Next Generation Oxime Therapeutic for Chemical Agent Inhibited CNS (Brain) ChEs

用于化学制剂抑制中枢神经系统（脑）ChE 的下一代肟疗法

• 批准号: 7494073
• 负责人: Richard K. Gordon
• 金额: $ 57.11万
• 依托单位: GENEVA FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494073
• 关键词: Abdomen; Acetylcholine; Acetylcholinesterase; Acute; Address; Animal Model; Anticonvulsants; Area; Astrocytes; Atropine; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Circulation; Bos taurus; Brain; Cattle; Cavia; Cells; Charge; Chemical Agents; Chemical Structure; Chemical Warfare Agents; Chemicals; Cholinergic Agents; Cholinesterase Reactivators; Cholinesterases; Class; Clinical Trials; Condition; Cultured Cells; Cyclodextrins; Czech Republic; Data; Diazepam; Doxorubicin; Drug Carriers; Drug Formulations; Drug Kinetics; Electrocardiogram; Electroencephalography; Emergency Situation; Encapsulated; Event; Excision; Excitatory Amino Acids; Exhibits; Exposure to; Family suidae; Goals; High Pressure Liquid Chromatography; Histopathology; Hour; Housing; In Vitro; Individual; Invasive; Isoflurophate; Kidney; Kinetics; Legal patent; Liposomes; MMB-4; Measures; Military Personnel; Modeling; Muscarinic Acetylcholine Receptor; Muscarinics; Nervous System Trauma; Neurons; Neuropathy; Neurotransmitters; Organophosphates; Outcome; Oximes; Patients; Penetration; Peripheral; Pesticides; Pharmaceutical Preparations; Pharmacologic Substance; Phase I Clinical Trials; Physical activity; Poisoning; Population; Pralidoxime chloride; Prodrugs; Public Health; Rate; Readiness; Recovery; Research Personnel; Respiratory Diaphragm; Sarin; Schedule; Self-Administered; Skin; Soman; Staining method; Stains; Status Epilepticus; Subway; Sus scrofa; Synaptic Transmission; System; Techniques; Telemetry; Temperature; Testing; Therapeutic; Time; Tokyo; Toxic effect; Treatment Protocols; United States; United States Food and Drug Administration; Work; base; chemical synthesis; cholinergic; concept; improved; in vivo; inhibitor/antagonist; nanoparticle; neurotoxicity; next generation; novel therapeutics; organophosphate poisoning; peripheral blood; prevent; programs; receptor; research study; response; skin patch; small molecule; tissue culture; toxic organophosphate insecticide exposure

DESCRIPTION (provided by applicant): Current treatment of acute pesticide or organophosphate (OP) poisoning includes a combined administration of a cholinesterase reactivator (oxime), a muscarinic receptor antagonist (atropine) and an anticonvulsant (diazepam). Since the oxime does not penetrate the blood brain barrier (BBS), removal of excessive accumulation of acetylcholine (ACh) is not accomplished by acetylcholinesterase (AChE). Pesticides and OPs are significant terrorist threats to civilian populations. The chemical agent sarin was used in the Tokyo subway terrorist event in 1995 and resulted in long-term neuronal sequelae. Clearly, a new formulation of oxime is required to improve CNS therapy. Because of their chemical structure, the positively charged small molecule oximes do not penetrate the BBB and therefore can not treat pesticide- and OP- induced toxicity in the brain. Our long term goal is to transport oxime (2-PAM, MMB-4) quickly and non-invasively into the CNS. CNS-penetrating oxime therapy will reactivate the brain AChE in a timely manner, reduce the requirement for anticonvulsant drug regimens, and improve the long term recovery of the exposed individual by reducing or eliminating CNS neuronal damage, (a) We will synthesize and evaluate more lipoidal forms (pro-oximes), that can be converted to their active (charged) form in the brain, (b) In addition, we will develop carrier(s) of oximes that will come from a class of FDA approved/phase 1 trial Pharmaceuticals that pass the BBB for treatment of CNS dancers, including Stealth liposomes, nanoparticles, or cyclodextrins. (c) Two additional advantages to the carriers: should permit a sustained delivery of oxime into the systemic circulation through the skin (via skin patch) and prolong the circulatory time of the oxime(s), which are rapidly cleared by the renal system (T1/2<2 hr). (d) For formulations that are successful in in vitro BBB tissue culture and pig skin penetration models, we will determine reactivation kinetics of the encapsulated oximes with pesticide- and OP-inhibited AChE and BuChE, the release rates of the oxime from the carrier in the peripheral and CNS of our animal model (guinea pig), and the pharmacokinetics of the pro-oxime and oxime carrier and distribution in diaphragm, blood, and brain, (d) The most efficacious formulation will be validated in our status epilepticus guinea pig model as a therapy for CNS chemical agent OP-induced toxicity of DFP, GB, GD, and VX using EEC radiotelemetry probe techniques. This program will address an important and potential threat to civilian populations, for post-exposure CNS treatment in response to exposure to chemical threat agents. Further, the outcome of this work could provide a non-invasive means of administrating appropriate therapeutics for deleterious effects of OP poisoning, directly relevant to emergency and preparedness response to chemical threats for Public Health.

描述（由申请人提供）：目前急性农药或有机磷（OP）中毒的治疗包括胆碱酯酶再活化剂（肟）、毒蕈碱受体拮抗剂（阿托品）和抗惊厥药（地西泮）的联合给药。由于肟不能穿透血脑屏障（BBS），因此不能通过乙酰胆碱酯酶（AChE）清除过量积累的乙酰胆碱（ACh）。农药和有机磷农药是对平民的重大恐怖主义威胁。1995年东京地铁恐怖事件中使用了化学毒剂沙林，造成了长期的神经后遗症。显然，需要一种新的肟制剂来改善CNS治疗。由于它们的化学结构，带正电荷的小分子肟不能穿透BBB，因此不能治疗脑中农药和OP诱导的毒性。我们的长期目标是将肟（2-PAM，MMB-4）快速且非侵入性地转运到CNS中。CNS穿透肟治疗将及时地重新激活脑AChE，减少抗惊厥药物方案的需求，并通过减少或消除CNS神经元损伤来改善暴露个体的长期恢复。（前肟），其可以在脑中转化为它们的活性（带电）形式，（B）此外，我们将开发肟的载体，这些载体将来自一类FDA批准的/1期试验药物，这些药物通过BBB用于治疗CNS舞者，包括隐形脂质体、纳米颗粒或环糊精。(c)载体的另外两个优点：应允许通过皮肤（经由皮肤贴剂）将肟持续递送到体循环中，并延长肟的循环时间，其被肾系统快速清除（T1/2<2小时）。(d)对于在体外血脑屏障组织培养和猪皮肤渗透模型中成功的制剂，我们将确定包封肟与农药和OP抑制的AChE和BuChE的再活化动力学，肟从载体在我们的动物模型的外周和CNS中的释放速率（豚鼠），以及前肟和肟载体的药代动力学和在隔膜、血液和脑中的分布，（d）将在我们的癫痫持续状态豚鼠模型中使用EEC无线电遥测探针技术验证最有效的制剂作为CNS化学剂OP诱导的DFP、GB、GD和VX毒性的治疗。该计划将针对平民面临的一个重要和潜在威胁，即暴露后中枢神经系统治疗，以应对暴露于化学威胁剂。此外，这项工作的结果可以提供一种非侵入性的手段，管理适当的治疗药物的有害影响的OP中毒，直接相关的应急和准备应对化学品威胁的公共卫生。