麻醉药物代谢酶CYP450酶系基因组学研究进展

遗传多态性是造成个体对药物反应差异的重要因素之一，其中CYP450酶系的基因多态性可能导致种族间及个体间对同一底物代谢能力的不同。现就镇静安定药、吸入麻醉药、局麻药、镇痛药的药物效应与CY450基因多态性的相关性进行综述，为临床个体化给药，实现个体优化治疗提供新思路。     

麻醉药物代谢酶CYP450酶系基因组学研究进展

遗传多态性是造成个体对药物反应差异的重要因素之一,其中CYP450酶系的基因多态性可能导致种族间及个体间对同一底物代谢能力的不同.现就镇静安定药、吸入麻醉药、局麻药、镇痛药的药物效应与CYP450基因多态性的相关性进行综述,为临床个体化给药,实现个体优化治疗提供新思路.     

麻醉药物代谢酶CYP45O酶系基因组学研究进展

遗传多态性是造成个体对药物反应差异的重要因素之一,其中CYP4 5 0酶系的基因多态性可能导致种族间及个体间对同一底物代谢能力的不同。现就镇静安定药、吸入麻醉药、局麻药、镇痛药的药物效应与CYP4 5 0基因多态性的相关性进行综述,为临床个体化给药,实现个体优化治疗提供新思路。     

疼痛与基因的研究进展

随着疼痛研究的不断深入,更多与疼痛相关的基因被发现,这使得人们对疼痛与基因的关系有了更深刻的了解。近年来,人们发现基因多态性,尤其是单核苷酸多态性（single nucleotide polymorphism, SNP）是导致个体疼痛差异的重要原因,而这些差异又与离子通道、神经递质、作用受体以及药物代谢酶等不同层面上的...     

肾细胞癌患者VEGFR3基因及CYP3A5*1基因单核苷酸多态性研究

目的:分析VEGFR3基因及CYP3A5*1基因单核苷酸多态性(SNP)在肾癌人群的分布特征,评价其与舒尼替尼药物治疗疗效及耐受性的相关性。方法:2012年6月~2013年6月,对198例肾癌患者进行外周血VEGFR3(rs307826)及CYP3A5*1(rs776746)位点的SNP检测,同时采集患者的自然信息、临床资料、治疗经过及预后。应用统计学方法评价中国人群与欧洲人群这两个基因位点SNP分布差异以及两个基因位点的SNP特征与舒尼替尼治疗晚期肾癌的疗效及耐受性的相关性。结果:VEGFR3(rs307826)位点SNP检测结果:野生型纯合子196例、杂合子2例;CYP3A5*1(rs776746)位点SNP检测结果:野生型纯合子115例、杂合子80例,与欧洲人群分布特征的差异有统计学意义(P0.01)。45例患者接受舒尼替尼药物治疗,CYP3A5*1(rs776746)SNP结果:野生型纯合子27例、杂合子18例,舒尼替尼初始剂量均为50mg/d,4/2周给药方案,主要不良反应包括高血压、血小板减低、白细胞减低、甲状腺功能低下等,Ⅲ~Ⅳ级不良反应发生率28.9%,15例患者因不良反应进行了剂量调整。结论:VEGFR3基因及CYP3A5*1基因的SNP分布特征在不同种族存在显著差异,CYP3A5*1(rs776746)位点SNP特征与中国肾癌患者接受舒尼替尼治疗的Ⅲ~Ⅳ级不良反应发生率及药物减量风险相关。     

肾病综合征药物反应差异与相关细胞色素P450酶遗传机制的研究进展

为揭示肾病综合征在治疗过程中个体间药物反应差异的机制，阐明CYP450酶遗传变异与药物代谢的基本规律和个体差异的作用，本文综述了几种CYP450同工酶的基因结构、多态性、底物及诱导等方面的研究进展。     

IL-28B单核苷酸基因多态性与CHB干扰素疗效的相关性

目的：探讨IL-28B单核苷酸基因多态性与慢性乙型肝炎（CHB）干扰素疗效的相关性。方法选取300例HBeAg阳性CHB患者，给予聚乙二醇化干扰素α（Peg-INF-α）规范治疗48周后以PCR法对IL-28B SNP rs12979860及IL-28B SNP rs8099917基因分型进行检测。结果治疗后HBV DNA定量、ALT、AST水平明显较治疗前下降（P＜0.05），HBeAg转移率53.13%，随访1年后应答率49.44%；Peg-INF-α应答患者与非应答患者IL-28B SNP rs12979860基因型CC、CT、TT分布及等位基因C、T频率比较差异无统计学意义（P＞0.05），IL-28B SNP rs8099917基因型TT、TG分布及等位基因T、G频率比较差异具有统计学意义（P＜0.05）。结论 IL-28B SNP rs8099917可能对干扰素治疗的应答反应性形成影响，其中等位基因G的频率升高可能提示着干扰素的成功应答，因而检测IL-28B SNP rs8099917对干扰素治疗的CHB患者治疗疗效有一定预测价值。     

基因单核苷酸多态性与肝癌肝移植术后复发的研究进展

肝癌移植术后肿瘤复发是影响肝移植远期预后重要的因素。病理学与基因组学发现术后肿瘤的复发是多因素、多步骤、多种基因调控的复杂生物过程。肝移植术后肿瘤复发的病理学相关研究国内外已有较多的文献报道,但是基因组学的研究相对较少。近几年研究发现基因单核苷酸多态性(SNP)与多种肿瘤发展密切相关。本文对基因SNP与肝癌移植术后术后肿瘤复发的关系进行综述。     

良性前列腺增生的基因多态性研究进展

良性前列腺增生(BPH)是泌尿系统的常见病和多发病之一。单核苷酸基因多态性(SNP)是基因组中最常见的变异。SNP对人群间BPH发病、进展和预后的不同产生影响。本文分析了已有的与BPH有关的SNP相关研究的文献,对不同的SNP在BPH发生发展所起的作用进行了阐述,对目前研究的现状、所存在的问题以及临床应用的前景进行了总结展望。     

生物信息学(5):药物设计与生物信息学

药物基因组学（pharmacogcnomics）是20世纪90年代末发展起来的基于功能基因组学（functional genomics）与分子药理学的一门科学。它从基因水平研究基因序列的多态性与药物效应多样性之间的关系。即研究基因本身及其突变体对不同个体药物作用效应差异的影响，并以此为平台开发药物．指导合理用药，提高用药的安全性和有效性。避免不良反应。减少药物治疗的费用和风险。     

Sodium cyanide antagonism of the vasodilator action of sodium nitroprusside in theisolated rabbit aortic strip

Resistance to sodium nitroprusside (SNP) is uncommon, but its occurrence has led to massive overdoses of SNP and sometimes death. To examine the mechanism responsible for resistance, aortic smooth muscle strips were prepared and dose-response curves for norepinephrine (NE) obtained. SNP alone caused a shift of the dose-response curve for NE to the right. However, this shift was less when the strips were exposed to both SNP and sodium cyanide (CN-). When CN- alone was added to the aortic strips, the response to NE was unchanged. In a further group of aortic muscle strips first contracted with NE and then relaxed with SNP, the addition of CN- caused the muscles to contract again. It is concluded that CN- antagonizes the action of SNP in vitro, and that this antagonism is specific for SNP.     

腰椎间盘退变性疾病与COL9A2基因多态性的关系

目的 探讨COL9A2基因多态性与腰椎间盘退变性疾病(DDD)的关系.方法 采用"病例-对照"研究方法:125例中国汉族DDD患者(DDD+)与126例中国汉族非DDD受访者(DDD-),用SNP分型系统-SNPstream UIT(Cenotyping System)对所有样本的所选SNP位点行基因型鉴定.对检测数据分别行拟和优度x2检验、基于等位基因频率/基因型的关联分析.结果 共筛查SNPl(rs12722877)、SNP2(rs3737820)、SNP3(rs209914)和SNP4(rs6676013)4个位点.病例组中和对照组中,两个位点的基因型分布均符合Hardy-Weinberg平衡;病例/对照组中等位基因频率分别为:SNP1C=228(91%)/22(9%)、SNP1G=235(93%)/17(7%),SNP2A=214(86%)/36(14%)、SNP2T=223(89%)/27(11%),SNP3A=237(95%)/13(5%)、SNP3C=238(94%)/14(6%),SNP4C=30(12%)/220(88%)、SNP4T=26(10%)/226(90%),差异无统计学意义(P＞0.05).病例/对照组中基因型频率差异无统计学意义(P＞0.05).结论 COL9A2基因可能不是决定中国汉族人群腰椎DDD的主要危险因素.

Abstract：

Objective To investigate the association between COL9A2 gene polymorphism with lumbar degenerative disc disease (DDD) in Chinese Han population. Methods A total of 125 DDD patients (58 males and 67 femals, aged 51.8 + 10. 6), and 126 controls matched in sex and age (64 males,62 femals, aged 45.7 + 8. 2) were recruited in the case-control study. Peripheral blood was collected for DNA isolation. Results Based on NCBI Genebank, corresponding single nucleotide polymorphisms-SNP1 ( rs12722877), SNP2 ( rs3737820), SNP3 (rs209914) and SNP4 (rs6676013) were identified. Hardy-Weinberg equilibrium was analyzed in both case and control groups. Genotying of all selected SNPs was done by SNPstream technology. The association analysis between phenotyepes and SNPs was conducted.Reslults NPI (rs12722877), SNP2 (rs3737820), SNP3 (rs209914) and SNP4 (rs6676013) were genttyped, and the polymorphisms distributed in line with Hardy-Weinberg equilibrium in case and contral groups. There was no significant difference in allele frequency of SNP1C, SNPIG, SNP2A, SNP2T,SNP3A, SNP3C, SNP4C and SNP4T between case group (91%, 93%, 86%, 89%, 95%, 94%, 12%,and 10%, respectively) and control group (9%, 7%, 14%, 11%, 5%, 6%, 88%, and 90% respectively). No significant difference in genotype frequencies of SNP was found between case group and control group, too (all P＞0.05). Conclusion COL9A2 gene may not be associated with lumbar DDD in ChineseHan population.     

Effect of intraventricular sodium nitroprusside on cerebral hemodynamics and oxygenation in poor-grade aneurysm patients with severe, medically refractory vasospasm

OBJECTIVE: Sodium nitroprusside (SNP) was recently suggested as a treatment for cerebral ischemia in patients with severe, medically refractory vasospasm after subarachnoid hemorrhage. In this study, we sought to objectify the effect on cerebral hemodynamics and oxygenation (PbrO2) when using intraventricular SNP as a last resort therapy in poor-grade patients with subarachnoid hemorrhage; severe, medically refractory vasospasm; and compromised cerebral blood flow. METHODS: Thirteen of 185 consecutive patients with subarachnoid hemorrhage developed severe, medically refractory vasospasm and were treated with intraventricular SNP. All of these patients' neurological conditions were classified as Hunt and Hess Grade IV. SNP doses ranged from 10 to 40 mg with single-dose treatment and from 2 to 8 mg/h with continuous infusion. Angiography or PbrO2 measurement was used to assess the treatment effects. RESULTS: In 6 of the 13 patients, SNP improved cerebral hemodynamics, as demonstrated by increased PbrO2 or decreased cerebral circulation time. Only 1 patient showed increased diameter of the spastic vessel, however. Maximum increase in PbrO2 ranged from 5 to 52 mmHg. Adverse effects were hypertension in five patients, vomiting in three patients, and cardiac arrhythmia in one patient. Cerebral infarctions caused by vasospasm occurred in 6 (46%) of the 13 patients. No differences between SNP responders and SNP nonresponders were noted. CONCLUSION: In patients with severe, medically refractory vasospasm, intraventricular SNP may improve PbrO2 and cerebral blood flow, but the effect is highly variable. On the basis of the improvements we observed in 6 of 13 patients, intraventricular SNP administration is justified as a last resort therapy in patients with cerebral ischemia and impending infarction. Our findings suggest that SNP may be more effective when initiated early and administered continuously.     

Comparison of isradipine with nitroprusside for control of blood pressure following myocardial revascularization: effects on hemodynamics, cardiac metabolism, and coronary blood flow

The effects of isradipine (ISR) on cardiac performance, myocardial metabolism, and coronary blood flow were compared with those of sodium nitroprusside (SNP) when used to control blood pressure following myocardial revascularization. Twenty patients were randomized to receive either intravenous ISR or SNP if arterial blood pressure increased above 130 mm Hg systolic. Hemodynamic and metabolic parameters were studied using radial, pulmonary arterial, and coronary sinus catheters. Cardiac output and coronary blood flows were measured by thermodilution and blood was taken for calculation of myocardial oxygen consumption and lactate extraction. Electrocardiographic changes were recorded by Holter monitoring throughout the study. ISR and SNP both produced a satisfactory reduction in blood pressure accompanied by a decreased systemic vascular resistance (P less than 0.001). ISR infusion was associated with increases in cardiac output and stroke index (P less than 0.01), which were not apparent in the SNP group. Tachycardia occurred with SNP (P less than 0.01) but not with ISR therapy. Right and left ventricular stroke work indices and myocardial oxygen consumption were reduced with SNP. The ISR group showed unchanged myocardial oxygen consumption with increased right ventricular stroke work index. Coronary vascular resistance decreased (P less than 0.01) during ISR infusion but decreased only slightly in the SNP group. Great cardiac vein blood flow was significantly increased with ISR but not with SNP, resulting in a significant difference between the groups (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The interaction of sodium nitroprusside, hypotension, and isoflurane in determining cerebral vasculature effects

Eighteen mongrel dogs were anesthetized with isoflurane and prepared for determining cerebral blood flow (CBF, sagittal sinus outflow), cerebral metabolic rate (CMRO2), and ICP. Dogs were divided into three groups of six each. Group 1 dogs were maintained on 1 MAC isoflurane and, following control measurements (step 1), sodium nitroprusside (SNP) was infused to decrease mean arterial pressure (MAP) to 60 mmHg (step 2). After 20 min SNP was discontinued and a second control period of 20 min followed (step 3). Thereafter, SNP was repeated for 20 min as in step 2, but MAP was maintained by inflating a balloon in the descending aorta (step 4). SNP was again discontinued followed by a final 20 min control period (step 5). During SNP with hypotension (step 2) there was a significant 21% decrease in CBF and no change in ICP. During SNP with normotension (step 4) both CBF and ICP increased (16 and 39%, respectively). In group 2 dogs isoflurane was discontinued and a spinal anesthetic was administered. Thereafter, these dogs were studied as in group 1. The only significant change in these dogs was a 35% increase in ICP during SNP with normotension. Group 3 dogs were studied identically to group 2, but hypotension was induced with trimethaphan (TMP). There were no significant changes in these dogs. The authors conclude that SNP, in the absence of isoflurane, dilates capacitance vessels because ICP increased without a concomitant increase in CBF at normotension. In the presence of isoflurane, SNP dilates both capacitance and resistance vessels because ICP and CBF increased concomitantly at normotension.(ABSTRACT TRUNCATED AT 250 WORDS)     

常染色体DAZL基因单核苷酸多态性与男性不育相关性研究

目的:探讨常染色体DAZL基因单核苷酸多态性(SNP)与男性不育的关系。方法:收集东北地区男性不育症患者(不育组,n=144)和健康并已育有一子女的男性(生育组,n=53)精液标本,不育组按照WHO(1999)少、弱和畸形精子分类标准分成少弱畸形精子症组(n=17)、少弱精子症组(n=33)、弱畸形精子症组(n=13)、弱精子症组(n=54)和非少弱畸形精子不育症组(n=27),应用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)筛选SNP260多态性,应用聚合酶链反应-单链构象多态性分析(PCR-SSCP)筛选SNP386多态性,并测序验证和进行统计学分析。结果:不育组及生育组中均检测到SNP260A→G多态性,统计学分析差异无显著性(P>0.05),但在少弱畸形精子症组SNP260AG基因型比例大于其他各组;各研究组均未发现SNP386多态性。结论:SNP260和SNP386多态性与中国东北地区男性不育无相关性。前者AG基因型与少弱畸形精子的关系尚需进一步证实;后者多态性可能仅分布在台湾的一些狭小地区,两者均不能作为东北地区男性不育基因诊断的分子标志。     

Sodium Nitroprusside as a Hypotensive Agent in Intracranial Aneurysm Surgery

Sodium nitroprusside (SNP) was used to induce hypotension during intracranial aneurysm surgery in 67 patients. The effects of SNP infusion (0.1 mg/ml) on blood pressure were rapid and it was easy to adjust blood pressure to desired levels in most patients. When SNP was stopped, the blood pressure returned instantly to the initial level. In eight patients an increase to about 25% or more above prehypotensive level was seen, counteracted in two patients by administration of small doses of halothane. There was a mean increase of 36% in heart rate. Total doses of SNP were 0.05--120 mg (mean: 10.8), corresponding to 0.08--6.8 micrograms/kg/min (mean: 1.9). No metabolic acidosis indicating cyanide intoxication was observed. Tachyphylaxis was seen in three patients, and SNP had to be discontinued in one. It is concluded that SNP gives a rapid and effective hypotension but tachyphylaxis and subsequent danger of cyanide intoxication exist. Therefore, in some cases SNP has to be replaced by or combined with some other hypotensive agent to achieve the desired effect. As there is a risk of impairment of cerebral autoregulation after the use of SNP, it is important to avoid sudden and prolonged blood pressure fluctuations, and to continue with controlled hyperventilation in the postoperative period to reduce the risk of brain oedema and high intracranial pressure.     

The effect of a nitric oxide donor on endogenous endothelin-1 expression in renal ischemia/reperfusion injury

The balance between nitric oxide (NO) and endothelin-1 (ET-1) production is essential to the vascular function that controls organ perfusion. Elevated ET-1 levels in the peritubular capillary network following renal transplantation may be associated with renal allograft rejection. Administration of a nitric oxide donor during the preischemic period has been shown to protect kidney against ischemia-reperfusion injury, but the mechanism underlying this therapeutic benefit remains incompletely understood. We hypothesized that early administration of the NO donor sodium nitroprusside (SNP) may suppress ET-1, thereby improving renal function in an ischemia/reperfusion injury. Sprague-Dawley rats were subjected to 60 minutes of renal warm ischemia and contralateral nephrectomy. Renal biopsies were performed prior to ischemia and reperfusion, and at 1 hour and 48 hours after reperfusion. The animals were divided into four groups: sham group without warm ischemia; early SNP group (SNP given before ischemia); late SNP group (SNP given before reperfusion); and ischemic control. ET-1 expression was assessed by semiquantitative analysis with immunohistochemical stain using ET-1 monoclonal antibody and hematoxylin-eosin staining. Serum creatinine was measured at 48 hours after reperfusion. There were significant improvements in all parameters of the early compared with the late SNP group and the ischemic control, but there was no difference between the late SNP group and the ischemic control. These data suggest that early administration of SNP in renal ischemia-reperfusion improves renal function by suppressing ET-1 expression.     

前列腺素E1与硝普钠控制性降压对犬血流动力学影响的对比研究

对比研究了普鲁卡因复合麻醉下前列腺素Ｅ１（ＰＧＥ１）与硝普钠（ＳＮＰ）控制性降压时犬血流动力学变化。结果表明，ＳＮＰ降压组有显著的反射性心动过速和反跳性高血压，ＰＧＥ；降压组两者均无。ＰＧＥ１降压时心指数、肺动脉压等其它血流动力学参数亦比ＳＮＰ稳定，提示在保证心肌氧供求平衡及防止血管意外方面ＰＧＥ１降压优于ＳＮＰ。     

A comparison of nitroglycerin and nitroprusside for inducing hypotension in children: a double-blind study

Intravenous nitroglycerin (NTG) and sodium nitroprusside (SNP) were compared as hypotensive agents in anesthetized children and adolescents. The drugs were studied in a prospective, randomized, double-blind fashion in 14 patients anesthetized with nitrous oxide: oxygen, morphine, and thiopental. NTG in doses as high as 40 micrograms X kg-1 X min-1 was ineffective at decreasing mean arterial pressure (MAP) below 55 mmHg or causing a decrease in MAP greater than one-third of baseline values. SNP was uniformly successful at inducing hypotension in all patients, including those patients in whom NTG failed. The dose of SNP required to induce hypotension was 6-8 micrograms X kg-1 X min-1. Both NTG and SNP decreased systemic vascular resistance, although SNP did so to a much greater degree than NTG (64% vs. 29%; P less than 0.01). Only SNP increased cardiac index significantly (2.27 +/- 0.35 to 4.44 +/- 1.36; P less than 0.003). Both drugs reflexly increased heart rate, necessitating the use of intravenous propranolol (range from 1 to 3 mg) in all patients. Both drugs produced small decreases in arterial oxygen tension and increases in the average alveolar-arterial oxygen tension gradient (SNP, 44 +/- 13 vs. NTG, 41 +/- 6). SNP use was associated with a slight metabolic acidosis (pH = 7.38 +/- 0.01; base excess [BE] = -6 +/- 1). Neither drug produced any other untoward reaction. SNP appears to be the agent of choice for the reliable and sustained induction of deliberate hypotension in children and adolescents.