氯氮平在18例精神分裂症患者中的血药浓度及其疗效

系统检测18例服氯氮平的精神分裂症患者血浆药物浓度。结果表明,血药浓度和服药剂量呈正相关;而不同患者血药浓度的个体差异很大。血药浓度和临床疗效以及脑、心电图异常改变均无明显联系。初步讨论了血药浓度检测的临床意义,认为对于某些疗效较差或药物副反应较重的患者,血药浓度测定具有临床参考价值。     

精神分裂症氯氮平剂量与血药浓度相关分析

目的：精神分裂症氯氮平服药剂量与血药浓度的相关分析。方法：６１５人次确诊为精神分裂症氯氮平治疗患者，按给药量分组，与氯氮平及其去甲基氯氮平的血药浓度进行回顾性统计分析。结果：氯氮平剂量与浓度作曲线成四个线段；各线段内给药量与血药浓度的相关系数远大于整体相关系数。结论：曲线说明其血药浓度与给药剂量虽然呈正相关，但各个线段有着更深刻的意义。氯氮平与去甲基氯氮平血药浓度稳态时，晚服药后次日晨分别不宜超过３５０ｎｇ，２００ｎｇ。     

群体药物动力学研究

近年来,群体药物动力学已引起制剂工业以及美国食品药物管理局(U.S Food and Dring Adminis-tration,FDA)专家们的极大关注,不少FDA法规文件中都引用了群体药物动力学来评价药物的有效性和安全性.本文综述了群体药物动力学研究中的群体方法、实验设计、数据处理和分析以及模型的验证等内容,旨在为药品开发和规范管理提供参考.1 研究背景某些疾病的生理病理特征能有规律地改变剂量-浓度之间的关系.例如主要通过肾消除的药物,肾衰通常会引起病人稳态血药浓度的明显升高.群体药物动力学就是研究个体间血药浓度差异的来源和联系,目的在于揭示引起剂量-浓度关系改变的生理病理因素,确定这种改变的大小,以便拟定合适的临床用药剂量.传统药物动力学的研究对象通常是健康志愿者或经严格挑选的病人,且仅对他们的平均情况感兴趣.对于个体间的差异往往采用复杂的实验设计或     

群体药物动力学简介

介绍了群体药物动力学的定义及统计理论、群体参数估计方法及在临床药理学与新药开发中的应用     

氯氮平治疗难治性精神分裂症10例报告

报告用氯氮平治疗难治性精神分裂症１０例，均获得病情稳定的效果。     

首选氯氮平治疗98例精神分裂症的疗效分析

本文回顾性研究９８便首选氯氮平治疗精神分裂症疗效对照分析，结果氯氮平与经典抗精神病药物氯丙嗪在消除精神症状方面无明显差异，在毒副作用料无明显差异，提出该药可以作为治疗精神分裂首选药物，且用药剂量小，易于被病人接受。     

群体药物动力学研究进展

本文综述了群体药物动力学近年来的发展,包括研究方法、模型建立与验证以及应用等.在研究方法中,以NONMEM模型法应用最广,而非参数期望值法也有其优点.模型的建立和验证是群体药动学研究的一项重要而复杂的工作,不同的模型采用不同的数据和方法来验证.群体药动学用应用范围在不断拓宽,已用于群体药动学分析、个体化给药、生物利用度研究、药效学研究和新药开发与临床评价等方面.     

利培酮和氯氮平治疗精神分裂症副反应对照研究

本文就两种非典型抗精神病药在治疗精神分裂症中出现的副反应进行对照研究，在有效性无显著差异的情况下，利培酮（维思通）在病人服药过程中，主要以锥体外系副反应为主，程度较轻，而氯氮平以流涎，嗜睡，便秘等副反应为主，尤为严重的是粒细胞缺乏，因此服用利培酮的安全性和依从性要比氯氮平佳，利培酮作为治疗精神分裂症的新药比氯氮平有更大优势。     

利培酮和氯氮平治疗精神分裂症对照研究

比较非经典抗精神病药物利培酮和氯氮平对治疗精神分裂症疗效,现将结果报道如下:1对象和方法1.1对象:来自桂林市六院自2005年1月～12月间新入院患者,符合CCMK-Ⅱ-R精神分裂症诊断标准,且PANSS总评分≥60分,共80例,按入院先后顺序分成利培酮组和氯氮平组各40例。     

Clinical pharmacokinetics of clozapine in chronic schizophrenic patients

Summary The clinical pharmacokinetics of clozapine, an atypical neuroleptic, was evaluated in 10 chronic schizophrenic male patients after intravenous and oral administration. The mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87. The average values for blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27, respectively. Plasma concentration peaked on average at 3 h. The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h, respectively. A large fraction of the dose is most probably metabolized by some extrahepatic presystemic routes. The large inter-individual variability in the bioavailability and clearance is probably the main reason for large variation in the steady-state plasma level in patients receiving the same oral dosage regimen.     

Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia

Aim:

To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters.

Methods:

Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors.

Results:

A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients.

Conclusion:

Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.     

Gender differences in plasma clozapine levels and its metabolites in schizophrenic patients

Forty refractory schizophrenic patients (21 females and 19 males) participated in a fixed-dose study with clozapine. After a 6-week trial of haloperidol and a 1-week washout time period, non-responding patients were placed on clozapine and the dosage titrated up to 400 mg/day for the next 5 weeks. Plasma clozapine levels and its two metabolites desmethylclozapine (DCLOZ) and clozapine N-oxide (CNO) were measured at weeks 2, 4 and 6. Blood samples were obtained 10–12 h post-evening dose and prior to the morning dose. Clozapine and its metabolites were assayed by HPLC with UV detection. Patients were assessed for clinical response with the Brief Psychiatric Rating Scale (BPRS) at baseline and at weeks 2, 4 and 6. BPRS scores were also divided into positive (+) and negative (−) symptoms subscales. Plasma clozapine and DCLOZ levels were significantly lower in males. Plasma CNO levels were slightly lower in males but it was not statistically significant. Decreased total BPRS, (+) and (−) symptoms subscale scores occurred during the study for both gender groups. A greater magnitude of change for the (−) symptom subscale score was observed in the male group. Gender was not a significant factor in the incidence or severity of side-effects. © 1997 John Wiley & Sons, Ltd.     

Low blood selenium concentrations in schizophrenic patients on clozapine

AIMS: To compare plasma and red-cell selenium concentrations of schizophrenic patients treated with clozapine, with healthy controls and patients with mood disorders. METHODS: Plasma and red-cell selenium concentrations were measured in random venous blood samples from four groups: mood disorder (n = 36), schizophrenics treated with clozapine (n = 54), schizophrenics not treated with clozapine (n = 41) and a healthy control group (n = 56). Assays were performed by an independent laboratory that was blinded to the patient groups and specializes in estimating trace metal concentrations. RESULTS: Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups. CONCLUSIONS: Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low selenium concentrations in clozapine-treated patients may be important in the pathogenesis of life threatening cardiac side-effects associated with clozapine. Further clinical studies are being conducted to explore this important clinical observation and its therapeutic implications.     

氯氮平引起精神分裂症患者的染色体畸变

用外周血培养制备染色体,观察30例长期服用国产氯氮平的精神分裂症患者染色体畸变率,以此检测氯氮平的遗传效应。与30例正常对照组相比初步认为服氯氮平患者体内染色体畸变率较高(P<0.05)。染色体畸变类型主要为染色体断裂、双着丝粒和环形染色体等。讨论了引起畸变的各种原因。     

上呼吸道感染对精神分裂症患者氯氮平血药浓度的影响

目的：分析上呼吸道感染与精神分裂症患者的氯氮平（clozapine,CLZ）血药浓度、不良反应三者的相关性。方法：纳入35例CLZ稳定治疗的精神分裂症伴有上呼吸道感染的住院患者,分别采集感染前后清晨服药前的空腹血,采用HPLC-MS测定CLZ稳态谷浓度。结果：35例患者在感染后CLZ血药浓度有不同程度的升高,基线期平均血药浓度为（481.6±258.0）μg·L^-1,感染期平均血药浓度为（853.8±452.4）μg·L^-1。17例患者发生了CLZ血药浓度升高后的不良反应,其中最多的是精神性不良反应。结论：上呼吸道感染对CLZ血药浓度的升高有一定影响,并导致不良反应的发生。所以住院感染期间CLZ血药浓度的监测是至关重要的,同时应注意剂量的调整,减少不良反应发生的风险。     

氯氮平和思瑞康对精神分裂症患者血糖代谢的影响

目的探讨服用抗精神病药物氯氮平和思瑞康对糖耐量的影响。方法92例精神分裂症患者随机分为氯氮平组和思瑞康组,各46例,两组患者治疗前和治疗后第4周末、8周末分别检测空腹血糖、餐后1h、2h和3h血糖,并分析糖耐量。结果治疗后4周末和8周末,氯氮平组餐后1h和2h血糖浓度与治疗前比较明显升高[(8.6±1.6)(8.8±1.8)mmol/Lvs.(7.1±1.1)mmol/L,(7.2±1.1)(7.4±1.2)mmol/Lvs.(5.8±0.8)];而思瑞康组无明显变化。治疗后氯氮平组(21.7%,10例)患者糖耐量减低的发生率高于思瑞康组(4.3%,2例),差异有显著性(χ2=6.13,P<0.05)。结论氯氮平对精神分裂症患者餐后血糖有影响,而思瑞康对血糖的影响甚微。     

Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method

Aims To evaluate the distribution of population kinetic parameters for clozapine and their relationship to age and gender in patients on continuous treatment with the drug.
Methods Retrospective therapeutic drug monitoring data (391 samples from 241 patients) were evaluated using the nonparametric maximum likelihood method. Patients treated concomitantly with drugs known to interact with clozapine were not included. The distribution of clozapine clearance was compared with the distribution of the activity of the drug metabolic enzyme CYP1A2 found in other populations, as recent studies indicate that CYP1A2 is a major determinant for clozapine elimination. The kinetic linearity for clozapine was studied in 41 patients who each provided data from more than one dose level.
Results Clozapine clearance was highly variable in the population and skewed towards high values. Men had higher clearances CL/ F (median with 25% and 75% quartiles 38.2 (22.0, 60.0) vs 28.3 (15.2, 48.6) l  h⁻¹ ) and a larger volume of distribution V  / F (694 (224, 970) vs 401 (189, 932) l) than women. Clearance did not decrease with age in any gender. Clozapine clearance was similarly distributed as the indices of CYP1A2-activity found in other populations by other authors. Evidence of nonlinear kinetics was not found.
Conclusion The large kinetic variability for clozapine found in this study implies that the dose of clozapine needs to be individualised over a wide dose range. The similarity of the distribution of clozapine clearance in this study and the CYP1A2-activity in other populations support the assumption that CYP1A2 is a major determinant for clozapine elimination.     

他克莫司在中国肾移植患者中的群体药物动力学研究

本研究旨在考察口服他克莫司(tacrolimus)在中国肾移植患者中的群体药物动力学特征并探讨群体药物动力学参数和相关因素间的关系。研究中回顾性搜集了58例肾移植患者的802份他克莫司稳态全血样本资料。患者随机分为模型建立组(41例)和模型验证组(17例)。用非线性混合效应模型(NONMEM)程序中的一级评估法(first-order estimation，FO)对模型建立组的数据进行分析。计算清除率(CL/F)、表观分布容积(V/F)的群体典型值，定量评价人口统计学指标、生化指标和合并用药等固定效应因素对药物动力学参数的影响。单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了移植术后时间(POD)、红细胞压积(HCT)、谷草转氨酶(AST)、合并使用佩尔地平(NICA)和地尔硫(DIL)等对CL/F的影响。用模型验证组数据进行验证的结果表明观测值和模型预测值之间没有明显的偏倚，模型的稳定性和准确度较好。CL/F和V/F的群体典型值分别为21.7 L·h^-1和241 L；相应的个体间变异分别为41.6%和49.7%。观测值与预测值之间的残差SD为2.19 μg·L^-1。本文建立的模型可以为临床他克莫司剂量选择提供一定参考。