灵长类动物恒河猴中 CW 1759-50 的临床前药理学研究，一种新型超短效非去极化神经肌肉阻断剂，可被 L-半胱氨酸降解和拮抗。

Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine.

机构信息

From the Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York (J.J.S., H.S., M.R.B., M.T.M., F.E.C.) Cedarburg Pharmaceuticals, Albany Molecular Research, Inc., Grafton, Wisconsin (J.D.M.) Animal Resources Facility, Albany Medical Center, Albany, New York (E.J.) the Department of Cardiovascular Pharmacology, Burroughs Wellcome Co., Research Triangle Park, North Carolina (W.B.W.) the Department of Anesthesiology, Yale School of Medicine, New Haven, Connecticut (P.M.H.) Current position: Jikei University School of Medicine, Tokyo, Japan (H.S.).

出版信息

Anesthesiology. 2018 Nov;129(5):970-988. doi: 10.1097/ALN.0000000000002408.

DOI:10.1097/ALN.0000000000002408

PMID:30212413

Abstract

WHAT WE ALREADY KNOW ABOUT THIS TOPIC

WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Structure-activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by L-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program.

METHODS

Adduction of CW 1759-50 with L-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee-approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by L-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared.

RESULTS

The half-time of adduction of L-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of L-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% Δ [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium.

CONCLUSIONS

CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by L-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.

摘要

关于这个主题我们已经了解的内容

这篇文章告诉我们的新内容：背景：为了寻找一种新的神经肌肉阻滞剂，保留加坦曲库铵的超短作用特性，包括与 L-半胱氨酸的降解和逆转，但缺乏其在人体内的类组氨酸特性，进行了构效关系研究。CW 1759-50 就是从这个项目中诞生的。

方法

通过高效液相色谱和质谱法研究 CW 1759-50 与 L-半胱氨酸的加成反应。在恒河猴中进行了 CW 1759-50 与加坦曲库铵的机构动物护理和使用委员会批准的比较研究。建立了神经肌肉阻滞的 ED95。在单次或输注的配对研究中比较 L-半胱氨酸逆转后的自发恢复。此外，还比较了非常大剂量（15 至 60 × ED95）后平均动脉压和心率的变化。

结果

CW 1759-50 与 L-半胱氨酸的加成反应的半衰期为 2.3 分钟。CW 1759-50 的 ED95 为 0.069 ± 0.02mg/kg；加坦曲库铵的 ED95 为 0.081 ± 0.05mg/kg（P=0.006）。作用持续时间（从 98%至 99%阻滞恢复到 95%肌颤搐高度的时间）如下：CW 1759-50，8.2 ± 1.5 分钟；加坦曲库铵，7.4 ± 1.9 分钟；（n=8 和 9，P=0.355）。给予 L-半胱氨酸（30mg/kg）可缩短 CW 1759-50 后的恢复（即诱导逆转）（无论是单次推注还是输注，P 均小于 0.0001）。从 0.10 至 0.50mg/kg 的单次推注以及对照输注后，恢复间隔（5 至 95%肌颤搐）为 6.1 至 6.7 分钟（差异无统计学意义）（方差分析 P=0.426）。与神经肌肉阻滞的 ED95 相比，比较平均动脉压或心率变化 30%的剂量比（ED30%Δ[平均动脉压或心率]/ED95）对于 CW 1759-50 比加坦曲库铵更高。