Intranasal CNS delivery of drugs against organophosphorous threat agents

鼻内中枢神经系统输送针对有机磷威胁物质的药物

• 批准号: 8551756
• 负责人: ARYAN Mangalam NAMBOODIRI
• 金额: $ 37.52万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551756
• 关键词: Acetylcholine; Acetylcholinesterase; Acute; Adult; Aging; Alzheimer' s Disease; Animal Model; Area; Atropine; Attention; Biological Models; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; Butyric Acids; Bypass; Cessation of life; Charge; Chemicals; Chronic; Clinical Medicine; Clinical Research; Clinical Trials; Defecation; Diazepam; Drug Delivery Systems; Drug Formulations; Effectiveness; Encapsulated; Exposure to; Goals; Human; Injury; Insulin; Intranasal Administration; Laboratories; Lacrimation; Legal patent; Lung; Memory; Methods; Midazolam; Military Personnel; Molecular Weight; Muscarinic Acetylcholine Receptor; Muscle; Neural Pathways; Neuroepithelial Cells; Neuromuscular Junction; Neurotransmitters; Nose; Olfactory Epithelium; Oximes; Parathion; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Physiological; Poisoning; Population; Pre-Clinical Model; Property; Resistance; Respiratory Failure; Risk; Seizures; Self-Administered; Status Epilepticus; Stream; Stroke; Symptoms; Synapses; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Trigeminal System; Trigeminal nerve structure; efficacy testing; gamma-Aminobutyric Acid; improved; innovation; nanoemulsion; nanoparticle; nervous system disorder; prevent; receptor; saliva secretion

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.

描述(由申请人提供)：有机磷化学威胁剂(CTA)是军事和平民人口的主要风险。CTA通过抑制乙酰胆碱酯酶(AChE)发挥毒性作用，导致乙酰胆碱在突触和神经肌肉连接处积聚，导致急性CTA中毒的症状，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。可用于治疗急性CTA中毒的药物包括：1)用来重新激活被抑制的AChE；2)用阿托品来拮抗在M受体上形成的过量乙酰胆碱的作用；3)用安定或咪达唑仑来变构地加强抑制性神经递质氨基丁酸(GABA)在GABAA受体上的作用。目前治疗策略的两个主要局限性是：1)血脑屏障(BBB)对肟的通透性差；2)由于快速的“老化”，CTA抑制的AChE不能重新激活。对大脑中迅速“老化”的疼痛进行重新激活，并保护大脑免受急性和随后的慢性损伤，将酮类化合物快速输送到大脑中是至关重要的。非侵入性的鼻腔给药提供了更快的治疗药物到大脑的输送。这一机制可能涉及到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，在生理条件下无法绕过血脑屏障的带电分子甚至高分子药物可以成功地输送到大脑。通过制造药物的粘附性纳米乳剂或将药物包裹在可生物降解的纳米颗粒中，可以显著提高鼻脑给药的效率。我们的中心假设是，在30分钟或以后的时间点，以纳米乳剂的形式鼻腔给药治疗剂型的肟、阿托品和咪达唑仑可以将这些药物迅速输送到大脑，除了肺部和血液循环外，还可以防止CTA。我们的长期目标是建立鼻腔脑递送系统的有效性，用于与化学威胁相关的治疗，这在平民大规模伤亡的情况下可以发挥巨大的作用。目前的目标是为此目的开发粘附性纳米乳剂方法，并在临床前模型系统中测试它们的有效性。使用纳米乳剂技术进行鼻腔脑内给药是绕过血脑屏障的一种高度创新的方法，许多实验室正在进行这方面的努力。建议的使用纳米乳剂的鼻腔脑给药技术需要进行研究，以防止CTA或任何其他涉及平民大规模伤亡的情况。成功使用这种非侵入性技术对抗CTA的主要优点是：1)除了肺部和血液外，它还可以将肟类(在生理条件下不能越过血脑屏障)迅速输送到大脑，以重新激活被抑制的AChE；2)暴露后可以立即自我给药，以防止被抑制的AChE‘老化’及其对重新激活的抵抗力。针对化学威胁剂的鼻腔脑给药技术的成功应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。