Canadian Journal of Anaesthesia

, Volume 41, Issue 3, pp 213–220 | Cite as

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

  • J. Mark K. H. Wierda
  • Anton M. Beaufort
  • Ursula W. Kleef
  • Nicky J. Smeulers
  • Sandor Agoston
Reports of Investigation


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.

Key words

Neuromuscular Relaxants: Org 9453, Org 9489, Org 9487 


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.


  1. 1.
    Lee C. Succinylcholine: its past, present and future.In: Katz RL (Ed.). Muscle Relaxants, Seminars in Anesthesia, 1984, 3. 293–302. Orlando: Grune and Stratton.Google Scholar
  2. 2.
    Donati F, Bevan DR. Suxamethonium — current status.In: Norman J (Ed.). Neuromuscular Blockade, Clinics in Anaesthesiology 1985; 3: 371–85. London: Saunders.Google Scholar
  3. 3.
    Bowman WC, Rodger IW, Houston J, Marshall RJ, Mclndewar I. Structure:action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat. Anesthesiology 1988; 69: 57–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Muir AW, Houston J, Green KL, Marshall RJ, Bowman WC, Marshall IG. Effects of a new neuromuscular blocking agent (Org 9426) in anaesthetized cats and pigs and in isolated nerve-muscle preparations. Br J Anaesth 1989; 63: 400–10.PubMedCrossRefGoogle Scholar
  5. 5.
    Agoston S. Pharmacological profile of neuromuscular blocking agents: present and future trends. Acta Anaesthesiol Belg 1988; 39: 235–7.PubMedGoogle Scholar
  6. 6.
    Booij LHDJ. The development of new non-depolarizing neuromuscular blocking agents. Acta Anaesthesiol Scand 1989; 33S: 101–3.Google Scholar
  7. 7.
    Wierda JMKH, De Wit APM, Kuizenga K, Agoston S. Clinical observations on the neuromuscular blocking action of Org 9426, a new steroidal non-depolarizing agent. Br J Anaesth 1990; 64: 521–3.PubMedCrossRefGoogle Scholar
  8. 8.
    Foldes FF, Nagashima H, Nguyen HD, Schiller WS, Mason MM, Ohta Y. The neuromuscular effects of Org 9426 in patients receiving balanced anesthesia. Anesthesiology 1991; 75: 191–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Booij LDHJ, Knape HTA. The neuromuscular blocking effect of Org 9426. Anaesthesia 1991; 46: 341–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Van den Broek L, Lambalk LM, Richardson FJ, Wierda JMKH. Dose-response relation, neuromuscular blocking action, intubation conditions and cardiovascular effects of Org 9273, a new neuromuscular blocking agent. Anesth Analg 1991; 72: 811–6.PubMedGoogle Scholar
  11. 11.
    Wierda JMKH, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S. The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. Can J Anaesth 1991; 38: 430–5.PubMedGoogle Scholar
  12. 12.
    Huizinga ACT, Vandenbrom RHG, Wierda JMKH, Hommes FDM, Hennis PJ. Intubating conditions and onset of neuromuscular block of rocuronium (Org 9426); a comparison with suxamethonium. Acta Anaesthesiol Scand 1992; 36: 463–8.PubMedGoogle Scholar
  13. 13.
    Rowaan CJ, Vandenbrom RHG, Wierda JMKH. The Relaxometer: a complete and comprehensive computercontrolled neuromuscular transmission measurement system developed for clinical research on muscle relaxants. J Clin Monit 1993; 9: 38–44.PubMedCrossRefGoogle Scholar
  14. 14.
    Kleef UW, Proost JH, Roggeveld J, Wierda JMKH. Determination of rocuronium and its putative metabolites in body fluids and tissue homogenates. Journal of Chromatography Biomedical Application 1993; 621: 65–76.CrossRefGoogle Scholar
  15. 15.
    Press WH, Flannery BP, Teukolsky SA, Vetterling WT. Numerical Recipes. Cambridge: Cambridge University Press, 1986.Google Scholar
  16. 16.
    Wagner JG, Fundamentals of Clinical Pharmacokinetics. Hamilton: Drug Intelligence Publications, 1975.Google Scholar
  17. 17.
    Kopman AF. Pancuronium, gallamine, and d-tubocurarine compared: is speed of onset inversely related to drug potency? Anesthesiology 1989; 70: 915–20.PubMedGoogle Scholar
  18. 18.
    Donati F, Meistelman C. A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs. J Pharmacokinet Biopharm 1991; 19: 537–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Armstrong DL, Lester HA. The kinetics of tubocurarine action and restricted diffusion within the synaptic cleft. J Physiol 1979; 294: 365–86.PubMedGoogle Scholar
  20. 20.
    Wierda JMKH, Proost JH, Muir AW, Marshall RJ. Design of drugs for rapid onset. Anaesthetic Pharmacology Review 1993; 1: 57–68.Google Scholar
  21. 21.
    Hof RP, Hof A, Scholtysik G, Menninger K. Effects of the new calcium antagonist PN-200-110 on the myocardium and the regional peripheral circulation in anesthetized cats and dogs. J Cardiovasc Pharmacol 1984; 6: 407–16.PubMedCrossRefGoogle Scholar
  22. 22.
    Drexler H, Truog AG, Just H, Zelis R. Effects of calciumblockade and converting-enzyme inhibition on regional blood flow in a conscious rat model of heart failure. Klin Wochenschr 1985; 63: 262–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Sohn YJ, Bencini AF, Scaf AHJ, Kersten UW, Agoston S. Comparative pharmacokinetics and dynamics of vecuronium and pancuronium in anesthetized patients. Anesth Analg 1986; 65: 233–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Agoston S, Vandenbrom RHG, Wierda JMKH. Clinical pharmacokinetics of neuromuscular blocking drugs. Clin Pharmacokinet 1992; 22: 94–115.PubMedCrossRefGoogle Scholar
  25. 25.
    Wierda JMKH, van den Broek L Proost JH, Verbaan BW, Hennis PJ. Time course of action and endotracheal intubating conditions of Org 9487, a new short-acting steroidal muscle relaxant; a comparison with succinylcholine. Anesth Analg 1993; 77: 579–84.PubMedCrossRefGoogle Scholar

Copyright information

© Canadian Anesthesiologists 1994

Authors and Affiliations

  • J. Mark K. H. Wierda
    • 1
  • Anton M. Beaufort
    • 1
  • Ursula W. Kleef
    • 1
  • Nicky J. Smeulers
    • 1
  • Sandor Agoston
    • 1
  1. 1.Research Group for Experimental Anesthesiology and Clinical Pharmacology, Department of AnesthesiologyUniversity Hospital of GroningenGroningenThe Netherlands

Personalised recommendations