卡马西平、左乙拉西坦对伴中央-颞区棘波的良性癫痫患儿脑电图的影响

目的观察左乙拉西坦对伴中央-颞区棘波的良性癫痫患儿脑电图的影响。方法符合诊断标准的癫痫儿童随机分为2组,卡马西平组(40例)用卡马西平治疗,左乙拉西坦组(40例)用左乙拉西坦治疗,治疗12周。治疗前后均做动态脑电图,用统计学方法分析2儿童治疗后脑电图的变化。结果治疗后2组间临床下痫样放电差异有统计学意义(P<0.05)。结论左乙拉西坦对伴中央-颞区棘波的小儿良性癫痫患儿脑电图β、α、θ、δ功率值无影响并可使临床下痫样放电消失或减少。     

2015—2017年解放军总医院抗癫痫药物的使用情况分析

目的 了解解放军总医院抗癫痫药物的应用情况与趋势。方法 采用世界卫生组织（WHO）推荐的以限定日剂量（DDD）为指标的分析方法,对2015-2017年解放军总医院抗癫痫药物的用药金额、用药频度（DDDs）、日均费用（DDC））和排序比（B/A）等进行统计分析。结果 左乙拉西坦、奥卡西平和丙戊酸钠的用药金额始终处于前3位,加巴喷丁的用药金额逐渐上升,托吡酯的用药金额逐渐下降;用药频度（DDDs）排序列前3位的是左乙拉西坦、奥卡西平和丙戊酸钠,左乙拉西坦的DDDs逐年上升,2017年已跃居至第1位;2015-2016年各种抗癫痫药物的DDC较为稳定,2016-2017年各种抗癫痫药物的DDC开始略有下降;除拉莫三嗪的排序比值始终小于1.00,其他抗癫痫药物的B/A均在1.00以上波动。结论 解放军总医院抗癫痫治疗以新型抗癫痫药物为主,其中左乙拉西坦和奥卡西平具有很好的市场前景。     

卡马西平、左乙拉西坦对伴中央-颞区棘波的小儿良性癫痫患儿认知功能的影响

目的观察左乙拉西坦对伴中央-颞区棘波的小儿良性癫痫患儿认知功能的影响。方法符合诊断标准的癫痫儿童80例随机分为2组,卡马西平组（40例）用卡马西平治疗,左乙拉西坦组（40例）用左乙拉西坦治疗,治疗12周。治疗前后分别测定患儿智商,分析2组儿童治疗前后认知功能的变化。结果治疗前后2组儿童语言智商（VIQ）、操作智商（PIQ）和总智商（FIQ）差异无统计学意义（P〉0.05）。但左乙拉西坦组知识、算术、词汇、图形拼凑五项得分高于卡马西平组（P〈0.05）;卡马西平组治疗前后VIQ、PIQ和FIQ差异无统计学意义（P〉0.05）,而治疗后木块图案、图形拼凑得分降低（P〈0.05）;左乙拉西坦组治疗前后VIQ、PIQ和FIQ差异无统计学意义（P〉0.05）,而治疗后知识、算术、词汇、图形拼凑得分增加（P〈0.05）。结论左乙拉西坦对伴中央-颞区棘波的小儿良性癫痫患儿认知功能无影响并可改善患儿的认知功能。     

左乙拉西坦治疗伴中央颞区棘波的儿童良性癫痫疗效观察

目的观察左乙拉西坦（Levetimcetam,Lev）治疗伴中央颞区棘波的小儿良性癫痫的疗效。方法将符合诊断标准的癫痫儿童30例随机分为2组,治疗组（15例）予Lev,对照组（15例）予丙戊酸钠（sodium valproate,VPA）,治疗12周。比较2组的疗效与不良反应。结果治疗组有效率为80％（12／15）,对照组有效率为40％（6／15）,两组有效率比较有显著性差异（P〈0．05）。结论Lev治疗伴有中央颞区棘波的小儿良性癫痫疗效好,值得临床广泛运用。     

儿童三种新型抗癫痫药物血药浓度监测结果分析

摘 要 目的：对我院开展左乙拉西坦、拉莫三嗪、奥卡西平3种新型抗癫痫药物血药浓度监测情况进行分析,为指导癫痫患儿的个体化药物治疗提供参考。方法: 收集我院2015～2016 年度癫痫患儿的就诊基本信息,左乙拉西坦、拉莫三嗪、奥卡西平等药物的给药剂量与浓度监测结果资料并进行统计分析。结果: 在奥卡西平给药平均剂量无明显差异的情况下,3~6岁、6~10岁、10~18岁组患儿的奥卡西平平均血浓度明显高于< 3岁组患儿（Ｐ＜0.05）,不同年龄段患儿的拉莫三嗪给药平均剂量及平均血浓度之间的差异均无统计学意义（Ｐ＞0.05）;< 3岁组患儿的左乙拉西坦平均血浓度明显高于3~6岁、6~10岁、10~18岁组患儿;且血药浓度在不同浓度范围的患儿的临床治疗有效率差异有统计学意义（Ｐ＜0.05）。结论: 不同年龄段的癫痫患儿中,抗癫痫药物血药浓度个体间差异大,为保证患儿用药安全有效,有必要进行血药浓度监测。     

左乙拉西坦与卡马西平对癫痫儿童情绪行为和骨代谢脂代谢的影响

目的 对比分析左乙拉西坦与卡马西平对癫痫儿童情绪行为和骨代谢、脂代谢的影响。方法 2015年4月至2017年10月郑州大学附属医院儿科收治的90例癫痫儿童根据治疗药物不同分为新型组48例、传统组42例,前者服用新型抗癫痫药左乙拉西坦,后者服用传统抗癫痫药卡马西平。治疗前、治疗6个月后评估两组患儿情绪行为、认知功能状况,并采血检测骨代谢、脂代谢水平。结果 治疗6个月后两组患儿Achenbach儿童行为量表（CBCL4/16）评分、韦氏智力量表评分均明显升高,但新型组治疗前后差值高于传统组,差异有统计学意义（P<0.05）。两组治疗前血钙、血磷、碱性磷酸酶（ALP）及骨密度（BMD）差异无统计学意义（P>0.05）,但新型组治疗前后血钙、血磷、ALP及BMD差值低于传统组,差异有统计学意义（P<0.05）。两组治疗前各项脂代谢指标比较差异无统计学意义（P>0.05）,但新型组治疗前后血清总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）差值明显低于传统组,差异有统计学意义（P<0.05）。结论 左乙拉西坦和卡马西平均可改善癫痫儿童情绪行为与认知功能,但前者对患儿骨代谢、脂代谢的影响更小。     

左乙拉西坦单药治疗伴中央-颞区棘波的小儿良性癫痫近期疗效观察

左乙拉西坦(LEV)是吡拉西坦衍生物中的左旋乙基吡拉西坦,其化学名称为(s)-α-乙基-2-氧代-1-吡咯烷乙酰胺,分子式为C8H14N2O2.于1999年经美国FDA批准最初用于成人部分性癫痫发作,2005年6月又批准其口服片剂和溶液剂用于4岁或以上儿童部分性癫痫发作的辅助治疗.在北美60个试验中心对4～16岁难治性癫痫部分性发作的儿童进行多中心随机双盲和安慰剂对照的临床研究,结果:本品治疗组每周部分性发作频度明显减少,整个随机治疗阶段的有效应答率明显高于安慰剂组[1].2005年左乙拉西坦在国内新药申报获得通过.我们对40例伴中央-颞区棘波的小儿良性癫痫患儿使用左乙拉西坦单药治疗,观察其疗效及不良反应,报告如下.     

1例二尖瓣机械瓣膜置换术后合并癫痫患者脑出血的用药分析

摘 要 目的：探讨华法林与丙戊酸镁联合使用导致出血高危因素的作用机制,为临床治疗中合理选择药物提供参考。方法: 临床药师对二尖瓣机械瓣膜置换术后合并癫痫患者脑出血患者联合使用华法林和丙戊酸镁导致脑出血的抗癫痫药物治疗方案进行分析及调整：停用丙戊酸镁,换用左乙拉西坦0.25 g,po,bid,14 d后加量至0.5 g,po,bid进行抗癫痫治疗,并对患者实施药学监护。结果: 患者住院20 d后,国际标准化比值（INR）控制在2.5～3.0之间,无癫痫症状发作,病情稳定出院。结论: 左乙拉西坦与华法林相互作用较小,可与华法林联合使用。     

2018年成都市妇女儿童中心医院门诊左乙拉西坦的使用合理性分析

目的 对成都市妇女儿童中心医院门诊左乙拉西坦的使用情况进行分析,为临床合理用药提供参考。方法 收集成都市妇女儿童中心医院门诊2018年包含左乙拉西坦的处方,并进行统计分析;结果 共收集处方172张,4岁以下患儿88例,构成比为51.16%;诊断为癫痫的共144张,构成比为83.72%;172张处方中选用左乙拉西坦口服溶液的有60例;剂量<10 mg/kg的60例,构成比为34.88%;单药治疗的患儿共132例,构成比为76.74%;不合理处方共36张,主要为诊断不合理,构成比为16.28%。结论 成都市妇女儿童中心医院门诊左乙拉西坦的使用在患儿年龄及单药治疗方面存在超说明书用药现象,有循证学依据,但对于这类超说明书用药应当加强管理;剂型选择基本合理;因未及时更新临床诊断,有少数用药与诊断不一致的处方;用法用量基本合理,少数处方的用药频率存在与说明书不一致的现象,建议通过在门诊开展处方前置审核来尽量减少此类处方的出现。     

左乙拉西坦联合丙戊酸口服液治疗伴中央-颞区棘波儿童良性癫痫分析

目的 探讨左乙拉西坦联合丙戊酸口服液对伴中央-颞区棘波儿童良性癫痫患者认知功能及免疫功能的影响.方法 选择我院收治的48例伴中央-颞区棘波儿童良性癫痫患者为研究对象,随机分为联合组及单一组各24例,两组患者均给予丙戊酸口服液治疗,联合组予左乙拉西坦联合丙戊酸口服液治疗,观察治疗前后两组认知功能[语言智商(VIQ)、操作智商(PIQ)、总智商(FIQ)]、免疫功能[免疫球蛋白G(IgG)、免疫球蛋白A(IgA)、免疫球蛋白M(IgM)]及药物安全性.结果 治疗前两组VIQ、PIQ、FIQ评分、IgG、IgA、IgM比较差异无统计学意义(P＞0.05);治疗后两组VIQ、PIQ、FIQ评分较治疗前显著升高,治疗后仅联合组IgG、IgA、IgM较治疗前明显降低,且治疗后联合组各项评分、IgG、IgA、IgM较单一组明显高、低,差异有统计学意义(P＜0.05).两组治疗后药物不良反应发生率比较,差异无统计学意义(P＞0.05).结论 左乙拉西坦联合丙戊酸口服液可有效提高患者认知功能及免疫功能,是一种疗效确切、安全可靠的药物方案.     

临床药师参与1例亚急性心肌梗死合并腔隙性脑梗及深静脉血栓患者的抗栓治疗体会

目的 探讨亚急性心梗合并腔梗及深静脉血栓患者的抗栓策略,协助临床制订个体化的用药方案。方法 临床药师通过分析血栓形成的原因,评估缺血及出血风险,查找循证医学证据,提出合理建议,并观察药物疗效、监护用药安全。结果 患者存在多个血栓危险因素,同时属于出血很高危人群。药师建议阿司匹林剂量减少为75 mg,qd,加用质子泵抑制剂,同时联合低分子肝素抗凝。药师建议被部分采纳。患者病情好转后出院,且住院期间未出现出血及血栓症状。结论 临床药师在协助医生积极抗栓的同时,最大程度地保证了用药安全。     

Antiepileptogenic effects of Ethosuximide and Levetiracetam in WAG/Rij rats are only temporary

BackgroundWAG/Rij rats represent a validated genetic animal model of epileptogenesis, absence epilepsy and depressive-like comorbidity. Some treatments (e.g. ethosuximide), using specific protocols, prevent the development of spontaneous absence seizures. Accordingly, ethosuximide increases remission occurrence in children with childhood absence epilepsy in comparison to valproic acid. Considering that in this animal model, antiepileptogenic effects are, in some cases, not retained over time, we studied whether the antiepileptogenic effects of both ethosuximide and levetiracetam (which also possesses antiepileptogenic effects in this and other animal epilepsy models) would be retained 5 months after drug suspension.MethodsWAG/Rij rats of ?1 month of age were treated long-term with one of the two drugs at a dose of ?80 mg/kg/day for 17 consecutive weeks; 1 and 5 months after drug suspension, the development of absence seizures as well as depressive-like behaviour were assessed by EEG recordings and the forced swimming test (FST).ResultsIn agreement with a previous report, both drugs continued to show antiepileptogenic effects 1 month after their discontinuation. Furthermore, ethosuximide improved depressive-like behaviour, whereas in contrast, levetiracetam worsened this symptom. However, none of the drugs maintained their antiepileptogenic effects 5 months after suspension, and in addition, animal behaviour in the FST returned to control conditions.ConclusionOverall, these results demonstrate that the antiepileptogenic effects of both ethosuximide and levetiracetam on absence seizure development and associated depressive-like behaviour in this model are only temporary.     

1例临床药师参与伊马替尼与伏立康唑联合用药的药学监护

目的 为伊马替尼与伏立康唑的联合用药提供药物用量调整思路。方法 对临床药师全程参与的１例费城染色体阳性的急性淋巴细胞白血病患者的治疗过程进行分析。该患者在伊马替尼治疗期间合并真菌感染，临床药师从药物的代谢特点、安全性等方面考虑，建议采用伏立康唑联合伊马替尼治疗，但需对伊马替尼进行剂量调整；结合患者病情将伊马替尼调整至每天0.2 g，后增加至每天0.3 g，并对伊马替尼进行血药浓度测定；联合用药期间评估和监测治疗过程中的药物不良反应。结果 医师采纳了临床药师的建议。采用伏立康唑联合伊马替尼联合用药期间，患者的感染得到了良好控制。伊马替尼血药浓度显示1 372.08 ng·mL^-1，监测患者肝功能、血常规等正常，病情平稳。结论 临床药师参与了该患者的治疗过程，为其制订了个体化的治疗方案并取得了良好的效果，为伊马替尼与伏立康唑的联合用药提供药物用量调整思路。     

Levetiracetam therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new anti-epileptic drug (AED) levetiracetam in a cohort of 100 adult patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two groups, otherwise comparable for age, gender, weight-adjusted daily dose of levetiracetam, and dosing frequency: group A (n = 65), receiving levetiracetam plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin; group B (n = 35), receiving levetiracetam plus AEDs without inducing properties of CYP metabolism, namely valproic acid and lamotrigine. Plasma levetiracetam concentrations were measured by HPLC with spectrophotometric detection. Median morning trough levetiracetam plasma concentrations were significantly lower in patients of group A than in patients of group B (10.4 microg/mL versus 14.7 microg/mL, P < 0.001). Median weight-normalized levetiracetam apparent oral clearance (CL/F) was 1.3-fold in patients receiving AED inducers compared with patients on AED noninducers (1.93 versus 1.45 mL x min(-1) x kg, P < 0.001). No gender-related difference was observed in CL/F values. Levetiracetam plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 500 to 5000 mg/d, although at a given daily dose an appreciable interpatient variability was observed in matched plasma drug concentrations. Concomitant AED inducers can contribute to variability in levetiracetam disposition in patients with epilepsy. The observed differences were moderate and possibly of minor clinical significance.     

Dose optimization with population pharmacokinetics of ritonavir-boosted lopinavir for Thai people living with HIV with and without active tuberculosis

BackgroundPrior to dolutegravir availability, ritonavir-boosted lopinavir (LPV/r) was an alternative recommendation when first-line drugs could not be used. A high concentration of protease inhibitors was observed in the Thai people living with HIV (PLWH). Thus, dose reduction of LPV/r may be possible. However, the pharmacokinetics and dose optimization of LPV/r have never been investigated. This study aimed to develop a population pharmacokinetic model of LPV/r and provide dosage optimization in Thai PLWH.MethodsLPV and RTV trough concentrations from Thai PLWH were combined with intensive data. The data were analyzed by the nonlinear mixed-effects modeling approach. The influence of RTV concentration on LPV oral clearance (CL/F) was investigated.ResultsRifampicin (RIF) use increased LPV and RTV CL/F by 2.16-fold and 1.99-fold, respectively. The reduced dose of 300/75 and 200/150 mg twice daily provided a comparable percentage of patients achieving LPV target trough concentration to the standard dose for PI-naïve patients. For HIV/TB co-infected patients receiving RIF who could not tolerate the recommended dose, the reduced dose of 600/150 mg twice daily was recommended.ConclusionThe population pharmacokinetic model was developed by integrating the interaction between LPV and RTV. The reduced LPV/r dosage offers sufficient LPV exposure for Thai PLWH.     

The effect of poor compliance on the pharmacokinetics of carbamazepine and its epoxide metabolite using Monte Carlo simulation

Aim:

To study the effects of delayed and missed doses (poor compliance) on the pharmacokinetics of carbamazepine (CBZ) and its main active metabolite carbamazepine-10,11-epoxide (CBZE) in Chinese epilepsy patients using Monte Carlo simulation.

Methods:

CBZ and CBZE time-concentration profiles in various scenarios were generated based on a population pharmacokinetic study in Chinese epilepsy patients using Monte Carlo simulation. The scenarios included patients given multiple doses of CBZ that ranged from 100 to 300 mg three times daily or from 200 to 300 mg every 12 h. The therapeutic range of CBZ and CBZE for each scenario was estimated to assess the effect of delayed or missed doses and to design corresponding rescue regimens. Moreover, the impact of body weight, absorption rate and co-therapy with other antiepileptic drugs (phenytoin, phenobarbital and valproic acid) on the dosage recommendation was investigated in the event of poor compliance.

Results:

The risk for a sub-therapeutic range of CBZ and CBZE was increased in a dose-dependent manner in both two and three times daily regimens when delayed or missed doses occurred. The effects of poor compliance was less prominent on the lower daily doses compared with those on the higher daily doses. The dose recommendations, in the event of poor compliance, were time related and dose dependent. Patient body weight, absorption rate and co-therapy with phenytoin, phenobarbital and valproic acid had no significant impact on the dose recommendation.

Conclusion:

Patients with epilepsy should take the delayed doses as soon as they remember, and partial missed doses may need to be taken near or at the next scheduled time.     

基于多元线性回归的癫痫患儿丙戊酸血药浓度影响因素分析

目的：探讨影响癫痫患儿丙戊酸（VPA）的血药浓度的因素。方法：回顾性分析我院218例VPA血药浓度监测报告,包括患儿性别、年龄、丙戊酸钠日总剂量、联合用药情况、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血浆白蛋白、血肌酐和稳态血药浓度。利用多元线性回归分析影响VPA血药浓度变化的因素。结果：多元线性回归分析显示,日总剂量与血药浓度呈正相关（P<0.05）,白蛋白含量与血药浓度呈负相关（P<0.05）,不同剂型对血药浓度有影响,丙戊酸钠缓释片与糖浆的血药浓度比较差异有统计学意义（P<0.05）。结论：丙戊酸钠的不同剂型、给药剂量和白蛋白含量会影响VPA血药浓度,患儿性别、年龄、是否联用左乙拉西坦或拉莫三嗪、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血肌酐与血药浓度无相关性     

Retrospective population pharmacokinetic analysis of levetiracetam in children and adolescents with epilepsy: dosing recommendations

OBJECTIVE: To characterize levetiracetam pharmacokinetics, identify significant covariate relationships and identify doses in children that achieve blood concentrations similar to those observed in adults. METHODS: Nonlinear mixed-effects modelling was used to analyse pooled data collected from 228 children with epilepsy aged 3 months to 18 years in five trials of adjunctive levetiracetam therapy. Simulations were used to identify dosing regimens achieving levetiracetam steady-state peak and trough plasma concentrations similar to those attained in adults receiving the recommended starting dose for adjunctive therapy (500 mg twice daily). The covariates considered for inclusion in the base model were age, bodyweight, gender, race, body surface area (BSA), body mass index (BMI), creatinine clearance (CL(CR)), levetiracetam dose, concomitant antiepileptic drug (AED) by category (neutral, enzyme inducer, inhibitor, combination of inducer and inhibitor), and benzodiazepines. RESULTS: A one-compartment model with first-order absorption and elimination best characterized the data. The following significant covariates were identified: (i) age on the absorption rate constant (k(a)); (ii) bodyweight, dose, CL(CR) and concomitant enzyme-inducing AED on plasma oral clearance (CL/F); and (iii) bodyweight on the apparent volume of distribution after oral administration (V(d)/F). The main explanatory covariates were age on k(a), bodyweight on CL/F and V(d)/F, and enzyme-inducing AED on CL/F, of which bodyweight was the most influential covariate. Dosing can be carried out with either 10 mg/kg of oral solution twice daily in children weighing <50 kg and a 500-mg tablet twice daily in those weighing >50 kg or, when patients favour a solid formulation, 10 mg/kg of oral solution twice daily in children weighing <20 kg, a 250-mg tablet twice daily in those weighing 20-40 kg, and a 500-mg tablet twice daily in those weighing >40 kg. All of these doses achieved steady-state peak and trough plasma concentrations similar to those observed in adults following the recommended starting dose for adjunctive therapy (500 mg twice daily). CONCLUSIONS: The most influential covariate of levetiracetam pharmacokinetics in children is bodyweight. A starting dose of levetiracetam 10 mg/kg twice daily ensures the same exposure in children as does 500 mg twice daily in adults.