Thakur Anamika, Sahai A K, Thakur J S
Department of Pharmacology, IG Medical College, Shimla, Himachal Pradesh - 171 001, India.
J Pharm Bioallied Sci. 2011 Apr;3(2):253-8. doi: 10.4103/0975-7406.80782.
Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy.
Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD(50) and CD(99) values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100-300 mg/kg), lamotrigine (3-12 mg/kg) and flunarizine (5-20 mg/kg), and then each group of mice was injected with CD(99) dose of PTZ (65mg/kg i.p.). Another group of mice received single ED(50) dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal-Wallis ANOVA on Ranks test.
As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection.
As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy.
实验研究发现了几种具有抗惊厥特性的钙通道阻滞剂。氟桂利嗪是最有效的钙通道阻滞剂之一，已显示出对戊四氮（PTZ）和最大电休克（MES）诱导的癫痫发作具有抗惊厥作用。然而，进一步的实验和临床试验结果各异。我们进行了一项PTZ模型实验研究，以重新评估氟桂利嗪在难治性癫痫治疗中作为附加治疗的潜力。
在涉及瑞士品系小鼠的PTZ模型中进行实验。通过剂量反应研究获得使50%和99%小鼠产生癫痫发作的剂量，即PTZ的半数惊厥剂量（CD(50)）和99%惊厥剂量（CD(99)）。动物接受分级单剂量的丙戊酸钠（100 - 300 mg/kg）、拉莫三嗪（3 - 12 mg/kg）和氟桂利嗪（5 - 20 mg/kg），然后每组小鼠腹腔注射CD(99)剂量的PTZ（65mg/kg）。另一组小鼠分别在腹部左右两侧接受单剂量的丙戊酸钠和氟桂利嗪的半数有效剂量（使50%小鼠产生癫痫发作保护作用的剂量）。结果采用Kruskal - Wallis秩和检验进行分析。
与对照组相比，250 mg/kg和300 mg/kg的丙戊酸钠产生了具有统计学意义的癫痫发作保护作用。在拉莫三嗪的任何预处理剂量水平下，PTZ诱导的癫痫发作评分与溶媒处理组相比均无显著差异。氟桂利嗪预处理显示出PTZ给药后癫痫发作评分呈剂量依赖性降低。与对照组相比，20 mg/kg的氟桂利嗪产生了具有统计学意义的癫痫发作保护作用。
由于丙戊酸钠和氟桂利嗪联合使用在PTZ模型中显示出显著的癫痫发作保护作用，氟桂利嗪在部分癫痫难治性病例中具有作为附加治疗的潜力。因此，我们得出结论，需要进一步进行涉及大样本量的实验研究和多中心临床试验，以确立氟桂利嗪作为难治性癫痫附加治疗的地位。
