Dose-Response Relation, Neuromuscular Blocking Action, Intubation Conditions, and Cardiovascular Effects of Org 9273, a New Neuromuscular Blocking Agent

Abstract

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. The ED,, and the ED,,, the time-course of the neuromuscular block, the intubation conditions, and the cardiovascular effects of Org 9273, a new steroidal nondepolarizing neuromuscular blocking agent, have been evaluated in 41 anesthetized patients. From cumulative dose-response curves the ED,, and ED,, were calculated to be 175 and 300 pglkg, respectively. The time-course of neuromuscular blockade after 300-and 500-pglkg doses of Org 9273 appeared to be similar to that of equipotent doses of vecuronium. The neuromuscular block was characterized by a fast initial rate of block development. High-dose Org 9273(1 mglkg = 3 4 times the ED,,) had a clinical duration comparable to an intubating dose of pancuronium, but a considerably more rapid onset and recovery index. Three hundred micrograms per kilogram and 500 pglkg Org 9273 produced good to excellent intubation conditions 1 min after administration. Org 9273 in a dose of 0.5-2 times the ED,, produced no cardiovascular changes; however, 3 4 times the ED,, increased heart rate 20%-25% (P < 0.001), probably due to a vagolytic effect.Key Words: NEUROMUSCULAR RELAXANT, Org 9273.As a result of the search for a nondepolarizing neuromuscular blocking agent as an alternative to succinylcholine for intubation and short surgical procedures, some new neuromuscular blocking agents have recently become available for clinical trials. One of these agents is Org 9273, the 2-morpholino, 3-desacetyl analogue of vecuronium (Figure l), which has been shown to be stable in aqueous solution.Preliminary animal studies (1,2) show that Org 9273 is 3-5 times less potent than vecuronium but with a faster onset of action and a similar duration of action. Furthermore, Org 9273 in doses of 1-3 times the ED90 produces only minor changes in heart rate and blood pressure in experimental animals.We have performed a dose-finding study to investigate the dose-response relationship, the time-course of neuromuscular blocking action, the intubation conditions, and the hemodynamic stability of Org 9273 in anesthetized patients. MethodsThe study was approved by the local medical ethical committee. Forty-one ASA physical status I and I1 patients, aged 18-60 yr, scheduled for elective surgery, participated in this study after they had given written informed consent.After oral premedication with 7.5 mg midazolam approximately 60 min before the expected start of anesthesia, anesthesia was induced with 1-5 &kg fentanyl and 3-7 mg/kg thiopental. After tracheal intubation, anesthesia was maintained with halothane, 0.5% inspiratory concentration, in a 2:l mixture Of nitrous Oxide and Oxygen and increments of 50-100 pg fentanyl. End-tidal k o 2 was kept between 32 and 42 mm Hg. After 290% recovery from the Org 9273 vecuronium was to maintain muscle relaxation if necessary. Cent...

Intubating conditions and onset of neuromuscular block of rocuronium (Org 9426); a comparison with suxamethonium

“…Alternatively, differences in local balance between pre-and post-junctional effects, or in sensitivity of the nicotinic receptors of the various muscle groups could be involved (18,19). Intubation following Org 9273, another new neuromuscular blocking agent, was also possible under good conditions at only partial blockade of the adductor pollicis muscle (20). It seems justified to reconsider the concept that optimal intubating conditions are only provided at neuromuscular block of peripheral muscles equal to or greater than 95% (21).…”

Clinical pharmacology of ORG 7617, a short-acting non-depolarizing neuromuscular blocking agent

“…In earlier clinical studies, under similar study conditions, with low potency steroidal compounds, i. e. rocuronium [8], Org 9273 [9] and Org 9487 [5], and in the current study of Org 7617, the time until the first measurable response (20-30 s) approximated the circulation time. Hence, diffusion to the site of action seemed to be rapid and similar to that of succinylcholine [10].…”

“…In the anaesthetised pig, using a series of 2-morpholino 16-amino (piperidino or pyrrolidino) androstane mono methobromides, it has been demonstrated that changes in the substituent in the 3-position (A-ring) and the 16- (7) 78 (14) 77 (8) 31 (7) 181 (6) 77 (18) 79 (10) 31 (9) 171 (12) 63 (18) 67 (15) the duration of the neuromuscular blockade [2]. This knowledge led to synthesis of a new series of steroidal structures with the anticipated non-depolarizing neuromuscular blocking activity, including Org 7617, the 16-Nallyl, 17-butyrate analogue of vecuronium (Fig.…”