Determination of the inorganic degradation products sulfate and sulfamate in the antiepileptic drug topiramate by capillary electrophoresis

A capillary electrophoresis (CE) method has been developed as an alternative method for the determination of the inorganic degradation products sulfate and sulfamate in topiramate drug product and drug substance, currently performed by ion chromatography. The anions are separated in a background electrolyte containing potassium chromate and boric acid, followed by indirect UV detection. By adding tetradecyltrimethylammonium bromide to the electrolyte, analysis is performed under co-electroosmotic flow conditions. Variations in injection volumes and migration times are compensated for by use of an internal standard. The validation of the method, which was performed according to ICH guidelines (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) [1], comprises specificity, accuracy, linearity, precision, sensitivity and robustness. In addition, the results of an actual tablet sample analysis obtained by this CE method are statistically shown to be in close agreement with those obtained by an ion chromatographic method.     

托吡酯与苯巴比妥对小儿癫痫患儿发作次数及痫样放电的影响对比

目的:研究托吡酯(topiramate,TPM)与苯巴比妥(phenobarbital,PB)对小儿癫痫(Epilepsy)患儿发作次数及痫样放电的影响。方法:将我院2010年8月至2013年8月入院接受诊治的200例癫痫患儿作为观察对象,随机分成两组。观察组采用TPM治疗,对照组采用PB治疗。对比两组患儿治疗前以及治疗后3个月癫痫发作次数、疗效以及不良反应情况。结果:观察组部分性发作减少次数、全身性发作减少次数及总发作减少次数,均显著高于对照组;观察组治愈率、愈显率、总有效率,均显著高于对照组;观察组不良反应情况显著少于对照组;差异均具有统计学意义(均P0.05)。结论:与PB相比,TPM治疗小儿癫痫疗效更佳,且不良反应更少,值得临床推荐。     

Topiramate modulates hippocampus NMDA receptors via brain Ca2+ homeostasis in pentylentetrazol-induced epilepsy of rats

Background: Increase in neuronal Ca²⁺, activation of hippocampus N-methyl-D-aspartate receptor (NMDAR) and defects in enzymes such as brain cortex microsomal membrane Ca²⁺-ATPase (MMCA) are thought to play a role in epilepsy. Topiramate (TOP) is a novel drug with broad antiepileptic effect, and its effect on brain cortex MMCA is not known. We investigated effects of TOP on pentylentetrazol (PTZ)-induced MMCA activity and NMDAR subunits in rat brain.

Materials and methods: Thirty-two rats were randomly divided into four equal groups. The first group and second groups were used for the control and PTZ groups, respectively. 50 and 100?mg TOP were administered to rats constituting the third (TOP50) and fourth (TOP100) groups for 7 days, respectively. At the end of 7 days, all groups except the first received a single dose PTZ. Brain and hippocampus samples were taken at 3?hrs after PTZ administration.

Results: The microsomal MMCA activity was lower in the PTZ group than in control although the MMCA activities were higher in the treatment group than in PTZ group. Brain cortex total calcium levels, the hippocampus NMDAR 2A and 2B subunit concentrations were higher in the PTZ group than in control although their concentrations were decreased by TOP50 and TOP100 administration. Total brain cortex calcium and hippocampus NMDAR 2A and 2B subunit concentrations were higher in TOP100 group than in TOP50 group.

Conclusion: The two doses of TOP modulated MMCA activity, total brain cortex calcium and hippocampus NMDAR 2A and 2B subunit concentrations in the epileptic rats.     

Topiramate attenuates cerebral ischemia/reperfusion injury in gerbils via activating GABAergic signaling and inhibiting astrogliosis

Impaired GABAergic inhibitory synaptic transmission plays an essential role in the pathogenesis of selective neuronal cell death following transient global ischemia. GABA_A receptor (GABA_AR), K⁺-Cl⁻ co-transporter 2 (KCC2), Na⁺-K⁺-Cl⁻ co-transporter 1 (NKCC1) and astrocytes are of particular importance to GABAergic transmission. The present study was designed to explore whether the neuroprotective effect of topiramate (TPM) was linked with the alterations of GABAergic signaling and astrocytes. The bilateral carotid arteries were occluded, and TPM (80 mg/kg/day (divided twice daily), i.p.) was injected into gerbils. At day 1, 3 and 7 post-ischemia, neurological deficit was scored and changes in hippocampal neuronal cell death were evaluated by Nissl staining. The apoptosis-related regulatory proteins (procaspase-3, caspase-3, Bax and Bcl-2) and GABAergic signal molecules (GABA_AR α1, GABA_AR γ2, KCC2 and NKCC1) were also detected using western blot assay. In addition, the fluorescent intensity and protein level of glial fibrillary acidic protein (GFAP), a major component of astrocyte, were examined by confocal and immunoblot analysis. Our results showed that TPM treatment significantly decreased neurological deficit scores, attenuated the ischemia-induced neuronal loss and remarkably decreased the expression levels of procaspase-3, caspase-3 as well as the ratio of Bax/Bcl-2. Besides, treatment with TPM also resulted in the increased protein expressions of GABA_AR α1, GABA_AR γ2 and KCC2 together with the decreased protein level of NKCC1 in gerbils hippocampus. Furthermore, fluorescent intensity and protein level of GFAP were evidently reduced in TPM-treated gerbils. These findings suggest that the therapeutic effect of TPM on global ischemia/reperfusion injury appears to be associated with the enhancement of GABAergic signaling and the inhibition of astrogliosis in gerbils.     

托吡酯联合拉莫三嗪对癫痫患者认知功能和生活质量的影响

目的:探讨托吡酯联合拉莫三嗪对癫痫患者认知功能和生活质量的影响。方法:选择2016年1月到2018年2月我院诊治的癫痫患者60例进行回顾性分析,根据治疗方法不同分为两组,各30例,对照组给予托吡酯治疗,观察组在对照组治疗的基础上给予拉莫三嗪治疗。两组均治疗观察3个疗程,记录和比较其认知功能和生活质量变化情况以及不良反应发生情况。结果:治疗后,观察组的总有效率显著高于对照组(96.6%vs.73.3%,P<0.05)。两组治疗期间的胃肠道反应、神经系统反应、精神症状、全身反应等不良反应情况对比差异无统计学意义(P>0.05)。两组治疗后的蒙特利尔认知评估量表(Montreal Cognitive Assessment,Mo CA)评分均显著高于治疗前(P<0.05),且观察组显著高于对照组(P<0.05)。此外,观察组治疗后的生活满意度、生活打扰、积极影响、身体健康、心理应对等生活质量评分均显著高于对照组(P<0.05)。结论:托吡酯联合拉莫三嗪用于治疗癫痫患者能显著改善认知功能,提高患者生活质量与治疗效果,且安全性较高。     

Topiramate reduced sweat secretion and aquaporin-5 expression in sweat glands of mice

Decreased sweat secretion is a primary side effect of topiramate in pediatric patients, but the mechanism underlying this effect remains unclear. This study aimed to better understand how topiramate decreases sweat secretion by examining its effect on the expression of carbonic anhydrase (CA) II and aquaporin-5 (AQP5), total CA activity, as well as on tissue morphology of sweat glands in mice. Both developing and mature mice were treated with a low (20 mg/kg/day) and high dose (80 mg/kg/day) of topiramate for 4 weeks. Sweat secretion was investigated by an established technique of examining mold impressions of hind paws. CA II and AQP5 expression levels were determined by immunofluorescence and immunoblotting and CA activity by a colorimetric assay. In mature mice, topiramate treatment decreased the number of pilocarpine reactive sweat glands from baseline in both the low and high dose groups by 83% and 75%, respectively. A similar decrease was seen in developing mice. Mature mice with reactive sweat glands that declined more than 25% compared to baseline were defined as anhidrotic mice. These mice did not differ from controls in average secretory coil diameter, CA II expression and CA activity. In contrast, anhidrotic mice did show a reduction in membrane AQP5 expression in sweat glands after topiramate delivery. Thus, sweat secretion and membrane AQP5 expression in mouse sweat glands decreased following topiramate administration. These results suggest dysregulation of AQP5 may be involved in topiramate-induced hypohidrosis and topiramate may serve as a novel therapy for hyperhidrosis.     

托吡酯、卡马西平与丙戊酸钠治疗脑炎继发癫痫的疗效比较

目的:观察和比较托吡酯、卡马西平与丙戊酸钠对治疗脑炎继发癫痫的临床疗效及安全性。方法:选择2013年1月~2015年9月在我院进行诊治的脑炎继发癫痫患者80例,随机分为托吡酯组、卡马西平组和丙戊酸钠组,分别采用托吡酯、卡马西平与丙戊酸钠治疗,比较三组的治疗有效率、执行能力与视空间、命名、抽象、注意、定向、语言以及延迟回忆等认知功能评分及不良反应的发生情况。结果:托吡酯组的有效率最高,为80.65%(25/31),卡马西平组的有效率最低,为70.00%(21/30),但三组间有效率相比差异无统计学意义(P0.05)。治疗后,托吡酯组患者的执行能力与视空间、命名、抽象、注意、定向、语言以及延迟回忆等认知功能评分均明显高于卡马西平组和丙戊酸钠组(P0.05);托吡酯组的不良反应发生率(12.90%)明显低于卡马西平组(36.67%)和丙戊酸钠组的(29.62%)(P0.05)。结论:托吡酯、卡马西平以及丙戊酸钠治疗脑炎继发癫痫疗效相当,但托吡酯对患者认知功能损害最小,安全性最高。     

Dose-finding study with nicotine as a proconvulsant agent in PTZ-induced seizure model in mice

The present study was conducted to investigate the possible interaction between low doses of nicotine and pentylenetetrazole (PTZ) in vivo and also to evaluate the influence of nicotine on the antiseizure efficacy of topiramate and sodium valproate in the PTZ-induced seizure model in mice. Graded dose–response study with nicotine showed the CD50 value for nicotine at 6.76 mg/kg. i.p. Subtheshold dose of nicotine (4 mg/kg, i.p.) pretreatment significantly decreased the CD50 value for PTZ from 47.86 mg/kg, i.p. (of PTZ per se) to 31.62 mg/kg, i.p. Sodium valproate but not topiramate, significantly inhibited PTZ-induced seizures in mice with an ED50 value of 177.83 mg/kg, i.p. Nonconvulsive dose of nicotine (1 mg/kg, i.p.) significantly antagonized the protective efficacy of sodium valproate against PTZ-induced seizures and increased the ED50 value to 338.84 mg/kg, i.p. PTZ-induced seizures significantly increased the mouse brain levels of MDA and reduced the level of GSH while sodium valproate reversed such changes. Nicotine pretreatment reversed the anti-lipid peroxidative action of sodium valproate in the PTZ-induced seizure model in mice. The study highlighted the convulsant as well as proconvulsant role of nicotine and established dose discrimination for nicotine as a proconvulsant agent and an anti-antiseizure agent. The study bears significant clinical relevance particularly amongst epileptic smokers who may show failure of efficacy of antiepileptic agents and present with breakthrough seizure attacks on exposure to nicotine.     

托吡酯与丙戊酸钠对癫痫患儿脑电活动及糖脂代谢的影响

目的:探讨托吡酯与丙戊酸钠对癫痫患儿脑电活动及相关代谢指标的影响。方法:选择66例癫痫患儿进行研究,并采用随机方法分为两组,其中观察组予托吡酯治疗,对照组予丙戊酸钠治疗。比较治疗前后患儿脑电活动及糖脂代谢指标差异。结果:治疗后,观察组患儿癫痫样放电(6.77±1.04)次、δ(12.77±2.32)次、θ(21.63±2.77)次、α(20.54±2.55)次、β(11.18±1.72)次均较治疗前和对照组明显减少(P0.05)。观察组患儿经治疗后体质指数(BMI)(14.43±1.29)kg/m2、空腹血糖(FPG)(4.53±0.51)mmol/L较治疗前和对照组明显减少(P0.05),空腹胰岛素(FINS)(9.78±1.44)m U/L较治疗前和对照组明显增加(P0.05)。两组患者经治疗后脂代谢各项指标甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(L-DLD)、高密度脂蛋白(H-DLD)均较治疗前无明显变化(P0.05),且两组间比较无显著差异(P0.05)。结论:托吡酯能更有效控制癫痫患儿的脑电活动,但会导致糖代谢异常及患儿体质量指数减少,而丙戊酸钠对癫痫患儿糖脂代谢及体质量指数的影响较小,临床应根据具体情况合理选择用药。