Niquet Jerome, Suchomelova Lucie, Thompson Kerry, Klitgaard Henrik, Matagne Alain, Wasterlain Claude
Department of Neurology, David Geffen School of Medicine at UCLA, and VA Greater Los Angeles Health Care System, VA Medical Center (127), West Los Angeles, California, U.S.A.
UCB Pharma, Braine l'Alleud, Belgium.
Epilepsia. 2017 Jul;58(7):1199-1207. doi: 10.1111/epi.13787. Epub 2017 Jun 9.
To evaluate acute and long-term effects of intravenous brivaracetam (BRV) and BRV + diazepam (DZP) combination treatment in a rat model of self-sustaining status epilepticus (SSSE).
Rats were treated with BRV (10 mg/kg) 10 min after initiation of perforant path stimulation (PPS) as early treatment; or BRV (10-300 mg/kg), DZP (1 mg/kg), or BRV (0.3-10 mg/kg) + DZP (1 mg/kg) 10 min after the end of PPS (established SSSE). Seizure activity was recorded electrographically for 24 h posttreatment (acute effects), and for 1 week at 6-8 weeks or 12 months' posttreatment (long-term effects). All treatments were compared with control rats using one-way analysis of variance (ANOVA) and Bonferroni's test, or Kruskal--Wallis and Dunn's multiple comparison tests, when appropriate.
Treatment of established SSSE with BRV (10-300 mg/kg) resulted in dose-dependent reduction in SSSE duration and cumulative seizure time, achieving statistical significance at doses ≥100 mg/kg. Lower doses of BRV (0.3-10 mg/kg) + low-dose DZP (1 mg/kg) significantly reduced SSSE duration and number of seizures. All control rats developed spontaneous recurrent seizures (SRS) 6-8 weeks after SSSE, whereas seizure freedom was noted in 2/10, 5/10, and 6/10 rats treated with BRV 200 mg/kg, 300 mg/kg, and BRV 10 mg/kg + DZP, respectively. BRV (10-300 mg/kg) showed a dose-dependent trend toward reduction of SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at 300 mg/kg. Combination of BRV (10 mg/kg) + DZP significantly reduced SRS frequency, cumulative seizure time, and spike frequency. In the 12-month follow-up study, BRV (0.3-10 mg/kg) + low-dose DZP markedly reduced SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at some doses. Early treatment of SSSE with BRV 10 mg/kg significantly reduced long-term SRS frequency.
These findings support clinical evaluation of BRV for treatment of status epilepticus or acute repetitive seizures.
评估静脉注射布立西坦（BRV）以及BRV与地西泮（DZP）联合治疗对自维持性癫痫持续状态（SSSE）大鼠模型的急性和长期影响。
在穿通通路刺激（PPS）开始10分钟后给予BRV（10毫克/千克）进行早期治疗；或者在PPS结束（已确立的SSSE）10分钟后给予BRV（10 - 300毫克/千克）、DZP（1毫克/千克），或BRV（0.3 - 10毫克/千克）+ DZP（1毫克/千克）。在治疗后24小时（急性影响）以及治疗后6 - 8周或12个月时记录1周的癫痫活动（长期影响）。所有治疗组与对照大鼠进行比较，适当情况下使用单因素方差分析（ANOVA）和Bonferroni检验，或Kruskal - Wallis和Dunn多重比较检验。
用BRV（10 - 300毫克/千克）治疗已确立的SSSE可使SSSE持续时间和累积癫痫发作时间呈剂量依赖性减少，剂量≥100毫克/千克时具有统计学意义。较低剂量的BRV（0.3 - 10毫克/千克）+低剂量DZP（1毫克/千克）可显著降低SSSE持续时间和癫痫发作次数。所有对照大鼠在SSSE后6 - 8周出现自发性反复癫痫发作（SRS），而分别用200毫克/千克、300毫克/千克BRV以及10毫克/千克BRV + DZP治疗的大鼠中，癫痫发作缓解的比例分别为2/10、5/10和6/10。BRV（10 - 300毫克/千克）显示出降低SRS频率、累积癫痫发作时间和棘波频率的剂量依赖性趋势，在300毫克/千克时具有统计学意义。BRV（10毫克/千克）+ DZP联合用药可显著降低SRS频率、累积癫痫发作时间和棘波频率。在12个月的随访研究中，BRV（0.3 - 10毫克/千克）+低剂量DZP可显著降低SRS频率、累积癫痫发作时间和棘波频率，在某些剂量下具有统计学意义。用10毫克/千克BRV对SSSE进行早期治疗可显著降低长期SRS频率。
这些发现支持对BRV治疗癫痫持续状态或急性反复性癫痫发作进行临床评估。
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