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。     

奥卡西平联合拉莫三嗪治疗癫痫的效果及对认知功能的影响

目的研究奥卡西平联合拉莫三嗪治疗癫痫的效果及对认知功能的影响。方法选取于我院确诊的85例癫痫患者为研究对象,随机将其分为观察组(42例,奥卡西平联合拉莫三嗪治疗)和对照组(43例,左乙拉西坦联合托吡酯治疗)。比较两组患者的治疗效果。结果两组的治疗总有效率及不良反应总发生率比较,差异无统计学意义(P>0.05)。治疗后,两组的BDNF、IGF-1水平均明显升高,且观察组显著高于对照组(P<0.05)。治疗后,两组的认知功能各项目评分均显著升高,且观察组明显高于对照组(P<0.05)。结论上述两组药物治疗癫痫效果明显,但奥卡西平联合拉莫三嗪能够显著改善患者的认知功能。     

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.     

Population pharmacokinetics of steady-state carbamazepine in Egyptian epilepsy patients

What is Known and Objective: Individualization of carbamazepine (CBZ) dosage regimen in patients with epilepsy based on based on therapeutic drug monitoring (TDM) followed by estimation of pharmacokinetic (PK) parameters can help in better control of epilepsy. Our objective was to establish a population (POP) PK model of CBZ for Egyptian adult and pediatric patients with epilepsy. Method: Single steady‐state (SS) trough plasma concentrations of CBZ were available for 302 patients with epilepsy (55·6% men and 44·4% women) who were categorized as children (n = 118) and adults (n = 184) with mean age (years) ± SD of 10·6 ± 4·8 and 29·4 ± 9·9, respectively. Carbamazepine was given as an oral suspension (n = 19) or controlled release tablet (n = 283) with average dose of 15·0 ± 7·8 mg/kg per day. A one‐compartment model with first‐order absorption and elimination for SS conditions (ADVAN2, SS2, TRANS2) was applied using NONMEM 6.2. Separate absorption rate constants were modelled for the two formulations. The mean POP CL, its intersubject variability (ISV), as well as residual error of CBZ concentration were estimated. Results and Discussion: The POP estimate for CL was 3·5 L/h with coefficient of variation value of 2·6%, which was consistent with literature data. The ISV on CL was 44·5%. The POP PK model was validated by bootstrap re‐sampling, and the individual estimates were within the 95% CI of the bootstrap results. Different covariates that might affect CBZ CL have been evaluated but the limited number of samples per individual prevented precise covariate analysis. What is New and Conclusion: The POP PK model we have developed for CBZ shows good predictive performance in Egyptian adult and pediatric patients with epilepsy. Another PK study to better define the effect of different covariates would improve on the model for dosage individualization.     

Effect of vigabatrin on the pharmacokinetics of carbamazepine

OBJECTIVE: To evaluate a possible interaction between vigabatrin and carbamazepine in epileptic patients. METHODS: Steady-state serum concentrations of carbamazepine with and without vigabatrin were compared. The study group consisted of 15 patients (eight females, seven males, and mean age 31 +/- 12 years), with refractory partial epilepsy. They received vigabatrin as add-on therapy. Patients received carbamazepine monotherapy for at least 6 months and the carbamazepine-vigabatrin combination for at least 3 months. Blood samples were obtained in the morning, before the first daily dose and the carbamazepine plasma concentrations were analysed by fluorescence polarization immunoassay (TDx System). RESULTS: No statistically significant differences were found in mean carbamazepine daily dose. Mean trough concentrations were 7.9 +/- 1.4 microg/mL with carbamazepine alone, and 6.5 +/- 2.0 microg/mL with carbamazepine-vigabatrin association (P < 0.03). The mean values of pharmacokinetic parameters were: level/dose ratio (L/D) = 0.59 +/- 0.20 vs. 0.45 +/- 0.15 (P < 0.05) and plasma clearance (Cl) = 78.5 +/- 25.8 vs. 105.8 +/- 38.9 mL/h/kg (P < 0.05), with carbamazepine alone and carbamazepine-vigabatrin combination, respectively. CONCLUSION: Vigabatrin produced a statistically significant increase in the plasma clearance of carbamazepine when the two drugs were given simultaneously.     

Clinical evaluation of five therapeutic drugs using dry film multilayer technology on the OPUS immunoassay system.

Five therapeutic drug assays, carbamazepine, phenobarbital, phenytoin, theophylline, and valproic acid, were evaluated using an automated random access system for performing thin dry film multilayer competitive immunoassays, the OPUS analyzer. All reagents for the therapeutic drug assays are contained in a coated multilayer film chip encased within a plastic bar-coded test module and require no external or supplementary reagents. A serum or plasma sample is applied to the test module by the instrument and the fluorescence intensity from the module is measured after 6 minutes. We found the OPUS assays acceptable for clinical use. Within-run coefficient of variations were 2.3-6.7%, between-run, 2.9-7.6%. These methods correlated well with the Abbott TDx, having correlation coefficients of 0.92-0.97. Because of the instrument design and the stability of the reagents, weekly calibration is not needed and samples can be run immediately upon receipt in a random access fashion or can be batched together.     

Adult-onset of Mitochondrial Myopathy,Encephalopathy, Lactic Acidosis,and Stroke-Like Episodes (MELAS) Syndrome Presenting as Acute Meningoencephalitis: A Case Report

Background: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder with a wide range of multisystemic symptoms. Epileptic seizures are common features of both MELAS and meningoencephalitis and are typically treated with anticonvulsants. Objectives: To provide the reader with a better understanding of MELAS and the adverse effects of valproic acid. Case Report: A 47-year-old man with a history of diabetes, hearing loss, sinusitis, and otitis media was brought to our emergency department due to acute onset of fever, headache, generalized seizure, and agitation. Because acute meningoencephalitis was suspected, the patient was treated with antibiotics on an empirical basis. The seizure activity was aggravated by valproic acid and abated after its discontinuation. MELAS was suspected and the diagnosis was confirmed by the presence of a nucleotide 3243 A→G mutation in the mitochondrial DNA. Conclusion: Detailed history-taking and systematic review help emergency physicians differentiate MELAS from meningoencephalitis in patients with the common presentation of epileptic seizures. Use of valproic acid to treat epilepsy in patients suspected of having mitochondrial disease should be avoided. Underlying mitochondrial disease should be suspected if seizure activity worsens with valproic acid therapy.     

健康行为训练对学龄期癫痫患儿治疗依从性及生活质量的影响

[目的]探讨健康行为训练对学龄期癫痫患儿治疗依从性及生活质量的影响。[方法]将学龄期癫痫患儿87例随机分为研究组和对照组,两组患儿均给予相同的健康教育,但仅研究组实施健康行为训练。在患儿出院6个月时进行效果评价。[结果]研究组患儿的服药依从性、药物自我管理能力及对药物治疗效果的满意程度均明显优于对照组(P<0.05);生活质量除精力状态外,其余因子分研究组明显高于对照组(P<0.01)。[结论]健康行为训练可提高学龄期癫痫患儿的治疗依从性、治疗效果及生活质量。     

健康行为训练对学龄期癫痫患儿治疗依从性及生活质量的影响

[目的]探讨健康行为训练对学龄期癫痫患儿治疗依从性及生活质量的影响。[方法]将学龄期癫痫患儿87例随机分为研究组和对照组，两组患儿均给予相同的健康教育，但仅研究组实施健康行为训练。在患儿出院6个月时进行效果评价。[结果]研完组患儿的服药依从性、药物自我管理能力及对药物治疗效果的满意程度均明显优于对照组（P〈0．05）；生活质量除精力状态外，其余因子分研究组明显高于对照组（P〈0．01）。[结论]健康行为训练可提高学龄期癫痫患儿的治疗依从性、治疗效果及生活质量。     

拉莫三嗪联合丙戊酸钠治疗小儿癫痫临床观察

目的探讨拉莫三嗪联合丙戊酸钠治疗小儿癫痫的效果及安全性。方法 116例癫痫患儿根据治疗方法分为联合组（拉莫三嗪联合丙戊酸钠治疗）58例,对照组（单用丙戊酸钠治疗）58例,比较2组总治疗效果、不同癫痫发作类型的治疗效果及不良反应。结果治疗12个月后,联合组无发作36例,显效10例,有效6例,无效6例,总有效率89.7%;对照组无发作30例,显效7例,有效5例,无效16例,总有效率72.4%,2组总有效率比较差异有统计学意义（P〈0.05）;联合组治疗单纯部分发作、复杂部分发作、继发性全身发作、全身强直阵挛发作及肌阵挛发作有效率均高于对照组（P〈0.05）;不良反应发生率联合组（12.1%）与对照组（10.3%）比较差异无统计学意义（P〉0.05）。结论拉莫三嗪联合丙戊酸钠治疗各种类型癫痫效果均较好,且不良反应轻。     

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.     

Hyperammonemia and Coma without Hepatic Dysfunction Induced by Valproate Therapy

The authors report a case of a 41-year-old mentally disabled man with bipolar disorder who presented to the emergency department with altered mental status. He was found to have a significantly elevated ammonia level (377 microM/L) with no signs of hepatic insufficiency. His coma and hyperammonemia were attributed to his chronic valproate therapy. This patient had the highest serum ammonia level ever reported with a therapeutic valproate level in the absence of any other anticonvulsant therapy, metabolic abnormality, or hepatic dysfunction. The authors discuss this case and review the current literature on hyperammonemia in valproic acid therapy and the use of L-carnitine in these patients.     

托吡酯与卡马西平治疗老年癫痫的疗效比较

目的:观察比较托吡酯与卡马西平治疗老年癫痫的临床效果。方法:将2014年2月~2015年2月我院纳入的80例老年癫痫患者分为对照组与观察组,每组40例。对照组给予卡马西平口服治疗,观察组则采用托吡酯口服治疗。比较两组疗效,统计用药结束后3、6个月时癫痫发作次数。结果:观察组治疗总有效率95.0%,较对照组明显更高,组间差异具有统计学意义(P0.05)。与对照组相比,用药结束后3、6个月观察组患者的癫痫发作次数更少(P0.05)。对照组中不良反应发生率27.5%,明显高于观察组的10.0%(P0.05)。结论:在老年癫痫患者临床用药中,托吡酯疗效确切,可有效控制患者癫痫发作次数,安全性高,值得推广应用。     

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.     

Influence of administration vehicles and drug formulations on the pharmacokinetic profile of lamotrigine in rats

Given that administration vehicles and drug formulations can affect drug bioavailability, their influence on the pharmacokinetic profile of lamotrigine (LTG), a new-generation anti-epileptic drug, was studied in rats. Three different formulations administered intraperitoneally at a dose of 10 mg/kg were used: (1) LTG suspended in a 0.25% methylcelulose solution, (2) LTG dissolved in a 50% propylene glycol solution, and (3) LTG isethionate dissolved in distilled water. Plasma and brain homogenate levels were determined in order to evaluate vehicle-dependent drug absorption. The results demonstrated rapid absorption of LTG when it was administered as an aqueous solution, in contrast to a slower and more erratic absorption after the injection of either the lipophilic solution or the suspension. A plasma peak was achieved 15 min post-dose with the aqueous solution, with a brain peak being achieved 15 min later, while with the other formulations both plasma and brain homogenate peaks were reached 2 h after LTG administration. This study suggests that LTG isethionate dissolved in distilled water is the most suitable formulation for successful LTG pharmacokinetic studies in rats.     

拉莫三嗪与碳酸锂治疗双相障碍急性抑郁发作对照研究

目的评价拉莫三嗪治疗双相障碍急性抑郁发作的疗效及安全性。方法采用随机、平行对照的方法将117例双相障碍抑郁发作患者分别以拉莫三嗪（n=59）和碳酸锂治疗（n=58）,疗程8周,分别于治疗前和治疗后第1周、2周、4周、6周、8周末以汉密尔顿抑郁量表、Young躁狂评定量表及临床疗效总评量表评价疗效,副反应量表评定不良反应。结果拉莫三嗪治疗组有效率为67．8％（40／59）,碳酸锂组为72．4％（42／58）,两组疗效差异无显著性（P〉0．05）。拉莫三嗪组的药物不良反应发生率（23．7％）显著低于碳酸锂组（41．3％）（P〈0．05）。结论拉莫三嗪与碳酸锂治疗双相障碍急性抑郁发作均有效,但前者不良反应较少,安全性好。     

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.     

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.