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Study Objectives: To determine the neuromuscular, cardiovascular, and histamine-releasing properties of doxacurium and pipecuronium at three times effective ED 95 doses (3XED 95 ). Design: Prospective, randomized clinical trial of adult patients. Setting: University teaching hospital. Patients: 20 ASA status I and II adult patients. Interventions: Subjects were anesthetized with thiopental sodium, fentanyl, and nitrous oxide and oxygen (N 2 O:O 2 ). Plasma samples were taken preoperatively, after thiopental, and 2 and 5 minutes after doxacurium 75 μg/kg or pipecuronium 123 μg/kg were given for the determination of histamine levels. The ulnar nerve was stimulated via surface electrodes using train-of-four stimulation at 0.1 Hz. The force of contraction of adductor pollicis was recorded using a mechanomyograph. Recovery of the twitch response, was followed and, if necessary, neuromuscular block was antagonized with neostigmine and glycopyrrolate. Measurements and Main Results: Three patients in the doxacurium group and one patient in the pipecuronium group exhibited a marked increase in plasma histamine levels. In both groups statistically significant changes were seen in heart rate (HR) measurements ( p vs. 1.8 ± 0.1 min ( p vs. 723 ± 9 min ( p Conclusion: Neither drug caused a clinically significant change in HR or histamine release. In the doses chosen for this study, the rate of onset of block is slower with doxacurium while recovery is more rapid. Histamine release in three patients was caused by thiopental, while in a fourth patient it may have been due to doxacurium.

Arterial hypertension and/or tachycardia may alter intracranial pressure in neurosurgical patients. We compared the effects of pancuronium 0.1 mg/kg and pipecuronium 0.1 mg/kg given as i.v. bolus on cerebrospinal fluid (CSF) pressure in 2 groups of 10 patients each scheduled for intracranial surgery in the supine position. Before surgery, no patient presented clinical symptoms of elevated intracranial pressure (ICP). Anesthesia was induced and maintained with fentanyl and midazolam. Ventilation with 50% nitrous oxide in oxygen was adjusted to maintain arterial pCO2 at 30-35 mmHg. After induction of anesthesia, CSF pressure was registered via a lumbar subarachnoid catheter before and 3, 5, 10, and 30 min after pipecuronium or pancuronium administration. Hemodynamics were monitored using radial and pulmonary artery catheters. All variables underwent analyses of variance for repeated measures with p0.05 considered significant. Mean CSF pressure decreased insignificantly from 15 +/- 5 mmHg (before injection) to 14 +/- 4 mmHg in patients given pipecuronium and from 13 +/- 4 mmHg to 10 +/- 3 mmHg in the pancuronium group without significant differences between the study groups. Heart rate and arterial pressure increased significantly (p0.001) in patients given pancuronium but remained stable after pipecuronium. Onset and duration of neuromuscular blockade were comparable between groups. Based on our results, pipecuronium is a safe alternative to pancuronium during neurosurgical procedures in patients without abnormally high intracranial pressure.

Clinical pharmacology of pipecuronium; a comparative study of its duration of action between balanced (propofol/fentanyl) and isoflurane anesthesia. Pipecuronium duration of action has been compared between patients under balanced (propofol/fentanyl) or 0.8-1 Mac isoflurane anesthesia. T1/TC 10-25-50-75-90% (T1/TC, 10, T1/TC, 25, T1/TC, 50 TOF, 75T1/TC 90) and TOF 10-25-50-75% (TOF 10%, TOF 25%, TOF 50%, TOF 75%) ratios were studied; T1/TC 10-75% (T1/TC 10/75) and TOF 10-75% (TOF 10-75%) recovery times were also derived. The muscle relaxant has been utilized in 55 patients divided into groups according to the method of its administration: in group I (33 patients) the drug was injected in small divided doses until ED95% was reached, according to the cumulative dosage method; in group II (8 patients) and III (12) the drug was injected at 0.35 micrograms/kg and 50 micrograms/kg respectively. Neuromuscular function was monitored by isometric force transduction, stimulating the adductor pollicis by tof every 12 sec. Pipecuronium duration of action (min) following single doses was longer than following the cumulative dosage method (TOF 25% vs 61%, TOF 50% 103 vs 76, TOF 75% 136 vs 102). The presence of isoflurane significantly prolonged recovery times (TOF 10%, from 55 to 70, TOF 25% from 61 to 88, TOF 50% from 75 to 120) in group I (cumulative doses) patients. Recovery times were dose related, while age did influence recovery only at the earlier intervals (T1/TC 10 and 25%). Keeping in mind the limited range of age and dosages, advantages and disadvantages of the drug are discussed, comparing the experimental results with those derived from the literature.

Pipecuronium effective doses 50,90,95 (ED50, ED90, ED95) have been obtained with the cumulative dosage method studying the influences of two different anesthetic techniques (TIVA vs isoflurane), of the patients age, of two different monitoring techniques, force transduction vs accelerometry, both evaluated by T1/TC ratio, ratio between Ist muscular response following the muscle relaxant and the values obtained before its injection, and TOFR, ratio between 4th and Ist response of every train. 33 patients, 55 years average age, 66 kgs average weight, ASA 12, scheduled for elective operations were anesthetized with propofol-fentanyl-N2O; tracheas were intubate under topical analgesia; maintenance of anesthesia included propofol and fentanyl or isoflurane 1 MAC. Neuromuscular monitoring included the simultaneous measurement of force of thumb adduction (FT 10 Grass) and its acceleration (Tofguard); neuromuscular blockade was evaluated by T1/TC and TOFR. Pipecuronium was administered in small decreasing boluses until 95% of T1/TC depression. Under force monitoring, ED50, ED90, ED95 values were 19, 28, 33 micrograms/kg respectively with T1/TC, being slightly lower with TOF stimulation (15, 24, 26 micrograms/kg); ED's were not influenced by anesthesia and were inversely related to age. Under accelerometry, EDs were always lower (16,27 e 27 micrograms/kg) under T1/TC, while with tof their values were similar to those derived from force measurements. ED's values obtained with T1/TC, either with force than accelerometry, while accelerometry was more sensitive than force for all ED's. EDs values, both under T1/TC than TOF, either with force transduction than accelerometry, resulted highly correlated each other, indicating a substantial agreement between the two mechanical methods of monitoring. It is concluded that the new instrument Tofguard offers the same reliability than force transduction, with the advantages of being smaller, portable and able to calculate directly the depth of neuromuscular blockade.

In order to explain the reported shorter clinical duration of action of cumulative ED95 of pipecuronium in infants as compared to children or adults, the pharmacokinetic profiles of pipecuronium were compared in infants (n = 6; mean age 6.8 months; mean weight 7.3 kg) in children (n = 6; mean age 4.6 years; mean weight 19.2 kg) and in adults (n = 7; mean age 42 years; mean weight 58.2 kg). Equipotent doses (2 x ED95) of pipecuronium were injected i.v. as single bolus and arterial blood was sampled for 4-5 h. Pipecuronium was quantified by complex formation with [125I]-labelled rose bengal. Pharmacokinetic parameters were calculated using a two-compartment open model. The median for the distribution half-life of pipecuronium was 2.54 min (interquartile range: 1.0-2.5 min) in infants and 2.04 min (0.26-2.04 min) in children; both were significantly shorter than in adults (5.75 [3.7-9.7] min). The plasma clearance of pipecuronium was significantly decreased in infants (1.50 [0.6-1.5] ml.min-1.kg-1; P0.05) as compared to children and adults (2.27 [0.88-2.27] and 2.45 [1.7-3.2] ml.min-1.kg-1, respectively). The total volume of distribution was similar in all three groups. We conclude that the pharmacokinetic features of pipecuronium are age-dependent: differences as compared to adults consisted of a faster distribution in both infants and children and a slower elimination in infants. The pharmacokinetic profile of pipecuronium does not explain the faster recovery from neuromuscular blockade in infants as compared to children. Because of the low total plasma clearance in infants, pipecuronium dosage should be carefully monitored to avoid accumulation and prolonged paralysis.

Pipecuronium bromide is a new non depolarising muscle relaxant with a long duration of action; we considered its haemodynamic effects during general anaesthesia.Eight surgical patients (4 males, 4 females), mean age 44 years (range 29-65 years), ASA I-II, were studied. All patients were undergoing elective neurosurgical procedures (Hunt-Hess I-II). A radial artery-cannula was put in for blood pressure monitoring and a Swan-Ganz volumetric/ejection fraction fiber optic catheter was put in pulmonary artery via right internal jugular vein (EFV/OTDC-Baxter). A diazo-analgesic high dose fentanyl anaesthesia was given. All patients received pipecuronium bromide 0,1 mg/kg during stable haemodynamic conditions. Haemodynamic determinations were performed over following three times: T0 before the pipecuronium administration, T1 and T2, 3 and 15 minutes after administration respectively. These parameters were analysed: HR, MAP, MPAP, RAP, PCWP, CI RVEDVI, RVESVI, RVEF, SVRI, LVWI, RVWI, SvO2, DO2I, VO2I, O2ER, Qs/Qt (statistics: analysis of variance (two ways ANOVA) and orthogonal decomposition; for all statistical comparison, differences were considered significant when p0.05).Only MAP and SVRI showed significant changes (p = 0.02 and p = 0.04), even if clinically modest. No other parameter showed any change at all.Pipecuronium bromide did not show adverse haemodynamic effects; its haemodynamic repercussions are clinically negligible. The drug could be considered as first choice in long lasting operations for patients with potential cardiovascular instability.

Previous studies have suggested that the increased duration of action of long-acting neuromuscular relaxants may make their pharmacologic antagonism more difficult and, thus, increase the likelihood of residual block. This hypothesis was tested in healthy, adult humans who received a background of isoflurane/N2O/fentanyl anaesthesia. Study subjects were paralyzed with either pancuronium (N=8), pipecuronium (N=8), or the longer-acting relaxant, doxacurium (N=8). Neuromuscular function was monitored, and, using a blinded, randomized study design, the relaxants were titrated to identify the ED95 dose in each patient. Thereafter, spontaneous recovery was observed until there was 25% ofbaseline response to the first supramaximal twitch (Tl) in a train-of-four (TOF). At this time, the block was antagonized with neostigmine 0.07 mg/kg and glycopyrrolate 0.014 mg/kg i.v., and recovery of TOF was recorded. Spontaneous recovery to 25% of the baseline Tl response occurred at 52± 14 min (mean±SD) following administration of either pancuronium and pipecuronium, and 85 ±33 min following doxacurium (P

Pipecuronium Bromide (Arduan, Organon, Inc, West Orange) is a long-acting, nondepolarizing neuromuscular blocking agent. The efficacy of pyridostigmine 170 micrograms/kg intravenously (approximately 10 mg/70 kg) for reversing pipecuronium has not been reported. This study was performed to determine the time required to obtain a train-of-four (TOF) ratio of 0.7 after administration of pyridostigmine 140 micrograms/kg at 25% recovery of T1 after pipecuronium-induced neuromuscular blockade. Sixteen, American Society of Anesthesiology (ASA) I or II patients undergoing surgical procedures of at least 90 minutes, requiring intubation and muscle relaxation were included. Neuromuscular blockade was assessed using the Puritan-Bennett/Datex NMT 221 placed for ulnar nerve stimulation. Anesthesia was maintained with a nitrous oxide/narcotic technique and the use of potent inhalational anesthetics was avoided. The mean reversal time was found to be 16.14 minutes, with a minimum of 10.3 minutes and a maximum of 24.3 minutes. The standard error was +/- 1.05 minutes with a variance of 17.68 minutes.

Since the introduction of the long-acting agent pancuronium in clinical practice several other related steroidal non-depolarizing neuromuscular blocking agents have been synthetized, developed and finally tested in clinical practice to investigate their safety and efficacy. Vecuronium, the monoquaternary analogue of pancuronium, was introduced in clinical practice as it showed two major improvements over pancuronium: a better time course of action, i.e., a shorter duration and a faster recovery, and an higher selectivity for the nicotinic cholinoceptor. This increased selectivity resulted in a remarkable, cardiovascularly clean profile comparable to that of the long-acting compound pipecuronium, the 2,16 piperazino analogue of pancuronium, which was developed at almost the same time. All mentioned compounds so far showed a significantly longer duration of action than the depolarizing agent succinylcholine. The main reason, however, to use this relatively “dirty” depolarizing agent in large numbers of patients, was its rapid onset of action, promoting safety by allowance of early intubation.

We studied 24 patients undergoing cardiac surgery or esophagectomy, and necessitating postoperative mechanical ventilation. The initial and maintenance doses of pipecuronium (0.08 mg/kg which is approximately 2 × ED95, and 0.04 mg/kg, respectively) were given during the surgery, and the continuous intravenous infusion of pipecuronium was given in the ICU after surgery. The neuromuscular blockades (NMBs) produced by the relaxant were evaluated with an evoked compound electromyogram. The plasma concentrations of pipecuronium were determined 5 min after the administration of pipecuronium, at 10 % recovery from the complete NMB during surgery and one time a day during the continuous intravenous infusion of the drug in the ICU. The clinical durations of the maintenance dose of pipecuronium in the hypothermic state (core temperature 25.8±0.3° C) during cardiopulmonary bypass (CPB) and in the normothermic states, before and after CPB (core temperature 36.0±0.2°C and 35.7±0.3°C) were 295±18, 107±13 and 143±18 minutes, respectively. The repeated administration of the maintenance dose did not produce prolongation of the clinical duration in the normothermic state of esophagectomy patients. The required infusion rates of pipecuronium were 0.035±0.004 mg/kg/h (0.02–0.06 mg/kg/h) in the ICU. The plasma concentrations of pipecuronium 5 min after the administration of it in cardiac surgery and esophagectomy patients were 508.0±71.3 ng/ml, 524.0±45.0 ng/ml in the initial dose, and 418.3±31.3 ng/ml, 413.7±31.5 ng/ml in the maintenance dose, respectively. The plasma concentrations of pipecuronium for 90% block in hypothermic state of cardiac surgery patients and in normothermic state of esophagectomy patients were 38.8±4.9 ng/ml (23.3–59.8 ng/ml) and 117.0±10.3 ng/ml (50.2–192.1 ng/ml), respectively.

The Council on Scientific Affairs of the California Medical Association presents the following epitomes of progress in anesthesiology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and clinical importance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of progress in medicine, whether in their own field of special interest or another. The epitomes included here were selected by the Advisory Panel to the Section on Anesthesiology of the California Medical Association, and the summaries were prepared under the direction of Dr Jackson and the panel.

In patients with impaired renal function Pipecuronium (Pip), a long acting relaxant, should not show a significantly prolonged effect, however the range of clinical duration is more variable [Canfell]. Aim of our study was to investigate if dose reduction according to glomerular filtration rate (GFR) and ideal body weight (IBW) varies the time course of action and the ranges.

It has been reported that there is no evidence of plasma histamine (HA) release by the intravenous administration of pipecuronium (PPB) in humans(1). It is well recognized that the half life of released plasma histamine (HA) is very short but that of n-methylhistamine (n-MHA) , a metabolite, is much longer. Assaying both HA and n-MHA would reveal the extent to which HA appears in plasma. This study was undertaken to assess pipecuronium (PPB) induced release of HA compared with tubocurarine (d-Tc) by measuring both HA and n-MHA in plasma.

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)

The effect of temperature on the potencies of neuromuscular blocking agents remains unclear. This study was undertaken to examine the effects of different neuromuscular blocking agents at 37 and 27 degrees C at a constant carbon dioxide content (alpha stat principle). The effect of neostigmine 1 mumol litre-1 induced antagonism of these agents was also investigated. Phrenic nerve-hemidiaphragm preparations of rats were mounted in modified Krebs solution, maintained at 37 degrees C and aerated with a 5% carbon dioxide-95% oxygen gas mixture, and at 27 degrees C with 4% carbon dioxide to maintain the carbon dioxide content of the solution constant. Phrenic nerves were stimulated with 0.1-Hz supra-maximal impulses of 0.2-ms duration and the elicited tension of the diaphragm recorded. The potencies of the steroidal neuromuscular blocking agents (rocuronium, vecuronium, pancuronium and pipecuronium) increased significantly at 27 degrees C (P0.05), while the potencies of the benzylisoquinolinium agents (tubocurarine and dimethyltubocurarine) did not change. Neostigmine-induced antagonism of the steroidal agents did not differ significantly between each other but differed significantly from the benzylisoquinolinium agents (P0.05) at both temperatures. The ratios of IC50 (inhibitory concentration, 50%) with and without neostigmine at hypothermia were slightly higher for the steroidal agents, indicating slight enhancement of antagonism by neostigmine at 27 degrees C. In contrast, the ratios were significantly greater at 27 degrees C (P0.05) for isoquinolinium agents, implying significant enhancement of antagonism. Our results indicate that at 27 degrees C the potency of all steroidal agents increased and neostigmine-induced antagonism was slightly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaesthetists choose daily among wide varieties of neuromuscular blocking drugs and rapidly acting hypnotic agents. This study sought to determine whether definitive, immediate knowledge of drug cost might influence clinician choices, ultimately reducing the cost of anaesthesia care. Faculty anaesthetists, residents in training, and nurse anaesthetists served as subjects in this prospective, sequential, blinded study of prescribing habits. Weekly inventories of selected neuromuscular blocking and rapidly acting hypnotic agents were performed over 24 wk at a tertiary- care hospital. Supermarket style price stickers plainly indicating the hospital cost of each unit of drug appeared continually for 13 wk following an initial 11 wk control period. Both actual usage data in priced units as well as data normalized by total anaesthesia duration underwent comparison between control and priced periods. The usage of pancuronium, vecuronium, atracurium, mivacurium, succinylcholine, thiopentone, etomidate, and propofol did not differ in the control from the priced periods. Pipecuronium decreased after sticker placement (2 vs 1 viab · wk−1 median, P < 0.05), as did methohexitone (39 ± 9.0 [SD] vs 29 ± 11 syringes · wk−1, P < 0.05). Ketamine usage normalized by total anaesthesia duration increased (P < 0.05) following sticker placement. The weekly cost of all drugs inventoried normalized for caseload did not differ during the measurement periods. Immediate cost awareness, implemented simply as price stickers on drug units, had minimal impact on clinicians’ drug usage in a tertiary care setting.

Neuromuscular blocking effects of pipecuronium bromide 0.04 mg.kg-1 were compared those of vecuronium bromide 0.08 mg.kg-1 in a double blind study. Fifty surgical patients (ASA I or II) were allocated randomly to two groups of each 25 cases and they were anesthetized with nitrous oxide 4 l.min-1, oxygen 2 l.min-1 and isoflurane 1 MAC. Neuromuscular blockade was monitored by using mechanical twitch responses of the thumb to electrical stimulations of the ulnar nerve. Adequate neuromuscular relaxation for surgery of 85.8% to 100% block was obtained by this dose of pipecuronium. The duration of action and recovery time from 75% to 25% block were longer than those produced by twice the dosage of vecuronium (62.3 +/- 37.15 vs. 40.4 +/- 16.09 min, and 48.1 +/- 22.0 vs. 19.9 +/- 10.8 min, P0.05). The blocks by both drugs responded to neostigmine. Cardiovascular side effects of the both agents were not found. From these results, it is concluded that pipecuronium is a useful nondepolarizing relaxant with a long duration of action and negligible side effects.

The half life of released plasma histamine (HA) is short but N-methylhistamine (N-MHA) which is a metabolite of HA has a longer life. Measuring both HA and N-MHA, it is possible to know the release of HA in the plasma. The purpose of this study was to ascertain the release of HA by pipecuronium (PPB) by measuring both HA and N-MHA in the plasma. Ten patients received 0.04 mg.kg-1 and other 10 patients received 0.08 mg.kg-1 of intravenous PPB. Plasma levels of HA and N-MHA were measured 1 minute before and 1, 3, 5 and 10 minutes after the administration of PPB. Release of plasma HA and N-MHA was not observed following administration of PPB. We concluded that PPB does not cause the release of histamine because there is no increase of the metabolite, N-MHA, of HA, and PPB can be used safely for patients with allergy.

Pipecuronium bromide, a new neuromuscular relaxant with steroidal structure, is devoid of effects on the autonomic nervous system and may be useful in patients where haemodynamic stability is mandatory. However, tracheal intubation may alter this haemodynamic profile. Therefore, we carried out a prospective double-blind study in 30 patients undergoing coronary artery bypass surgery with the purpose (1) of determining if intubation influenced the haemodynamic stability in patients paralyzed with pipecuronium and (2) of comparing plasma catecholamine concentrations after pipecuronium with those after pancuronium. Thirty patients were randomized into two groups receiving either pipecuronium 100 micrograms.kg-1 or pancuronium 150 micrograms.kg-1 after induction of anaesthesia with midazolam and fentanyl. Haemodynamic variables and plasma catecholamines were measured before and after induction, after the muscle relaxant three times and twice after intubation. After anaesthesia induction decreases in heart rate (HR), mean arterial pressure (MAP) and cardiac index (CI) were observed in both groups. These haemodynamic variables were unchanged after pipecuronium whereas after pancuronium HR increased from 53 +/- 11 b.min-1 to 64 +/- 9 b.min-1 after induction (P0.05) and CI from 2.5 +/- 0.5 L.min-1 to 3.0 +/- 0.8 L.min-1 (P0.05). Furthermore ECG signs of myocardial ischaemia appeared in four patients after pancuronium and the decay of plasma norepinephrine concentration was slower than with pipecuronium. We conclude that pipecuronium given after induction of anaesthesia is free of sympathomimetic or vagolytic activity and does not influence haemodynamic variables for up to ten minutes after tracheal intubation.

This study was performed to determine the optimum dose of pancuronium (n = 30) and pipecuronium (n = 30) under continuous sedation and analgesia in the intensive care unit (ICU). This was an open clinical investigation in 60 critically ill patients with head injury, multiple trauma (in some complicated with sepsis and multi-organ failure), requiring neuromuscular block for ventilation for at least 48 h. Emphasis was placed on the neuromuscular monitoring with a peripheral nerve stimulator and adequate sedation and analgesia. Satisfactory block was achieved in all cases with an average dose of 3 mg/h with either compound. None of the patients experienced prolonged paralysis, muscle weakness, or other neuromuscular dysfunctions in the postventilatory period. We suggest that adequate use of sedative hypnotics and opioids plus neuromuscular monitoring allowed us to optimize the dose of muscle relaxants according to the need of individual patients.

We have studied the dose-response relationships for neostigmine and edrophonium during antagonism of neuromuscular block induced by pipecuronium bromide. Fifty-six ASA physical status I or II adults were given pipecuronium 70 micrograms/kg during fentanylthiopental-nitrous oxide-halothane anesthesia. Train-of-four (TOF) stimulation was applied to the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height reached 20% of its initial control value, edrophonium (0.125, 0.25, 0.75, or 1 mg/kg) or neostigmine (0.015, 0.03, 0.045, or 0.06 mg/kg) was administered by random allocation. Neuromuscular function in another seven subjects was allowed to recover spontaneously. This study demonstrated that the dose-response curves for these two drugs for reversal of first twitch and TOF ratio were not parallel. The doses of neostigmine required to achieve 50% (ED50) and 80% (ED80) recovery of the first twitch after 10 min were 8.5 (7.3-9.7) and 17.4 (16.2-18.7) microgram/kg [mean (95% confidence intervals)], respectively. Corresponding ED50 and ED80 values for endrophonium were 84.1 (72.9-96.9) and 233 (215.7-253.3) microgram/kg, respectively. These values corresponded to neostigmine:edrophonium potency ratios of 9.89 (7.4-12.3) and 13.4 (11.8-14.9) for first twitch ED50 and ED80 height, respectively. The calculated doses producing 50% (ED50) recovery of the TOF ratio at 10 min were 18.8 (17.5-20.2) and 271.3 (246.5-298.6) microgram/kg for neostigmine and edrophonium, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuromuscular blocking drugs are valuable adjuncts to the practice of pediatrics. Monitoring of drug effects is technically more difficult in the younger patient. Nevertheless, careful observation of drug effects will improve the usefulness of NMB and safeguard the patient from prolonged weakness. Although there are differences in neuromuscular function with age in the pediatric age range, the differences between the NMB currently available are greater than the differences between the patients. Thus, the only uniform finding across age and all drugs is that onset of drug effect is more rapid in the infant than in the child when circulatory function is normal. In general, children require more of all NMB on a mg/kg basis than do infants or adults to obtain the same effect. Children recover from NMB more rapidly than do patients of other ages. Infants, however, may recover more rapidly than do any other patients from the effects of drugs such as mivacurium which are metabolized in the plasma. Tables 4 and 5 summarize doses, onset of action, and duration of NMB. Please note in Table 4 that succinylcholine is only used for endotracheal intubation, whereas the other nondepolarizing muscle relaxants can be used for endotracheal intubation or to maintain some degree of muscle paralysis in the child whose trachea is already intubated. Nondepolarizing muscle relaxants (e.g., mivacurium, ORG 9426, atracurium, vecuronium) are used both for initial bolus for endotracheal intubation and maintenance of muscle relaxation. Long-acting drugs (e.g., pancuronium, pipecuronium, and doxacurium), however, are used more commonly in small incremental doses to maintain muscle paralysis in patients already intubated. The advantages of these long-acting drugs are minimal cardiovascular side effects (i.e., tachycardia or hypotension from histamine release) and longer dosing interval. In all children, the dosing interval should be adjusted to the needs of the individual. In children with renal insufficiency or in those receiving drugs which impair neuromuscular function (e.g., aminoglycosides), the interval at which supplemental doses are required is longer than normal.

We investigated the influence of CO2-induced acid-base changes on the potencies of the monoquaternary relaxants (rocuronium, vecuronium, and d-tubocurarine) and bisquaternary relaxants (pancuronium, pipecuronium, and metocurine), and on the antagonism of their neuromuscular block by neostigmine. Phrenic nerve-hemidiaphragm preparations of rats were used. The pH changes were induced by changing the CO2 concentration aerating the modified Krebs solution. The potencies of the monoquaternary relaxants increased at 9% CO2 (pH 7.2) and decreased at 2.5% CO2 (pH 7.6) from those of 5% CO2 (pH 7.4) both with and without neostigmine (P < 0.05), whereas the potencies of the bisquaternary drugs did not change significantly at different pH levels from control (pH 7.4) both with and without neostigmine. The slopes of the log concentration-percent response curves of each drug were not significantly different at each pH level. The ratios of inhibitory concentrations, 50% (IC50) values with and without neostigmine at each pH value for each drug were not significantly different indicating that the neostigmine-induced antagonism for each drug was not affected by the CO2-induced acid-base changes. But the ratios of the IC50 values of the steroidal relaxants (rocuronium, vecuronium, pancuronium, and pipecuronium) were significantly lower (P < 0.05) than those of the isoquinolinium drugs (d-tubocurarine and metocurine) at each pH level, suggesting that the antagonism is enhanced at each pH level for the isoquinolinium relaxants. The difference was independent of their monoquaternary or bisquaternary nature. These results suggest that CO2 increases the potency of the monoquaternary relaxants but does not affect the bisquaternary relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)

Four neuromuscular blocking drugs, doxacurium, mivacurium, pipecuronium, and rocuronium have been or are about to be introduced into clinical practice. The purpose of this MiniReview is to describe their pharmacology, to consider their place in clinical anaesthetic practice, and to examine whether the needs of the clinician have been met. Two of the agents (doxacurium, mivacurium) are benzylisoquinolines resembling atracurium and two (pipecuronium, rocuronium) are aminosteroids related to pancuronium and vecuronium. Two (doxacurium, pipecuronium) are long-acting compounds, similar in duration of action to pancuronium, although the need for such a profile is questionable. Rocuronium has an intermediate duration of action and produces its maximum effect within two minutes which is much more rapid than any other non-depolarizing relaxant and this is probably a result of its poor potency. However, the onset of paralysis is not as quick as after succinylcholine. Mivacurium is unique because it is metabolized by plasma cholinesterase which produces a rapid recovery although slower than succinylcholine. All of the new drugs are devoid of serious cardiovascular or other side effects. The anaesthetist is now presented with an armamentarium of safe, nondepolarizing muscle relaxants with varying durations of action. However, the rapid onset and recovery associated with succinylcholine are unique and important in the urgent control of a patient's airway and respiration. The indications for succinylcholine will not disappear and the search for a non-polarizing replacement will continue.

To determine the effect of liver cirrhosis on the pharmacokinetics and pharmacodynamics of pipecuronium, the authors administered 100 micrograms/kg of pipecuronium intravenously to eight patients with liver cirrhosis and eight patients with normal liver and renal function undergoing elective abdominal surgery. All patients were anesthetized with thiopental (5-7 mg/kg), nitrous oxide (50-70% in oxygen), and fentanyl in repeated doses (2 micrograms/kg). Plasma concentrations of pipecuronium were determined by high-pressure liquid chromatography. A two-compartment open model was used for pharmacokinetic analysis. Thumb-elicited mechanical response to single-twitch ulnar nerve stimulation was also measured. Total plasma clearance did not differ between controls (2.96 +/- 1.05 mL.min-1.kg-1, mean +/- SD) and cirrhotics (2.61 +/- 1.16 mL.min-1.kg-1). Terminal elimination half-life was 111 +/- 46 min in controls and 143 +/- 25 min in cirrhotics. The total apparent volume of distribution at steady state did not differ between controls (350 +/- 81 mL/kg) and cirrhotics (452 +/- 222 mL/kg). The volume of the central compartment was not different between the two groups. The onset of neuromuscular blocking effect was longer in cirrhotics (233 +/- 112 s) (P0.05) than in controls (170 +/- 33 s). The clinical duration (injection until single twitch returned to 25%) was similar between the two groups: 167 +/- 41 min in controls and 165 +/- 48 min in cirrhotics. The authors conclude that hepatic insufficiency due to cirrhosis does not alter the pharmacokinetics and pharmacodynamics of pipecuronium (100 micrograms/kg).

The effects of pipecuronium bromide (Pi.) and pancuronium bromide (Pa.) on the contractile response of rat-phrenic nerve diaphragm and frog's musculus rectus abdominis preparation were studied. Pi. and Pa. were found to have a dose-dependent reduction in the contractile response of the tested preparation. Trials were made to estimate the potency of Pi. in a comparison with Pa. In this respect Pi. exhibited a more potent effect than Pa. The duration of action is about twice as long as that of Pa. in equieffective doses. Neostigmine rapidly and completely antagonises the neuromuscular blockade caused by Pi. and Pa.

Preliminary results of intraoperative monitoring of the degree of neuromuscular blockade using a portable device based on the technique of evoked electromyography are presented. The device has an analogue outlet for the connection with a computer. The technique used is simple and reliable and makes it possible to work out a computerized system for automatic graded supply of current myorelaxants on a feedback principle. Such a system does not only ensure an adequate level of myorelaxation with a minimum expenditure of expensive drugs, but also gives a new approach to the study of neuromuscular conduction during anesthesiological supply in various surgical interventions.

Haemodynamic effects of pipecuronium bromide (Pi.) and pancuronium bromide (Pa.) were studied on isolated rabbit's heart, guinea pig's tracheal chain as well as the blood pressure in pentobarbital anaesthetized dogs. Pi. induced negative inotropic and chronotropic effects on the isolated rabbit's heart especially in lower concentrations. However, higher concentrations provoked two opposite effects, negative chronotropic and positive inotropic activity. In addition, Pa. in lower concentrations caused positive inotropic and negative chronotropic activity, while higher concentrations induced negative inotropic and chronotropic activity. Cardioinhibitory actions of both tested drugs are not due to either cholinergic or beta 1-adrenergic blocking effect but it may be due to nicotine-like activity. In anaesthetized dogs, i.v. injections of both tested drugs produced a transient decrease in systolic and diastolic pressure in doses above the therapeutic level. This effect may be referred to the partial ganglion blocking effect of both tested drugs.

Patients with compromised cardiovascular function who are undergoing cardiothoracic or other lengthy surgical procedures are at risk of complications from the hemodynamic effects of the long-acting nondepolarizing neuromuscular blocking agents (NMBs), which have been in use for several decades. The development of agents that maintain a stable hemodynamic profile is a potential advantage to this patient population. This literature review, which was completed in May 1992, describes the profiles of doxacurium and pipecuronium, two recently developed long-acting NMBs with increased potency over d-tubocurarine, metocurine, and pancuronium. Doxacurium is a benzylisoquinolinium compound with an ED95 of 0.025 mg/kg. Pipecuronium, a steroidal agent, has an ED95 of 0.04 mg/kg. Twice the ED95 of either agent produces a duration of action comparable to that with 2 times ED95 of pancuronium, but neither doxacurium nor pipecuronium possesses vagolytic or histamine-releasing properties at therapeutic doses. Although no significant differences in serum elimination half-life or plasma clearance of doxacurium have been noted between young and elderly patients, as with other NMBs, the duration of action of doxacurium may be somewhat prolonged and seems to be more variable in older patients and in patients with impaired hepatic or renal function. A similar pattern appears to occur with pipecuronium. Children seem to require higher doses of doxacurium than adults to achieve the same degree of neuromuscular block but recover from the effects more rapidly. Doxacurium and pipecuronium produce no dose-dependent or clinically significant changes in heart rate, mean arterial pressure, or cardiac output either in patients with normal cardiac function or in those with coronary artery disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors evaluated the cumulative dose response of pipecuronium under isoflurane anesthesia, and the efficacy as well as safety of priming principle in 52 patients who underwent elective surgery. The ED95 of pipecuronium was 34.24 +/- 5.34 micrograms.kg-1 in 10 patients and 70 micrograms.kg-1 (not equal to ED95 x 2) was used as total dose (T). The 42 patients were divided to receive either no prime or, 5%, 10%, 15% or 20% of T as a prime followed 5 minutes later by the remaining (intubating) dose. The muscle weakness in awake patients was determined after the priming doses by examining several clinical symptoms and by evaluating the effect of intubating doses on neuromuscular blockade. The priming using 10% of T provided rapid intubating conditions. However, the priming dose caused a significant incidence of symptoms of muscle weakness. Therefore, the priming principle should be used with caution.

Pipecuronium, a new muscle relaxant, was examined in surgical patients in a multi-center cooperative study. Neuromuscular blocking action, circulatory effect and side effects of pipecuronium were investigated in comparison with those of pancuronium bromide. Mechanical twitch responses of adductor pollicis muscle evoked by supramaximal stimulation of the ulnar nerve every ten seconds were recorded. The following results were obtained. 1. Approximately 100% twitch depression was obtained after the administration of pipecuronium 0.04 mg.kg-1. 2. Enflurane and halothane did not influence the onset time and recovery time. But enflurane showed more prolonging effect on the duration of pipecuronium induced block than halothane. 3. No clinically significant changes in heart rate and blood pressure were observed. It was concluded that the minimum of 0.04 mg.kg-1 of pipecuronium is necessary for an initial dose and the maintenance dose of pipecuronium can be reduced under enflurane anesthesia.

Ten patients received increasing doses of pipecuronium at induction of anaesthesia. A dose response relationship was then constructed from which ED90 and ED95 values were measured as 43.4 micrograms.kg-1 and 50.5 micrograms.kg-1 respectively. A further 30 patients received pipecuronium in a dose sufficient to produce greater than 90% neuromuscular block. When the first contraction of the train-of-four had returned to 10% of control, a small increment of atracurium (1.1 mg), vercuronium (0.25 mg) or pipecuronium (0.21 mg) was administered, and this was repeated subsequently using the same criterion of recovery on each occasion. The duration and intensity of the block with pipecuronium increments remained constant. The duration of the block following atracurium or vecuronium was progressively less with subsequent increments until steady state was reached. The final mean durations at steady state were pipecuronium 7.37 min, atracurium 6.99 min, and vecuronium 5.15 min.

Study Objective: To determine whether chronic anticonvulsant therapy affects recovery time from pipecuronium. Design: Open-labeled, controlled study. Setting: Inpatient neurosurgical service at a university medical center. Patients: ASA physical status II and III patients within 30% of their ideal body weight and without significant history of ethanol abuse or renal or hepatic disease. Nineteen patients were admitted into the study and were divided into three groups based on the number of anticonvulsant medications (MED) they were taking: MED=0, control group (6 patients); MED=1, one anticonvulsant (6 patients); MED=2, two or more anticonvulsants (7 patients). Interventions: Intravenous (IV) administration of pipecuronium 80 μg/kg with general anesthesia after thiopental sodium 4 to 6 mg/kg IV, maintained with 70% nitrous oxide in oxygen, 0.2% to 0.3% end-tidal isoflurane, and fentanyl. Measurements and Main Results: The evoked compound electromyogram (ECEMG) of the adductor pollicis brevis muscle was measured after stimulation of the ulnar nerve by train-of-four (TOF) supramaximal impulses at 2 Hz repeated every 20 seconds. Measurements include T-1 % (ECEMG signal at 25%, 50%, and 75% of baseline), TR% (TOF ratio), and recovery index (RI). Patients administered chronic anticonvulsant therapy recovered more rapidly from pipecuronium than untreated patients. For instance, time to 25% recovery of baseline (T-1 25%) was 123 ± 13 minutes for MED=0, 91 ± 7 minutes for MED=1, and 58 ± 5 minutes for MED=2 (p Conclusions: Patients treated with chronic anticonvulsant therapy recovered from pipecuronium more rapidly than unmedicated patients. Furthermore, there seemed to be a dose-effect relationship between the number of anticonvulsants received and a decreased time to recovery from pipecuronium neuromuscular blockade.

We compared the pharmacodynamic effects and hospital costs of three long-acting neuromuscular blocking drugs in a prospective, randomized, double-blind manner. Each neuromuscular blocking drug was administered with fentanyl (50 μg/kg) for intravenous induction of anesthesia for coronary artery bypass surgery. Each patient received twice the 95% effective dose (ED95) of either pancuronium (0.14 mg/kg, n = 10), pipecuronium (0.10 mg/kg, n = 10), or doxacurium (0.05 mg/kg, n = 10). Hemodynamic measurements were recorded at baseline, 5 min after completion of anesthetic induction, immediately after endotracheal intubation, and 5 min after intubation. Only small hemodynamic differences between neuromuscular blocking drugs were observed. Doxacurium (but not pancuronium or pipecuronium) significantly decreased mean arterial blood pressure (from 94 ± 4 mm Hg before induction to 83 ± 3 mm Hg 5 min after intubation); nevertheless, there were no significant between-group differences at any time. Pancuronium increased heart rate (from 68 ± 4 beats/min before induction to 76 ± 5 beats/min 5 min after intubation); however, pancuronium differed significantly from doxacurium and pipecuronium only 5 min after induction and 5 min after intubation. Central venous pressure, pulmonary artery occlusion pressure, cardiac index, and systemic and pulmonary vascular resistance indices did not change. Electrocardiographic abnormalities were observed in two pipecuronium patients: ST segment depression in one and premature ventricular contractions in another. No other electrocardiographic changes were observed. There were no significant between-group differences in the need for hemodynamic interventions. The time from muscle relaxant administration to 95% twitch depression was significantly longer for doxacurium (530 ± 49 s) than for either pancuronium (264 ± 31 s) or pipecuronium (234 ± 23 s). The cost to a 70-kg patient of twice the ED95 dose was: pancuronium, $1.69; pipecuronium, $22.88; and doxacurium, $19.60. We conclude that whereas doxacurium and pipecuronium may be less likely than pancuronium to increase heart rate during induction of anesthesia, these two neuromuscular blocking drugs are no less likely to produce hemodynamic aberrations requiring drug interventions and are considerably more expensive.

Norcuron injection was administered before intubation in the course of anaesthesia in 57 gynaecological operations. Surgical relaxation was performed with Arduan. The patients received varying premedication, introduction, and maintenance narcosis. The combined use of the two non-depolarizing neuromuscular blocking agents proved to be favourable and useful from the anaesthesiological aspect.

To determine the effects of pancuronium and vecuronium on heart rate, 90 patients scheduled for aortocoronary bypass were randomly assigned to one of three groups (30 patients each) which received vecuronium 100 micrograms[sdot]kg-1, pancuronium 100 micrograms[sdot]kg-1, or a mixture of vecuronium (50 micrograms[sdot]kg-1) and pancuronium (50 micrograms[dot]kg-1) in a double-blind fashion during induction of anesthesia. All patients were premedicated with lorazepam prior to surgery, hence avoiding the effects of scopolamine. Our results showed no significant increase in heart rate from the administration of pancuronium, following administration of this drug the heart rate increased by only four beats per minute. The heart rate was unchanged after the mixture, but decreased by twelve beats per minute after vecuronium (P < 0.05). The heart rate response differed by 16 beats per minute between pancuronium and vecuronium. All patients who received either of the neuromuscular relaxants and who were on beta blockers showed a decrease in heart rate. In this study, the administration of pancuronium after an adequate induction dose of fentanyl did not cause tachycardia. We therefore feel that pancuronium still has a role in cardiac anesthesia, especially as the newer muscle relaxants such as vecuronium, pipecuronium and doxacurium are significantly more expensive.

This study was designed to determine the capacity of several anesthetics to augment pipecuronium neuromuscular blockade. The potency of pipecuronium was determined with single-bolus administration of 20-50 micrograms/kg in 160 patients. Patients were anesthetized with N2O/O2 (60:40) supplemented with fentanyl (4-5 micrograms/kg), halothane (0.8%), isoflurane (1.2%), or enflurane (1.7%). Neuromuscular blockade was measured by an acceleration-responsive transducer (the Accelograph, Biometer International, Odense, Denmark). Responses were defined in terms of percent depression in first-twitch height and train-of-four response, and the dose-response curves were constructed after probit transformation of the responses. The dose-response curves were found to be parallel for both first twitch height and train-of-four responses. The dose-response lines for the enflurane and isoflurane groups were displaced significantly (P less than 0.01) to the left of the line for the fentanyl-N2O group. The calculated doses producing 50% depression of first twitch height were 21.9, 21.2, 18.9, and 17.8 micrograms/kg for the N2O-fentanyl, halothane, isoflurane, and enflurane groups, respectively. Corresponding calculated doses for 50% depression of train-of-four response were significantly smaller (15.5, 14.4, 13.7, 11.9 micrograms/kg, respectively). The enhancing effects of the volatile anesthetics were reflected by significant prolongation of the clinical duration of neuromuscular blockade by pipecuronium. It is concluded that the potency of pipecuronium is enhanced more by enflurane and isoflurane than halothane or fentanyl-N2O anesthesia.

We studied the suitability of pipecuronium for maintenance of neuromuscular block during 20 elective Caesarean sections under light general anaesthesia with a rapid-sequence technique facilitated by i.v. suxamethonium 0.6-0.8 mg kg-1. An initial dose of 0.035 mg kg-1 or 0.05 mg kg-1 of pipecuronium provided satisfactory relaxation of similar speed of onset (3.1 +/- 0.3 vs 3.8 +/- 0.6 min, p = 0.25); however the higher dose had a significantly longer duration of action than the lower dose (from injection to recovery to 20% of baseline 13.1 +/- 1.8 vs 39.3 +/- 6.9 min, p0.05). A spontaneous recovery of the T1 twitch of the train-of-four to 25% of baseline (residual block 75%) assured rapid antagonism of the residual block with either edrophonium 0.5 mg kg-1 or neostigmine 0.04 mg kg-1. A residual block greater than 80% depression of T1 markedly prolonged the time taken to achieve a satisfactory reversal. Pipecuronium had negligible cardiovascular effects and placental transfer. It had no observable effect on the newborn. In spite of some advantages, we conclude that pipecuronium is a suitable alternative during Caesarean section only when used judiciously in small doses for maintenance of neuromuscular block and recommend that the initial dose be no greater than 0.035 mg kg-1.

Seventy-five ASA Grades I-III patients (18-85 years, 45-90 kg) were randomized into five groups. All patients received N2O/O2 (2/1) and alfentanil: loading dose (LD) 0.015 mg kg-1 and maintenance dose (MD) 0.045 mg kg-1 h-1 (groups 1-4). Group 1 received propofol (LD 2 mg kg-1 and MD 6 mg kg-1 h-1); Group 2 etomidate (LD 0.3 mg kg-1 and MD 0.6 mg kg-1 h-1); Group 3 midazolam (LD 0.2 mg kg-1 and MD 0.120 mg kg-1 h-1); Group 4 methohexitone (LD 1.5 mg kg-1 and MD 4 mg kg-1 h-1); Group 5 dehydrobenzperidol 0.05-0.23 mg kg-1 and alfentanil (LD 0.100 mg kg-1 and MD 0.060 mg kg-1 h-1). The neuromuscular block induced by pipecuronium (50 micrograms kg-1) was evaluated. No statistically significant differences were found between the five groups as concerned degree of block (expressed as % twitch amplitude in response to the first of the TOF stimuli (Ta1) at intubation, T1 minimum and recovery to Ta1 = 20%, 25% and 75%. Slightly faster intubation was possible when midazolam was used in comparison with propofol, methohexitone or NLA and when etomidate was used in comparison with propofol. A wide range of individual values of maximal neuromuscular blocking activity was found.

The following methods are described for the analytical investigation of pipecuronium bromide. 1. HPLC method. Of the several systems tried for the separation and quantification of impurities and degradation products the best results were obtained using silica as the stationary phase and 43:43:14 mixture of methanol, acetonitrile and concentrated aqueous ammonia containing 0.1 mole/l each of ammonium chloride and ammonium carbonate as the eluent. The validation of this method is presented. The above described aggressive eluent can be successfully replaced by an ion-pairing system using silica as the stationary phase and 96:4 mixture of acetonitrile and water containing 0.1 mole/l sodium perchlorate as the eluent. 2. Thin-layer chromatography. TLC systems are described for the separation and densitometric quantification of the impurities and degradation products of pipecuronium bromide. 3. Spectrophotometry. Two methods are described. The ester groups of the molecule can be determined by the iron(III)-hydroxamate method while for the ion-pair extraction of the quaternary ammonium steroid picric acid or bromthymol blue are used as the reagents. 4. Titrimetry. In addition to the titration with acetous perchloric acid for the assay of the bulk material a microtitration method is described for the determination of pipecuronium bromide in individual lyophylized ampoules (potentiometric titration with 0.1 M silver nitrate).

The mass spectral behaviour of the bis-quaternary salt pipecuronium bromide and some related Cn+ A-n type ammonium salts (n = 1, 2, 3) has been studied and compared. Under EI-MS conditions the evaporation of the samples preceded by in situ dealkylation led to formation of alkyl bromide and amine bases. It has been demonstrated that this technique, completed with quantitation of the relative amount of the decomposition products is applicable to get structure information about the basis part as well as the number and positions of the quaternary centres and the substituents at these centres. The FAB mass spectra of these mono-, bis- and this quaternary ammonium salts were found to be very interesting and provide direct structural information about the salt. They exhibit primary Cn+ intact cations and (Cn+ A-n + 1)+ single charged cluster ions and also fragments characteristic of partial structures at the quaternary centres.

The paper presents clinicopharmacological investigations of Arduan carried out in Hungary and in other countries. The aim of the research work is to find an ideal muscle relaxant without side-effects, which are mainly cardiovascular. Pipecuronium bromide (Arduan) is a compound with steroid structure; it has a long duration of action and, most importantly, it does not affect circulation. The properties of pipecuronium bromide will be discussed and compared to those of pancuronium and vecuronium bromide.

As a consequence of the presence of two ester groups in its molecule the main decomposition route of pipecuronium bromide (active ingredient of Arduan injection) is hydrolysis. In addition to this, autoxidation can also take place. In order to obtain a stable dosage form liophylized ampoules containing mannitol were prepared. Mannitol is not only a filling material but its role is also to decrease the dielectric constant of the solvent water thus increasing the stability of the drug substance before and during the liophylization procedure and after the dissolution of the content of the ampoules for administration. In order to protect the drug molecule against oxidation inert gas atmosphere was used during the production of the ampoules. The preparation is compatible with basic infusion solutions.

A series of bisquaternary ammonio steroids having androstane skeleton have been prepared some of which possessed high neuromuscular blocking activity. One of the series 3 alpha, 17 beta-diacetoxy-2 beta, 16 beta-bis (4,4-dimethyl-1-piperazinyl)-5 alpha-androstane dibromide (19, pipecuronium bromide, ARDUAN) has proved to be a clinically useful agent of long duration of action without side effects. The preparation of pipecuronium bromide and its metabolites and the impurities are also described. The structure of 19 and related compounds was elucidated by spectrometric methods IR, NMR and MS.

The synthesis of Pipecuronium bromide together with the investigation of its impurity profile required the solution of a number of analytical and structural problems. NMR spectroscopical methods received a major role in the structure elucidation of the synthesized compounds. The quantitative assessment of contaminations was also realized by 1H NMR spectroscopy. Out of the large amount of undertaken investigations, here we provide the structural characterization of the contaminating regiosimers of an important intermediate (5 alpha-androst-2-en-17-on) formed in the course of the synthesis, together with the NMR signal assignments of the end-product (Pipecuronium bromide) as measured in D2O and a mixture of CDCl3/DMSO-d6. The structure of a minor contamination of the end-product is also given.

The following methods are described for the analytical investigation of the intermediates of the synthesis of pipecuronium bromide (Arduan) (for the numbering of the intermediates and their impurities see Figure 1.). 1. Gas chromatographic methods (capillary GC using fused silica capillaries Ultra-2 and Silar 10C WCOT) for the impurity profiling of intermediates I, II, IV and V including the identification and spectroscopic characterization of their impurities; 2. TLC methods for the similar characterisation of the further intermediates (III, VI, VII and VIII); 3. Gas chromatographic assay methods for IV and V using fused silica capillary technique and internal standards; 4. Potentiometric titration methods for the determination of VII and VIII using 0.1 M hydrochloric acid as the titrant.

Pipecuronium bromide molecule contains two slightly basic nitrogen atoms in its two piperazine rings. Their pK values are quite similar to each other in consequence of their almost equivalent surroundings. Although the potentiometric titration used mostly for determination of pK values of organic compounds can be performed in this case too, but the polarimetric titration applied by us is more advantageous. Change of pH considerably influences the values of optical rotation; consequently, the curve obtained in this way is more utilizable than that of potentiometric titration. Protonation of two nitrogen atoms one after the other changes the optical rotation of the molecule in opposite direction. Consequently, a minimum can be seen on the curve of optical rotation versus pH value. The exact pK values were determined on the basis of the estimated parameters of a curve established corresponding to an equation and fitted to the measuring points. The sequence of deprotonation of nitrogen atoms could only be ascertained on the basis of the curves of polarimetric titration of compounds containing one piperazine ring; on the basis of the pK values and of the changing direction of optical rotation.