Comparative study of ORG NC 45 and pancuronium during anesthesia

The muscle relaxant effects of ORG NC 45 and pancuronium were compared in anesthetized patients with normal liver and renal functions. In all patients, the muscle relaxant effect was monitored by measuring the strength of the adductor pollicis muscle elicited by supramaximal stimulation of the ulnar nerve at the wrist. Different modes of administration of the muscle relaxants were used. In order to facilitate tracheal intubation, a dose of 100 mu X kg-1 of ORG NC 45 or pancuronium was administered. This dose was followed or not according to the type of surgery by repeated doses of 25 micrograms X kg-1. The results of this study indicate that ORG NC 45 is much shorter acting than pancuronium, and non cumulative. The dose of 100 micrograms X kg-1 produced adequate conditions for tracheal intubation 3 to 4 min after the administration of the muscle relaxant. The recovery of the muscle strength to 75% of control value was achieved 46 min and 100 min after a single dose of 100 micrograms X kg-1 of ORG NC 45 and pancuronium respectively. The interval of time between repeat injections averaged 20 min for ORG NC 45 and 40 min for pancuronium.     

The neuromuscular blocking effects of ORG 9426]

ORG 9426 is a new non-depolarizing steroidal muscle relaxant with a short onset time and intermediate duration of action. Its ED90 ist estimated to be between 0.25 and 0.36 mg/kg. The present study investigated the onset time, duration of action and time to spontaneous recovery after 0.3 and 0.9 mg/kg ORG 9426, respectively (i.e. about single or triple ED90). METHODS. Following the consent of the ethics committee and informed patient consent, two groups of 18 patients (ASA I or II) were formed, each scheduled for general or ORL surgery. After premedication with lormetazepam, anesthesia was induced with midazolam (0.07 mg/kg) and etomidate (0.3 mg/kg) and maintained with N2O/O2 at a 65:35 ratio, enflurane (0.8-1.5%) and supplements of fentanyl as needed. The ulnar nerve was stimulated with supramaximal 2 Hz Train-of-four (TOF) every 20 s. Neuromuscular twitch response was registered with EMG. Muscle relaxation was achieved by administration of ORG 9426 0.3 (group 1) and 0.9 mg/kg (group 2), respectively. The following parameters were measured: onset time (time interval from injection to maximal or total block), T125/75 (time for T1 to reach 25% or 75% of control), TOF70 (time for TOF ratio to reach 70% of control), heart rate and blood pressure. RESULTS. (mean +/- SD). At a dosage of 0.3 mg/kg, the onset time was 3.1 +/- 0.8 min and the maximum blockade was 87 +/- 9%. A dosage of 0.9 mg/kg led to complete paralysis (100%) in all patients within 1.2 +/- 0.3 min. The time for recovery of T1 to 25 and 75% of baseline was 18 +/- 7 and 26 +/- 8 min in group 1, in group 2 46 +/- 11 and 53 +/- 17 min, respectively. TOF70 (i.e., time to adequate spontaneous recovery of neuromuscular function) was achieved after 30 +/- 10 and 63 +/- 14 min, respectively. CONCLUSIONS. At a dosage of 0.3 mg/kg, ORG 9426 has an onset time of about 3 min and a duration of activity of nearly half an hour. Its neuromuscular effects are similar to a single ED90 dose of vecuronium. In contrast to a previous study, we observed a much shorter onset time of 70 s following the administration of 0.9 mg/kg. The clinical duration of action and spontaneous recovery of neuromuscular function, however, were significantly prolonged to more than 1 h. The hemodynamic parameters showed only slight alterations.     

The neuromuscular blocking effects and pharmacokinetics of ORG 9426 and ORG 9616 in the cat

The neuromuscular blocking effects and pharmacokinetics of ORG 9426, 1.5 mg/kg and ORG 9616, 1.2 mg/kg iv, two new nondepolarizing neuromuscular blocking drugs, were studied in 28 cats (i.e., 14 cats with each drug) with and without renal pedicle ligation. A gas chromatographic assay was used to determine the concentrations of ORG 9426 and ORG 9616 and its desacetyl metabolites in plasma, urine, bile, and liver. The duration of neuromuscular blockade of both drugs was not altered by ligation of renal pedicles. Plasma clearance of ORG 9426 was slower in cats with ligated renal pedicles (P less than 0.01). With ORG 9616, mean elimination half-life was slower and mean residence time longer in cats with renal pedicle ligation. Otherwise, there was no significant differences with any pharmacokinetic variables in cats with and without renal pedicle ligation. Only 8.7 +/- 5.7% (SD) and 6.0 +/- 2.8% of an injected dose of ORG 9426 and ORG 9616 was excreted into the urine, respectively. Conversely, 54.4 +/- 9.2% and 52.4 +/- 9.2% of an injected dose of ORG 9426 and 35.7 +/- 12.2% and 46.8 +/- 9.7% of ORG 9616 were excreted into the bile in cats without and with renal pedicle ligation, respectively. Finally, 21.3 +/- 6.5% and 33.5 +/- 15.6% of ORG 9426 and 14.0 +/- 3.2% and 18.1 +/- 5.6% of ORG 9616 were in the liver 6 h after injection in cats without and with renal pedicle ligation respectively. The authors were able to account for the biodisposition of 84.4% and 85.9% of an injected dose of ORG 9426 in cats without and with renal pedicle ligation respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal and biliary elimination of vecuronium (ORG NC 45) and pancuronium in rats

The urinary excretion of ORG NC 45 (Vecuronium) and of pancuronium was studied in unanesthetized rats and the biliary excretion was studied in anesthetized rats. Urine and bile were analyzed for unchanged drug by a new and specific mass spectrometric assay. Pancuronium was eliminated primarily in the urine (85% +/- 6% of the dose in 12 hours), but little ORG NC 45 appeared in the urine (3.5% +/- 1.1% in 12 hours). Biliary excretion accounted for 46% +/- 4% of the ORG NC 45 dose in 7 hours, but only 7.5% +/- 5.3% of an injected dose of pancuronium appeared in the bile. Thus, it appears that ORG NC 45 (a monoquaternary ammonium compound) has a higher biliary clearance than pancuronium (a bisquaternary ammonium compound). The different biodisposition of these two compounds may be due to the greater lipophilicity and concomitant enhanced permeability into the hepatocyte of ORG NC 45. We conclude that in the rat elimination of pancuronium is primarily via the kidney whereas elimination of ORG NC 45 is dependent on nonrenal mechanisms.     

Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC45) and pancuronium in anesthetized humans

The pharmacokinetics and pharmacodynamics of vecuronium (25-50 micrograms/kg) and pancuronium (25-50 micrograms/kg) were determined in nine ASA class I or II patients anesthetized with nitrous oxide and halothane. Force of thumb adduction in response to supramaximal stimulation of the ulnar nerve was quantified and recorded. Serum concentrations of the muscle relaxants were determined for eight hours after their administration using a mass spectrometry assay. Data were analyzed by nonlinear regression and fit to a three-compartment pharmacokinetic model and a four-compartment pharmacodynamic model. Vecuronium had a more rapid clearance (5.2 +/- 0.7 ml X kg-1 X min-1; mean +/- SD) and a shorter elimination half-life (71 +/- 20 min) as compared with pancuronium (1.8 +/- 0.4 ml X kg-1 X min-1; 140 +/- 25 min). No other pharmacokinetic differences were found between the drugs. Pharmacodynamic analysis showed that the plasma concentration at steady state which produced a 50% neuromuscular blockade (Cpss 50) was similar for vecuronium and pancuronium. The authors conclude that the drugs are equivalent in their onset and potency; however, the more rapid clearance and shorter elimination half-life for vecuronium provides a kinetic basis for its shorter duration of neuromuscular blockade as compared with pancuronium.     

The cardiovascular effects of vecuronium (ORG NC45) and pancuronium in patients undergoing coronary artery bypass grafting

Vecuronium is a new nondepolarizing muscle relaxant which has been shown to cause no significant cardiovascular effects. Utilizing invasive monitoring in patients undergoing coronary artery bypass grafting, the authors compared the cardiovascular effects of vecuronium (0.28 mg/kg) in seven anesthetized patients with those of pancuronium (0.1 mg/kg) in five anesthetized patients. This dose of pancuronium represents three times its ED90 (dose producing a 90% depression of evoked twitch tension), while the vecuronium dose represents twelve times its ED90. This relatively large dose of vecuronium was chosen deliberately in an attempt to manifest any possible cardiovascular effects. Following administration of vecuronium, cardiac output increased 9% and systemic vascular resistance decreased 12%, while pancuronium produced a significantly greater 17% increase in cardiac output without change in systemic vascular resistance. Heart rate and systemic mean arterial pressure did not change following vecuronium, while increasing 22% and 24%, respectively, following pancuronium. The authors conclude that large doses of vecuronium have minimal cardiovascular effects and thus offer an advantage over pancuronium in patients anesthetized for coronary artery surgery.     

Cardiovascular and neuromuscular effects of three steroidal neuromuscular blocking drugs in dogs (ORG 9616, ORG 9426, ORG 9991)

Developmental research has been directed toward creating nondepolarizing muscle relaxants with an onset time and duration of actions shorter than that of vecuronium or atracurium. We determined the cardiovascular and neuromuscular effects of three new and promising nondepolarizing muscle relaxants in six dogs anesthetized with halothane. Each dog was anesthetized four times (each time separated from the others by at least 1 wk); one muscle relaxant was studied each time. Three doses (one, three, and five times the ED90) were given as intravenous bolus injections. ORG 9616 and ORG 9991 had shorter durations of action than ORG 9426. The duration of action of the doses that were five times the ED90 was 18 +/- 5.88 and 15.8 +/- 4.41 min (mean +/- SD) with ORG 9616 and ORG 9991, respectively, as compared with 39.7 +/- 17.15 min with ORG 9426 (P less than 0.05). ORG 9426 was virtually free of cardiovascular effects. The ED90 doses of ORG 9616 and ORG 9991 did not cause cardiovascular effects; the doses of three and five times the ED90 caused small decreases in mean arterial blood pressure and increases in heart rate. Mean arterial blood pressure decreased from 99 +/- 10.2 to 88 +/- 13.1 mm Hg and from 98 +/- 11.7 to 77 +/- 8.1 mm Hg with five times the ED90 dose of ORG 9616 and ORG 9991, respectively. The authors conclude that ORG 9426 has a duration of neuromuscular blockade that is probably similar to vecuronium, and one that is free of cardiovascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical use of vecuronium (ORG NC 45) in balanced anesthesia. Comparison with pancuronium

In 2 groups of 25 patients 0.1 mg/kg vecuronium (Org NC 45) or pancuronium, according to a randomised basis, was injected during balanced anesthesia (thiopental, fentanyl, dehydrobenzperidol and N2O). Intubation conditions 120 seconds after injection were satisfactory. After intubation, a heart rate increase was present with pancuronium (p less than 0.01), but not with vecuronium (difference: p less than 0.05); heartrate decreased 15 and 30 minutes after injection of vecuronium (p less than 0.01). The clinical duration of action of vecuronium was 32.7 +/- 2.4 min (Mean +/- SEM) and of pancuronium 73.5 +/- 4.8 min (p less than 0.01). Successive maintenance doses of 0.025 mg/kg of vecuronium had a duration of action of 23.1 +/- 1.7, 26.8 +/- 2.1, 27.6 +/- 4.0 and 24.0 +/- 2.8 min (diff. NS), showing no cumulative activity. The duration of action of identical doses of pancuronium were 56.9 +/- 3.1, 52.1 +/- 7.2 and 61.3 +/- 17.6 min (diff. NS), values nearly +/- 220% above those of vecuronium (p less than 0.01). Reversion of neuromuscular blockade after vecuronium with small amounts of neostigmine was clinically adequate.     

CLINICAL EVALUATION OF ORG NC 45

Org NC 45, a new non-depolarizing neuromuscular blocking drug,was evaluated in 200 adult patients. The drug was administeredin doses of 0.1, 0.15 or 0.2 mg kg^–1. Intubation couldbe satisfactorily carried out at around 90s in 90% of patients.The duration of clinical relaxation varied from 23 min with0.1 mgkg^–1 and neuroleptanaesthesia to 71 min with 0.2mg kg^–1 and anaesthesia with halothane or enflurane. Theduration of clinical relaxation following repeated administrationof 2 – 3 mg was remarkably constant (between 17 and 20min) thus showing lack of cumulation. The antagonism of residualblock was prompt and easy following administration of neostigmine,and the drug lacked any significant cardiovascular effects asseen by routine monitoring     

MYONEURAL ACTIONS OF ORG NC 45

In the toad sartorius preparation Org NC 45 reduced the meanquanta] content of the end-plate potential both in magnesiumand tubocuraine-treated preparations, as well as blocking post-junctionalreceptors. In a concentration which permits recording of theminiature end-plate current no channel block was demonstrated.     

Intubating conditions with ORG NC45

The case of tracheal intubation using two doses of the new steroid neuromuscular blocking compound ORG NC45 (Norcuron) 0.1 and 0.15 mg/kg was compared with a standard dose of pancuronium 0.1 mg/kg at 60, 90 and 120 seconds. The results did not reveal any statistically significant benefit of the new drug within 2 minutes of administration over the control.     

ORG NC45 for short intra-abdominal operations: a comparison with succinylcholine

ORG NC45 was compared with succinylcholine to produce muscle relaxation for short, intra-abdominal operations in 40 patients during nitrous oxide-oxygen-enflurane anaesthesia. Intubating conditions after ORG NC45, 100 micrograms/kg, were similar to those after succinylcholine 1 mg/kg, although this was achieved at a mean time of 229.9 +/- 10.8 sec compared with 129.8 +/- 14.2 sec after succinylcholine. Muscle relaxation during surgery, mean duration 32.5 minutes, was provided in the succinylcholine group with an infusion and in the ORG NC45 group by repeated boluses, 10 micrograms/kg, which were required in four patients. At the end of surgery ORG NC45 was antagonized with atropine, 17 micrograms/kg, and neostigmine, 36 micrograms/kg, which were repeated in two patients. Postoperative recovery of neuromuscular function was indistinguishable between the two groups. We conclude that ORG NC45 is a suitable relaxant for short, intra-abdominal operations if sufficient time, three to four minutes, is allowed to produce good intubating conditions.     

A comparison of the neuromuscular blocking effects and reversibility of cisatracurium and atracurium

The neuromuscular blocking effects and the reversibility of cisatracurium 0.1 or 0.15 mgkg⁻¹ were compared with those of atracurium 0.5 mgkg⁻¹ during anaesthesia with propofol, nitrous oxide and isoflurane. Neuromuscular block was monitored using train-of-four stimulation while recording the mechanomyographic response of the adductor pollicis muscle. The block was either allowed to recover spontaneously or was antagonised with neostigmine 50 μgkg⁻¹ at 10% or 25% recovery of the first twitch of the train-of-four. The median times to maximum block were 2.7, 2.2 and 1.5 min following cisatracurium 0.1 and 0.15 mgkg⁻¹ and atracurium 0.5 mgkg⁻¹, respectively. After cisatracurium 0.1 mgkg⁻¹ had been given, the median time to recovery of the train-of-four ratio to 0.8 ('adequate recovery') was 74 min during spontaneous recovery, 48 min after reversal with neostigmine when the first twitch of the train-of-four had returned to 10% of control and 50 min after reversal when the first twitch of the train-of-four had returned to 25% of control. These times for cisatracurium 0.15 mgkg⁻¹ and atracurium 0.5 mgkg⁻¹ were 90, 66 and 57 min and 75, 56 and 54 min, respectively. Administration of neostigmine significantly shortened the time to adequate recovery for both drugs but there were no significant differences in the case of either neuromuscular blocking drug between the groups of patients given neostigmine at 10 or 25% recovery of the first twitch of the train-of-four.     

A vagolytic action of neuromuscular blocking agents at the pacemaker of the isolated guinea pig atrium

To examine the basis of tachycardia seen clinically with some neuromuscular blocking agents, the potencies of d-tubocurarine, dimethyltubocurarine, gallamine, and pancuronium in antagonizing the effects of vagal stimulation on the guinea pig atrial pacemaker were determined and expressed as an ED50 for vagal blockade. These ED50 values were compared with the respective potency values of these agents at the motor endplate. This comparison showed that in clinical doses, gallamine and pancuronium may reach levels that produce vagal blockade. Comparison with atropine indicated that the vagolytic action of the neuromuscular blocking agents was not attributable to receptor occlusion, but reflected instead an action on the vagus nerve itself.     

Accelerated onset of non-depolarizing neuromuscular blocking drugs: pancuronium, atracurium and vecuronium. A comparison with succinylcholine

The time of onset and degree of neuromuscular blockade (NMB) in 80 anaesthetized patients, following either a single bolus injection of pancuronium 0.95 mg kg-1, atracurium 0.53 mg kg-1 or vecuronium 0.07 mg kg-1, or divided doses of pancuronium 0.15 mg kg-1, atracurium 0.07 mg kg-1 or vecuronium 0.01 mg kg-1 administered 3 min or 5 min before the second dose of pancuronium 0.08 mg kg-1, atracurium 0.46 mg kg-1 or vecuronium 0.06 mg kg-1, were determined and compared to the same parameters measured following succinylcholine administration (1 mg kg-1). The time to maximum NMB (100%) following the administration of succinylcholine was 58.1 +/- 5.3 s, whereas the time to maximum NMB (100%) following a single bolus injection of either pancuronium, atracurium or vecuronium was 130.6 +/- 22.2, 93.0 +/- 6.4, 127.5 +/- 13.0 s, respectively. These values for time to maximum NMB are significantly longer than the time required for succinylcholine to achieve maximal blockade. The time to attain maximum NMB following divided doses of pancuronium, atracurium or vecuronium separated by 3 min decreased significantly to 77.9 +/- 4.3, 77.5 +/- 7.6, 89.0 +/- 8.6 s, respectively. However, when the two doses of drug were separated by 5 min, only small, non-significant further decreases occurred in the time required to achieve maximum blockade. Although the time to maximum NMB following divided doses of pancuronium, atracurium or vecuronium is significantly longer than that for succinylcholine, divided dosing significantly decreases the time required to reach maximal NMB.     

Potency determination for vecuronium (ORG NC45): comparison of cumulative and single-dose techniques

To compare two methods of estimating the potency of neuromuscular relaxants of medium duration, the authors determined the potency of vecuronium (ORG NC45) using cumulative dose-response (CDR) techniques, and compared these data with published values from our group obtained using the single bolus technique. During 60% N2O-halothane anesthesia, patients received 10 micrograms/kg vecuronium; additional incremental doses of vecuronium, 5 micrograms/kg, were given when no change occurred in the height of three successive twitches. Using these dose-response data, the authors determined least-squares regression lines and ED20, ED50, and ED80. These results were compared to values obtained by the single bolus technique under comparable conditions. The CDR and single bolus technique yielded ED50 values of 19.9 and 15.0 micrograms/kg, respectively. All potency estimates by CDR were larger than those obtained by the single bolus dose technique. It was concluded that, for vecuronium, a medium duration neuromuscular relaxant, CDR yields potency estimates which are larger than those obtained by the traditional single bolus dose technique. Because the single bolus dose technique is the accepted method for construction of dose-response curves, the authors recommended that CDR not be used for potency determination of muscle relaxants of medium and short duration such as vecuronium.