Roozekrans M, Olofsen E, van der Schrier R, van Gerven J, Peng S, McLeod J, Dahan A
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Centre for Human Drug Research, Leiden, The Netherlands.
Clin Pharmacol Ther. 2015 Jun;97(6):641-9. doi: 10.1002/cpt.99. Epub 2015 May 2.
Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.
阿片类药物引起的呼吸抑制（OIRD）是阿片类药物过量、滥用和误用导致的一种严重且可能危及生命的并发症。避免OIRD的一种方法是使用不与阿片类系统相互作用从而不损害阿片类镇痛效果的呼吸兴奋剂来治疗使用强效阿片类药物的患者。BK通道阻滞剂GAL021是一种作用于1型颈动脉体细胞上表达的K(+)通道的呼吸兴奋剂。作者采用等容高碳酸血症实验设计，对12名男性志愿者进行了群体药代动力学-药效学（PKPD）分析，以研究GAL021逆转阿芬太尼引起的呼吸抑制的能力。分析表明：（1）GAL021与阿芬太尼以相乘方式相互作用，这预示着在低通气水平时GAL021的疗效会降低；（2）GAL021起效/失效迅速，血-效应部位平衡半衰期与零无差异；（3）GAL021在逆转OIRD的疗效方面存在天花板效应。
