Sudaxine as an analgesia sparing respiratory stimulant for use in critical care

Sudaxine 作为一种镇痛、省呼吸兴奋剂，用于重症监护

• 批准号: 10505268
• 负责人: Benjamin Gaston
• 金额: $ 55.74万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505268
• 关键词: ADME Study; Absence of pain sensation; Address; Admission activity; Anti-Anxiety Agents; Anxiety; Benzodiazepines; Breathing; Businesses; Canis familiaris; Cells; Cessation of life; Chronic Obstructive Pulmonary Disease; Combined Modality Therapy; Critical Care; Cysteine; Cystic Fibrosis; Cystine; Data; Deposition; Diagnosis; Diazepam; Dose; Ensure; Equilibrium; Esters; Excretory function; Fentanyl; Funding; Health Expenditures; Heart failure; In Vitro; Institutes; Intensive Care Units; Intubation; Lead; Lung; Measures; Mechanical ventilation; Medicine; Metabolism; Modeling; Morbidity - disease rate; Mus; Naloxone; Narcotics; Neurons; Opioid; Pain; Pain management; Patients; Pharmaceutical Preparations; Phase; Physicians; Postoperative Period; Potassium; Proteins; Published Comment; Rattus; Respiratory Stimulants; Rodent; Secure; Sedation procedure; Temperature; Testing; Time; Tissues; Ventilator; Ventilatory Depression; Voltage-Gated Potassium Channel; Work; absorption; cost; experience; experimental study; extracellular; meetings; mortality; novel; preservation; prevent; respiratory; stability testing; therapeutic target; uptake

PROJECT SUMMARY/ABSTRACT In the intensive care unit, pulmonary and critical care physicians must often balance between ensuring that their patients have both adequate drive to breathe and adequate analgesia and sedation. Extubation can be difficult in patients with opioid-induced respiratory depression (OIRD), particularly when benzodiazepine anxiolytics are also needed. Healthcare expenditures for prolonged intubation in patients with respiratory depression approach $1 billion annually. Our group is developing a novel class of respiratory stimulants to meet this need. These molecules are safe precursors of the potent respiratory stimulant, S-nitrosocysteine, which engages therapeutic targets in the class of voltage gated potassium channel (Kv) proteins, including Kv 1.1,1.2 and β2. We have two lead compounds that prevent OIRD but do not reverse analgesia in mice, rats and beagles. They also reverse respiratory depression caused by non-narcotic agents. Preliminary market analysis shows that use of respiratory stimulants in this class could prevent many post-operative ICU admissions and, for those patients who do require ICU admission, decrease the time on mechanical ventilation. The net effect will be reduced morbidity, mortality and cost. We also anticipate benefit for patients with advanced heart failure, COPD, cystic fibrosis - diagnoses associated with marginal ventilatory reserve - who require opioid pain management and/or anxiolytics. In this project, we will obtain: 1) more data to help choose a lead compound; 2) a comparison with naloxone (though naloxone is not analgesia-sparing, it is still information that investors want); 3) data with regard to respiratory stimulation during combined treatment with narcotics and benzodiazepines; 4) more data regarding the cellular metabolism; and 5) an optimized business model. With the assistance of our Accelerator partner and Project Manager, additional preliminary comparisons of stability and of Absorption, Distribution, Metabolism and Excretion (ADME) can be made and a pre-IND meeting arranged during the R33 phase. This product class is unique. Its mechanism of action has not previously been described or developed for any drug. It is also uniquely able safely to stimulate respiratory drive without blunting analgesia.

项目摘要/摘要 在重症监护病房中，肺部和重症监护医师必须在确保 他们的患者既有足够的呼吸动力，又有足够的镇痛和镇静。拔管可以 阿片类药物诱导的呼吸抑郁症患者很难 还需要抗焦虑药。呼吸道患者长时间插管的医疗保健支出 抑郁症每年接近10亿美元。我们的小组正在开发一种新颖的呼吸刺激剂来满足 这需要。这些分子是潜在的呼吸刺激剂S-亚硝糖类半胱氨酸的安全前体，它 参与电压门控钾通道（KV）蛋白的热目标，包括KV 1.1,1.2 和β2。我们有两种铅化合物，可以预防小鼠，大鼠和小蛋糕中的镇痛。 它们还反向由非麻醉药物引起的呼吸抑制。初步市场分析表明 在此类中，使用呼吸兴奋剂可以防止许多术后ICU入院，对于那些人来说 确实需要ICU入院的患者，减少机械通气的时间。网络效果将是 发病率，死亡率和成本降低。我们还期望患有晚期心力衰竭的患者COPD， 囊性纤维化 - 与边缘通气储备相关的诊断 - 谁需要阿片类药物疼痛管理 和/或抗焦虑药。在此项目中，我们将获得：1）更多数据以帮助选择铅化合物； 2）比较 使用纳洛酮（尽管纳洛酮不是镇痛，但投资者仍然想要的信息）； 3）数据 关注与麻醉品和苯二氮卓类药物联合治疗期间的呼吸刺激； 4）更多数据 关于细胞代谢； 5）优化的业务模型。在我们的加速器的帮助下 合作伙伴兼项目经理，稳定性和吸收，分配的其他初步比较， 可以在R33阶段进行代谢和排泄（ADME），并在R33阶段安排了预定的会议。这 产品类是独一无二的。以前尚未针对任何药物进行描述或开发其作用机理。 它也具有独特的能力，可以安全地刺激呼吸驱动而不会造成镇痛。