能受体与学习记忆.国外医学·精神病学分册,2004,31(1):61
[83]Frindnma JI,Temporini H,Dvis KL.Pharmocologic strategies for augmenting cognitive performance in schizophrenia[J].Biol Psychiatry,1999,45:1-16
[84]Lolin Y,Ratnarai N,Hjelm M,et al.Antiepileptic drugpharmacokinetics and neuropharacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid:phenytoin[J].Epilepsy Res,1994,19:99-110
[2]Christensen JA,Hermestam S,Buus-Lassen J,et al.Pharmacological and toxicological studies on γ-(4-methylpiperidino)-ρ-fluorobutyrophenone(FG5111)-a new neuroleptic agent[J].Acta Pharmacol Toxicol,1965,23:109-132
[3]Meltzer HY,Koenig JI,Nash JF,et al.Melperone and clozapine:neuroendocrine effects of atypical neuroleptic drugs[J].Acta Psychiatr Scand Suppl,1989;80(s352):24-30
[4]Christensson E G.Pharmacological data of the atypical neuroleptic compound melperone(Buronil~@),Actapsychiatr.scand.Suppl.1989,352.:7-15
[5]http://www.ncbi.nlm.nih.gov/sites/entrez.Melperone-PubChem Substance Results.
[6]Neuroleptic action of metyleperone.Dissert.Pharm.Pharmacol,1970,ⅩⅫ,2/3
[7]Richelson E,Souder T.Binding of antipsychotic drugs to human brain receptors:Focus on newer generation compounds[J].Life Scienses,2000,68(1):29-39
[8]Roth B L,Craigo S C,Choudhary M S,et al.Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-and 5-hydroxytryptaminereceptors [J].J.Pharmacol.Exp.Ther,1994,268(3):1403-1410
[9]Ichikawa J,Meltzer HY.The effect of chronic atypical antipsychotic drugs and haloperidol on amphetamine-induced dopamine release in vivo[J].Brain Res.1992,574(1-2):98-104
[10]Distribution in mice of ~(14)C-γ-(4-methylpiperidino)-ρ-fluorobutyrophenone hydrochloride(FG 511),a butyrophenone derivative with tranquillizing propertiey,Acta pharmacol.et toxicol.,1965(23),65-72
[11]Uhr M,NamendorfC,Grauer MT,et al.P-glycoprotein is a factor in the uptake of dextromethorphan,but not ofmelperone,into the mouse brain:evidence for an overlap in substrate specificity between P-gp and CYP2D6.J Psychopharmacol.2004,18(4):509-515
[12]Bjerkenstedt L.Melperone in the treatment of schizophrenia[J].Acta Psychiatrica Scandinavica,1989,80(s352):35-39
[13]Bjerkenstedt L,Harnryd C,Grimm V.A double-blind comparison of melperone and thiothixene in psychotic women using a new rating scale,the CPRS[J].Arch Psychiatr Nervenkr, 1978, 226(3): 157-172
[14]Harnryd C, Bjerkenstedt L, Gullberg B .A clinical comparison of melperone and placebo in schizophrenic women on a milieu therapeutic ward[J].Acta Psychiatrica Scandinavica, 1989, 80(s352):40-47
[15]Sumiyoshi T, Jayathilake K , Meltzer H Y. A comparison of two doses of melperone, an atypical antipsychotic drug, in the treatment of schizophrenia[J]. Schizophrenia Research , 2003 , 62 (1-2) : 65- 72
[16]Haldun Soygu¨r , O¨ zden Palaog(?)lu , Nur Alt(?)no¨rsa, Melperone treatment in an organic delusional syndrome induced by hyperprolactinemia: a case report[J] .European Neuropsychopharmacology, 1997, 7 (2) 161 -163
[17] Meltzer HY, Sumiyoshi T, Jayathilake K . Melperone in the treatment of neuroleptic-resistant schizophrenia[J].Psychiatry Research , 2001, 105 (3) : 201-209
[18] Sumiyoshi T, Jayathilake K, Meltzer H Y . The effect of melperone, an atypical antipsychotic drug , on cognitive function in schizophrenia[J]. Schizophrenia Research , 2002 , 59 (1) : 7-16
[19] Barbato L, Monge A, Stocchi F, et al. Melperone in the treatment of iatrogenic psychosis in Parkinson's disease[J]. Funct Neurol, 1996 , 11(4):201-207
[20] http://clinicaltrialsfeeds.org/clinical-trials/show/NCTOO 125138.Melperone (an Anti-Psychotic) in Patients With Psychosis Associated With Parkinson's Disease.Ovation Pharmaceuticals, Date First Received: July 29, 2005, Last Updated: June 4, 2007
[21]Poldinger WJ. Melperone in low doses in anxious neurotic patients.A double-blind placebo -controlled clinical study[J]. Neuropsychobiology, 1984,11(3):181-186
[22]Carlsson C, Gullberg B.A double blind study with melperone and placebo in the treatment of chronic alcoholics[J]. Int J Clin Pharmacol Biopharm, 1978, 16 (7):331-332
[23] Gunne L M, Johansson P. Chronic melperone administration does not enhance oral movements in rats[J]. Acta Psychiatrica Scandinavica, 1989, 80 (s352) : 48-50
[24]Kirkegaard A, Kirkegaard G, Geismar L, et al. Additional studies on side effects of melperone in long-term therapy for 1 to 15 years in psychiatric patients[J]. Arzneimittelforschung,1981:31(4):737-740
[25]Christensen I,Geismar L,Kirkegaard A,et al.Additional studies on side effects of melperone in long-term therapy for 1 to 20 years in psychiatric patients[J].Arzneimittelforschung,1986,36(5):855-860
[26]Grozinger M,Dragicevic A,Hiemke C.Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation ofvenlafaxine[J].Pharmacopsychiatry,2003,36(1):3-6
[27]Kohnke MD,Lutz U,Wiatr G,Schwarzler,et al.Cytochrome P450 2D6dependent metabolization of risperidone is inhibited by melperone[J].Eur J Clin Pharmacol,2006,62(4):333-334
[28]Venton B J,Robinson T E,Kennedy RT.In vivo measurements of neurotransmitters by microdialysate sampling[J].Analytical Chemistry,2006,78(5),1391-1399
[29]Delgado JM,Defeudis FV,Roth RH,et al.Dialytrode for long term intracerebral perfusion in awake monkeys[J].Arch Int Pharmacodyn Ther,1972,198(1):9-21
[30]Ungerstedt U,Pycock C.Functional correlates ofdopamine neurotransmission [J].Bull Schweiz Akad Med Wiss,1974,30(1-3):44-55
[31]Bourne JA.Intracerebral microdialysate:30 years as a tool for the neuroscientist [J].Clin Exp Pharmacol Physiol,2003,30(1-2):16-24
[32]Khan SH,Shuaib A.The technique of intracerebral microdialysate[J].Methods,2001,23(1):3-9
[33]韩慧婉,舒鸿钧,刘国诠.微透析技术及其应用[J].化学通报,2000,(12):52-56
[34]张金兰,刘颖,周同惠.微透析取样技术在药物代谢研究中的应用及前景[J].药学学报,2001,36(7):555-558
[35]韩冬,班春林,崔黎丽等.微透析技术及在药学中的应用进展[J].药学实践杂志,2005,23(3):139-142
[36]张英丰.微透析法进行青藤碱贴剂透皮特性及药物动力学的研究.广州中医药大学博士学位论文,2006
[37]李智平,施孝金,李中东等.在体微透析技术应用于神经药动学研究进展[J].中国医院药学杂志,2003,23(6):362-364
[38]Benveniste H.Brain microdialysate[J].J.Neurochem,1989,52(6):1667-1679
[39]Alexander GM,Grothusen JR,Schwartzman RJ.Flow dependent changes in the effective surface area of microdialysate probes[J].Life Sci,1988,43(7):595-601
[40]Levine JE,Powell KD.Microdialysate for measurement of neuroendocrine peptides[J].Methods Enzymol,1989,168:166-181
[41]李范珠,冯健.脑微透析技术及其在脑内药动学中的应用[J].中国药学杂志,2006,41(6):405-407
[42]Horn T,Bauce L,Landgraf R,et al.Microdialysate with high NAC1 causes central release of amino acids and dopamine[J].JNeurochem,1995,64(4):1632-1644
[43]Westeink BH,Hofsteede HM,Damsma G,et al.The significance of extracellular calcium for the release of dopamine,acetylcholine and amino acids in conscious rats,evaluated by brain microdialysate[J].Naunyn Schmiedebergs Arch Pharmacol,1988,337(4):373-378
[44]Osborne P G,O'Connor WT,Ungersted TU.Effect of varying the ionic concentration of a microdialysate perfusate on basal striatal dopamine levels in awake rats[J].J Neurochem,1991,56(2):452-456
[45]Bungay PM,Morrison PF,Dedrick RL.Steady-state theory for quantitative microdialysate of solutes and water in vivo and in vitro.Life Sci,1990,46(2),105-119
[46]Malonne I,Davies.A review of microdialysate sampling for pharmacokinetic application[J].Analytica Chimica Acta,1999,379(3):227-249
[47]Pepeu G,Giovannini MG.Changes in acetylcholine extracellular levels during cognitive processes.Learn Mem.2004;11(1):21-27
[48]Zhang M Y,Beyer C E.Measurement of neurotransmitters from extracellular fluid in brain by in vivo microdialysate and chromatography-mass spectrometry [J].Journal of Pharmaceutical and Biomedical Analysis.2006,40(3)492-499
[49]Stavinoha WB,Weintraub ST.Estimation of choline and acetylcholine in tissue by pyrolysis gas chromatography[J].Anal.Chem,1974,46(6):757-760
[50]Fidone SJ,Weintraub ST,Stavinoha WB,Acetylcholine content of normal and denervated cat carotid bodies measured by pyrolysis gas chromatography/mass fragmentometry[J].J.Neurochem,1976,26(5):1047-1049
[51]郑红,石力夫,胡晋红.微透析与现代分析技术联用的研究进展[J].国外医学药学分册,2005,(32)4:275-278
[52]王俏.脑乙酰胆碱分析技术研究进展[J].西北药学杂志,2007,22(1):43-45
[53]Ichikawa J , Dai J , Meltzer H Y .Acetylcholinesterase Inhibitors Are Neither Necessary nor necessary nor desirable for microdialysate studies of brain acetylcholine[J].Current seperations, 2000. 19(2):37-43
[54]De Boer P , Westerinck BHC , Horn A S.The effect of acetylcholinesterase inhibition on the release of acetylcholine from the striatum in vivo: interaction with autoreceptor responses[J]. Neurosci. Lett, 1990, 116:357-360
[55]Acquas E, Fibiger HC.Dopaminergic Regulation of Striatal Acetylcholine Release: The Critical Role of Acetylcholinesterase Inhibition[J].J. Neurochem. , 1998, 70(3): 1088-1093
[56]Parada MA, Hernandez L, De Parada MP. Selective Action of Acute Systemic Clozapine on Acetylcholine Release in the Rat Prefrontal Cortex by Reference to the Nucleus Accumbens and Striatum[J]. J Pharmacol ExpTher ,1997, 281(1): 582-588
[57]Ichikawa J, O'Laughlin IA, Dai J , et al. Clozapine increased extracellular acetylcholine (ACh-ext) levels in rat medial prefrontal cortex (mPFC) but not striatum (STR) or nucleus accumbens (NAC) in the absence of AChesterase (AChE) inhibition[J]. Society for Neuroscience Abstracts , 1999, 25( pt1): 452
[58]DeBoer P, Abercrombie ED. Physiological release of striatal acetylcholine in vivo: modulation by D1 and D2 dopamine receptor subtypes[J]. J Pharmacol Exp Ther, 1996, 277(2):775-783
[59]Huang T, Yang L, Gitzen J, et, al. Detection of basal acetylcholine in rat brain microdialysate[J].J. Chromatogr. B, 1995, 670 (2) :323-327
[60]KatoT, Liu JK, Yamamoto K, et al .Detection of basal acetylcholine release in the microdialysate of rat frontal cortex by high-performance liquid chromatography using a horseradish peroxidase-osmium redox polymer electrode with pre-enzyme reactor[J]. J. Chromatogr.B , 1996, 682 (1) :162-166
[61] Hows MEP, Andrew JO, Murray S, et al. High-performance liquid chromatography/ tandem mass spectrometry assay for the rapid high sensitivity measurement of basal acetylcholine from microdialysates [J].J. Neurosci.Methods , 2002, 121(1):33-39
[62]Zhang MY, Li P, Lin Q, et al.52nd ASMS, Nashville, TN, 2004 May , 24-27
[63]ZhuY, Wong PSH, Cregor M, et , al. In vivo microdialysate and reverse phase ion pair liquid chromatography/tandem mass spectrometry for the determination and identification of acetylcholine and related compounds in rat brain[J].Rapid Comrnun.Mass Spectrom,2000,14(18):1695-1700
[64]景富春,刘小莉,陈虹.HPLC-ECD法测定大鼠脑微透析液中的多巴胺及其代谢产物[J].中国临床药理学与治疗学,2006,11(9):1003-1005
[65]Zhang W,Xie YF,Ai SY.Liquid chromatography with amperometric detection using functionized multi-wall carbon nanotube modified electrode for the determination of monoamine neurotransmitters and their metabolites[J].J Chromatogr B,2003,791:217-225
[66]Xu F,Gao MN,Shi GY.Simultaneous detection of monoamines in rat striatal microdialysate at poly(para2aminobenzoic acid)modified electrode by highperformance liquid chromatography[J].Analytica Chirnica Acta,2001;439:239-246
[67]王巍,赵德忠,王卫霞.应用HPLC-ED同时测定脑匀浆8种生物胺及其代谢产物含量[J].中国药理学通报,2004;20:119-120
[68]Virag L,Whittington RA.Highly sensitive chromatographic assay for dopamine determination during in vivo cerebral micro dialysate in the rat[J].J Chromatogr B,2002;772:267-272
[69]马爱梅,赵永波,陈英辉.苯妥英钠在大鼠血液和脑细胞外液药动学研究[J].中国临床神经科学,2005,13(2):118-122
[70]Borgstrom L.Pharmacokinetics of parenteral and oral melperone in man[J].Eur J Clin Pharmacol,1982,23(2):173-176
[71]Chan KY,Okerholm RA.Quantitative analysis of melperone in human plasma by gas chromatography-mass spectrometry-selected ion monitoring[J].J Chromatogr.1983,274:121-127
[72]Koppel C,Tenczer J,Ibe K.Gas chromatographic-mass spectrometric study of urinary metabolism of melperone[J].J Chromatogr.1988,427(1):144-150
[73]Carsten Kratzsch,Frank T.Peters,Thomas Kraemer.Screening,library-assisted identification and validated quantification of fifteen neuroleptics and three of their metabolites in plasma by liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization[J].J.Mass Spectrom.2003;38:283-295
[74]Winkeler H D,Szigan J,Gerhards P.Development Of A Robust And Sensitive Analytical Method For The Measurement Of Pharmaceutical Compounds In Serum Using LC/MS[J].Consumable Products Application Note A02100,2004,8.
[75]赵靖平,杨德森.精神分裂症单胺病理假说的药理学研究进展[J].国外医学精神病学分册,1999,26(3):140-143
[76]黄继忠,张明园.非典型抗精神病药治疗精神分裂症的评价(一)[J].上海精神医学2005,17(4):230-232
[77]Cai JX,Arnsten AFT.Dose dependent effects of the doparaine Dl receptor agonistsA77636 or SKF 81297 on spatial working memory in aged monkeys[J].J Pharmacol Exp Ther,1997,283:183-189
[78]Okubo Y,Suhara T,Suzuki K,et al.Decreased prefrontal dopamine Dl receptor in schizophrenia revealed by PET[J].Nature,1997,385:634-636
[79]张秀娟,徐满英.伏隔核功能的研究进展[J].哈尔滨医科大学学报,2002,36(4):334-335
[80]Rupniak NM,Tye S J,FieldMJ.Enhanced performance of spatial and visual recognition memory tasks,by the selective acetylcholinesterase inhibitor E2020in rhesus monkeys[J].Psychopharmacology,1997,131:406-410
[81]牛雅娟,吉中孚.精神分裂症认知功能障碍的烟碱机制.国外医学·精神病学分册,2001,28(2):79
[82]王向兵,顾钧,周文华.中枢毒蕈碱能受体与学习记忆.国外医学·精神病学分册,2004,31(1):61
[83]Frindnma JI,Temporini H,Dvis KL.Pharmocologic strategies for augmenting cognitive performance in schizophrenia[J].Biol Psychiatry,1999,45:1-16
[84]Lolin Y,Ratnarai N,Hjelm M,et al.Antiepileptic drugpharmacokinetics and neuropharacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid:phenytoin[J].Epilepsy Res,1994,19:99-110