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 R21 提案“重新利用 L-NAC 预防芬太尼引起的呼吸抑制”旨在扩大根据我们的证据，静脉推注临床批准的药物 N-乙酰基-L-半胱氨酸 (L-NAC)，逆转芬太尼输注引起的大鼠严重呼吸抑制的临床效果。芬太尼等阿片类镇痛药因其对呼吸和动脉血的不良作用而受到损害。阿片受体 (OR) 可以逆转阿片类药物引起的呼吸抑制 (OIRD)。拮抗剂，但这些拮抗剂也可以逆转阿片类药物引起的镇痛作用，我们正在报告以下药物的功效 L-和D-硫醇酯，例如D-半胱氨酸乙酯（D-CYSee）可逆转 OIRD，同时保持镇痛和我们目前的 NIDA 资金使我们能够检查 D-CYSee 作为逆转剂的功效芬太尼及其类似物在大鼠中的作用（PI：Stephen Lewis，NIH/NIDA U01DA051373：新型硫醇酯的优化作为对抗阿片类药物过量和滥用的治疗策略）和山羊（PI：Matt Hodges，NIH/NIDA 1RF1DA050571：用硫醇类药物逆转阿片类药物引起的低氧血症而不影响镇痛 N-乙酰基-L-半胱氨酸（L-NAC），在全身/口服后很容易进入中枢外周和细胞。管理，对人类/实验动物有许多有益作用，并被批准用于人类虽然 L-NAC (a) 很明显，但没有报道表明 L-NAC 克服了 OIRD。为细胞提供还原当量，(b) 增加细胞内 L-半胱氨酸/L-谷胱甘肽的浓度， (c) 通过多种酶途径发挥许多其他细胞内作用。我们已经开始研究。我们的硫醇化合物能够克服持续静脉输注芬太尼引起的 OIRD 这种输注广泛用于成人/儿童患者，但其缓解疼痛的能力非常强。该项目将扩展我们的研究结果，即静脉注射。注射 L-NAC 可立即且持续地逆转持续注射 L-NAC 的有害副作用。芬太尼输注对麻醉大鼠呼吸和 ABG 化学的影响，但不影响镇痛作用阿片类药物的作用似乎是连续输注芬太尼以某种方式建立了一个允许的场景。 L-NAC 调节细胞内信号级联，介导芬太尼诱导的 OIRD，但不介导镇痛。研究结果提出了一种可能性，即 L-NAC 可以很容易地评估由 OIRD 引起的潜在逆转。该项目的具体目标是：目标 1 – 确定芬太尼的功效。推注 L-NAC 来抵消芬太尼引起的 OIRD：这将确定 L-NAC 的有效性逆转芬太尼输注对早期呼吸和 ABG（但不是镇痛）的有害影响（例如 5 分钟）和延长（例如 24 小时）输注时间 AIM 2 – 确定 L-NAC 联合输注的功效。对抗芬太尼诱导的 OIRD：这些研究将确定共输注 L-NAC 逆转的功效芬太尼输注开始时对呼吸和 ABG（但不包括镇痛）的不利影响。