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Background: A model of an antegrade, perfused, isolated rat peroneal nerve anterior tibial muscle was developed to study potentially important factors governing the time course of action of (nondepolarizing) neuromuscular blocking agents such as concentration, blood flow, and temperature. The model allows observation of the effects of selective changes in these factors. Methods: The authors isolated the anterior tibial muscle and cannulated the anterior tibial artery and vein, providing a way for single-pass perfusion with blood from a donor rat. A force transducer was connected to the tiblalis anterior muscle and a stimulator was connected to the tibial nerve. The influence of intrinsic potency (EC90) and muscle blood flow rate on the time course of pancuronium and rocuronium was investigated. Results: The model remained stable for at least 4 h with respect to twitch height, muscle structure and function, and blood chemistry. Doubling the muscle-blood flow resulted in a significantly faster onset and offset for both pancuronium and rocuronium. Trebling the intrinsic potency (EC90) was not associated with significant changes in the time course of action of the relaxants. Conclusion: The authors developed and validated a model that allows us to study biophase kinetics of neuromuscular blocking agents in the anterior tibial muscle of the rat. in this model, muscle-blood How rather than EC90 appears to predominantly determine the onset and offset time of nondepolarizing muscle relaxants.

To obtain more insight in the relationship between physicochemical properties of neuromuscular blocking agents (NMBAs) and their pharmacokinetic characteristics, a series of 12 aminosteroidal NMBAs, supplemented with data on five related NMBAs from the literature, was investigated in anaesthetized cats. After i.v. bolus injection, plasma concentration decreased very rapidly, showing a biphasic pattern, with half-lives ranging from 0.4 to 1.4 min, and from 3 to 10 min, respectively. Clearance was in the range from 24 to 58 ml . min(-1) . kg(-1). Compounds containing an acetyl-ester group at position 3 were partly metabolized to the 3-OH derivative. The urinary excretion of the parent drug and metabolites amounted to

Dynamic cardiomyoplasty is a surgical treatment to improve cardiac performance in patients with end-stage heart failure by wrapping the latissimus dorsi muscle around the heart. The use of skeletal muscle raises concerns about the safety of neuromuscular blocking agents used during general anaesthesia in noncardiac surgery in patients after cardiomyoplasty. We describe the administration of rocuronium to a patient undergoing carotid endarterectomy 18 months after cardiomyoplasty. No clinically relevant effects on haemodynamics were observed. We conclude that the use of nondepolarising neuromuscular blocking agents for noncardiac surgery in patients after cardiomyoplasty does not compromise cardiac performance in a clinically relevant way, although the time between the cardiomyoplasty procedure and the use of nondepolarising neuromuscular blocking agents remains a concern.

Objective. To determine whether the twitch force of the adductor pollicis remains stable when 0.1 Hz single twitch stimulation is started after stabilization of the thumb preload at a constant degree of thumb abduction; also to study any possible increase in twitch force before the onset of and after the recovery from neuromuscular block. Methods. Measurements were performed in thirty patients under general anaesthesia. Twitch forces were first allowed to stabilize after allowing the preload to drift to its resting tension at a constant degree of thumb abduction. Three groups of ten patients then each received either vecuronium (2, 4, 8, 16 and 32 mu g/kg(-1), successively at intervals of 2 min), d-tubocurarine (5, 10, 20, 40 and 80 mu g/kg(-1), successively at intervals of 2 min), or suxamethonium (0.025, 0.05, 0.1, 0.2 and 0.4 mg/kg(-1), successively at intervals of 2 min). Measurements were continued until twitch forces had recovered from neuromuscular block and were stable. Results. Twitch forces stabilized at 114% (sd = 8.9) of the initial value after 10.9 (6.1) min of stimulation. Increase in twitch force before the onset of neuromuscular block was seen in two patients receiving vecuronium and in two patients receiving d-tubocurarine. Increase in twitch force after recovery from neuromuscular block was seen in all patients receiving suxamethonium. Conclusions. Twitch forces may increase when stimulation is started after stabilization of thumb preload at a constant degree of thumb abduction. In some patients twitch forces may increase before the onset of neuromuscular block with vecuronium or d-tubocurarine; twitch forces increase after recovery from suxamethonium.

Objective. To investigate the effects of maintaining a constant preload and of maintaining a constant degree of thumb abduction on the isometric twitch force during mechanomyography of the thumb, we monitored neuromuscular function in patients anaesthetized without the use of a neuromuscular blocking agent. In addition, we studied the relationship between the degree of thumb abduction, twitch force and preload. Methods.Fourteen patients were divided randomly into two groups, determining the sequence of the experiments in respect of correcting the preload and maintaining a constant degree of abduction after allowing the twitch forces to stabilize. Both experiments lasted 15 minutes. In both groups the relationship between the degree of thumb abduction, twitch force and preload was studied. Results. We found a progressive increase in twitch force both with (6.6%; CI: 3.7-9.3%; p

Objective. In order to study the stabilization time, the increase in twitch force during stabilization and the maintenance of stability during mechanomyography of the adductor pollicis muscle, neuromuscular function was monitored in 20 patients anaesthetized without the use of a neuromuscular blocking agent. The effect of the type of stimulation (single twitch [ST; 0.1 Hz], or train-of-four [TOF; 4 stimuli at 2 Hz, repeated every 12 s]) on these variables was studied. When applying TOF stimulation, the variables were also investigated for the TOF percentage [quotient of fourth and first twitch of a TOF stimulus x 100%]. Methods. Two groups of ten patients were monitored with either ST or TOF stimulation. Measurements continued for at least 45 minutes. Multiple linear regression analysis was applied to examine the effect of stimulation on the stabilization time and the increase in twitch force. Results. According to our criteria for stability, we found that thr stabilization time did not differ for ST (13.7 [10.2] min; mean [sd]) and TOF stimulation (18.1 [9.6] min) (p > 0.10). Stabilized twitch forces were larger during TOF than during ST stimulation (134% [19] and 113% [11]; p = 0.01). In both groups of stimulation, sis patients showed an interruption of stability. The TOF percentage was stable throughout rile measurement period in all patients. Conclusions. Stabilization of twitch force takes too long for many studies of neuromuscular function in the clinical research setting. Therefore, we do not recommend its routine use when performing mechanomyography of the adductor pollicis muscle.

Since 1964 approximately 20 steroidal neuromuscular blocking agents have been evaluated clinically. Pancuronium, a bisquaternary compound designed on the drawingboard, was the first steroidal relaxant introduced into clinical practice worldwide in the 1970's. Although a major improvement, pancuronium was still a potent, long-acting agent with moderate cardiovascular effects. The search for a potent cardiovascularly "clean" compound with a shorter time course has resulted in the development of pancuronium's monoquaternary derivative, vecuronium. Vecuronium gained widespread popularity in the 1980's due to its intermediate duration and lack of side-effects. However, its 3-hydroxy metabolite is also a potent neuromuscular blocker and may contribute to neuromuscular block after long periods of vecuronium administration. Further research was directed towards the development of compounds with a faster onset of action. In 1994 the vecuronium analog, rocuronium, was introduced, a less potent compound with a rapid onset and intermediate duration and without a pharmacologically active metabolite. Rocuronium is the first non-depolarizing relaxant which allows intubation within 60-90 seconds of its administration. Recently, a relatively low potency, fast onset and short-acting vecuronium analog, Org 9487, has been selected to undergo clinical evaluation as a potential alternative for succinylcholine. Org 9487 combines early satisfactory intubating conditions with a short time course and early reversibility at the cost of moderate cardiovascular effects.

The time-course of action after an initial 2 x ED(90) dose and after maintenance doses of 0.5 x ED(90), and intubating conditions at 90 s after a 2 x ED(90) dose following rocuronium, vecuronium and mivacurium were evaluated in anaesthetized adult patients. Neuromuscular measurements were performed with mechanomyography. Rocuronium produced a significantly deeper neuromuscular block at 90 s (mean and (standard deviation)) (91; (11)%), compared to vecuronium (61 (22)%) and mivacurium (58 (23)%). The onset time following rocuronium (172 (71)s) was significantly shorter than that following mivacurium (229 (60)s). At 90s, intubating conditions were significantly better in the rocuronium group than in the vecuronium or mivacurium group. Mivacurium offered a significantly faster recovery of neuromuscular block following the 2 x ED(90) dose and following an average of 45 min of clinical muscle relaxation (single twitch response less than or equal to 25%) compared to rocuronium and vecuronium: clinical duration 13 (4), 28 (9) and 33 (9) min, respectively, and recovery time from 25 to 75% recovery of the single twitch response: 6 (2), 11 (4)and 14 (7) min, respectively.

Several new steroidal non-depolarizing muscle relaxants have been synthesized and tested in humans recently. Results from these studies suggest that the differences in time-course of action between these compounds are mainly, if not totally, related to differences in biodisposition. Biodisposition, in turn, is determined largely by the physico-chemical characteristics of the drug, such as degree of lipophilicity and protein binding. The various pharmacodynamic and pharmacokinetic variables of a series of structurally related steroidal relaxants, varying in the ester substituent at the 17th position of the androstane skeleton, have been related to the degree of lipophilicity. Significant positive relationships could be shown between lipophilicity (logP at pH 7.4) and, among other things, potency (ED(90)), effective concentration (EC(50)), unbound plasma clearance (CLupt) and rate constant of transport between plasma and biophase (k(eo)). The aforementioned relationships between lipophilicity and pharmacokinetic variables resulted in significant inverse relationships between lipophilicity and time course parameters, such as onset time and duration of neuromuscular blocking effects. It is concluded that changes in the molecular structure of steroidal relaxants which enhance lipophilicity coincide with a decrease of (intrinsic) potency and a shorter time course of action. Protein binding appears to be of minor importance for the biodisposition and time course characteristics, since there were only small differences in degree of protein binding between most of the investigated compounds. However, the surprisingly fast initial rate of block development observed with rocuronium may in part result from its relatively high unbound fraction in plasma.

The neuromuscular and cardiovascular effects of neostigmine, 40 mug kg-1, and methyl-atropine, 7 mug kg-1, administered at different degrees of rocuronium-induced (600 mug kg-1) neuromuscular block were evaluated. In one group of patients spontaneous recovery was awaited (Group A; n = 20). Neostigmine and methyl-atropine were administered 2 minutes after rocuronium (Group B; n = 20) or at 25% twitch recovery (Group C; n = 20). Neuromuscular transmission was monitored mechanomyographically. Data are presented as mean (SD) [95%-Cl]. The initial rate of recovery (time until a TOF ratio of 0.2) in group B, i.e. 14.2 (4.5) [12.1-16.3] min, was significantly faster than in group C, i.e. 28.7 (5.3) [26.3-31.1] min. However, the time until clinically sufficient recovery (time until a TOF ratio of 0.7) was similar for groups B, i.e. 29.3 (9.5) [24.9-33.7] min and group C, i.e. 31.8 (5.6) [29.2-34.4] min, both significantly different from that of group A, i.e. 53.2 (14.5) [46.5-59.9] min. The increase in heart rate following neostigmine/methyl-atropine was more pronounced in the group reversed at 2 min after rocuronium (P

A computer simulation has been developed based on pharmacodynamic-pharmacokinetic modelling of the effect of neostigmine on rocuronium-induced neuromuscular blockade. The results of a previous study involving 60 patients were used as a test of the model. The model predicts that administration of neostigmine 40 mug kg-1 within 20 min of the administration of rocuronium does not decrease the duration of the block until 90% recovery has taken place. The optimum dose of neostigmine depends on the degree of block at the time of administration: for a more intense block the optimum dose is 80 mug kg-1 and for a less intense block is about 30 mug kg-1. The pharmacokinetic behaviour rather than the potency of the relaxant determines its reversibility.

The existing human pharmacokinetic studies have been reviewed and compared with data derived from animals. The earliest study confirms the similarity of rocuronium to vecuronium with respect to the variables derived from the plasma concentration decay curves and the proportion excreted renally. Other studies led to the conclusion that concurrent administration of volatile anaesthetics did not significantly influence rocuronium pharmacokinetics and that the potentiation must be due to an increased sensitivity of the neuromuscular junction. These studies do not provide an explanation for the clinical observation of a more rapid onset of action. One possible explanation was the finding of a more rapid onset of block in the laryngeal muscles than in the adductor pollicis. However, no pharmacokinetic explanation for this observation has emerged. Alternative concepts need to be modelled. There is a need for comparative pharmacokinetic studies which focus on the period immediately following administration of rocuronium and vecuronium.

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 function 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 ED(90) valuesfor 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 X ED(90)), Org 9489 (0.9 mg.kg(-1) 2 X ED(90)) and Org 9487 (1.5 mg.kg(-1), 1.3 X ED(90)) 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.

Study Objective: To evaluate the time course of action, dose requirement, reversibility, and pharmacokinetics of rocuronium (Org 9426) under 3 anesthetic techniques (nitrous oxide-fentanyl supplemented with propofol halothane, or isoflurane). Design: Prospective, randomized study. Setting: Operating suite at a university hospital. Patients: 36 ASA physical status I-III patients aged 18 to 65 years who were scheduled for elective surgery. Interventions: The time course of action of an intubation, close of rocuronium 600 mu g/kg was investigated in 36 patients. In 18 of these patients, the maintenance dose requirement of rocuronium and reversibility by neostigmine were evaluated. In the remaining 18 patients, the pharmacokinetics of rocuronium rocuronium after the intubating dose were studied. Neuromuscular transmission was monitored by mechanomyography. Venous blood samples and urine were analyzed by high-performance liquid chromatography. Measurements and Main Results: With the exception of a longer clinical duration of rocuronium-induced neuromuscular block in the isoflurane group compared with the propofol group (p = 0.03), time course of action variables were similar in the 3 groups. In patients receiving maintenance doses of rocuronium, the dose requirement until reversal was 636 +/- 191 mu/g/kg/hr, 496 +/- 107 mu g/kg/hr, and 384 +/- 127 mu g/kg/hr for the propofol halothane, and isoflurane groups, respectively (p = 0.02 for the isoflurane group vs. the propofol group). With respect to the reversal of a rocuronium-induced neuromuscular block, there were no differences in the percentage recovery or rate of recovery among the 3 groups. Pharmacokinetic analysis showed no significant differences for rocuronium during the 3 anesthetic techniques. Conclusion: Isoflurane potentiates the rocuronium-induced neuromuscular block resulting in a longer clinical duration and lower maintenance dose requirement. This difference is not explained by differences in pharmacokinetics but is probably due to increased sensitivity of the neuromuscular junction to rocuronium during isoflurane anesthesia.

Cyclosporine A (CsA) bioavailability after i.v. and oral administration was studied in six stable liver transplant patients with open and clamped bile drain. CsA levels were determined by the high-performance liquid chromatography method (HPLC). External bile drainage decreased CsA absorption considerably. Clamping the bile drain resulted in higher and earlier peak CsA levels. Clamping the bile drain increased the bioavailability (9.6% vs. 7%, p

Background: Hypothermia prolongs the time course of action of nondepolarizing muscle relaxants. It is not known whether this prolongation is caused by a reduced rate of extrahepatic distribution or elimination, liver uptake, metabolic clearance, or biliary excretion. Therefore, the authors studied the effects of hypothermia on the net hepatic uptake, metabolism, and biliary excretion of vecuronium in Isolated perfused rat liver. Methods: Livers of Wistar rats were perfused with Krebs Ringer solution (1% albumin, 3.3% carbon dioxide in oxygen, pH 7.36-7.42, 38 degreesC), Each perfusion experiment (recirculatory perfusion system) was divided into three phases. In phase 1, a bolus dose of vecuronium (950 mug) was followed by a continuous infusion of vecuronium (63 mug/min) throughout the perfusion experiment. In phase 2, the temperature was reduced to 28 degreesC, In phase 3, temperature was restored. In controls, the temperature was kept constant throughout the perfusion. Concentrations of vecuronium and its metabolites were measured in perfusion medium, bile, and liver homogenate. Parameters of a multicompartmental Liver model were fitted to the concentration patterns in perfusion medium and in bile. Results: Hypothermia increased vecuronium concentrations in the perfusion medium from 4.0 mug/ml (range, 2.5-6.6) to 15.6 mug/ml (11.5-18.4 mug/ml; P = 0.018). Hypothermia reduced the biliary excretion rate of 3-desacetyl vecuronium from 18% (range, 6-37%) to 16% (range, 4-19%) of that of vecuronium (P = 0.018), Pharmacokinetic analysis confirmed that hypothermia reduced the rate constants of hepatic uptake and metabolism from 0.219 to 0.053 and from 0.059 to 0.030, respectively. Conclusions: Hypothermia significantly and reversibly reduced the net hepatic uptake of vecuronium. Hypothermia reduced the metabolism of vecuronium and the biliary excretion rate of 3-desacetyl vecuronium.