Reversal of Deep Pipecuronium-Induced Neuromuscular Block With Moderate Versus Standard Dose of Sugammadex: A Randomized, Double-Blind, Noninferiority Trial.

BACKGROUND: Certain surgical interventions may require a deep neuromuscular block (NMB). Reversal of such a block before tracheal extubation is challenging. Because anticholinesterases are ineffective in deep block, sugammadex 4 mg/kg has been recommended for the reversal of rocuronium- or vecuronium-induced deep NMB. However, this recommendation requires opening 2 vials of 200 mg sugammadex, which results in an increase in drug costs. Therefore, we sought a less expensive solution for the induction and reversal of deep NMB. Although the optimal dose of sugammadex for antagonism of deep block from pipecuronium has not been established, data pertaining to moderate block are available. Accordingly, we hypothesized that sugammadex 2 mg/kg would be a proper dose to reverse deep pipecuronium block, enabling us to avoid cost increases. In the present study, we compared sugammadex 2 mg/kg with the standard dose of 4 mg/kg for reversal of deep block from pipecuronium. METHODS: This single-center, randomized, double-blind, 2 parallel-arms, noninferiority study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX). Noninferiority margin was specified beforehand as an increase in reversal time of no >10% (corresponding to 1 minute for the primary outcome). When the block spontaneously recovered to posttetanic count 1, the patients randomly received sugammadex 2 or 4 mg/kg, and the time from the injection to the train-of-four (TOF) ratio of 1.0 was measured. Primary outcome was the time to achieve the normalized TOF ratio of 0.9 in a particular patient. Residual or recurrent postoperative NMB was additional end point. RESULTS: Each patient recovered to the normalized TOF ratio of 0.9. In the 2 mg/kg group, reversal time was 1.73 ± 1.03 minutes (95% confidence interval [CI], 1.33-2.13; n = 25), and in the 4 mg/kg group, reversal time was 1.42 ± 0.63 minutes (mean ± standard deviation) (95% CI, 1.17-1.67; n = 25). The mean difference in reversal times between the 2 groups was 0.31 minutes (95% CI, -0.18 to 0.8), and the upper limit of CI was below the noninferiority margin of 1 minute. Postoperative block did not occur. CONCLUSIONS: The effect of sugammadex 2 mg/kg was noninferior to that of 4 mg/kg in reversing posttetanic count-1 degree pipecuronium block. Sugammadex reversal of deep pipecuronium block appears to be effective.

[CORRECTION OF INTRAABDOMINAL PRESSURE IN RATS IN AN ACUTE PANCREATITIS, USING INFUSION OF MYORELAXANT OF A DURABLE ACTION PIPECURONIUM BROMIDE].

Impact of a durable action of myorelaxant pipecuronium bromide on intraabdominal pressure (IAP) in rats in experimentally simulated acute peritonitis was studied. In the rats in purulent pancreatitis, іnduced by L-аrginin, IAP was in 4,5 times high (p < 0.001), than in intact laboratory animals. Pipecuronium bromide have lowered IAP by 33.4%, witnessing efficacy of application of myorelaxants in treatment of intraabdominal hypertension in purulent pancreatitis.

Reversal of Pipecuronium-Induced Moderate Neuromuscular Block with Sugammadex in the Presence of a Sevoflurane Anesthetic: A Randomized Trial.

BACKGROUND: Pipecuronium is a steroidal neuromuscular blocking agent. Sugammadex, a relaxant binding γ-cyclodextrin derivative, reverses the effect of rocuronium, vecuronium, and pancuronium. We investigated whether sugammadex reverses moderate pipecuronium-induced neuromuscular blockade (NMB) and the doses required to achieve reversal. METHODS: This single-center, randomized, double-blind, 5-group parallel-arm study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX) according to international standards. When the NMB recovered spontaneously to train-of-four count 2, patients randomly received 1.0, 2.0, 3.0, or 4.0 mg/kg of sugammadex or placebo. Recovery time from sugammadex injection to normalized train-of-four (TOF) ratio 0.9 was the primary outcome variable. The recovery time from the sugammadex injection to final T1 was the secondary end point. Postoperative neuromuscular functions were also assessed. RESULTS: Each patient who received sugammadex recovered to a normalized TOF ratio of 0.9 within 5.0 minutes (95% lower confidence interval for the lowest dose 70.1%; for all doses 90.8%) and 79% of these patients reached a normalized TOF ratio 0.9 within 2.0 minutes (95% lower confidence interval for the lowest dose 26.7%; for all doses 63.7%). T1 recovered several minutes after the TOF ratio. No residual postoperative NMB was observed. CONCLUSIONS: Sugammadex adequately and rapidly reverses pipecuronium-induced moderate NMB during sevoflurane anesthesia. Once the train-of-four count has spontaneously returned to 2 responses following pipecuronium administration, a dose of 2.0 mg/kg of sugammadex is sufficient to reverse the NMB.

[Residual neuromuscular blockade after muscle relaxants administration in neurosurgical patients].

The paper analyzes the incidence of residual neuromuscular blockade (NMB) after pipecuronium and rocuronium administration in 124 neurosurgical patients. We analyzed neuromuscular conductance with TOF-Watch SX Residual NMB incidence after neuromuscular blocking agents administration in neurosurgical patients is 87.7%. Use of pipecuronium accompanied by a greater incidence and duration of residual NMB in comparison with rocuronium. Sugammadex administration is effective method of residual NMB reversal and can restore NMC in 3-5 minutes.

Low-dose ketamine combined with pentobarbital in a miniature porcine model for a cardiopulmonary bypass procedure: a randomized controlled study.

BACKGROUND AND OBJECTIVE: Porcine anaesthesia remains a great problem for cardiac surgery research and especially with cardiopulmonary bypass procedures. This study was designed to develop a suitable anaesthesia model in which miniature pigs could be induced smoothly and be maintained stably during and after a cardiopulmonary bypass procedure. METHODS: Thirty-one miniature pigs were randomly divided into two groups and induced using ketamine and pentobarbital (K-P group, n = 15) or pentobarbital (P group, n = 16) alone, respectively. Animals in group K-P were induced with intramuscular injections of ketamine 5 mg kg and pentobarbital 20 mg kg body weight, and those in group P were induced with pentobarbital 30 mg kg alone. After intubation and intravenous catheterization, group K-P was maintained by continuous infusion of ketamine and pentobarbital, and pentobarbital was withdrawn after cardiopulmonary bypass started. Group P received a continuous infusion of pentobarbital throughout the operation. In addition, both groups were injected hourly with midazolam and pipecuronium bolus to achieve optimal surgical conditions. RESULTS: All of the group K-P animals survived for 24 h postoperatively. Five of the group P animals died from anaesthesia-related respiratory and cardiac arrest: three after induction and two after extubation. The animals in group K-P had more stable haemodynamics and arterial blood gas indices than animals in group P. Furthermore, the percentage of animals achieving satisfactory anaesthetic effects was significantly higher in group K-P than in group P. CONCLUSION: Combination anaesthesia with low-dose ketamine and pentobarbital demonstrated superior haemodynamic and respiratory indices in comparison with pentobarbital. The combination regimen can achieve both hypnosis and analgesia effects with stable circulatory parameters.

Determination of pipecuronium bromide and its impurities in pharmaceutical preparation by high-performance liquid chromatography with coulometric electrode array detection.

A sensitive and selective HPLC method with coulometric electrode array detection for the determination of pipecuronium bromide and its four impurities has been developed. The coulometric electrode array detection at increasing potentials from +300 to +900mV of the porous graphite electrode versus the palladium reference electrode was used. The limit of detection and quantitation for pipecuronium bromide was 8 and 25ngml(-1), respectively. This elaborate method for the simultaneous analysis of pipecuronium bromide and its impurities proved to be fast, precise, accurate, sensitive, and could be applied to analysis in substances and in pharmaceutical preparations.

Effect of magnesium sulphate on urinary catecholamine excretion in severe tetanus.

Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium (n = 92) or placebo (n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

Design and evaluation of artificial receptors for the reversal of neuromuscular block.

Applying patient friendly and cost-efficient medications in healthcare will be a real challenge in the 21st century. Sugammadex is a selective, yet expensive agent used for the post-surgical reversal of neuromuscular block since 2008. A wide library of cyclodextrin-based follow-ups, having potentially similar affinity towards target aminosteroid type neuromuscular blocking agents has been established. Almost 20 compounds were assessed with respect to in vitro affinity against three commonly applied drugs. Based on the capillary electrophoretic screening, carboxymethylated and sulfobutylated gamma-cyclodextrin derivatives have the potential to be promising lead molecules for their affinity towards pipecuronium was identical or even superior to Sugammadex. Carboxymethylated gamma-cyclodextrin showed efficient and complete reversal of the pipecuronium induced neuromuscular block in an ex vivo rat diaphragm experiment.

Development of bronchoconstriction after administration of muscle relaxants in rabbits with normal or hyperreactive airways.

Neuromuscular blocking drugs can induce intraoperative bronchospasm. We characterized the magnitude and the temporal profile of the constriction in normal or in hyperresponsive airways after injections of neuromuscular blocking drugs. Respiratory system impedance (Zrs) was measured continuously over a 90-s apneic period in naïve and rabbits sensitized to allergens by ovalbumin. Fifteen s after the start of Zrs recordings, succinylcholine, mivacurium, or pipecuronium was administered in random order. Zrs was then also recorded during the administration of increasing doses of exogenous histamine. To monitor the changes in the airway mechanics during these maneuvers, Zrs was averaged for 2-s time windows, and the airway resistance (Raw) was determined by model fitting. The increases in Raw were significantly larger in the sensitized rabbits than in the naïve animals. The largest increases in Raw and the maximum rate of change in Raw were obtained for succinylcholine (146% +/- 29% and 0.80 +/- 0.12 cm H2O/L, respectively) and mivacurium (80% +/- 25% and 0.71 +/- 0.13 cm H2O/L) and the smallest were obtained for pipecuronium (40% +/- 12% and 0.41 +/- 0.04 cm H2O/L). Allergic sensitization leads to severe and rapidly developing bronchospasm after administrations of mivacurium or succinylcholine. These deleterious side effects should be considered when succinylcholine or mivacurium is administered in the presence of bronchial hyperreactivity.

Clinical pharmacokinetics of the newer neuromuscular blocking drugs.

The pharmacokinetics of 6 new neuromuscular blocking drugs are described. These are the aminosteroids pipecuronium bromide, rocuronium bromide and rapacuronium bromide (ORG-9487) and the benzylisoquinolinium diesters doxacurium chloride, mivacurium chloride and cisatracurium besilate. In healthy individuals, these drugs all have similar volumes of distribution. Their pharmacokinetics are influenced little by age or anaesthetic technique, but renal and hepatic disease may significantly alter their distribution and elimination. Pipecuronium resembles pancuronium in its pharmacokinetic and neuromuscular blocking profile, but is devoid of cardiovascular effects. It has a low clearance (0.16 L/h/kg) and long elimination half-life (120 minutes). It is largely eliminated through the kidney. Rocuronium has a similar pharmacokinetic profile to vecuronium but its onset of action is more rapid and duration of action slightly shorter. Its clearance (0.27 L/h/kg) is intermediate between those of pipecuronium and rapacuronium, but its elimination half-life is long (83 minutes). The pharmacokinetics of rocuronium are altered by renal and hepatic disease; the latter probably has the more significant effect. Rapacuronium has a rapid onset, and a bolus dose has a short duration of action. It has a high clearance (0.59 L/h/kg) but a long elimination half-life (112 minutes). Doxacurium has a pharmacokinetic and pharmacodynamic profile similar to pipecuronium. It has a high potency and is devoid of cardiovascular effects. In adults, it has a low clearance (0.15 L/h/kg) and long elimination half-life (87 minutes). Mivacurium is a mixture of 3 stereoisomers. It has a short to intermediate duration of action. It is hydrolysed by plasma cholinesterase. Inherited or acquired alterations in plasma cholinesterase activity are associated with changes in the pharmacokinetics and time course of action of mivacurium. The 2 active isomers (cis-trans and trans-trans) have a high clearance (4.74 L/h/kg) and very short elimination half-lives (approximately 2 minutes). Cisatracurium is the 1R-cis 1'R-cis isomer of atracurium. It has similar pharmacokinetics and pharmacodynamics to atracurium. It is mainly broken down by Hofmann (non-enzymatic) degradation. Cisatracurium has an intermediate clearance (0.3 L/h/kg) and short elimination half-life (26 minutes). Hepatic and renal disease have little effect on its pharmacokinetics.

Newer neuromuscular blocking drugs. An overview of their clinical pharmacology and therapeutic use.

Four new nondepolarising muscle relaxants, pipecuronium bromide, doxacurium chloride, mivacurium chloride and Org 9426 (rocuronium) offer alternatives to the established agents atracurium besilate and vecuronium bromide. Pipecuronium and Org 9426 are steroidal compounds, the latter being a monoquaternary agent, whereas doxacurium and mivacurium are bisquaternary benzylisoquinolinium compounds. Pipecuronium and doxacurium have a relatively slow onset and a long duration of action. Pipecuronium produces maximum block in 3 to 6 min when given in a dose of 45 to 80 micrograms/kg, and a duration of clinical relaxation of between 40 and 110 min. Doxacurium is more potent, but is the least rapid and the longest acting relaxant currently available. When administered in doses of 37 to 80 micrograms/kg, it produces maximum block within 3.5 to 10 min, with a duration of clinical relaxation of 77 to 164 min. The advantage of both pipecuronium and doxacurium is their cardiovascular stability. Both agents are primarily eliminated via the kidneys and both have now been licensed for use in the US. Mivacurium is a muscle relaxant with a short duration of action. When administered in doses of 0.1 to 0.25 mg/kg it produces maximum block in 2 to 4 min, but the duration of clinical relaxation is less than 20 min. Higher doses which could induce a faster neuromuscular block are unfortunately associated with some histamine liberation. The drug is metabolised by plasma cholinesterase. Mivacurium has also been licensed for use in the US. Org 9426 is an agent with a rapid onset but an intermediate duration of action. A dose of 0.5 to 0.6 mg/kg induces maximum block in about 1.5 min and has a duration of clinical relaxation of about 30 min. The rapid onset of effect could be useful for early intubation as an alternative to suxamethonium chloride. However, much more clinical experience is needed with this agent, particularly with regard to duration of action of larger doses and occurrence of side effects. The drug is mainly eliminated via the liver.

Inhibition of histamine N-methyltransferase (HNMT) in vitro by neuromuscular relaxants.

There have been reports of hypotension and flushing following vecuronium administration. The etiology of these symptoms, which are similar to those of histamine release, is not clear. The steroidal neuromuscular relaxants (NMRs), unlike muscle relaxants structurally similar to curare, have been shown not to cause histamine release after the administration of typical clinical doses. Histamine levels in plasma reflect a balance between release and catabolism. In humans, histamine N-methyl-transferase (HNMT) is the enzyme primarily degrading for histamine. Therefore, we performed in vitro kinetic studies of purified HNMT to determine the effects of the steroidal and curare-like NMRs and also of gallamine on histamine catabolism. We demonstrated that all NMRs tested were inhibitors of HNMT in vitro. The inhibition was competitive with respect to the cosubstrate S-adenosyl-L-[3H-methyl] methionine, and noncompetitive with respect to histamine. The rank order of inhibition was vecuronium greater than pancuronium greater than gallamine greater than d-tubocurarine greater than metocurine greater than atracurium greater than pipecuronium, with Ki values ranging from 1.2 to 44.8 microM. Our data suggest that HNMT-based radioenzymatic assays for histamine should be susceptible to inhibition by concurrent use of NMRs, particularly vecuronium.

Forearm blood flow responses to handgripping after local neuromuscular blockade.

To test the hypothesis that acetylcholine "spillover" from motor nerves contributes significantly to skeletal muscle vasodilation during exercise, we measured the forearm blood flow responses during attempted handgripping after local paralysis of the forearm with the neuromuscular-blocking drug pipecuronium. This compound blocks postsynaptic nicotinic receptors but has no impact on acetylcholine release from motor nerves. The drug was administered selectively to one forearm by using regional intravenous drug administration techniques in five subjects. Pipecuronium reduced maximum forearm grip strength from 40.0 +/- 3.2 kg before treatment to 0.0 kg after treatment. By contrast, drug administration had no effect on maximum voluntary contraction in the untreated forearm (41.3 +/- 3.3 vs. 41.4 +/- 2.7 kg). During 2 min of attempted maximal contraction of the paralyzed forearm, the forearm blood flow increased from only 3.4 +/- 0.8 to 4.8 +/- 1.2 ml.100 ml-1.min-1 (P < 0.05). Heart rate increased from 63 +/- 3 to 73 +/- 8 beats/min (P > 0.05) during attempted contraction, and only three of five subjects showed obvious increases in heart rate. Mean arterial pressure increased significantly (P < 0.05) from 102 +/- 6 to 109 +/- 9 mmHg during attempted contractions. When these increases in flow are considered in the context of the marked (10-fold or greater) increases in flow seen in contracting forearm skeletal muscle, it appears that acetylcholine spillover from motor nerves has, at most, a minimal impact on the hyperemic responses to contraction in humans.

A dose-response evaluation of pipecuronium bromide in elderly patients under balanced anesthesia.

Pipecuronium bromide is a new steroidal non-depolarizing muscle relaxant currently under investigation. It is similar to pancuronium with respect to the duration of action, but lacking its cardiovascular side effects. We examined the dose-response relation of pipecuronium in 27 patients, ages 66-79 years, utilizing the incremental dose method under balanced anesthesia. The ED50, ED90 and ED95 were 22.42 (5.2) mcg/kg, 31.81 (6.9) mcg/kg and 35.12 (7.8) mcg/kg, respectively (log probit method). Our recovery data also demonstrate that residual neuromuscular blockade due to pipecuronium can easily be antagonized with neostigmine as long as spontaneous recovery of T1- at the time of reversal administration is greater than 13%. The authors conclude that under balanced anesthesia the cumulative dose-response of pipecuronium in the elderly patients is consistent with those previously described for younger population. Therefore, no dose adjustment appears necessary for the elderly. However, as with all medications, careful administration is appropriate.

Effects of respiratory and metabolic alkalosis and acidosis on pipecuronium neuromuscular block.

Acute respiratory and metabolic acidosis as well as metabolic alkalosis increased (by 11, 11, 21%) whereas respiratory alkalosis antagonized (by 10%) the partial steady state block produced by pipecuronium infusion on the anterior tibialis muscle of the cat. The duration of neuromuscular block following six successive doses of pipecuronium was prolonged 1.4-fold during long-lasting metabolic alkalosis while this parameter was shortened to half of that in control cats during acidosis. Pipecuronium block could be fully antagonized by neostigmine.

Systemic anti-inflammatory effect of somatostatin released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig.

The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45+/-3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46+/-5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.

Comparative evaluation of the neuromuscular and cardiovascular effects of pipecuronium, pancuronium, atracurium, and vecuronium under isoflurane anesthesia.

The neuromuscular and cardiovascular effects of intubating doses of pipecuronium 80 micrograms/kg, pancuronium 100 micrograms/kg, atracurium 500 micrograms/kg, and vecuronium 100 micrograms/kg were compared in 62 patients under isoflurane (end-tidal concentration = 0.5-1%) anesthesia. Pipecuronium, pancuronium, and vecuronium had no significant effect on systolic or diastolic blood pressure. In one patient the administration of atracurium resulted in significant hypotension. Heart rate was significantly increased only after the administration of pancuronium. The neuromuscular-blocking effect of pipecuronium and pancuronium appears to be twice as long as that of vecuronium and atracurium. Administration of neostigmine resulted in significantly faster recovery of muscle function in patients receiving vecuronium or atracurium. Although pipecuronium's neuromuscular-blocking effect is similar to that of pancuronium, its lack of cardiovascular effects more closely resembles that of vecuronium.

Effect of plasma anticonvulsant level on pipecuronium-induced neuromuscular blockade: preliminary results.

Patients receiving anticonvulsants are resistant to nondepolarizing muscle relaxants (NDMR). This study examines the effect of plasma anticonvulsant levels on pipecuronium-induced neuromuscular blockade. Twenty adult patients scheduled for neurosurgery were assigned to one of two groups. Group 0 (G0) consisted of 10 patients not on anticonvulsant therapy; group 1 (G1) included 10 patients treated either with phenytoin or carbamazepine. G1 patients were further divided into G1u (n = 4) and G1w (n = 6) subgroups, according to the plasma anticonvulsant level measured the day before surgery--under (G1u) or within (G1w) the therapeutic range. Neuromuscular transmission was monitored with a Biometer International A/S Accelograph. Anesthesia was induced and maintained using propofol and sufentanil. After calibration of the accelograph, a bolus of pipecuronium 0.08 mg/kg was given IV. The time from pipecuronium injection to the peak reduction of T1 was taken as the onset time. The time in min from pipecuronium injection to recovery of T1% (first accelograph response/baseline response) x 100 and TR% (fourth accelograph response/first accelograph response) x 100 were recorded at 25, 50, and 75% of baseline. The recovery index (RI) was taken as the time from 25 to 75% of baseline. The recovery index (RI) was taken as the time from 25 to 75% recovery of the baseline response. The onset time was not different in G0 (203 +/- 60.4 s), G1 (230.5 +/- 79.3 s), and G1u (181.8 +/- 60.4 s) but prolonged in G1w (279.2 +/- 67.7 s).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the onset, spontaneous recovery and train of four fade of the clinical neuromuscular block produced by pancuronium and pipecuronium.

The following study was performed to delineate the possible differences in the onset, recovery and "train of four" (TOF) fade characteristics of pancuronium (Pan) and pipecuronium (Pip). Eighty adult American Society of Anesthesiologists (ASA) class I and II surgical patients were studied with institutional approval. After premedication, general anesthesia was induced with thiopental sodium i.v. followed by N2/O2 halothane and fentanyl. The lungs were ventilated. Normocarbia and normothermia were maintained. Two groups of 40 patients received pancuronium (0.1 mg/kg i.v.) or pipecuronium (0.07 mg/kg i.v.). Neuromuscular block (NMB) was measured simultaneously by mechanomyography (MMG) and electromyographically (EMG) on the thumb adductor muscle. Supramaximal (TOF) stimuli were applied to the ulnar nerve every 20 seconds. The onset of neuromuscular blocking action, duration of action (to 25% recovery of twitch response). TOF fade during onset and up to 25% T1 response recovery, hemodynamic changes following induction of anesthesia and after the muscle relaxant and subsequent oral intubation were determined. Mean values and the differences in the two treatments groups were statistically analyzed. The onset of action of the two agents were similar: 3.62 +/- 0.02 minutes (MMG) and 4.94 +/- 0.05 minutes (EMG, Pan) and 3.74 +/- 0.02 minutes (MMG) and 4.36 +/- 0.012 minutes (EMG, Pip). TOF fade ratios during the onset phase were similar. TOF fade at the 25% twitch responses recovery level was 100% with the MMG responses and (96% (Pan) and 94.8% (Pip) with the EMG responses at the 25% twitch response recovery level. Hemodynamic changes were similar after the single dose administration of the bolus administration of the two NMB agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of impurity profiles of drugs and related materials. Part VIII: Combined application of high-performance liquid chromatography and NMR spectroscopy in the impurity profiling of drugs.

The usefulness of the joint application of HPLC and NMR spectroscopy in drug impurity profiling is demonstrated by the following examples: (1) identification of Z and E isomers of 17 alpha-ethynyl-4-oestrene-3 beta, 17-diol-3-acetate-17-(3'-acetoxy-2'-butenoate) in ethynodiol diacetate; (2) identification of the p-tolyl analogue as the impurity of enalapril maleate; (3) identification and quantification of 2'-dehydro-pipecuronium bromide in pipecuronium bromide. The possibilities of utilizing NMR spectroscopy for the identification and quantification of the impurities with and without their isolation are discussed.