抗癫痫药物对血清叶酸水平的影响

【目的】探讨抗癫痫药物对癫痫患 者血清叶酸水平的影响。【方法】测定了８３ 名使用单一药物治疗的癫痫患者和４ ４ 名癫痫对照者及３５ 名健康对照者的血清叶酸浓度。另对２５ 名癫痫患者 作服 药 前后 的自 身 对照 观 察。【结果】单 独服用 卡马西 平和 苯妥 因钠 的癫痫 患者,其叶酸 浓度较服药前明显下降,前 后比较差异有显著性（ 均 Ｐ ＜ ０ ．０１） ;而服用丙戊酸者则服药前后叶酸浓度无明显变化（ Ｐ ＞ ０ ．０ ５） 。【结论】卡马西平、苯妥因钠可降低癫痫患者的血清叶酸水平,而丙戊酸无此效应。     

Influence of age and comedication on steady-state clonazepam serum level–dose ratios in Japanese epileptic patients

BACKGROUND: In antiepileptic drugs, the marked inter- and intrapatient variability of the level-dose ratio makes it difficult to predict serum concentrations from the administered per kg dose. It is therefore important to identify factors, such as age and comedication, that could contribute to this observed variability. OBJECTIVE: To investigate the effect of age and comedication on clonazepam (CZP) level-dose (L/D) ratios. METHOD: A retrospective evaluation of data from 137 epileptic patients who had received clonazepam. RESULTS: The CZP L/D ratio increased slowly with age up to 15 years in patients on monotherapy. Associated antiepileptic therapy affected the CZP L/D ratio, which was significantly reduced in patients on polytherapy as compared to patients on monotherapy. CONCLUSION: The study therefore suggests that routine monitoring of CZP serum levels is extremely useful, especially in the paediatric age group, and in patients who require associated antiepileptic medication.     

Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients

Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam-valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0.3-32.6 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 144.0 TBW-0.172 1.14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 17.2 TBW-0.264 DOSE0.159 0.821CZP 0.896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17.9% decrease in valproic acid clearance.     

High-Dose Versus Low-Dose Valproic Acid as a Prophylactic Medication

Valproic acid has been shown to be effective in migraine prophylaxis. Its method of action is believed to be the inhibition of gamma-aminobutyric acid transaminase. The therapeutic dose needed to prevent migraine headaches has been examined in several studies, yet the optimum dose has not been found. In this case report, valproic acid was given to a 24-year-old woman with chronic headaches at 1000 mg per day. Her headaches resolved for 2 months. She tapered herself off of the medication, and her headaches returned. She was restarted at 500 mg per day of valproic acid and again, her headaches resolved. She preferred being on the lower dose which she found as effective as the higher dose. Her case makes two interesting points. The first is that lower dosages of valproic acid may be as effective as higher ones in headache prophylaxis. The second is that more studies looking at dose ranges are needed to correlate effectiveness with daily requirements.     

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.     

Epileptic seizures caused by low valproic acid levels from an interaction with meropenem

A 55-year-old woman was diagnosed with pneumonia and was treated with meropenem; 5 days later she developed epileptic seizures. She had been treated with valproic acid for 16 years to control her epileptic seizures. Her serum valproic acid concentration was low during treatment with meropenem than previously recorded despite an increase of valproic dose. As soon as administration of meropenem was withdrawn, valproic acid concentration increased to previous levels and her seizures stopped. Meropenem decreases valproic acid concentration, and may promote the development of epileptic seizures in previously controlled epileptic patients. The acute lowering of serum valproate produced by meropenem probably precludes their concomitant use.     

Efficacy and tolerability of intravenous valproic acid in acute adolescent migraine

OBJECTIVE: To describe the efficacy and tolerability of rapid intravenous valproic acid (VPA) infusions in children with severe migraine headache. BACKGROUND: Intravenous VPA is an emerging treatment option for acute migraine headache. Adult data suggests both efficacy and tolerability of rapid VPA infusions as abortive therapy, but little data exist in children. METHODS: We conducted a retrospective chart review of all children who received intravenous VPA at The Children's Hospital Headache Clinic during an 18--month study period. Baseline intensity of headache pain, time at which maximum relief was attained, pain reduction following therapy, dose and duration of VPA infusion(s), patient's pulse, blood pressure, respiratory rate, and pulse oximetry were collected. Adverse events were also recorded. RESULTS: Thirty-one children (age=15+/- 2 years; 81% female) requiring 58 clinic visits and 71 VPA infusions were included. Most visits (n=45; 78%) resulted in only one dose of VPA (976+/- 85 mg infused over 12+/- 4 minutes) for desired pain relief. Percent pain reduction in those children was 39.8%, with time to maximum relief of 63+/- 31 minutes. Some children required a second dose of 500 mg (n=13 visits; 22%), that was infused over 14+/- 6 minutes and produced a 57% reduction in pain intensity from baseline. VPA infusions were well tolerated. Adverse events described included cold sensation (1), dizziness (3), nausea (1), possible absence seizure (1), paraesthesia (2), and tachycardia (2). CONCLUSIONS: Rapid infusion of intravenous VPA is generally well tolerated and may play a role in the management of children with acute migraine headache. Prospective, controlled trials to further investigate this treatment in children are warranted.     

Benign juvenile myoclonic epilepsy

Two patients with long-standing, poorly controlled seizures presented to a university hospital emergency department. Both patients had myoclonic jerks on waking and evidence of absence seizures as well as generalized tonic-clonic seizures. A diagnosis of benign juvenile myoclonic epilepsy was made, and the seizures were controlled with valproic acid.     

添加叶酸对服丙戊酸钠癫痫患者疗效影响的研究

[目的]研究添加叶酸（FA）治疗对服丙戊酸钠（VPA）癫痫患者疗效的影响.[方法]观察20例单服VPA及20例服VPA加FA两组癫痫患者治疗前后月均发作频率、临床疗效、脑电图（EEG）变化、血药浓度,并进行比较.[结果]单服VPA组及VPA加FA组治疗后的月均发作频率均较治疗前明显减少,分别为92.82%及95.23%,两组间差异无显著性（P＞0.05）;两组治疗后的显效率及总有效率差异无显著性（P＞0.05）;两组治疗后VPA血药浓度平均值及EEG改善率比较差异无显著性（P＞0.05）.[结论]服VPA癫痫患者每天添加叶酸5 mg不影响患者疗效.     

均相酶增强免疫法监测丙戊酸浓度及临床应用

目的探讨均相酶增强免疫(Emit)法监测丙戊酸的方法评价及其在癫痫患者中的临床意义。方法采用均相酶增强免疫法测定质控品和癫痫患者血清丙戊酸浓度,并对测定结果进行分析。结果均相酶增强免疫法测定丙戊酸的精密度;批内变异系数(CV)值为2.52%～5.70%,批间CV值为2.70%～4.85%;回收率为98.4%～105.4%,平均102.1%。210例癫痫患者391例次丙戊酸血药浓度测定中,205例次(52.4%)丙戊酸血药浓度在有效治疗范围(50～100mg/L)内;152例次(38.9%)血药浓度小于50mg/L;34例次(8.7%)血药浓度大于100mg/L。结论均相酶增强免疫法监测丙戊酸浓度简便、可行、快速,是一种理想的检测方法;合理设定丙戊酸有效血药浓度范围(50～100mg/L),临床治疗过程加强丙戊酸血药浓度监测,是保证疗效和安全的重要措施。     

Lack of pharmacokinetic interaction between valproic acid and a traditional Chinese medicine, Paeoniae Radix, in healthy volunteers

BACKGROUND AND OBJECTIVE: In addition to the standard antiepileptic drugs, traditional Chinese medicines (TCMs) are used for the treatment of epilepsy in oriental countries. The interactions between antiepileptic drugs and TCMs represent a potential problem in clinical application. Because valproic acid (VPA), one of the most widely prescribed antiepileptic drugs, may be administered concomitantly with Paeoniae Radix (PR), one of the famous TCMs, in some epileptic patients, the present study was conducted to evaluate the influences of PR on the pharmacokinetics of VPA. METHOD: The pharmacokinetics of VPA were investigated in a randomized, open-label, two-way crossover study. Six healthy volunteers received the following treatments in a crossover design: (i) 1.2 g extract powder of Paeoniae Radix once daily for 7 days and one 200 mg VPA gastro-resistant tablet on day 7 and (ii) one 200 mg VPA gastro-resistant tablet alone on day 7. Serial plasma samples were obtained on day 7. Total and free (unbound) VPA plasma concentrations were determined by fluorescence polarization immunoassay (FPIA). Safety measures included laboratory tests (haematology, serum chemistry and urinalysis) and adverse event monitoring. Statistical comparisons of pharmacokinetic parameters were performed with the Student paired t-test. RESULTS: Overall clinical safety was satisfactory. The mean maximum plasma concentration of VPA was attained at within 6 h after oral administration of VPA alone and 3-4 h after oral administration of VPA in combination with PR. The plasma level of VPA declined with a half-life of 11.71 and 11.91 h, respectively. No statistically significant difference was obtained in any of the pharmacokinetic parameters (Tmax, Cmax, AUC, t1/2, MRT, CL/F and Vd/F) of VPA between the two treatments. Also, there was no significant difference in the protein binding rates of VPA. CONCLUSION: PR did not significantly affect the absorption, distribution, metabolism and elimination of VPA in healthy volunteers.     

丙戊酸钠与氟西丁联合治疗躯体形式障碍的疗效现察

[目的]比较丙戊酸钠联用氟西丁与单用氟西丁治疗躯体形式障碍的临床疗效和安全性.[方法]将73例躯体形式障碍的患者,随机分为丙戊酸钠联用氟西丁组及氟西丁组,疗程4周,用汉密尔顿抑郁量表(HAMD)评定疗效,用副反应量表(TESS)评定不良反应.[结果]丙戊酸钠联用氟西丁组显效率67.6%,总有效率91.9%;氟西汀组显效率44.4%,总有效率75%,二组显效率比较,u=2.06,P＜0.05,有显著差异,副反应无显著性差异.[结论]丙戊酸钠联用氟西汀治疗躯体形式障碍,疗效好于单用氟西丁治疗,而且安全.     

Analytical performance evaluation of a new turbidimetric immunoassay for valproic acid on the ADVIA 1650 analyzer: effect of gross hemolysis and high bilirubin

Valproic acid is an anticonvulsant that requires careful therapeutic drug monitoring. Valproic acid is also used in psychiatric patients. Bayer Diagnostics (Tarrytown, NY) recently marketed a turbidimetric immunoassay for monitoring valproic acid concentrations in serum or plasma using the ADVIA 1650 analyzer. We evaluated the performance of this new assay by comparing it with a widely used fluorescence polarization immunoassay (FPIA) on the AxSYM analyzer (Abbott Laboratories, Abbott Park, IL). The total coefficient of variation (CV) for the low control of this new assay was 6.8% (mean = 30.7, SD = 2.1 microg/mL, n = 44) while the corresponding CVs for the medium and high controls were 3.3% (mean = 81.0, SD = 2.7 microg/mL, n = 44) and 5.9% (mean = 142.9, SD = 8.4 microg/mL, n = 44), respectively. The assay is linear up to a serum valproic acid concentration of 170 microg/mL, and the detection limit is 4.4 microg/mL. We observed an excellent correlation between the FPIA of valproic acid and the turbidimetric assay using specimens from 52 different patients who were receiving valproic acid. Using the valproic acid concentrations obtained by the FPIA as the x-axis, and the corresponding valproic acid concentrations obtained by the turbidimetric assay as the y-axis, we developed the following regression equation: y = 1.03 x+1.55 (r = 0.98). With this new assay, high concentrations of bilirubin (unconjugated 30 mg/dL and conjugated 30 mg/dL) and gross hemolysis (4+, hemoglobin: 1,500 mg/dL) have no effect on measurements of valproic acid concentration. We conclude that the new turbidimetric assay for valproic acid can be used for routine therapeutic drug monitoring of valproic acid in clinical laboratories.     

Valproic Acid Treatment of Chronic Daily Headache

The efficacy of valproic acid in the treatment of intractable chronic daily headache, unresponsive to traditional prophylactic medications, was examined prospectively in 16 patients. Dosage of the medication was adjusted to maintain serum valproic acid levels between 50 and 100 μg/mL, provided there were no significant side effects at that level. Valproic acid prophylaxis was of some benefit in only 2 of 16 patients. One of these two patients discontinued therapy due to side effects. Eight of the 16 patients reported side effects which included nausea, diarrhea, anorexia, lethargy, sleepiness, confusion, blurred vision, and decreased libido. In conclusion, valproic acid was not effective in controlling chronic daily headache in the majority of patients in whom conventional therapy had failed, and 50% of patients reported side effects. There is a significant disparity in the reported efficacy of this drug in treating chronic daily headache. This disparity is most likely due to the poorly-defined nature of this variety of headache. It is, therefore, recommended that more stringent definition of this disorder be developed before therapeutic regimens are evaluated.     

Successful reintroduction of valproic acid after the occurrence of pancytopenia

Background

Valproic acid is associated with a variety of hematologic abnormalities, most commonly thrombocytopenia. Pancytopenia is much less common and potentially much more serious. Little is known about the natural course of valproate-induced pancytopenia.

Case summary

We present a patient who developed pancytopenia while taking valproic acid for bipolar illness. After failing to respond to several other mood stabilizers, valproic acid was cautiously reintroduced with close hematologic monitoring. The pancytopenia has not recurred in the past 6 months.

Conclusions

Pancytopenia may not represent an absolute contraindication to continuing valproate therapy, although caution is warranted.     

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.     

癫痫患者中拉莫三嗪联合治疗转为单药治疗的血药浓度变化

目的:研究小剂量拉莫三嗪(LTG)与丙戊酸(VPA)联合治疗新诊断癫痫转为LTG单药治疗后的血药浓度变化。方法:选取经小剂量LTG与VPA联合治疗6个月后发作完全控制的癫痫患者35例,逐渐减掉VPA,采用LTG单药治疗,随访6个月。记录患者的癫痫发作频率、不良反应及LTG血药浓度。结果:35例患者中有2例失访,33例完成半年随访,其中转LTG单药治疗后出现癫痫发作2例(6.1%),无发作31例(93.9%);药物转换期LTG血药浓度较转单药治疗前LTG血药浓度增高(P0.05),停用VPA1周时、单药治疗6个月时的LTG血药浓度与单药治疗前对比差异无统计学意义(P0.05),2例复发患者发作时血药浓度与无发作患者血药浓度相比差异无统计学意义(P0.05)。结论:LTG与VPA联用能使LTG的血药浓度加倍且临床疗效显著增强,小剂量LTG与VPA联合治疗新诊断癫痫转为LTG单药治疗时应将LTG剂量加倍。