Rational polytherapy in the treatment of cholinergic seizures

胆碱能性癫痫发作的合理综合治疗

基本信息

批准号：
8144604
负责人：
CLAUDE G WASTERLAIN
金额：
$ 60.55万
依托单位：
BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144604
关键词：
Address Affinity Agonist Agreement Anesthetics Anticonvulsants Applications Grants Atropine Authorization documentation Award Behavioral Benzodiazepines Boxing Budgets Calcium Channel Categories Certification Collaborations Complication Confidential Information Conscious Country Development Diazepam Direct Costs Disclosure Dose Drug Combinations Epileptogenesis Equilibrium FDA approved Face Facilities and Administrative Costs Funding Goals Grant Income Individual Inorganic Sulfates Institution Instruction Intoxication Investments Ketamine Left Levetiracetam Ligands Lithium Mails Mediation Mental Depression Midazolam Military Personnel Modeling N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Names Neuronal Injury Organophosphates Pharmaceutical Preparations Pharmacopoeias Pilocarpine Policies Polypharmacy Potassium Channel Primates Principal Investigator Refractory Reporting Residual state Rodent Seizures Site Sodium Channel Soman Source Status Epilepticus Synapses System Telephone Testing Therapeutic Time Toxic effect Unspecified or Sulfate Ion Sulfates Vesicle Wages Work base cholinergic cost dizocilpine felbamate interest nerve agent peer presynaptic prevent programs receptor research study response standard care trafficking valproate

Address Affinity Agonist Agreement Anesthetics Anticonvulsants Applications Grants Atropine Authorization documentation Award Behavioral Benzodiazepines Boxing Budgets Calcium Channel Categories Certification Collaborations Complication Confidential Information Conscious Country Development Diazepam Direct Costs Disclosure Dose Drug Combinations Epileptogenesis Equilibrium FDA approved Face Facilities and Administrative Costs Funding Goals Grant Income Individual Inorganic Sulfates Institution Instruction Intoxication Investments Ketamine Left Levetiracetam Ligands Lithium Mails Mediation Mental Depression Midazolam Military Personnel Modeling N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Names Neuronal Injury Organophosphates Pharmaceutical Preparations Pharmacopoeias Pilocarpine Policies Polypharmacy Potassium Channel Primates Principal Investigator Refractory Reporting Residual state Rodent Seizures Site Sodium Channel Soman Source Status Epilepticus Synapses System Telephone Testing Therapeutic Time Toxic effect Unspecified or Sulfate Ion Sulfates Vesicle Wages Work base cholinergic cost dizocilpine felbamate interest nerve agent peer presynaptic prevent programs receptor research study response standard care trafficking valproate

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项目摘要

DESCRIPTION (provided by applicant): The seizures generated by organophosphates quickly become self-sustaining, independent of their original cholinergic trigger, and refractory to standard treatment (benzodiazepines), and represent an unresolved problem and potentially a very serious military and terrorist threat. This proposal is based on the hypothesis that in the treatment of cholinergic seizures, polypharmacy is superior to monotherapy. Based on our observations that these seizures cause internalization and loss of synaptic GABAA receptors, and increases in synaptic NMDA receptors, we proposed to study triple therapy for those seizures. This would combine 1/ a GABAA receptor agonist, which would partially restore inhibition by stimulating the residual synaptic GABAA receptors; 2/ an NMDA antagonist which would reduce excitation by blocking some NMDA receptors; and 3/ an anticonvulsant which would increase inhibition at non-GABA sites. We propose to explore combinations of the following drugs: 1/ Midazolam, a GABAA receptor agonist which is easily delivered intra-muscularly. 2/ a NMDA receptor antagonist which could be non-specific (dizocilpine or ketamine) or NR2B subunit-preferring (R025-6981 or felbamate), and 3/ an anticonvulsant acting at a non-GABA site such as rapidly inactivating sodium channels (valproate); or slowly inactivating sodium channels (lacosamide); or potassium channels (ezogabine); or presynaptic vesicles (levetiracetam). Our preliminary results suggest that such three-drug combinations can, with little depression of consciousness, stop seizures induced by high-dose lithium and pilocarpine and refractory to a profoundly anesthetic dose of benzodiazepine, the best 2- and 3-drug combinations in a lithium-pilocarpine model will be studied in a model of soman-induced seizures. At the end of this project, we will have identified an effective three-drug combination which can stop benzodiazepine-refractory cholinergic seizures at the cost of little or no behavioral toxicity, and is ready to be tested in subhuman primates and then included in our therapeutic kits. PUBLIC HEALTH RELEVANCE: Because of the ease with which they are synthesized, concealed and of their potential for mass casualties, nerve agents are among the most serious terrorist and military threats to day. Seizures are the most treatment-refractory complication of nerve agent intoxication. Finding a treatment for those seizures is clearly an important national goal. We are proposing to do this using new combinations of FDA-approved drugs.

描述（由申请人提供）：有机磷酸盐产生的癫痫发作迅速变得自我维持，独立于其原始的胆碱能触发因素，对标准治疗（苯二氮卓类药物）的难治性（苯二氮卓类），代表了一个尚未解决的问题，并可能是非常严重的军事和恐怖主义威胁。该提议基于以下假设：在治疗胆碱能癫痫发作时，多药剂优于单一疗法。基于我们的观察，这些癫痫发作会导致突触GABAA受体的内在化和丧失，并增加突触NMDA受体，我们建议研究这些癫痫发作的三重治疗。这将结合1/ A GABAA受体激动剂，这将通过刺激残留的突触Gabaa受体来部分恢复抑制作用； 2/ an NMDA拮抗剂，可以通过阻断某些NMDA受体来减少激发； 3/抗惊厥药会增加非GABA部位的抑制作用。我们建议探索以下药物的组合：1/咪达唑仑，一种GABAA受体激动剂，很容易在肌内输送。 2/ A NMDA受体拮抗剂，可能是非特异性（二唑胺或氯胺酮）或NR2B亚基抗脱发（R025-6981或Felbamate）的2/ A NMDA受体拮抗剂，3/3/抗惊厥药在非GABA部位作用在非GABA部位上，例如快速灭活的钠含量sodium insodium insodium insodium insodium insodium inseels（valprotoares）（瓣膜）;或缓慢失活的钠通道（lacosamide）；或钾通道（Ezogabine）；或突触前囊泡（Levetiracetam）。我们的初步结果表明，这种三个药物的组合几乎没有意识抑郁，高剂量锂和毛果皮诱导的停止癫痫发作以及对苯并二氮卓的深刻麻醉剂量的耐火，这是最佳的2和3制度组合，是一种模型中的锂含量模型。在该项目结束时，我们将确定有效的三药结合组合，可以阻止苯二氮卓类胆碱能癫痫发作，而造成很少或没有行为毒性的代价，并准备在亚人类灵长类动物中进行测试，然后包括在我们的治疗套件中。公共卫生的相关性：由于他们容易被合成，隐藏并遭受大规模伤亡的潜力，因此神经因素是白天最严重的恐怖分子和军事威胁之一。癫痫发作是神经毒剂中毒的最难治疗并发症。为这些癫痫发作寻找治疗方法显然是重要的国家目标。我们建议使用FDA批准的药物的新组合来做到这一点。