Factors Affecting the Pharmacokinetic Characteristics of Rapacuronium

Background: Rapacuronium is a new nondepolarizing muscle relaxant with rapid onset and offset. As part of a study to determine its neuromuscular effects, the authors sampled plasma sparsely to determine the influence of age, gender, and other covariates on its pharmacokinetic characteristics.

Methods: Of 181 patients receiving a single bolus dose of 0.5-2.5 mg/kg rapacuronium, 43 (aged 24-83 yr) had plasma sampled 3 or 4 times to determine plasma concentrations of rapacuronium and its metabolite, ORG9488. Pharmacokinetic analysis was performed using a population approach (mixed-effects modeling) to determine the influence of demographic characteristics and preoperative laboratory values on the pharmacokinetic parameters.

Results: Rapacuronium's weight-normalized plasma clearance was 7.03 [middle dot] (1 - 0.0507 [middle dot] (HgB - 13)) ml [middle dot] kg-1 [middle dot] min-1, where HgB is the patient's preoperative value for hemoglobin (g/100 ml); however, rapacuronium's blood clearance (11.4 +/- 1.4 ml [middle dot] kg-1 [middle dot] min-1, mean +/- SD) did not vary with hemoglobin. Rapacuronium's weight-normalized pharmacokinetic parameters were not influenced by age, gender, or other covariates examined. Plasma concentrations of ORG9488 were typically less than 14% those of rapacuronium during the initial 30 min after rapacuronium administration.     

Effect of renal failure and cirrhosis on the pharmacokinetics and neuromuscular effects of rapacuronium administered by bolus followed by infusion

BACKGROUND: Recent trials indicate that rapacuronium's pharmacokinetic characteristics are influenced by both renal failure and cirrhosis but the time course of a single bolus dose of 1.5 mg/kg is affected minimally. The authors reassessed these pharmacokinetic findings and examined the time course of the same bolus dose followed by a 30-min infusion. METHODS: During nitrous oxide-isoflurane anesthesia, patients with normal renal and hepatic function (n = 25), those with renal failure (n = 28), and those with cirrhosis (n = 6) received a bolus dose of rapacuronium (1.5 mg/kg) followed by a 30-min infusion adjusted to maintain 90-95% twitch depression. At 25% recovery, neostigmine was administered. Blood was sampled until 8 h after the infusion to determine concentrations of rapacuronium and its active metabolite ORG9488. Rapacuronium's pharmacokinetic parameters were determined using mixed-effects modeling. RESULTS: Onset and facilitated recovery of twitch depression were similar in the three groups. Patients with renal failure required 22% less rapacuronium to maintain target twitch depression during the infusion. Rapacuronium's plasma clearance was 24% smaller in renal failure and decreased 0.5%/yr of age; rapid distribution clearance was 51% smaller in men than in women. After the infusion, ORG9488 concentrations decreased markedly more slowly in patients with renal failure. Cirrhosis did not alter the pharmacokinetics of rapacuronium. CONCLUSION: Rapacuronium's plasma clearance and infusion requirement were decreased by renal failure. By dosing to maintain target twitch depression, recovery was not prolonged. Cirrhosis does not affect the pharmacokinetics or neuromuscular effects of rapacuronium. Persistence of ORG9488 in patients with renal failure might prolong recovery after rapacuronium if target twitch depression is not maintained or with administration of rapacuronium for more than 30 min.     

Neuromuscular blocking effects, pharmacokinetics and safety of Org 9426 (rocuronium bromide) in Japanese patients

BACKGROUND: The purpose of this study was to examine pharmacodynamics, pharmacokinetics and safety of Org 9426 (rocuronium bromide) in Japanese patients. METHODS: Seventy-eight patients anesthetized with thiopental, droperidol, fentanyl and nitrous oxide, were randomized to receive either a single dose of Org 9426 0.3 mg x kg(-1), 0.6 mg x kg(-1) or 0.9 mg x kg(-1). Contraction of the adductor pollicis to the ulnar nerve stimulation (0.1 Hz) was measured by acceleromyography. Blood was sampled over 6 hr and pharmacokinetic variables were calculated by plasma concentrations of Org 9426. RESULTS: Onset times for patients receiving 0.3 mg x kg(-1), 0.6 mg x kg(-1) or 0.9 mg x kg(-1) were 271.5 s, 140.0s and 125.4s, respectively. There was a dose-dependent increase in clinical durations until 25% recovery of twitch height (17.4 min in 0.3 mg x kg(-1) group, 37.2 min in 0.6 mg x kg(-1) and 60.4 min in 0.9 mg x kg(-1) group). Pharmacokinetic study revealed that elimination half life, steady state volume of distribution and plasma clearance of Org 9426 were 48-76 min, 146-181 ml x kg(-1), and 3.8-4.5 ml x min(-1) x kg(-1), respectively. No adverse effects were found except a case of local erythema on a forearm. CONCLUSIONS: The efficacy of neuromuscular block, stable pharmacokinetic behavior and excellent safety of Org 9426 were also confirmed in Japanese surgical patients.     

The potency (ED50) and cardiovascular effects of rapacuronium (Org 9487) during narcotic-nitrous oxide-propofol anesthesia in neonates, infants, and children.

We studied the neuromuscular blocking effects of rapacuronium (Org 9487) (dose-response curve, onset, and 50% effective dose [ED50] value), and changes in heart rate and blood pressure, as well as evidence of histamine release in neonates, infants, and children in an open-label, randomized, two-center study. Fifteen neonates, 30 infants, and 30 children were studied. Anesthesia was induced and maintained with propofol, nitrous oxide:oxygen (60:40), and fentanyl. Mechanomyographic monitoring of neuromuscular function was performed at the thumb. The potency (ED50) for neonates, infants, and children were 0.32 (95% confidence interval [CI] 0.15-0.61), 0.28 (95% CI 0.11-0.61), and 0.39 (95% CI 0.17-0.85) mg/kg, respectively. Neonates who received 0.3, 0.6, or 0.9 mg/kg Org 9487 developed a maximum T1 twitch depression of 34 +/-28%, 98 +/- 3%, and 99 +/- 2%, respectively. Time-to-peak effect (onset time) for 0.9 mg/kg Org 9487 was 57 +/- 20 s. Maximum percent T1 twitch depression (+/-SD) in infants who received 0.3, 0.6, or 0.9 mg/kg rapacuronium was 41 +/- 34%, 96 +/- 7%, and 100 +/- 1%, respectively. Time-to-peak effect for 0.9 mg/kg Org 9487 was 62 +/- 29 s. In children 0.3, 0.6, and 0.9 mg/kg rapacuronium resulted in an average percent T1 twitch suppression of 29 +/- 23, 83 +/- 11, and 90 +/- 16, respectively. Time-to-peak effect of 0.9 mg/kg Org 9487 was 96 +/- 33 s, respectively. There was no evidence of histamine release or significant changes in heart rate or blood pressure in either group at any dose. Rapacuronium is a low-potency nondepolarizing muscle relaxant with a fast onset of relaxation and minimal cardiovascular effects. Its potency (ED50) is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg). T1 suppression (90% +/- 16) is less and time to peak effect (96 +/- 33 s) is greater (0.9 mg/kg rapacuronium) in children, compared with the combined group of infants and neonates. IMPLICATIONS: This study assesses the potency of rapacuronium (Org 9487) in pediatric patients. The potency of rapacuronium is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg).     

Rapacuronium for modified rapid sequence induction in elective caesarean section: neuromuscular blocking effects and safety compared with succinylcholine, and placental transfer

We have compared rapacuronium 2.5 mg kg-1 (n = 20) with succinylcholine 1.5 mg kg-1 (n = 22) in a multicentre, blinded, randomized study in full-term parturients undergoing elective Caesarean section under general anaesthesia. Thiopental 5 mg kg-1 was given i.v. followed by the neuromuscular blocking agent. Sixty seconds later intubation was performed. Intubating conditions, evaluated as excellent, good or poor, were good to excellent in 95% and 91% in the intent-to-treat patients after rapacuronium and succinylcholine, respectively (ns). Mean onset times at the adductor pollicis muscle for rapacuronium and succinylcholine were 80.4 (SEM 14.4) s and 63.9 (5.6) s (ns) while maximum block was 96 (1.9)% and 99 (0.4)%, respectively (ns). Rate of recovery was significantly longer after rapacuronium; times for return of T1 to 25% were 16.9 (1.5) min and 9.6 (1.1) min for rapacuronium and succinylcholine, respectively (P = 0.0004). Maternal side effects included more tachycardia and skin erythema with rapacuronium; no maternal mortality or morbidity, including bronchospasm, occurred in either group. There were no neonatal adverse effects in either group based on: Apgar scores at 1 and 5 min; times to sustained respiration; neuroadaptive capacity scores at 15 min, 2 h and 24 h; and umbilical venous and arterial blood-gas values and acid-base status. At delivery (17.7 (3.2) min), mean maternal plasma concentrations of rapacuronium were 9041.4 (1259.1) ng ml-1 and 506.4 (24.9) ng ml-1 for Org 9488 (the main metabolite). Corresponding values for umbilical venous plasma were 808.0 (92.1) ng ml-1 and 59.1 (6.5) ng ml-1, and for umbilical arterial plasma, 361.4 (56.4) ng ml-1 and 29.7 (4.6) ng ml-1, respectively. Umbilical venous to maternal venous ratios for rapacuronium and Org 9488 were 8.8% (1.3)% and 10.2 (1.7)%, respectively.      

Effect of Renal Failure and Cirrhosis on the Pharmacokinetics and Neuromuscular Effects of Rapacuronium Administered by Bolus Followed by Infusion

Background: Recent trials indicate that rapacuronium's pharmacokinetic characteristics are influenced by both renal failure and cirrhosis but the time course of a single bolus dose of 1.5 mg/kg is affected minimally. The authors reassessed these pharmacokinetic findings and examined the time course of the same bolus dose followed by a 30-min infusion.

Methods: During nitrous oxide-isoflurane anesthesia, patients with normal renal and hepatic function (n = 25), those with renal failure (n = 28), and those with cirrhosis (n = 6) received a bolus dose of rapacuronium (1.5 mg/kg) followed by a 30-min infusion adjusted to maintain 90-95% twitch depression. At 25% recovery, neostigmine was administered. Blood was sampled until 8 h after the infusion to determine concentrations of rapacuronium and its active metabolite ORG9488. Rapacuronium's pharmacokinetic parameters were determined using mixed-effects modeling.

Results: Onset and facilitated recovery of twitch depression were similar in the three groups. Patients with renal failure required 22% less rapacuronium to maintain target twitch depression during the infusion. Rapacuronium's plasma clearance was 24% smaller in renal failure and decreased 0.5%/yr of age; rapid distribution clearance was 51% smaller in men than in women. After the infusion, ORG9488 concentrations decreased markedly more slowly in patients with renal failure. Cirrhosis did not alter the pharmacokinetics of rapacuronium.     

Pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis.

BACKGROUND: Delayed elimination kinetics of steroidal neuromuscular blocking agents have been observed in patients with cirrhosis. Like other steroidal muscle relaxants, rapacuronium may, in part, be eliminated by the liver. To determine the influence of liver disease on its neuromuscular blocking effect, we studied the pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis. METHODS: Sixteen patients undergoing elective surgery or endoscopy with general anesthesia, eight with cirrhosis and eight with normal liver function, were studied. Anesthesia was induced with fentanyl 2 microg/kg and thiopental 5-7 mg/kg and maintained with 60% nitrous oxide and 0.6-0.8% isoflurane in oxygen and repeated doses of fentanyl 1 microg/kg. Rapacuronium 1.5 mg/kg was administered intravenously before tracheal intubation. Thumb adduction force evoked by supramaximal ulnar nerve stimulation was recorded in 16 patients. Venous blood was sampled at frequent intervals for 8 h. Rapacuronium and its breakdown product Org 9488 were measured in plasma by high-pressure liquid chromatography. Values are reported as median (range). RESULTS: The central volume of distribution was increased to 131 (104-141) ml/kg in patients with cirrhosis (P < 0.01), compared with 75 (47-146) ml/kg in controls. The total apparent volume of distribution was also increased (P < 0.05) to 331 (284-488) ml/kg in patients with cirrhosis, compared with 221 (124-285) ml/kg in controls. The elimination half-life was 88 (77-102) min in controls and 90 (76-117) min in patients with cirrhosis. Plasma clearance was increased (P < 0.05) to 6.9 (6.1-8.9) ml x min(-1) x kg(-1) in patients with cirrhosis, compared with 5.3 (4.2-8.4) ml x min(-1) x kg(-1) in controls. Rapacuronium neuromuscular blocking effect was similar between the two groups. Onset time was 65 (40-110) s in controls and of 60 (52-240) s in patients with cirrhosis. Time to return to 90% of thumb adduction force control value was of 49 (28-80) min in controls and 47 (28-71) min in patients with cirrhosis. CONCLUSION: The neuromuscular blocking effect of a single bolus dose of rapacuronium in patients with cirrhosis is not different from that of patients with normal hepatic function. No decrease in plasma clearance of rapacuronium was observed in patients with cirrhosis.     

The potency of new muscle relaxants on recombinant muscle-type acetylcholine receptors

We studied the inhibition of fetal (gamma-nAChR) and adult (epsilon-nAChR) muscle-type nicotinic acetylcholine receptors by the two new nondepolarizing muscle relaxants (NDMRs) rocuronium and rapacuronium, the metabolite 3-desacetyl rapacuronium (Org 9488), and five other, longer-used NDMRs (pancuronium, vecuronium, mivacurium, d-tubocurarine, and gallamine). Receptors were expressed in Xenopus laevis oocytes by cytoplasmic injection of subunit complementary RNAs. Functional channels were activated with 10 microM acetylcholine, alone or in combination with various concentrations of the NDMRs. Currents were recorded with a whole-cell two-electrode voltage clamp technique. All NDMRs reversibly inhibited acetylcholine-activated currents in a dose-dependent fashion. Potencies of rapacuronium and Org 9488 were not statistically different at either gamma-nAChR (half-maximal response = 58.2 and 36.5 nM, respectively) or epsilon-nAChR (half-maximal response = 80.3 and 97.7 nM, respectively). The rank order of potencies at the epsilon-nAChR (pancuronium > vecuronium similar mivacurium > rocuronium similar d-tubocurarine > rapacuronium similar Org 9488 > gallamine) correlated highly with the clinical doses needed to produce 50% twitch depression at the adductor pollicis muscle in adults. Neuromuscular blockade by rapacuronium may be enhanced by its metabolite Org 9488. Different drug-receptor affinities of the tested NDMRs contribute to the differences in clinical dose requirements of these drugs needed to achieve appropriate muscle relaxation. IMPLICATIONS: Potencies of nondepolarizing muscle relaxants, studied at muscle nicotinic acetylcholine receptors expressed in a recombinant expression system, correlate highly with the clinical doses needed in adults to produce 50% twitch depression at the adductor pollicis muscle.     

Pharmacokinetics of rapacuronium in infants and children with intravenous and intramuscular administration

BACKGROUND: A nondepolarizing muscle relaxant with an onset and offset profile similar to succinylcholine is desirable for pediatric anesthesia. The onset and offset of rapacuronium are rapid in children. In the current study, the authors determined its pharmacokinetic characteristics in children. In addition to administering rapacuronium by the usual intravenous route, the authors also gave rapacuronium intramuscularly to determine uptake characteristics and bioavailability. METHODS: Forty unpremedicated patients aged 2 months to 3 yr were anesthetized with halothane, 0.82-1.0% end-tidal concentration. When anesthetic conditions were stable, rapacuronium was injected either into a peripheral vein (2 mg/kg for infants, 3 mg/kg for children) or a deltoid muscle (2.8 mg/kg for infants, 4.8 mg/kg for children). Four venous plasma samples were obtained from each subject 2-240 min after rapacuronium administration. A mixed-effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak plasma concentration with intramuscular administration. RESULTS: Plasma clearance was 4.77 ml x kg(-1) x min(-1) + 8.48 ml/min. Intramuscular bioavailability averaged 56%. Absorption from the intramuscular depot had two rate constants: 0.0491 min(-1) (72.4% of absorbed drug) and 0.0110 min(-1) (27.6% of the absorbed drug). Simulation indicated that plasma concentration peaks 4.0 and 5.0 min after intramuscular rapacuronium in infants and children, respectively, and that, at 30 min, less than 25% of the administered dose remains to be absorbed from the intramuscular depot. CONCLUSIONS: In infants and children, rapacuronium's clearance and steady state distribution volume are less than in adults. After intramuscular administration, bioavailability is 56%, and plasma rapacuronium concentrations peak within 4 or 5 min.     

Influence of Renal Failure on the Pharmacokinetics and Neuromuscular Effects of a Single Dose of Rapacuronium Bromide

Background: Because renal function affects the elimination of muscle relaxants, each new muscle relaxant must be evaluated in patients with renal failure. Accordingly, the neuromuscular effects and pharmacokinetics of rapacuronium were identified in patients with renal failure.

Methods: Rapacuronium (1.5 mg/kg) was administered to 10 healthy volunteers and 10 patients with renal failure who were undergoing non-transplant surgery, were 18-45 yr old, and were anesthetized with propofol. The adductor pollicis muscle twitch tension was monitored. Plasma samples were obtained frequently for a period of 8 h to measure the concentrations of ORG9487 and its metabolite, ORG9488. Pharmacokinetic parameters were determined using mixed-effects modeling.

Results: One patient was excluded from analysis because he was taking phenytoin chronically. Twitch depression at 1 min was less in patients than in healthy volunteers (median values: 92% in patients, 99% in volunteers). The times to 90% and peak twitch depression; to 10%, 25%, and 75% twitch recovery; and to 70% and 80% train-of-four ratios were similar in volunteers and patients. Rapacuronium's clearance was 32% less in patients with renal failure; in both groups, clearance decreased 0.909% per year of age compared with the value in a 30 yr old. The steady state distribution volume was 14% less in women than in men and 16% less in patients than in volunteers. For ORG9488, clearance was 85% less in patients than in volunteers.     

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.     

Neuromuscular blocking effects of Org 9426 (rocuronium bromide); a comparative study with vecuronium bromide in Japanese patients

BACKGROUND: Efficacy and safety of Org 9426 were compared with those of vecuronium bromide in Japanese patients. METHODS: We studied 88 Japanese patients undergoing surgery requiring general anesthesia. Patients were allocated randomly to receive intubation dose of 0.6 mg x kg(-1), 0.9 mg x kg(-1) of Org 9426 or 0.1mg x kg(-1) of vecuronium. Following an intubation dose, patients received maintenance doses of 0.1, 0.15 or 0.2 mg x kg(-1) of Org 9426 or 0.025 mg x kg(-1) of vecuronium. The neuromuscular block was monitored with acceleromyography using TOF stimuli. Sevoflurane was administered to all treatment groups after intubation. RESULTS: The onset times of the 0.6 and 0.9 mg x kg(-1) of Org 9426 groups were 84.6 and 77.1 sec respectively, which showed statistical difference between the onset time of 0.1 mg x kg(-1) of vecuronium, 125.7 sec. The intubation condition was similar among three treatment groups. The clinical durations of 0.6 and 0.9 mg x kg(-1) of Org 9426 and 0.1 mg x kg(-1) of vecuronium were 53.4, 73.4 and 59.9 min, respectively. Clinical duration and spontaneous recovery time of maintenance dose of 0.15 mg x kg(-1) of Org 9426 were similar to those of 0.025 mg x kg(-1) of vecuronium. CONCLUSIONS: Org 9426 showed more rapid onset time than that of vecuronium and similar clinical duration and recovery times to those of vecuronium in Japanese patients.     

Pharmacodynamics and pharmacokinetics of an infusion of Org 9487, a new short-acting steroidal neuromuscular blocking agent

We have evaluated in 10 anaesthetized patients the time courseof action, infusion requirements, reversibility and pharmacokineticsof Org 9487. Org 9487 was administered as a bolus dose of 1.5mg kg^–1 followed by an infusion to maintain a block of75–85% for 60 min. After recovery from the bolus dose,a mean dose of Org 9487 3.4 (SD 1.0) mg kg^–1 h^–1was administered to maintain a mean neuromuscular block of 83(3)%. During the final 15 min of infusion, the infusion requirementswere 2.5 (1.1) mg kg^–1 h^–1 In the five patientswho were allowed to recover spontaneously, a TOF ratio of 0.7was reached 37.9 (12.4) min after stopping the infusion of Org9487. In the five patients who received neostigmine, a TOF ratioof 0.7 was reached after 14.5 (6.1) min. Plasma clearance was8.5 (30%) ml kg^–1 min^–1. Volume of distributionat steady state was 293 (55%) ml kg^–1 Terminal half lifeand mean residence time were 71.7 (34%) and 33.4 (31%) min,respectively. The concentration of the 3-OH metabolite remainedrelatively low. Urinary excretion of Org 9487 and its metaboliteswas 22% in 24 h. In conclusion, a 1-h infusion of the short-actingdrug Org 9487 changed its time course characteristics graduallyfrom that of a short-acting neuromuscular blocking agent tothat of a neuromuscular blocker with an intermediate durationof action.     

Comparison of intubating conditions after rapacuronium (Org 9487) and succinylcholine following rapid sequence induction in adult patients

We have assessed intubating conditions provided by rapacuronium (Org 9487) and succinylcholine after rapid sequence induction of anaesthesia in adult patients undergoing elective surgery. We studied 335 patients, ASA I and II, in five centres. Two hundred and thirty-four subjects with normal body weight and 101 obese subjects were allocated randomly to one of four treatment groups differing in the neuromuscular blocking drug administered (rapacuronium 1.5 mg kg-1 or succinylcholine 1 mg kg- 1) and in the technique used for induction of anaesthesia (fentanyl 2-3 micrograms kg-1 with thiopental 3-6 mg kg-1 or alfentanil 20 micrograms kg-1 with propofol 1.5-2 mg kg-1). Intubation was started at 50 s by an anaesthetist blinded to the drugs used. Intubating conditions were clinically acceptable (excellent or good) in 89.4% of patients after rapacuronium and in 97.4% after succinylcholine (P = 0.004), the estimated difference being 8.1% (95% confidence interval (CI) 2.0- 14.1%). Neither anaesthetic technique nor subject group had an influence on intubating conditions. After intubation, the maximum increase in heart rate averaged 23.1 (SD 25.4%) and 9.4 (26.1%) after rapacuronium and succinylcholine, respectively (P < 0.001). Pulmonary side effects (bronchospasm and increased airway pressure) were observed in 10.7% (95% CI 5.8-17%) and 4.1% (95% CI 1.3-8.8%) of patients given rapacuronium and succinylcholine, respectively (P = 0.021). We conclude that after rapid sequence induction of anaesthesia in adults, clinically acceptable intubating conditions were achieved less frequently after rapacuronium 1.5 mg kg-1 than after succinylcholine.      

Effects of sevoflurane and propofol on neuromuscular blocking action of Org 9426 (rocuronium bromide) infused continuously in Japanese patients

BACKGROUND: The purpose of this study was to investigate the interaction of anesthetic agents with Org 9426 (rocuronium bromide) infused continuously. The effect of intubation dose of Org 9426 on its infusion rate was also investigated. METHODS: Total of 38 Japanese patients were randomly allocated either to receive intubation dose of 0.6 or 0.9 mg x kg(-1) of Org 9426. These patient groups were anesthetized with either sevoflurane or propofol. Infusion of Org 9426 was started with the initial infusion rate of 7 microg x kg(-1) x min(-1) when T1 reappeared after the intubation dose. The infusion rate was adjusted to keep the height of T1 between 3-10% of the control value. RESULTS: The rates of infusion 90 min after the start of infusion were 3.4, 7.5, 3.9 and 7.7 microg x kg(-1) x min(-1) for the 0.6 mg x kg(-1)-sevoflurane, 0.6 mg x kg(-1) propofol, 0.9 mg x kg(-1)-sevoflurane and 0.9 mg x kg(-1) propofol groups, respectively. Sevoflurane significantly reduced the infusion rate with both intubation doses. The mean infusion rates of 0.9 mg x kg(-1) groups were slower than those of 0.6 mg x kg(-1) groups up to 60 min after the start of infusion. Mean clearance of Org 9426 during infusion was not different between sevoflurane and propofol anesthesia. CONCLUSIONS: Patients receiving sevoflurane anesthesia required a markedly lower Org9426 infusion rate compared with patients receiving propofol anesthesia.     

Antagonism of rapacuronium using edrophonium or neostigmine: pharmacodynamics and pharmacokinetics

We have studied the pharmacodynamics and pharmacokinetics of rapacuronium (Org 9487) in 70 healthy patients. Neuromuscular transmission was monitored using TOF stimulation of the ulnar nerve and mechanomyography of the adductor pollicis muscle. Half of the patients were given a single dose of rapacuronium 1.5 mg kg-1 and the remainder rapacuronium 1.5 mg kg-1 with three incremental doses of 0.5 mg kg-1, each given when T1/T0 had recovered to 25%. In all patients, neuromuscular block was antagonized using neostigmine 0.05 mg kg-1 or edrophonium 1.0 mg kg-1 (allocated randomly), 2 min after the final dose of rapacuronium. All patients developed complete block after rapacuronium 1.5 mg kg-1. Mean onset time was 66 (SD 24) s. In patients who received an antagonist 2 min after the first dose of rapacuronium, time to recovery of T1/T0 to 25% was similar after neostigmine (9.8 (3.8) min) and edrophonium (10.3 (4.3) min): in patients who received incremental doses of rapacuronium, spontaneous recovery of T1/T0 to 25% after the first dose was 18.9 (4.7) min. In those who received an antagonist 2 min after the first dose of rapacuronium, times to recovery of T4/T1 to 0.7 were also similar after neostigmine (23.7 (7.7) min) and edrophonium (29.1 (10.7) min). After three incremental doses of rapacuronium, there was a longer time to recovery of T1/T0 = 25% after neostigmine compared with edrophonium (5.1 (1.0) vs 3.3 (1.3) min; P < 0.05) but more rapid recovery to T1/T0 = 75% (10.1 (2.9) vs 16.8 (10.1) min; P < 0.05) and T4/T1 = 0.7 (19.8 (6.3) vs 35.1 (10.4) min; P < 0.05). A three-compartment pharmacokinetic model was justified. Typical values for clearance and initial volume of distribution (V1) were 4.4 ml kg-1 min-1 and 94.8 ml kg-1, respectively. In females, clearance was decreased by 38.5% compared with males and V1 was decreased by 25% in patients aged more than 65 yr.      

Pharmacokinetics, neuromuscular effects, and biodisposition of 3-desacetylvecuronium (Org 7268) in cats.

The pharmacokinetics, biodisposition, and neuromuscular blocking properties of 3-desacetylvecuronium were studied in 17 adult cats. Animals were divided into three groups: five cats with kidney failure induced by bilateral ligation of the renal pedicles, six cats with galactosamine-induced fulminant hepatitis, and six control cats. An intravenous bolus of 300 micrograms.kg-1 of 3-desacetylvecuronium was rapidly injected into the jugular vein. Arterial blood, urine, and bile samples were collected at regular intervals for 6 h in control cats and for 8 h in cats with kidney or liver failure. The liver was excised for analysis at the end of the experiment. In cats with renal failure, 3-desacetylvecuronium pharmacokinetic and pharmacodynamic variables did not differ from those in control cats. In cats with liver failure, plasma clearance was significantly less and mean residence time greater than in control cats (2.8 +/- 0.6 vs. 14.1 +/- 6.5 ml.kg-1.min-1 and 334 +/- 225 vs. 49 +/- 29 min, mean +/- SD, respectively). Volume of distribution at steady state in cats with liver failure and in control cats was not different. Also, in cats with liver failure, the duration of action and recovery index of 3-desacetylvecuronium was significantly greater than in control cats (168 +/- 62 vs. 82 +/- 32 min, and 39 +/- 19 vs. 10 +/- 4 min, respectively). Onset time of neuromuscular blockade was similar in all three groups. Total recovery of 3-desacetylvecuronium, for all three groups, in urine, bile, and liver was 90 +/- 11% (mean +/- SD). In control cats, 70 +/- 18% of 3-desacetylvecuronium was recovered in bile and liver and 19 +/- 14% in urine. No 3,17-bidesacetylvecuronium (a putative 3-desacetylvecuronium metabolite) was detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of Rapacuronium in Infants and Children with Intravenous and Intramuscular Administration

Background: A nondepolarizing muscle relaxant with an onset and offset profile similar to succinylcholine is desirable for pediatric anesthesia. The onset and offset of rapacuronium are rapid in children. In the current study, the authors determined its pharmacokinetic characteristics in children. In addition to administering rapacuronium by the usual intravenous route, the authors also gave rapacuronium intramuscularly to determine uptake characteristics and bioavailability.

Methods: Forty unpremedicated patients aged 2 months to 3 yr were anesthetized with halothane, 0.82-1.0% end-tidal concentration. When anesthetic conditions were stable, rapacuronium was injected either into a peripheral vein (2 mg/kg for infants, 3 mg/kg for children) or a deltoid muscle (2.8 mg/kg for infants, 4.8 mg/kg for children). Four venous plasma samples were obtained from each subject 2-240 min after rapacuronium administration. A mixed-effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak plasma concentration with intramuscular administration.

Results: Plasma clearance was 4.77 ml [middle dot] kg-1 [middle dot] min-1 + 8.48 ml/min. Intramuscular bioavailability averaged 56%. Absorption from the intramuscular depot had two rate constants: 0.0491 min-1 (72.4% of absorbed drug) and 0.0110 min-1 (27.6% of the absorbed drug). Simulation indicated that plasma concentration peaks 4.0 and 5.0 min after intramuscular rapacuronium in infants and children, respectively, and that, at 30 min, less than 25% of the administered dose remains to be absorbed from the intramuscular depot.     

Pharmacokinetics and Pharmacodynamics of Rapacuronium in Patients with Cirrhosis

Background: Delayed elimination kinetics of steroidal neuromuscular blocking agents have been observed in patients with cirrhosis. Like other steroidal muscle relaxants, rapacuronium may, in part, be eliminated by the liver. To determine the influence of liver disease on its neuromuscular blocking effect, we studied the pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis.

Methods: Sixteen patients undergoing elective surgery or endoscopy with general anesthesia, eight with cirrhosis and eight with normal liver function, were studied. Anesthesia was induced with fentanyl 2 [mu]g/kg and thiopental 5-7 mg/kg and maintained with 60% nitrous oxide and 0.6-0.8% isoflurane in oxygen and repeated doses of fentanyl 1 [mu]g/kg. Rapacuronium 1.5 mg/kg was administered intravenously before tracheal intubation. Thumb adduction force evoked by supramaximal ulnar nerve stimulation was recorded in 16 patients. Venous blood was sampled at frequent intervals for 8 h. Rapacuronium and its breakdown product Org 9488 were measured in plasma by high-pressure liquid chromatography. Values are reported as median (range).

Results: The central volume of distribution was increased to 131 (104-141) ml/kg in patients with cirrhosis (P < 0.01), compared with 75 (47-146) ml/kg in controls. The total apparent volume of distribution was also increased (P < 0.05) to 331 (284-488) ml/kg in patients with cirrhosis, compared with 221 (124-285) ml/kg in controls. The elimination half-life was 88 (77-102) min in controls and 90 (76-117) min in patients with cirrhosis. Plasma clearance was increased (P < 0.05) to 6.9 (6.1-8.9) ml [middle dot] min-1 [middle dot] kg-1 in patients with cirrhosis, compared with 5.3 (4.2-8.4) ml [middle dot] min-1 [middle dot] kg-1 in controls. Rapacuronium neuromuscular blocking effect was similar between the two groups. Onset time was 65 (40-110) s in controls and of 60 (52-240) s in patients with cirrhosis. Time to return to 90% of thumb adduction force control value was of 49 (28-80) min in controls and 47 (28-71) min in patients with cirrhosis.     

Comparison of the Intubation Conditions Provided by Rapacuronium (ORG 9487) or Succinylcholine in Humans during Anesthesia with Fentanyl and Propofol

Background: Currently, the only approved muscle relaxant with a rapid onset and short duration of action is succinylcholine, a drug with some undesirable effects. Rapacuronium is an investigational nondepolarizing relaxant that also has a rapid onset and short duration and consequently should be compared with succinylcholine in its ability to facilitate rapid tracheal intubation.

Methods: This prospective, randomized clinical trial involved 336 patients. Anesthesia was induced with fentanyl and propofol and either 1.5 mg/kg rapacuronium or 1.0 mg/kg succinylcholine. The goal was to accomplish tracheal intubation by 60 s after administration of the neuromuscular blocking drug. Endotracheal intubation was performed, and conditions were graded by a blinded investigator. Recovery of neuromuscular function was assessed by electromyography.

Results: Intubation conditions were evaluated in 236 patients. Intubation by 60 s after drug administration occurred in 100% of patients with rapacuronium and in 98% with succinylcholine. Intubation conditions were excellent or good in 87% of patients with rapacuronium and in 95% with succinylcholine (P < 0.05). The time (median and range) to the first recovery of the train-of-four response was 8.0 (2.8-20.0) min with rapacuronium and 5.7 (1.8-17.7) min with succinylcholine (P < 0.05). The overall incidence of adverse effects was similar with both drugs.