Pharmacology of G-1-64, a new nondepolarizing neuromuscular blocking agent with rapid onset and short duration of action.
BACKGROUND
Chances are slim that a clinically useful ultra-short-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 microg/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.


CONCLUSIONS
With favorable neuromuscular blocking characteristics and modest side effects, G-1-64 and similar derivatives may have clinical potential.
Department of Anesthesiology, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
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L
Gyermek
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C
Lee
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Nguyen
D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001279:Atracurium / Q000494:pharmacology; D002415:Cats; D004576:Electromyography; D005289:Ferrets; D005977:Glutarates / Q000737:chemistry / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006614:Hindlimb / Q000294:innervation; D066298:In Vitro Techniques; D008251:Macaca; D019148:Neuromuscular Blockade; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D000077123:Rocuronium; D013329:Structure-Activity Relationship; D013552:Swine; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D014326:Tropanes / Q000737:chemistry / Q000494:pharmacology*
D000732:Androstanols; C121502:G-1-64; D005977:Glutarates; D003473:Neuromuscular Nondepolarizing Agents; D014326:Tropanes; D001279:Atracurium; D000077123:Rocuronium