53例癫癎患者抗癫癎药物使用情况分析

目的了解癫癎患者抗癫癎药物使用情况,为合理使用抗癫癎药提供依据.方法采用回顾性调查方法,分析2002年9～12月住院的53例癫癎患者病历,对患者的一般情况、药物治疗情况和药物不良反应进行统计和分析.结果入选患者病情好转46例（86.79%）,未愈7例（13.21%）.使用的抗癫癎药物主要有7种,分别是丙戊酸钠、卡马西平、苯巴比妥、苯妥英钠、氯硝西泮、托吡酯和拉莫三嗪.所有入选的患者均联合使用抗癫癎药,其中35例（66.04%）合并使用两种抗癫癎药,12例（22.64%）联合使用3种抗癫癎药,4例（9.43%）联合使用4种抗癫癎药,另有1例患者同时使用5种抗癫癎药.共监测到药物不良反应3例,其中卡马西平引起的药物不良反应2例,包括白细胞降低和转氨酶升高各1例;另外丙戊酸引起转氨酶升高1例.结论该院住院癫癎患者的用药基本合理.临床抗癫癎治疗时应加强对患者进行用药宣传,规范抗癫癎药使用,注意监测药物浓度和不良反应,合理联合用药,以保证癫癎患者的用药安全,提高疗效.     

136例癫癎患儿联合用药分析

目的:为临床癫癎患儿合理用药提供参考.方法:采用荧光偏振免疫法对136例联合用药的癫癎患儿进行血药浓度监测,并对其结果及疗效进行分析总结.结果:两药合用时有55.1%未达到有效血药浓度范围,5.6%超过有效血药浓度范围;3药合用时有61.1%未达到有效血药浓度范围,8.9%超过有效血药浓度范围.结论:抗癫癎药物的联合应用须慎重.     

抗癫(癎)药物联合使用时血药浓度分析

目的研究抗癫药物联合使用时各药的血药浓度是否达到有效水平。方法武汉大学人民医院收治的各种原因所致的癫患者75例。两药合用者71例,占94.7%;3药合用者4例,占5.3%。采用抗癫药物联合治疗并测定达稳态后的各种药物的血药浓度。结果75例中仅21例所合用药物的血药浓度在有效范围,占28.0%。其余54例所合用药物的1种或多种药物的血药浓度不在有效范围,占72.0%。结论抗癫药物联合使用时多数病例会发生药物相互作用而导致血药浓度不在有效范围,因此联合用药时应注意调整各药的剂量。     

53例癫患者抗癫药物使用情况分析

目的了解癫患者抗癫药物使用情况,为合理使用抗癫药提供依据。方法采用回顾性调查方法,分析2002年9~12月住院的53例癫患者病历,对患者的一般情况、药物治疗情况和药物不良反应进行统计和分析。结果入选患者病情好转46例(86.79%),未愈7例(13.21%)。使用的抗癫药物主要有7种,分别是丙戊酸钠、卡马西平、苯巴比妥、苯妥英钠、氯硝西泮、托吡酯和拉莫三嗪。所有入选的患者均联合使用抗癫药,其中35例(66.04%)合并使用两种抗癫药,12例(22.64%)联合使用3种抗癫药,4例(9.43%)联合使用4种抗癫药,另有1例患者同时使用5种抗癫药。共监测到药物不良反应3例,其中卡马西平引起的药物不良反应2例,包括白细胞降低和转氨酶升高各1例;另外丙戊酸引起转氨酶升高1例。结论该院住院癫患者的用药基本合理。临床抗癫治疗时应加强对患者进行用药宣传,规范抗癫药使用,注意监测药物浓度和不良反应,合理联合用药,以保证癫患者的用药安全,提高疗效。     

53例癫患者抗癫药物使用情况分析

目的了解癫患者抗癫药物使用情况，为合理使用抗癫药提供依据。方法采用回顾性调查方法，分析2002年9～12月住院的53例癫患者病历，对患者的一般情况、药物治疗情况和药物不良反应进行统计和分析。结果入选患者病情好转46例（86.79%），未愈7例（13.21%）。使用的抗癫药物主要有7种，分别是丙戊酸钠、卡马西平、苯巴比妥、苯妥英钠、氯硝西泮、托吡酯和拉莫三嗪。所有入选的患者均联合使用抗癫药，其中35例（66.04%）合并使用两种抗癫药，12例（22.64%）联合使用3种抗癫药，4例（9.43%）联合使用4种抗癫药，另有1例患者同时使用5种抗癫药。共监测到药物不良反应3例，其中卡马西平引起的药物不良反应2例，包括白细胞降低和转氨酶升高各1例;另外丙戊酸引起转氨酶升高1例。结论该院住院癫患者的用药基本合理。临床抗癫治疗时应加强对患者进行用药宣传，规范抗癫药使用，注意监测药物浓度和不良反应，合理联合用药，以保证癫患者的用药安全，提高疗效。     

药源性癫372例分析

通过回顾性分析药源性癫癎发生情况与药物品种及给药方法的关系,提示诱发癫癎的药物以抗微生物药物、中枢神经系统用药所占比例较大;氯氮平、异烟肼、环丙沙星、青霉素、硝西泮等诱发癫癎;正常用法、用量下给药所致癫癎多为药物不良反应,而服用剂量过量或突然减量是诱发药源性癫癎发作的主要原因.     

多药转运蛋白参与难治性癫(癎)耐药机制的研究

癫(癎)是神经科仅次于脑血管意外的常见疾病,患病率达到5‰.在新确诊的癫(癎)患者中,50%以上的患者通过单药治疗,癫(癎)发作得到有效控制.另外近20%的患者接受2种抗癫(癎)药物联合治疗后,病情得到改善.大约有30%的患者,经过单药治疗以及多药联合治疗,血药浓度已达到治疗剂量,癫(癎)发作仍得不到控制,我们称之为难治性癫(癎).     

多药转运蛋白参与难治性癫(癎)耐药机制的研究

癫(癎)是神经科仅次于脑血管意外的常见疾病,患病率达到5‰.在新确诊的癫(癎)患者中,50%以上的患者通过单药治疗,癫(癎)发作得到有效控制.另外近20%的患者接受2种抗癫(癎)药物联合治疗后,病情得到改善.大约有30%的患者,经过单药治疗以及多药联合治疗,血药浓度已达到治疗剂量,癫(癎)发作仍得不到控制,我们称之为难治性癫(癎).     

药源性癫癎372例分析

通过回顾性分析药源性癫癎发生情况与药物品种及给药方法的关系，提示诱发癫癎的药物以抗微生物药物、中枢神经系统用药所占比例较大；氯氮平、异烟肼、环丙沙星、青霉素、硝西泮等诱发癫癎；正常用法、用量下给药所致癫痫多为药物不良反应，而服用剂量过量或突然减量是诱发药源性癫癎发作的主要原因。     

卡马西平治疗癫血药浓度监测及合理用药

目的探讨卡马西平抗癫作用与血药浓度的关系,以指导临床合理用药。方法采用萤光偏振免疫法(FPIA)测定128例癫患者卡马西平的血药浓度。结果血药浓度在有效治疗范围且癫发作得以基本控制的占82.56%,25.00%的患者血药浓度低于有效治疗范围而癫发作仍得到有效控制,其中联合用药中42.86%的患者癫发作得以控制。结论血药浓度监测有利于提高癫治疗药物的安全性、有效性及合理性,减少毒副作用,但需考虑一些影响因素,如卡马西平肝药酶诱导作用,代谢物卡马西平10,11-环氧化物对临床疗效的影响,药物相互作用,以及给药方案等。     

Evaluation of therapeutic drug monitoring of antiepileptic drugs

Results of the therapeutic drug monitoring (TDM) of the concentration of antiepileptic drugs (AEDs), performed at Aseer Central Hospital over a 1-year period were evaluated. Most of the requests were for phenytoin (PHT) determination followed by carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB). Serum concentrations of PB, CBZ, VPA and PHT within the presumed therapeutic range constituted 87%, 73%, 45% and 33%, respectively. Valproic acid exhibited age differences in the proportion of concentrations below the presumed therapeutic range, such that subtherapeutic concentrations increased while therapeutic concentrations decreased with age. When the requests were related to particular patients, 71% of patients were on monotherapy with PHT as the most commonly used single drug and PB the least. Patients using 2 AEDs were found to constitute 23.5% of all patients with "PHT + CBZ" and "CBZ + VPA" being the most commonly prescribed 2 drugs combination. The frequency of concentrations within the therapeutic ranges decreased when 1 or 2 more drugs were used with either PHT or VPA. In addition, combination with PHT was associated with a reduction in mean CBZ concentration, while combination with CBZ was associated with a reduction in mean VPA concentration.     

Interactions between zonisamide and conventional antiepileptic drugs in the mouse maximal electroshock test model.

Despite the major advances in antiepileptic drug (AED) therapeutics, about one third of patients with epilepsy still do not have adequate seizure control with currently available AEDs when prescribed as monotherapy. Typically, in this setting polytherapy with two or more AEDs is used. Zonisamide (ZNS) is a new AED effective in the treatment of refractory epilepsy and since it is only prescribed in polytherapy regimens, its interactions with other AEDs is of particular importance. The aim of this study was to isobolographically determine interactions between ZNS and four conventional AEDs: carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA), in the mouse maximal electroshock (MES)-induced seizure model. The total brain concentrations of conventional AEDs and ZNS were measured with immunofluorescence and high-pressure liquid chromatography (HPLC), respectively, in order to determine any pharmacokinetic contribution in any observed interactions. With isobolography, synergistic interactions were observed for the combination of ZNS plus VPA and ZNS plus PHT at the fixed-ratio of 1:1, while additivity was observed for their combinations at the remaining dose ratios of 1:3 and 3:1. In contrast, the interactions between ZNS and PB and between ZNS and CBZ, applied at the fixed-ratios of 1:3, 1:1 and 3:1 proved to be additive. None of these AED combinations were associated with motor and long-term memory impairment. Furthermore, whilst brain AED concentrations were unaffected by ZNS, PHT significantly increased and PB reduced brain ZNS concentrations. Thus, the resultant interactions between ZNS and PHT and between ZNZ and PB were consequent to both pharmacodynamic and pharmacokinetic components. Finally, one can conclude that because of the synergistic pharmacodynamic interaction between ZNS and VPA, this combination might be useful in clinical practice.     

Protein binding of antiepileptic drugs during pregnancy, labor, and puerperium

Twenty-four epileptic women were followed-up during late pregnancy, labor, and early puerperium in order to detect possible alterations in serum protein binding of antiepileptic drugs (AEDs). The total and free concentrations of carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA) in maternal serum were measured. In addition, the concentrations of albumin, alpha 1-acid glycoprotein (AGP), and free fatty acids (FFA) were also measured. Total AED concentrations during labor were influenced by changes in drug dosages; total PHT increased during the first puerperal weeks. During labor the free fraction of CBZ remained stable, whereas PHT and particularly VPA free fractions increased. This phenomenon was parallel to the increase in FFA concentration; FFA concentrations decreased again during the first days postpartum. Albumin and AGP concentrations were low during pregnancy and labor, and increased after delivery. The total umbilical CBZ and PHT concentrations were not significantly different from maternal concentrations. The total VPA concentration in umbilical serum was significantly higher than that in maternal serum. The free fraction of CBZ was higher and that of PHT and VPA lower in umbilical than in maternal serum at delivery. Umbilical cord serum had a higher albumin but a lower AGP and FFA concentration than maternal serum. The changes in PHT and particularly VPA free fraction associated with changes in FFA concentration should be considered when assessing the total concentration of these drugs in maternal and umbilical serum.     

7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

7-Nitroindazole (7NI, a nitric oxide synthase [NOS] inhibitor) administered intraperitoneally (ip), 30 min before the test, at doses ranging between 50-200 mg/kg, raised the threshold for electroconvulsions in mice. Linear regression analysis revealed that the doses increasing the threshold by 50% (TID50) and 100% (TID100) over the control value for 7NI were 115.2 and 173.4 mg/kg, respectively. Moreover, 7NI dose-dependently potentiated the anticonvulsant effects of four conventional antiepileptic drugs (AEDs: carbamazepine - CBZ, phenobarbital - PB, phenytoin - PHT, and valproate - VPA) in the mouse maximal electroshock-induced seizure (MES) model. 7NI at 50 mg/kg enhanced only the anticonvulsant effect of PB, whereas the drug at 75 and 100 mg/kg potentiated the antiseizure effects of PB, PHT and VPA, but not those of CBZ against MES-induced seizures. Only 7NI at 150 mg/kg enhanced considerably the antielectroshock action of all studied AEDs in the MES test. Pharmacokinetic evaluation of interactions between 7NI and the investigated AEDs revealed that 7NI (150 mg/kg; ip) did not alter total brain concentrations of conventional AEDs in mice. L-arginine (L-Arg - a natural precursor of NO; administered ip, 500 mg/kg, 60 min before electroconvulsions) did not reverse the activity of 7NI (150 mg/kg), but in contrast, it significantly potentiated the anticonvulsant action of conventional AEDs combined with 7NI (150 mg/kg). Pharmacokinetic increase in total brain AED concentrations was observed for the combinations of L-Arg (500 mg/kg) with 7NI (150 mg/kg) and PHT (by 32%; p<0.01) or VPA (by 22%; p<0.05). Neither total brain CBZ nor PB concentrations were altered following the co-administration of L-Arg (500 mg/kg) with 7NI (150 mg/kg). 7NI at doses of 100-200 mg/kg significantly impaired spontaneous ambulatory activity in mice subjected to the Y-maze task. The NOS inhibitor at doses of 50 and 75 mg/kg had no significant effect on locomotor activity of animals, although the number of arm entries within the 5 min of observational time was reduced. Finally, it can be concluded that the enhancement of anticonvulsive efficacy of CBZ, PB, PHT and VPA by 7NI alone or in combination with L-Arg in the MES test, deserves more attention and further neurochemical studies are required to elucidate the exact role of NO in the brain.     

Pharmacodynamic interaction between phenytoin and sodium valproate changes seizure thresholds and pattern

1. In this study we used cortical stimulation to assess the effects of phenytoin (PHT), sodium valproate (VPA), and their interaction on total motor seizure and on the constituent elements of the seizure.
2. PHT (40 mg kg⁻¹) was administered as an intravenous bolus infusion to animals receiving either a continuous infusion of VPA or saline. VPA plasma concentration was maintained at levels that produced no detectable anticonvulsant effect.
3. Analysis of ictal components (eyes closure, jerk, gasp, forelimb, clonus, and hindlimb tonus) and their durations revealed both qualitative and quantitative differences in drug effects.
4. The anticonvulsant effect is represented by the increase in the duration of the stimulation required to reach a given seizure threshold. PHT significantly increased the duration of the stimulation and of the motor seizure. This increase was greatly enhanced by VPA. In addition, ictal component analysis revealed that the combination of PHT and VPA causes the reduction of a specific seizure component (JERK).
5. Neither the free fraction of PHT nor the biophase equilibration kinetics changes in the presence of VPA. It is concluded that the synergism may be due to a pharmacodynamic rather than a pharmacokinetic interaction.

     

Influence of coadministered antiepileptic drugs on serum antiepileptic drug 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 dose of antiepileptic drugs (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 epileptic patients treated with the multiple oral administration of valproic acid (VPA), carbamazepine (CBZ), zonisamide (ZNS), phenobarbital (PB), and phenytoin (PHT) were used for the analysis. Employing the ideal body weight or the extracellular water volume as a transforming factor, allowed the level/dose (L/D) ratio to be independent of the patient's age and gender for monotherapy with VPA or CBZ, ZNS, PB, and PHT, respectively. Each C(t) was revealed to be dependent on only one variable in terms of the transformed daily dose (D'). C(t) was proportional to the power function of D' for VPA and CBZ and was linearly proportional to D' for ZNS and PB. The L/D ratio is expressed as a linear function of C(t) for PHT. For a detailed analysis of the influences of the coadministered antiepileptic drugs, we defined the parameter as an alteration ratio, representing the influence of each antiepileptic drug on the C(t) of VPA and CBZ alone, and on the L/D ratio of ZNS and PB alone, respectively. A model based on the assumption that each value of an alteration ratio was independent from one other and multiplicative for VPA, CBZ, and ZNS, and that the coadministered drug inhibited the drug-metabolizing enzyme competitively for PB, was adopted. The Michaelis-Menten kinetic model was adopted for PHT. The analysis clarified that CBZ, PB, and PHT significantly lowered (P<0.05) C(t) to 0.81, 0.88, and 0.83 compared with the value of VPA alone, that PB and PHT significantly lowered C(t) to 0.77 and 0.71 compared with the value of CBZ alone, and that VPA, CBZ, PB, and PHT significantly lowered the L/D ratio of ZNS alone to 0.87, 0.85, 0.85, and 0.80, respectively. VPA, CBZ, and PHT significantly increased (P<0.05) the L/D ratio of PB to 1.47, 1.18, and 1.19, respectively. The daily PHT dose was decreased to 0.89, 0.91, 0.90, and 0.84 the dose of PHT alone to maintain C(t) in the therapeutic range when VPA, CBZ, ZNS, and PB were coadministered, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated C(t) values were calculated using the value of each alteration ratio and compared with the measured ones. Each mean of prediction error was about 20%. Our results appear valid and these alteration ratios should be available for clinical use.     

Antiepileptic drug combinations and experimental background: The case of phenobarbital and phenytoin

Summary In view of the trend towards single drug therapy of epilepsy, the experimental background for thr combination of phenobarbital (PB) and phenytoin (PHT) was reassessed. Since potentiation of the anticonvulsant activity is in itself neither sufficient nor necessary to demonstrate the superiority of a drug combination, protection against maximal electroshock seizures as well as neurotoxicity were determined in mice. This allowed one to separate the neurotoxic from the anticonvulsant interaction and to base the analysis on changes in the therapeutic index (TI). Pharmacokinetic interactions were excluded from the analysis by expressing all results in terms of brain concentrations. The anticonvulsant interaction between PB and PHT was found to be additive, whereas the neurotoxic interaction was antagonistic. These results provide experimental documentation of one of the theories behind antiepileptic drug combinations. However, because PB had a markedly lower TI than PHT in this model, the TI of the drug combination was lower than the TI of PHT. Thus, the antagonism with regard to neurotoxicity was not sufficient to raise the TI of the combination above the TI of PHT.     

Influence of concomitant antiepileptic drugs on plasma lamotrigine concentration in adult Japanese epilepsy patients

Lamotrigine (LTG) is an antiepileptic drug (AED) that was approved in Japan in 2008. We evaluated the influence of AEDs that induce hepatic enzymes (including phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ)), valproic acid (VPA), and various combinations of these drugs, on plasma LTG concentration in adult Japanese epilepsy patients. A total of 621 patients (mean age 34.4±11.8 years) were evaluated retrospectively. We calculated the concentration to dose ratio (CD ratio) for LTG with different AED regimens, and employed multiple regression analysis to determine factors influencing the LTG concentration. There was a linear correlation between the dose and concentration of LTG in patients treated with LTG (group I), LTG+VPA (group II), LTG+inducers (group III), or LTG+VPA+inducers (group IV). The mean CD ratio of patients on LTG monotherapy was 1.43±0.4 (μg/mL)/(mg/kg). When LTG was combined with VPA, the CD ratio increased about 2.2-fold, but there was no significant correlation between the CD ratio and VPA concentration. The mean CD ratios calculated in patients receiving LTG+PHT, LTG+PB, and LTG+CBZ were 0.56, 0.84, and 0.91, respectively. Addition of PHT significantly reduced the CD ratio in a concentration-dependent manner, in comparison with PB and CBZ (p<0.005 and p<0.001, respectively). Stepwise multiple regression analysis showed that the coefficient of determination of groups I, II, III, and IV were 0.94, 0.94, 0.90, and 0.91, respectively. In the clinical setting, these findings can help to estimate LTG concentrations and predict the inducing or inhibiting effects of concomitant AEDs.     

Isobolographic analysis of interactions between losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model.

The aim of this study was the isobolographic evaluation of interactions between losigamone (LSG), valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, and tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor coordination) and the passive avoidance task (long-term memory). Brain concentrations of antiepileptic drugs (AEDs) were measured by immunofluorescence or high-performance liquid chromatography. Isobolographic analysis indicated synergistic interactions between LSG and VPA. For example, in the proportion of 1:1 the theoretically calculated 50% effective dose for additivity (ED(50add)) was 138 mg/kg, while the experimentally derived ED(50) for the mixture (ED(50mix)) was 85.2 mg/kg. The difference was significant at p<0.001. LSG combined with CBZ or PHT showed additivity, whereas the combinations of LSG with PB were either additive, for the fixed ratios of 1:3 and 1:1, or antagonistic for the ratio of 3:1 (ED(50add)=18.4 mg/kg versus ED(50mix)=26.7 mg/kg, p<0.05). Impairment of long-term memory was noted only in the case of VPA given at its ED(50), however this AED did not affect motor performance. LSG, CBZ, PHT and PB (applied at their ED(50) values) and co-administration of LSG with conventional AEDs (including VPA) impaired neither motor performance nor long-term memory. LSG did not affect the brain concentration of VPA or PB, but significantly elevated the brain concentrations of CBZ and PHT. In contrast, VPA, CBZ and PHT significantly increased the brain concentration of LSG, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. Although LSG exhibited some favorable pharmacodynamic interactions with various AEDs, these were complicated by pharmacokinetic interactions and emphasize the importance of measuring AED concentrations in studies designed to identify desirable AED combinations.     

Influence of ethacrynic acid on the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock seizure model

The aim of this study was to determine whether ethacrynic acid (EA), a loop diuretic with anticonvulsant activity, would affect the protective action of the conventional antiepileptics (AEDs) carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and phenobarbital (PB) in the mouse maximal electroshock seizure (MES) model. The effects of acute and chronic treatment with EA on these AEDs were examined. At a single dose of 100 mg/kg ip, EA enhanced the antielectroshock activity of VPA, decreasing its ED₅₀ value from 225.6 to 146.6 mg/kg (p < 0.05), but enhancement was not observed following continuous administration of EA (12.5 mg/kg) for seven days. Combined treatment of EA with other AEDs had no effect on their ED₅₀ values. The observed interaction between EA and VPA was pharmacodynamic in nature as EA did not alter free plasma (non-protein-bound) and total brain concentrations of VPA. Taking into consideration the clinical use of both drugs, this interaction between EA and VPA can be important for patients receiving these drugs.