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：
8508575
负责人：
CLAUDE G WASTERLAIN
金额：
$ 21万
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/8508575
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

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.

描述（由申请人提供）：有机磷酸盐引起的癫痫发作很快就会自我维持，不依赖于其最初的胆碱能触发因素，并且对标准治疗（苯二氮卓类药物）难以治疗，并且代表了一个未解决的问题，并且可能构成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，多药治疗优于单一疗法。根据我们的观察，这些癫痫发作会导致突触 GABAA 受体的内化和丧失，以及突触 NMDA 受体的增加，我们建议研究这些癫痫发作的三联疗法。这将结合 1/ a GABAA 受体激动剂，通过刺激残留的突触 GABAA 受体来部分恢复抑制作用； 2/ 一种 NMDA 拮抗剂，可通过阻断某些 NMDA 受体来减少兴奋； 3/ 一种抗惊厥药，可增强非 GABA 位点的抑制作用。我们建议探索以下药物的组合： 1/ 咪达唑仑，一种易于肌内递送的 GABAA 受体激动剂。 2/ 一种 NMDA 受体拮抗剂，可能是非特异性的（地佐西平或氯胺酮）或 NR2B 亚基优先型（R025-6981 或非氨酯），以及 3/ 一种作用于非 GABA 位点的抗惊厥药，例如快速灭活钠通道（丙戊酸钠））；或缓慢失活钠通道（拉科酰胺）；或钾通道（ezogabine）；或突触前囊泡（左乙拉西坦）。我们的初步结果表明，这种三药组合可以在几乎没有意识抑制的情况下，停止由高剂量锂和毛果芸香碱引起的癫痫发作，并且对深度麻醉剂量的苯二氮卓类药物难以治疗，这是锂盐中最好的 2 种和 3 种药物组合-毛果芸香碱模型将在梭曼诱发的癫痫发作模型中进行研究。在该项目结束时，我们将确定一种有效的三药组合，可以阻止苯二氮卓类难治性胆碱能癫痫发作，而几乎没有或没有行为毒性，并准备在亚人类灵长类动物中进行测试，然后纳入我们的治疗中套件。