Repurposing L-NAC to prevent fentanyl-induced respiratory depression

摘要 这一R21提案，“重新利用L-NAC，以防止芬太尼诱导的呼吸抑制”，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-L-半胱氨酸（L-NAC）， 在大鼠中逆转由输注芬太尼引起的深度呼吸抑制。的临床疗效 阿片类镇痛药如芬太尼由于其对呼吸和动脉血的不良作用而受到损害， 气体（ABG）化学。阿片受体可逆转阿片诱导的呼吸抑制（OIRD） 拮抗剂，但这些拮抗剂也逆转阿片类药物诱导的镇痛。 L-和D-硫醇酯，如D-半胱氨酸乙酯（D-CYSee），以逆转OIRD，同时保持镇痛， 我们目前的NIDA资金使我们能够检查D-CYSee作为逆转剂的有效性， 芬太尼和类似物在大鼠中的作用（PI：Stephen刘易斯，NIH/NIDA U 01 DA 051373：Optimization of Novel Thiolesters 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 1 RF 1DA 050571：使用基于巯基的药物逆转阿片类药物诱导的低氧血症而不影响镇痛 在山羊中）。N-乙酰-L-半胱氨酸（L-NAC），在全身/口服后容易进入中枢外周和细胞 给药，在人类/实验动物中具有许多有益效果，并且被批准用于人类用途， 许多条件。没有关于L-NAC克服OIRD的报道，尽管很明显L-NAC（a） 向细胞提供还原当量，（B）增加L-半胱氨酸/L-谷胱甘肽的细胞内浓度， 和（c）通过多种酶途径发挥许多其它细胞内作用。我们已经开始研究 我们的硫醇化合物克服芬太尼连续静脉输注引起的OIRD的能力 对大鼠这种输注广泛用于成人/儿科患者，但其提供疼痛缓解的能力大大降低。 因为它们有抑制呼吸的能力这个项目将扩大我们的发现，静脉注射， 注射L-NAC可立即和持续逆转持续性化疗的有害副作用， 芬太尼输注对麻醉大鼠呼吸和ABG化学的影响，而对镇痛作用无影响。 阿片类药物的作用。似乎持续输注芬太尼以某种方式建立了一个场景， L-NAC调节介导芬太尼诱导的OIRD但不镇痛的细胞内信号级联。我们 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OIRD的潜在逆转。 芬太尼在人体中的输注。该项目的具体目标是：目标1 -确定 推注L-NAC以抵消芬太尼诱导的OIRD：这将确定L-NAC如何有效地 在早期逆转芬太尼输注对呼吸和ABG（但不是镇痛）的有害作用（例如，5 min）和延长（例如，24 h）输注时间。目的2 -确定L-NAC的共输注对 取消芬太尼诱导的OIRD：这些研究将确定联合输注L-NAC逆转OIRD的疗效。 芬太尼输注开始时对呼吸和ABG（但非镇痛）的不良影响。

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.