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目的研究人体内参与沙利度胺代谢的CYP2C19基因多态性在多发性骨髓瘤(MM)中的分布以及对含沙利度胺方案治疗MM疗效的影响,探讨抗血管生成在MM治疗中的作用。方法采用PCR-限制性片段长度多态性(PCR-RFLP)方法检测92例MM患者的CYP2C19基因型,观察弱代谢型(PM)在中国人MM患者中的发生率,比较强代谢型(EM)和PM患者经沙利度胺治疗后的有效率。结果92例MM患者中PM18例(19.5%),与健康汉族人中PM的发生率相当;EM和PM患者治疗后的有效率分别为62.6%和33.3%,差异有统计学意义(P〈0.05);按治疗方案分组后。沙利度胺联合地塞米松组中EM和PM有效率分别为60.8%和27.3%,差异有统计学意义(P〈0.05);沙利度胺联合传统化疗组EM有效率(65.2%)高于PM(42.7%),但差异无统计学意义。结论CYP2C19基因多态性与MM的发生无明显相关性,但影响沙利度胺的药效,PM患者有效率较低可能与沙利度胺抗血管生成作用减弱有关。 相似文献
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细胞色素酶CYP2C19介导的沙利度胺体外抗血管生成作用研究 总被引:1,自引:0,他引:1
本研究探讨人肝细胞微粒体代谢系统对治疗多发性骨髓瘤的沙利度胺体外抗血管生成的影响及细胞色素酶CYP2C19在其中的作用。采用沙利度胺原药或与人肝细胞微粒体在体外共孵育后用MTY法检测人脐带静脉内皮细胞(human umbilical cord vein endothelial cells,hUCVEC)增殖活力,用流式细胞术测定hUVCEC细胞周期和细胞凋亡,以改良的Boyden小室法检测hUCVEC细胞迁移力,以体外小管形成实验检测hUCVEC分化。结果表明:沙利度胺原药对hUCVEC活力无明显抑制作用,细胞凋亡比例也无明显增加,轻度影响细胞迁移,无抗小管形成作用;当与人肝细胞微粒体共孵育后hUCVEC增殖活力明显受抑。100μg/ml沙利度胺与肝细胞微粒体共孵育后hUCVEC增殖活力的抑制率达(11.7±3.9)%,凋亡细胞增加达27.2%,明显下调细胞迁移力并抑制体外小管形成。在共孵育体系中加入CYP2C19特异性抑制剂奥美拉唑,可减弱沙利度胺抑制hUCVEC增殖活力和诱导凋亡的作用,减低细胞迁移力和部分逆转抗小管形成的作用。结论:沙利度胺的体外抗血管生成作用依赖于人细胞微粒体的作用,细胞色素酶系中的CYP2C19可能参与了这一过程。 相似文献
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沙利度胺对多发性骨髓瘤细胞Survivin表达的影响 总被引:2,自引:1,他引:1
多发性骨髓瘤(MM)是一种恶性浆细胞增殖性疾病,由于致病机制不十分清楚和缺乏有效的治疗手段,其中位生存率仅3年,完全缓解率不到10%。沙利度胺作为新一代抗肿瘤药物[1],近年来已广泛用于治疗MM,并取得了较好疗效。目前细胞淍亡的明显受抑被认为是此病的原因之一,而Survivin是新 相似文献
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沙利度胺治疗多发性骨髓瘤的临床疗效 总被引:1,自引:0,他引:1
多发性骨髓瘤(MM)是一种起源于骨髓单克隆浆细胞的恶性增生肿瘤性疾病。临床上治疗骨髓瘤方案虽多,但并无高效者。作者2004年12月-2006年2月使用沙利度胺(反应停)治疗多发性骨髓瘤(MM)19例,取得满意疗效,现总结如下。 相似文献
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体外沙利度胺抑制骨髓瘤细胞生长及其机制的研究 总被引:8,自引:1,他引:8
为了解沙利度胺对初治和复发难治多发性骨髓瘤患者离体瘤细胞生长的影响及其机制 ,用甲基纤维素集落培养法观察不同浓度沙利度胺对初治、复发难治多发性骨髓瘤患者瘤细胞集落形成的影响 ,用IL 6依赖性细胞系和流式细胞术检测 2 0 0 μg/ml沙利度胺作用下骨髓瘤细胞自分泌IL 6和瘤细胞表面IL 6受体的变化。结果表明 ,当沙利度胺浓度分别为 75和 10 0 μg/ml以上时对初治骨髓瘤细胞和复发难治的多发性骨髓瘤细胞集落形成有抑制作用 ,这种抑制作用随着沙利度胺浓度的增加而增强。沙利度胺浓度为 2 0 0 μg/ml时 ,骨髓瘤细胞自分泌IL 6的浓度在初治组和复发难治组分别为 (14 8.5± 96 .7)ng/ml和 (2 86 .2± 189.1)ng/ml,明显低于沙利度胺作用前的水平 (P <0 .0 0 1和 <0 .0 5 )。沙利度胺浓度为 2 0 0 μg/ml时骨髓瘤细胞表面IL 6受体水平在初治组和复发难治组分别为 16 .7%和 2 0 .2 % ,明显低于沙利度胺作用前的水平 (P <0 .0 0 1和 <0 .0 5 )。结论提示 ,沙利度胺不仅对复发难治患者的多发性骨髓瘤细胞体外生长有抑制作用 ,对初治患者也有作用。此外 ,体外沙利度胺可以抑制瘤细胞IL 6分泌和减少瘤细胞表面IL 6受体表达 ,这可能是沙利度胺治疗多发性骨髓瘤有效的机制之一。 相似文献
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多发性骨髓瘤(MM)是浆细胞克隆性恶性肿瘤,传统化疗和自体造血干细胞移植虽可取得一定疗效,但平均总生存期并没有得到明显提高,大多数患者将进展为难治性MM或疾病复发,目前仍被认为是不可治愈的疾病。近来研究表明:三氧化二砷(ATO)、沙利度胺(T)药或与化疗联合治疗复发难治性MM均有一定疗效。我们采用ATO联合沙利度胺及维生素C(VitC)治疗难治性或复发性MM患者14例,取得了较好疗效,现报告如下。 相似文献
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低剂量沙利度胺治疗多发性骨髓瘤的疗效分析 总被引:1,自引:0,他引:1
目的观察低剂量沙利度胺联合化疗治疗多发性骨髓瘤(MM)的疗效及不良反应。方法分析22例初治和8例复发难治MM患者应用低剂量沙利度胺联合化疗治疗的总有效率和不良反应;分析治疗前后患者M蛋白量、骨髓浆细胞比例以及血红蛋白浓度变化情况。结果 30例MM,完全缓解7例,部分缓解7例,微小反应4例,总有效率60%。治疗前后患者M蛋白量、骨髓浆细胞比例以及血红蛋白浓度相比差异有统计学意义(P〈0.05)。应用沙利度胺不良反应轻,均可耐受。结论低剂量沙利度胺联合化疗治疗多发性骨髓瘤安全有效。 相似文献
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沙利度胺治疗多发性骨髓瘤的临床疗效 总被引:3,自引:6,他引:3
多发性骨髓瘤(MM)是一种起源于骨髓单克隆浆细胞的恶性增生肿瘤性疾病。临床上治疗骨髓瘤方案虽多,但并无高效者。作者2004年12月~2006年2月使用沙利度胺(反应停)治疗多发性骨髓瘤(MM)19例,取得满意疗效,现总结如下。1资料与方法本组病例19例,均为住本院确诊为多发性骨髓瘤患者,诊断标准符合《血液病诊断及疗效标准》[1]。其中女性14例,男性5例。临床分期[2-3]:初治多发性骨髓瘤10例,难治性多发性骨髓瘤9例。初治多发性骨髓瘤10例,确诊后未经任何化疗方案治疗;难治性多发性骨髓瘤9例,为正规使用过MP、M2、VDA、VBMCP等方案化疗2~4疗程… 相似文献
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目的:探讨沙利度胺联合VAD方案治疗多发性骨髓瘤(multiple myeloma,MM)的疗效及不良反应。方法:选取2011年1月—2012年12月住院治疗的38例MM患者,将其随机分为对照组和观察组。对照组(VAD组)16例,采用长春新碱+阿霉素+地塞米松治疗;观察组(TVAD组)22例,在对照组治疗方法的基础上加用沙利度胺。比较两组的疗效及不良反应。结果:TVAD组总有效率(77.2%)明显高于VAD组(50.0%),差异有统计学意义(P0.05)。TVAD组治疗后较治疗前血清β2-微球蛋白(β2-microglobulin,β2-MG)、C-反应蛋白(C-reactive protein,CRP)、红细胞沉降率(erythrocyte sedimentation rate,ESR)、浆细胞比例的下降及血红蛋白(haemoglobin,Hb)的升高幅度均大于VAD组,差异有统计学意义(均P0.05)。TVAD组不良反应发生率高于VAD组,不良反应经对症处理后均消失,不影响治疗。结论:沙利度胺联合VAD方案治疗MM疗效显著、给药方便、患者耐受性好。 相似文献
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目的探讨CYP2C19基因型在江苏及其周边地区汉族人群中基因多态性的分布。方法取81名汉族健康人的外周血,应用聚合酶链反应(PCR)-限制性片段长度多态性分析(RFLP)CYP2C19等位基因分型。结果在81名检测标本中,CYP2C19纯合子强代谢型、杂合子强代谢型和弱代谢型的发生率分别为38.3%、45.7%和16.0%。结论江苏及其周边地区汉族人群存在CYP2C19的基因多态性,其弱代谢型的发生率与中国汉族人总体发生率基本一致。 相似文献
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Background and objective: CYP2C19 is a drug‐metabolizing enzyme showing various genetic polymorphisms that may cause marked interindividual and interethnic variability in the disposition of its substrates. We assessed CYP2C19 genetic polymorphisms in a Korean population using a newly developed multiplex pyrosequencing method. Method: A multiplex pyrosequencing method to simultaneously detect CYP2C19*2, *3, and *17 alleles was designed. We established the frequency of these CYP2C19 alleles in 271 Korean subjects using the multiplex pyrosequencing method. Results: The results showed 100% concordance between single and multiplex pyrosequencing methods. We also validated the polymorphisms identified by pyrosequencing with direct sequencing method. The allele frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 were 0·284, 0·101 and 0·015 respectively. These frequencies are similar to that reported for other Asian populations including Japanese and Chinese but different from that of Caucasians and Africans. Conclusions: The multiplex pyrosequencing method to detect CYP2C19*2, CYP2C19*3, and CYP2C19*17 concurrently, seems to be a rapid and reliable genotyping method for the detection of important CYP2C19 genetic polymorphisms. Similar to studies conducted on other Asian populations, this study reported that in the Korean population tested, the CYP2C19*2 and CYP2C19*3 alleles were relatively frequently found, whereas the frequency of CYP2C19*17 was very low. 相似文献
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Jose R Chandrasekaran A Sam SS Gerard N Chanolean S Abraham BK Satyanarayanamoorthy K Peter A Rajagopal K 《Fundamental & clinical pharmacology》2005,19(1):101-105
The aim of the study was to establish the frequencies of CYP2C9*1, *2, *3 and CYP2C19*1, *2 and *3 in the south Indian population and to compare them with the inter-racial distribution of the CYP2C9 and CYP2C19 genetic polymorphisms. Genotyping analyses of CYP2C9 and CYP2C19 were conducted in unrelated, healthy volunteers from the three south Indian states of Andhra Pradesh, Karnataka and Kerala, by the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). The allele frequencies of the populations of these three states were then pooled with our previous genotyping data of Tamilians (also in south India), to arrive at the distribution of CYP2C9 and CYP2C19 alleles in the south Indian population. Frequencies of CYP2C9 and CYP2C19 alleles and genotypes among various populations were compared using the two-tailed Fisher's exact test. The frequencies of CYP2C9*1, *2 and *3 in the south Indian population were 0.88 (95% CI 0.85-0.91), 0.04 (95% CI 0.02-0.06) and 0.08 (95% CI 0.06-0.11), respectively. The frequencies of CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 were 0.78 (95% CI 0.74-0.82), 0.05 (95% CI 0.03-0.07), 0.15 (95% CI 0.12-0.18), 0.01 (95% CI 0.0-0.02), 0.01 (95% CI 0.0-0.02) and 0.0, respectively. CYP2C19*1, *2 and *3 frequencies were 0.64 (95% CI 0.60-0.68), 0.35 (95% CI 0.31-0.39) and 0.01 (95% CI 0.0-0.03), respectively. As a result of a significant heterogeneity, the data on CYP2C19 genotype frequencies were not pooled. The frequency of CYP2C9*2 mutant alleles in south Indians was higher than in Chinese and Caucasians, while CYP2C9*3 was similar to Caucasians. CYP2C19*2 was higher than in other major populations reported so far. The relatively high CYP2C19 poor-metabolizer genotype frequency of 12.6% indicates that over 28 million south Indians are poor metabolizers of CYP2C19 substrates. 相似文献
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Arvanitidis K Ragia G Iordanidou M Kyriaki S Xanthi A Tavridou A Manolopoulos VG 《Fundamental & clinical pharmacology》2007,21(4):419-426
The aim of the present study was to determine the prevalence of the most common allelic variants of the polymorphic cytochrome P450 (CYP) enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 and to predict the genotype frequency for each polymorphism in the Greek population. DNA isolated from peripheral blood samples derived from 283 non-related Greek ethnic subjects was used to determine the frequency of CYP2D6*3, CYP2D6*4, CYP2C9*2, CYP2C9*3 and CYP3A5*3 allelic variants by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method, CYP2C19*2 and CYP2C19*3 with allelic specific amplification (PCR-ASA), and CYP2D6*2 (gene duplications) by long PCR analysis. The allelic frequencies (out of a total of 566 alleles) for CYP2D6*3 and CYP2D6*4, were 2.3% and 17.8%, respectively, while gene duplications (CYP2D6*2) were found in 7.4% of the subjects tested. For CYP2C9*2 and CYP2C9*3 polymorphisms the allelic frequencies were 12.9% and 8.13% respectively. For CYP2C19, the *2 polymorphism was present at an allelic frequency of 13.1%, while no subjects were found carrying the CYP2C19*3 allele. Finally, the CYP3A5*3 allele was abundantly present in the Greek population with an allelic frequency of 94.4%. Overall our results show that the frequencies of the common defective allelic variants of CYP2C9, CYP2C19 and CYP3A5 in Greek subjects are similar to those reported for several other Caucasian populations. Finally, a high prevalence of CYP2D6 gene duplication among Greeks was found, a finding that strengthens the idea that a South/North gradient exists in the occurrence of CYP2D6 ultrarapid metabolizers in European populations. 相似文献
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Effect of antituberculosis treatment on CYP2C19 enzyme activity in genetically polymorphic South Indian Tamilian population 下载免费PDF全文
Alphienes Stanley Xavier Saka Vinod Kumar Rajan Sundaram Jose Francis Deepak Gopal Shewade 《Fundamental & clinical pharmacology》2016,30(6):607-615
Patients on antituberculosis therapy (ATT) are more prone to drug interactions in the presence of coexisting illnesses which require drug therapy. Rifampicin is a pleiotropic inducer of CYP enzymes, and isoniazid is an enzyme inhibitor. Genetic variations are common in the gene coding for CYP2C19 enzyme. These variations would be important in predicting the individual variations in CYP2C19 activity. The objectives of the study were to find the net effect of 1‐month ATT on CYP2C19 enzyme activity and its association with CYP2C19 genetic polymorphisms. Newly diagnosed tuberculosis patients (n = 125) were included in the study. Before commencing ATT, they were given a single dose of omeprazole 20 mg as a probe drug for CYP2C19. Blood sample was collected after 3 h to carry out phenotyping for CYP2C19 enzyme by measuring omeprazole hydroxylation index (OHI) using LC‐MS/MS. The phenotyping procedure was repeated after 1 month of ATT. CYP2C19 genotyping was carried out by PCR‐RFLP method. Significant reduction in OHI was observed after 1 month of ATT in all the metabolizer groups. The percentage reduction in OHI was maximum with poor metabolizers, 84.1 (IQR – 74.6, 86.6), and minimum with ultra‐rapid metabolizers, 39.6 (IQR – 12.7, 54.7). CYP2C19 enzyme induction is predominant in patients after 1 month of antituberculosis treatment (ATT). Genetic variations in the enzyme could not clearly explain the interindividual differences in induction. There is a potential risk of drug failure/adverse effect in poor metabolizers regardless of their genotype after ATT. 相似文献
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S. K. Jin† MS T. S. Kang MS S. O. Eom MS J.-I. Kim PhD H. J. Lee† PhD J. Roh‡ MD PhD 《Journal of clinical pharmacy and therapeutics》2009,34(4):437-446
Background and objective: CYP2C19 is clinically important in Korea because of the relatively high incidence of poor metabolizers in the population. To fully understand the genetic mechanism of the CYP2C19 defect in poor metabolizers, all variants need to be studied simultaneously. The aim of this study was to investigate the usefulness of CYP2C19 haplotypes as a marker of CYP2C19 enzyme activity in Koreans.
Methods: We analysed the single nucleotide polymorphisms and haplotypes of the CYP2C19 gene in 150 healthy Koreans and found three major (frequency > 0·1) haplotypes (H1, H2 and H3). One oral dose of 40 mg omeprazole (Losec® ) was administered to 30 subjects grouped as H1/H1, H2/H2, H1/H2, H1/H3 and H2/H3. The pharmacokinetics of omeprazole and its metabolites, 5-hydroxyomeprazole and omeprazole sulphone, in those groups was analysed.
Results and discussion: The area under the plasma concentration–time curve (AUC0→∞ ) and elimination half-life ( T 1/2 ) of omeprazole were significantly greater in the H2/H2 and H2/H3 groups than in the H1/H1 group ( P < 0·05), whereas the metabolic ratios of omeprazole to 5-hydroxyomeprazole were also markedly higher.
Conclusion: Although a specific SNP of CYP2C19 may be predictive of enzyme activity, haplotyping is more reliable for identifying poor metabolizers in populations with variant alleles other than CYP2C19*2 and *3 alleles. 相似文献
Methods: We analysed the single nucleotide polymorphisms and haplotypes of the CYP2C19 gene in 150 healthy Koreans and found three major (frequency > 0·1) haplotypes (H1, H2 and H3). One oral dose of 40 mg omeprazole (Losec
Results and discussion: The area under the plasma concentration–time curve (AUC
Conclusion: Although a specific SNP of CYP2C19 may be predictive of enzyme activity, haplotyping is more reliable for identifying poor metabolizers in populations with variant alleles other than CYP2C19*2 and *3 alleles. 相似文献
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目的:探讨细胞色素P450(CYP)2C19基因多态性与新疆维吾尔族人群冠心痛的相关性.方法:采用聚合酶链反应-限制性片段长度多态性方法,对234例冠心痛患者(冠心病组)和132例健康受试者(对照组)CYP2C19基因rs6583954位点进行多态性分析.结果:CYP2C19基因rs6583954住点等住基因CT在冠心病组分别为84.83%和15.17%,在对照组分别为78.79%和21.21%,2组等位基因频率差异有统计学意义(P<0.05);冠心痛组CC基因型为73.1%,对照组为61.4%,2组比较差异有统计学意义(P=0.0201);Logistic回归分析显示在调整了年龄、性别、高血压、糖尿痛、高胆固醇血症等传统危险因素之后,CYP2C19基因多态性仍是维吾尔族冠心病发生的重要危险因素,基因型CC:OR值=3.25,95%CI为0.73~14.36;基因型CT:OR值=1.59,95%CI为0.34~7.35.结论:CYP2C19基因多态性可增加维吾尔族吸烟者冠心病的发生风险. 相似文献
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目的 探讨奥美拉唑治疗十二指肠溃疡合并幽门螺旋菌感染的疗效及其与CYP2C19基因多态性的关系.方法 应用奥美拉唑+阿莫西林+克拉霉素三联用药1周后单用奥美拉唑抑酸3周的方案治疗65例经胃镜证实的十二指肠溃疡合并幽门螺旋菌( Hpylori)感染患者.记录治疗前和用药后症状的变化,并于治疗结束时复查胃镜.患者CYP2C19的基因型检测采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析方法.结果 65例十二指肠溃疡患者中,24例为纯合子强代谢者,31例为杂合子强代谢者,10例为弱代谢者.纯合子强代谢组、杂合子强代谢组和弱代谢组有效率分别为75.0%、90.3%和100%,纯合子强代谢组的治愈率显著低于弱代谢组(P<0.05).弱代谢型组患者的Hpylori清除率显著高于纯合子强代谢型和杂合子强代谢型(P<0.05).结论 CYP2C19基因多态性与奥美拉唑治疗十二指肠溃疡合并幽门螺旋菌感染的疗效密切相关.CYP2C19基因分型检测是临床治疗酸相关性疾病中的一个重要的工具. 相似文献