Influence of coadministered antiepileptic drugs on serum zonisamide concentrations in epileptic patients: quantitative analysis based on suitable transforming factor

We conducted a study to clarify the most suitable transforming factor related to the daily zonisamide dose (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from a total of 175 epileptic patients treated with the multiple oral administrations of zonisamide (ZNS) as a powder/tablets, were used for the analysis. Employing the extracellular water volume (V(ECW)) as a transforming factor, led the level/dose (L/D) ratio (:C(t)/(D/V(ECW))) to be independent of the patient's age and sex for the administration of ZNS alone. C(t) was revealed to be dependent on only one variable regarding D/V(ECW) and expressed as C(t)=0.604x(D/V(ECW)). Phenytoin (PHT) significantly lowered (p<0.01) the L/D ratio to 0.76 of the value for ZNS alone. For a more detailed analysis, we defined the parameter R(i) (i=1, 2, em leader, 6) as an alteration ratio, representing the influence of each antiepileptic drug on the L/D ratio of ZNS alone. A model based on the assumption that each R(i) value was independent from one another and multiplicative, was adopted. The analysis clarified that phenobarbital, valproic acid, carbamazepine, and PHT significantly lowered (p<0.05) the L/D ratio of ZNS to 0.849, 0.865, 0.846, and 0.804, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated L/D ratios were calculated using the value of each R(i) and compared with the measured ones. The mean of prediction error was calculated as 22.9%. Our results appear valid and R(i) should be available for clinical use.     

Influence of coadministered antiepileptic drugs on serum phenobarbital concentrations in epileptic patients: quantitative analysis based on a suitable transforming factor

This study investigated most suitable transforming factor related to the daily Phenobarbital dose (D) providing a steady-state serum concentration (Ct) and analyzed the influences of concomitant antiepileptic drugs on Ct quantitatively. Data obtained by routine therapeutic drug monitoring from a total of 326 epileptic patients treated with multiple oral administrations of phenobarbital (PB) as a powder, were used for the analysis. A total of 156 patients were administered PB alone, and 92, 57, and 21 patients were coadministered one, two, and three different antiepileptic drugs, respectively. Valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), zonisamide (ZNS), clonazepam, and ethosuximide were coadministered with PB. For administration of PB alone, four types of transforming factor corresponding to clearance, i.e., total body weight, total body water volume, body surface area and extracellular water volume (VECW) were proposed. With VECW as a transforming factor, the level/dose (L/D) ratio (:Ct/(D/VECW)) was independent of the patient's age and gender. Ct was dependent on only one variable regarding D/VECW and expressed as Ct=0.989 x (D/VECW). The coadministration of one drug caused a difference in the gradient of the regression line of PB alone, and the influence of each drug was detected by dividing each mean L/D ratio of PB plus one other drug by that of PB alone. VPA, CBZ, and PHT significantly increased (p<0.01) the L/D ratio to 1.48, 1.35, and 1.23 of the value for PB alone, respectively. With coadministration of multiple drugs, the L/D ratio rose significantly (p<0.05) as the number (< or =2) of drugs coadministered increased regardless of the type, and also increased with the concomitant use of 3 drugs compared with 2 drugs. For a more detailed analysis, we defined the parameter eta(i) (i=1, 2, ..., 6) and an alteration ratio Ri, representing the influence of each antiepileptic drug on the L/D ratio of PB alone. A model based on the assumption that each coadministered drug competitively inhibited PB-metabolizing enzyme, was adopted. The analysis clarified that VPA, CBZ, and PHT significantly increased (p<0.05) the L/D ratio of PB to 1.466, 1.177, and 1.186, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated L/D ratios were calculated using the value of each Ri and compared with the measured value. The mean of prediction error was calculated as 23.1%. Our results appear valid and Ri should be available for clinical use.     

Effects of concomitant antiepileptic drugs on serum carbamazepine concentration in epileptic patients: quantitative analysis based on extracellular water volume as a transforming factor

The effects of concomitant antiepileptic drugs on the serum carbamazepine concentration (C1) were analyzed quantitatively. Primidone (PRM), phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), zonisamide (ZNS), clonazepam (CZP), and ethosuximide (ETS) were coadministered with carbamazepine (CBZ). Routine therapeutic drug monitoring data, obtained from epileptic patients who were treated with the repetitive oral administration of CBZ fine granules/tablets, were used for the analysis. A total of 119 patients were administered CBZ alone, and 91, 39, 19, and 6 patients were coadministered one, two, three, and more than four different antiepileptic drugs, respectively. Using the data obtained from the patients administered CBZ alone, Ct could be expressed approximately as a function of the daily dose per extracellular water volume (D/VECW) as Ct = A(D/VECW)B (A, B: parameter). By comparing the regression line on log Ct vs. log(D/VECW) for CBZ alone with that for CBZ plus another concomitant drug, Ct was thus found to be affected at each definite ratio by PB and PHT, but not by VPA and ZNS. We postulated a model showing that Ct is affected by each concomitant antiepileptic drug i at each definite ratio. We defined the parameter Ri(i = 1, 2, ..., 7) representing the effect of each concomitant antiepileptic drug on Ct. A linear polynomial expression, in which both members of this model are converted into common logarithms, was used for a multiple regression analysis. The analysis clarified that PB and PHT lowered Ct to 0.770 and 0.710 the value of CBZ alone, respectively. On the other hand, VPA and ZNS did not affect Ct. The number of patients coadministered PRM, CZP, and/or ETS was not sufficient to detect the effect on Ct based on a test of significance. In the case of the addition or discontinuation of concomitant antiepileptic drugs in the same patient, the estimated Ct values were calculated using the value of each Ri and compared with the measured Ct values. Both values were in good agreement, and thus our results appear valid.     

Postmortem serum protein binding and brain concentrations of antiepileptic drugs in autoptic specimens from 45 epileptic patients

The free fraction of antiepileptic drugs can, in certain diseases, be greatly increased in the serum. In order to study the significance of this increase for the concentration in the brain, the postmortem concentrations of phenytoin (PT), phenobarbital (PB), carbamazepine (CBZ), and its metabolite carbamazepine-10,11-epoxide (CE) in the serum (total and free), as well as in specimens of the frontal cortex of 45 epileptic patients who died from various causes, were determined. The postmortem free fractions were higher than reported in the literature and varied considerably from subject to subject. For PT the free fraction was 21.7% (median), for PB 68.0%, for CBZ 33.4%, and for its metabolite CE 53.6%. The values for a control group of 236 otherwise healthy epileptic patients were in agreement with those given in the literature, namely 10.4% for PT, 55.6% for PB, 20.9% for CBZ, and 42.5% for CE. Using a nonparametric correlation coefficient (Kendall T), the concentrations in the frontal cortex of the autopsied patients correlated with the postmortem free serum concentrations, especially for the substances with high protein binding (PT and CBZ), better (PT r = 0.88, PB r = 0.86, CBZ r = 0.87, CE r = 0.79) than with the total concentrations (PT r = 0.69, PB r = 0.80, CBZ r = 0.77, CE r = 0.77). The study indicates that in critically ill patients the determination of the free concentration in serum is indispensable. If treatment is orientated solely on the total concentration, unexpectedly high concentrations in the brain and hence possible intoxication of the patient in the critical or final state can result.     

Effects of antiepileptic drugs on concentration of serum proteins and immunoglobulins of epileptic patients

Serum of normal volunteers and serum of epileptic patients receiving either a single drug or combined antiepileptic therapy with Phenytoin (Phen); Carbamazepine (Cbz); Primidone (Prim); Phenobarbital (Phb) were examined and showed: No differences with regard to total proteins, albumins and A/G ratio. The alpha 1-globulin fraction increased to 4.4% with Phen/Cbz (P less than 0.001) and decreased to 1.7% with Phen/Prim = (P less than 0.001). The alpha 2-globulins corresponded to 7.2% (P less than 0.001) with Phen/Prim and 15.5% (P less than 0.001) with Phen/Phb treatments. beta-Globulins decreased to 7.1% (P less than 0.05) when received Phen/Phb treatment. Low concentrations of serum gamma-Globulins were found in Phb (P less than 0.001), Prim (P less than 0.001, Phen (P less than 0.001) treated patients. However, with Cbz, Phen/Phb, Phen/Prim this electrophoretic fraction remained within the upper range of normal. IgA of patients treated with Phen showed a mean of 60 mg/dl. Those patients with Phen serum levels below or above 12-20 micrograms/ml remained normal. Prim and Phb treatment also decreased IgA. IgD was normal in patients treated with Phen/Prim. Alterations of immune humoral responses to all antiepileptic drugs were found.     

Effect of phenothiazines on serum antiepileptic drug concentrations in psychiatric patients with seizure disorder

The intrapatient effect of starting (group A, n = 16), increasing (group B, n = 19), decreasing (group C, n = 23), and discontinuing (group D, n = 34) the phenothiazines (PHZs) thioridazine, chlorpromazine, or mesoridazine on serum phenytoin (PHT), phenobarbital (PB), and primidone (PRI) was studied at a constant antiepileptic drug regimen and between two consecutive steady-state concentration determinations in 92 institutionalized epileptic patients with psychiatric disorders. For PHZ initiation or dosage increase (groups A and B), serum PHT and PHT concentration-to-dose ratio (C/D) decreased by 44 (p less than 0.001) and 41.6% (p less than 0.001) in group A, and 32.9 (p less than 0.001) and 35.3% (p less than 0.005) in group B, respectively. For PHZ dosage decrease or discontinuation (groups C and D), serum PHT and C/D ratio increased by 54.8 (p less than 0.001) and 51.3% (p less than 0.01) in group C, and 71.2 (p less than 0.001) and 69.2% (p less than 0.001) in group D, respectively. The changes for PB were in the same direction, although to a lesser extent. No statistically significant differences were noted for PRI. For groups A and B, the clinical trend was for increase in number of seizures when PHZs were started or dosage increased. For groups C and D, a clear trend for PHT intoxication was evident when PHZ dosages were decreased or discontinued.     

The problem of osteoporosis in epileptic patients taking antiepileptic drugs

Introduction: Epilepsy is a common neurological disorder associated with recurrent seizures. Therapy with antiepileptic drugs (AEDs) helps achieve seizure remission in approximately 70% of epileptic patients. Treatment with AEDs is frequently lifelong and there are reports suggesting its negative influence on bone health. This is especially important in terms of general occurrence of osteoporosis, affecting over 50 million people worldwide.

Areas covered: This study refers to two main groups of AEDs: hepatic enzyme inducers (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone and topiramate) and non-inducers (clobazam, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, tiagabine, valproate, vigabatrin and zonisamide). Some reports indicate that enzyme inducers may exert a more negative influence on bone mineral density (BMD) compared to non-inducers. Bone problems may appear in both sexes during AED therapy, although women are additionally burdened with postmenopausal osteoporosis. Supplementation of vitamin D and calcium in patients on AEDs is recommended.

Expert opinion: Apart from enzyme inducers, valproate (an even enzyme inhibitor) may also negatively affect BMD. However, the untoward effects of AEDs may depend upon their doses and duration of treatment. Although the problem of supplementation of vitamin D and calcium in epileptic patients on AEDs is controversial, there are recommendations to do so.     

抗癫痫药物血药浓度检测的临床分析

目的通过对临床常用一线抗癫痫药物的血药浓度检测结果进行分析,为临床个体化给药治疗提供参考依据,确保用药安全。方法选择2011年1月至2012年12月新乡医学院第三附属医院药剂科收治的癫痫患者350例,根据患者的自愿原则分为卡马西平组（110例）、苯妥英钠组（90例）、苯巴比妥组（80例）和丙戊酸钠组（70例）。采用高效液相色谱法测定卡马西平、苯妥英钠、苯巴比妥、丙戊酸钠4种抗癫痫药物在各组患者体内的血药浓度,并对结果进行分析评价。结果不同年龄与血药浓度差异有统计学意义（P〈0．01）。结论对抗癫痫药物的血药浓度进行检测,有利于临床医师为患者设计个体化给药方案,保证用药安全,减少药物不良反应的发生。     

Dosing accuracy of antiepileptic drug regimens as determined by serum concentrations in outpatient epilepsy clinic patients

To evaluate the ability of clinicians to accurately dose antiepileptic drugs (AEDs), 2,958 serum concentrations in two outpatient epilepsy clinics were studied. Serum concentrations of phenytoin (PHT) were significantly less likely to fall within the therapeutic range (TR) when compared to carbamazepine (CBZ) or phenobarbital (p less than 0.0001) even when there was evidence that patient compliance was good. This difference remained significant when the second through fourth follow-up serum concentrations were analyzed. PHT concentrations were more likely to be below than above the TR (p less than 0.0001). CBZ concentrations were least likely of the three AEDs to be below the TR (p less than 0.01). Analysis of factors influencing AED metabolism and of data from previous studies implies that saturable metabolism and variable time to steady state for PHT are responsible for these findings. These results support the increased use of dosing aids for PHT that may help clinicians more accurately choose PHT doses and estimate time to steady state.     

223例小儿抗癫(间)药物血药浓度监测及其临床意义

目的 :探讨小儿抗癫药物 (AED)治疗过程中血药浓度的改变及其临床意义。方法 :采用HPLC法 ,测定 2 2 3例 6 44人次患儿单一AED治疗时的血药浓度 ,比较血药浓度与疗效及不良反应的关系。结果 :40 %以上监测浓度在有效血药浓度(治疗窗 )范围内 ;苯妥英钠 (PHT)血药浓度为 (13 6 8± 6 79)mg·L-1,卡马西平 (CBZ)为 (6 48± 2 6 6 )mg·L-1,苯巴比妥 (PB)为(2 4 0 5± 15 73)mg·L-1,丙戊酸钠 (VPA)为 (6 6 5 6± 2 1 2 0 )mg·L-1。调整剂量后癫发作控制率平均接近 70 % ,以VPA效果最佳 ,CBZ次之。虽然PHT血药浓度在治疗窗内时发作控制率优于治疗窗外 ,但差异并无显著性意义 (P >0 0 5 ) ,CBZ及VPA的监测浓度在治疗窗内时的疗效较优于非治疗窗者 (P <0 0 5 )。PB的组内控制率比较与PHT相似。EEG的改善与临床症状不一致 ,好转趋势以VPA最显著 ,其次为PB ,PHT最差。全部药物均有一定的不良反应 (12 5 0 % ) ,且大部分与血药浓度正相关。结论 :治疗小儿癫应监测AED血药浓度 ,尽可能单一药物治疗及剂量个体化投药     

应用不同抗癫痫药治疗儿童癫痫与肥胖的关系

目的　了解应用不同抗癫痫药 (AEDs)所导致癫痫患儿肥胖的情况。方法　根据患儿服用的不同AEDs,将 6 6例癫痫病人分为丙戊酸钠治疗组和非丙戊酸钠治疗组两组 ,对其体重 (Wt)及身高 (H)从服用AEDs开始进行为期 6个月的观察 ,观察肥胖指标 (BMI)的变化情况。结果　丙戊酸钠治疗组从治疗后 3个月开始出现肥胖 ,到治疗后 6个月时 ,男、女性的肥胖指标才有统计学的差异 ;丙戊酸钠治疗组的肥胖指标与非丙戊酸钠治疗组的统计学差异 ,也是从治疗后 3个月开始。结论　应用丙戊酸钠后可导致癫痫病人出现肥胖 ,其肥胖发生的时间一般在开始应用此药治疗后 3个月 ,因此 ,临床上应用丙戊酸钠时 ,要注意导致癫痫病人出现肥胖的问题。     

对长期服用含西药的中成药的癫痫患者血药浓度监测

目的分析本院癫痫患者因长期服用外院自制中成药导致中枢性神经系统反应的病例。方法用荧光偏振免疫法,测定患者丙戊酸、卡马西平、苯巴比妥、苯妥英钠的血药浓度。结果丙戊酸、卡马西平、苯巴比妥、苯妥英钠血药浓度分别为38.09,0.34,0.18,0.65μg·mL-1。每单一成分均低于最低有效血药浓度;但4种药合并使用,可产生大协同作用。结论尽可能减少合并用药品种,广泛开展治疗药物监测。     

Retrospective analysis of drug treatment in epileptic patients

An epidemiological analysis was performed of the adult, out-patient epilepsy clinic population of a university hospital during the period from 1 January 1981 through 30 June 1985. The number of patients that could be traced amounted to 590. An at random sample of 207 were retrospectively analysed. Gender distribution was male:female = 1.46. The mean age was 37.4 years. The diagnoses were classified according to the classification of the International League Against Epilepsy (ILAE). A preponderance of partial seizures was present, reflecting the selection in a university out-patient clinic of more difficult to treat forms of epilepsy. Antiepileptic drugs used in the treatment varied; monotherapy was obtained in 46% of the cases and carbamazepine was the most frequently prescribed drug (49%). Changes in seizure severity and factors associated with epilepsy are described. A discrepancy was found between the suspected drug levels, based upon the physician's judgement, and the plasma level measured in those patients in whom drug levels were monitored; factors interfering with clinical judgement are discussed.     

抗癫痫药物对癫痫患儿的骨代谢影响研究

目的分析抗癫痫药物对癫痫患儿骨代谢相关指标及生活质量的影响。方法选取2013年1月至2015年2月在我院接受抗癫痫药物治疗的癫痫患儿42例为观察组,另选取同时期未接受癫痫药物治疗的癫痫患儿36例为对照组,对比两组患儿治疗前后血清碱性磷酸酶(ALP)、血钙(Ca~(2+))、血磷(P)、骨密度(BMD)、磷酸酶(BAP)等骨代谢相关指标,并应用生活质量评估量表(QOLIE-31)对治疗前后两组患儿的生活质量进行评价。结果治疗后,观察组患儿的Ca~(2+)水平显著降低,BAP水平显著升高,差异均有统计学意义(P<0.05),ALP、P及BMD均无显著变化(P>0.05);观察组患儿的Ca2+水平低于对照组,BAP水平显著高于对照组,差异有统计学意义(P<0.05);对照组患儿各项骨代谢指标无显著变化(P>0.05)。治疗前,两组患儿的生活质量评分比较差异无统计学意义(P>0.05),治疗后,观察组患儿生活质量评分升高,且高于对照组,差异均有统计学意义(P<0.05)。结论抗癫痫药物能够提高癫痫患儿的生活质量,其对癫痫患儿的骨代谢具有一定的影响,对BAP的影响最显著。BAP可以作为指导正确应用癫痫药物的指标。     

高效液相色谱法与荧光偏振免疫法在抗癫痫药血清浓度测定中的相关性比较分析

目的探究HPLC与FPIA两种方法在抗癫痫药血清浓度测定中的相关性。方法采集本院收治的经苯妥英钠（PT）、苯巴比妥（PB）、卡马西平（CBZ）治疗的103例癫痫患者血清,分别采用高效液相色谱法、荧光偏振免疫法测定其血药浓度并进行线性回归分析。结果所得的线性回归方程为YPV=-1．421＋1．141X（r=O．963）;YPB=-0．128＋0．956）（（r=0．949）;YcBz=0．183＋0．954X（r=0．944）,且两种方法测得的值呈线性相关;经配对t检验后,两者差异有统计学意义（P〉0．05）。结论高效液相色谱法与荧光偏振免疫法两种方法测定抗癫痫药血清浓度具有相关性。采用HPLC法和FPIA法进行CBZ、PT、PB的血清浓度测定各有利弊,须结合检测药物种类数目、受检人数等合理选择监测方式