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1.
目的 探讨细胞色素P450 2D6(cytochromes P450 2D6,CYP2D6)基因多态性、多巴胺D2受体(dopamine D2 receptor,DRD2)基因多态性与利培酮疗效的相关性.方法 对199例首发精神分裂症患者给予利培酮治疗8周,治疗前后采用阳性和阴性症状量表(Positive and Negative Syndrome Scale,PANSS)评定疗效,同时收集198例正常对照进行病例-对照分析.采用聚合酶链反应序列特异性引物扩增技术检测CYP2D6/C188T、DRD2 TaqIA基因型,分析二者与利培酮临床效应的相关性.结果 病例组和对照组CYP2D6/C 188T的基因型和等位基因频率相比,差异有统计学意义(CC:40.7% vs.21.2%,CT:25.6% vs.45.5%,TT:33.7%vs.33.3%,P<0.05;C:53.5% vs.43.9%,T:46.5% vs.56.1%,P<0.05),病例组和对照组DRD2 TaqIA的基因型和等位基因频率相比,差异有统计学意义(A1A1:29.1% vs.35.9%,A1A2:37.7% vs.47.5%,A2A2:33.2% vs.16.6%,P<0.05; A1:48.0% vs.59.6%,A2:52.0% vs.40.4%,P<0.05);CYP2D6/C 188T与DRD2TaqIA的交互作用对PANSS减分率的影响没有统计学意义(F=0.735,P>0.05);CYP2D6/C188T,DRD2TaqIA与性别的交互作用对PANSS减分率的影响具有统计学意义(F=3.214,P<0.05).结论 CYP2D6基因C188T多态性和DRD2基因TaqIA多态性不是影响精神分裂症患者利培酮临床疗效的易感因素,但是在协变量性别的作用下,上述基因多态性的交互作用可能影响利培酮的疗效. 相似文献
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利培酮治疗与细胞色素P4502D6/C188T酶基因多态性的关联分析 总被引:2,自引:0,他引:2
目的 研究利培酮临床效应的个体差异与其代谢酶细胞色素P4 5 0 2D6 (cytochromeP4 5 02D6 ,CYP2D6 )酶基因多态性的相关性。方法 对 88例符合CCMD 3精神分裂症诊断标准的患者和 96例健康对照者作病例 -对照分析。精神分裂症患者给予利培酮治疗 8周 ,用阳性和阴性症状量表 (posi tiveandnegativesymptomscale ,PANSS)评分评价利培酮疗效。采用聚合酶链反应扩增及限制性片段长度多态性 (PCR RFLP)技术对CYP2D6exonⅠ的C188T位点突变进行检测 ,分析利培酮临床效应与其主要代谢酶CYP2D6 /C188T酶基因多态性的相关性。结果 中国上海地区人群的CYP2D6 /C188T突变率(弱代谢型 )为 36 .3% ,病例组和正常对照组间基因型频率总体分布比较无显著差异 (χ2 =1.15 ,df=2 ,P >0 .0 5 ) ,两组间的等位基因频率之间比较也无显著性差异 (χ2 =0 .78,df=1,P >0 .0 5 )。进行性别及有否家族史分组后分析 ,亦无差异存在 ,且CYP2D6 /C188T突变与利培酮临床效应之间并无相关性 (χ2 =1.12 ,df=2 ;χ2 =0 .0 3,df=1,P >0 .0 5 )。结论 未发现中国人CYP2D6 /C188T多态性与利培酮临床效应的个体差异有相关性。 相似文献
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In contrast to several authors who found hepatic cytochrome P 450 2D6 (CYP2D6) metabolising status to be clinically unimportant in treatment with the CYP2D6 substrate, risperidone, we report on a 17-year-old schizophrenic patient who suffered from severe extrapyramidal side effects (EPS) while being treated with risperidone at 4 mg per day. He was genotyped as a CYP2D6 poor metaboliser (PM). The active moiety of risperidone (sum of risperidone and 9-hydroxyrisperidone) was elevated and increased even further under co-medication with haloperidol and biperiden. We conclude that the PM phenotype for CYP2D6 of this patient had major clinical importance in treatment with risperidone. Most likely metabolic pathways other than CYP2D6 were also involved that are probably inhibited by haloperidol. 相似文献
4.
精神分裂症患者细胞色素P450 2D6酶基因多态性与利培酮治疗效应的关系 总被引:12,自引:1,他引:11
目的研究精神分裂症患者细胞色素P450 2D6酶(CYP2D6)多态性是否与利培酮治疗效应有关.方法采用阳性和阴性症状量表(PANSS)、大体评定量表(GAS)、治疗时需处理的副反应量表(TESS)以及锥体外系副反应量表(RSESE)对52例精神分裂症[PANSS基线分(105.59±17.30)分;GAS基线分(31.75±3.32)分]患者,分别在利培酮治疗前及治疗[(5±3)mg/d]第1~8周末各进行一次药物反应评定,采用聚合酶链反应技术对CYP2D6 exon Ⅰ C/T188和CYP2D6 G/A1934两个多态性位点进行检测.根据CYP2D6 exonI C/T188基因型将患者分为三组(C/C组 13例,C/T组20例,T/T组19例);采用治疗前后PANSS 30%减分率为标准 ,将52例患者分为治疗有效组和治疗无效组,比较组间药物治疗效应的差异.结果从利培酮治疗后第5周末开始,三组之间PANSS评分的差异有显著性(P<0.01);两两比较发现,C/C组PANSS分低于T/T组(P<0.01);三组之间GAS评分的差异从第6周开始出现显著性(P<0.01),其中C/C组GAS分明显高于T/T组(P<0.01).多因素方差分析显示,三组的PANSS总分 (F=2.64, P<0.01)及GAS评分(F=1.85,P<0.05)差异有非常显著性;CYP2D6 exon Ⅰ C/T188多态性基因型频率(χ2=6.56,P<0.05)和等位基因频率(χ2=5.03,P<0.05,相对风险=2.54,95%可信区间=1.40~8.32).利培酮治疗有效组与无效组之间的差异有显著性.样本中未发现CYP2D6 G/A1934多态性.结论中国人群精神分裂症CYP2D6 exon Ⅰ C/T188多态性可能是影响利培酮临床疗效的遗传易感因素. 相似文献
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细胞色素P450CYP2D6*10B缺陷等位基因与利培酮治疗效应的关系 总被引:1,自引:0,他引:1
目的探讨CYP2D6+10B缺陷等位基因与利培酮治疗效应的关系。方法采用等位基因的特异性扩增法,根据是否含有突变型CYP2D6+10B缺陷等位基因将70例精神分裂症患者分为野生型等位基因的纯合型(w/w)组(16例),突变型等位基因的纯合型(m/m)组(16例)以及野生型和突变型等位基因的杂合型(m/w)组(38例),观察3组患者利培酮4—6mg/d治疗6周后疗效与不良反应。采用阳性和阴性症状量表(PANSS)评价疗效,副反应量表(TESS)和锥体外系不良反应量表(RSESE)评定药物不良反应。PANSS减分率≥30%为有效。结果治疗6周后,有效者58例。有效组W等位基因频率(0.43)明显低于无效组(0.83),有效组的in等位频率(0.57)明显高于无效组(0.17)。自第4周起,m/w,m/m型PANSS减分值明显多于w/w型。3种基因型患者组间不良反应差异无统计学意义。结论利培酮治疗携带CYP2D6*10B缺陷等位基因患者的疗效优于治疗野生型等位基因患者的疗效。CYP2D6t10B缺陷等位基因与利培酮不良反应无关联。 相似文献
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Someya T Suzuki Y Shimoda K Hirokane G Morita S Yokono A Inoue Y Takahashi S 《Psychiatry and clinical neurosciences》1999,53(5):593-597
We investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5. Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean +/- SD, 0.66+/-0.25, n = 47) ng/mL/mg and 0.03-3.00 (mean+/-SD, 0.36+/-0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.88 (mean +/- SD, 0.48+/-0.32, n = 47). The analysis was performed among the four genotype groups: CYP2D6*1/CYP2D6*1 (n = 11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity. 相似文献
8.
Pierre Vandel 《The world journal of biological psychiatry》2003,4(2):74-80
Depression, the most common mental health problem of the elderly, is often under-diagnosed and under-treated. As patients age, antidepressant pharmacologic treatment becomes more complicated due to an increased risk of adverse drug events. These risks are associated with age-related physiological changes and individual variability in drug metabolism related to several factors, the most frequent of which is polymedication as a result of coexisting chronic illnesses. Comedications induce drug interactions that depend on the patient's metabolic capacity linked to the genetically determined cytochrome P450 enzyme (CYP450) function. The effect of some isoenzyme polymorphism on the pharmacokinetics of many antidepressants and other psychotropic drugs is well characterized. The author approaches successively the notions of the cytochrome P450 (2D6), its role in the drug biotransformation, and the importance of knowing its substrates, inhibitors and inducers in order to predict drug interactions. The clinical significance of this notion, and the help that could be given by genotyping and phenotyping, are also explained. The author's experience on the relation between drug side effects and patient metabolic status, and on the antidepressant interactions with fluoxetine, fluvoxamine and citalopram, is given in order to rationalize and individualize antidepressant choice in elderly. 相似文献
9.
Ochi S Kawasoe K Abe M Fukuhara R Sonobe K Kawabe K Ueno S 《General hospital psychiatry》2011,33(6):640-640.e2
We present a schizophrenic patient who experienced neuroleptic malignant syndrome with risperidone treatment due to variants of the CYP2D6 gene with reduced function. Clinicians need to be aware of this potential complication. 相似文献
10.
Matsumoto C Shinkai T De Luca V Hori H Hwang R Ohmori O Kennedy JL Nakamura J 《Neuromolecular medicine》2006,8(3):381-388
The underlying pathophysiology of polydipsia in schizophrenia is poorly understood. Several studies, however, have suggested that there might be a genetic predisposition to polydipsia. In the present study, using a case-control sample that is independent from the previous family sample, we examined a possible association between polydipsia and functional polymorphisms in the genes of cytochrome P450 (CYP) 1A2 and 2D6, primarily important enzymes to the pharmacokinetics of antipsychotic drugs. Japanese patients with schizophrenia (63 polydipsics and 78 nonpolydipsics) were genotyped for two functional polymorphisms, the 734C/A polymorphism in the CYP1A2 gene and the 2D6*10 allele of the CYP2D6 gene. Neither of the polymorphisms was found to be associated with polydipsia nor was any evidence found that the two polymorphisms have an additive effect on the liability to polydipsia. Our results suggest that the CYP1A2 and CYP2D6 polymorphisms are not likely to play a major role in the development of polydipsia in schizophrenia, although further studies testing other alleles of CYP1A2 and CYP2D6 using different ethnic populations are warranted. 相似文献
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Cytochrome P450 2D6 genotyping and association with tardive dyskinesia in Chinese schizophrenic patients. 总被引:1,自引:0,他引:1
L C Lam M M Garcia-Barcelo G S Ungvari W K Tang V K Lam S L Kwong B S Lau P P Kwong M M Waye H F Chiu 《Pharmacopsychiatry》2001,34(6):238-241
BACKGROUND: The discovery of Cytochrome P450 2D6 (CYP 2D6) polymorphism is implicated in individual differences in drug metabolism rate. Mutation with defective alleles is associated with reduced metabolism of many anti-psychotic drugs metabolized by CYP 2D6. This may contribute to the development of tardive dyskinesia (TD) in patients with prolonged exposure to anti-psychotic drugs. METHODS: In this controlled study, the genotype of CYP 2D6*10 alleles, movement disorders and clinical characteristics in 38 Chinese schizophrenic patients with TD were compared with 38 age- and sex-matched schizophrenia patients without TD. RESULTS: There was no significant correlation between CYP 2D6*10 genotypes and TD in men. However, a significant increase in the frequency of CYP 2D6*10 allele was found in female patients with TD. CONCLUSIONS: The sex differences in CYP 2D6 genotyping and vulnerability to develop TD suggest that a biological predisposition that affects pharmacokinetics may be more significant in women, whereas other factors may be more important in men. 相似文献
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细胞色素P4502D6 基因多态性与帕金森病遗传易感性的关系 总被引:4,自引:1,他引:3
目的研究机体解毒系统多态性在帕金森病(PD)遗传易感性中的作用,以阐明PD遗传易感性的实质。方法选择PD病人100例和年龄、性别基本匹配的正常人100名,利用聚合酶链反应-限制性片段长度多态等技术检测细胞色素P45O2D6(CYP2D6)基因的A、B两种引起酶活性缺乏的突变率和C188→T、G4268→C及C2938→T三种引起酶活性降低的多态性频率。结果结果发现PD病人CYP2D6基因A、B突变的频率高于正常对照组,它们的危险度均在2倍以上;而且,PD病人CYP2D6基因的C188→T、G4268→C和C2938→T的频率也较正常对照组高,尤其是具有C2938→T等位基因者患PD的危险度提高了2.58倍。结论PD病人CYP2D6酶活性缺乏和降低的基因突变率均高于正常人,提示解毒酶CYP2D6缺陷与PD发病有一定的关系 相似文献
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《The world journal of biological psychiatry》2013,14(2):74-80
Depression, the most common mental health problem of the elderly, is often under-diagnosed and under-treated. As patients age, antidepressant pharmacological treatment becomes more complicated due to an increased risk of adverse drug events. These risks are associated with age-related physiological changes and individual variability in drug metabolism related to several factors, the most frequent of which is polymedication as a result of coexisting chronic illnesses.Comedications induce drug interactions that depend on the patient's metabolic capacity, linked to the genetically determined cytochrome P450 enzyme (CYP450) function. The effect of some isoenzyme polymorphisms on the pharmacokinetics of many antidepressants and other psychotropic drugs is well characterized.The author approaches successively the notions of the cytochrome P450 (2D6), its role in drug biotransformation, and the importance of knowing its substrates, inhibitors and inducers in order to predict drug interactions. The clinical significance of this notion, and the help that could be given by genotyping, and phenotyping are also explained. The author's experience on the relationship between drug side effects and patient metabolic status, and on the antidepressant interactions with fluoxetine, fluvoxamine and citalopram, is given in order to rationalize and individualize antidepressant choice in elderly. 相似文献
15.
Findling RL McNamara NK Branicky LA Schluchter MD Lemon E Blumer JL 《Journal of the American Academy of Child and Adolescent Psychiatry》2000,39(4):509-516
OBJECTIVE: To examine whether risperidone is superior to placebo in the treatment of youths with conduct disorder. METHOD: This was a 10-week, randomized, double-blind, placebo-controlled study with 2 parallel arms. Ten youths were randomly assigned to receive placebo and 10 youths were randomly assigned to receive risperidone. Patients were seen weekly throughout the trial. Medications could be increased at weekly intervals during the first 6 weeks of the study from an initial dose of 0.25 mg or 0.50 mg each morning, depending on patient weight. Patients weighing less than 50 kg had a maximum total daily dose of risperidone of 1.5 mg. Patients weighing 50 kg or greater had a maximum total daily dose of risperidone of 3.0 mg. The primary outcome measure was the Rating of Aggression Against People and/or Property Scale. RESULTS: Risperidone was superior to placebo in ameliorating aggression on most measures. Risperidone was reasonably well tolerated, with none of the risperidone-treated patients developing extrapyramidal side effects. CONCLUSIONS: These data provide preliminary evidence that risperidone may have efficacy in the treatment of youths with conduct disorder. Because of the small sample size and the brief length of this study, further research is necessary to confirm these findings. 相似文献
16.
INTRODUCTION: Astrocytes are involved in multiple brain functions in physiological conditions. Cytochromes P450 are expressed in astrocytes and play a role in brain metabolism and in neuroprotection. BACKGROUND: Although the levels of various cytochromes P450 in brain regions are low, these enzymes were reported to be expressed at relatively high level in astroglial cells and may play a critical role in the biotransformation of endogenous or exogenous compounds. Astroglial cytochromes P450 expression suggests a putative capacity to metabolize psychoactive or lipophilic xenobiotics in situ, associated with pharmacological and/or toxicological consequences. Astrocytes appear to be the most active steroidogenic cells in the brain, expressing neurostero?dogenic cytochromes P450 and producing various neurosteroids. Cytochrome P450 epoxygenase enzymes, which catalyze the formation of vasoactive compounds are also present in astrocytes, contributing to the regulation of the cerebral blood flow. PERSPECTIVES AND CONCLUSION: This review underlines the crucial roles of astroglial cytochromes P450 in brain functions. Identification of the molecular mechanisms involved in the regulation of these enzymes could open therapeutic perspectives and improve our understanding in neuroprotection. 相似文献
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细胞色素P450 2D6酶基因多态性与氟西汀临床效应的相关性研究 总被引:5,自引:0,他引:5
目的:研究中国人P450 2D6酶(CYP2D6)基因多态性与氟西汀临床效应之间的关系。方法:用氟西汀对108例抑郁患者(抑郁症89例,精神分裂症后抑郁7例,分裂情感性精神病抑郁型4例,强迫性神经症2例,焦虑性神经症1例,抑郁性神经症4例,分裂样精神病(伴抑郁症状)1例)进行治疗, 和汉密尔顿抑郁量表(HAMD)和治疗中需处理的副反应症状量表(TESS)评定疗效和副反应,用聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP)分析患者CYP2D6基因型。结果:(1)PCR-RFLP分析表明,在108例抑郁患者中,CYP2D6基因型为wt/wt者26例,wt/Ch者55例,Ch/Ch者26例,wt/A者1例,未发现B等位基因。CYP2D6等位基因频率分别为CYP2D6wt(50%),CYP2D6Ch(49.5%),CYP2DY6A(0.5).(2)入组时,不同基因型的患者之间HAMD基础评分的差异无显著性(P>0.05)。经氟西汀治疗后4周和8周后,不同CYP2D6基因型患者的HAMD量表评分比治疗前 降低,差异均有非常显著性(P=0.000);8周后减分率达80%左右,TESS评分较低。在不同基因型的患者之间,治疗后的HAMD评分、HAMD减分率及TESS评分的差异均无显著性(P>0.05)。患者治疗前后的HAMD评分及HAMD减分率、TEWW评分等与CYP2D6基因型及CYP2D6突变等位基因数目的相关关系均无显著性(P>0.05)。结论:未发现中国人CYP2D6基因多态性与氟西汀临床效应之间的关联。 相似文献
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Thomas Dodsworth David D. Kim Ric M. Procyshyn Colin J. Ross William G. Honer Alasdair M. Barr 《Child and adolescent psychiatry and mental health》2018,12(1):37
The second generation antipsychotic drug risperidone is widely used in the field of child and adolescent psychiatry to treat conditions associated with disruptive behavior, aggression and irritability, such as autism spectrum disorders. While risperidone can provide symptomatic relief for many patients, there is considerable individual variability in the therapeutic response and side-effect profile of the medication. One well established biological factor that contributes to these individual differences is genetic variation in the cytochrome P450 enzyme 2D6. The 2D6 enzyme metabolizes risperidone and therefore affects drug levels and dosing. In the present review, we summarize the current literature on 2D6 variants and their effects on risperidone responses, specifically in children and adolescents. Relevant articles were identified through systematic review, and after irrelevant articles were discarded, ten studies were included in the review. Most prospective studies were well controlled, but often did not have a large enough sample size to make robust statements about rarer variants, including those categorized as ultra-rapid and poor metabolizers. Individual studies demonstrated a role for different genetic variants in risperidone drug efficacy, pharmacokinetics, hyperprolactinemia, weight gain, extrapyramidal symptoms and drug–drug interactions. Where studies overlapped in measurements, there was typically a consensus between results. These findings indicate that the value of 2D6 genotyping in the youth population treated with risperidone requires further study, in particular with the less common variants. 相似文献
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The metabolism of chlorpromazine by expressed recombinant cytochromes P450 4F4 and 4F5 cloned from rat brain was analyzed to characterize the individual activities of the isoforms. Both isoforms metabolized chlorpromazine to both the N-demethylated and the S-oxide products. When isoforms were incubated with chloropromazine in the presence of increasing concentrations of imipramine, imipramine significantly inhibited both N-demethylation and S-oxidation of chlorpromazine. A dilution of the serum fraction of anti-4F antibody was also found to significantly inhibit both S-oxidation and N-demethylation of chlorpromazine by both 4F4 and 4F5. 相似文献