Belmont Matthew R, Lien Cynthia A, Tjan Joseph, Bradley Eleanor, Stein Brenna, Patel Sanjay S, Savarese John J
Department of Anesthesiology, New York Presbyterian-Weill Medical Cornell Medical Center, New York, New York 10021, USA.
Anesthesiology. 2004 Apr;100(4):768-73. doi: 10.1097/00000542-200404000-00004.
An ultrashort-acting nondepolarizing neuromuscular blocking agent that could be an alternative to succinylcholine has been the focus of a concerted effort in the field of muscle relaxants. GW280430A showed a promising pharmacodynamic profile in preclinical work and a wide margin of safety and so was selected for study in humans.
Thirty-one volunteers participated in this study, which determined the dose producing 95% block (ED95) and the safety and pharmacodynamics of increasing ED95 multiples. Anesthesia was induced and maintained with propofol, midazolam, and fentanyl. Neuromuscular transmission was measured at the adductor pollicis using ulnar nerve stimulation, and responses were recorded continuously by standard mechanomyographic monitoring.
The ED95 for GW280430A is 0.19 mg/kg. The time to onset of 90% block ranged from 1.3 to 2.1 min, depending on the dose. Clinical durations ranged from 4.7 to 10.1 min and increased with increasing dose. Five to 95% and 25-75% recovery rates were approximately 7 and 3 min, respectively, and were independent of the dose administered. Transient cardiovascular side effects were observed at doses beginning at 3 x ED95 and above and were suggestive of histamine release. Most volunteers receiving 4 x ED95 exhibited plasma histamine concentrations indicative of significant histamine release.
GW280430A has a rapid onset and ultrashort duration of action. The recovery rate is rapid, predictable, and independent of dose. Doses at least up to 2.5 x ED95 seem to be free of side effects and seem to be able to provide relaxation within 60-90 s.
一种可替代琥珀酰胆碱的超短效非去极化神经肌肉阻滞剂一直是肌肉松弛剂领域共同努力的焦点。GW280430A在临床前研究中显示出有前景的药效学特征以及广泛的安全范围，因此被选用于人体研究。
31名志愿者参与了本研究，该研究确定了产生95%阻滞的剂量（ED95）以及增加ED95倍数时的安全性和药效学。使用丙泊酚、咪达唑仑和芬太尼诱导并维持麻醉。通过尺神经刺激在内收拇指肌测量神经肌肉传递，并通过标准肌机械图监测连续记录反应。
GW280430A的ED95为0.19mg/kg。达到90%阻滞的起效时间根据剂量不同在1.3至2.1分钟之间。临床持续时间在4.7至10.1分钟之间，并随剂量增加而延长。从5%恢复到95%和从25%恢复到75%的时间分别约为7分钟和3分钟，且与给药剂量无关。在剂量达到3倍ED95及以上时观察到短暂的心血管副作用，提示组胺释放。大多数接受4倍ED95的志愿者血浆组胺浓度表明有明显的组胺释放。
GW280430A起效迅速且作用持续时间超短。恢复速度快、可预测且与剂量无关。至少高达2.5倍ED95的剂量似乎没有副作用，并且似乎能够在60 - 90秒内提供肌肉松弛。
