精神分裂症患者氯氮平治疗的血浆、红细胞内浓度与临床效应关系的初步探讨

目的探讨氯氮平治疗精神分裂症的血浆、红细胞内浓度与临床效应的关系.方法59例符合<国际疾病分类>第10版(ICD-10)精神分裂症诊断标准的病人,氯氮平150～600mg·d-1治疗8周.采用常用量表评定临床效应,同时测定血浆、红细胞内氯氮平和去甲氯氮平浓度.结果①血浆、红细胞之间的氯氮平及其代谢物浓度呈正相关(P<0.001),氯氮平、去甲氯氮平红细胞/血浆浓度比值分别为26.7%±5.5%、50.5%±10.5%.②血浆、红细胞内氯氮平浓度与疗效和药物不良反应指标均不相关(P>0.05).③利用受试者工作曲线(ROC)未能找出血浆和红细胞内最低有效阈浓度(受试者工作曲线下面积均<0.5,P>0.05).④有效组在入组前简明精神病评定量表(BPRS)总分和思维障碍因子分、阳性和阴性症状量表(PANSS)一般情况量表分方面显著高于无效组(P<0.05).结论①氯氮平及其代谢产物在红细胞内浓度与血浆浓度相关良好,比例稳定.②血浆和红细胞内氯氮平最低有效阈浓度未能找到,患者对氯氮平的疗效是影响阈浓度值的重要因素.     

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。     

度洛西汀短期治疗精神分裂症的增效作用及对认知损害变化的影响

目的探讨度洛西汀对阴性症状为主的精神分裂症患者临床疗效的增效作用、安全性和对认知损害的影响。方法将40例以阴性症状为主的精神分裂症患者随机分为研究组(氯氮平联合度洛西汀治疗)和对照组(单用氯氮平治疗)各20例,疗程8周,采用阳性和阴性症状量表(PANSS)评定疗效变化,采用Stroop色词测验(SCWT)、连线测验(TMT)A和B、词语和语义流畅性、威期康星卡片分类测验(WCST)评价认知功能变化,治疗中需处理的不良反应采用副反应量表(TESS)评定其安全性。结果经重复测量方差分析,两组的PANSS量表中阳性因子分、阴性因子分和总分的时间主效应,分组主效应,时间与分组交互效应差异均有显著意义(P<0.05或P<0.01)。两组间不良反应发生率及TESS评分均无显著差异(P>0.05)。治疗8周后,两组SCWT(Z=-3.468,P=0.001)和TMT-B(Z=-2.083,P=0.037)与治疗前相比具有显著差异;研究组语义流畅性测试优于对照组(Z=-2.137,P=0.033),其余各认知量表评分的组间无显著差异(P>0.05)。结论度洛西汀合并氯氮平治疗阴性症状为主的精神分裂症患者的疗效优于单用氯氮平,在短期内能起到一定增效作用,对认知损害症状有部分改善作用。     

5-羟色胺2A受体基因T102C多态性与氯氮平疗效个体差异的关联分析

目的　探讨5-羟色胺2A受体基因T102C多态性与氯氮平疗效个体差异之间的关系。方法81例精神分裂症患者单用氯氮平治疗6~8周,用阳性与阴性症状量表评定氯氮平的疗效,并根据量表的减分率将患者分为有效和无效2组(≥50%,为有效;<50%,为无效)。检测患者的血清氯氮平浓度。用聚合酶链式反应-限制性片段长度多态性技术,检测精神分裂症患者基因型和等位基因的频率。结果5-羟色胺2A受体基因T102C多态性的基因型和等位基因的频率在氯氮平总疗效、改善阳性和阴性症状疗效上,2组间比较无显著性差异。结论氯氮平治疗精神分裂症的总疗效、改善阳性及阴性症状疗效的个体差异与5-羟色胺2A受体基因T102C多态性无关。     

大蒜素对甲基磺酸甲酯和环磷酰胺诱发果蝇伴性隐性致死的影响

用果蝇伴性隐性致死试验进行大蒜素的抗诱变性研究。大蒜素与甲基磺酸甲酯(MMS)同时喂饲果蝇,未能抑制MMS诱导的伴性隐性致死效应。而在先给MMS 24h后再给大蒜素则有抑制效应。大蒜素与环磷酰胺(Cy)同时给药有一定的抑制作用。提示大蒜素有一定抗诱变作用。     

硫酸二乙酯和紫外线对金霉素链霉菌的诱变育种

考察了硫酸二乙酯 (DES)和紫外线 (UV)对金霉素链霉菌进行诱变的效果。其中 2 ?S诱变剂对金霉素链霉菌无明显的致死效应 ,但在含有金霉素 2 2 0 μg/ml的培养基上筛选结果表明 ,DES对金霉素产生菌产生了较强的诱变效果 ,菌株正突变率达 5 2 %。对金霉素链霉菌进行紫外诱变的结果表明 ,在营养贫瘠培养基上筛选的诱变效果较营养丰富培养基上的效果好 ,且遗传特性稳定。     

抗生素产生的数量遗传学:多基因控制数量性状的一般原理

所有有机体中的许多特性显示出连续的变异;天然群体中的个体,杂交的后代或诱变处理后的存活细胞经常构成一个连续排列的类型。这样的连续变异被认为是许多“多基因”共同的作用所造成,而每个基因对总的基因型变异只是一微小效应。当这些遗传效应与环境影响的未弄清的效应相结合时,单个基因所引起的差     

单服氯氮平与氯丙嗪对血糖的影响

目的:比较氯氮平和氯丙嗪对精神分裂症患者空腹血糖的影响情况。方法:对长期持续单一服用氯氮平(n=65)和氯丙嗪(n=66)的患者在用药前和疗后3年内,每月进行1次血糖测定,分析其变化。结果:氯氮平引起空腹血糖升高为26.15%,氯丙嗪引起空腹血糖升高为9.09%,两者治疗后存在统计学差异性(P<0.01)。结论:氯氮平与氯丙嗪会引起部分患者空腹血糖升高,且氯氮平较明显。     

长波紫外线和8-甲氧基补骨脂素对红霉素链霉菌诱变效果的初步考查

在菌种选育中,最常用的物理诱变剂是远紫外线(FUV),但长期使用,诱变效应会出现饱和现象。亚硝基胍(NTG)是一种较强的化学诱变剂,诱发营养缺陷型的效果很好,但毒性很大。文献报道,长波紫外线(NUV,波长为365.5nm)和光敏化物质8-甲氧基补骨脂素(8-methoxypsoralen,简称8-MOP)共同的诱变作用强,诱发营养缺陷型的效果可与亚硝基胍相比,特别是对工业放线菌。因此,我们以红霉素链霉菌(Streptomyces erythreus)14-74为出发菌株,初步考查了长波紫外线和8-MOP的诱变效果,并与远紫外线、NTG的诱变效果进行了初步比较。     

氯氮平和利培酮对人体姿态平衡效应的对比分析

目的:比较氯氮平和利培酮对人体姿态平 衡的效应。方法:给17例精神分裂症病人用氯氮平 治疗,39例精神分裂症病人用利培酮治疗,入组和 治疗d28各评价简明精神病量表1次,治疗d3和 d28分别检测人体姿态平衡试验。结果:(1)在治 疗d3,服氯氮平100mg·d-1病人的外围面积比服 利培酮1mg·d-1的明显为大[(485±s236)mm2vs (361±191)mm2,P<0.05];(2)在治疗d28,服氯 氮平(315±63)mg·d-1的外围面积比服利培酮 (3.6±0.9)mg·d-1的明显为大[(485±191)mm2 vs(334±196)mm2,P<0.05],氯氮平组的单位面积 轨迹长比利培酮组明显为短[(1.9±0.8)mmvs (2.9±1.6)mm,P<0.05];(3)所有病人(56例) 的病程与治疗d3及d28的5个平衡试验参数均无 显著相关性(P>0.05)。结论:在短期治疗(3d) 时,氯氮平组对平衡功能的损害比利培酮组明显;在 长期治疗(28d)时,氯氮平组对平衡功能的损害仍 然比利培酮组明显;精神分裂症的病程对平衡功能无明显影响。     

在线柱切换高效液相色谱法测定人血清中奥氮平、氯氮平和N-去甲氯氮平的浓度

目的：建立简单并能同时测定人血清中奥氮平、氯氮平及N-去甲氯氮平的血药浓度方法。方法：采用在线柱切换高效液相色谱法,紫外检测器检测,血清直接进样分析血清中奥氮平、氯氮平及N-去甲氯氮平的浓度。结果：奥氮平、氯氮平及N-去甲氯氮平均具有良好的专属性、线性、精密度、回收率和稳定性。结论：在线柱切换高效液相色谱法简单、准确,适用于奥氮平、氯氮平及N-去甲氯氮平血药浓度监测。此方法可以血清直接进样分析,省去了烦琐的预处理,同时保证检测的准确性。     

Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients withneuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.     

Cyproheptadine resembles clozapine in vivo following both acute and chronic administration in rats

Cyproheptadine is a cheap, widely available anti-allergy drug with a broad receptor binding profile which resembles that of clozapine. In rats discriminating clozapine from vehicle cyproheptadine mimicked clozapine very closely. Acutely it induced full generalization in the absence of response suppression, as observed with clozapine. Chronic administration of clozapine and cyproheptadine induced tolerance and cross-tolerance respectively to the clozapine stimulus. This was characterized by circa 3.5-fold parallel shifts to the right in the clozapine generalization curves. Such tolerance and cross-tolerance was spontaneously reversible, suggesting that it was pharmacodynamic, and that clozapine and cyproheptadine induce similar neuroadaptations when administered chronically. Administration of chlordiazepoxide at a very high dose induced no cross-tolerance to the clozapine stimulus showing the pharmacological specificity of tolerance. The clozapine stimulus is a compound cue involving actions at various receptors, and various clozapine-like antipsychotic (APD) drugs generalize fully to it. These data demonstrate that in vivo cyproheptadine resembles clozapine both acutely and chronically. Our findings, in conjunction with other actions of cyproheptadine -- induction of weight gain, alleviation of clozapine withdrawal, anxiolytic actions, alleviation of 'typical' APD-induced motoric side effects, and some preliminary clinical findings -- suggest that further study of cyproheptadine in conjunction with a 'typical' APD for the possible treatment of schizophrenia is merited at both pre-clinical and clinical levels.     

Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance

Aims N -Desmethylclozapine and clozapine N -oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney.
Methods From 15  psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2  h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis.
Results The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N -desmethylclozapine 9.7%, and clozapine N -oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N -desmethylclozapine and clozapine N -oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N -desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose.
Conclusions Clozapine, N -desmethylclozapine and clozapine N -oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N -demethylation and N -oxidation must make major contributions to the total fate of clozapine in patients.     

Therapeutic drug monitoring data: risperidone does not increase serum clozapine concentration

BACKGROUND: Two case reports suggest that serum clozapine concentration may increase when risperidone is added to clozapine treatment. However, risperidone is not a significant inhibitor of the most important clozapine metabolising cytochrome P(450) (CYP) enzymes (e.g. CYP1A2). OBJECTIVE: To study whether serum clozapine concentrations are affected by risperidone. METHODS: Intraindividual comparison of serum clozapine therapeutic drug monitoring data from 18 patients during and without risperidone use. RESULTS: Addition of risperidone (mean +/-SD dose 2.9+/-0.9 mg/day, range 2-4 mg/day) to clozapine treatment (mean clozapine dose 451+/-207 mg/day) did not result in any significant changes in serum clozapine concentration or clozapine concentration/dose (C/D) ratio relative to the values without risperidone (mean clozapine dose 437+/-168 mg/day). During risperidone use mean serum clozapine concentration was 3% (P=0.75) and C/D ratio 8% (P=0.46) lower than without concomitant risperidone. The mean ratio mu(test)/mu(reference) for clozapine C/D ratios was 0.99 (90% CI 0.82-1.15), confidence interval being within the equivalence interval of 0.80-1.25. CONCLUSIONS: Risperidone does not affect serum clozapine concentrations to any significant degree.     

CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients

Clozapine is an effective atypical antipsychotic drug applied in the treatment of resistant schizophrenia. The drug is mainly metabolized by cytochrome P-450 (CYP) enzymes especially the isozyme CYP1A2. Remarkably, the effective dosage varies widely among patients, making it necessary to individualize drug therapy with clozapine. The explanation for dosage variation may be differences in drug metabolism, and more specifically of CYP1A2 activity. This study is aimed at determining to what extent variability in clozapine dose can be explained by pharmacokinetic (PK) factors and more specifically by CYP1A2 activity in effectively treated psychiatric patients.

In 22 evaluable patients with a schizophrenic disorder chronically using clozapine, the CYP1A2 activity and the clozapine clearance were estimated. For calculation of the pharmacokinetic parameters of clozapine, population PK software based upon Bayesian analysis was used. Caffeine clearance was estimated with the paraxanthine/caffeine ratio and served as estimate of CYP1A2 activity.

A significant linear relationship was found between the clozapine dose and clozapine clearance (R: 0.71; P<0.05), whereas no relationship was found between clozapine dosage and clozapine serum trough concentration. Moreover, individual caffeine and clozapine clearances were found to be significantly related (R: 0.62; P<0.05) as were clozapine dose per kg body weight and P/C mol ratio (R: 0.44; P<0.05).

We conclude that CYP1A2 activity is an important determinant of the variability of effective clozapine doses in psychiatric patients.     

哌泊噻嗪氯氮平治疗精神分裂症阴性症状26例

目的;研究哌泊噻嗪合并氯氮平对阴性症状的疗效。方法：将５０例以阴性症状为主的精神分裂症患者随机分为氯氮平合并哌泊噻嗪组２６例和单用氯氮平组２４例,采用临床疗效评定,简明精神病量表（ＢＰＲＳ）,阴性症状量表（ＳＡＮＳ）。结果：哌泊噻嗪合并氯氮平组显效率５８．０％,ＳＡＮ减分率６６．０％,氯氮平组显效率３５．０％,ＳＮＡＳ减分率５３．４％,经ｕ检查,两者均差异显著（Ｐ〈０．０５）。结论：哌泊噻嗪合并氯     

Clozapine concentrations in brain regions: Relationship to dopamine metabolite increase

Levels of clozapine in rat striatum and tuberculum olfactorium were quantitated by a gas chromatographic technique. The relationship of the increase in 3,4-dihydroxyphenylacetic acid (DOPAC) in these regions produced by clozapine to the concentration of clozapine was explored. One hour after 10, 20 or 40 mg/kg clozapine i.p. the concentration of drug increased in proportion to the dose and at each dose was similar in striatum and T.O. The percent increase in DOPAC in both areas was related to the clozapine concentration in a typical dose-response manner and was greater in the striatum than the T.O. A relatively high concentration of clozapine (40 μM) was required to produce a half-maximal elevation of DOPAC. Striatal clozapine levels were similar in acutely and chronically treated animals. The concentrations of clozapine in straitum and T.O. reflect the dose injected and do not account for its atypical properties.     

Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients

RATIONALE: Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established. OBJECTIVE: We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response. METHODS: Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design. RESULTS: Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations. CONCLUSIONS: These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.     

Predictors of clozapine discontinuation in patients with schizophrenia

Clozapine has superior efficacy for treating patients with schizophrenia. Its discontinuation could have detrimental consequences. We attempted to identify the clinical parameters that could predict clozapine discontinuation in patients diagnosed as having schizophrenia by conducting a retrospective analysis of all of those who started on clozapine treatment during their hospitalization in our institution between 2002 and 2008 (n=100). Demographic and clinical parameters were analyzed and compared between the 58 patients who continued and the 42 who discontinued clozapine treatment during a follow-up period of 8.1 years. Twenty of the latter patients (47.6%) discontinued clozapine because of nonadherence and 11 (26.2%) because of side effects. Thirty-three of them (78.6%) stopped taking clozapine during the first year of treatment. The duration of clozapine use correlated significantly with the time to readmission (P<0.001). The decrease in number of suicide attempts was higher in those who continued clozapine treatment compared with those who discontinued it (P=0.02). Predictors for drug discontinuation were old age at clozapine initiation and comorbid substance abuse. These findings indicate that patients with schizophrenia with those risk factors need special incentives to be compliant during the first year of clozapine treatment to minimize the negative sequelae of clozapine discontinuation.