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

项目摘要/摘要 在重症监护病房，肺部和重症监护医生经常必须在确保 他们的病人既有足够的呼吸动力，也有足够的止痛和镇静。拔管可以 对于阿片类药物引起的呼吸抑制(OIRD)患者来说是困难的，特别是当苯二氮卓类药物 抗焦虑药物也是必要的。呼吸系统疾病患者长时间插管的医疗费用 抑郁症每年接近10亿美元。我们小组正在开发一种新型的呼吸兴奋剂，以满足 这种需要。这些分子是强效呼吸刺激剂S-亚硝半胱氨酸的安全前体， 参与电压门控性钾通道(Kv)蛋白类的治疗靶点，包括Kv 1.1，1.2 和β2。我们有两种先导化合物可以预防OIRD，但不能逆转小鼠、大鼠和比格犬的镇痛作用。 它们还能逆转非麻醉剂引起的呼吸抑制。初步市场分析显示 在这一类中使用呼吸兴奋剂可以防止许多术后ICU入院，对于那些 需要住ICU的患者，减少机械通气的时间。最终的结果将是 降低发病率、死亡率和成本。我们还预计晚期心力衰竭、慢性阻塞性肺疾病、 囊性纤维化-与边缘呼吸储备相关的诊断-谁需要阿片类疼痛治疗 和/或抗焦虑药。在这个项目中，我们将获得：1)更多的数据来帮助选择先导化合物；2)比较 纳洛酮(尽管纳洛酮不是止痛药，但它仍然是投资者想要的信息)；3) 关于麻醉药物和苯二氮卓类药物联合治疗中的呼吸刺激；4)更多数据 关于细胞代谢；5)优化商业模式。在我们加速器的帮助下 合作伙伴和项目经理，稳定性和吸收、分配、 在R33阶段，可以进行代谢和排泄(ADME)，并安排一次IND前会议。这 产品类别是唯一的。它的作用机制以前没有对任何药物进行过描述或开发。 它还独一无二地能够安全地刺激呼吸动力，而不会削弱止痛效果。

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.