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。     

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。     

肾移植术后糖尿病的遗传药理学

本综述介绍了肾移植术后糖尿病(PTDM)的遗传药理学特点, 对肾移植术后糖尿病患者与胰岛素抵抗和胰岛素的分泌相关易感基因的关键变异做了详细的描述。共挑选出与PTDM发生密切相关的16个基因的20个单核苷酸多态性(SNP)位点并逐一阐述, 以期为PTDM的早期诊断与治疗提供实验依据。     

代谢酶基因多态性与胰腺癌易感性研究进展

代谢酶基因多态性与肿瘤的关系是近来国内外研究的热点。代谢酶基因多态性使酶的活性发生改变,是胰腺癌遗传易感性的重要机制。现综述了与胰腺癌癌变过程中有关的代谢酶基因多态性与其易感性的关系。     

精子特异性表达基因的遗传多态性与男性不育

精子发生需要精子特异基因的表达,这些特异表达基因的遗传多态性可能影响精子的发生,导致男性不育。国内外学者已对精子发生特异表达的一些候选基因进行多态性研究,分析其多态性与不育的相关性及其可能的致病机制,进一步从基因角度阐明不育的病因。本文对于精子发生相关的基因多态性研究进展做一综述。     

生精障碍相关基因单核苷酸多态性研究进展

生精相关基因遗传多态性是生精障碍的一个重要的遗传病因.通过基因敲除技术现已鉴定出大量与精子发生密切相关基因.此类生精障碍基因包括表达酶类、受体类、细胞凋亡类、转录调控类等基因.上述基因的遗传易感性、感染和环境等因素共同作用导致男性非梗阻性无精子症和少精子症.生精障碍相关基因单核苷酸多态性(SNP)分析可从分子水平上阐述...     

他克莫司转运蛋白基因多态性在器官移植中的研究进展

他克莫司(Tac)是器官移植术后常用的免疫抑制剂,具有良好的免疫抑制效果,但Tac的药代动力学存在较大个体差异,其中基因多态性是主要的影响因素.近年来,药物转运蛋白基因多态性成为新的研究热点,但转运蛋白基因多态性对Tac药代动力学的影响尚存在争议,因此探讨转运蛋白基因多态性与Tac血药浓度的相关性对于指导Tac个体化免...     

雌激素受体α基因PvuⅡ、XbaⅠ遗传多态性与乳腺增生症的关系

目的探讨雌激素受体(ER)α基因PvuⅡ和XbaⅠ遗传多态性与乳腺增生症的相关性。方法应用聚合酶链反应-限制性片段长度多态性分析技术检测89例乳腺增生症患者(研究组)和35例健康体检者(对照组)ERα基因PvuⅡ和XbaⅠ遗传多态性。结果 ERα基因XbaⅠ位点的基因型频率及等位基因频率在研究组和对照组中的分布差异均有统计学意义(P<0.05),等位基因频率的相对风险分析,携带X等位基因者患乳腺增生症的风险是x等位基因的0.551倍;PvuⅡ位点的基因型频率及等位基因频率在研究组和对照组中的分布差异均无统计学意义(P>0.05)。结论 ERα基因XbaⅠ遗传多态性与乳腺增生症发病有关,突变基因增加了乳腺增生症的发病风险。     

细胞色素酶CYP3A4基因多态性研究进展

背景 药物代谢酶的基因多态性是导致药物在体内处置和反应存在明显个体差异的重要因素之一,而细胞色素酶P450家族的CYP3A4 (cytochrome P450 3A4)酶是药物及外源性物质的主要代谢酶.CYP3A4基因多态性是导致这些药物代谢个体差异的主要原因.目的 就CYP3A4基因多态性对药物代谢的影响作一综述.内容 CYP3A4主要分布于肝脏和小肠内,其基因结构、酶活性的个体差异以及遗传多态性的种族差异,是导致药物作用和副作用个体差异的主要原因,甚至与许多疾病包括肿瘤等的发病有关.趋向 对CYP3A4基因多态性的研究将有助于提高药物疗效,避免副作用发生,预防和治疗某些疾病尤其是肿瘤等疾病.     

Antiepileptic treatment in cerebral lesions: what are the indications and the main practical use?

The aim of this report is to review the indication and the practical use of the antiepileptic drugs in patients with cerebral lesions. The use of antiepileptic drugs to treat seizure or status epilepticus in an emergency is well catalogued and reported in this paper. Practical use of antiepileptic drugs, after a first seizure or to prevent a seizure, in patients with a cerebral lesion, is controversial. The question of antiepileptic drugs in seizures and in prophylaxis is discussed in different types of cerebral lesions: head injury, stroke, cerebral arteriovenous malformation and cerebral tumour.     

Perioperative exacerbation of valproic acid-associated hyperammonemia: a clinical and genetic analysis

We present a case of significant deterioration of chronic hyperammonemia after general anesthesia for neurosurgery despite aggressive treatment. Preoperative evaluation demonstrated that hyperammonemia was most likely related to valproic acid treatment. Genomic analysis revealed that the patient was heterozygotic for a missense polymorphism in the carbamoyl phosphate synthase 1 gene (4217C>A, rs1047891). This mutation was previously suggested to be associated with chronic hyperammonemia. Replacement of threonine with asparagine decreases the activity of carbamoyl phosphate synthase in the urea cycle. Genetic screening can potentially identify a population at risk before initiation of antiepileptic therapy.     

Using new antiepileptic drugs as monotherapy

Opinion statement Since 1993, with the advent of felbamate, physicians have been blessed with the addition of eight new antiepileptic medications for the treatment of epilepsy. Increasing evidence is accumulating that these drugs are effective as monotherapy agents. The use of monotherapy minimizes side effects, and newer drugs have fewer interactions than many of the older antiepileptic medications with comparable efficacy. Using the newer antiepileptic agents in monotherapy, even as an initial therapy would appear to be an appropriate clinical decision.     

Unruptured intracranial aneurysms: seizures and antiepileptic drug treatment following surgery

Twenty-one patients operated on for unruptured intracranial aneurysms were studied retrospectively in order to identify the incidence of postoperative seizures, factors predictive of seizures, and the response to discontinuation of antiepileptic drugs. The overall risk of postoperative seizures in initially seizure-free patients was 15.7%. Although seizures were not uncommon, antiepileptic drugs were successfully tapered in most of the patients before 12 months.     

Unusual presentation of altered bone metabolism with long-term antiepileptic therapy: pathological fracture of neck of femur due to brown tumor at calcer

The antiepileptic drugs are known to alter the bone metabolism and result in various range of pathological conditions (osteoporosis, osteomalacia, vitamin D deficiency, secondary hyperparathyroidism). These clinical conditions developed either due to direct effect of these therapeutic agents on bone or due to alteration in the homeostasis of other regulators of bone metabolism like serum calcium, vitamin D, and parathyroid hormone. Long-term therapy with antiepileptic agents results in higher incidence of pathological fracture, which is a consequence of either osteoporotic or osteomalasic (secondary to vitamin D deficiency) changes in bone produced by these drugs. Secondary hyperparathyroidism due to vitamin D deficiency following long-term polytherapy of antiepileptic drug ultimately leading to development of brown tumor and pathological fracture is very unusual.     

氯胺酮治疗难治性癫痫持续状态的研究进展

背景 难治性癫痫持续状态(refractory status epileptieus,RSE)发病机制不明,具有高致残率和致死率.大量研究发现氯胺酮对RSE具有良好的治疗效果.目的 综述RSE发病机制、氯胺酮用于治疗RSE的研究进展以及其副作用的防止策略,为氯胺酮的临床应用提供参考.内容 RSE的发病机制主要与γ-氨基丁酸(γ-aminobutyric acid,GABA)受体的变化、谷氨酸(glutamine,Glu)过量释放等有关.氯胺酮复合用药能够安全有效地终止RSE发作.趋向 氯胺酮复合用药早期介入RSE的治疗可能改善其结局,其远期应用前景尚需进一步研究.     

Cytochrom-P450-Enzyme und ihre Bedeutung für Medikamenteninteraktionen

One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorised as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic, or combined toxicity. Knowledge of the mechanism by which a given drug interaction occurs is often clinically useful and may help to avoid serious adverse events and perioperative morbidity. Although every tissue has some ability to metabolise drugs, the liver is the principal organ of drug metabolism and at the subcellular level the cytochrome P450 enzyme system is the main source of drug interaction. This article reviews the basic principles of drug metabolism and the role of cytochrome P450 in this scenario. Drugs frequently used in anaesthesia and critical care medicine such as benzodiazepines, opioid analgesics, antihypertensive and antiarrhythmic agents, antibiotics and antifungal drugs, antiemetics, histamine-receptor-antagonists, theopylline and paracetamol will be considered. The development of methods and tools which are practical and also economic, are of utmost importance since drug interaction is predictable if the metabolic pathway and the activity (genetic polymorphism) of the enzyme is known.     

Specificities of the epileptic women (oral contraceptives, pregnancy)

The enzyme-inducing antiepileptic drugs such as carbamazepine, phenytoin, barbiturates, oxcarbazepine do not allow oral contraceptives. The pregnancy must be planned. Every patient in childbearing age should be informed by her practitioner. The rule is to optimize the antiepileptic treatment before the pregnancy: less drugs, less dosages. This optimization will depend on the epileptic syndrome and the nature of the treatment. Valproate of sodium should be avoided, if possible, during pregnancy. Preconceptional supplementation by folic acid should be considered. Antiepileptic drugs monitoring is required during pregnancy. Natural delivery with peridural anaesthesiology is mandatory. The breast feeding must be considered individually.     

Impacto de diferentes medicamentos antiepilépticos na sedação de crianças durante a ressonância magnética

Background and objectives

The induction and inhibition of cytochrome P450 isoenzymes by antiepileptic drugs lead to changes in the clearance of anesthetic drugs eliminated via hepatic metabolism. We investigated the duration of the sedation and additional anesthetic needs during magnetic resonance imaging in epileptic children receiving antiepileptic drugs that cause either enzyme induction or inhibition.

Methods

In American Society of Anesthesiology I–II, 120 children aged 3–10 years were included. Group 1: children using antiepileptic drugs that cause cytochrome P450 enzyme induction; Group 2: those using antiepileptic drugs that cause inhibition; and Group 3: those that did not use antiepileptic drugs. Sedation was induced with the use of 0.05 mg kg⁻¹ midazolam and 1 mg kg⁻¹ propofol. An additional 0.05 mg kg⁻¹ of midazolam and rescue propofol (0.5 mg kg⁻¹) were administered and repeated to maintain sedation. The duration of sedation and the additional sedation needed were compared.

Results

The duration of the initial dose was significantly shorter in Group I compared with groups II and III (p = 0.001, p = 0.003, respectively). It was significantly longer in Group II compared with groups I and III (p = 0.001, p = 0.029, respectively). The additional midazolam needed for adequate sedation was increased in Group I when compared with groups II and III (p = 0.010, p = 0.001, respectively). In addition, the rescue propofol dose was significantly higher only in Group I when compared with Group III (p = 0.002).

Conclusion

In epileptic children, the response variability to the initial sedative agents during the magnetic resonance imaging procedure resulting from the inhibition or induction of the cytochrome P450 isoenzymes by the antiepileptic drugs mandated the titration of anesthetic agents.