Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.
Anesthesiology. 2013 Jun;118(6):1437-45. doi: 10.1097/ALN.0b013e318291079c.
Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea.
The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem-spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart-brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats.
In vitro, respiratory depression caused by propofol (2 μM, n = 11, mean ± SEM, 41 ± 5% of control frequency, 63 ± 5% of control duration) was alleviated by CX717 (n = 4, 50-150 μM). In situ, a decrease in respiratory frequency (44 ± 9% of control), phrenic burst duration (66 ± 7% of control), and amplitude (78 ± 5% of control) caused by propofol (2 μM, n = 5) was alleviated by coadministration of CX717 (50 μM, n = 5). In vivo, pre- or coadministration of CX717 (20-25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30 mg/kg).
Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.
丙泊酚（2,6-二异丙基苯酚）用于人类和兽医医学的麻醉诱导和维持。丙泊酚的缺点包括呼吸抑制和呼吸暂停。在这里，作者报告了一种临床可行的药理学解决方案，通过一种不干扰麻醉的机制来减少丙泊酚引起的呼吸抑制。具体来说，他们测试了 AMPAKINE CX717 的假设，该物质已被证明在人体中代谢稳定且安全，可以预防和挽救丙泊酚引起的严重呼吸暂停。
通过（1）新生大鼠脑干-脊髓标本的腹根记录，（2）在体工作心脏-脑干标本的膈神经记录，以及（3）未受约束的新生和成年大鼠的体积描记记录来测量丙泊酚和 AMPAKINE CX717 的作用。
在体外，丙泊酚（2 μM，n = 11，平均值 ± SEM，41 ± 5%的对照频率，63 ± 5%的对照持续时间）引起的呼吸抑制被 CX717（n = 4，50-150 μM）缓解。在体内，丙泊酚（2 μM，n = 5）引起的呼吸频率下降（44 ± 9%的对照）、膈神经爆发持续时间（66 ± 7%的对照）和幅度（78 ± 5%的对照）被 CX717（50 μM，n = 5）共同给药缓解。在体内，CX717（20-25mg/kg）与丙泊酚的预先或共同给药显著减少了丙泊酚引起的呼吸抑制（n = 7；20mg/kg）和丙泊酚引起的致命呼吸暂停（n = 6；30mg/kg）。
在给予丙泊酚之前或同时给予 CX717 可提供更大的安全裕度，以防止严重的呼吸暂停和死亡。
