BK-通道阻滞剂ENA-001逆转异丙酚引起的缺氧通气反应抑制:随机对照试验。

IF 9.1 1区 医学 Q1 ANESTHESIOLOGY Anesthesiology Pub Date : 2024-06-01 DOI:10.1097/ALN.0000000000004915
Simone C Jansen, Maarten van Lemmen, Erik Olofsen, Laurence Moss, Joseph V Pergolizzi, Thomas Miller, Robert D Colucci, Monique van Velzen, Philip Kremer, Albert Dahan, Rutger van der Schrier, Marieke Niesters
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引用次数: 0

摘要

背景:使用麻醉剂可能会抑制缺氧通气反应。由于大多数麻醉剂没有受体特异性拮抗剂,因此需要不可知的呼吸兴奋剂,这种兴奋剂能增加呼吸动力,而不管其原因如何。我们测试了阻断颈动脉体 BK 通道的不可知呼吸兴奋剂ENA-001 是否能恢复异丙酚输注过程中的缺氧通气反应。我们假设ENA-001能够完全恢复缺氧通气反应:在这项随机双盲交叉试验中,14 名男性和女性健康志愿者被随机分为三次分别接受安慰剂、低剂量和高剂量的ENA-001。在每次输注安慰剂、低剂量异丙酚和高剂量异丙酚的固定顺序过程中,都测量了异丙酚缺氧通气反应。我们进行了包括氧气和二氧化碳动力学在内的群体药代动力学/药效学分析:结果:12 名受试者完成了三个疗程,无严重不良事件发生。低剂量和高剂量的异丙酚浓度分别为 0.6 和 2.0 µg/mL。ENA-001的低剂量和高剂量浓度分别为0.6和1.0微克/毫升。使缺氧通气反应降低50%的异丙酚浓度为1.47±0.20 µg/mL。使缺氧通气反应增加 50%的ENA-001 稳态浓度为 0.51±0.04 µg/mL。需要1 µg/mL ENA-001浓度才能完全逆转丙泊酚的C50效应:在这项试验研究中,我们证明了ENA-001能恢复异丙酚所损害的缺氧通气反应。这一发现不仅具有重要的临床意义,还从机理上揭示了ENA-001对呼吸的外周刺激可克服异丙酚对呼吸的中枢抑制。
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Reversal of Propofol-induced Depression of the Hypoxic Ventilatory Response by BK-channel Blocker ENA-001: A Randomized Controlled Trial.

Background: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response.

Methods: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics.

Results: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%.

Conclusions: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol.

Editor’s perspective:

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来源期刊
Anesthesiology
Anesthesiology 医学-麻醉学
CiteScore
10.40
自引率
5.70%
发文量
542
审稿时长
3-6 weeks
期刊介绍: With its establishment in 1940, Anesthesiology has emerged as a prominent leader in the field of anesthesiology, encompassing perioperative, critical care, and pain medicine. As the esteemed journal of the American Society of Anesthesiologists, Anesthesiology operates independently with full editorial freedom. Its distinguished Editorial Board, comprising renowned professionals from across the globe, drives the advancement of the specialty by presenting innovative research through immediate open access to select articles and granting free access to all published articles after a six-month period. Furthermore, Anesthesiology actively promotes groundbreaking studies through an influential press release program. The journal's unwavering commitment lies in the dissemination of exemplary work that enhances clinical practice and revolutionizes the practice of medicine within our discipline.
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