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Background: Residual neuromuscular block at the end of surgery may compromise the patient's safety. The risk of airway complications can be minimized through monitoring of neuromuscular function and reversal of neuromuscular block if needed. Effective reversal can be achieved with selective relaxant binding agents, however, sugammadex is the only clinically approved drug in this group. We investigated the concentration-response properties of a novel selective relaxant binding agent, carboxymethyl-γ-cyclodextrin for the reversal of neuromuscular block. We evaluated the hypothesis that it is equally potent for reversing neuromuscular block as sugammadex., Methods: Phrenic nerve - hemidiaphragm tissue preparations were isolated from male Wistar rats and suspended in a tissue holder allowing electrical stimulation of the nerve and monitoring of muscle contraction force. Concentration-response relationships were constructed for the neuromuscular blocking agents rocuronium, pipecuronium, and vecuronium. The half-effective concentrations of sugammadex and carboxymethyl-γ-cyclodextrin for reversal of neuromuscular block were determined., Results: The half effective concentrations (95% confidence interval, CI) were 7.50 (6.93-8.12) μM for rocuronium, 1.38 (1.33-1.42) μM for pipecuronium, and 3.69 (3.59-3.80) μM for vecuronium. The half effective concentrations (95% CI) of carboxymethyl-γ-cyclodextrin and sugammadex were 35.89 (32.67-39.41) μM and 3.67 (3.43-3.92) μM, respectively, for the reversal of rocuronium-induced block; 10.14 (9.61-10.70) μM and 0.67 (0.62-0.74) μM, respectively, for the reversal of pipecuronium-induced block; and 376.1 (341.9-413.8) μM and 1.45 (1.35-1.56) μM, respectively, for the reversal of vecuronium-induced block., Conclusions: Carboxymethyl-γ-cyclodextrin is an effective, but less potent agent for reversal of neuromuscular block than sugammadex., (© 2021. The Author(s).)

Intraoperative correction of preload in patients with acquired valvular disease (AVD) complicated by right-ventricular failure and severe pulmonary hypertension necessitates search for pathogenetically based algorithms of anesthesiological strategy. The objective of this study was to develop a strategy of assessing and treating the preload at the stage of induction anesthesia in patients with right-ventricular failure. During surgery central hemodynamic parameters and their response to a short head-down-tilt (15-20 degrees) were evaluated in patients (n = 42) with cardiac index (CI) less than 2 l/min/m2 after induction anesthesia. The patients were divided into 2 groups with different severity of preoperative status. Group 1 (main) included 24 patients with stages II-III cardiac failure (according to N. Strazhesko and B. Vasilenko) and group 2 (control) consisted of 18 patients with stage IIA cardiac failure. Progressing preoperative cardiac failure resulted in decrease of cardiac index and failure of compensatory hemodynamic mechanisms in AVD patients. The level of right-ventricular preload, pulmonary resistance, and stroke index were lower in group 1 than in the controls; however, 8% of group 1 patients responded positively to increased preload. In the control group 50% responded favorably to head-down-tilt. Hence, comprehensive assessment of cardiac index, central hemodynamic parameters and their response to head-down tilt help individually choose the anesthesiological strategy.

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.

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)

We have examined the prolongation of a maintenance dose of vecuronium after an intubating dose of pipecuronium in 45 patients who received either pipecuronium 70 micrograms kg-1 or vecuronium 200 micrograms kg-1 i.v. for tracheal intubation, followed by either pipecuronium 10 micrograms kg-1 or vecuronium 15 micrograms kg-1 for maintenance of neuromuscular block. The duration of the vecuronium maintenance dose was greater after pipecuronium (40 (SD 12) min) than after vecuronium (29 (9) min) (P = 0.02). The duration of pipecuronium after pipecuronium (49 (15) min) was similar to that of vecuronium after pipecuronium. We conclude that the duration of action of vecuronium is prolonged by prior administration of pipecuronium.

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.

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.

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 neuromuscular response to pipecuronium bromide (Arduan), 70 micrograms/kg, was studied in 20 elderly (greater than 70 yr) and 10 younger patients (less than 60 yr) during nitrous oxide, fentanyl, and droperidol anesthesia. The adductor pollicis response to single 0.2-ms supramaximal pulses was recorded. Although all younger patients were completely paralyzed, 2 of 20 elderly patients did not attain 90% paralysis. Onset time in the elderly was prolonged (6.9 +/- 2.6 vs 4.3 +/- 1.5 min, P less than 0.02). Spontaneous recovery was similar in both groups, with 75% recovery occurring at 133 +/- 52 min in the elderly and 146 +/- 46 min in the younger patients. The pharmacokinetic variables were similar for the two groups, and pharmacodynamic analysis revealed a similar sensitivity at the neuromuscular junction. The pharmacologic actions of pipecuronium in otherwise healthy patients do not differ between young and elderly adults.

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.

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.

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).

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.

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 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.

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 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.

The experimental results in animals suggest that pipecuronium bromide offers the possibility of a neuromuscular blocking agent without side effects for surgical procedures of long duration. Its mechanism of action is twofold: 1. antagonism of acetylcholine effect at neuromuscular junction (postsynaptic nicotine receptors), 2. inhibition of acetylcholine release (presynaptic nicotine receptors). Its neuromuscular blocking potency is somewhat greater (2.0-3.0) than that of pancuronium in all species studied, and the duration of action is twice of that. It has no remarkable cumulative effect. Neostigmine rapidly and completely antagonises the neuromuscular blockade caused by pipecuronium. Certain structural properties (e.g. pipecuronium has no acetylcholine-like fragments in contrast with pancuronium and the interonium distance is also considerably larger than in pancuronium) may predict advantages. This has been proved by low vagal blocking--and ganglion--blocking potencies. On the basis of these a wide margin of safety can be expected in humans as well in preventing cardiovascular side effects. Pipecuronium is also characterized by interactions--only slight interactions--with other drugs used mainly in perioperative period.

The pharmacokinetics of pipecuronium bromide (Arduan) studied in animals (rat, dog, cat) and in humans can be described by a two-compartment open model. The elimination half-life in animals was found to be around 40 min, in humans between 44-137 min. The main route of elimination is the excretion of the unchanged molecule in urine. In kidney patients the elimination becomes longer. The metabolism in the elimination is less important, in rats 3-hydroxy-, 17-hydroxy and 3,17-dihydroxy metabolites have been identified.

Pipecurium bromide, a new non-depolarizing myorelaxant, was administered intravenously, at a dose of 0.06 mg/kg, to 10 patients suffering from expansive endocranial lesions, who had been anesthetised to undergo neurosurgery. The following parameters were recorded simultaneously, before and after drug administration: intracranial pressure, mean arterial blood pressure, central venous pressure, heart rate and end tidal CO2. No statistically significant changes in the above parameters were observed following the administration of the myorelaxant; these observations, which were considered together with the long duration of action, confirm that pipecurium bromide is a valuable tool in anesthesia for neurosurgery.

The use of pipecuronium in two patients with myasthenia gravis undergoing thymectomy is described. Neuromuscular function was monitored throughout using the train-of-four (TOF) mechanical twitch response. The cumulative dose-response to pipecuronium was determined in both patients during nitrous oxide-oxygen-narcotic anaesthesia. Both patients were sensitive to pipecuronium. The ED50 doses of pipecuronium were 11.6 and 11.1 micrograms.kg-1 and the ED95 doses were 35 and 33.3 micrograms.kg-1 in patients #1 and 2 respectively. Edrophonium 1 mg.kg-1 and neostigmine 0.06 mg.kg-1 were administered to patients #1 and 2 respectively for antagonism of residual neuromuscular blockade at 25 per cent spontaneous recovery of first twitch (T1) of the TOF stimulation. As with other non-depolarizing muscle relaxants pipecuronium in reduced dosage and with careful neuromuscular monitoring can be used to provide surgical relaxation safely in patients with controlled myasthenia gravis.

The onset time and tendency to cumulation of pipecuronium and high-dose vecuronium were studied during nitrous oxide anaesthesia supplemented with isoflurane. Pipecuronium 0.06 mg.kg-1 had a similar duration of action to vecuronium 0.015 mg.kg-1 (42 vs 49 min). Patients who received vecuronium had a shorter onset time of neuromuscular blockade (p less than 0.01). The use of pipecuronium was associated with marked cumulation.

The onset time and tendency to cumulation of pipecuronium and high-dose vecuronium were compared during nitrous oxide anaesthesia supplemented with a propofol infusion. Pipecuronium 0.06 mg.kg-1 had a similar duration of action to vecuronium 0.2 mg.kg-1 (49 vs 43). Patients who received vecuronium had a shorter onset time of neuromuscular blockade (p less than 0.01). Neither pipecuronium nor vecuronium showed marked cumulation.

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.

The neuromuscular and cardiovascular effects of three different doses of pipecuronium were studied in 60 adult patients. Neuromuscular blockade was measured using electromyographic activity of the adductor pollicis muscle after supramaximal stimulation of the ulnar nerve at 0.1 Hz and 2 Hz. Three subgroups (A, B, C) of 20 patients received pipecuronium doses of 60, 80 and 100 micrograms kg-1, respectively, as an intubating dose and, when necessary, maintenance doses were administered at 25% single twitch recovery in a dose of one-quarter of the initial one. The onset time was 5.4 +/- 2.0 min for 60 micrograms kg-1 and similar for 80 and 100 micrograms kg-1 (3.9 +/- 1.1 and 3.6 +/- 1.1 min). The duration of action was 45 +/- 10 min for 60 micrograms kg-1, 74 +/- 25 and 94 +/- 21 for 80 and 100 micrograms kg-1, respectively. The recovery indices were measured in all patients after neostigmine administration (Groups B and C) and after neostigmine and edrophonium (Subgroup A, 10 patients each). TOF ratio was significant only 2 min after edrophonium administration in Group A patients. Variations of heart rate and blood pressure were not significant.

The pharmacodynamics and -kinetics of pipecuronium were studied in 12 patients, six of whom received 100 micrograms kg-1 for laryngectomy (Group L), and six who underwent choledochotomy after insertion of the T-drain and were given 50 micrograms kg-1 (Group C). Onset time and clinical duration were 2.3 and 109 min and 2.8 and 39 min in Groups L and C, respectively. All patients could be sufficiently reversed with neostigmine. Terminal half-lives were 101.5 min (Group L) and 179 min (Group C) in a three-exponent decay; the distribution volumes at steady state 0.339 l kg-1 (Group L) and 0.506 l kg-1 (Group C); the plasma clearance 3.4 ml kg-1 min-1 (Group L) and 2.5 ml kg-1 min-1 (Group C). Within 24 h, 38.6% and 37% were excreted unchanged in the urine and 4.4% and 1% as 3-desacetyl pipecuronium in Groups L and C, respectively. Within 24 h only 2% was excreted into the bile in Group C. Distribution volume and terminal half-life in Group C were positively correlated with pre-operative serum aminotransferase levels (P less than 0.005).

We have examined the effects of a rapid bolus dose of pipecuronium 0.1 mg kg-1 or tubocurarine 0.5 mg kg-1 on plasma histamine concentration, heart rate and arterial pressure in 20 patients (n = 10 in each group). Anaesthesia was induced with thiopentone 6 mg kg-1 i.v. and maintained with 70% nitrous oxide and halothane in oxygen. Neuromuscular blocking drugs were administered 4 min after administration of thiopentone. Venous blood samples were obtained before induction, 1 min after thiopentone and 1, 3 and 5 min after the administration of the neuromuscular blocking drugs. Tubocurarine caused 240% and 210% increases in plasma concentration of histamine at 1 and 3 min, respectively. These changes were significant (P less than 0.05) at 1 min and associated with a decrease in mean arterial pressure and an increase in heart rate. None of the 10 patients receiving pipecuronium had a significant change in plasma concentration of histamine or in haemodynamic variables.

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.

Study Objective: To determine the intubating conditions following the administration of pipecuronium bromide in doses of two (0.07 mg/kg) or three (0.1 mg/kg) times ED95 (average dose that gives 95% block of the first twitch)., Design: To compare intubating conditions at 11/2 and 21/2 minutes in 41 patients receiving balanced anesthesia., Setting: Surgical patients at Thomas Jefferson University Hospital., Patients: Forty-one patients undergoing surgical procedure who received general anesthesia., Interventions: After obtaining a stable baseline of train-of-four (TOF), 41 patients randomly received either 0.07 mg/kg or 0.1 mg/kg of pipecuronium as a single intravenous (IV) bolus dose, and the trachea was intubated either at 11/2 or 21/2 minutes., Measurements and Main Results: Intubating conditions at 21/2 minutes appeared significantly better than those at 11/2 minutes, regardless of the pipecuronium dose. The mean time for T1 (first twitch of TOF) to reach 50% and 90% suppression was 1.36 +/- 0.51 minutes and 2.29 +/- 0.8 minutes, respectively, for the 0.07 mg/kg dose and 1.07 +/- 0.27 minutes and 1.72 +/- 0.45 minutes, respectively, for the 0.1 mg/kg dose. This did not make a significant difference in intubating conditions at either time. The time to 25% recovery of T1 was 68.2 +/- 22 minutes for the 0.07 mg/kg dose and 121.5 +/- 49 minutes for the 0.1 mg/kg dose. In patients who had spontaneous recovery of T1 to between 10% and 25% of control, administration of neostigmine or edrophonium resulted in identical recovery in 10 minutes. However, in patients with less than 10% spontaneous recovery of T1, neostigmine appeared to be superior to edrophonium., Conclusion: Pipecuronium has a relatively rapid onset. The trachea could be intubated successfully in 11/2 minutes with a dose of either 0.07 mg/kg or 0.1 mg/kg. If the clinical situation requires perfect relaxation with no movement or bucking, we recommend waiting at least 21/2 minutes.

This study was designed to compare the cardiovascular effects of pipecuronium bromide (PIP) to vecuronium (V) when combined with sufentanil (SF) in patients undergoing coronary artery bypass surgery. Eighty-two patients were studied; 40 were normotensive and 42 had hypertension currently controlled by pharmacological therapy. All patients were randomly assigned to receive either intravenous V, 0.12 mg/kg, or PIP, 0.10 mg/kg. Anesthesia was induced with SF, 6 micrograms/kg, while breathing 100% oxygen. Hemodynamic data including heart rate, mean arterial pressure, pulmonary capillary wedge pressure, central venous pressure, cardiac index, systemic vascular resistance, pulmonary vascular resistance, and left ventricular stroke work index were collected at five points: prior to induction, 3 and 6 minutes after the complete administration of PIP or V, and 3 and 6 minutes after intubation. There were no statistical differences in hemodynamic changes associated with either PIP or V. In addition, there were no statistical differences in the hemodynamic parameters measured at the five time points between the normotensive and hypertensive patient groups. This study demonstrates that there are no significant hemodynamic changes between SF/PIP and SF/V when used during coronary artery surgery. Due to its associated stable hemodynamics, as well as its long duration of action, PIP could become a commonly used muscle relaxant for anesthesia for cardiac surgery.

Haemodynamic variables were measured following administration of pipecuronium 70 micrograms.kg-1 and pancuronium 90 micrograms.kg-1 (approximately equivalent to 1.5 x ED95) in patients anaesthetised with fentanyl 50 micrograms.kg-1 and scheduled to undergo coronary artery bypass grafting. There were significant increases in heart rate (22%), mean arterial pressure (10%), cardiac index (16%), and the rate pressure product (35%) following administration of pancuronium. The absolute values of these parameters were, however, within acceptable clinical limits. Administration of pipecuronium produced minimal and insignificant changes in these parameters. Other measured or derived indices showed only small changes with both agents and these were generally insignificant. There were no incidences of significant bradycardia following pipecuronium administration. The results from the present study suggest that pipecuronium would have advantages for use in patients with significant cardiovascular disease.

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 less than 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 less than 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 less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

The neuromuscular effects of pipecuronium bromide have been evaluated in 90 adult patients anaesthetized with thiopentone, nitrous oxide in oxygen and intravenous fentanyl with or without halothane. Eighty patients received pipecuronium 45 micrograms kg-1 and the remaining ten 70 micrograms kg-1. A separate group of 10 patients received pancuronium in a dose of 60 micrograms kg-1 (equipotent to pipecuronium 45 micrograms kg-1). Neuromuscular block was measured using a single-twitch or train-of-four mode of stimulation. The time to onset of maximum block with pipecuronium 45 micrograms kg-1 varied between 3.5 and 5.7 min depending on the mode of stimulation and the anaesthetic technique used. The time to 25% recovery of this dose varied between 41 and 54 min. The recovery index (time from 25 to 75% recovery) averaged 29 min. These values were generally similar in the group receiving pancuronium 60 micrograms kg-1. The time to onset of complete block with 70 micrograms kg-1 of pipecuronium averaged 2.5 min and the duration to 25% recovery 95 min. There were no significant changes in heart rate and arterial pressure with the use of pipecuronium. The results show pipecuronium to be a drug resembling pancuronium in its neuromuscular effects when used in equipotent doses.

To study the effects of succinylcholine on subsequent pharmacodynamics of nondepolarizing muscle relaxants, a comparative pharmacodynamic study was carried out in patients having balanced anesthesia (thiopental, fentanyl, nitrous oxide/oxygen) in whom equipotent doses of pipecuronium (80 micrograms/kg) and pancuronium (100 micrograms/kg) were given with or without prior administration of succinylcholine (1 mg/kg). Fifty-two patients were randomly assigned to one of the following four groups: 1, pancuronium (100 micrograms/kg); 2, pipecuronium (80 micrograms/kg); 3, succinylcholine (1 mg/kg) plus pancuronium (100 micrograms/kg); and 4, succinylcholine (1 mg/kg) plus pipecuronium (80 micrograms/kg). In groups 3 and 4, the nondepolarizing relaxant was given after succinylcholine when the twitch height recovered to 75% of its control value. For maintenance of neuromuscular blockade, additional increments of pancuronium (20 micrograms/kg) or pipecuronium (15 micrograms/kg) were given. Neuromuscular function was monitored throughout induction, maintenance, spontaneous recovery, and pharmacologic reversal of the neuromuscular block. Mean onset times for pancuronium (group 1) and pipecuronium (group 2) given without succinylcholine were (mean +/- SEM) 2.5 +/- 0.3 and 2.8 +/- 0.2 min, respectively. Mean onset times (times to maximum twitch depression) of the two drugs given after succinylcholine (groups 3 and 4) were significantly shorter (1.4 +/- 0.4 and 1.6 +/- 0.1 min, respectively). Clinical durations (i.e., until 25% twitch recovery of pancuronium and pipecuronium) were not significantly different among the four groups, varying from 81.1 +/- 5.4 (group 4) to 107.0 +/- 17.0 (group 2) min.(ABSTRACT TRUNCATED AT 250 WORDS)

Norcuron injection has been applied for the prolongation of the duration of muscle relaxing action of Arduan in 104 patients. The patients underwent major surgery and 1/5 of them were of advanced age. Neuromuscular blockade could be prolonged for the required duration of operation with lower doses of Norcuron (2 mg, 1 mg) than the currently used ones. For avoiding eventual cumulation or synergism the repetition of lower doses to meet the requirements seems to be the most advantageous method.

Pancuronium, vecuronium and pipecuronium are quaternary ammonium steroidal neuromuscular blocking agents. These drugs are typical nondepolarizing muscle relaxants. The steroidal compounds and/or their metabolites have been determined using mass spectrometry or gas chromatography. In this review, these analytical methods and application of the methods to pharmacokinetics are introduced.

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.

We have studied five pigs undergoing bilateral clamping of the renal pedicles, seven pigs undergoing orthotopic liver transplantation and three control animals without surgery in order to examine the roles of the kidney and liver in the plasma clearance of pipecuronium. An i.v. infusion of pipecuronium was controlled to maintain a constant 90-95% twitch depression throughout the investigation. The right sciatic nerve was stimulated continuously with supramaximal stimuli at 0.1 Hz and the force of the corresponding evoked isometric muscle contraction was recorded continuously. Control pigs needed an infusion rate of pipecuronium 8-10.7 micrograms kg-1 min-1. In the renal group, it was necessary to reduce the infusion rate of pipe-curonium by about 25% after clamping both renal vascular pedicles (P less than 0.05 compared with controls); in pigs undergoing liver transplantation, it was necessary to reduce the rate by approximately 80% after clamping hepatic vessels (P less than 0.05 compared with controls and from the period after clamping of renal vessels). After hepatic recirculation, the infusion rate of pipecuronium was increased progressively to a rate which corresponded to 50% of baseline values (P less than 0.05 compared with the anhepatic phase and from controls). Plasma concentrations of pipecuronium were comparable in the three animal groups and did not change significantly during the study. These data suggest that the liver plays a more important role than the kidney in the plasma clearance of pipecuronium in pigs.

We determined the cumulative dose-response relations of pipecuronium in infants and children during nitrous oxidehalothane anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. Patients were stratified into four groups according to age: 3 mo or older but not yet 6 mo (n = 10), 6 mo or older but not yet 12 mo (n = 10), 1 yr or older but not yet 3 yr (n = 10), and 3 yr or older but not yet 6 yr (n = 9). The mean ED50 of pipecuronium in these age groups was 18, 20, 21, and 24 micrograms/kg, respectively; the mean ED95 was 33, 38, 47, and 49 micrograms/kg, respectively. The ED95 of pipecuronium was statistically significantly less for the 3-6-mo-old patients than for children between 1 and 6 yr of age. Similarly, pipecuronium dosage requirements calculated on the basis of body surface area were significantly less in infants 3-12 mo of age than in children 1-6 yr of age. Thus, compared with children, infants appear to be more sensitive to the neuromuscular blocking effects of pipecuronium. Duration (T25) of action after cumulative dosing with pipecuronium was approximately 20 min in infants and 30 min in children. Spontaneous recovery indices were not prolonged in the younger patients. The average T25-75 recovery index was 27.1 +/- 9.6 min. There were no changes in cardiac rhythm, heart rate, or blood pressure attributable to pipecuronium during this study.

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)

The pharmacokinetics of pipecuronium bromide was studied in 9 male patients (ASA class 1-2, 20-65 years of age). Following a single intravenous dose of pipecuronium 0.08 mg.kg-1, plasma levels were measured by capillary gas chromatography. Plasma concentration-time curves were evaluated by fitting the data to a bi-exponential equation. The pharmacokinetic parameters of pipecuronium were compared with those of pancuronium (0.08 mg.kg-1) and vecuronium (0.08 mg.kg-1) previously obtained under the same anesthesia (66% N2O, 33% O2 and 1% halothane). With pipecuronium, following pharmacokinetic parameters were obtained; distribution half-life; T1/2 alpha = 3.9 +/- 0.7 min (mean +/- SEM), elimination half-life; T1/2 beta = 102 +/- 12 min, volume of the central compartment; V1 = 95 +/- 13 ml.kg-1, volume of distribution at steady state; Vdss = 264 +/- 41 ml.kg-1, clearance; Cl = 1.8 +/- 0.2 ml.min-1.kg-1. Microconstants of two-compartment open models (k12, k21, k10) were also calculated. Using Mann-Whitney's U-test, these parameters of pipecuronium were compared with those of pancuronium (n = 3) and vecuronium (n = 4). V1 and Vdss of pipecuronium were significantly larger than those of pancuronium (V1; 38 +/- 12 ml.kg-1 and Vdss; 120 +/- 4 ml.kg-1) (both P less than 0.10). Reflecting the larger central volume of pipecuronium, pipecuronium tended to have a larger clearance than that of pancuroniumu (Cl; 1.1 +/- 0.2 ml.min-1.kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanomyoscopy as an objective method for determining the degree of decurarisation is particularly useful in the case of uncooperative patients and those who are incapable of adequate neck flexion mostly for spinal column diseases. The authors use for that purpose a Czechoslovak-made neuromuscular stimulator (LSN 110), with constant 50 Hz frequency of stimulation, 0.3 ms impulse duration, max. 50 mA and, depending on skin impedance, 5-140 V. The stimulator switch is manually controlled. The absence of muscular fatigue (fade) on single as well repeated stimulation lasting only a fraction of a second necessary to elicit muscular response does not rule out residual curarisation despite the fact that less than 70% of the cholinergic receptors are blocked. The only reliable sign of clinically sufficient decurarisation is the ability of the muscles of the hand to maintain contraction on tetanic stimulation of the motor point of the ulnar nerve in the wrist for at least 5 seconds without fatigue, and that even on a repeated exercise. This corresponds to a block of less than 60% of the cholinergic receptors. The patient's ability to raise his or her head and to keep it raised at 4 fingerbreaths for a period of 4 seconds is also a manifestation of clinically sufficient decurarisation. The value of forced expiratory volume is not conclusive evidence of sufficient decurarisation, it only gives a rough idea of its degree. The final decision is up to the an anaesthesiologist, his knowledge and experience based on objective data.

Neuromuscular blocking and circulatory actions of pipecuronium bromide (PPB) were evaluated in patients under halothane-nitrous oxide-oxygen anesthesia in comparison with those of pancuronium bromide (PCB) in a multi-center cooperative study. Twitch tension of the adductor pollicis muscle was elicited by supramaximal stimulation of the ulnar nerve every 10 seconds. The study was performed according to the following 4 steps and the results were obtained. 1) Cumulative administration of 0.01 mg.kg-1 of PPB or PCB resulted in the potency ratio of 1.3:1.0 and the dose response curves of the two agents paralleled with each other. 2) With PPB 0.05 mg.kg-1 or 0.1 mg.kg-1, almost 100% block of the twitch was obtained. Both duration of action and the recovery time were shorter with 0.05 mg.kg-1 group. 3) After the first dose of 0.04 mg.kg-1 when the twitch recovered to 25% of the initial height 0.02 mg.kg-1 was given and this was repeated. Intervals between the doses showed large individual differences and no significant change was observed with repeated doses. 4) Safety of the drug. No significant change in heart rate or blood pressure was observed with PPB but with PCB a significant increase in heart rate was observed. The study revealed that PPB is slightly more potent than PCB and the duration of action is longer, but it has no untoward cardiovascular action in man under halothane anesthesia.