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A system is proposed for the classification of related organic impurities in drugs and drug products including among others (separated and non-separated) intermediates, various kinds of by-products, among them products of different side reactions, epimeric/diastereomeric, enantiomeric impurities, impurities in natural products, and finally degradation products. Examples are taken mainly from the author's own experience and from among the named impurities in the European Pharmacopoeia with focus on impurities in hydrocortisone, prednisolone, enalapril maleate, lisinopril, ethynodiol diacetate, pipecuronium bromide, cimetidine, and ethynylsteroids. The methodological aspects of impurity profiling from the detection to the identification/structure elucidation and quantitative determination of impurities are briefly summarized.

Purpose. The kinetics of the inhibition of human plasma cholinesterase (ChE) and erythrocyte acetylcholinesterase (AChE) by alcuronium, atracurium, d-tubocurarine, pancuronium, pipecuronium, and vecuronium were studied in blood drawn from 35 surgical patients. Methods. The activities of plasma ChE and erythrocyte AChE were determined by the calorimetric method of Ellman et al., using acetylthiocholine as the substrate. Lineweaver-Burk plots and Dixon plots were used for the analysis of the kinetics of both enzymes. Results. The dissociation constants (K m) of plasma ChE and erythrocyte AChE were 5.00 × 10−5 M and 5.28 × 10−5 M, respectively, indicating that both enzymes have similar affinity to acetylthiocholine. Both Lineweaver-Burk plots and Dixon plots indicated that the six nondepolarizing neuromuscular blocking agents (NMBAs) at different concentrations induce linear mixed-type inhibition. The apparent inhibition constants (K i) of pancuronium (8.72 × 10−8 M) and vecuronium (3.53 × 10−7 M) for plasma ChE inhibition were lower than that of neostigmine (7.36 × 10−7 M), whereas those of the six nondepolarizing NMBAs for erythrocyte AChE were markedly higher than that of neostigmine. Conclusions. Both plasma ChE and erythrocyte AChE were inhibited by six nondepolarizing NMBAs, and the pattern of inhibition of both enzymes was of mixed type. The inhibitory potencies of pancuronium and vecuronium for plasma ChE were larger than that of neostigmine, whereas those of the six nondepolarizing NMBAs for erythrocyte AChE were markedly lower than that of neostigmine. The rank order of relative potency for plasma ChE was pancuronium > vecuronium > pipecuronium > alcuronium > d-tubocurarine > atracurium.

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.

There is a large difference in sensitivity between respiratory muscles and other limb muscles. This phenomenon, known as the respiratory sparing effect (RSE), is well established withd-tubocurarine, pancuronium, and succinylcholine. The purpose of this study is to evaluate the RSE of these new relaxants, vecuronium, pipecuronium, and ORG9426. The study was done in vivo using rats. Mechanical twitch responses of tibialis anterior muscle and diaphragm stimulated with the sciatic nerve and phrenic nerve, respectively, were recorded simultaneously to monitor neuromuscular transmission. Changes of mechanical twitch responses from both muscles were compared following the injection of four kinds of muscle relaxants (pancuronium, picuronium, recuronium, and ORG9426). T, D (%) represents the maximum depression in tibialis anterior and diaphragm, respectively. T−D (%), which means the sensitivity difference between the two kinds of muscle, was calculated by subtracting D from T. The T−Ds of pancuronium, pipecuronium, vecuronium, and ORG9426 were 86.0±2.6%, 81.4±1.9%, 77.7±2.1%, and 74.6±2.7%, respectively. The results indicated that the blockade produced by each muscle relaxant was lower in the diaphragm than in the anterior tibialis muscle. T−D was significantly smaller with vecuronium or ORG9426 than with pancuronium.

Grundlagen: Vecuronium und Atracurium als nicht depolarisierende Muskelrelaxantien mit mittellanger Wirkdauer und Erholungszeit haben seit nunmehr uber 10 Jahren wesentlich zur optimalen Steuerung der bedarfsgerechten neuromuskularen Blockade in Anasthesie und Intensivmedizin beigetragen. Neue Substanzen sollen nun entweder durch kurzere Anschlagzeit und Wirkdauer oder durch hamodynamische Stabilitat Eingang in die klinische Praxis finden.

The objective of this study was to compare the haemodynamic and myocardial effects of pipecuronium and pancuronium in patients undergoing coronary artery bypass grafting (CABG) during benzodiazepine/sufentanil anaesthesia. Twenty-seven ASA III-IV patients received lorazepam (1-3 mg) po and midazolam ( < 0.1 mg.kg-1) i.v. before induction of anaesthesia with sufentanil (3-8 micrograms.kg-1) was administered to facilitate tracheal intubation. According to random allocation, each patient received either pipecuronium (150 micrograms.kg-1) or pancuronium (120 micrograms.kg-1) after sternotomy but before heparinization. Mean arterial pressure, central venous pressure (CVP), pulmonary artery pressure (PAP), ST segment position and ECG (leads III, V5, AVF) were monitored continuously throughout the procedure. Thermodilution determinations of CO in triplicate were made immediately before, and at two and five minutes after muscle relaxant administration. Multiplane transoesophageal echocardiography (TEE, midpapillary short axis views of the left ventricle) images were continuously recorded from ten minutes before until ten minutes after muscle relaxant administration and graded by two experienced echocardiographic readers. Heart rate, MAP and CO increased after administration of pancuronium (by 13.6 beats.min-1, 10.8 mmHg and 1.0 L.min-1 respectively) but not after pipecuronium (P < 0.05). Evidence of myocardial ischaemia was not detected in any patients using ECG ST segment analysis or TEE assessment of left ventricular wall motion. We conclude that pancuronium caused increases in HR, MAP and CO but that neither pancuronium nor pipecuronium caused myocardial ischaemia.

Two groups of 15 patients each, with American Society of Anesthetists’ (ASA) physical status I or II, were administered two single bolus doses of propofol 2 mg/kg or thiopental 4 mg/kg, followed by pipecuronium 0.08 mg/kg. Neuromuscular block was studied using both single twitch and train-of-four (TOF) nerve stimulation. The onset time, duration of clinical action and TOF recovery of pipecuronium were measured. The onset time of pipecuronium was significantly more rapid in patients receiving propofol compared with those administered thiopental (2.75 ± 0.54 vs 3.85 ± 1.08 minutes; p

Various new muscle relaxants are available: atracurium, rocuronium and vecuronium all have an intermediate duration of action, whereas doxacurium and pipecuronium are long-acting and mivacurium is a short-acting nondepolarizing muscle relaxant. The duration of action of atracurium and mivacurium is determined by their degradation, which makes them unique among the nondepolarizing muscle relaxants in this respect. The time of onset is shortest with rocuronium, while vecuronium is probably the muscle relaxant with the fewest undesirable side-effects. In clinical practice, muscle relaxants of short and intermediate duration of action should be preferred, since such agents carry the least risk of residual neuromuscular block postoperatively. Because recovery from them is slow, long-acting agents should preferentially be used only when postoperative mechanical ventilation is intended. The use of a peripheral nerve stimulator is the only reliable guide to appropriate administration of muscle relaxants.

The dose-response relation of pipecuronium, the time course of its neuromuscular blocking effects, and the reversibility of the residual block by neostigmine have been investigated in patients under sevofluraney N2O Anesthesia using a neuromuscular transmission analyzer (Accelograph®, Biometer, Denmark). After an initial dose of pipecuronium (0.04 mg·kg−1, i.v., the maximum block rate, onset time, the time from administration until 25% recovery and 50% recovery of control twitch height of the first response to train-of-four nerve stimulation and the interval time of administration of maintenance dose (0.005 mg·kg−1, i.v.) were 93.7±7.68%, 5.0±1.84, 55.4 ±23.92,73.0±29.44 and 38.7±15.50 minutes, respectively. The average intubation score (excellent; 0, good; 1 fair; 2, poor; 3) was 0.63±0.56 at the level of 95.88±5.06% block. Neostigmine (1.5 mg) promptly reversed the residual neuromuscular blockade induced by pipecuronium (reversal time: 10.1±2.98 minutes). No side effects attributable to pipecuronium was seen in this study.

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.

In this study, combined neuromuscular blocking effects of ORG9426 with other non-depolarizing neuromuscular blocking agents were investigated. About 20% steady state neuromuscular block was established by a continuous infusion of one of 6 neuromuscular blocking agents (ORG9426, vecuronium, pancuronium, pipecuronium, d-tubocurarine and metocurine). Then 1/7 of the ED50 of ORG9426 or one of other neuromuscular blocking agents was administered in a single injection, and the increase in the neuromuscular block was observed. The combined neuromuscular blocking effect of ORG9426 and d-tubocurarine or ORG9426 and metocurine was significantly (P < 0.05) greater than that of each corresponding control (the combination of same neuromuscular blocking agent). The effect of d-tubocurarine was also potentiated by vecuronium, pancuronium and pipecuronium. These potentiations were not observed between ORG9426 and pancuronium, pipecuronium or vecuronium. Possible mechanisms of these synergistic interactions were discussed.

This study was designed to investigate the effect of divided administration of edrophonium on the course of neuromuscular recovery from a pipecuronium neuromuscular blockade. During thiopentone-nitrous oxide-halothane anaesthesia 48 patients were given pipecuronium 70 micrograms.kg-1. Patients were randomly assigned to one of four groups (n = 12 in each) to receive either edrophonium 1 mg.kg-1 (Groups I and II) or edrophonium 0.75 mg.kg-1 (Groups III and IV). In Groups I and III (single-dose groups), edrophonium was administered as a single bolus dose. In Groups II and IV (divided-dose groups) edrophonium was administered as an initial dose of 0.25 mg.kg-1 followed three minutes later by either 0.75 or 0.50 mg.kg-1 respectively. Reversal was attempted at 20% spontaneous recovery of twitch height. Administration of edrophonium in divided doses (Groups II and IV) accelerated the reversal of the pipecuronium neuromuscular blockade. At ten minutes post-reversal, train-of-four (TOF) ratio recovery reached 0.75 or more in 12 (100%) and in ten (83%) patients in Groups II and IV respectively. Similarly, times to attain a TOF of 0.75 (SEM) were shorter in the divided-dose groups than in the single-dose groups (P less than 0.05), being 354.5 (38.7) and 398.3 (49.1) sec in Groups II and IV vs 705.4 (66.6) and 651.2 (54.3) sec in Groups I and III respectively. Time was counted from the first administration of edrophonium. It is concluded that administration of edrophonium in divided doses produced a faster reversal of residual pipecuronium-induced neuromuscular blockade than single bolus administration. Also, administration in divided doses reduced the requirements of edrophonium needed for reversal of pipecuronium neuromuscular blockade.

Neostigmine 0.06 mg · kg−1 or edrophonium 1 mg · kg−1 were administered to two groups of 15 patients each for antagonism of pipecuronium-induced neuromuscular block at 20% spontaneous recovery of the first twitch (T1) of the train-of-four (TOF) stimulation. The mean onset of action (± SEM) of edrophonium (18.1 ± 2.4 sec) was significantly more rapid (P < 0.01) than that of neostigmine (47.6 ± 4 sec), as were the times taken to attain a TOF ratio of 0.25 and 0.5. Nevertheless, the reversal time (time taken from the end of injection of the antagonist until TOF ratio value had reached 0.75) was significantly shorter (P < 0.01) in the neostigmine than in the edrophonium group (499.3 ± 62 vs 767 ± 52 sec respectively). The TOF ratio ten minutes after reversal was greater in the neostigmine group than in the edrophonium group (P < 0.01), 0.78 ± 0.02 vs 0.68 ± 0.02 min respectively. At that time, 33% (5 out of 15) and 80% (12 out of 15) patients failed to be reversed adequately (TOF ratio of 0.75) after neostigmine 0.06 mg · kg−1 and edrophonium 1 mg · kg−1, respectively. Administration of one additional dose (one-third of the initial dose) of the same antagonist resulted in adequate antagonism in the remaining five patients in the neostigmine group and in nine patients in the edrophonium group. Two such doses were required in the remaining three patients in the latter group. The mean total dose of neostigmine and edrophonium employed in this study was 0.067 ± 0.002 and 1.3 ± 0.05 mg · kg−1, respectively. Under the conditions of this study, edrophonium in a dose of 1 mg · kg−1 did not consistently antagonize residual neuromuscular blockade induced by pipecuronium at 20% recovery of T1.

Pipecuronium bromide (Arduan) is a bisquaternary, steroid-type neuromuscular blocking agent in clinical use in Eastern Europe. Before its introduction into clinical practice in the USA, in the first phase of this study the neuromuscular potency of pipecuronium was determined under "balanced" and enflurance anaesthesia by the cumulative log dose-response method in 30 patients each. In the second phase the intubation and onset times, clinical duration of the first and repeated doses, spontaneous recovery index, reversibility of its residual neuromuscular effect by an anticholinesterase and its effect on heart rate and blood pressure was compared with the same variables observed in patients, anaesthetized with identical techniques but who had received vecuronium or pancuronium. The neuromuscular potency of pipecuronium was greater under enflurane (ED95 = 23.6 +/- 1.1 micrograms.kg-1 (mean +/- SEM)] than under balanced (ED95 = 35.1 +/- 17 micrograms.kg-1) anaesthesia. Pipecuronium was more potent than vecuronium under both balanced (ED95 = 45.8 micrograms.kg-1) and enflurane anaesthesia (ED95 = 27.4 micrograms.kg-1). Following the administration of 2 x ED95 doses there were no clinically significant differences in the intubation or onset times of pipecuronium, vecuronium and pancuronium. Under balanced anaesthesia the clinical duration of 2 x ED95 dose of pipecuronium (110.5 +/- 0.3 min) or pancuronium (115.8 +/- 8.1 min) were similar and about three times longer than that of vecuronium (36.3 +/- 2.1 min). The recovery indices of pipecuronium (44.5 +/- 8.2 min) and pancuronium (41.3 +/- 4.2 min) were also similar and about three times longer than that of vecuronium (14.3 +/- 1.4 min).(ABSTRACT TRUNCATED AT 250 WORDS)