稳态试验丙戊酸镁缓释片人体生物利用度的研究

目的　比较稳态下丙戊酸镁缓释片与普通片的相对生物利用度和药代动力学参数。方法　采用气相色谱(GC)法测定人体血中丙戊酸浓度。结果　达峰浓度Cmax 普通片为(69. 57±12.80)μg/ml,缓释片为(58.45±11.83)μg/ml;达峰时间Tmax普通片为(1.8±0.7)h,缓释片为(3.9±1.8)h;峰谷浓度普通片为(48.91±12.00)mg/ml,缓释片为(52.87±11.03)mg/ml,波动系数DF普通片为(37±9)%,缓释片为(10±4)%,Csavg普通片为(57.12±11.93)μg/ml,缓释片为(59.16±24.22)μg/ml,相对生物利用度为103.97%。结论　丙戊酸镁缓释片与其普通片比较具有缓释特征,血药浓度稳定,其生物利用度与其普通片剂相似。     

丙戊酸镁缓释片联合赛乐特片治疗脑卒中后抑郁

目的探讨丙戊酸镁缓释片辅助治疗脑卒中后抑郁的疗效。方法筛选出卒中后抑郁患者86例,随机分为治疗组(丙戊酸镁缓释片)和对照组各43例,治疗组:用丙戊酸镁缓释剂500mg/d,连用14d;赛乐特片20mg,每天早饭后顿服。对照组:单服赛乐特片20mg,每天早饭后顿服,对症处理(抗血小板聚集、改善循环、稳压、降糖)2组相同。结果丙戊酸镁缓释片组在治疗后6d,汉密尔顿(HAMD)抑郁量表评分开始下降,与治疗前比较差异有统计学意义(P<0.01);对照组在治疗后9d,HAMD评分开始下降,与治疗前比较差异有统计学意义(P<0.01)。2组疗效比较丙戊酸镁缓释片组有效率93.02%,对照组有效率79.07%,差异有统计学意义(P<0.01)。结论丙戊酸镁缓释片辅助抗抑郁药治疗卒中后抑郁效果更佳,起效时间早,不良反应少,故临床应用丙戊酸镁缓释片辅助治疗抑郁症,患者耐受性好,可以缩短病程,改善抑郁症状,解除患者病痛,效果令人满意。     

丙戊酸镁缓释片联合奥氮平治疗阿尔茨海默病的疗效观察

目的探讨丙戊酸镁缓释片联合奥氮平治疗阿尔茨海默病的临床疗效。方法阿尔茨海默病患者56例,随机分为观察组和对照组各28例,对照组给予奥氮平片治疗,观察组在对照组基础上加用丙戊酸镁缓释片,观察治疗前后患者BRMS评分和用药不良反应。结果治疗后2组不同时间BRMS评分均低于治疗前,差异具有统计学意义(P0.05);观察组治疗后1~4周末BRMS评分下降均优于对照组,差异具有统计学意义(P0.05);2组不良反应发生率差异无统计学意义(P0.05)。结论丙戊酸镁缓释片联合奥氮平治疗阿尔茨海默病疗效可靠,不良反应小,安全性好,值得临床推广应用。     

丙戊酸镁缓释片治疗精神分裂症的辅助作用

目的:探讨阿立哌唑合用丙戊酸镁缓释片治疗难治性精神分裂症患者的疗效及安全性。方法:60例难治性精神分裂症患者随机分为两组,分别给予阿立哌唑合用丙戊酸镁缓释片与阿立哌唑单用治疗,疗程8周。用阳性与阴性症状量表(PANSS)和治疗中出现的症状量表(TESS)评定疗效和不良反应。结果:阿立哌唑合用丙戊酸镁缓释片治疗难治性精神分裂症的疗效优于单用阿立哌唑(P<0.05);两组不良反应差异无统计学意义(P>0.05)。结论:阿立哌唑合用丙戊酸镁缓释片治疗难治性精神分裂症疗效好,安全性好。     

丙戊酸镁缓释片对精神分裂症暴力攻击行为的疗效观察

目的:探讨丙戊酸镁缓释片联合抗精神病药治疗精神分裂症暴力攻击行为疗效及安全性.方法:将64例有暴力攻击行为的精神分裂症患者随机分为两组,丙戊酸镁缓释片联合抗精神病药组(合用组)32例,单用抗精神病药组(单用组)32例治疗4周.采用简明精神病量表(BPRS)、外显攻击行为量表(MOAS )和治疗中出现的症状量表(TESS...     

奥氮平合并丙戊酸镁缓释片治疗双相躁狂发作临床研究

目的 观察奥氮平与丙戌酸镁缓释片联合治疗双相躁狂发作的疗效及安全性.方法 将48例双相躁狂发作患者随机分为两组,各24例,研究组给予奥氮平与丙戊酸镁缓释片联合治疗,对照组单用丙戊酸镁缓释片治疗,观察8周,治疗前和治疗后第1、2、4、8周丰分别予以Bech-Rafae1sen躁狂量表(BR MS)、临床疗效总评量表(CGI)和治疗中出现的症状量表(TESS)评定病情的严重程度、疗效和不良反应进行比较.结果 两组患者治疗后的BRMS及CGI总分均低于治疗前(P＜0.01);两组惠者治疗后第1、2周末BRMS、CGI总分差异有统计学意义,研究组低于对照组(P＜0.05),第4、8周末两组BRMS、CGI总分差异无统计学意义(P＞0.05);治疗第1、8周末,研究组在药物副反应的严重程度及痛苦感觉的评分均要高于对照组,早期以嗜睡、头昏明显,晚期主要是体重增加.结论 奥氮平联合丙戊酸镁缓释片治疗对双相躁狂发作起效较快,但副作用较明显,临床选药应权衡风险和效益.     

丙戊酸镁缓释片致全血细胞减少1例

丙戊酸镁对各型癫痫的治疗效果较好，同时也是美国食品药品监督管理局（FDA）批准用于治疗双相情感障碍的药物。丙戊酸盐的临床反应个体差异较大，消化道功能紊乱和肝功能异常是丙戊酸镁缓释片常见不良反应，而丙戊酸镁引起全血细胞减少鲜有报道。本案例报道了一例丙戊酸镁缓释片致全血细胞减少，以供临床参考。     

丙戊酸镁缓释片联合帕罗西汀治疗老年脑卒中后抑郁的疗效

目的观察丙戊酸镁缓释片联合帕罗西汀治疗老年脑卒中后抑郁的疗效及安全性。方法将76例老年脑卒中后抑郁患者随机分为实验组(帕罗西汀联合丙戊酸镁缓释片治疗)和对照组(单用帕罗西汀治疗)。采用汉密尔顿抑郁量表(HAMD-17)评定疗效,用副反应量表(TESS)评定不良反应,中国神经功能缺损评分(CSS)量表评定神经功能改善程度。结果实验组显效率为73.68%,对照组为52.63%。实验组从第2周末起HAMD分、CSS分低于对照组,差异有统计学意义。2组间不良反应差异无统计学意义(P0.05)。结论丙戊酸镁缓释片联合帕罗西汀治疗脑卒中后抑郁较单用帕罗西汀起效更快,疗效更好,不良反应低,且能更好的促进神经功能的恢复。     

丙戊酸镁缓释片与碳酸锂治疗躁狂发作的临床对照研究

目的评价丙戊酸镁缓释片与碳酸锂治疗躁狂发作的临床疗效和不良反应。方法随机对60例躁狂发作患者分别给予丙戊酸镁释片与碳酸锂治疗,疗程6周。结果丙戊酸镁缓释片与碳酸锂治疗躁狂发作疗效相近,前者起效快,且不良反应显著低于后者,患者耐受性好。结论丙戊酸镁缓释片治疗躁狂发作疗效肯定,起效快,不良反应小,治疗安全性高,可作为治疗躁狂发作的首选药物。     

丙戊酸镁缓释片与碳酸锂对躁狂发作的疗效及生存质量的对照研究

目的比较丙戊酸镁缓释片与碳酸锂治疗对躁狂发作患者的疗效及对生存质量的影响。方法采用入院顺序分层随机法,将120例躁狂发作患者平均分为研究组(丙戊酸镁)和对照组(碳酸锂),在治疗前,治疗后1、3、6、12月末分别用Bech-Rafaelsen躁狂量表(BRMS)和临床疗效总评量表(CGI)及不良反应表(TESS)评定疗效和副作用,用世界卫生组织生存质量测定量表(WHOQOL-BREF)评估患者的生存质量,分析量表中各领域的计分。结果两组BRMS总分在治疗后与治疗前比较有显著性差异(P<0.01),及各因子分比治疗前明显降低(P<0.01),研究组有效率96.7%,显效率70%;对照组有效率93.3%,显效率66.7%。两组间疗效无显著性差异(P>0.05),研究组副作用比对照组少。经12个月治疗,研究组与对照组两组生存质量各分指标均较治疗前有显著改善(P<0.01),在心理领域、社会关系和环境领域三方面,丙戊酸镁优于碳酸锂(P<0.01)。结论丙戊酸镁缓释片和碳酸锂对治疗躁狂发作均有效。丙戊酸镁缓释片由于副作用小,对生存质量的改善更彻底,而优于碳酸锂。     

Extracellular Magnesium and Anticonvulsant Effects of Valproate in Young Rat Hippocampus

Summary Extracellular field potential recordings were made in CA3 subfield of hippocampal slices from rats aged 11–22 days. In these experiments, we analyzed the effects induced by modifying [Mg²⁺] in the medium (1 or 2 mM) on (a) 4-aminopyridine (4-AP, 50 μM)-induced synchronous events (including ictal- and interictal-like epileptiform discharges as well as γ-aminobutyric acid (GABA)-mediated potentials), and (b) the changes induced by the antiepileptic drug (AED) valproate (VPA 2 mM) on such activities. Changing [Mg²⁺] from 1 to 2 mM induced age-dependent effects consisting of reduction in rate of occurrence of ictal-like discharges at 11–13 days (55% reduction, p <0.005) and 14–16 days (46% reduction, p <0.025) postpartum. At any age, the rate of occurrence and the amplitude of the GABA-mediated synchronous potentials tended to decrease in 1 mM [Mg²⁺] Similar effects were noted when changes in [Mg²⁺] were made during continuous application of the competitive antagonist of the N -methyl-D-aspartate (NMDA) receptor DL-2-amino-5-phosphonovalerate (APV 50 μM). As previously reported, interictal and ictal discharges were blocked by addition of VPA to medium containing 2 mM [Mg²⁺] Such an effect was not observed when [Mg²⁺] was decreased to 1 m M. In 1 m M , but not in 2 m M [Mg²⁺], VPA increased the amplitude of GABA-mediated synchronous potentials. Our results indicate that [Mg²⁺] plays a role in modulating occurrence of 4-AP-induced ictal activity and that it can influence the effects of VPA in this in vitro model of epileptogenesis. Because these findings are also observed in the presence of the NMDA receptor antagonist APV, we conclude that they are nof mediated by a mechanism linked to the NMDA receptor-ionophore.     

Valproate

Objectives: This article summarizes the role of valproate as a treatment for bipolar disorder and related conditions. Methods: Published studies and reviews were systematically reviewed. Results from randomized, parallel group, double‐blind, placebo‐controlled studies that included an active comparator are emphasized. Results: Valproate is an effective treatment for manic patients. Valproate was superior to placebo in one 1‐year randomized, parallel group study in rate of recurrence requiring discontinuation, rate of depression requiring discontinuation, total early termination and time to 25% of patients relapsing with mania, and in controlling mild depressive symptoms. On some measures, including time to development of a manic episode, valproate did not differ from placebo. Assessments of maintenance efficacy of valproate and other putative prophylactic treatments for bipolar disorder are problematic, because of the need to analyze multiple indices of efficacy, and practical and ethical issues that limit generalizability of results of placebo‐controlled studies. Valproate has some advantages over lithium in treatment of mania for persons with more severe illnesses. Valproate benefits a broader spectrum of bipolar conditions than lithium. Valproate appears at best modestly effective for bipolar depression. Used in combination with several other treatments, additive benefits result, that are greater than with any of the treatments as monotherapy. Side effects are generally mild and manageable, particularly with divalproex. Weight gain and pharmacokinetic interaction with lamotrigine are perhaps the most consistent problems in use. Valproate contributes to neural tube defects if taken during the first trimester of pregnancy, and this risk must be conveyed to women. Conclusions: Valproate is an effective and useful treatment for bipolar disorder. Studies clarifying its spectrum of efficacy, its safety and efficacy in combination regimens, and its mechanisms of action are warranted.     

Associations Between Risk Factors for Valproate Hepatotoxicity and Altered Valproate Metabolism

The effects of three risk factors for valproate (VPA) hepatotoxicity (i.e., young age, polypharmacy, and high VPA serum level) on the metabolism of VPA to its monounsaturated metabolites [2-en-VPA (2-en), 3-en-VPA (3-en) and 4-en-VPA (4-en)] were investigated in 106 patients treated with VPA (56 cases of monotherapy and 50 cases of polytherapy). In the monotherapy group, there was a significant negative correlation between age and 4-en/VPA ratio. In the same group, the 4-en/VPA ratio showed a significant positive correlation with serum VPA level, while 3-en/VPA and 2-en/VPA ratios showed significant negative correlations. In patients greater than 10 years, the 4-en/VPA ratio was significantly higher, while the 2-en/VPA ratio was significantly lower in the polytherapy group than in the monotherapy group. Our results indicate that all three risk factors clearly increase the metabolic conversion of VPA to 4-en, the most toxic VPA metabolite, and that polytherapy and high VPA serum level result in the inhibited beta-oxidative metabolism of VPA to 2-en. These altered VPA metabolic profiles are strikingly similar to the abnormal VPA metabolism previously reported in cases with fatal hepatic failure. Although VPA-induced fatal hepatotoxicity has been regarded as an idiosyncratic reaction, it is possible that these three factors enhance susceptibility to VPA hepatotoxicity by altering the metabolism of VPA.     

Valproate Metabolites in High-Dose Valproate Plus Phenytoin Therapy

Summary: Purpose: We wished to determine the relation between liver function, β-, and ω-, and ω-1-oxidation metabolites and 4-en-valproate (VPA).
Methods: We measured the serum levels of VPA and its metabolites in children and adolescent receiving high-dose VPA plus phenytoin (PHT) therapy using gas chromatography-mass spectrometry with selected ion monitoring (GC/MS/SIM).
Results: In high-dose VPA plus PHT polytherapy, the total VPA serum concentration was distinctly low, the concentrations of total β -oxidation metabolites were decreased, the percentage values of VPA (percent of VPA) of total β -oxidation metabolites were increased, and the E-2-en-VPM3-keto-VPA ratios were decreased, as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT polytherapy, 4-en-VPA (μ M ) was decreased and the concentrations of (ω+ (ω - 1)]-oxidation metabolites (μ M) were decreased as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT, serum glutamic-oxaloacetic transarninase (GOT), glutarnic-pyruvic transaminase (GPT) and lactic dehy-drogenase (LDH) did not correlate significantly with the (β/ω+ (ω - 1) metabolites ratio and 4-en-VPA levels, but serum GOT, GPT, and LDH were increased as compared with those in high-dose VPA therapy. We were not able to establish a significant relation between the formation of metabolites of VPA metabolites and liver dysfunction in patients receiving high-dose VPA and PHT concurrently.
Conclusions: Metabolic levels do not appear to be a reliable predictor of hepatotoxicity in children receiving pharrnacological antiepileptic drug (AED) therapy.     

Valproate tremors

We made accelerometric recordings of the tremor induced by valproic acid. The tremor was similar to essential tremor and appeared within a month of starting therapy. It was present at rest and exacerbated by action or antigravity positioning. There was no close correlation of tremor severity and plasma valproate level, but the tremor usually appeared at dosages greater than 750 mg per day. This tremor has appeared in 20 of 25 patients recently studied. In some patients the tremor is markedly active; however, others note only minimal tremor activity.