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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 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.

Acute toxicity studies with 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, revealed an order of sensitivity as follows: rabbits greater than mice greater than rats. Subchronic toxicity was tested on conscious dogs by 20 daily doses of 150 microgram/kg i.v. corresponding to 4-fold the planned clinical dose followed by daily intubation and artificial ventilation until recovery of spontaneous respiration. Dosage was limited by prolonged paralysis time requiring artificial ventilation. Apart from daily stress of paralysis preceding intubation no irreversible toxic changes were detected by laboratory and morphological tests. ECG changes were restricted to paralysis time, they were characterized by transitory arrhythmia and variation of the ST-segment. In additional studies on conscious and unconscious dogs no lethal ECG changes could be induced with cumulative dose totalling 10 mg/kg i.v. Short-term in vivo and in vitro mutagen tests did not reveal either mutagenic and clastogenic effects or increase of chromosomal aberrations. Intravenous local tolerance in rats was satisfactory.

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.

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.

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 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 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.

The effect of a new sterane-structure, 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 studied in 42 mongrel dogs under general anaesthesia (ether, halothane, methoxyflurane, thiobutobarbital, hydroxydione and dehydrobenzperidol-fentanyl (NLA II). Onset and duration of action and the presence of circulatory side effects were examined. It was found that the mean onset of respiration paralysing action was 156.1 s and apnea lasted for 38 min. In the thiobutobarbital group apnea lasted for 74 min. Arterial systolic blood pressure and central venous pressure did not change, but the heart rate was mildly decreased by pipecurium bromide. ECG intervals (PQ, QT and TP) did not change considerably, and the variations ran parallel with the prolongation of RR intervals due to the decrease of heart rate. Pipercurium bromide is a non-depolarizing muscle relaxant of medium duration, without any significant circulatory effects. Its duration of action was prolonged in the presence of thiobutobarbital, indicating a drug interaction between the two preparations.

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.

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 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.

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.

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.