CYP3A4*1G基因多态性对老年患者全髋置换术后舒芬太尼药效学的影响

目的探讨CYP3A4*1G基因多态性对老年患者全髋置换术后舒芬太尼药效学的影响。 方法选择2016年1月至2017年8月台州市中心医院择期行全髋置换手术的老年患者116例,术后患者静脉自控镇痛（PCIA）。采用焦磷酸测序法检测CYP3A4*1G基因多态性,根据基因型将患者分成野生型纯合子（AA）组69例、突变型杂合子（GA）组39例和突变型纯合子（GG）组8例。记录并比较所有患者术后6、12、24、48 h静息状态下的视觉模拟疼痛评分（VAS）,术后48 h的舒芬太尼总用量、PCIA次数。 结果三组患者术后6、12、24、48 h的VAS的比较差异均无统计学意义（F=0.907、0.192、0.757、0.256,P均>0.05）。而达到相同镇痛效果的GG组患者术后48 h舒芬太尼消耗量[（89.8 ± 0.8）、（95.8 ± 0.5）、（96.0 ± 0.4）μg,F=25.113,P<0.001]及PCIA次数[（10.9 ± 2.0）、（17.4 ± 4.5）、（18.3 ± 3.7）次,F=35.227,P<0.001]均显著少于AA组和GA组患者。而GA组和AA组术后48 h舒芬太尼消耗量及PCIA次数比较差异均无统计学意义（P均>0.05）。 结论结合患者基因型调整舒芬太尼药量可减少老年患者药物使用量。     

Effect of CYP3A4*1G on the fentanyl consumption for intravenous patient-controlled analgesia after total abdominal hysterectomy in Chinese Han population

What is known and Objective: Clinical investigations into postoperative intravenous patient‐controlled analgesia (PCA) have indicated interindividual differences in fentanyl consumption. Cytochrome P450 3A4 (CYP3A4) is the main metabolism enzyme of fentanyl, and single nucleotide polymorphisms within the CYP3A4 gene may contribute to the variability of fentanyl analgesic efficacy. The aim of this study was to investigate whether the most common genetic variation in Chinese, CYP3A4*1G, has an impact on the fentanyl consumption for intravenous PCA in Chinese Han women undergone abdominal total hysterectomy. Methods: A total of 79 female patients (American Society of Anesthesiologist physical status I or II) scheduled to undergo elective abdominal total hysterectomy were enrolled. All patients received combined spinal–epidural anaesthesia with bupivacaine. Intravenous fentanyl PCA was provided postoperatively for satisfactory analgesia. The doses of fentanyl consumption were recorded 2, 4, 24 and 48 h after the initiation of PCA postoperatively. Pain at rest and adverse effects were measured with rating scales. CYP3A4*1G was screened by means of direct sequencing and further confirmed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Results and Discussion: Forty‐six patients were GG homozygotes, 27 patients were GA heterozygotes, and six patients were AA homozygotes, respectively. The distribution of the CYP3A4*1G allele was consistent with Hardy–Weinberg equilibrium (P > 0·05). At 2 and 4 h, the doses of fentanyl required for patients with GA/AA genotypes were 80·0 (45·0, 112·5) μg and 120·0 (80, 173·8) μg, respectively, and significantly lower than those for GG homozygotes [91·3 (80·0, 125·0) μg and 169·0 (112·5, 226·3) μg, respectively, P < 0·05]. There was trend of decreasing fentanyl consumption at 24 and 48 h in patients with GA/AA genotypes, relative to GG homozygotes, but the difference was not statistical significant (P > 0·05). What is new and Conclusions: CYP3A4*1G has an impact on the analgesic effect of fentanyl in Chinese Han subjects. Further validation of our results in a well‐powered study would be helpful.     

CYP3A5*3 and CYP3A4*18 single nucleotide polymorphisms in a Chinese population

BACKGROUND: Human cytochrome P450 3A evolved to catalyze the metabolism of numerous common therapy drugs and endogenous molecules. Members of the CYP3A are the majority expressed in human liver and intestine, and there are marked interindividual differences in their protein expression and activity. The activity of CYP3A enzyme in Chinese is highly variable, exceeding 14-fold, and contributes greatly to variation in oral bioavailability and systemic clearance of CYP3A substrates. The genetic factors play an important role in the interindividual variability in CYP3A activity. Detection of CYP3A5 and CYP3A4 variant alleles and knowledge about their allelic frequency in specific ethnic groups are important to lead to individualized drug dosing and improved therapeutics. METHODS: We determined the allelic frequency of the CYP3A5*3 and CYP3A4*18 in a group of 302 Chinese subjects by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. RESULTS: In the group of 302 unrelated individuals, the frequency of the CYP3A5*3 and CYP3A4*18 variant allele in Chinese population were 0.778 (95% CI: 0.754, 0.802) and 0.01 (95% CI: 0, 0.02), respectively. CONCLUSIONS: We developed a simple assay for the detection of the CYP3A4*18 allele and showed that in a Chinese population, CYP3A4*18 and CYP3A5*3 allelic frequencies are similar to that reported previously in Chinese resident in Taiwan. The frequency of the CYP3A5*3 allele in Chinese population is similar to the Japanese but lower than Caucasians. Meanwhile, our findings suggest that an approximate 62% of the Chinese population carrying CYP3A5*3/*3 genotype may appear not to express CYP3A5 protein.     

国产舒芬太尼在腹部外科手术患者的药代动力学研究

目的 观察腹部外科手术患者国产舒芬太尼单次静脉注射的药代动力学特征.方法 随机选择腹部外科手术患者10例,ASA Ⅰ、Ⅱ级,年龄51～65岁,体重58～68 kg.全身麻醉后经前臂一次性静脉注射国产舒芬太尼2 μg,于注药后1、3、5、10、20、30、60、120、180、240 min和360 min采集桡动脉抗凝全血3ml,离心后吸取血浆1 ml注入真空试管中,-80℃低温保存待测.用液相色谱-质谱联用法测定血浆舒芬太尼浓度,3P97药理学程序判别房室模型并计算药代动力学参数:中心分布容积(Vc),表观分布容积(Vd),快速分布半衰期(t1/2π)、缓慢分布半衰期(t1/2α)、排除半衰期(t1/2β),常数(P、A、B、π、α、β)和速率常数(k10、k12、k21、k13、k31)、清除率(CL)和血药浓度与时间曲线下面积(AUC)等.结果 国产舒芬太尼在腹部手术患者的血药浓度与时间曲线可用三指数函数方程表示:Cp(t)=2.86e-0.8241t+0.75e-0.0604t+0.14e-0.0050t.主要药代动力学参数t1/2π=(1.29±0.81)min、t1/2α=(12.20±2.84)min,t1/2β=(150.50±48.71)min,Vc=(0.552±0.104)L/kg、Vd=(9.008±0.754)L/kg,CL=(0.044±0.011)L/(kg·min)和AUC=(47.58±11.88)ng/(ml·min).结论 国产舒芬太尼在腹部外科手术患者的药代动力学符合三室开放模型,其药代动力学特征与其临床药理学特性相一致.     

CYP3A4、CYP3A5和CYP2D6基因单核苷酸多态性对肾移植术后稳定期患者他克莫司代谢的影响

目的探讨肾移植患者细胞色素P450 CYP3A4、CYP3A5和CYP2D6基因单核苷酸多态性与他克莫司(FK506)代谢的相关性以及根据基因多态性制定FK506个体化治疗方案的可行性。方法收集随访的138例肾移植稳定期患者,均采用含FK506、吗替麦考酚酯、糖皮质激素的三联治疗方案。记录单位体重用药剂量数据、FK506谷浓度和CYP3A4、CYP3A5、CYP2D6基因单核苷酸多态性测序法检测结果。分析单核苷酸多态性与浓度调整的单位体重用药剂量的相关性。结果在138例患者中,CYP3A4野生型TT等位基因频率为0.993、杂合子TC等位基因频率为0.007;CYP3A5野生型AA等位基因频率为0.529、杂合子AG等位基因频率为0.399、纯合子GG等位基因频率为0.072;CYP2D6野生型(76例)CC等位基因频率为0.550、杂合子CT等位基因频率为0.449。为了达到相应的稳态浓度,CYP3A5野生型(AA)患者与突变型(AG、GG)相比需要更高剂量的FK506(P0.001);而CYP2D6野生型(CC)和突变型(CT)之间FK506剂量差异无统计学意义(P0.05)。结论CYP3A4的基因多态性以野生型常见,对FK506代谢的影响较少。CYP3A5的基因多态性与FK506的代谢密切相关,野生型患者需要较高剂量的FK506才能达到相应的稳态浓度。CYP2D6的基因多态性与FK506代谢无明显相关性。     

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities,targeting CYP3A4*1G allele function

The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup’ik Alaska Native people living in the Yukon‐Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska. We identified low frequencies of novel and known variation in CYP3A4 and CYP3A5, including low frequencies of the CYP3A4*1G and CYP3A5*1 variants, and linkage disequilibrium patterns that differed from those we previously identified in an American Indian population in western Montana. We also identified increased activity of the CYP3A4*1G allele in vitro and in vivo. We demonstrated that the CYP3A4*1G allele confers increased protein content in human lymphoblastoid cells and both increased protein content and increased activity in human liver microsomes. We confirmed enhanced CYP3A4‐mediated 4β‐vitamin D hydroxylation activity in Yup’ik people with the CYP3A4*1G allele. AIAN people in Alaska and Montana who carry the CYP3A4*1G allele—coupled with low frequency of the functional CYP3A5*1 variant—may metabolize CYP3A substrates more rapidly than people with the reference CYP3A4 allele.

Study highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Alleles in CYP3A4 and CYP3A5 are highly variable in populations globally, but have not been well‐characterized in American Indian and Alaska Native (AIAN) populations. The functional effects of some variants are not well known, including the CYP3A4*1G allele, which we identified in unique linkage disequilibrium patterns in prior work with an American Indian population in Montana.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study characterizes the CYP3A4*1G allele using in vitro and in vivo models. It also improves our understanding of genetic variation across AIAN populations in North America.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We show increased activity of the CYP3A4*1G allele, and identify low frequencies of CYP3A4 and CYP3A5 variants, including CYP3A4*1G and functional CYP3A5*1, in Alaska Native people.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Inclusion of diverse populations in estimating diplotype frequencies and their function is important for ensuring equitable access to the benefits of personalized medicine for all. We showed that people with the CYP3A4*1G allele may require dose escalation of CYP3A4‐metabolized medications due to increased activity of the CYP3A4 enzyme.     

Impact of the haplotype CYP3A4*16B harboring the Thr185Ser substitution on paclitaxel metabolism in Japanese patients with cancer

OBJECTIVE: Paclitaxel is one of the most important anticancer drugs for the treatment of various tumors such as non-small cell lung cancer. We investigated the association between CYP3A4 haplotypes and pharmacokinetic parameters of paclitaxel metabolism. METHODS: This study enrolled 235 Japanese patients with cancer who were receiving paclitaxel. These patients were screened for CYP3A4 gene polymorphisms by either direct sequencing or pyrosequencing. Plasma concentrations of paclitaxel and its 3 metabolites were determined by HPLC in 229 patients. RESULTS: Median values of paclitaxel clearance, normalized for body surface area, were lower in the high-dose group (>or=175 mg/m2, n = 199) than in the low-dose group (相似文献   

CYP3A4、CYP3A5、COMT及OPRM1基因多态性对术后芬太尼镇痛剂量的影响

目的 探讨代谢酶相关基因（CYP3A4*1G、CYP3A5*3、COMT Val158Met）和药物作用靶点基因（OPRM1rs563649）的多态性与芬太尼术后镇痛剂量个体差异的相关性。方法 选择2018年10月至2020年3月复旦大学附属中山医院收治的择期全麻下行腹腔镜辅助结肠癌根治术患者91例，抽取患者外周静脉血，通过Sanger测序技术检测CYP3A4*1G、CYP3A5*3、OPRM1 rs563649及COMT Val158Met各基因多态性，随访患者术后芬太尼镇痛剂量和视觉模拟评分（VAS）分值，分析基因多态性与腹腔镜术后芬太尼镇痛用量的关系。结果 CYP3A4*1G、CYP3A5*3、OPRM1 rs563649及COMT Val158Met各位点在结肠癌患者中突变频率分别为31.87%、65.93%、9.40%、26.92%。携带CYP3A4*1G/*1G突变纯合子基因型的患者术后第1天、第2天芬太尼消耗量减少（P<0.05）。CYP3A5*3、OPRM1rs563649及COMT Val158Met各基因型的芬太尼术后消耗量差异无统计学意义。CYP3A4*1G...     

CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5'-promoter region polymorphism

OBJECTIVE: Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability. Possible differences in CYP3A activity were investigated in European American and African American men with the use of midazolam as an in vivo probe. METHODS: Midazolam was simultaneously administered intravenously (1 mg, [15N3]-labeled) and orally (2 mg, unlabeled in capsule form) to 15 young healthy European American men and a similar group of men of African American descent. Plasma concentration-time curves were measured. The subjects were subsequently genotyped with respect to the CYP3A4*B1 polymorphism (A-290G) in the 5'-promoter (nifedipine-specific element) region. RESULTS: The oral bioavailability of midazolam was about equally determined by intestinal and hepatic extraction with CYP3A activity at the former site exhibiting greater variability. Oral bioavailability was related to intestinal metabolism (r = 0.98), whereas hepatic CYP3A activity contributed little to the interindividual variability (r = 0.03). A lower systemic clearance (265+/-54 versus 310+/-56 mL/min; P = .04), but not oral clearance, was observed in African Americans. With one exception, the African Americans possessed a variant CYP3A4*1B allele (4 heterozygotes A/G and 10 homozygote G/G), whereas all of the European Americans were wild-type homozygotes (A/A). Hepatic CYP3A activity and the systemic clearance of midazolam were about 30% lower in G/G homozygotes than in A/A homozygotes (252+/-53 versus 310+/-54 mL/min; P = .02), and a gene-dose effect was present (P = .01). There was no genotype/phenotype relationship with respect to the oral clearance of midazolam. CONCLUSION: Comparison of CYP3A activity between populations is complicated by frequency distribution differences in the regulatory CYP3A4*1B polymorphism and lower hepatic CYP3A activity associated with the variant allele. However, this reduction is modest; therefore no major and clinically important difference in CYP3A activity is present between Americans of African or European descent.     

Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis

What is known and Objective: Tacrolimus (TAC) is metabolized mainly by the CYP3A subfamily and extruded into the intestine by P‐glycoprotein, which is encoded by the ABCB1 gene. Several studies have suggested that the CYP3A5*3 genotype influenced the pharmacokinetics (PK) of TAC. The CYP3A4*18B and CYP3A5*3 alleles are clinically important in Chinese subjects because of their relatively high frequency. The present study aimed at evaluating the effects of ABCB1 (C1236T‐G2677T/A‐C3435T), CYP3A4*18B and CYP3A5*3 genetic polymorphisms on TAC PK in healthy Chinese subjects. Methods: Data were obtained from a comparative bioavailability study of oral TAC formulations (n = 22). TAC whole blood concentrations were measured by LC‐MS/MS. Genetic polymorphisms were determined using a direct sequencing method. Nonlinear mixed‐effects modelling (NONMEM) was performed to assess the effect of genotypes and demographics on TAC PKs. Results and Discussion: Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the TAC PK, whereas ABCB1 genetic polymorphisms and other demographic characteristics did not. The combined genotypes of CYP3A4*18B and CYP3A5*3 had a greater impact than either genotype alone, and they were estimated to account for 28·4% of the inter‐subject variability of apparent clearance (CL/F) by NONMEM. The CL/F in subjects with CYP3A4*1/*1‐CYP3A5*3/*3 was 10·3 L/h and was 48·5% in those not carrying CYP3A4*1/*1‐CYP3A5*3/*3. What is new and Conclusion: This is the first study to extensively explore the influence of CYP3A4*18B, CYP3A5*3 and ABCB1 genetic polymorphisms on TAC PK in healthy Chinese subjects. The results demonstrated that subjects with a combined genotype of CYP3A4*1/*1‐CYP3A5*3/*3 may require lower TAC doses to achieve target concentration levels and further investigation is needed in larger populations to confirm the clinical benefits.     

术后早期活动对腹部手术病人快速康复影响的Meta分析

[目的]评价术后早期活动对腹部手术病人术后快速康复进程的影响。[方法]利用计算机检索万方、CNKI、维普、PubMed、the Cochrane Library、EMbase、Sciencedirect数据库建库至2018年8月31日发表的有关腹部手术病人术后采取早期活动的随机对照试验、病例对照试验。由2名研究者分别对符合纳入标准的研究进行质量评价和数据提取,采用RevMan 5.3.5对术后结局指标进行Meta分析。[结果]共纳入10项随机对照试验,纳入分析的971例病人中实验组(术后早期活动采取精细化护理流程)485例,对照组(术后早期活动采取传统护理流程)486例。与对照组相比,实验组术后首次排气时间较短[WMD=-13.10,95%CI(-19.88,-6.32),P<0.05],术后首次排便时间较短[WMD=-14.23,95%CI(-22.15,-6.31),P<0.05],术后第1天疼痛评分较低[WMD=-0.41,95%CI(-0.56,-0.26),P<0.05],术后第1天睡眠时间较多[WMD=0.87,95%CI(0.58,1.16),P<0.05],术后第2天睡眠时间较多[WMD=1.08,95%CI(0.85,1.32),P<0.05],术后第3天睡眠时间较多[WMD=0.96,95%CI(0.76,1.16),P<0.05],术后胃肠道不适发生率较低[OR=0.24,95%CI(0.14,0.41),P<0.05]。[结论]现有证据表明,术后早期活动的精细化护理能够有效促进腹部手术病人的胃肠功能恢复,缓解疼痛,改善睡眠质量,促进病人快速康复。     

Recombinant CYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and the CYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing a new putative defective CYP3A haplotype

Genetic variation in CYP3A activity may influence the rate of the metabolism and elimination of CYP3A substrates in humans. We previously reported four new CYP3A4 coding variants in three different racial groups. In the present study, we examined metabolism of nifedipine by the recombinant forms of these allelic variants. Metabolism of nifedipine by the L293P (CYP3A4*18), M445T (CYP3A4*3), and P467S (CYP3A4*19) allelic variants was not significantly different from wild-type CYP3A4*1. However, F189S (CYP3A4*17) exhibited a >99% decrease in both V(max) and CL(max) of nifedipine compared with CYP3A4*1. Of 72 racially diverse individuals, CYP3A4*17 was identified in 1 of 24 Caucasian samples [1:5 Eastern European (Adygei ethnic group)]. Genotyping of an extended set of 276 genomic DNAs of Caucasians (100 from the Coriell Repository and an additional 176 from the United States) for CYP3A4*17 detected no additional individuals containing the CYP3A4*17 allele. However, additional genotyping of four more Adygei samples available from Coriell detected an additional individual carrying the CYP3A4*17 allele. New specific polymerase chain reaction-restriction fragment length polymorphism genotyping procedures were developed for the major splice variant of CYP3A5 (CYP3A5*3) and CYP3A4*17. Genotyping revealed that the two individuals carrying CYP3A4*17 were either homozygous or heterozygous for the more frequent CYP3A5*3 allele, suggesting that the two alleles may exist on the same chromosome as a new putative CYP3A poor metabolizer haplotype. We predict that individuals who are homozygous for defective alleles of both of these genes would metabolize CYP3A substrates poorly. The new genetic tests will be useful in future clinical studies to investigate genotype/phenotype associations.     

CYP3A4*1B and NAT2*14 alleles in a native African population.

Single nucleotide polymorphisms were examined in the cytochrome 450 3A4 (CYP3A4) and N-acetyltransferase 2 (NAT2) genes, which code for major mediators of the metabolism of a wide variety of therapeutic drugs, as well as xenobiotics. We determined, in a population from Guinea-Bissau, the frequencies of CYP3A4 and NAT2 variants expected to be prevalent among Africans, due to the high frequency previously observed in African Americans. The observed frequencies were 72% for CYP3A4*1B and 19.2% for the NAT2 191 G>A variant. The high frequency found for these potentially function-altering polymorphisms suggests the possibility of impaired metabolism through CYP3A4 and NAT2 in this population. Strikingly, the frequency observed for the NAT2 191 G>A single nucleotide polymorphism (SNP), associated with the slow acetylator phenotype, was significantly higher than found in other African populations, suggesting the existence of a west to east gradient across Sub-Saharan Africa. The prevalence of these variants may be relevant with regard to therapeutic efficacy in African populations for it may potentially affect drug clearance and consequently, increase the incidence of side effects and drug-drug interactions.     

Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity

BACKGROUND: The major drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 is genetically conserved. One outlier of Brazilian descent was found in a clinical pharmacokinetic trial exhibiting a 6-fold higher exposure than expected to an investigational drug, shown to be a CYP3A4 substrate. We aimed to investigate the genetic background of this finding. METHODS: The allelic variant of the CYP3A4 gene present in the outlier was sequenced, and the corresponding complementary deoxyribonucleic acid was expressed in yeast and human embryonic kidney cells. The outlier was phenotyped by use of intravenous administration of 1 mg midazolam. Analysis of phenotype and genotype correlation was carried out. The prevalence of the new allele was screened for in a white population. RESULTS: We identified a subject who heterozygously carried a novel CYP3A4 allele, named CYP3A4*20, with a premature stop codon yielding a truncated protein. Heterologous expression revealed that the CYP3A4.20 enzyme does not incorporate heme and thus is devoid of catalytic activity. CYP3A phenotyping in vivo showed that CYP3A4*20 exhibits a clear genotype-phenotype correlation, demonstrated by the subject's low systemic midazolam clearance (2.99 mL x min(-1) x kg(-1)). Genotyping of a white German population (n = 428) and relatives of the subject, as well as a review of published CYP3A4 sequencing data, suggests that CYP3A4*20 is a rare variant allele (<0.06% in white subjects). CONCLUSIONS: CYP3A4*20 represents the first CYP3A4 allele to be identified that has been shown to be devoid of functional activity. It causes an intermediate CYP3A4 metabolizer phenotype in a heterozygous carrier. Subjects of this genotype might be susceptible to side effects during drug therapy with substrates or inhibitors of CYP3A4.     

盐酸右美托咪定对老年腹部手术患者术后认知功能障碍的影响

目的:探讨右美托咪定对老年患者术后认知功能障碍的影响.方法:选择我院择期行腹部手术的老年患者100例,年龄70～ 85岁,ASAⅡ～Ⅲ级,随机分为两组:右美托咪定组(D组)和对照组(C组),每组50例.两组患者均采用咪唑安定0.04 mg/kg,芬太尼4μg/kg,丙泊酚0.5 ～ 1.5 mg/kg,顺阿曲库铵0.15 mg/kg静脉注射进行麻醉诱导.D组在全麻诱导气管插管开始,15 min内静脉泵入1μg/kg盐酸右美托咪定,随后以0.2 ～ 0.7 μg/(kg·h)维持泵注,根据患者心率、血压等变化及时调整输注速率;C组静脉泵注等量生理盐水.应用简易智力状态检查(MMS)测试方法评定两组患者术前1d,术后5h、术后1d的认知功能.结果:(1)两组患者一般情况的比较(P＜0.05);(2)D组患者术中芬太尼、瑞芬太尼和丙泊酚用量均 比C组明显减少(P＜0.05);(3)两组患者术前MMS评分无明显差异(P＞0.05),D组患者术后5h、术后1d的MMS评分均明显低于C组(P＜0.05);(4)两组患者术前1d和术后1d血清TNF-α、IL-6水平无明显差异(P＞0.05);(5)D组患者术后5h血清TNF-α、IL-6水平均明显低于C组(P＜0.05).结论:右美托咪定在老年患者腹部手术中应用,可减少术后认知功能障碍的发生,可能与其抗炎作用和减少全麻药用量有关.     

Effect of the CYP2C9*3 allele on lornoxicam metabolism

BACKGROUND: We investigated whether the CYP2C9 genotypes would affect lornoxicam metabolism in healthy volunteers. METHODS: Twelve healthy volunteers who had been genotyped for CYP2C9 gene were selected to participate in our study. After 8 mg lornoxicam was taken, blood samples were drawn from 0 to 36 h. The plasma concentrations of lornoxicam and 5'-hydroxylornoxicam were determined by HPLC method. 5'-hydroxylornoxicam was purified from rabbits'urine by semi-preparative HPLC. RESULTS: Lornoxicam and 5'-hydroxylornoxicam both exhibit CYP2C9 genotype-dependent pharmacokinetic profiles. The area under the plasma concentration-time curve (AUC) of lornoxicam increased by 60 +/- 9.78% (P <0.05) and the AUC of 5'-hydroxylornoxicam decreased by 65 +/- 11.75% (p <0.001) in heterozygous CYP2C9*1/*3 subjects (n=6) compared with CYP2C9*1/*1 group (n=6). t1/2 value of lornoxicam and 5'-hydroxylornoxicam prolonged by 39 +/- 8.35% and curtailed by 59 +/- 6.83% respectively in CYP2C9*1/*3 subjects. But no significant differences in Tmax of lornoxicam and 5'-hydroxylornoxicam were observed between these 2 genotypes. In addition, for the first time we exploit the purification method for 5'-hydroxylornoxicam from rabbits' urine. CONCLUSION: The CYP2C9*3 allele significantly affected the metabolism of lornoxicam. The pharmacokinetic parameters of both lornoxicam and 5'-hydroxylornoxicam were significantly different between these 2 genotypes.