Search

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.

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.

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 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 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).