The efficacy and pharmacokinetics of the aqueous co-formulation contents of the Trobigard™ (atropine sulfate, obidoxime chloride) auto-injector were evaluated in a sarin exposed guinea pig model. Two subcutaneous (sc) sarin challenge doses were evaluated in guinea pigs instrumented with brain and heart electrodes for electroencephalogram (EEG) and electrocardiogram (ECG). Sarin challenge doses were chosen to reflect exposure subclasses with sublethal (moderate to severe clinical signs) and lethal consequences. The level of protection of intramuscular human equivalent doses of the co-formulation was defined by (1) the mitigation of signs and symptoms at a sublethal level and (2) the increase of survival time at the supralethal sarin dose levels.

Pharmacokinetics of both atropine sulfate and obidoxime were proportional at 1 and 3 human equivalent doses, and only a small increase in heart rate was observed briefly as a side effect.

At both sarin challenge doses, 54 μg/kg and 84 μg/kg, the co-formulation treatment was effective against sarin-induced effects. Survival rates were improved at both sarin challenge levels, whereas clinical signs and changes in EEG activity could not in all cases be effectively mitigated, in particular at the supralethal sarin challenge dose level. Reactivation of sarin inhibited cholinesterase was observed in blood, and higher brain cholinesterase activity levels were associated with a better clinical condition of the co-formulation treated animals.

Although the results cannot be directly extrapolated to the human situation, pharmacokinetics and the effects over time related to plasma levels of therapeutics in a freely moving guinea pig could aid translational models and possibly improve prediction of efficacy in humans.

在暴露于沙林的豚鼠模型中，评估了Trobigard™（硫酸阿托品，氯化obidoxime）自动注射器的水性共制剂内容物的功效和药代动力学。在装有脑和心脏电极的豚鼠中，评估了两种皮下（sc）沙林刺激剂量的脑电图（EEG）和心电图（ECG）。选择Sarin激发剂量以反映具有亚致死（中度到严重的临床体征）和致命后果的暴露亚类。肌内人等效剂量共制剂的保护水平定义为：（1）在亚致死水平上缓解体征和症状，以及（2）在超上沙林剂量水平下延长生存时间。

硫酸阿托品和奥比多肟的药代动力学在1和3人当量剂量下成比例，并且作为副作用仅短暂观察到心率的小幅升高。

在两种沙林激发剂量（分别为54μg/ kg和84μg/ kg）下，共制剂治疗均有效对抗沙林诱导的效应。在两种沙林刺激水平下，存活率均得到改善，而在所有情况下，尤其是在上ral上沙林刺激剂量水平下，临床体征和脑电活动的改变均不能得到有效缓解。在血液中观察到了沙林蛋白抑制的胆碱酯酶的再活化，并且较高的脑胆碱酯酶活性水平与共同配制治疗的动物的更好的临床状况有关。

尽管结果不能直接推断到人类的情况，但是在自由移动的豚鼠中，药代动力学和与血浆中药物水平有关的随时间变化的影响可以帮助建立翻译模型，并可能改善对人类功效的预测。