Steady-state kinetics of valproic acid in epileptic patients.

Pharmacokinetic evaluation and prediction were carried out in 20 epileptic patients. Using conventional pharmacokinetic techniques and a one-compartment model, predicted and observed valproic acid plasma concentrations were compared. Valproic acid assay was performed by gas-liquid chromatography. There was good agreement between predicted and observed plasma concentrations. Most patients had predicted half-lives (t1/2s) of 6 to 8 hr, independent of the plasma concentration of valproic acid. Five patients had predicted t1/2s of 12 hr. The correlation between dose and plasma level was poor. Most patients had valproic acid plasma levels between 55 and 100 microgram/ml. Administration of valproic acid three times a day with determination of individual plasma concentrations offers a reliable method of monitoring. Constant levels are maintained in individual patients, but there is substantial intersubject variation.     

The effect of carnitine on the metabolism of valproic acid in epileptic patients.

The half-life of valproic acid (VPA) was studied in 8 epileptic and severely mental retarded patients before and after one month of carnitine supplementation. Serum carnitine concentration was significantly decreased and VPA half-life was prolonged especially in adult patients before carnitine supplementation. After the treatment with carnitine, serum carnitine concentration was increased, and prolonged half-lives of VPA were corrected near to the normal range (from 12.2 +/- 4.2 hr to 9.7 +/- 2.2 hr; p < 0.05). Controlled state of epilepsy was unchanged during the short period of observation.     

Synergistic anticonvulsant effect of valproic acid and ethosuximide on pentylenetetrazole-induced epileptic phenomena in rats

The possible synergistic effect of valproic acid and ethosuximide in combination on pentylenetetrazole-induced epilepsy was investigated in rats. Valproic acid and ethosuximide administered intraperitoneally both showed dose-dependent anti-epileptic activity towards pentylenetetrazole-induced myoclonias and tonic-clonic seizures. The valproic acid-ethosuximide combination had a synergistic pharmacological effect. Against myoclonias combined valproic acid-ethosuximide produced a non-significant decrease in the effective dose of both drugs compared with treatment with either drug alone. In the case of tonic-clonic seizures the protective effect against the seizures was significantly increased by combined treatment compared with treatment with either drug alone. Neither plasma concentrations nor any other pharmacokinetic parameters were significantly changed when the same doses of valproic acid and ethosuximide were given, singly or in combination.     

Five doubly unsaturated metabolites of valproic acid in urine and plasma of patients on valproic acid therapy

The urine and plasma of epileptic patients receiving therapeutic doses of valproic acid (2-propyl- pentanoic acid) was found to contain five doubly unsaturated metabolites of valproic acid, which were identified as their trimethylsilyl derivatives by GC/MS. A series of reference substances was synthesized but only two of them were identical with native metabolites: 2(2-propenyl)-4-pentenoic acid (= 4.4'-diene) and E-2-propyl-2.4- pentadienoic acid (E-2.4-diene). The mass-spectra of the five native metabolites are given. Preliminary quantitative data obtained from four groups of patients indicate increased formation of doubly unsaturated metabolites when valproic acid-induced side-effects are present, and in cases of fatal hepatic failure. The 4.4'-diene has hitherto been found only in fatal cases with hepatic injury. Quantitative data are presented as % of the sum of valproic acid plus all its detected metabolites.     

小剂量丙戊酸联合奥卡西平治疗老年癫痫46例疗效分析

目的分析小剂量丙戊酸联合奥卡西平对老年癫痫患者的疗效。方法选取92例老年癫痫患者,根据不同治疗方案将其纳入奥卡西平组(46例)与丙戊酸+奥卡西平组(46例)。奥卡西平组予以奥卡西平治疗,丙戊酸+奥卡西平组予以小剂量丙戊酸联合奥卡西平治疗。对比两组患者的癫痫发作情况(发作次数、发作持续时间)、临床疗效、脑电图变化(痫样放电、累及导联数)、脑电图改善效果。结果丙戊酸+奥卡西平组的癫痫发作次数与发作持续时间[(0.45±0.17)次/月、(1.21±0.56)分钟/次]均少于奥卡西平组[(0.86±0.33)次/月,(2.25±0.84)分钟/次)],P<0.05;丙戊酸+奥卡西平组的总有效率(93.48%)高于奥卡西平组(78.26%),P<0.05;丙戊酸+奥卡西平组治疗后脑电图的痫样放电与累及导联数[(7.38±1.43) t/180 s、(3.45±1.29)/180s]均优于奥卡西平组[(10.20±2.16) t/180s、(5.50±1.52)/180s,P<0.05];丙戊酸+奥卡西平组的脑电图总改善率(91.30%)高于奥卡西平组(73.91%),P<0.05。结论小剂量丙戊酸联合奥卡西平对老年癫痫患者的疗效显著,可明显减少癫痫发作次数与发作持续时间。     

Relationship between valproic acid dosage, plasma concentration and clearance in adult monotherapy patients with epilepsy

Significant variability has been reported in the plasma concentration–dose relationship for the anticonvulsant compound valproic acid (VPA). Several factors may contribute to this observed variability, including heterogeneous patient populations of children and adults, polytherapy, and timing of plasma concentration sampling. To optimally determine the relationship between trough VPA plasma concentration and dose, we evaluated a homogeneous group of adult ambulatory patients with epilepsy receiving VPA monotherapy. Furthermore, we sought to evaluate whether a relationship existed between VPA dosage and plasma clearance for both total and unbound or free drug. Steady–state trough plasma concentrations were determined in thirty–two patients. Mean VPA dose was 22.8 ± 10.3 mg/kg/day. Mean total and unbound VPA plasma concentrations were 97.9 ± 34.9 and 13.2 ± 10.6 μ/ml, respectively. Significant correlations between VPA dose and total and unbound plasma concentrations were found (r= 0 82 and r= 0 85, P= 0 001, respectively). Significant relationships were also observed between VPA dose and clearance. A positive correlation was noted for dose and total plasma clearance (r= 0 61, P= 001), while an inverse correlation existed between dose and unbound VPA plasma clearance (r=– 0 51, P < 0 01). Although a statistically significant correlation does exist between VPA dosage and both total and unbound plasma concentrations, significant interpatient variability still remains even under ‘optimal’ therapeutic drug monitoring conditions.     

Population pharmacokinetics of intravenous valproic acid in Korean patients

OBJECTIVE: To determine population-based pharmacokinetic parameters for intravenous valproic acid, and the factors influencing these parameters, in Korean adults. METHODS: Valproic acid concentrations were obtained using a peak and trough sampling scheme for 102 Korean epileptic patients who were not taking concurrent antiepileptic medication. Three hundred and fifty-four serum concentrations were analysed according to a one-compartment model with a mixed effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg), height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age on volume of distribution (Vd) and clearance (CL) was assessed in the course of analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No significant influence of the other screened covariates was observed. The final regression model was: [equation: see text]. Interindividual variabilities (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual error including intraindividual variability was 26.7%. CONCLUSION: The current results may be used as a basic reference to optimize drug therapy with intravenous valproic acid. Further research on the paediatric population is necessary to confirm the non-linearity of the relation between body-weight and Vd.     

The use of valproic acid in HIV-positive patients.

OBJECTIVE: To review the use of valproic acid in HIV-positive patients. DATA SOURCES: Clinical literature was accessed through a MEDLINE search (January 1966-November 1998). Key search terms included HIV, AIDS, seizures, valproic acid, and glutathione. DATA SYNTHESIS: Patients with HIV often develop neurologic manifestations; therefore, valproic acid may be considered in the management of this population. It has been demonstrated that valproate may increase viral burden by potentiating replication. An evaluation of studies addressing the use of valproic acid in HIV-positive patients was conducted. CONCLUSIONS: The potential for valproate-induced increases in viral replication exists. Although further studies are warranted, clinicians should exercise caution when using valproate in HIV-positive patients.     

Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children

Objective: To establish a regression equation to properly estimate the unbound serum concentration of valproic acid (VPA) from its total serum concentration; the relationship between total and unbound serum VPA concentrations was retrospectively characterized. Methods: Data were obtained from the clinical examination records that were routinely archived during therapeutic drug monitoring. The screening encompassed 342 records of 108 paediatric patients whose total and unbound VPA concentrations had been determined. The relationship between total and unbound VPA concentrations was characterized according to the Langmuir equation by taking account of inter‐individual variability with the nonmem program. Results: The total VPA concentration (C_t) in the screened patients ranged from 5·5 to 179·8 μg/mL, and the unbound VPA concentration (C_f) increased in a non‐linear manner as the total VPA concentration increased. Taking account of the effects of antiepileptics concurrently administered, the VPA dissociation constant (K_d) and maximum binding site concentration (B_m) were 7·8 ± 0·7 and 130 ± 4·5 μg/mL respectively, for the regression equation, C_t = C_f + B_m·C_f/(K_d + C_f). An alteration in the unbound concentration was seen in patients who were treated with the combination of VPA and ethosuximide and in those who received two additional antiepileptics. Conclusions: A regression equation for estimation of the unbound VPA concentration, based on total VPA concentration collected during routine therapeutic drug monitoring was established. Use of two additional antiepileptics and ethosuximide treatment was considered as potential factors affecting unbound VPA concentration.     

Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects

In five of six epileptic children who were taking 18 to 49 mg/kg/day valproic acid (VPA), the steady-state serum free fractions of VPA rose from 12% to 43% when antipyretic doses of aspirin were also taken. Mean total VPA half-life (t1/2) rose from 10.4 +/- 2.7 to 12.9 +/- 1.8 hr and mean free VPA t1/2 rose from 6.7 +/- to 2.1 to 8.9 +2- 3.0 hr when salicylate was present in the serum. The in vitro albumin binding association constant (ka) for VPA was decreased by salicylate, but the in vivo ka value was not affected. The 12-hr (trough) concentrations of both free and total VPA were higher in the presence of serum salicylate in five of six patients. Renal excretion of unchanged VPA decreased in five of six patients, but the VPA carboxyl conjugate metabolite-excretion patterns were not consistently affected. Salicylate appeared to displace VPA from serum albumin in vivo, but the increased VPA t1/2 and changes in VPA elimination patterns suggest that serum salicylate also altered VPA metabolism.     

艾司西酞普兰治疗成年癫痫患者并发抑郁的疗效及安全性研究

目的探讨艾司西酞普兰治疗癫痫患者并发抑郁的疗效及安全性。方法 84例健康问卷抑郁量表(patient health questionnaire 9-item depression scale,PHQ-9)评分≥15分的成年癫痫并发抑郁患者,按随机数字表法分为观察组(n=43)和对照组(n=41),两组均给予常规抗癫痫药物治疗,治疗组在此基础上,给予艾司西酞普兰(10 mg/d)抗抑郁治疗。比较两组治疗前、治疗3月后癲痫发作频率及PHQ-9评分等。结果观察组和对照组分别有41例和40例完成试验。治疗3月后,两组患者PHQ-9评分及癫痫发作频率均较治疗前显著降低(均P<0.05),观察组患者PHQ-9评分及癫痫发作频率降低较对照组更显著(均P<0.05)。两组患者不良反应差异无统计学意义(P>0.05)。结论艾司西酞普兰可以明显改善癫痫患者的抑郁症状,与抗癫痫药物联合应用,可使癫痫发作次数减少,且安全性好。     

Pharmacokinetic parameters of total and unbound valproic acid and their relationships to seizure control in epileptic children

The aims of this study were to define the relationship between total and unbound valproic acid (VPA) concentrations, to compare pharmacokinetic parameters of total and unbound VPA, and to determine the difference in pharmacokinetic parameters between the seizure-controlled and -uncontrolled groups. Total and unbound steady-state serum concentration of VPA were determined at trough and at 5 hours after the morning dose from 29 pediatric patients with epilepsy who were receiving valproic acid as monotherapy every 8 or 12 hours. Pharmacokinetic parameters were calculated and compared by t test (alpha=0.05). A strong relationship between total and unbound concentrations was found. The equation for predicting unbound concentration from total concentration was unbound concentration=-6.01+0.18 * total concentration (r=0.78, P<0.001). A higher percentage of free fraction was found at higher concentrations. There were significant differences between total and unbound VPA pharmacokinetic parameters. Both the elimination rate constant (Ke) and volume of distribution (Vd) of the unbound VPA were much higher than those of the total VPA; clearance (CI) was approximately 10-fold higher. The seizure-uncontrolled group could eliminate VPA much faster than the seizure-controlled group, as indicated by a much higher Ke and a much shorter t1/2 (P<0.05). Vd of the unbound VPA was also much smaller in the seizure-uncontrolled group (P<0.05). There were significant differences in pharmacokinetic parameters between seizure- controlled and -uncontrolled pediatric epileptic patients. Further study with a larger sample size is strongly recommended.     

左乙拉西坦治疗丙戊酸无效型成人难治性癫痫疗效观察

目的探讨左乙拉西坦治疗丙戍酸无效型难治性癫痫患者部分性发作的临床疗效和安全性.方法将68例丙戊酸无效型难治性癫痫部分性发作患者按奇偶数法随机分为治疗组与对照组各34例,均维持其原用丙戊酸治疗方案,在上述基础上治疗组联合口服左乙拉西坦治疗,对照组联合安慰剂治疗,观察6个月.比较两组治疗后临庆疗效、脑电信号背景波情况及药物不良反应发生率.结果治疗组总有效率(67.7%)显著高于对照组(20.6%)(P<0.01);治疗后两组脑电信号背景波δ、θ、α、β频段功率与治疗前比较无显著性变化(P>0.05),同期两组间比较差异无统计学意义(P>0.05);治疗期间两组不良反应发生率比较差异无统计学意义(P>0.05).结论左乙拉西坦治疗丙戊酸无效型难治性癫痫部分性发作患者疗效显著,安全性高.     

Poor applicability of estimation method for adults to calculate unbound serum concentrations of valproic acid in epileptic neonates and infants

Objective:  To characterize the relationship between total and unbound concentrations of valproic acid (VPA) in epileptic neonates and infants, the clinical examination records of those patients archived via therapeutic drug monitoring (TDM) activities were retrospectively analyzed.
Methods:  The screening encompassed 249 records of 114 epileptic patients aged 0–19 years old, who were treated with VPA monotherapy and whose total and unbound VPA concentrations were determined. These data were divided into groups according to the patients' age. In each group, the relationship between total and unbound VPA concentrations was compared to a reference profile, and the deviation from the reference was evaluated. The reference profile was calculated using the Langmuir equation, in which two parameters Kd and Bm were set to 7·8 and 130 μg/mL, respectively, according to our previous findings.
Results:  The relationship between total and unbound VPA concentrations of patients of 0 years old considerably deviated from the reference, and their unbound VPA concentrations were generally higher compared to the corresponding reference values. It is suggested that the large deviation is related to the fact that the serum albumin concentrations of patients younger than 1 year old tend to be lower than those of patients in other age groups.
Conclusion:  Since the relationship between the VPA concentrations of epileptic neonates and infants is noticeably different from the reference, the unbound serum VPA concentrations of these patients are not adequately estimated using the same method as that for grown-ups. The unbound VPA concentrations of neonates and infants should be explicitly determined via TDM activities.     

Diurnal variation in valproic acid clearance

Diurnal variation in total and unbound valproic acid concentrations was measured at steady state in seven healthy men and three healthy women after 250-mg oral doses every 12 hr. Total average steady-state concentration (Css) during the morning dosage interval was 50.4 mg/l. During the evening dosage interval, total Css was 45.7 mg/l. Unbound Css was also less during the evening (2.9 and 3.4 mg/l). These changes were due to higher total and unbound clearance rates during the evening dosage interval. Total peak concentrations were lower (56.8 and 64.3 mg/l) and time of peak concentrations slightly longer (2.2 and 1.8 hr) during the evening. There was marked interindividual variability in all these changes. For best reproducibility of steady-state valproic acid concentrations, our results suggest that total and unbound levels be drawn at the same time of day.     

美罗培南显著影响高龄患者丙戊酸血药浓度2例

目的：分析美罗培南使用期间对丙戊酸钠血药浓度的影响。方法：通过观察2例患者的诊治经过和文献复习的方法进行分析。结果：美罗培南和丙戊酸钠联合应用时会使丙戊酸钠浓度明显降低至治疗水平之下。结论：丙戊酸钠浓度降低可能会导致癫痫发作,临床上应避免碳青霉烯类药物和丙戊酸钠合用。两药合用时应密切监测丙戊酸钠血药浓度和患者的临床表现,必要时换用其他抗癫痫药物。     

辛伐他汀和丙戊酸钠对K562细胞增殖和凋亡的影响

目的 实验以人K562细胞株为研究对象,观察辛伐他汀及丙戊酸钠对K562细胞的增殖和凋亡的影响.方法 实验分3组,辛伐他汀组,丙戊酸钠组,辛伐他汀+丙戊酸钠组,以等客积的RPMI1640培养液为空白对照组.经瑞士-姬姆萨(Wright-Giemsa)染色,光镜下观察经辛伐他汀和丙戊酸钠处理后细胞的形态改变.MTT法检测细胞增殖抑制率.用AnnexinV-FITC/PI双重标记,经流式细胞仪检测细胞凋亡率的变化.结果 与对照组比较,10、20、40μmol/L辛伐他汀作用K562细胞48小时后凋亡半分别为(17.36±1.91)%、(23.26±2.35)%、(34.15±2.54)%;72小时后凋亡率分别为(31.43±2.15)%、(49.42±1.05)%、(56.57±3.06)%.1、2、4 mmol/L丙戊酸钠作用48小时后细胞凋亡率分别为(14.30±1.39)%、(22.90±2.35)%、(39.79±2.65)%;72小时后凋亡率分别为(22.79±2.31)%、(34.67±2.78)%、(49.51±2.37)%.细胞凋亡率随浓度和时问的增加而升高.结论 辛伐他汀和丙戊酸钠均可对K562细胞发挥增殖抑制和诱导凋亡作用,两者联合应用有一定增效作用.     

The effect of aspirin on valproic acid metabolism

Urinary valproic acid (VPA) and VPA metabolite profiles were determined before (day 1) and after (day 2) the administration of antipyretic doses of acetylsalicylic acid (ASA) to seven subjects with steady-state levels of VPA. Of the 13 metabolites assayed by GC/MS, levels of (E)-2-ene VPA and 3-keto VPA were significantly decreased on day 2, whereas those of the VPA conjugates (glucuronide) and 4-ene VPA were significantly increased. The beta-oxidation pathway consisting of (E)-2-ene VPA, 3-OH VPA, and 3-keto VPA was decreased from 24.5% +/- 10.3% of total metabolites excreted on day 1 to 8.3% +/- 4.2% on day 2, a decrease of 66% (P less than 0.05). VPA glucuronide content increased from 50.5% +/- 12.6% on day 1 to 65.5% +/- 14% of total excreted on day 2, an increase of 30% (P less than 0.05). The day 2/day 1 ratios of VPA glucuronide correlated significantly with the day 2/day 1 ratios of VPA mean free fraction (r = 0.9424; P = 0.005) in six of the seven subjects. Inhibition of VPA beta-oxidation by salicylate was sufficient to counterbalance the increased elimination of VPA as its conjugates and explains why total clearance of VPA after salicylate remains unchanged even though the free fraction of VPA is increased. Metabolic profiles indicate that salicylate likely inhibits VPA beta-oxidation by reducing valproyl-coenzyme A formation.