丙戊酸钠基因组学的研究进展

丙戊酸钠是临床常用广谱抗癫痫药物。该药治疗窗窄、代谢个体差异大,体内代谢受多种因素影响,其中,药物代谢酶的遗传多态性是影响该药代谢的重要因素。通过查阅相关文献,总结了基因组学对丙戊酸钠临床用药的影响,为丙戊酸钠临床个体化给药提供参考。     

丙戊酸钠在癫痫患者中的群体药动学

目的建立丙戊酸钠在癫痫患者治疗中的群体药动学模型,为临床个体化给药提供参考。方法收集我院门诊60名癫痫患者丙戊酸钠稳态血药浓度监测数据和相应的人口学数据,应用非线性混合效应模型(non linearm ixed-effectmodel,NONMEM)程序对收集的数据进行分析,建立群体药动学模型。结果建立了癫痫患者口服丙戊酸钠群体药代动力学模型:CL/F=0.959×1.04x,(x=0,1),V/F=1.35,ka=2.38 h-1,说明丙戊酸的清除率与患者性别相关,即男性患者的清除率大于女性。结论初步建立癫痫患者口服丙戊酸钠群体药动学模型,为丙戊酸钠个体化用药提供理论基础。     

临床应用丙戊酸钠治疗小儿癫痫分析

目的:分析和探讨合理应用丙戊酸钠治疗小儿癫痫。方法:根据丙戊酸钠药代学和药动学特点,并结合临床药师参与的丙戊酸钠治疗小儿癫痫的实际案例,对丙戊酸钠治疗小儿癫痫的合理应用进行分析和阐述。结果:根据患儿具体生理、病理情况选择给药剂量,综合分析和避免治疗方案中的药物相互作用,以血药浓度监测结果为依据,及时调整药物及剂量,制定动态、合理的个体化给药方案及用药监护,使丙戊酸钠治疗小儿癫痫的临床应用更加安全、有效。结论:临床应用丙戊酸钠时应考虑各种相关因素,制定个体化给药方案,避免药物间相互作用;开展药学监护,有效促进丙戊酸的合理应用。     

抗癫痫药的群体药代动力学与CYP450基因多态性的研究进展

抗癫痫药代谢的个体差异较大，需要个体化用药。群体药代动力学的研究是设计个体化治疗方案的有效方法。国内外对新老抗癫痫药的群体药代动力学进行了广泛研究，分析了一般生物学特征对药物代谢的影响。CYP450基因多态性是影响抗癫痫药物代谢的主要遗传因素，是个体差异的重要原因。目前，已有研究将CYP450基因多态性的因素引入群体药代动力学的模型，将其对抗癫痫药物代谢的影响进行了量化，并且，可以依据不同的基因型选择不同的初始剂量，促进个体化治疗，取得了新的进展。但是，有项研究提示基因多态性对群体药代动力学（PPK）参数的影响没有统计学意义。因此，目前的结论尚不完全一致，需要进一步研究。     

UGT基因多态性对丙戊酸药动学影响研究

癫痫是慢性反复发作性短暂脑功能失调综合征,是神经系统常见疾病之一。丙戊酸(valproate acid,VPA)是一线抗癫痫药物,具有疗效好、起效快、复发率低等优点。但在临床应用中个体差异较大。丙戊酸在体内大部分经尿苷二磷酸葡萄糖醛酸基转移酶(UDP-glucuronosyltransferase,UGT)代谢。现综述UGT基因多态性对丙戊酸代谢影响的研究情况,为临床丙戊酸的个体化用药提供参考。     

美罗培南个体化给药的研究进展

美罗培南作为第二代碳青霉烯类抗生素往往是治疗严重感染的最后选择,其个体化给药的研究近年来备受关注.药代/药效学(PK/PD)参数可用于优化美罗培南给药方案,但美罗培南的体内代谢和消除受多种因素影响,因此需进行群体药代动力学(PPK)研究以更好地表证个体差异.利用PPK模型,结合患者个体资料、病原菌最低抑菌浓度(MIC)和临床药效学参数可实现美罗培南的个体化给药,从而在保证疗效的前提下避免治疗过度.本文就近年来美罗培南个体化给药的研究进展作一综述.     

基因多态性与丙戊酸的药物代谢

丙戊酸(valproate,VPA)是对多种发作类型有效的一线广谱抗癫痫药,同时也用于精神疾病的治疗。但由于其体内药代动力学过程复杂,药物代谢的个体差异大,使得其应用复杂,难以掌握。另外,长期使用VPA对消化系统、肝脏及血液系统均有潜在的毒副作用,甚至发生急性肝坏死,也使其安全性     

丙戊酸钠的合理应用简述

目的概述丙戊酸钠的合理应用,减少其药品不良反应的发生。方法对国内近期相关文献进行分析归纳,并结合实际工作经验,阐明避免丙戊酸钠不良反应发生的相关因素,总结出最佳个体化给药方案。结果丙戊酸钠在血药浓度超过120μg/mL时,可出现消化不良等不良反应,与服药时间、剂型及制剂质量等因素有关。结论临床应用时应考虑多种相关因素,采用个体化给药,以减少丙戊酸钠不良反应的发生。     

儿童丙戊酸血药浓度与剂量疗效关系及临床意义探讨

目的 :分析临床癫痫患儿丙戊酸血药浓度与服药剂量、年龄的相关性 ,通过对治疗药物监测有助于个体化给药、鉴别诊断和了解患儿的依从性 ,以便更好地发挥抗癫痫药的作用。方法 :采用荧光偏振免疫分析法 (TDxFLx仪 )测定儿童丙戊酸血药浓度153 3例 /次 ,将患儿的药历等详细资料逐一录入数据库 ,利用SPSS 10 0forWindows软件辅助分析。结果 :不同年龄儿童丙戊酸血药浓度与剂量有一定的差异 ,体内的代谢过程个体差异较大。结论 :抗癫痫治疗的血药浓度不必过分强调低限     

癫痫患儿丙戊酸钠血药浓度监测结果回顾分析

目的探讨癫痫患儿丙戊酸钠血药浓度与临床疗效、给药剂量、药物剂型、性别、年龄和体质量的相关性。方法回顾性查阅我院临床药学室337例癫痫患儿丙戊酸钠血药浓度监测记录,将浓度值、性别、年龄等资料录入数据库,利用SPSS 13.0软件进行分析处理。结果癫痫患儿丙戊酸钠血药浓度值与性别不存在明显的相关性,但与临床疗效、给药剂量、药物剂型、年龄和体质量密切相关。结论丙戊酸钠在患儿体内的代谢过程存在一定的个体差异性,应根据每位患儿自身的具体情况并结合血药浓度监测结果来制订个体化给药方案。     

丙戊酸中毒临床救治的文献分析

丙戊酸是一线广谱抗癫痫药物,可单药或联合用药治疗各种类型癫痫,对双向情感障碍也有较好的疗效,临床应用广泛。丙戊酸呈非线性药代动力学特点,安全范围窄,个体差异大,常规需要监测血药浓度。近年来,多有丙戊酸中毒的报道,但关于其中毒的解救,尚无标准的方案。本文回顾性分析了1980-2019年文献报道的有关丙戊酸中毒的病例及相关指南推荐,从体外循环、卡尼汀补充及与碳青霉烯类药物相互作用3个方面,讨论了丙戊酸中毒的救治,旨在为临床治疗提供参考。     

A multivariable analysis of factors governing the steady-state pharmacokinetics of valproic acid in 52 young epileptics

A number of factors have been implicated in the interpatient variability of valproic acid (VPA) pharmacokinetics. These include patient age, concurrent anticonvulsant therapy, and dosage of VPA. In the clinical setting, it is important to determine which of these variables exert a major effect on the observed differences in VPA disposition. Accordingly, we analyzed the data from 52 young epileptic patients using multivariate statistical methods. Concurrent anticonvulsant therapy was the major determinant of VPA clearance in this patient population. The half-life of VPA was significantly related to age, but volume of distribution and clearance were not. The dosage of VPA affected the volume of distribution of VPA but not the half-life or clearance of this drug. These results provide a more rational understanding of VPA pharmacokinetics in the clinical setting and have implications for the monitoring and manipulation of VPA therapy in the epileptic population.     

Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver

Valproic acid (VPA) is used clinically to treat epilepsy, however it induces hepatotoxicity such as microvesicular steatosis. Acute hepatotoxicity of VPA has been well documented by biochemical studies and microarray analysis, but little is known about the chronic effects of VPA in the liver. In the present investigation, we profiled gene expression patterns in the mouse liver after subchronic treatment with VPA. VPA was administered orally at a dose of 100 mg/kg/day or 500 mg/kg/day to ICR mice, and the livers were obtained after 1, 2, or 4 weeks. The activities of serum liver enzymes did not change, whereas triglyceride concentration increased significantly. Microarray analysis revealed that 1325 genes of a set of 32,996 individual genes were VPA responsive when examined by two-way ANOVA (P<0.05) and fold change (>1.5). Consistent with our previous results obtained using an acute VPA exposure model (Lee et al., Toxicol Appl Pharmacol. 220:45-59, 2007), the most significantly over-represented biological terms for these genes included lipid, fatty acid, and steroid metabolism. Biological pathway analysis suggests that the genes responsible for increased biosynthesis of cholesterol and triglyceride, and for decreased fatty acid beta-oxidation contribute to the abnormalities in lipid metabolism induced by subchronic VPA treatment. A comparison of the VPA-responsive genes in the acute and subchronic models extracted 15 commonly altered genes, such as Cyp4a14 and Adpn, which may have predictive power to distinguish the mode of action of hepatotoxicants. Our data provide a better understanding of the molecular mechanisms of VPA-induced hepatotoxicity and useful information to predict steatogenic hepatotoxicity.     

New perspectives of valproic acid in clinical practice

Introduction: Valproic acid (VPA) has been used in clinical practice as an anticonvulsant for more than four decades. Its pharmacokinetics and toxicity are thus well documented. VPA is also a potent class-selective histone deacetylase (HDAC) inhibitor at nontoxic therapeutic concentrations. New areas of application for VPA are currently opening up in clinical practice.

Areas covered: The authors discuss VPA and how it may serve as an effective drug for cancer therapy. This is due to its ability to induce differentiation of a number of cancer cells in vitro and also to decrease tumor growth and metastases in animal models. The authors highlight how the utilization of VPA as an HDAC inhibitor is not limited to a single-agent therapy. Early clinical studies have also revealed promising potency of VPA in combination treatment with classic anticancer drugs. The authors do this by summarizing the published results and providing insight into the potential future developments for this field.

Expert opinion: VPA was shown to restore or improve responsiveness of tumors to conventional therapeutic agents, to enhance the efficacy of adenoviral gene therapy, to sensitize TRAIL-resistant tumor cells to apoptosis, and to enhance radiosensitivity of tumor cells. Drawbacks in VPA medical applications include its teratogenicity and complexity of its effects.     

Teratogenicity of sodium valproate

The teratogenicity of the widely popular antiepileptic drug (AED) and mood stabiliser sodium valproate (also known as valproate, VPA) has been evidenced by previous research; however, these findings have often been limited by a small population sample of exposed women and a retrospective study design. Many factors contribute to the teratogenicity of VPA. These include the number of drugs that are co-administered, drug dosage, differences in maternal and/or infant metabolism, the gestational age of the fetus at exposure, and hereditary susceptibility. VPA has been associated with a variety of major and minor malformations, including a 20-fold increase in neural tube defects, cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrinological disorders, limb defects, and autism. It has been suggested that polytherapy treatment in epileptic pregnant women increases the risk of teratogenicity in offspring. Furthermore, there is an established relationship between VPA dose and adverse outcome. Large single doses of VPA potentially cause high peak levels in the fetal serum resulting in deleterious effects. Currently there is an increase in the number of national and international pregnancy registries being formed in an effort to better identify the teratogenic effects of AEDs. These efforts hope to enhance our understanding of AEDs and their associated risks by addressing past study limitations.     

Teratogenicity of sodium valproate

The teratogenicity of the widely popular antiepileptic drug (AED) and mood stabiliser sodium valproate (also known as valproate, VPA) has been evidenced by previous research; however, these findings have often been limited by a small population sample of exposed women and a retrospective study design. Many factors contribute to the teratogenicity of VPA. These include the number of drugs that are co-administered, drug dosage, differences in maternal and/or infant metabolism, the gestational age of the fetus at exposure, and hereditary susceptibility. VPA has been associated with a variety of major and minor malformations, including a 20-fold increase in neural tube defects, cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrinological disorders, limb defects, and autism. It has been suggested that polytherapy treatment in epileptic pregnant women increases the risk of teratogenicity in offspring. Furthermore, there is an established relationship between VPA dose and adverse outcome. Large single doses of VPA potentially cause high peak levels in the fetal serum resulting in deleterious effects. Currently there is an increase in the number of national and international pregnancy registries being formed in an effort to better identify the teratogenic effects of AEDs. These efforts hope to enhance our understanding of AEDs and their associated risks by addressing past study limitations.     

造血干细胞移植预处理药物白消安的群体药动学研究进展

白消安在临床中常用于异基因造血干细胞移植前预处理方案,然而,白消安体内吸收、分布、代谢、排泄在个体间差异较大,尤其在代谢过程中受到年龄、体重、基因多态性、昼夜节律和药物相互作用等多种因素影响,为临床预测白消安剂量增加了难度。研究表明,使用群体药动学（PPK）模型能良好地预测白消安的血药浓度,因此通过查阅国内、外相关文献,对相关文献进行分析、归纳、总结,为开展中国各群体中PPK研究提供思路,有助于提高白消安临床疗效、降低移植后并发症风险。     

丙戊酸钠个体化剂量预防复杂热性惊厥复发的研究

目的:通过对照研究的方法,探讨丙戊酸钠个体化治疗预防复杂热性惊厥复发的优越性.方法:将我院神经内科新诊断为复杂热性惊厥并愿服用丙戊酸钠治疗的患儿随机分为2组,其中实验组进行个体化剂量治疗,对照组使用经验性用药治疗,2组进行对照研究.结果:丙戊酸钠个体化给药预防热性惊厥复发达稳态时的血药浓度低;个体化治疗用药剂量较经验用...