Suzuki Motohisa, Shiraishi Eri, Cronican James, Kimura Haruhide
Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Neuroscience Therapeutic Area Unit, Takeda Development Centre Americas, Inc., Cambridge, MA, USA.
Br J Anaesth. 2024 Mar;132(3):541-552. doi: 10.1016/j.bja.2023.12.032. Epub 2024 Feb 1.
Delayed emergence from general anaesthesia, opioid-induced sedation, and opioid-induced respiratory depression is associated with perioperative complications. We characterised the preclinical effects of the orexin receptor 2 (OX2R)-selective agonist danavorexton (TAK-925) on emergence from anaesthesia and reversal of fentanyl-induced sedation, respiratory depression, and analgesia.
Emergence from isoflurane- or propofol-induced anaesthesia and fentanyl-induced sedation were investigated by righting reflex, rotarod, and electroencephalography in rats or monkeys. Fentanyl-induced respiratory depression was assessed by arterial blood gas analysis and whole-body plethysmography in rats and monkeys. Analgesia was evaluated using formalin- and skin incision-induced pain models in rats.
Danavorexton shortened emergence from isoflurane- or propofol-induced anaesthesia and from fentanyl-induced sedation at 1 (P=0.005), 3 (P=0.006), and 3 mg kg s.c. (P=0.022), respectively, by righting reflex in rats. Danavorexton (10 mg kg s.c.) accelerated recovery from isoflurane-, propofol- and fentanyl-induced motor impairment in separate rotarod tests in rats (P=0.008, P=0.007, P=0.017, respectively), and reversed anaesthesia and fentanyl-induced delta-power increases. Danavorexton shortened emergence (return of righting reflex) from isoflurane- or propofol-induced anaesthesia at 1 (P=0.002) and 3 mg kg (P=0.004), respectively, in cynomolgus monkeys. Danavorexton (10 mg kg s.c.) reversed fentanyl-induced increase in Pco (P=0.006), and decrease in Po (P=0.015) and pH (P<0.001) in rats, and at 3 mg kg s.c. reversed fentanyl-induced increase in Pco (P=0.007), and decrease in Po (P=0.013) and SO (P=0.036) in monkeys. Danavorexton increased minute volume and tidal volume in fentanyl-treated animals. Danavorexton at ≤10 mg kg s.c. did not compromise fentanyl analgesia in rat formalin- and skin incision-induced pain models.
Danavorexton promoted recovery from anaesthesia and fentanyl-induced sedation, and antagonised fentanyl-induced respiratory depression without compromising fentanyl analgesia.
全身麻醉后苏醒延迟、阿片类药物引起的镇静及呼吸抑制与围手术期并发症相关。我们对食欲素受体2（OX2R）选择性激动剂达那沃雷克斯（TAK-925）在麻醉苏醒及芬太尼引起的镇静、呼吸抑制和镇痛逆转方面的临床前效应进行了表征。
通过翻正反射、转棒试验和脑电图在大鼠或猴中研究异氟烷或丙泊酚诱导麻醉后的苏醒及芬太尼诱导的镇静。通过动脉血气分析和全身体积描记法在大鼠和猴中评估芬太尼诱导的呼吸抑制。使用福尔马林和皮肤切口诱导的疼痛模型在大鼠中评估镇痛作用。
在大鼠中，通过翻正反射，达那沃雷克斯分别在皮下注射1（P=0.005）、3（P=0.006）和3mg/kg（P=0.022）时缩短了异氟烷或丙泊酚诱导麻醉后的苏醒以及芬太尼诱导镇静后的苏醒时间。在大鼠单独的转棒试验中，达那沃雷克斯（皮下注射10mg/kg）加速了异氟烷、丙泊酚和芬太尼诱导的运动功能障碍的恢复（分别为P=0.008、P=0.007、P=0.017），并逆转了麻醉和芬太尼诱导的δ波功率增加。在食蟹猴中，达那沃雷克斯分别在皮下注射1（P=0.002）和3mg/kg（P=0.004）时缩短了异氟烷或丙泊酚诱导麻醉后的苏醒（翻正反射恢复）时间。在大鼠中，达那沃雷克斯（皮下注射10mg/kg）逆转了芬太尼诱导的二氧化碳分压升高（P=0.006），以及氧分压降低（P=0.015）和pH值降低（P<0.001）；在猴中，皮下注射3mg/kg时逆转了芬太尼诱导的二氧化碳分压升高（P=0.007），以及氧分压降低（P=0.013）和氧饱和度降低（P=0.036）。达那沃雷克斯增加了芬太尼处理动物的分钟通气量和潮气量。在大鼠福尔马林和皮肤切口诱导的疼痛模型中，皮下注射≤10mg/kg的达那沃雷克斯未损害芬太尼的镇痛作用。
达那沃雷克斯促进了麻醉苏醒及芬太尼诱导的镇静的恢复，并拮抗了芬太尼诱导的呼吸抑制，而未损害芬太尼的镇痛作用。
