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Preliminary investigations of the clinical pharmacology of three short-acting non-depolarizing neuromuscular blocking agents, Org 9453, Org 9489 and Org 9487

Canadian Journal of Anaesthesia volume 41, pages 213–220 (1994)Cite this article

Abstract

Three muscle relaxants, Org 9453, Org 9489 and Org 9487, short-acting in animals, were investigated to establish their profiles in humans. Potency, time course of action, and pharmacokinetic behaviour were studied in 90 healthy patients during fentanyl/halothane/N2O anaesthesia. Neuromuscular Junction was monitored mechanomyographically. Plasma and urine concentrations (three patients per compound) were measured by HPLC, and these data were analyzed by iterative linear least square regression analysis. The ED90 values for Org 9453, Org 9489 and Org 9487 were 1.4, 0.45 and 1.15 mg · kg−1 respectively. The onset times of Org 9453 (1.5 mg · kg−1,1.1 × ED90), Org 9489 (0.9 mg · kg−1, 2 × ED90) and Org 9487 (1.5 mg · kg−1, 1.3 × ED90) were 1.2, 1.6 and 1.5 min, and the durations until 25% twitch recovery were 8.6, 22.0 and 8.9 min, respectively. Clearances of these doses were 6.9, 5.8, and 11.1 ml · kg−1 · min−1, and mean residence times 26, 79, and 41 min, respectively. Mean renal excretion (parent compound and metabolites) within 24 hr amounted to 5, 11.3 and 12.2% respectively. No side effects other than a moderate short-lasting decrease of blood pressure and a concomittant increase in heart rate were noted. It is concluded that Org 9453 and Org 9487 are short-acting muscle relaxants in humans.

Résumé

Trois myorelaxants à courte durée d’action chez l’animal, l’Org 9453, l’Org 9489 et l’Org 9487 sont étudiés pour déterminer leurs caractéristiques chez l’homme. La puissance, le décours temporel de leur activité et leur comportement pharmacologique sont étudiés chez 90 adultes bien portants pendant une anesthésie constituée de fentanyl/halothane/protoxyde d’azote. La fonction neuromusculaire est monitorisée par électromyographie. Les concentrations urinaires et plasmatiques (trois patients par produit) sont thrées par chromatographie en phase liquide et ces données analysées par régression linéaire itérative multiple. Les valeurs de l’ED90 pour l’Org 9453, l’Org 9489 et l’Org 9487 sont de 1,4, 0.45 et 1,15 mg · kg−1 respectivement. Le début d’action de l’Org 9453 (1,5 mg · kg−1, 1,1 × ED90), l’Org 9489 (0,9 mg · kg−1, 2 × ED90) et l’Org 9487 (1,5 mg · kg−1, 1,3 × ED90 sont de 1,2, 1,6 et 1,5 min respectivement. A ces doses, la clairance est de 6,9, 5,8 et 11,1 ml · kg−1 respectivement et les temps de séjour moyen 26, 79 et 41 min, respectivement. En-deça de 24 h, l’excrétion rénale moyenne (produit et métabolites) se situe à 5, 11,3 et 12,2% respectivement. On ne note pas d’effets secondaires à l’exception d’une baisse modérée transitoire de la pression artérielle accompagnée d’une augmentation de la fréquence cardiaque. En conclusion, l’Org 9453 et l’Org 9487 sont des myorelaxants à courte durée d’action.

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Affiliations

  1. Research Group for Experimental Anesthesiology and Clinical Pharmacology, Department of Anesthesiology, University Hospital of Groningen, PB 30001, 9700 RB, Groningen, The Netherlands

    J. Mark K. H. Wierda, Anton M. Beaufort, Ursula W. Kleef, Nicky J. Smeulers & Sandor Agoston

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  1. J. Mark K. H. Wierda
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  2. Anton M. Beaufort
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  3. Ursula W. Kleef
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  4. Nicky J. Smeulers
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  5. Sandor Agoston
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Supported by Organon Teknika International, Turnhout, Belgium.

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Wierda, J.M.K.H., Beaufort, A.M., Kleef, U.W. et al. Preliminary investigations of the clinical pharmacology of three short-acting non-depolarizing neuromuscular blocking agents, Org 9453, Org 9489 and Org 9487. Can J Anaesth 41, 213–220 (1994). https://doi.org/10.1007/BF03009833

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Key words

  • Neuromuscular Relaxants: Org 9453, Org 9489, Org 9487