Intramuscular atenolol and levetiracetam reduce mortality in a rat model of paraoxon‐induced status epilepticus,Annals of the New York Academy of Sciences

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Intramuscular atenolol and levetiracetam reduce mortality in a rat model of paraoxon‐induced status epilepticus
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2020-09-22 , DOI: 10.1111/nyas.14500
Laxmikant S Deshpande _{1,

2} , Robert E Blair ₁ , Matthew Halquist ₃ , Leon Kosmider ₃ , Robert J DeLorenzo _{1,

2}

Affiliation

Organophosphorus (OP) compounds are chemical threat agents and are irreversible inhibitors of the enzyme acetylcholinesterase that lead to a hypercholinergic response that could include status epilepticus (SE). SE particularly targets the heart and brain and despite existing therapies, it is still associated with significant mortality and morbidity. Here, we investigated the effect of intramuscular (i.m.) adjunct therapy consisting of atenolol (AT) and levetiracetam (LV) when administered after paraoxon (POX)‐induced SE. The combination therapy was administered twice daily for 2, 7, or 14 days. POX exposure in rats produced rapid SE onset that was treated with atropine, pralidoxime chloride, and midazolam. Here, AT + LV therapy produced significant reductions in POX SE mortality assessed at 30 days post‐SE. AT + LV therapy exhibited muscle pathology inflammation scores that were not significantly different from saline‐treated controls. Pharmacokinetic analyses revealed that the i.m. route achieved faster and stabler plasma therapeutic levels for both AT and LV under OP SE conditions compared with oral administrations. Our data provide evidence of the safety and efficacy of i.m. AT + LV therapy for reducing mortality following POX SE.

中文翻译：

肌内注射阿替洛尔和左乙拉西坦降低对氧磷诱导的癫痫持续状态大鼠模型的死亡率

有机磷 (OP) 化合物是化学威胁剂，是乙酰胆碱酯酶的不可逆抑制剂，可导致高胆碱能反应，包括癫痫持续状态 (SE)。SE 特别针对心脏和大脑，尽管存在现有疗法，但它仍与显着的死亡率和发病率相关。在这里，我们研究了由阿替洛尔 (AT) 和左乙拉西坦 (LV) 组成的肌内 (im) 辅助疗法在对氧磷 (POX) 诱导的 SE 后给药时的效果。联合疗法每天给药两次，持续 2、7 或 14 天。大鼠 POX 暴露产生快速 SE 发作，用阿托品、解磷定和咪达唑仑治疗。在这里，AT + LV 治疗显着降低了 SE 后 30 天评估的 POX SE 死亡率。AT + LV 治疗表现出的肌肉病理炎症评分与盐水治疗的对照组没有显着差异。药代动力学分析表明，与口服给药相比，IM 途径在 OP SE 条件下对 AT 和 LV 实现了更快和更稳定的血浆治疗水平。我们的数据提供了 im AT + LV 治疗降低 POX SE 后死亡率的安全性和有效性的证据。

更新日期：2020-09-22

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