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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

基本信息

批准号：
10242946
负责人：
Benjamin Gaston
金额：
$ 56.1万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242946
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 Airway 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 stimulant use therapeutic target uptake

项目摘要

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.

项目总结/摘要在重症监护室，肺科和重症监护医生必须经常在确保他们的病人有足够的呼吸动力和足够的镇痛和镇静。拔管可以在阿片类药物诱导的呼吸抑制（OIRD）患者中，尤其是当苯二氮卓类药物还需要抗焦虑药。呼吸道疾病患者延长插管的医疗费用抑郁症每年造成的损失接近10亿美元。我们的团队正在开发一种新型的呼吸兴奋剂，这种需要。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，结合电压门控钾通道（Kv）蛋白类的治疗靶点，包括Kv 1.1、1.2 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，在这类患者中使用呼吸兴奋剂可以防止许多术后ICU住院，需要ICU的患者，减少机械通气时间。净效应将是降低发病率、死亡率和成本。我们还预计晚期心力衰竭、慢性阻塞性肺病、囊性纤维化-与边缘性疼痛储备相关的诊断-需要阿片类药物疼痛管理的患者和/或抗焦虑药。在这个项目中，我们将获得：1）更多的数据，以帮助选择一个铅化合物; 2）比较与纳洛酮（虽然纳洛酮是不是肺动脉高压，它仍然是投资者想要的信息）; 3）数据与关于麻醉剂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;和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， R33阶段可以进行代谢和排泄（ADME）并安排IND前会议。这产品类别是独一无二的。其作用机制以前没有描述或开发任何药物。它也是唯一能够安全地刺激呼吸驱动而不减弱镇痛。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

D-cysteine ethyl ester and D-cystine dimethyl ester reverse the deleterious effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient in anesthetized rats.

DOI：
10.1016/j.resp.2022.103912
发表时间：
2022-08
期刊：
RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY
影响因子：
2.3
作者：
Getsy, Paulina M.;Young, Alex P.;Grossfield, Alan;Seckler, James M.;Wilson, Christopher G.;Gaston, Benjamin;Bates, James N.;Lewis, Stephen J.
通讯作者：
Lewis, Stephen J.

L-NAC reverses of the adverse effects of fentanyl infusion on ventilation and blood-gas chemistry.

DOI：
10.1016/j.biopha.2022.113277
发表时间：
2022-09
期刊：
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
影响因子：
0
作者：
通讯作者：

D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception.

DOI：
10.1038/s41598-021-89455-2
发表时间：
2021-05-11
期刊：
Scientific reports
影响因子：
4.6
作者：
Gaston B;Baby SM;May WJ;Young AP;Grossfield A;Bates JN;Seckler JM;Wilson CG;Lewis SJ
通讯作者：
Lewis SJ

Hypoxia releases S-nitrosocysteine from carotid body glomus cells-relevance to expression of the hypoxic ventilatory response.