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The clinical trial of the new non-depolarizing muscle relaxant 2 beta,16 beta-bis-(4'-dimethyl-1'-piperazino)-3 alpha,17 beta diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan) was performed on 80 patients who had to undergo medium and major size intraabdominal operation on the basis of chronic surgical indication. Four types of general anaesthetic methods were applied, neuroleptanalgesia, halothane, halothane-fentanyl combination and hydroxydione. The clinical applicability of pipecurium bromide was tried to establish the dose needed for complete muscle relaxation initially and repeatedly and the effect of antagonist drugs on the muscle relaxation. We investigated the duration of the first and repeated dose of the relaxant. Heart rate and arterial blood pressure were measured, mean arterial pressure and pulse pressure were calculated. In 10 patients of the halothane group the behaviour of some haemodynamic parameters was investigated. The changes of acid base parameters, blood gases, serum electrolytes and blood sugar were also observed. The administered doses were initially 3.88 mg/h, repeated doses 2.32 mg/h, this means 0.052 mg/kg body weight initially and 0.026 mg/kg body weight repeatedly The duration of effect after the first dose was 53 min, after the repeated doses 45 min. There were no direct effects on heart rate and arterial blood pressure. It did not affect myocardial contractility or work function, there was no remarkable changes in cardiac output. There were no direct metabolic changes due to pipecurium bromide. The relaxant has no histamine releasing effect. At the end of the anaesthesia the effect can be antagonized with neostigmine. During our observations there were no side effects or allergic reactions caused by pipecurium bromide.

Cases of suicide committed with neuromuscular blocking agents have been investigated. Both cases involved anesthesiologists who took the muscle relaxants suxamethonium chloride (Sukolin) or pipecuronium bromide (Arduan) and a rapid-acting barbiturate, 5-sec-butyl-5-ethyl-2-thiobarbituric acid (Inactin). The examinations were performed by using gas chromatography and mass spectrometry. The quantitative data obtained showed that doses useful in general anesthesiological practice were applied. Metabolites were found despite their fast metabolizing character.

2 beta, 16 beta-Bis-(4'-dimethyl-1'-piperazino)-3 alpha, 17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan), a newly synthetized bisquaternary steroid, produces competitive neuromuscular blockade in chicks, rats, cats, rabbits and dogs. The onset of paralysis is rapid. Pipecurium bromide is 2-4 times as potent as pancuronium bromide. The duration of action is about twice as long as that of pancuronium bromide in equiactive doses. Neostigmine rapidly and completely antagonises the neuromuscular blockade caused by pipecurium bromide. Even one hundred times higher dose than the effective blocking dose (2-6 microgram/kg) does not influence the cardiovascular system. Higher doses (1-2 mg/kg) cause transient decrease in blood pressure, in 10-20 mg/kg doses pipecurium bromide has ganglion blocking effect. In 1 mg/kg dose pipecurium bromide does not release histamine. Many times higher doses than the effective dose administered for 20 days, do not cause any toxic damage to respirated beagle dogs. According to examinations in rats, the placentary transfer of pipecurium bromide is lower than 0.1%. According to preliminary clinical examinations pipecurium bromide is free from side effects, and elicits as well controllable muscle relaxation.

The pharmacokinetics and hepatic disposition of pipecuronium have been investigated in cats with normal and absent renal function. A combined fluorimetric and chromatographic technique was used to determine the concentrations of pipecuronium and its metabolites in the samples. Following intravenous injection of 150 micrograms kg-1, pipecuronium disappeared from the plasma bi-exponentially with half-lives of 9.8 +/- 5.4, 77.7 +/- 9.7 min and 7.2 +/- 5.0, 100, 6 +/- 23.7 min; the Vd was 362.3 +/- 74.9 ml kg-1 and 123.7 +/- 14.6 ml kg-1 and the clearance was 5.0 +/- 0.9 ml min-1 kg-1 and 1.0 +/- 0.1 ml min-1 in the animals with and without renal function, respectively. In the animals with normal kidney function 53%, 12% and 8% of the administered dose of pipecuronium were recovered within 8 h in the urine, bile and liver, respectively. In 'nephrectomized' cats the lack of renal elimination was to a great extent compensated for by increased hepato-biliary elimination. Absence of renal function significantly altered the pharmacokinetic parameters and prolonged the time-course of the neuromuscular blocking effects of pipecuronium. Neither temporary hepatic exclusion nor intraportal administration of pipecuronium indicated any significant role of the liver in handling pipecuronium. Renal excretion seems to be the predominant route of elimination. No metabolites were found in this study.

The creatine kinase activity in the skeletal muscles and heart of rats is investigated under the effect of preparations of the depolarizing (myorelaxin) and nondepolarizing (tubocurarin, arduan) action. It is stated that arduan and tubocurarin inhibit the enzyme activity in the myocardium but not in skeletal muscles. The creatine kinase activity in the myocardium extract decreases twice under the tubocurarin effect and more than thrice under the arduan effect. Inhibition of the enzyme activity in the myocardium mitochondria under arduan effect is pronounced more greatly.

A series of bisquaternary ammonio steroids having androstane skeletons have been prepared some of which possessed high neuromuscular blocking activity. One of the series 2 beta,16 beta-bis-(4'-dimethyl-1'-piperazino)-3 alpha, 17 beta-diacetoxy-5 alpha-androstane-dibromide (9, pipercurium bromide, Arduan) has proved to be a clinically useful agent of medium duration of action without side effects. The preparation of these ammonio steroids and structure-activity relationships within the series are described. The structure of 9 and related compounds was elucidated by spectrometric methods IR, NMR and MS.

A method for the determination of 2 beta, 16 beta-bis (4'dimethyl-1'-piperazino)-3a, 17 beta-diacetoxy-5 alpha-androstane is described. After deproteinization a pipecurium bromide Rose Bengal complex is formed and extracted with chloroform from a mildly basic medium. The amount of pipecurium bromide is proportional to the amount of Rose Bengal in the complex, and the quantity of the latter can easily be determined by measuring its iodine content. The method is sufficiently sensitive to be used for the analysis of human serum.

The authors determined the pharmacokinetics and duration of action of a bolus dose of pipecuronium bromide (0.07 mg.kg-1) in 40 patients anesthetized with halothane and nitrous oxide. Twenty were patients with normal renal function, undergoing a variety of surgical procedures, and 20 were undergoing cadaver renal transplantation because of end-stage renal disease. Plasma concentrations of pipecuronium were measured for 6 h after administration using a sensitive and specific capillary gas chromatographic assay. Plasma concentration versus time data were analyzed by nonlinear regression and fit to a two-compartment or three-compartment model; in addition, the data were analyzed by a non-compartmental method based on statistical moments. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The pharmacokinetic parameters derived by compartmental modelling were (normal vs. renal failure, respectively): volume of distribution at steady state (309 +/- 103 vs. 442 +/- 158 ml.kg-1, mean +/- SD), plasma clearance, (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (140 +/- 63 vs. 329 +/- 198 min), and elimination half-life (137 +/- 68 vs. 263 +/- 168 min). The same parameters as derived by the non-compartmental method were (normal vs. renal failure, respectively): volume of distribution at steady state (307 +/- 80 vs. 426 +/- 119 ml.kg-1, mean +/- SD), plasma clearance (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (134 +/- 41 vs. 323 +/- 228 min), and elimination half-life (118 +/- 35 vs. 247 +/- 168 min).(ABSTRACT TRUNCATED AT 250 WORDS)

In experiments on cats it has been shown that 2 beta, 16 beta-bis (4'-dimethyl-1'-piperazino)-3 alpha, 17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan), is a non-depolarizing muscular blocker. The order of myorelaxation evoked by this agent is characteristic: first the chewing and limb muscles, then abdominal muscles and diaphragm and at the end intercostal muscles are relaxed. Pipercurium bromide has no cardiotropic, atropine-like, or ganglion-blocking activity. It fails to influence the coronary blood-supply or myocardial oxygen consumption. No acetylcholinesterase inhibiting action of the compound was seen. It does not affect the central nervous system.

There are many new neuromuscular blocking drugs now going through the clinical trials required before new drugs can be used clinically on a routine basis. It is safe to say that within the next five years the muscle relaxants now in common use will be replaced by new and more "ideal" muscle relaxants. This review has attempted to define for the practicing anesthesiologist the goals of muscle relaxant research and the drugs that have been developed from that research. It is hoped that some familiarity with these drugs before they become widely available may hasten their extensive use by practitioner in the interest of better anesthetic patient care.

In two groups of patients the neuromuscular and circulatory effects of pipecuronium bromide (Arduan R), a new steroid type muscle relaxant were compared with those of pancuronium during balanced anaesthesia. Pipecuronium (n = 18) was found to be about 20% more potent than pancuronium (n = 20). The 95% blocking doses were: 0.059 mg kg-1 for pipecuronium and 0.075 mg kg-1 for pancuronium; these doses provided equal intubating conditions and relaxation. The onset, clinical relaxation time (clinical duration), recovery and the reversibility of the neuromuscular effects of the two agents in equipotent doses were similar. No cardiovascular or other side effects were observed with the use of pipecuronium.

Experience gained in applying to 102 surgery patients a steroid muscle relaxant 2 beta,16 beta-bis-(4'-dimethyl-1'-piperazino)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH 1106, Arduan) is reported. Pipercurium bromide proved to be a potent muscle relaxant with a medium duration of action. It can successfully be applied for intubation. Residual relaxation can be antagonized with neostigmine. Pipecurium bromide did not influence circulation, is free of side effects and can be applied in anaesthesiologically high-risk patients.

The pharmacokinetics of pipecuronium bromide have been studied in anesthetized beagle dogs with and without ligated renal pedicles. A gas chromatographic assay was used to measure the plasma, urine, bile concentrations, and liver content of pipecuronium, the later of which was obtained 8 h after injection. Following an iv bolus injection of 0.1 mg/kg, pipecuronium disappeared from the plasma exponentially with distribution half-lives of 3.9 +/- 1.1 min and 12.7 +/- 9.5 min (mean +/- SD), and elimination half-lives of 44.8 +/- 2.6 min and 196.7 +/- 102.0 min in animals with and without renal pedicle ligation, respectively. Except for the volume of central compartment, all other pharmacokinetic variables differed significantly between the two experimental groups. The elimination half-life was longer (196.7 +/- 102 (SD) vs. 44.8 +/- 2.6 min), plasma clearance slower (5.9 +/- 0.8 ml.kg-1.min-1 vs. 0.9 +/- 0.1 ml.kg-1.min-1) and mean residence time longer (221 +/- 73 vs. 51.1 +/- 1.8 min) in dogs with ligated renal pedicles. Eight hours after injection, the recovery of the parent form of pipecuronium approximated 77% of the administered dose in the urine, 4.5% in the bile, and 3.3% in the liver of normal animals. In animals with ligated renal pedicles 16% of the unchanged pipecuronium was excreted into the bile and 10% of the administered dose was recovered from the liver. Since the total recovery of unaltered pipecuronium approximated 85% of the administered dose in the intact animals, biotransformation seems to play an insignificant role in disposition of this new neuromuscular blocking drug.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors elaborated a method for the determination of Arduan and its desacetyl metabolites in biological fluids. The method is based on the use of labelled Arduan and on the determination of radioactivity of the parent drug and metabolites separated by ion-pair TLC in the development system of chloroform-dichloromethane-methanol 6 : 2 : 2 (v/v) 3% NaI (w/v).

The disposition of 2 beta,16 beta-bis-(4'-dimethyl-1'-piperazino)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan), a new neuromuscular blocking agent, was studied in rats by using labelled substance. Radioactive substance is rapidly taken up by the liver and to a lesser extent by the kidneys. The compound is retained by the liver for a longer period of time, some 6% of the administered 14C-activity can be recovered from the liver 21 days after the i.v. administration of the drug. Only traces of radioactivity could be detected in the brain and less than 0.1% of the dose could be found in the foetus. Binding to rat plasma protein is of about 30%. The compound seems to be eliminated with urine, the excreted amount being 37.55 +/- 11.91% and 45.44 +/- 17.29% during 24 and 48 h, respectively. No radioactivity was detected in the expired air.

Circulatory effects of 2 beta,16 beta-bis-(4.-dimethyl-1'-piperazino)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan) were investigated in severe cardiac patients during the induction of anaesthesia, in the course of nitrous oxide-oxygen anaesthesia and during extracorporeal circulation. In a dose of 0.05 mg . kg-1 the drug did not cause significant changes in any of the circulatory parameters studied. It is a safe muscle relaxant which can be used in patients with valvular and ischaemic heart diseases as well.

The pharmacokinetics of 2 beta, 16 beta-bis-(4'-dimethyl-1'-piperazino)-3 alpha, 17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, Arduan), a new non-depolarizing neuromuscular blocking agent, was studied in surgical patients. Plasma concentration-time curves of pipecurium bromide were evaluated by fitting the data to a bi-exponential equation. The average half-lives were T 1/2 alpha = 4.1 +/- 1.4 (n = 8) and T 1/2 beta = 44 +/- 7 (n = 8) min. The pharmacokinetic parameters of pipecurium bromide were found as follows: apparent distribution volume V beta = 261 +/- 28 (n = 8) ml/kg, plasma clearance Cl = 320 +/- 55 (n = 8) ml/min. The microconstants of two-compartment open models were also calculated.

We experienced an autopsy case in which a 29-year-old woman committed suicide by parenteral application of a neuromuscular blocker combined with thiobarbital. These medicines were easily accessible to the victim who was an anesthesiologist in a hospital. Paralyzing the respiratory muscles the usual dose of neuromuscular blockers can cause death unless a breathing apparatus is used. Unusual medicines given in small doses are difficult to detect in the autopsy materials. In our case in the course of forensic investigation we successfully identified the traces of a neuromuscular blocker by mass spectrometry.

Although many studies have presented data based on administration of nondepolarizing neuromuscular blocking agents to patients given inhalation anesthesia for 30-45 min, no data exist on the interaction in a clinical situation where the relaxant is administered immediately after the start of anesthesia. We therefore studied the effect of the commonly used inhalation anesthetics, halothane and enflurane, on the clinical pharmacology of atracurium, vecuronium, pipecuronium, and pancuronium. No significant influence of the anesthetic technique on the onset time of the various neuromuscular blocking agents was observed. The duration of action of atracurium, pipecuronium, and pancuronium was significantly prolonged during enflurane anesthesia as compared with the other two anesthetic techniques. The duration of vecuronium blockade was not significantly influenced by enflurane. Halothane, in contrast to enflurane, did not significantly prolong the blockade induced by these agents. The prolongation of atracurium blockade was clinically irrelevant. A fact that is statistically significant but clinically irrelevant is that a cumulative effect with atracurium and vecuronium was only seen during enflurane anesthesia and after the fourth maintenance dose. We conclude that there is no clinical indication that the dosage of atracurium and vecuronium during inhalation anesthesia should be reduced, but the doses of pipecuronium and pancuronium should be reduced when prolonged paralysis is not desired.

Pipecuronium bromide is a nondepolarising muscle relaxant which is an analogue of pancuronium. Doses of 0.025 and 0.05 mg kg-1 produced neuromuscular block in the anaesthetised dog. Previous work would suggest that the drug has minimal effects on the cardiovascular system. However, a dose of 0.05 mg kg-1 produced a profound hypotension in one dog on one occasion. The neuromuscular blocking action of the drug would appear to be extremely variable as indicated by the wide range of the results. The neuromuscular block was readily reversible with neostigmine preceded by atropine.

The properties and the effects of a new steroid muscle relaxant preparation 2 beta,16 beta-bis(4'-dimethyl-1'-piperazino)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan) were compared to those of pancuronium bromide in a controlled randomized clinicopharmacological study using ataranalgesic anaesthesiological technique. In 45 cases pipecurium bromide, in other 45 cases pancuronium bromide was used as long-acting muscle relaxant in anaesthesia for general surgical procedures. According to the results, pipecurium bromide is approximately 20% more potent than pancuronium bromide, it induces mechanical response characteristic for non-depolarizing muscle relaxants, and the residual neuromuscular blockade can be antagonized completely by neostigmine. There were no ECG alterations or specific serum enzyme (CPK, GOT. LDH) level changes observed. Pipecurium bromide did not influence blood pressure but in contrast to the heart rate increasing effect of pancuronium bromide, it caused mild bradycardia. On the basis of the study the drug can be used for further wide scale clinical investigations.

We have studied the effects of pipecuronium and pancuronium on myocardial contractility and heart rate in two different animal preparations. Pipecuronium and pancuronium produced no change in isometric contraction of rabbit atria. The chronotropic effects of pipecuronium, pancuronium and vecuronium were investigated using acetylcholine as an agonist in isolated perfused rabbit heart. Pancuronium but not pipecuronium or vecuronium, produced a significant degree of antagonism to the bradycardia produced by acetylcholine.

The neuromuscular blocking and cardiovascular effects of pipecuronium, in doses ranging 2-3 times its ED95, were evaluated in 46 patients during thiopental, fentanyl, N2O/O2 anesthesia. The neuromuscular blocking effect of pipecuronium was evaluated by recording of the mechanical twitch of the adductor pollicis muscle in response to stimulation of the ulnar nerve at the wrist. Heart rate, systolic and diastolic blood pressures, and cardiac output were non-invasively measured during the onset of the neuromuscular blockade and compared to a saline control group to separate the effect of anesthesia from those of pipecuronium. The mean +/- SD time from administration of pipecuronium to 90% suppression of the first twitch (T1) of the train-of-four was 2.6 +/- 0.8, 2.0 +/- 0.6, and 2.1 +/- 0.6 min following the 70 micrograms/kg, 85 micrograms/kg, and 100 micrograms/kg dose, respectively. There was no significant difference between the different doses of pipecuronium in the time to 90% suppression of T1. In general, all three doses of pipecuronium provided good to excellent intubating conditions within 3 minutes after its administration. The time from the administration of pipecuronium to 5% recovery of T1 was 52.3 +/- 18.2 min in the group given 70 micrograms/kg. This was significantly longer in patients given 85 micrograms/kg (71.9 +/- 15.7 min) or 100 micrograms/kg (71.8 +/- 22.1 min). Times to the start of recovery of T1 and to 25% recovery of T1 showed a similar significant pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

The actions of a new steroid 3alpha-pyrrolidino-17alpha-methyl-17alpha-aza-D-homo-5alpha-androstane-dimethobromide (RGH-4201) have been studied on the skeletal muscle, autonomic and cardiovascular systems in the conscious dog and in the anaesthetized cat and dog. In the cat and dog RGH-4201 exhibited a potent, non-depolarizing neuromuscular blocking action that was rapid in onset and of short duration. RGH-4201 was equipotent with suxamethonium and chandonium as a neuromuscular blocking agent in the conscious dog but was 2-3 times less active in the anaesthetized cat. Paralysis in the conscious dog was rapid in onset and of shorter duration than that of suxamethonium and chandonium. In the anaesthetized cat onset and duration of action was shorter than that of suxamethonium and chandonium. The neuromuscular block produced by RGH-4201 was rapidly and completely reversed by neostigmine releasing actions were observed. RGH-4201 has a cardiovagolytic activity similar to that of chandonium and diadonium. In open-chest dog, neuromuscular paralysing dose of RGH-4201 did not cause haemodynamic changes. Duration of action of a medium-term neuromuscular blocking agent (pipecurium bromide) was not affected by a preliminary dose of RGH-4201. Pathological alterations were not found in conscious beagle dogs treated daily for 14 days with 100 and 500 microgram . kg-1 of RGH-4201, however, a transient elevation on heart rate occurred during the paralysis.

The depolarising muscle relaxant suxamethonium (0.3 mg kg-1) and the non-depolarising muscle relaxant pipecuronium (0.05 mg kg-1) were administered to four dogs. In the first series of experiments pipecuronium was administered intravenously, followed at 50 per cent of return of neuromuscular activity by suxamethonium. At 50 per cent return of activity atropine and neostigmine were administered to reverse the neuromuscular block. In the second series the sequence was reversed and pipecuronium was administered after suxamethonium. At 50 per cent recovery atropine and neostigmine were given. In the first series of experiments the time for the onset of suxamethonium block was significantly increased after prior administration of pipecuronium. However, in the second series of experiments the prior administration of suxamethonium had no significant effect on the duration of action of pipecuronium.

The actions of the new depolarization-blocking muscle relaxant agent; 2 beta,16-beta-bis-(4'-dimethyl-1'-piperazino)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan), were studied in fentanyl-N2O, in halothane-N2O and in methoxy-flurane-N2O anaesthesia in a total of 94 patients. The drug in a dose of 0.05 mg/kg body weight (recommended by the manufacturer), elicited complete muscle relaxation, which was satisfactory even for performing abdominal operations. The effect occurred within 3-4 min, and subsided after 40-50 min. The residual effect had to be antagonized in 82% of the cases, and neostigmine had a satisfactory antagonizing effect in all patients. Transient fall of blood pressure and bradycardia (in 40.4% of the cases) were observed as side effects. Further studies are needed for the determination of the pathomechanism of bradycardia and to judge to what extent the inhalation anaesthetic agents influence the duration of action of pipecurium bromide.

The acetylcholinesterase (AchE) inhibitory effect of a muscle relaxant 2 beta,16 beta-bis-(4'-dimethyl-1'-piperazino)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan), was studied in vitro. The inhibition of AchE activity of human red blood cells, expressed as pI50, was 3.99, whereas that of serum cholinesterase (ChE) was 4.33. The AchE inhibitor action was reversible. The inhibition was not influenced by the combined administration of promethazine or atropine. The combined effect of pipecurium bromide and of some other diamino-azasteroid agent proved to be additive. Pipecurium bromide showed mixed-type inhibitory effect both on AchE and ChE.

The forced oscillatory impedance of the total respiratory system (Zrs) was measured in seven anaesthetized, paralysed rats weighing 351 +/- 55 g. Tracheotomy was performed, and the animals were placed in the supine position in a body box. Pseudo-random pressure variations between 0.5 and 10 Hz were applied around the chest. Central airflow was measured with a heated screen pneumotachograph. Total respiratory resistance (Rrs) and elastance (Ers), corrected for the impedance of the tracheal cannula, were markedly frequency-dependent: Rrs fell from 37.3 +/- 19.1 kPa.l-1.s at 0.5 Hz to 17.6 +/- 4.4 at 2 Hz and 10.3 +/- 3.3 at 10 Hz; the corresponding Ers values were 453 +/- 14, 594 +/- 90 and 713 +/- 104 kPa.l-1, respectively. This indicates that in the frequency range encompassing spontaneous breathing rates the classical resistance-intertance-compliance model provides an inadequate description of the respiratory mechanics in the rat.