Pharmacology of G-1-64, a new nondepolarizing neuromuscular blocking agent with rapid onset and short duration of action
Pharmacology of G-1-64, a new nondepolarizing neuromuscular blocking agent with rapid onset and short duration of action
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DOI：
10.1034/j.1399-6576.1999.430610.x
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发表时间：
1999-07-01
影响因子：
2.1
通讯作者：
Nguyen, N
中科院分区：
文献类型：
--
作者：
Gyermek, L;Lee, C;Nguyen, N
背景资料：从苄基异喹啉或氨基类固醇系列（目前所有流行的松弛剂都属于这类药物）中产生一种临床上有用的起效迅速的超短效神经肌肉阻滞剂的可能性很小。G-1-64是我们在实验室合成和研究的一系列新的bistropinyl双酯衍生物的双季铵盐的一个有前途的原型。方法：在麻醉大鼠、兔、猫、雪貂、猪和猴的适当制剂上研究神经肌肉阻滞（NMB）和自主神经和心血管副作用。测定神经肌肉阻滞特性、累积性和药理学可逆性。通过抑制猫、大鼠、雪貂和猪对迷走神经刺激的心动过缓反应来评价心脏迷走神经阻滞。在猫的上级颈神经节/瞬膜制备物上评价交感神经节阻滞。结果：G-1-64产生非去极化的肌松，具有四联反应（TOF）和强直性衰减，抗胆碱酯酶剂可逆转。在这些物种中，其ED 50介于60至800微克/千克之间。与阿曲库铵或米伐库铵相比，其起效时间（0.9-2.1 min）和/或作用持续时间（5-12 min）明显更快。在重复给药或输注时未显示累积性。存在不同程度的心脏迷走神经阻滞，这取决于超过NMB ED 80的剂量下的种属。结论：G-1-64及其类似衍生物具有良好的神经肌肉阻滞特性和适度的副作用，可能具有临床应用潜力。
Background: Chances are slim that a clinically useful ultrashort-acting neuromuscular blocking agent of rapid onset will emerge from the benzylisoquinolinium or the aminosteroid series to which all currently popular relaxants belong. G-1-64 is a promising prototype of a new series of bis-quaternary ammonium salt of bistropinyl diester derivatives we have synthesized and studied in the laboratory.Methods: Neuromuscular block (NMB) and autonomic and cardiovascular side effects were studied on appropriate preparations of anesthetized rats, rabbits, cats, ferrets, pigs and monkeys. Neuromuscular blocking characteristics, cumulativeness, and pharmacological reversibility were determined. Cardiac vagal block was evaluated by the inhibition of the bradycardic response to stimulation of the vagus in the cat, rat, ferret, and pig. Sympathetic ganglion block was evaluated on the cat's superior cervical ganglion/nictitating membrane preparation. Arterial blood pressure and heart rate were determined in all species.Results: G-1-64 produced nondepolarizing NMB with train-of-four (TOF) and tetanic fades, and reversible with anticholinesterases. Its ED50 ranged between 60 and 800 mu g/kg in these species. It showed a significantly faster onset (0.9-2.1 min) and/or shorter duration of action (5-12 min) than either atracurium or mivacurium. It did not show cumulativeness on repeated doses or infusion. A varying degree of cardiac vagal block was present, dependent on the species at doses exceeding the ED80 for NMB. Cardiovascular changes, ganglion block or signs suggesting histamine release were absent.Conclusion: With favorable neuromuscular blocking characteristics and modest side effects, G-1-64 and similar derivatives may have clinical potential.