Che Magnus M, Conti Michele, Chanda Soma, Boylan Megan, Sabnekar Praveena, Rezk Peter, Amari Ethery, Sciuto Alfred M, Gordon Richard K, Doctor Bhupendra P, Nambiar Madhusoodana P
Department of Biochemical Pharmacology, Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA.
Toxicol Appl Pharmacol. 2009 Sep 15;239(3):251-7. doi: 10.1016/j.taap.2009.06.002. Epub 2009 Jun 11.
We evaluated the protective efficacy of nasal atropine methyl bromide (AMB) which does not cross the blood-brain barrier against sarin inhalation exposure. Age and weight matched male guinea pigs were exposed to 846.5 mg/m(3) sarin using a microinstillation inhalation exposure technique for 4 min. The survival rate at this dose was 20%. Post-exposure treatment with nasal AMB (2.5 mg/kg, 1 min) completely protected against sarin induced toxicity (100% survival). Development of muscular tremors was decreased in animals treated with nasal AMB. Post-exposure treatment with nasal AMB also normalized acute decrease in blood oxygen saturation and heart rate following sarin exposure. Inhibition of blood AChE and BChE activities following sarin exposure was reduced in animals treated with nasal AMB, indicating that survival increases the metabolism of sarin or expression of AChE. The body weight loss of animals exposed to sarin and treated with nasal AMB was similar to saline controls. No differences were observed in lung accessory lobe or tracheal edema following exposure to sarin and subsequent treatment with nasal AMB. Total bronchoalveolar lavage fluid (BALF) protein, a biomarker of lung injury, showed trends similar to saline controls. Surfactant levels post-exposure treatment with nasal AMB returned to normal, similar to saline controls. Alkaline phosphatase levels post-exposure treatment with nasal AMB were decreased. Taken together, these data suggest that nasal AMB blocks the copious airway secretion and peripheral cholinergic effects and protects against lethal inhalation exposure to sarin thus increasing survival.
我们评估了不能透过血脑屏障的鼻用甲基溴化阿托品（AMB）对沙林吸入暴露的防护效果。采用微量滴注吸入暴露技术，使年龄和体重匹配的雄性豚鼠暴露于846.5 mg/m³的沙林环境中4分钟。此剂量下的存活率为20%。鼻用AMB（2.5 mg/kg，1分钟）暴露后治疗可完全预防沙林诱导的毒性（存活率100%）。接受鼻用AMB治疗的动物肌肉震颤的发生有所减少。鼻用AMB暴露后治疗还使沙林暴露后血氧饱和度和心率的急性下降恢复正常。接受鼻用AMB治疗的动物，沙林暴露后血液乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）活性的抑制作用降低，这表明存活率的提高增加了沙林的代谢或AChE的表达。暴露于沙林并接受鼻用AMB治疗的动物体重减轻情况与生理盐水对照组相似。暴露于沙林并随后接受鼻用AMB治疗后，在肺副叶或气管水肿方面未观察到差异。作为肺损伤生物标志物的总支气管肺泡灌洗液（BALF）蛋白，其变化趋势与生理盐水对照组相似。鼻用AMB暴露后治疗后的表面活性剂水平恢复正常，与生理盐水对照组相似。鼻用AMB暴露后治疗后的碱性磷酸酶水平降低。综上所述，这些数据表明鼻用AMB可阻止大量气道分泌物和外周胆碱能效应，预防沙林致死性吸入暴露，从而提高存活率。
