Intranasal CNS delivery of drugs against organophosphorous threat agents

描述（由申请人提供）：有机磷化学威胁剂（cta）对军事和平民人口都是主要风险。CTA通过抑制乙酰胆碱酯酶（AChE）发挥毒性作用，导致突触和神经肌肉连接处乙酰胆碱积聚，导致急性CTA中毒症状，包括流涎、流泪、排便、肌肉抽搐、癫痫发作/持续状态，最终因呼吸衰竭而迅速死亡。急性CTA中毒的现有治疗包括：1)肟重新激活被抑制的乙酰胆碱酯酶；2)阿托品对抗毒蕈碱受体形成的过量乙酰胆碱的作用，3)安定或咪达唑仑变构增强GABAA受体上抑制性神经递质氨基丁酸（GABA）的作用。目前治疗策略的两个主要限制是：1)血脑屏障（BBB）对氧肟的渗透性差；2)由于快速“衰老”，cta抑制的乙酰胆碱酯酶（AChE）难以再激活。快速向大脑输送氧对于重新激活大脑中快速“衰老”的乙酰胆碱酯酶，保护大脑免受急性和随后的慢性损伤至关重要。非侵入性鼻内经脑给药可以更快地将治疗药物输送到大脑。其机制可能包括通过嗅觉上皮的神经上皮细胞以及三叉神经通路进行运输。这种方法的主要优点是，在生理条件下不能绕过血脑屏障的带电分子甚至高分子量药物可以成功地输送到大脑。通过制作药物的黏附纳米乳剂或将药物包封在可生物降解的纳米颗粒中，可以显著提高鼻子到大脑的递送效率。我们的中心假设是，鼻内给药肟、阿托品和咪达唑仑的纳米乳状治疗制剂可以在30分钟或更晚的时间点将这些药物快速输送到大脑、肺部和血液循环中，以防止cta。我们的长期目标是建立与化学威胁相关的治疗方法一起使用的鼻内脑输送系统的功效，这可以在平民大规模伤亡情况下发挥巨大作用。当前的目标是为此目的开发黏附纳米乳方法，并在临床前模型系统中测试其有效性。使用纳米乳技术经鼻给药是绕过血脑屏障的一种高度创新的方法，许多实验室正在沿着这条路线进行努力。建议使用纳米乳剂的鼻内脑输送技术需要进行研究，以防止cta或任何其他涉及平民大规模伤亡的情况。这种非侵入性技术成功用于cta的主要优点是：1)它可以快速将氧（在生理条件下不能穿过血脑屏障）除肺和血液外，还可以将脑重新激活被抑制的乙酰胆碱酯酶；2)暴露后可立即自行给药，以防止被抑制的乙酰胆碱酯酶的“老化”及其对再激活的抵抗。针对化学威胁剂的鼻内脑输送技术的成功使用将在临床医学和研究的许多其他领域开辟更广泛的应用。

DESCRIPTION (provided by applicant): Organophosphorous Chemical Threat Agents (CTAs) are major risks for military and civilian population alike. CTAs exert their toxic effects by inhibiting acetylcholinesterase (AChE) leading to the accumulation of acetylcholine at synaptic and neuromuscular junctions leading to symptoms of acute CTA poisoning including salivation, lacrimation, defecation, muscular twitching, seizures/status epilepticus and ultimately rapid death due to respiratory failure. Available treatment for acute CTA poisoning includes combinations of: 1) oxime to reactivate the inhibited AChE; 2) atropine to antagonize the action of excess acetylcholine formed at muscarinic receptors and 3) diazepam or midazolam to allosterically potentiate the action of inhibitory neurotransmitter -amino butyric acid (GABA) at GABAA receptors. The two major limitations of the current therapeutic strategies are: 1) poor blood-brain barrier (BBB) permeability of oximes and 2) resistance for reactivation of the CTA-inhibited AChE due to rapid 'aging'. Quick delivery of oximes to the brain is critical to reactivat the rapidly 'aging' AChE in the brain and protect the brain from acute and subsequent chronic injuries. Non-invasive intranasal nose-to-brain delivery offers faster delivery of therapeutics to the brain. The mechanism involves possible transport through the neuroepithelial cells of olfactory epithelium as well as through trigeminal nerve pathways. The major advantage of this approach is that charged molecules or even high molecular weight drugs which cannot bypass the BBB under physiological conditions can be successfully delivered to the brain. Efficiency of nose-to- brain delivery can be significantly improved by either making formulations such as mucoadhesive nanoemulsions of the drugs or by encapsulating the drugs in biodegradable nanoparticles. Our central hypothesis is that intranasal administration of therapeutic formulations of oxime, atropine and midazolam in a nanoemulsion form can rapidly deliver these drugs to the brain in addition to lungs and blood circulation to protect against CTAs at 30 min or later time points. Our long term objective is to establish the efficacy of intranasal brain deliver systems for use with chemical threat- related therapeutics, which can be of tremendous use in civilian mass casualty situations. The immediate goal is to develop the mucoadhesive nanoemulsion approach for this purpose and test them for effectiveness in a preclinical model system. Use of nanoemulsion technology for intranasal brain delivery of drugs is a highly innovative approach to bypass BBB and efforts along these lines are underway in many laboratories. The proposed intranasal brain delivery technique using nanoemulsion needs to be investigated for protection against CTAs or any other situations involving civilian mass casualty. The major advantages of the successful use of this non-invasive technology against CTAs are: 1) it can rapidly deliver oximes (which cannot cross the BBB under physiological conditions) to the brain in addition to lungs and blood to reactivate the inhibited AChE; and 2) it can be self administered immediately after exposure to prevent 'aging' of the inhibited AChE and its resistance for reactivation. The successful use of an intranasal brain delivery technology against chemical threat agents will open up its wider application in numerous other areas of clinical medicine and research.