Efficacy and Safety of an Aerosolized Recombinant Butyrylcholinesterase Pretreatm

雾化重组丁酰胆碱酯酶预处理的功效和安全性

• 批准号: 8523566
• 负责人: Yvonne J Rosenberg
• 金额: $ 75.34万
• 依托单位: PLANTVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-08 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523566
• 关键词: Acute; Aerosols; Agriculture; Animals; Antidotes; Atropine; Award; Bioshield; Blood; Blood Circulation; Breathing; Butyrylcholinesterase; Cardiac; Cessation of life; Chemicals; Chicago; Chinese Hamster Ovary Cell; Chronic; Cocaine; Data; Deposition; Development; Devices; Disadvantaged; Dose; Drug Formulations; Drug Kinetics; Engineering; Enzymes; Exhibits; Exposure to; Feasibility Studies; Functional disorder; Glycoproteins; Grant; Health; Human; In Situ; Individual; Industry; Inhalation Device; Inhalation Therapy; Injection of therapeutic agent; Insecticides; Intoxication; Intramuscular Injections; Lead; Lung; Macaca; Measures; Medical; Medicine; Military Personnel; Modification; Monitor; Morbidity - disease rate; Mus; National Institute of Neurological Disorders and Stroke; Nebulizer; Neuromuscular Junction; Neuropathy; Neurotoxins; Oral cavity; Organophosphates; Oximes; Paraoxon; Pharmaceutical Preparations; Phase; Physiological; Poison; Poisoning; Production; Rattus; Recombinants; Route; Running; Safety; Small Business Innovation Research Grant; Subcutaneous Injections; Supportive care; Symptoms; Testing; Therapeutic; Time; Toxic effect; Toxicology; Universities; Writing; aerosolized; animal rule; bioscavenger; carbamate insecticide; cholinergic; design; efficacy testing; experience; innovation; manufacturing process; meetings; nerve agent; neuromuscular; neurotoxic; neurotoxicity; particle; pesticide exposure; phase 2 study; prevent; programs; public health relevance; research study; respiratory; response; safety study; safety testing; stoichiometry; vapor

DESCRIPTION (provided by applicant): Organophosphorus (OPs) compound are potent neurotoxic chemicals that are widely used in medicine, industry and agriculture; most notably as insecticides. The neurotoxicity which is primarily a result of AChE inhibition, may take the form of cholinergic crisis and death as a consequence of acute exposure or psychiatric symptoms and may lead to delayed neuropathy following chronic exposure. Usually, treatment of insecticide poisoning consists of supportive care and specific therapy e.g. atropine and oximes, which often fail to prevent morbidity or death. Currently, recombinant (r) BChE is a leading pre-exposure treatment candidate for OP toxicity due to its potent bioscavenging ability but because of its 1:1 stoichiometry with OP, large doses will be required and without post-transitional modification, rBChRE exhibits poor circulatory stability when administered im, iv or sc. To overcome the potential challenges associated with parenteral delivery, PlantVax has taken advantage of the large size of the BChE molecules and has developed an innovative delivery approach using an aerosolized (aer) form of rBChE. Thus BChE delivered as an aerosol coats the airways of the lungs forming a "pulmomary bioshield" that can scavenge incoming (inhaled) OPs in situ: preventing both their entry into the systemic circulation and their inhibition of AChE on RBC and in neuromuscular junctions. This route of administration is highly relevant since inhalation of vapors and particles is the predominant form of exposure to insecticides and G-type nerve agents and serves as a major means of intoxication because of rapid accesses of the OP to the blood. In Phase I Phase I feasibility studies, aer-rBChE was shown to protect against paraoxon (Px) toxicity in mice while in Phase II, unmodified aer-rMaBChE and aer-rHuBChE were shown to almost totally protect macaques even when aer-Px exposure occurred 40 hr following pretreatment. Since, in these experiments, aer-rBChE and aer-Px were delivered using a microsprayer, the proposed Phase IIB studies will extend these findings and will perform efficacy and early non-GLP safety testing using aerosl inhalation (nebulizer) devices to directly assess whether an inhaled "pulmonary bioshield" is efficacious in preventing OP toxicity and whether it is safe. These studies represent the first time BChE has been shown to protect against an insecticide and bode well for an aer-rHuBChE pre-exposure treatment against inhaled OPs in humans even when repurposed for use against nerve agents and inhaled cocaine toxicity.

描述（由申请人提供）：有机磷（OP）化合物是一种强效神经毒性化学品，广泛用于医学、工业和农业;最主要的是作为杀虫剂。神经毒性主要是乙酰胆碱酯酶抑制的结果，可能表现为胆碱能危象和急性接触或精神症状导致的死亡，并可能导致慢性接触后的迟发性神经病。通常，杀虫剂中毒的治疗包括支持性护理和特殊治疗，如阿托品和肟，这往往不能防止发病或死亡。目前，重组（r）BChE是一种领先的暴露前治疗候选人OP毒性，由于其强大的生物清除能力，但由于其1：1的化学计量与OP，将需要大剂量，没有过渡后的修改，rBChRE表现出不良的循环稳定性时，肌肉注射，静脉注射或SC。为了克服潜在的挑战与肠胃外交付，PlantVax已利用大尺寸的BChE分子，并已开发出一种创新的交付方法，使用雾化（aer）形式的rBChE。因此，BChE以气雾剂的形式包裹在肺部的气道中，形成“肺部生物屏障”，可以原位阻挡进入（吸入）的OP：防止它们进入体循环并抑制AChE 在RBC和神经肌肉接头中。这种给药途径具有高度相关性，因为吸入蒸汽和颗粒是暴露于杀虫剂和G型神经毒剂的主要形式，并且由于OP快速进入血液而成为中毒的主要手段。在I期I期可行性研究中，aer-rBChE显示出保护小鼠免受对氧磷（Px）毒性，而在II期中，未修饰的aer-rMaBChE和aer-rHuBChE显示出几乎完全保护猕猴，即使在预处理后40小时发生aer-Px暴露。由于在这些实验中，aer-rBChE和aer-Px是使用微型喷雾器递送的，因此拟定的IIB期研究将扩展这些发现，并将使用aerosl吸入（雾化器）装置进行有效性和早期非GLP安全性测试，以直接评估吸入的“肺生物盾”是否有效预防OP毒性以及是否安全。这些研究代表了BChE首次被证明可以防止杀虫剂，并且预示着即使在重新用于对抗神经毒剂和吸入可卡因毒性时，也可以对人体吸入OP进行aer-rHuBChE暴露前治疗。