基于肟的分子用于治疗患者,以在有机磷中毒后重新激活乙酰胆碱酯酶(AChE)功能。然而,它们的功效受到通过血脑屏障的低渗透和快速消除的限制。在这项工作中,葫芦[7]脲(CB[7])载体用于包封临床药物asoxime,以提高脑生物利用度和治疗窗.我们提出了在体内小鼠模型中对asoxime和asoxime-CB[7]复合物的药代动力学研究。在彻底优化色谱条件后,开发了具有电喷雾电离质谱检测功能的超高效液相色谱法来测定生物流体和组织中的肟和CB[7]。使用亲水相互作用液相色谱条件的二羟基丙烷-二氧化硅固定相提供了最佳的色谱性能。最后的方法经过验证,并应用于小鼠血浆的药代动力学研究,尿液,胆汁,肝脏,肾,和脑样本在不同的时间后服用的胺肟和胺肟-CB[7]复合物。结果表明,相对于单独使用asoxime,以CB[7]复合物形式使用asoxime的大脑曲线下面积(AUC)增加了3倍以上。使用再激活研究和功能观察电池评估了治疗策略的有效性。保护脑AChE活性对于挽救人类生命或减少中毒后果至关重要。与单独使用阿托品相比,以复合物形式施用的胺肟使脑活动增加了约30%。CB[7]共同施用将AChE活性提高了11%,这与药代动力学研究中评估的较高的胺肟AUC一致。
Oxime-based molecules are used for the treatment of patients to reactivate acetylcholinesterase (AChE) function after organophosphate intoxication. However, their efficacy is limited by low penetration through the blood-brain barrier and fast elimination. In this work, the cucurbit[7]uril (CB[7]) carrier was used for the encapsulation of the clinical agent asoxime to enhance brain bioavailability and the treatment window. We present a pharmacokinetic
study of asoxime and the asoxime-CB[7] complex in an in vivo mouse model. Ultrahigh-performance liquid chromatography with electrospray ionization-mass spectrometry detection was developed to determine asoxime and CB[7] in biological fluids and tissues after thorough optimization of chromatographic conditions. The dihydroxypropane-silica stationary phase using hydrophilic interaction liquid chromatography conditions provided the best chromatographic performance. The final method was validated and applied for the pharmacokinetic
study of mouse plasma, urine, bile, liver, kidney, and brain samples at different times after administration of asoxime and the asoxime-CB[7] complex. The results showed a greater than 3-fold increase in the area under the curve (AUC) in the brain for asoxime administered as a complex with CB[7] relative to that for the administration of asoxime alone. The effectiveness of the treatment strategy was evaluated using a reactivation
study and a functional observatory battery. Protection of brain AChE activity is crucial for saving human lives or reducing the consequences of poisoning. The asoxime administered as a complex increased the brain activity by approximately 30% compared to that with atropine alone. CB[7] coadministration improved the AChE activity by 11%, which agrees with the higher asoxime AUC assessed in the pharmacokinetic
study.