左乙拉西坦血药浓度与剂量以及疗效分析

目的探讨左乙拉西坦(LEV)与其他抗癫痫药物的相互作用及对癫痫发作频率的影响、不同年龄组LEV效果,分析LEV血药浓度与剂量疗效的关系。方法对收集的200病例进行分组,对所得的数据进行卡方检验、方差分析与相关性分析。结果各组疗效无明显差异,单药LEV服药剂量与血药浓度明显相关(r=0.832,P<0.05),对LEV血药浓度的有影响是LTG/CBZ/PB,影响不明显的是TPM/OXC/VPA。结论 LEV的血药浓度与服药剂量、联合用药、患者的个体差异均有关系,在治疗的过程中需要对LEV进行治疗药物监测以便更好的控制癫痫。     

左乙拉西坦血药浓度影响因素探讨及参考区间的初步建立

目的建立癫痫患儿左乙拉西坦血药浓度的参考区间,并探讨血药浓度相关的影响因素,为临床个体化用药提供参考。方法收集规律服用左乙拉西坦不少于3个月的0~14岁门诊及住院的332例患儿血样,用高效液相色谱串联质谱(HPLC-MS/MS)法测定左乙拉西坦的血药浓度,分析单用药组、联合用药组及不同性别对左乙拉西坦血药浓度的影响。结果血药浓度数据分析显示,单用药组与联合用药组的左乙拉西坦血药浓度差异无统计学意义(P>0.05)。单用药组男性血药浓度为9.40(5.90~12.50)μg·mL^-1,女性为7.73(5.59~10.42)μg·mL^-1;联合用药组男性血药浓度为9.57(6.82~12.90)μg·ml-1,女性为7.62(5.84~10.40)μg·mL^-1;总用药组男性血药浓度为9.06(5.22~12.40)μg·mL^-1,女性为7.73(5.41~11.20)μg·mL^-1,单用药组与总用药组不同性别间血药浓度差异均有统计学意义(均P<0.05)。本研究总样本左乙拉西坦血药浓度参考区间为2.5~24μg·mL^-1。结论儿童抗癫痫治疗时血药浓度与剂量存在相关性;而性别及联合用药等因素的影响,后续还需扩大样本量进一步研究验证。     

左乙拉西坦临床应用研究进展

目的探讨左乙拉西坦的临床应用,为其临床合理用药和推广提供参考。方法对左乙拉西坦的给药途径、治疗癫痫的特点、机制和在非癫痫领域的作用进行了综述。结果与结论左乙拉西坦可单一用药或配合其他药物治疗癫痫,在非癫痫领域疗效显著。左乙拉西坦的临床应用广泛。     

左乙拉西坦治疗药物监测的研究进展

左乙拉西坦（LEV）是第二代广谱抗癫痫药物,具有起效快、半衰期短、疗效确切、耐受性好、药物相互作用少等优点。为提高LEV的临床效果,减少不良反应的发生,应对儿童、妊娠期妇女、老年人、肾功能不全等特殊人群予以治疗药物监测（TDM）。临床上LEV监测样本常选择血浆或血清,监测方法多选择免疫分析法或色谱分析法。LEV的有效浓度范围目前尚无统一意见,血药浓度与不良反应的相关性也不明确。影响LEV血药浓度的因素主要有年龄、妊娠及患者用药依从性等。如何解读TDM结果并根据结果调整给药剂量是今后工作的重点。     

左乙拉西坦的合成

目的：研究左乙拉西坦的合成方法。方法：采用后闭环路线，优化氨解反应的工艺条件。结果：该路线的反应条件温和，副反应少，产品质量得到提高，总收率达46％左右。结论：该工艺路线适合于工业化大规模生产。     

左乙拉西坦及其衍生物的合成

目的:探讨左乙拉西坦及其衍生物的制备方法。方法:以2-吡咯烷酮为起始原料,经成盐和取代得外消旋中间体(±)-α-乙基-(2-氧-1-吡咯烷基)乙酸(1),再以R-α-苯乙胺为拆分剂,得中间体(S)-α-乙基-(2-氧-1-吡咯烷基)乙酸(3),3分别与相应的氨、胺或醇发生酰化反应,得到左乙拉西坦及其衍生物。结果:得到左乙拉西坦及其9个衍生物,8个作者未见文献报道。经红外光谱1、HNMR或元素分析认定结构正确。结论:本合成工艺有助于工业化生产,9个目标化合物对提高药物促智作用,降低不良反应能起到积极作用。     

左乙拉西坦致皮疹2例

2例女性癫痫患者(例1 15岁,例2 54岁),服用传统抗癫痫药物效果不佳,给予口服左乙拉西坦0.25 g2,次/d,分别在治疗第75、天,四肢及躯干部皮肤出现红色斑疹伴瘙痒。考虑皮疹与左乙拉西坦有关。例1停用左乙拉西坦后3 d皮疹消褪。例2停用左乙拉西坦并接受氯雷他定10 mg、1次/d治疗,1周后皮疹消褪。     

左乙拉西坦治疗癫痫的临床应用

无发作是癫痫治疗的主要目标,实现无发作能降低癫痫患者病死率,改善生活质量.新型抗癫痫药物左乙拉西坦,辅助或单药治疗均可降低癫痫部分性发作,安全性好,不良反应少,长期治疗未见肝、肾功能异常及血液和生化指标改变,不产生耐药性,对认知功能无不良影响,临床值得推荐.     

儿童体内左乙拉西坦血药浓度与单药治疗临床疗效的关系

目的:探讨左乙拉西坦(LEV)单药治疗时的血药浓度水平与其临床疗效的关系,以促进合理用药。方法:对245例5个月~16岁口服左乙拉西坦单药治疗的癫痫患儿进行开放性自身对照随访研究,观察疗效和不良反应。采用固相萃取-高效液相色谱法(SPE-HPLC)测定患儿血样中LEV的稳态谷浓度,运用受试者操作特征(ROC)曲线分析该浓度水平与疗效的关系。结果:左乙拉西坦单药治疗本组癫痫患儿的有效率为88.6%(217例),其中完全控制率为66.1%(162例)。对于本组患儿临床有效的LEV稳态谷浓度参考范围为5~19 mg·L^-1,相应的LEV日剂量的95%分布区间为13.9~50.0 mg·kg^-1·d^-1。以谷浓度作为疗效预测因子构建的ROC曲线下面积AUC(95% CI)=0.925(0.884~0.967),显示出较高的预测准确性。Youden指数最大(0.717)时对应的ROC曲线上最佳界值切点为6.05 mg·L^-1,说明当LEV稳态谷浓度超过6 mg·L^-1时大多病例会获得满意疗效。本组研究中左乙拉西坦的不良反应发生率在初始加量阶段为14.3%(35例),剂量稳定后自然消除,未发现严重不良反应。结论:左乙拉西坦的临床疗效和其谷浓度水平密切相关,为保证疗效和安全性,有必要监测血药浓度。     

左乙拉西坦基础研究进展

目的 介绍新型抗癫痫药物左乙拉西坦(LEV)基础动物实验研究方面的进展。方法 通过查阅近年来的报道,概括了LEV作用于癫痫动物模型的机制、以及与癫痫耐药相关蛋白、脑保护的关系。结果 LEV具有与既往抗癫痫药物不同的作用机制,不仅有抗癫痫作用,还具有抑制癫痫源产生和发展的作用。多数报道LEV不是常见耐药蛋白如P-gp和MRP1/2,MDR1的底物,在难治性癫痫的治疗中具有理论基础,同时LEV在神经保护方面急性期多具积极作用,而在慢性期效果不明显。结论 大量动物实验证明LEV具有全新的作用机制,对于临床癫痫的治疗具有重要指导意义,但在不同癫痫模型及组织中结果不尽相同,值得进一步探讨,为开发新的抗癫痫药物提供借鉴。     

Lack of pharmacokinetic interaction between retigabine and phenobarbitone at steady-state in healthy subjects

AIMS: To evaluate potential pharmacokinetic interactions between phenobarbitone and retigabine, a new antiepileptic drug. METHODS: Fifteen healthy men received 200 mg of retigabine on day 1. On days 4-32, phenobarbitone 90 mg was administered at 22.00 h. On days 26-32, increasing doses of retigabine were given to achieve a final dose of 200 mg every 8 h on day 32. The pharmacokinetics of retigabine were determined on days 1 and 32, and those for phenobarbitone on days 25 and 31. RESULTS: After administration of a single 200 mg dose, retigabine was rapidly absorbed and eliminated with a mean terminal half-life of 6.7 h, a mean AUC of 3936 ng x ml(-1) x h and a mean apparent clearance of 0.76 l x h(-1) x kg(-1). Similar exposure to the partially active acetylated metabolite (AWD21-360) of retigabine was observed. After administration of phenobarbitone dosed to steady-state, the pharmacokinetics of retigabine at steady-state were similar (AUC of 4433 ng x ml(-1) x h and t1/2 of 8.5 h) to those of retigabine alone. The AUC of phenobarbitone was 298 mg x l(-1) x h when administered alone and 311 mg x ml(-1) x h after retigabine administration. The geometric mean ratios and 90% confidence intervals of the AUC were 1.11 (0.97, 1.28) for retigabine, 1.01 (0.88, 1.06) for AWD21-360 and 1.04 (0.96, 1.11) for phenobarbitone. Individual and combined treatments were generally well tolerated. One subject was withdrawn from the study on day 10 due to severe abdominal pain. Headache was the most commonly reported adverse event. No clinically relevant changes were observed in the electrocardiograms, vital signs or laboratory measurements. CONCLUSIONS: There was no pharmacokinetic interaction between retigabine and phenobarbitone in healthy subjects. No dosage adjustment is likely to be necessary when retigabine and phenobarbitone are coadministered to patients.     

反相高效液相色谱法同时测定苯巴比妥和卡马西平血药浓度

目的：建立同时测定微量血浆中苯巴比妥和卡马西平浓度的方法。方法：采用ＲＰ－ＨＰＬＣ法,以艾司唑仑为内标,同时测定微量血浆中苯芭巴比妥和卡马西平浓度。色谱柱ｓｈｉｍａｄｚｕ ｓｈｉｒｍｐａｃｋ ＣＬＣ－Ｃ１８不锈钢柱,流动相为醇－水（６０：４０）,流速０．８ｍｌ．ｍｉｎ＾－１,检测波长２５４ｎｍ。结果：苯巴比妥在４～６０μｇ．ｍｌ＾－１浓度范围内线性良好（ｒ＝０．９９９８）,卡马西平在２～１６μｇ．ｍｌ＾－１浓度范围内线性良好（ｒ＝０．９９９５）,最低检测限分别为１１．５７ｎｇ．ｍｌ＾－１和４．９２ｎｍ．ｍｌ＾－１,两者高、中、低３种浓度的平均回收率分别为９９．９２％,１０１．３０％,９７．９２％和９９．４１％,１０１．５２％,９８．２２％（ｎ＝９）,日内ＲＳＤ分别为３．１％,２．６％,３．８％和１．９％,１．６     

Evaluation of a pharmacokinetic interaction between remacemide hydrochloride and phenobarbitone in healthy males

AIMS: To determine whether there is a pharmacokinetic interaction between the antiepileptic drugs remacemide and phenobarbitone. METHODS: In a group of 12 healthy adult male volunteers, the single dose and steady-state kinetics of remacemide were each determined twice, once in the absence and once in the presence of phenobarbitone. The effect of 7 days remacemide intake on initial steady-state plasma phenobarbitone concentrations was also investigated. RESULTS: Apparent remacemide clearance (CL/F) and elimination half-life values were unchanged after 7 days intake of the drug in the absence of phenobarbitone (1.25 +/- 0.32 vs 1.18 +/- 0.22 l kg(-1) h(-1) and 3.29 +/- 0.68 vs 3.62 +/- 0.85 h, respectively). Concomitant administration of remacemide with phenobarbitone resulted in an increase in the estimated CL/F of remacemide (1.25 +/- 0.32 vs 2.09 +/-0.53 l kg-1 h-1), and a decreased remacemide half-life (3.29 +/- 0.68 vs 2.69 +/- 0.33 h). The elimination of the desglycinyl metabolite of remacemide also appeared to be increased after the phenobarbitone intake (half-life 14.72 +/- 2.82 vs 9.61 +/- 5.51 h, AUC 1532 +/- 258 vs 533 +/- 281 ng ml(-1) h). Mean plasma phenobarbitone concentrations rose after 7 days of continuing remacemide intake (12.67 +/- 1.31 vs 13.86 +/- 1.81 microgram ml(-1)). CONCLUSIONS: Phenobarbitone induced the metabolism of remacemide and that of its desglycinyl metabolite. Remacemide did not induce its own metabolism, but had a modest inhibitory effect on the clearance of phenobarbitone.     

Difference in the central actions of phenytoin and phenobarbitone in man,measured by critical flicker fusion threshold

Summary The central effects of single oral doses of phenobarbitone and phenytoin have been determined in six normal volunteers by measuring the critical flicker fusion threshold (CFF) under double-blind, placebo controlled conditions at intervals of up to 7 h after ingestion of the drug. Blood samples were taken at the same time for estimation of the serum concentration of the drugs by gas chromatography. Phenobarbitone in a dose of 180 mg produced a significant fall in CFF, and the time-course of this change mirrored the time-course of the serum concentration of the drug, which reached a peak of 21.8 µM (5.2 µg/ml) at 1.5 h. Phenytoin in doses of 200 mg, 300 mg and 400 mg produced no significant change in CFF even though an adequate serum concentration of the drug had been achieved (28.8 µM, 7.2 µg/ml, with the 400 mg dose). It was concluded that the two drugs differ in their action on the neural mechanisms tested by this procedure.     

反相高效液相色谱法同时测定血浆中氯胺酮,苯巴比妥和阿托品的浓度

本文采用ＺｏｒｂａｘＣ８色谱柱，甲醇－磷酸盐缓冲液（６９∶３１）为流动相，２２０ｎｍ为检测波长，非那西丁为内标，建立了同时测定人血浆中氯胺酮、苯巴比妥和阿托品浓度的反相高效液相色谱法。本法简便、快速、灵敏、重现性好。氯胺酮、苯巴比妥和阿托品的平均回收率分别为９９．２０％，９９．１３％和９７．６２％；不同浓度水平测定结果的日内和日间相对标准偏差均小于５％；其检测限分别为０．２μｇ／ｍｌ，０．０５μｇ／ｍｌ和０．５μｇ／ｍｌ（Ｓ∶Ｎ＝３∶１）。     

左乙拉西坦仿制药与原研药临床疗效及安全性的真实世界研究

目的:评价真实世界左乙拉西坦(LEV)仿制药与原研药的安全性和有效性。 方法:回顾分析 2019 年 4 月至 2020 年 5 月西安交通大学第二附属医院使用 LEV 治疗的 600 例癫痫患儿临床资料,采用高效液相色谱检测 LEV 仿制药和原研药血药浓度,并分析两种药物剂量与血药浓度关系以及治疗效果和不良反应发生率。 结果:600 例癫痫患儿中,使用 LEV 仿制药 125 例,单药治疗 71 例,联合用药 54 例;使用 LEV 原研药 475 例,单药治疗 266 例,联合用药 209 例。 LEV 仿制药单药治疗血药浓度为(9. 31±3. 34)μg / mL,与肝酶诱导剂(奥卡西平、苯巴比妥)联用时血药浓度分别(10.26±4. 72)μg / mL 和(11. 05±2. 41)μg / mL,与肝酶抑制剂(丙戊酸、托吡酯)联用时血药浓度分别为(10. 69±5. 78)μg / mL 和(8. 16±4. 37)μg / mL,与肝酶诱导剂、抑制剂(奥卡西平+丙戊酸)联用时血药浓度为(8. 74±5. 56)μg / mL,与 LEV 原研药比较差异均无统计学意义。 LEV 仿制药单药治疗有效率为 78. 9%,原研药为 74. 1%;联用肝酶诱导剂,LEV 仿制药有效率为 64. 3%,原研药为 62. 7%;联用肝酶抑制剂,LEV 仿制药有效率为 59. 3%,原研药为 78. 2%;联用肝酶诱导剂、抑制剂,LEV 仿制药有效率为 69. 2%,原研药为 71. 4%。 LEV仿制药与原研药临床疗效比较差异均无统计学意义。 LEV 仿制药不良反应发生率与原研药相似,常见不良反应均为异常行为及入睡困难。 结论:LEV 仿制药和原研药在真实世界临床疗效及不良反应比较差异无统计学意义,LEV 仿制药替换原研药是安全且有效的。     

反相高效液相色谱法测定人血中利福平浓度

目的 :建立测定人血清中利福平浓度的高效液相色谱法 (HPLC)。方法 :血清加 4倍量的甲醇沉淀后离心 ,取上清液用 0 45 μ微孔滤膜滤过后进样。采用Nova-PakC1 8柱 ,以甲醇 -醋酸盐缓冲液 (62∶40 )为流动相 ,氯氮作为内标 ,在 3 3 4nm波长处测定。结果 :利福平的线性范围为 1～2 5 μg/ml,平均回收率为 (1 0 0 9± 4 2 ) % ,日内、日间RSD均小于 4%。最低检测限为 0 5 μg/ml(信噪比≥ 3 )。结论 :本法简便、可靠 ,适用于临床监测。     

双波长分光光度法测定勃氏合剂中苯巴比妥钠含量

勃氏合剂（Ｂｒｏｄｓｋｙ＇ｓｍｉｘｔｕｒｅ）系含苯巴比妥钠、咖啡因等的复方制剂。本文介绍用双波长法测定制剂中苯巴比妥钠的含量。结果：苯巴比妥钠在４～２０μｇ／ｍｌ浓度范围内线性关系良好，回归方程△Ａ＝０．０４１１３Ｃ－０．００２５，相关系数ｒ＝０．９９９９，平均回收率为９９．９％，相对标准偏差为０．６％。     

A case of levetiracetam induced bullous pemphigoid

Bullous pemphigoid is a chronic, acquired autoimmune skin disease. Certain drugs such as furosemide, penicillins, sulfonamides, ciprofloxacins, penicillamines, angiotensin converting enzyme inhibitors, chloroquine, and phenacetin were reported to cause bullous pemphigoid. This is a case report of a 70-year-old female, who presented with the formation of diffuse cutaneous blister in month after starting to use levetiracetam. Dermatological exam and histopathological findings were consistent with bullous pemphigoid. To the best of our knowledge this is the first case of bullous pemphigoid in the literature associated with levetiracetam use.     

Brain concentrations of phenytoin,phenobarbitone and primidone in epileptic patients

Summary Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10–14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.