Molecular Pharmacology of Topiramate: Managing Seizures and Preventing Migraine

Topiramate is a neuromodulatory compound with stabilizing properties that was initially introduced for the management of partial seizures. Topiramate has been demonstrated to modify several receptor-gated and voltage-sensitive ion channels, including voltage-activated Na⁺ and Ca²⁺ channels and non-NMDA receptors. These receptors have been implicated in the pathophysiology of both epilepsy and migraine. The pharmacological mechanisms of action for topiramate that may explain its antiepileptic and migraine preventive activities will be discussed in this review. In addition, the potential relationship between the molecular activities of topiramate and its efficacy in epilepsy and migraine prevention will be emphasized.     

Use of topiramate, a new anti-epileptic as a mood stabilizer

Rationale: Because some anti-epileptic drugs (AEDs) are effective in bipolar affective disorders, the new AED topiramate (TPM) may be effective in psychiatric illnesses. TPM was evaluated in mood disorders refractory to previous therapies including newer AEDs. Methods: Charts of 58 consecutive patients, 39 outpatients (15 males, 24 females) and 19 inpatients (6 males, 13 females) were reviewed. TPM 25 mg. b.i.d. was added to existing therapy and titrated in 50 mg increments every 3–7 days. Improvement was rated on a Likert global assessment scale of marked, moderate, mild, or no improvement or worse, based on quality of sleep, appetite, mood, and concentration. Results: Of the 58 patients with psychiatric disorders, 44 patients had rapid cycling bipolar disorders characterized by manic, hypomanic, or mixed episodes. Eighteen patients had previously failed to respond to lamotrigine and/or gabapentin in addition to conventional mood stabilizers. Fourteen were Bipolar I, six Bipolar II, and seven mixed, ten patients had cyclothymic disorder, seven had bipolar disorder not otherwise specified. Of the remaining 14 patients, nine had schizoaffective disorder, three patients had dementia and two had psychosis. Mean duration of TPM treatment was 16.0 weeks; mean TPM dosage approximately 200 mg/day. Thirty-six of 58 (62%) patients exhibited marked or moderate improvement, usually within days or weeks. Twenty-three of 44 (52%) patients with bipolar affective disorders showed marked or moderate improvement. Minimal/no improvement was observed in 16; six were rated as worse. Adverse events included delirium in one patient with Bipolar Disorder Type I who overmedicated with TPM (800 mg) and tranylcypromine sulfate (170 mg) combined with alcohol. Other adverse effects were minor and included: paresthesias, somnolence, fatigue, impaired concentration and memory, nausea, and diarrhoea. Limitations: This study was performed in a nonrandom open and retrospective fashion. Therefore, any findings are limited by the design of this study. Conclusion: TPM may be useful in patients with mood disorders unresponsive to traditional therapy and warrants further clinical investigation.     

液相色谱-电喷雾质谱联用法测定人血浆中托吡酯

目的:建立测定人血浆中托吡酯的液相色谱-电喷雾质谱联用(LC/ESI-MS)法。方法:待测血浆0.2 mL经甲醇沉淀除去蛋白,离心,取上清液10μL在Diamonsil C18柱上分离,流动相为甲醇-2.5 mmol·L-1醋酸铵(80:20),流速0.4 mL·min-1,LC/ESI-MS选择离子检测,负离子模式,用于定量分析的离子分别为m/z338(托吡酯)和m/z 356(吲哚美辛,内标)。结果:血浆中无干扰测定的内源性物质,每个样品分析时间小于7 min;本法线性范围为40-2560 ng·mL-1,最低定量浓度为40 ng·mL-1;日内、日间RSD分别小于3.8％和13.4％,相对偏差小于5.9％。结论:该法操作简便、快速、准确、灵敏度高,适用于临床药物动力学研究。     

卡马西平和托吡酯联合治疗复杂部分性癫痫29例

目的观察卡马西平和托吡酯联合治疗复杂部分性癫痫的临床疗效及安全性.方法对29例患儿在单用卡马西平治疗的基础上,加用托吡酯联合治疗.结果加用托吡酯后疗效明显,总有效率达69%,发作完全控制率占38%.结论研究结果表明,两药联合治疗复杂部分性癫痫是安全有效的.     

托吡酯治疗儿童抽动秽语综合征

目的:观察托吡酯治疗儿童抽动秽语综合征(Tourettesyndrome, TS)的疗效及其不良反应。方法:将96例TS病儿分为治疗组和对照组各48例。治疗组采用托吡酯按0. 5 ~ 1. 5mg·kg-1·d-1,分2 次口服, 对照组采用硫必利100 ~400mg·d-1,分2~3次口服,疗程6mo。治疗期间每月定期门诊复诊。结果:治疗组有效率为87 %,对照组有效率为85 %。2组疗效比较差异无显著意义(P> 0. 05); 2组不良反应率相比有非常显著差异(P <0. 01)。结论:托吡酯与硫必利治疗TS疗效相似,且不良反应较硫必利明显减少,同时可有效减轻合并症状。     

联用托吡酯治疗难治性癫痫临床观察

目的:观察联用托吡酯(TPM)治疗难治性癫痫(IE)的疗效与安全性.方法:采用开放性试验的方法,对20例IE患者进行治疗,以加用TPM前3个月的月均发作频率为基数,并与加用TPM后3个月的稳定期月均发作频率进行比较,同时观察其不良反应.结果:联用TPM治疗IE,总有效率达到75.0%,显效率为55.0%,其中3例(15.0%)完全控制;不良反应发生率为30.0%,为一过性,主要涉及中枢神经系统,其中2例出现体重减轻.结论:联用TPM对IE有良好疗效,安全性好.     

复方减肥药物——Qsymia

Qsymia是由美国Vivus公司开发的新型复方减肥药,2012年7月17日,美国FDA批准其作为节食和锻炼疗法的辅助治疗药,适用对象为体质指数(BMI)为30及以上或27及以上且患有与体重相关的疾病(如高血压、高血胆固醇、2型糖尿病等)的成人肥胖者。Qsymia是迄今为止效果最好的减肥药,平均能降低受试者10%的体重,减肥效果是目前市场上其他药物的2倍。Vivus公司已申请Qsymia在中国开展临床试验,其后续进展值得关注。笔者就Qsymia的研发历程、基本性质、作用机制、药动学、药效学、临床试验及应用等研发动态作一概述,以期能为医院临床用药起到指导作用。     

The Role of Topiramate in the Management of Cocaine Addiction: A Possible Therapeutic Option

Topiramate (TPM) is an antiepileptic drug able to play a role in both neurological and psychiatric disorders. TPM facilitates gamma-aminobutyric acid (GABA) transmission and inhibits glutamatergic transmission (i.e. AMPA/kainate receptors).Several studies reported that the modulation of GABAergic and glutamatergic synaptic transmission may reduce cocaine reinforcement. Therefore, TPM could be used in the management of cocaine dependence.     

Topiramate ameliorates abdominal aorta cross-clamping induced liver injury in rats

Background and Aim:

Ischemia/reperfusion (I/R) injury in the liver occurs after a prolonged period of ischemia followed by restoration of hepatic blood perfusion. During the surgery of abdominal aorta, I/R injury causes damage to lower extremities and many organs, especially liver. The antioxidant and tumor necrosis factor-alpha (TNF-α) suppression effects of topiramate (TPM) have been reported in several studies. We evaluated the potential protective effect of TPM on cellular damage in liver tissue during I/R injury.

Materials and Methods:

Thirty male Wistar albino rats were divided into three groups: Control, I/R, and I/R plus TPM (I/R + TPM) groups. Laparotomy without I/R injury was performed in the control group. After laparotomy, cross-ligation of infrarenal abdominal aorta was applied for 2 h in I/R groups that was followed by 2 h of reperfusion. TPM (100 mg/kg/day) was orally administrated to the animals in the I/R + TPM group for seven consecutive days before I/R procedure.

Results:

The I/R group''s TNF-α and interleukin-6 (IL-6) levels were significantly higher than those of the control (P = 0.010; P = 0.002) and I/R + TPM groups (P = 0.010; P = 0.002, respectively). Asymmetric dimethyl arginine (ADMA) levels of I/R group were higher than the control (P = 0.015) and I/R + TPM groups. I/R caused serious histopathological damage to liver tissue; however, TPM led to very low histopathological changes.

Conclusion:

Our data demonstrated that TPM treatment prominently decreases the severity of liver I/R injury. TPM pretreatment may have preventive effects on liver injury via I/R during intra-abdominal surgery.