丙戊酸钠对氯氮平血药浓度和疗效的影响

目的:探讨合用丙戊酸钠对氯氮平治疗精神分裂症时的血药浓度和疗效的影响。方法:将80例男性精神分裂症患者随机分为两组,单用组40例患者单服氯氮平,合用组40例患者同时服用氯氮平及丙戊酸钠,分别于治疗前、治疗1周和4周末测定氯氮平的血药浓度,同时评定阳性与阴性症状量表(PANSS)、治疗中出现的症状量表(TESS)。结果:合用组治疗1周和4周末有部分患者氯氮平血药浓度升高,部分患者降低,与基线期相比,治疗4周末有显著降低。结论:合用丙戊酸钠后氯氮平血药浓度治疗4周末显著降低;丙戊酸钠可以提高氯氮平对阳性症状的疗效。     

Intravenous sodium valproate aborts migraine headaches rapidly

Shahien R, Saleh SA, Bowirrat A. Intravenous sodium valproate aborts migraine headaches rapidly.
Acta Neurol Scand: 2011: 123: 257–265.
© 2010 John Wiley & Sons A/S. Objectives – This preliminary study was designed to evaluate the efficacy and safety of intravenous sodium valproate in managing severe migraine headache. Design/methods – In a preliminary prospective open‐label study, we treated patients with severe migraine headache using intravenous sodium valproate, after obtaining written informed consent. Thirty‐six patients, hospitalized with acute established migraine, were infused with sodium valproate. The diagnosis of migraine was based on the International Headache Society classification criteria. Severity of headache was reported on 10‐point visual analog. Disability was assessed on a five‐point scale. Primary and secondary endpoints were measured as sustained pain relief and symptoms improvement at 2 h, respectively. Results  – The study participants had a mean ± SD age of 35.7 ± 9.3 years. The loading dose of sodium valproate was 900–1200 mg, and the average time to best response for headache severity was 50 min. A reduction in pain from severe or moderate to mild or no pain in 60 min was reported in 75% of patients [OR = 7.187 (95% confidence intervals: 1.32–38.95)]. After treatment with sodium valproate, headache severity was significantly decreased (P < 0.0001). No serious adverse events were reported. Conclusions – Intravenous Sodium Valproate (iVPA) seems to be safe and rapidly effective for intractable migraine attack. Randomized, double‐blinded, controlled studies are warranted.     

小剂量丙戊酸钠对利培酮疗效及血药浓度的影响

目的 观察小剂量丙戊酸钠对利培酮疗效、不良反应及血药浓度的影响.方法 将55例精神分裂症患者随机分为对照组（利培酮组）30例和研究组（利培酮＋丙戊酸钠组）25例.对照组单纯使用利培酮治疗,限定治疗剂量为4 mg;研究组同时联合丙戊酸钠片（400～600 mg/d）.分别于治疗前与治疗2周末、治疗4周末采用阳性与阴性症状量表（PANSS）评定疗效,采用不良反应量表（TESS）评定治疗中不良反应.于治疗2周末、4周末测定利培酮血药浓度.结果 2组利培酮血药浓度测定结果在治疗2周末、4周末比较差异无统计学意义（P＞0.05）.PANSS评分结果显示：在治疗2周末,研究组与对照组相比,差异有统计学意义（P=0.015）,而4周末的差异无统计学意义（P=0.740）.2组TESS评分结果比较差异无统计学意义.结论 联用小剂量丙戊酸钠不会增加利培酮血药浓度,疗效与血药浓度无明显相关,其不良反应未受影响.     

Concentration of valproate during pregnancy, in the newborn and in breast milk

The serum-valproate level of four patients with epilepsy was followed during pregnancy. A decrease in serum level occurred late in pregnancy and was followed by a pronounced increase in the first week after delivery. The maternal serum concentration of valproate was compared to that of the umbilical cord. The level in cord blood was 145-219% higher than that in maternal blood. The concentration of valproate in breast milk was found to be 5-10% of the maternal serum concentration. The serum concentration was measured in one breastfed child. The level was 7.6% of the maternal serum concentration. All children were healthy without any signs of intoxication or malformation. Based on our experience, pregnant patients treated with valproate must be carefully controlled especially during the last month of pregnancy and in the first two weeks after delivery. The amount of valproate excreted into the breast milk was negligible and should not prevent breast feeding.     

Rectal administration of sodium valproate in children

A study of VPA based on a comparison of mean plasma levels, plasma peak latency times and plasma half-lives after rectal and oral administration was conducted in 9 children between 6 months and 10 years of age suffering from various forms of epileptic seizure, before they received chronic VPA treatment. Each child received an oral dose of 20 mg/kg and after two days a rectal dose of 20 mg/kg and the mean plasma concentrations were determined at intervals for both modes of administration. An identical plasma concentration for both after 24 h showed that the quantity of drug absorbed was the same. The mean half-life varied according to age: 11 ± 2 h for children over 3 years of age and 9 ± 1 h for those under 3. The results of the study, in line with the few other available published data, thus confirm the validity of rectal VPA administration.

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Sommario È stato intrapreso uno studio sul V.P.A. basato sul confronto tra livello plasmatico medio, tempo di latenza del picco plasmatico, valori di emivita del farmaco somministrato per via rettale e per via orale. Nove pazienti di età compresa tra i 6 mesi ed i 10 anni affetti da diverse forme di crisi epilettiche e non ancora sottoposti a terapia, ricevevano da prima per via orale e dopo due giorni per via rettale, una dose dapprima unica di 20 mg/kg di V.P.A. sotto forma di soluzione. Per le due vie di somministrazione e per ogni tempo si calcolava la concentrazione plasmatica media del farmaco. Una identica concentrazione plasmatica, ottenuta con le due diverse vie di somministrazione, dopo 24 ore confermava che la quantità di farmaco assorbita era la medesima. L'emivita media variava in base all'età: 11 h. ± 2 per i bambini di età superiore ai 3 anni, 9 h. ± 1 per l'età inferiore ai 3 anni. I risultati del nostro studio, in accordo con i pochi altri dati esistenti in letteratura, confermano quindi la validità della somministrazione rettale del V.P.A..

     

丙戊酸钠与碳酸锂治疗躁狂发作对照研究

目的：比较丙戊酸钠与碳酸锂治疗躁狂发作的疗效和不良反应。方法：对80例躁狂发作患者随机均分为丙戊酸钠组和碳酸锂组，在治疗前，治疗2、4、8周末分别用Bech-Rafaelsen躁狂量表(RBRMS)和临床疗效总评量表(CGI)及副反应量表(TESS)评定疗效和不良反应。结果：丙戊酸钠组治疗2周后BRMS总分，及各因子分比治疗前明显降低，且显著低于碳酸锂组，两组治疗8周BRMS总分各因子分均显著低于治疗前，差异显著。治疗2、4、8周末TESS评分，丙戊酸钠组显著低于碳酸锂组，差异有显著性。结论：丙戊酸钠治疗躁狂发作疗效好，起效快，不良反应小。     

Pharmacokinetics of lithium preparations in patients

Equivalent oral dosages (800 mg, 21.6 mmol) of standard ( Lithicarb ) and sustained-release ( Priadel ) lithium carbonate preparations were administered using a randomised cross-over design to six patients receiving long-term lithium maintenance and eight healthy student volunteers. In both patients and students there were no significant differences between the two lithium preparations for plasma lithium level curves, bioavailability or total urinary excretion rates. There were no differences in peak lithium concentrations (C max) between the two preparations in both patients and students, although the times to maximal levels (T max) were delayed after Priadel in patients and volunteers. These data indicate that Priadel is a delayed-release rather than a true sustained-release preparation.     

托吡酯和丙戊酸钠预防小儿偏头痛的对比研究

目的探索托吡酯预防小儿偏头痛发作的有效性、安全性和耐受性。方法采用前瞻性的方法,给予小儿偏头痛患者口服托吡酯25~50mg/d,分早晚两次口服,从第1周12.5 mg/d开始,每周递增12.5mg,最大量至50 mg/d;丙戊酸钠则从200mg/d,分早晚两次口服,必要时增至400 mg/d。观察患者治疗前后头痛发作频率、天数和疼痛程度,同时将托吡酯和丙戊酸钠的上述指标进行对比。结果平均每月发作频率均较前减少,托吡酯组和丙戊酸钠组分别从12.38次减至3.52次和14.33次减至6.48次,2组差别无显著性;平均每月头痛天数均较前减少,分别从12.43d减至3.38d和14.58d减至7.19d,2组差别无显著性。头痛程度均较前减轻,分别从7.52分减轻至2.00分和7.24分减轻至3.19分,2组无显著差别。托吡酯的不良反应为记忆力下降、食欲减退、发热、上呼吸道感染、头痛加重。结论托吡酯和丙戊酸钠均能有效预防偏头痛发作,且二者疗效无显著性差异。     

丙戊酸钠辅助治疗难治性精神分裂症的作用

目的：评价氯氮平合并丙戊酸钠治疗难治性精神分裂症的疗效和安全性。方法：62例难治性精神分裂症患者随机分为合用组和单用组,分别给予氯氮平合并丙戊酸钠和氯氮平治疗,疗程12周。采用阳性与阴性症状量表（PANSS）及治疗中出现的症状量表（TESS）评定疗效和不良反应结果：单用组显效率为16．7％,有效率为50．0％;合用组显效率43．3％,有效率73．3％,以合用组疗效显著较好（P〈0．05）,两组不良反应差异无显著性（P〉0．05）。结论：氯氮平合用丙戊酸钠治疗难治性精神分裂症疗效优于单用氯氮平,不良反应少。     

Comparisons of drug efficacy and time-effect among magnesium valproate, sustained-release magnesium valproate tablet and depakine chrono for epilepsy An experiment of determining cortical convulsive threshold In rats undergoing electrical stimulation

BACKGROUND: Scholars have investigated the differences in drug metabolism and pharmacodynamics between valproate and its sustained-release tablets only from the angle of pharmaceutical sciences or clinical practice. Whether the fact that differences in drug efficacy and time-effect of different doses of valproate and different types of sustained-release valproate tablets at the same concentration can be quantitatively reflected by determining the changes in convulsive threshold pre- and post-administration in rat models of determining the convulsive threshold developed by direct cortical electrical stimulation remains unclear. OBJECTIVE: This study aimed to compare the drug efficacy and time-effect among magnesium valproate, sustained-release magnesium valproate tablet and depakine chrono in the treatment of epilepsy by determining the convulsive threshold of rat models created by direct cortical electrical stimulation, and human serum drug concentration before and after administration. DESIGN: A controlled observational experiment. SETTING: Research Institute of Epilepsy, Shanxi Medical University. MATERIALS: Adult health male SD rats of clean grade, weighing 200–220 g, provided by the Laboratory Animal Center of Shanxi Medical University. The protocol was carried out in accordance with requests from Animal Ethics Committees for guidance. Magnesium valproate (Lot No. 041004) and sustained-release magnesium valproate tablet (Lot No. 050501) were produced in Hunan Xiangzhong Pharmaceutical Co., Ltd. METHODS: This study was carried out in the Laboratory for Epilepsy, Shanxi Medical University between June and August 2005. ①All the SD rats were created into models for determining cortical convulsive threshold. They were randomly divided into 4 groups with 20 rats in each: magnesium valproate tablet group , sustained-release magnesium valproate tablet group, depakine chrono group and control group. After being modeled, the rats in the first 3 groups were intragastrically administrated with magnesium valproate, sustained-release magnesium valproate tablet and depakine chrono, respectively, while the control group were intragastrically administrated with the same volume of normal saline. ②Convulsive threshold of each fasting rat was determined 0.5 hour before, and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 and 24 hours after single administration, separately. ③ Convulsive threshold was determined repeatedly 2 weeks after single administration. Each rat was administrated two times daily successively. Convulsive threshold was determined 0.5 hour before, and 0.5, 2.5, 7 and 12 hours after administration, separately. ④Hepatic and renal tissues were harvested for pathological examination after 1 month of administration. ⑤Nine healthy voluntary medical stuffs were recruited in this study. Written informed consents of experiment were obtained each involved subject. The study was given an approval by the Ethics Committee of Shanxi Medical University. According to the scheme, the 9 volunteers were randomly assigned into 3 groups, in which, volunteers were asked to take magnesium valproate 500 g, sustained-release magnesium valproate tablet 500 g and depakine chrono 500 g, respectively, in the morning under the condition of fasting. Serum drug concentration of each drug was determined by fluorescence polarization immunoassay at different time points. MAIN OUTCOME MEASURES: ① Rat convulsive threshold after single and repeated administrations. ②Hepatic and renal pathological examination results. ③ Serum drug concentration in vivo. RESULTS:①Rat convulsive threshold after single and repeated administrations: Drug efficacy in the magnesium valproate tablet group reached to a peak level 1 to 2 hours after single administration, and was obviously higher than that in the other groups 1 hour after administration (P < 0.05). Drug efficacy in the sustained-release magnesium valproate tablet group and depakine chrono group both reached to a peak level 7 hours after administration, and was significantly higher than that in the control group (P < 0.05). After repeated administrations, the average peak valley deviation of the convulsive threshold in the magnesium valproate tablet group was 120–150 μA, which was 2 and 2.5 times as that in the sustained-release magnesium valproate tablet group and depakine chrono group, respectively. After repeated administrations for 10 times, convulsive threshold was increased by 440μA in the sustained-release magnesium valproate tablet group, and by 230 μA in the depakine chrono group in comparison with before administration. ②Hepatic and renal pathological examination results: No obvious differences in hepatic and renal impairment were found among the 4 groups after 1 month of administration successively. ③ Serum drug concentration in vivo: Serum-drug concentration of magnesium valproate was increased fast and reached to a peak level 0.5–2 hours after administration, remained at a relatively stable level 2–4 hours after administration, and then was slowly decreased. The drug efficacy of sustained-release magnesium valproate tablet and depakine chrono was slowly released 1–6 hours after administration, reached to a peak level at about 7 hours, and could last for about 16 hours. CONCLUSION: Magnesium valproate has a rapid onset and offset of action. Sustained-release magnesium valproate tablet has a slow onset but long duration of drug efficacy. Depakine chrono can be easier to be absorbed than sustained-release magnesium valproate tablet, but its long-term effect on improving the convulsive threshold is inferior to sustained-release magnesium valproate tablet.     

丙戊酸钠治疗迟发性运动障碍的双盲对照研究

目的：探讨丙戊酸钠治疗抗精神病药所致迟发性运动障碍(TD)的疗效及安全性。方法：对80例长期服用抗精神病药治疗且符合TD诊断标准的男性精神分裂症患者，随机分为治疗组和对照组，分别给予丙戊酸钠和安慰剂治疗。采用异常不自主运动量表(AIMS)和简明精神病评定量表(BPRS)及副反应量表(TESS)在治疗前及治疗后1、2、4、6周末分别评定疗效及不良反应。结果：治疗组于治疗后4周AIMS评分有显著下降，治疗后6周较对照组显著为低。有效率64．1％，显著较对照组的25．0％为高。结论：丙戊酸钠治疗抗精神病药所致TD有效，但以低剂量为宜，应注意监测血象。     

A pilot study of loading versus titration of valproate in the treatment of acute mania

Objective:  This double-blind pilot study compares the effectiveness and incidence of adverse effects of oral loading versus titration schedules of valproate in acute mania.
Method:  Consecutive new admissions for an acute manic episode were prescribed either an oral loading dose (20 mg/kg/day; n=5; mean age=33.4) or slower titration dose (10 mg/kg/day; n=6, mean age=30.6) of valproate for 7 days without other psychotropic agents, with the exception of benzodiazepines. Daily outcome measures included: serum valproic acid levels, the Young Mania Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical Global Impression Scale (CGI) and the Adverse Effect Rating Scale.
Results:  The mean serum valproic acid levels were significantly higher in the loading group when compared with the titration group after 1 and 2 days following the initiation of treatment (p < 0.05). After 3 days of treatment there was a trend for the group that received the loading regimen to have slightly more improvement in YMRS scores compared with the titration group. Side-effects were minor for both treatments, however, a higher incidence of side-effects was reported in the titration group, with 50% of patients reporting sedation most likely because of increased use of benzodiazepines.
Conclusion:  This suggests that a loading dose of valproate is likely safe and may provide an earlier onset of antimanic effects in patients with bipolar disorder. Future studies with larger sample sizes are indicated.     

An observational study of first-line valproate monotherapy in focal epilepsy

The objective of this multinational open-label, prospective study was to collect, under naturalistic conditions, data on the effectiveness and tolerability of first-line monotherapy with valproate in subjects newly or recently diagnosed with focal onset epilepsy. Patients were treated with sustained release sodium valproate. Seizure control and occurrence of adverse events were assessed after 6 months. Around 1192 adults and 792 children were included. The mean daily valproate dose was 683 mg in children and 987 mg in adults. The retention rate at 6 months was 90.0%. At this time, 77% of subjects were seizure free (83.7% of children and 72.7% of adults). Adverse events possibly related to treatment were observed in 10.2% of subjects, leading to treatment modification for 1.7%. The most common adverse events were weight gain, gastro-intestinal, neurological and skin disorders. Sustained release sodium valproate is effective and shows acceptable tolerability as first-line monotherapy in focal onset epilepsy.     

Low dose sodium valproate in the treatment of juvenile myoclonic epilepsy

Fourteen patients with juvenile myoclonic epilepsy (JME) were treated with a single low dose of a sustained-release preparation of sodium valproate (VPA, 500 mg daily). The mean age of the onset of the low dose treatment was 19.2 years (range 14–26). Before this treatment, six patients had been treated with high dose VPA for a period of more than 2 years, three patients for 1 to 2 years, three patients less than 1 year and two patients initiated the treatment from the begining with a low dose. The mean duration of low dose treatment is 35.6 months (range 25–59 months). (All patients are still under medication). Generalized tonic-clonic and absence seizures were controlled in all patients. Myoclonic jerks relapsed only in one patient, a young mother who was looking after her newly born baby and was deprived of sleep. No adverse reactions have been reported. We suggest that JME patients can effectively be treated with single low VPA dose (500 mg daily), while at the same time seizure precipitating factors, such as sleep deprivation and alcohol ingestion, should be avoided. Received: 26 January 2001, Received in revised form: 30 July 2001, Accepted: 3 August 2001     

Pharmacokinetics of free and total sodium valproate in adolescents and young adults during maintenance therapy

Summary The pharmacokinetics of total and free valproic acid (VPA) in plasma and whole blood was investigated in seven adolescents and young adults (mean age 17.3 years) during a dosage interval at steady state. The concentration curves of VPA in whole blood after an oral morning dose (mean 8.2 mg/kg body wt.) closely followed those in plasma but at a reduced level. The apparent volume of distribution (Vd) of total VPA was 0.150–0.197l/kg body wt. and of free VPA 0.911–1.58l/kg body wt., which indicates considerable distribution of unbound VPA as well as drug binding to extravascular proteins. The terminal half-life of free VPA (6.4–6.7h) was significantly shorter (P<0.05) than the half-life of total VPA (10.4–11.9h). The binding of VPA in plasma was concentration dependent and fluctuated considerably within the individual dosage intervals. Concentrations of unbound VPA in plasma water of whole blood varied to a corresponding degree, since distribution to blood cells was low (mean 2.2%). It is concluded that there are substantial differences in the pharmacokinetics of free and total VPA. This may contribute to the well-known poor correlation between dose, plasma concentrations and effect of VPA.     

丙戊酸钠改善精神分裂症患者认知功能障碍的对照研究

目的 探讨丙戊酸钠改善精神分裂症患者认知功能障碍的疗效.方法 将80例精神分裂症患者随机分成研究组(40例)和对照组(40例),研究组患者使用新型抗精神病药合并丙戊酸钠系统治疗,对照组患者单用新型抗精神病药物系统治疗,共治疗8周.全部病例在治疗前后分别进行阳性和阴性综合征量表(PANSS)、韦氏成人智力量表(WAIS-RC)、韦氏记忆量表(WMS)、威斯康星卡片分类测验(WCST)进行疗效评定,应用治疗中需处理的不良反应症状量表(TESS)评定不良反应.结果 与基线时比较,两组在治疗后第4、8周末PANSS总分及各因子分均有明显降低(P＜0.05),研究组治疗后第8周末PANSS总分及各因子分均显著低于对照组(P＜0.05).治疗后第8周末,两组WMS、WAIS-RC、WCST评分与基线时比较,除即刻记忆评分外其余各项评分差异均有统计学意义(P＜0.05),两组间比较,除即刻记忆评分外其余各项评分均有显著性差异(P ＜0.05,P＜0.01).结论 丙戊酸钠对精神分裂症患者的认知功能障碍有明显改善效果.     

氯氮平合并丙戊酸钠治疗难治性精神分裂症的疗效分析

目的：探讨氯氮平合并丙戊酸钠治疗难治性精神分裂症的疗效。方法：抽取64例难治性精神分裂症患者给予氯氮平≥400mg/日，合并丙戊酸钠≥800mg/日，治疗3个月，用简明精神病量表（BPRS）及药物副反应量表（TESS）评定疗效及副作用，并对其它相关因素进行分析。结果：发现氯氮平合并丙戊酸钠治疗难治性精神分裂症阳性，阴性症状均有效，总有效率为56．2％，尤其对女性及＜22岁的患者疗效好，对激活因子及敌对猜疑因子疗效亦佳，副作用轻微，结论：氯氮平合并丙戊酸钠是治疗难治性精神分裂症（尤其是对女性及＜22岁患者）较为理想的方法。     

丙戊酸钠与卡马西平治疗躁狂发作临床观察

目的：评价丙戊酸钠与卡马西平对锂盐治疗无效的躁狂发作的疗效和副反应。方法：将符合CCMD－2－R躁狂发作诊断标准的5例患者随机分为丙戊酸钠组和卡马西平组,治疗6周。使用Bech-Rafaelsen躁狂量表及临床疗效总评量表的疗效总评评定疗效,用副反应量表及有关实验室检查评定副反应。结果：丙戊酸钠与卡马西平均能有效减轻躁狂症状,疗效相近,丙戊酸钠起效时间迟于卡马西平。丙戊酸钠的副反应主要为肠道反应、震颤等、而卡马西平以共济失调、头晕、嗜睡等多见。结论：丙戊酸钠与卡马西平均可用于锂盐治疗无效的躁狂发作。     

Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse features associated with higher doses of sodium valproate

The risk of an adverse outcome to pregnancy is increased in women with epilepsy. This is partly attributable to antiepileptic drugs. Guidelines for the management of pregnancy in women with epilepsy generally advise against polytherapy but make no distinction between the risks of different drugs. Several recent studies have however shown greater risk of adverse outcome in offspring exposed to sodium valproate in utero, particularly at higher doses. The outcome of pregnancy was monitored to identify antiepileptic drug treatment associated with a poor outcome in a mainly prospective study of women attending an outpatient clinic. From January 1990 to December 1999 all 69 pregnancies in women referred to the clinic were monitored. Drug treatments and other risk factors were recorded. In each child dysmorphic features, developmental delay and structural anomalies were assessed and graded. Data were analysed for drug- and dosage-dependent differences in outcome. In each assessment area a positive association between adverse outcome and dose was found for sodium valproate but not for carbamazepine. Severe adverse outcomes were found only in children exposed to sodium valproate at maternal doses above 1000 mg per day.