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

说明(申请人提供)：目前急性杀虫剂或有机磷(OP)中毒的治疗包括联合应用胆碱酯酶激活药(酮)、毒扁豆碱受体拮抗剂(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)。杀虫剂和有机磷农药是对平民人口的重大恐怖主义威胁。化学毒剂沙林在1995年东京地铁恐怖事件中被使用，并导致长期的神经元后遗症。显然，需要一种新的肟类药物来改善中枢神经系统的治疗。由于它们的化学结构，带正电荷的小分子肟不能穿透血脑屏障，因此不能治疗农药和OP在大脑中的毒性。我们的长期目标是将(2-PAM，MMB-4)肟以快速和非侵入性的方式输送到中枢神经系统。中枢神经系统穿透性肟疗法将及时激活大脑AChE，减少对抗惊厥药物方案的需求，并通过减少或消除中枢神经系统损伤来促进暴露个体的长期康复，(A)我们将合成和评估更多可在大脑中转化为活性(带电)形式的脂类形式(前体)，(B)此外，我们还将开发来自FDA批准/一期试验药物的肟类载体(S)，用于治疗中枢神经系统舞者，包括隐形脂质体、纳米粒或环糊精。(C)对携带者有两个额外的好处：应允许肟通过皮肤(通过皮肤贴片)持续进入体循环，并延长肟的循环时间(S)，它可被肾脏系统迅速清除(t1/2和lt；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取得成功的制剂，我们将测定杀虫剂和OP抑制的AChE和BuChE胶囊的再激活动力学，载体上的肟在动物模型(豚鼠)外周和中枢神经系统中的释放速率，以及前体和肟载体的药代动力学和在横隔膜、血液和脑中的分布；(D)在我们的癫痫持续状态豚鼠模型中，将利用EEC无线电测量探针技术验证最有效的配方作为治疗中枢神经系统化学制剂OP诱导的DFP、GB、GD和VX毒性的方法。该计划将解决对平民人口的一个重要和潜在的威胁，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，这项工作的结果可能提供一种非侵入性的方法，对OP中毒的有害影响进行适当的治疗，直接与对公共卫生的化学品威胁的应急和准备反应有关。

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.