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.

项目概要/摘要 在重症监护病房，肺科和重症监护医生必须经常在确保 他们的患者有足够的呼吸动力和足够的镇痛和镇静。拔管即可 对于阿片类药物引起的呼吸抑制 (OIRD) 患者来说，这很困难，尤其是使用苯二氮卓类药物时 还需要抗焦虑药。呼吸系统疾病患者长期插管的医疗费用 抑郁症每年造成的损失接近 10 亿美元。我们的小组正在开发一类新型呼吸兴奋剂来满足 这个需要。这些分子是强效呼吸兴奋剂 S-亚硝基半胱氨酸的安全前体， 涉及电压门控钾通道 (Kv) 蛋白类的治疗靶标，包括 Kv 1.1,1.2 和β2。我们有两种先导化合物可以预防 OIRD，但不会逆转小鼠、大鼠和比格犬的镇痛作用。 它们还可以逆转非麻醉剂引起的呼吸抑制。初步市场分析显示 使用此类呼吸兴奋剂可以防止许多术后入住 ICU，并且对于那些 确实需要入住 ICU 的患者，减少机械通气时间。净效应将是 降低发病率、死亡率和费用。我们还预计晚期心力衰竭、慢性阻塞性肺病、 囊性纤维化 - 与边缘通气储备相关的诊断 - 需要阿片类药物疼痛治疗的人 和/或抗焦虑药。在这个项目中，我们将获得：1）更多数据来帮助选择先导化合物； 2）比较 与纳洛酮（尽管纳洛酮不具有镇痛作用，但这仍然是投资者想要的信息）； 3）数据与 关于麻醉药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）优化的商业模式。在我们的加速器的帮助下 合作伙伴和项目经理，稳定性和吸收、分布的额外初步比较， 可以在 R33 阶段进行代谢和排泄 (ADME) 并安排 IND 前会议。这 产品类别是独一无二的。此前尚未针对任何药物描述或开发其作用机制。 它还能够安全地刺激呼吸驱动而不减弱镇痛作用。