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

描述（由申请人提供）：目前急性农药或有机磷（OP）中毒的治疗包括联合使用胆碱酯酶活化剂（肟）、毒蕈碱受体拮抗剂（阿托品）和抗惊厥药（安定）。由于肟不能穿透血脑屏障（BBS），乙酰胆碱酯酶（AChE）不能清除过量积累的乙酰胆碱（ACh）。农药和OPs是平民面临的重大恐怖威胁。1995年东京地铁恐怖事件中使用了化学制剂沙林，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中枢神经系统的治疗。由于其化学结构，带正电的小分子氧胺不能穿透血脑屏障，因此不能治疗农药和OP引起的脑毒性。我们的长期目标是快速、无创地将肟（2-PAM, MMB-4）转运到中枢神经系统。穿透中枢神经系统肟治疗将及时重新激活脑乙酰胆碱酯酶，减少对抗痉挛药物方案的需求，并通过减少或消除中枢神经系统神经元损伤来改善暴露个体的长期恢复，(a)我们将合成和评估更多的脂质形式（前肟），它们可以在大脑中转化为活性（电荷）形式，(b)此外，我们将开发用于治疗中枢神经系统舞蹈症的肟类载体，这些肟类载体将来自FDA批准的/通过血脑屏障的i期试验药物，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：允许肟通过皮肤（通过皮肤贴片）持续地进入体循环，延长肟的循环时间，使其迅速被肾脏系统清除（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配方，我们将测定包封的肟与农药和抑磷AChE和BuChE的再激活动力学，肟从载体在我们的动物模型（豚鼠）的外周和中枢神经系统中的释放率，以及前肟和肟载体的药代动力学及其在膈肌、血液和大脑中的分布。(d)最有效的配方将在我们的癫痫持续状态豚鼠模型中进行验证，作为CNS化学剂op诱导的DFP、GB、GD和VX毒性的治疗方法，使用EEC无线电遥测探针技术。该项目将解决对平民人口的重要和潜在威胁，用于暴露后中枢神经系统治疗，以应对暴露于化学威胁剂。此外，这项工作的成果可提供一种非侵入性手段，为有机磷中毒的有害影响提供适当的治疗方法，这与公共卫生化学品威胁的应急和准备反应直接相关。

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.