Repurposing L-NAC to prevent fentanyl-induced respiratory depression

重新利用 L-NAC 预防芬太尼引起的呼吸抑制

基本信息

批准号：
10641050
负责人：
stephen john lewis
金额：
$ 24.15万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641050
关键词：
Absence of pain sensation Adult Adverse effects Affect Alveolar Analgesics Anesthesia procedures Animal Experiments Animals Apnea Blood gas Bolus Infusion Breathing Cells Chemistry Childhood Clinical Clinical Trials Clinical effectiveness Continuous Infusion Continuous Intravenous Infusion Cysteine Cystine Dose Esters Female Fentanyl Funding Gases Glutathione Goat Human Hypoxemia Infusion procedures Injections Intravenous Bolus Mediating Methamphetamine Modification Morphine N-acetylcysteine lysinate National Institute of Drug Abuse Operative Surgical Procedures Opioid Opioid Analgesics Opioid Antagonist Opioid Receptor Oral Administration Oral Ingestion Outcome Overdose Oxygen Parents Pathway interactions Patients Peripheral Pharmaceutical Preparations Rattus Reporting Respiration S-Nitrosothiols S-ethyl glutathione Serine Signal Transduction Sulfhydryl Compounds Sulfur Therapeutic Toxic effect United States National Institutes of Health Ventilatory Depression Vertebral column analog antagonist carfentanil cell preparation discount efficacy evaluation human subject in vivo indexing intravenous injection male mecysteine novel opioid abuse opioid epidemic opioid overdose pain relief pediatric patients preservation prevent sedative side effect ventilation

项目摘要

Abstract This R21 proposal, “Repurposing L-NAC to prevent fentanyl-induced respiratory depression” seeks to expand on our evidence that a bolus intravenous injection of the clinically-approved drug, N-acetyl-L-cysteine (L-NAC), reverses the profound respiratory depression elicited by infusion of fentanyl in rats. The clinical effectiveness of opioid analgesics such as fentanyl are compromised by their adverse actions on breathing and arterial blood- gas (ABG) chemistry. Opioid-induced respiratory depression (OIRD) can be reversed by opioid receptor (OR) antagonists but these antagonists also reverse opioid-induced analgesia We are reporting on the efficacies of L- and D-thiolesters such as D-cysteine ethyl ester (D-CYSee) to reverse OIRD while preserving analgesia and our current NIDA funding is allowing us to examine the efficacy of D-CYSee as a reversal agent against fentanyl and analogues in rats (PI: Stephen Lewis, NIH/NIDA U01DA051373: Optimization of Novel Thiolesters as a Therapeutic Strategy for Combating Opioid Overdoses and Abuse) and goats (PI: Matt Hodges, NIH/NIDA 1RF1DA050571: Reversing opioid-induced hypoxemia with thiol-based drugs without compromising analgesia in goats). N-acetyl-L-cysteine (L-NAC), which readily enters central peripheral and cells upon systemic/oral administration, has many beneficial effects in humans/experimental animals and is approved for human use for numerous conditions. There are no reports that L-NAC overcomes OIRD although it is evident that L-NAC (a) provides reducing equivalents to cells, (b) increases intracellular concentrations of L-cysteine/ L-glutathione, and (c) exerts numerous other intracellular actions via multiple enzymatic pathways. We have begun studying the ability of our thiol compounds to overcome the OIRD elicited by continuous intravenous infusion of fentanyl in rats. Such infusions are used widely in adult/pediatric patients but their ability to provide pain relief is greatly compromised by their ability to depress respiration. This project will expand upon our findings that intravenous injection of L-NAC elicits an immediate and sustained reversal of the deleterious adverse effects of continuous fentanyl infusion on breathing and ABG chemistry in anaesthetized rats whereas it did not affect the analgesic effects of the opioid. It appears that continuous infusion of fentanyl somehow sets up a scenario that allows for L-NAC to modulate intracellular signaling cascades that mediate fentanyl-induced OIRD but not analgesia. Our findings raise the possibility that L-NAC could be readily evaluated for potential reversal of OIRD elicited by the infusion of fentanyl in human subjects. The Specific AIMS of this project are: AIM 1 – determine the efficacy of bolus injections of L-NAC to countermand fentanyl-induced OIRD: This will establish how effectively L-NAC reverses the deleterious effects of fentanyl infusion on breathing and ABG (but not analgesia) at early (e.g., 5 min) and prolonged (e.g., 24h) infusion times. AIM 2 – determine the efficacy of co-infusions of L-NAC to countermand fentanyl-induced OIRD: These studies will establish the efficacy of co-infusion L-NAC to reverse the adverse effects of fentanyl on breathing and ABG (but not analgesia) from onset of fentanyl infusion.

抽象的这项R21提案是“重新利用L-NAC来防止芬太尼引起的呼吸抑郁”，试图扩展在我们的证据中，临床批准的药物N-乙酰L-半胱氨酸（L-NAC）的静脉注射大通注射逆转大鼠芬太尼输注引起的严重呼吸抑制。临床有效性阿片类镇痛药（例如芬太尼）因其对呼吸和动脉血液的不利作用而受到损害气（ABG）化学。阿片受体可以逆转阿片类药物诱导的呼吸抑郁症（OIRD）（OR）拮抗剂但这些拮抗剂也反向OioID引起的镇痛，我们正在报告有关的效率 L-和D-硫醇，例如D-结晶乙酯（D-Cysee），以逆转OIRD，同时保持镇痛和我们目前的NIDA资金使我们能够研究D-Cysee作为反向代理的效率大鼠的芬太尼和类似物（PI：Stephen Lewis，NIH/NIDA U01DA051373：新型硫醇的优化作为打击阿片类药物过量和滥用的治疗策略）和山羊（PI：Matt Hodges，NIH/NIDA 1RF1DA050571：用基于硫醇的药物反转阿片类药物诱导的低氧血症，而不会损害镇痛在山羊中）。 N-乙酰L-半胱氨酸（L-NAC），它很容易进入中央外围，并在全身/口腔上进入细胞管理，对人类/实验动物具有许多有益的影响，并被批准用于人类众多条件。没有报道说L-NAC克服了OIRD，尽管有证据表明L-NAC（a）（b）增加了与细胞相同的等效物，增加细胞内L-半胱氨酸/ L-甲状腺素的浓度，（c）通过多种酶促途径发挥许多其他细胞内作用。我们已经开始学习我们的硫醇化合物克服连续静脉输注芬太尼引起的OIRD的能力在老鼠中。此类输注在成人/小儿患者中广泛使用，但提供缓解疼痛的能力很棒由于其降低呼吸的能力而受到损害。该项目将扩大我们静脉注射的发现注射L-NAC会引起连续的有害不利影响的直接和持续的逆转芬太尼在麻醉大鼠中呼吸和ABG化学的输注，而它不影响镇痛药阿片类药物的作用。似乎连续输注芬太尼以某种方式设置了一个允许的情况 L-NAC调节细胞内信号传导级联反应，以介导芬太尼诱导的Oird但不是镇痛。我们的调查结果提出了可以轻易评估L-NAC的可能性在人类受试者中输注芬太尼。该项目的具体目的是：目标1 - 确定注射l-NAC对芬太尼诱导的Oird注射：这将确定L-NAC的有效程度如何逆转芬太尼输注对呼吸和ABG（但不是镇痛）的删除影响（例如5 最小）和延长（例如24小时）输注时间。 AIM 2 - 确定L-NAC共同吸收的效率芬太尼诱导的OIRD：这些研究将确定共连接L-NAC对反向的效率芬太尼从芬太尼输注开始时对呼吸和ABG（但不是镇痛）的不利影响。