[Randomized, multicenter study of interaction between Org 9426 (rocuronium bromide) and anesthetic agents in Japanese population].

BACKGROUND: The purpose of this randomized, multi-center phase III trial was to investigate the influence of sevoflurane and propofol on the neuromuscular blocking effects and pharmacokinetic parameters of Org 9426 (rocuronium bromide) in Japanese population. METHODS: Thirty-nine adult Japanese patients participated in this randomized, multi-center study. Neuromuscular function was monitored continuously with TOF-Watch SX (Organon NV, Netherlands) after anesthetic induction with propofol. These subjects randomly received either 0.6 mg x kg(-1) or 0.9 mg x kg(-1) of rocuronium for endotracheal intubation. These two groups were further divided to two anesthetic regiments : sevoflurane group and propofol group. The difference in onset and recovery of rocuronium-induced neuromuscular block was statistically analyzed with two-way ANOVA. RESULTS: Mean duration for maximal block was 76 seconds and 66 seconds, respectively. The duration between Org 9426 administration and 25% recovery of first twitch response was significantly prolonged in patients given 0.9 mg x kg(-1) of Org 9426. Sevoflurane also significantly increased this duration. However, the serum concentration of Org 9426 was not statistically different between the four study groups. CONCLUSIONS: The duration of Org 9426-induced neuromuscular blockade was significantly increased under sevoflurane anesthesia compared to propofol anesthesia. This difference may be attributed to pharmacodynamic change.

The application of pancuronium bromide (Pavulon) forensic analyses to tissue samples from an "Angel of Death" investigation.

The case report of a serial killer who worked at several hospitals as a respiratory therapist is presented. The suspect was initially labeled a benevolent Angel of Death who ended the suffering of elderly patients through mercy killing. However, his subsequently declared motive for homicide was very different from other similar cases in medical settings. The application of new analysis techniques for the detection of pancuronium bromide in a series of aged exhumation tissues gave positive results and led to the resultant conviction of the therapist.

Fuzzy logic for model adaptation of a pharmacokinetic-based closed loop delivery system for pancuronium.

In this paper, we investigate the ability of fuzzy to adapt the parameters of a pharmacokinetic and pharmacodynamic model-based controller for the delivery of the muscle relaxant pancuronium. The system uses the model to control the rate of drug delivery and uses feedback from a sensor which measures muscle relaxation level to adapt the model using fuzzy logic. The control strategy administers mini-bolus doses of pancuronium and modulates the magnitude and time interval between the bolus doses to maintain a patient's muscle relaxation within an allowable range specified by the user. Before each new dose is given, the fuzzy logic adaptation scheme uses the error between the predicted patient response and the measured response to adapt the model. The system was tested using computer simulation by varying the parameters of the model by 50% from their nominal values. It was also evaluated in a clinical trial of five patients undergoing surgical procedures lasting 5 h or longer.

Effects of enflurane and isoflurane anesthesia on the pharmacokinetics of pancuronium in adult patients.

OBJECTIVE: To evaluate the effects of 1 MAC of enflurane or isoflurane anesthesia on the pharmacokinetics of pancuronium. METHODS: Eighteen adult patients undergoing the elective plastic surgery were randomly divided equally into 3 groups, namely, Group 1 (control group), Group 2 (enflurane group) and Group 3 (isoflurane group). Anesthesia was maintained with thiopental and 67% N2O-O2 in Group 1, 1 MAC enflurane in Group 2 and 1 MAC isoflurane in Group 3. After administration of a bolus of pancuronium 100 micrograms/kg, an improved fluorimetric assay was used to determine the serum concentrations of pancuronium and the pharmacokinetic variables of pancuronium were calculated with a 3P87 program. RESULTS: The disposition of pancuronium may be well described mathematically by a two-compartment open model. The results showed that in comparison with the control group, patients in Group 2 and Group 3 had a longer T1/2 beta and MRT. The patients in Group 2 had the slower K10 and lower CL than those in the control group. There were no significant differences among the three groups in T1/2 alpha, V1, V2, Vdss, V beta, K21, K12 and AUC. CONCLUSION: During enflurane and isoflurane anesthesia, CL of pancuronium decreased, and T1/2 beta and MRT of pancuronium were prolonged in our patients, so duration of the effective plasma concentrations of pancuronium was much longer. As a result, the effects of enflurane and isoflurane of the pharmacokinetics of pancuronium may be part of reason why two drugs extended the duration of neuromuscular depression produced by pancuronium.

[The pharmacokinetics of pancuronium bromide in infants, children and adults].

Twenty-four patients scheduled for elective plastic surgery were selected to study the pharmacokinetics of pancuronium bromide under enflurane anesthesia. The patients were divided into three groups by their ages; Group 1 consisted of 5 infants (0.75-2.95 years); Group 2 contained 13 children (4-14 years); Group 3 included 6 adults (16-27 years). An improved fluorimetric assay was used to measure the plasma concentrations of pancuronium bromide after administration of pancuronium bromide at a dose of 100 micrograms/kg. The results showed that the disposition of pancuronium bromide may be best described mathematically by a two-compartment open model in all patients. The younger the patients, the larger the distribution volumes and the higher the Cl. There were significant differences among the three groups with regard to V1, V2, Vdss, Cl, AUC. The T1/2 beta and MRT were longer in Group 1 than in Group 2 and Group 3.

Role of cholinesterase activity on pharmacodynamics of mivacurium preceded by pancuronium in elderly and young adults.

Mivacurium- pancuronium combination proved to be more potent than either drug given alone. The goal of this study was to evaluate the safety and efficacy of this combination in elderly group and its correlation to plasma butyryl cholinesterase (Bche) activity. Forty patients, ASA I or II scheduled for elective open cholecystectomy were allocated into two groups of twenty patients each: young group (18- 55 years) and elderly group (60-75 years). Anesthesia was induced with midazolam, fentanyl, and propofol then maintained with isoflurane and opioid supplementation. Neuromuscular blockade (NMB) was monitored by train-of-four (TOF) stimulation of the ulnar nerve. After calibration, NMB was achieved by 16 microg kg(-1) pancuronium followed by 32 microg kg(-1) mivacurium. The following parameters were recorded: The onset time, clinical duration, recovery index and the total dose of mivacurium and pancuronium together with hemodynamic data. Three blood samples for Bche activity were collected: before pancuronium injection, 3 min. and 30 min. afterwards in both groups. The onset time and the recovery index of NMB were comparable in both groups. The duration of action was significantly prolonged in elderly group (49.8 +/- 10.48 min.) compared to young one (37.13 +/- 7.81 min.). The total dose of mivacurium was significantly less in the elderly group (22.56 +/- 2.39 microg kg(-1) hr(-1)) when compared to the young group (25.78 +/- 3.05 microg kg(-1) hr(-1)). For all patients, the preoperative Bche activity was within the normal range. After pancuronium injecttion, it showed a significant reduction in both groups at three and thirty minutes except a non significant value in young at thirty minutes. This reduction showed a significantly higher percent change in the elderly group (30.37 +/- 22.01) than the young group (8.60 +/- 19.19) at thirty minutes. There were significant intra operative variations in the percent changes of hemodynamic data compared to the preoperative values, yet, still within the clinically acceptable range. So, the use of a small dose of pancuronium followed by a small dose of mivacurium with a ratio of 1:2 can produce synergism without affecting either the recovery profile of mivacurium or the clinical hemodynamic stability even in the elderly group.

Modeling of twitch fade based on slow interaction of nondepolarizing muscle relaxants with the presynaptic receptors.

Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.

Interaction between mivacurium and pancuronium: impact of the order of administration.

INTRODUCTION: Potentiation of mivacurium by low-dose pancuronium is mostly due to an inhibition of plasma butyryl cholinesterase (BchE) resulting in a decreased rate of hydrolysis of mivacurium. Nevertheless, an interaction at the receptor site could not be ruled out. By changing the order of the muscle relaxant injections, we may lessen the pharmacokinetic interaction and assess the impact at the acetylcholine receptor level. METHODS: Twenty patients scheduled for general anesthesia with propofol and fentanyl, and isoflurane were randomized into two groups receiving, mivacurium 100 microg kg-1 followed by pancuronium 15 microg kg-1 (group 1) or pancuronium 15 microg kg-1 followed by mivacurium 100 microg kg-1 (group 2). BchE before and after injection of each relaxant was measured. Neuromuscular block was assessed with a force transducer at the adductor pollicis measuring the elicited twitch to ulnar nerve stimulation. RESULTS: The neuromuscular block was greater when pancuronium was administered before mivacurium (100% versus 96+/-3%; P<0.05). Times to recovery of the elicited twitch response to 25% and 75% of control value were increased by 100% (P<0.05). After pancuronium, decreases in BchE of 11% and 14% in groups 1 and 2 were observed, respectively. CONCLUSION: Interaction between mivacurium and low dose pancuronium is significant only when mivacurium is injected after pancuronium.

Decreased number of acetylcholine receptors is the mechanism that alters the time course of muscle relaxants in myasthenia gravis: a study in a rat model.

BACKGROUND: In myasthenic patients, the time course of action of non-depolarizing neuromuscular blocking agents is prolonged and the sensitivity is increased. We used our antegrade perfused rat peroneal nerve anterior tibialis muscle model to investigate if this altered time course of effect and sensitivity can be explained by the decreased acetylcholine receptor concentration that is caused by the disease. METHODS: Functional acetylcholine receptors were reduced by administration of alpha-bungarotoxin or by injecting monoclonal antibodies against rat acetylcholine receptors (experimental autoimmune myasthenia gravis). After induction of anaesthesia, the model was set up and perfusion of the tibialis anterior muscle with blood was started. After stabilization of the twitch, rocuronium or pancuronium were infused until 90% block was obtained. Twitch data and infusion data were recorded and used to calculate the time course of effect and potency. RESULTS: The potency of neuromuscular blocking agents was increased and the offset of the neuromuscular block was prolonged in both the alpha-bungarotoxin groups and the experimental autoimmune myasthenia gravis groups compared to controls. CONCLUSION: This study shows that the increased sensitivity to neuromuscular-blocking agents in myasthenia gravis can be accounted for by a decreased number of acetylcholine receptors. It also shows that the antegrade perfused rat peroneal nerve anterior tibialis muscle model is a suitable model to study the effects of myasthenia gravis on the time course of effect of neuromuscular blocking agents.

Porcine model for studying the passage of non-depolarizing neuromuscular blockers through the blood-brain barrier.

A method has been developed for blood-brain barrier disruption to provide reproducible access to the cerebrospinal fluid of the cerebello-medullary cistern. The technique was used successfully to investigate transfer of pancuronium to the cerebral CSF compartment in pigs. After osmotic disruption of the blood-brain barrier, pancuronium concentrations increased significantly in the cerebrospinal fluid.

Pipecuronium and pancuronium: comparison of pharmacokinetics and duration of action.

The pharmacokinetics of pipecuronium 0.07 mg kg-1 and pancuronium 0.1 mg kg-1 were compared in 39 ASA class I or II patients. Plasma concentrations of these agents were measured for 6 h following administration, using a sensitive and specific capillary gas chromatographic assay. Concentration v. time data were analysed by non-linear regression and fitted to a two- or three-compartment model as appropriate. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. Pipecuronium had a larger steady-state volume of distribution (Vss) (309 (SD 103) ml kg-1) and greater plasma clearance (Cl) (2.4 (0.6) ml kg-1 min-1) than pancuronium (199 (54) ml kg-1 and 1.5 (0.4) ml kg-1 min-1, respectively). The volumes of the central compartment, distribution and elimination half-lives and mean residence times were similar for both agents and within the range expected for drugs of this type. The durations of action (injection to 25% recovery of twitch tension) of pipecuronium and pancuronium were similar: 98.0 (36.1) min and 117.2 (35.8) min, respectively. We conclude that the time courses of neuromuscular blockade following pipecuronium and pancuronium are similar, despite the differences in Vss and Cl.

Pharmacokinetics of cisatracurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia.

BACKGROUND: Cisatracurium, one of the ten isomers in atracurium, is a nondepolarizing muscle relaxant with an intermediate duration of action. It is more potent and less likely to release histamine than atracurium. As one of the isomers composing atracurium, it presumably undergoes Hofmann elimination. This study was conducted to describe the pharmacokinetics of cisatracurium and its metabolites and to determine the dose proportionality of cisatracurium after administration of 2 or 4 times the ED(95). METHODS: Twenty ASA physical status 1 or 2 patients undergoing elective surgery under nitrous oxide/opioid/barbiturate anesthesia were studied. Patients received a single rapid intravenous bolus does of 0.1 or 0.2 mg x kg-1 (2 or 4 times the ED(95), respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio > or = 0.70 after cisatracurium-induced neuromuscular block. Plasma was extracted, acidified, and stored frozen before analysis for cisatracurium, laudanosine, the monoquaternary acid, and the monoquaternary alcohol metabolite. RESULTS: The clearances (5.28 +/- 1.23 vs. 4.66 +/- 0.67 ml x min(-1) x kg(-1) and terminal elimination half-lives (22.4 +/- 2.7 vs. 25.5 +/- 4.1 min) were not statistically different between patients receiving 0.1 mg x kg(-1) and 0.2 mg x kg(-1), respectively. Maximum concentration values for laudanosine averaged 38 +/- 21 and 103 +/- 34 ng x ml(-1) for patients receiving the 0.1 and 0.2 mg x kg(-1) doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101 +/- 27 and 253 +/- 51 ng x ml(-1), respectively. Monoquaternary acid was not quantified in any plasma sample. CONCLUSIONS: Cisatracurium undergoes Hofmann elimination to form laudanosine. The pharmacokinetics of cisatracurium are independent of dose after single intravenous doses of 0.1 and 0.2 mg x kg(-1).

A model for determining the influence of hepatic uptake of nondepolarizing muscle relaxants in the pig.

Hepatic uptake and distribution of nondepolarizing muscle relaxants in pigs was investigated. A portocaval shunt preparation enabled the determination of the pharmacodynamics of nondepolarizing muscle relaxants both during temporary liver exclusion and intraportal injection in the same animal. To demonstrate the validity of the model in pigs, in a pilot study the influence of hepatic uptake on neuromuscular blockade by pancuronium (n = 3) and its congener Org 6368 (n = 3) was determined. Thereafter, the influence of hepatic uptake on neuromuscular blockade by gallamine (3.4 mg/kg, n = 5), Org 6368 (0.3 mg/kg, n = 5), and vecuronium (0.1 mg/kg, n = 4 and 0.15 mg/kg, n = 5) was studied in pigs anesthetized with pentobarbital. Each pig received one relaxant, which was injected four consecutive times under different conditions. The first injection was into the jugular vein (iv) the second into the portal vein, the third was iv while the liver was excluded for 10 min and the fourth was iv (control). After each injection the onset time, intensity, recovery rate, and total duration of neuromuscular blockade were measured. These variables were compared between the four injections for each relaxant. In the pilot study the influence of hepatic uptake on neuromuscular blockade was similar for pancuronium and Org 6368. For gallamine the onset time, intensity, recovery rate, and duration of action were similar after all four injections. For Org 6368 the variables of neuromuscular blockade were similar after iv and intraportal injection, but exclusion of the liver prolonged the neuromuscular block.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative potency of pipecuronium bromide and pancuronium bromide.

Cumulative dose-response curves were constructed to determine the comparative potency of pipecuronium and pancuronium. From these, the ED50 and ED95 values were calculated. These were 24.96 micrograms kg-1 and 44.96 micrograms kg-1, respectively, for pipecuronium and 30.42 micrograms kg-1 and 61.12 micrograms kg-1, respectively, for pancuronium.

Calculation of an effect compartment rate constant using recovery indices obtained with an isolated arm technique.

We have examined the implications of the theoretical single pharmacokinetic compartment associated with blocker-induced paralysis, in relation to the isolated arm technique. It is assumed that the blocker concentration-effect relationship can be characterized by a sigmoid curve, which incorporates an exponent, s. After tourniquet release, the concentration gradient between the effect compartment and plasma should be large, and elimination related to the rate constant, keo. The major measurement of spontaneous recovery with the isolated arm is the time interval between 75% and 25% twitch depression, T25-T75. The general equation relating these three variables is developed: keo = 2.2/(s x (T25-T75)). Insertion of published values for T25-T75 with isolated arm studies into this equation gave estimates for an intrinsic keo for atracurium, vecuronium, rocuronium and pancuronium.

Pharmacokinetics of 51W89: preliminary data.

The pharmacokinetics of the 1R cis-1'R cis-isomer of atracurium (51W89) and its metabolite, laudanosine, were studied in 11 healthy patients with normal renal function and in 12 patients with chronic renal failure undergoing regular dialysis. A bolus dose of 51W89 (0.1 mg/kg) was given, and the plasma concentration was measured at regular intervals for 480 min. The elimination half-life of 51W89 was significantly longer in renal failure patients than in healthy controls (38.9 min vs 30.6 min; P < 0.05). The plasma laudanosine levels were lower than those reported after an equipotent dose of atracurium besylate. 51W89 may have a prolonged effect in renal failure patients.

Atracurium, cisatracurium, vecuronium and rocuronium in patients with renal failure.

AIM: The cumulative index, the recovery, the onset and the duration of action, of atracurium, cisatracurium, vecuronium and rocuronium in uremic patients undergoing kidney transplantation compared to healthy patients undergoing general surgery were studied. METHODS: In all patients (64 uremic vs 62 "healthy" patients) after anesthesia induction, atracurium 0.5 mgxkg(-1) or cisatracurium 0.15 mgxkg(-1) or vecuronium 0.1 mgxkg(-1) or rocuronium 0.6 mgxkg(-1) were administered, and at the end of surgery when T1 reached 25% neostigmine 0.05 mgxkg(-1) was given. Neuro-muscu-lar transmission was monitored by accelerometry (TOF-GUARD, Organon). RESULTS: Cumulative index of vecuronium (1.3+/-0.1 vs 1.06+/-0.11, p<0.001) and rocuronium (1.45+/-0.18 vs 1.04+/-0.16, p<0.001), recovery index (time of T1 25-75) of atracurium (14.2+/-5 vs 9+/-4, p<0.005), cisatracurium (18.7+/-3 vs 9.1, p<0.001), vecuronium (18.5+/-3 vs 12.5+/-3, p<0.001) and rocuronium (18+/-6 vs 11+/-4, p<0.001) and interval T1 25% to TOF 0.8 of cisatracurium (20.5+/-1.2 vs 16+/-2.1, p<0.001) and vecuronium (27+/-6.3 vs 20+/-3.3, p<0.001) were longer in uremic patients. The onset time and the duration of action of atracurium, cisatracurium, vecuronium and rocuronium were similar in all groups compared to controls one. CONCLUSION: In patients with renal failure the use of atracurium, cisatracurium, vecuronium and rocuronium is suitable and predictable in terms of onset, and duration of action. Care has to be taken to vecuronium and rocuronium cumulative index. Neuromuscular trasmission has to be always monitored.

Potentiation of mivacurium blockade by low dose of pancuronium: a pharmacokinetic study.

BACKGROUND: Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. METHODS: After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. RESULTS: Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P < 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P < 0.05). CONCLUSIONS: A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.

Clinical pharmacology of the neuromuscular blocking agents.

Neuromuscular blocking agents are among the most commonly used drugs during general anesthesia. They compete with acetylcholine and interfere with the transmission of nerve impulses resulting in skeletal muscle relaxation. Based on their mechanism of action, neuromuscular blocking agents are classified as either depolarizing or nondepolarizing. Succinylcholine is a short-acting depolarizing agent. Commonly used nondepolarizing agents are curare (long-acting), pancuronium (long-acting), atracurium (intermediate-acting), and vecuronium (intermediate-acting). Neuromuscular blocking agents are used clinically to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery. This article provides an overview of the physiology of the neuromuscular transmission and summarizes our current knowledge on the use of these agents during general anesthesia.