Biomedical subjects

S Agoston

Publications and source records attributed to S Agoston.

At least 37 records · Page 2Linked to original sources

PubMed1991

Dose-response relationship and time course of action of Org 9426. A new muscle relaxant of intermediate duration evaluated under various anaesthetic techniques.

The dose-response relationship of Org 9426, its time course of action and the reversibility of the residual block by neostigmine have been investigated in 100 patients undergoing various anaesthetic techniques. The dose-response was measured immediately following induction of anaesthesia. Doses of Org 9426, required for 50% and 90% depression of the twitch height, were 202 and 328 micrograms.kg-1, respectively. The clinical duration of the maintenance doses, 150 micrograms.kg-1, ranged from 9.5 to 13.4 min and from 12.8 to 18.9 min for the first and fifth maintenance doses, respectively. Spontaneous recovery indices (25%-75%) were between 9.5 and 16.7 min; neostigmine methylsulphate administered at 25% recovery of the twitch height promptly reversed the residual block. No side effects were observed. The extent of the influence of the anaesthetic on the time course of Org 9426 appears to be fractional considering the variation of the time course within the separate groups.

Adolescent↗

PubMed1991

A method for studying the pharmacodynamic profile of neuromuscular blocking agents on vocal cord movements in anaesthetized cats.

1. A new in vivo experimental method is described whereby the neuromuscular blocking effects of muscle relaxants can be investigated on the intrinsic laryngeal muscles of anaesthetized cats. The peripheral tibialis anterior muscle preparation is employed in the same animal to compare the blocking effect on both preparations. 2. The intrinsic laryngeal muscles react with different sensitivities to the neuromuscular blocking agents when compared to the tibialis anterior muscle. 3. The neuromuscular response in both muscle preparations is similar with steroidal agents but appeared to be different after suxamethonium or isoquinoline analogues. 4. It is concluded that this preparation may become a useful tool for studying new muscle relaxants developed to facilitate rapid intubation conditions.

Anesthesia↗

PubMed1991

The pharmacokinetics, urinary and biliary excretion of pipecuronium bromide.

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).

Alanine Transaminase↗

PubMed1990

Pharmacokinetics and cardiovascular dynamics of pipecuronium bromide during coronary artery surgery.

The haemodynamic effects of 200 micrograms.kg-1 pipecuronium and pancuronium were compared under etomidate/piritramide anaesthesia in 20 patients scheduled for elective coronary artery surgery. Following the completion of the haemodynamic measurements (ten minutes), anaesthesia was maintained by etomidate/sufentanil infusion. The mean changes in cardiac output were approximately -19 and -2 per cent and in heart rate -1 and +26 per cent for pipecuronium and pancuronium respectively. Plasma and urine concentrations of pipecuronium were also measured and the pharmacokinetic variables obtained indicated rapid initial decrease in plasma concentration (t1/2 = 7.6 minutes) followed by a longer terminal phase (t1/2 = 161 minutes). The central compartment volume was 102 +/- 24 ml.kg-1 and plasma clearance was 1.8 +/- 0.4 ml.kg-1 min-1. Approximately 56 per cent of the dose was recovered from the urine within 24 hours of administration and about 25 per cent of this was the metabolite, 3-desacetyl pipecuronium. High-dose pipecuronium administration under the anaesthetic regimen employed did not produce deleterious haemodynamic effects. The pharmacokinetic variables after bolus injection of pipecuronium did not deviate from those reported under normothermic conditions.

Adjuvants, Anesthesia↗

PubMed1990

Clinical observations on the neuromuscular blocking action of Org 9426, a new steroidal non-depolarizing agent.

The neuromuscular blocking effects of Org 9426, the 2-morpholino, 16-allyl-pyrrolidino derivative of the 3-desacetoxy analogue of vecuronium have been investigated in anaesthetized patients. Based on data from a pilot study, two doses, 250 and 500 micrograms kg-1 (estimated as the ED90 and 2 x ED90, respectively) were chosen. Org 9426 appeared to be six to eight times less potent than vecuronium and showed a faster rate of development of neuromuscular block, with good to excellent intubation conditions within 60 s after administration of a dose of 500 micrograms kg-1. The duration of action and the recovery index appeared to be similar to those of vecuronium. Side effects were not noted. Org 9426 may have advantages over existing non-depolarizing neuromuscular blocking agents with respect to rate of development of good intubating conditions, and is stable in aqueous solutions.

Adolescent↗

PubMed1990

The neuromuscular blocking effects and pharmacokinetics of ORG 9426 and ORG 9616 in the cat.

The neuromuscular blocking effects and pharmacokinetics of ORG 9426, 1.5 mg/kg and ORG 9616, 1.2 mg/kg iv, two new nondepolarizing neuromuscular blocking drugs, were studied in 28 cats (i.e., 14 cats with each drug) with and without renal pedicle ligation. A gas chromatographic assay was used to determine the concentrations of ORG 9426 and ORG 9616 and its desacetyl metabolites in plasma, urine, bile, and liver. The duration of neuromuscular blockade of both drugs was not altered by ligation of renal pedicles. Plasma clearance of ORG 9426 was slower in cats with ligated renal pedicles (P less than 0.01). With ORG 9616, mean elimination half-life was slower and mean residence time longer in cats with renal pedicle ligation. Otherwise, there was no significant differences with any pharmacokinetic variables in cats with and without renal pedicle ligation. Only 8.7 +/- 5.7% (SD) and 6.0 +/- 2.8% of an injected dose of ORG 9426 and ORG 9616 was excreted into the urine, respectively. Conversely, 54.4 +/- 9.2% and 52.4 +/- 9.2% of an injected dose of ORG 9426 and 35.7 +/- 12.2% and 46.8 +/- 9.7% of ORG 9616 were excreted into the bile in cats without and with renal pedicle ligation, respectively. Finally, 21.3 +/- 6.5% and 33.5 +/- 15.6% of ORG 9426 and 14.0 +/- 3.2% and 18.1 +/- 5.6% of ORG 9616 were in the liver 6 h after injection in cats without and with renal pedicle ligation respectively. The authors were able to account for the biodisposition of 84.4% and 85.9% of an injected dose of ORG 9426 in cats without and with renal pedicle ligation respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstanols↗

PubMed1990

Cardiovascular and neuromuscular effects of three steroidal neuromuscular blocking drugs in dogs (ORG 9616, ORG 9426, ORG 9991).

Developmental research has been directed toward creating nondepolarizing muscle relaxants with an onset time and duration of actions shorter than that of vecuronium or atracurium. We determined the cardiovascular and neuromuscular effects of three new and promising nondepolarizing muscle relaxants in six dogs anesthetized with halothane. Each dog was anesthetized four times (each time separated from the others by at least 1 wk); one muscle relaxant was studied each time. Three doses (one, three, and five times the ED90) were given as intravenous bolus injections. ORG 9616 and ORG 9991 had shorter durations of action than ORG 9426. The duration of action of the doses that were five times the ED90 was 18 +/- 5.88 and 15.8 +/- 4.41 min (mean +/- SD) with ORG 9616 and ORG 9991, respectively, as compared with 39.7 +/- 17.15 min with ORG 9426 (P less than 0.05). ORG 9426 was virtually free of cardiovascular effects. The ED90 doses of ORG 9616 and ORG 9991 did not cause cardiovascular effects; the doses of three and five times the ED90 caused small decreases in mean arterial blood pressure and increases in heart rate. Mean arterial blood pressure decreased from 99 +/- 10.2 to 88 +/- 13.1 mm Hg and from 98 +/- 11.7 to 77 +/- 8.1 mm Hg with five times the ED90 dose of ORG 9616 and ORG 9991, respectively. The authors conclude that ORG 9426 has a duration of neuromuscular blockade that is probably similar to vecuronium, and one that is free of cardiovascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstanols↗

PubMed1990

Pharmacokinetics and neuromuscular blocking effects of atracurium besylate and two of its metabolites in patients with normal and impaired renal function.

The pharmacokinetics of atracurium, laudanosine and the quaternary alcohol were studied in patients with normal and impaired renal function following intravenous administration of atracurium. Anaesthesia consisted of thiopental, fentanyl, halothane and nitrous oxide in oxygen. Plasma and urine concentrations of the parent compound and its degradation products were measured by high performance liquid chromatography. Renal failure was defined as a creatinine clearance of less than 5 ml/min; it caused no significant differences in the pharmacokinetics of atracurium but did result in a different pharmacokinetic profile of laudanosine, with a 3-fold increase in the mean ( +/- SD) terminal half-life (176 +/- 84 and 516 +/- 262 minutes for patients with normal and impaired renal function, respectively). Moreover, the half-life of the quaternary alcohol increased from 27.1 +/- 8.3 minutes in patients with normal renal function to 42.5 +/- 8.3 minutes in those with impaired renal function (mean +/- SD). Renal elimination of unchanged atracurium accounted for 11% of the administered dose and at least 27% of the total degradation of atracurium occurred via ester hydrolysis. The neuromuscular function was monitored by measuring the twitch tension of the adductor pollicis muscle elicited by stimulation of the ulnar nerve at 0.1 Hz. The total duration of neuromuscular blockade (51.8 +/- 11.5 minutes) and the recovery index (9.6 +/- 2.0 minutes) are shortened in patients with impaired renal function, compared with those with normal renal function (64.1 +/- 7.2 and 16.7 +/- 4.1 minutes, respectively), indicating that sensitivity to the neuromuscular blocking action of atracurium may be altered by renal failure.

Adult↗

PubMed1990

Pharmacokinetics of pancuronium in patients undergoing coronary artery surgery with and without low dose dopamine.

Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancuronium were studied in 2 groups of coronary artery surgery patients, with and without dopamine 2 micrograms/kg/min, administered during and after cardiopulmonary bypass. Dopamine in the administered dose did not influence the systemic haemodynamics. The pharmacokinetic variables in both groups did not differ from those found in an earlier study in healthy normothermic patients. Total renal clearance was not influenced by dopamine, due to post-bypass rebound hyperperfusion in the control group. Pancuronium was shown to be subject to considerable tubular reabsorption, and its elimination was found to be increased during hypothermia. Dopamine increases pancuronium elimination by an increase in glomerular filtration rate. The dopamine-induced decrease in tubular solute reabsorption did not enhance the elimination of pancuronium.

Adult↗

PubMed1990

[The dose-response relationship and time course of the neuromuscular blockade by alcuronium].

Although alcuronium has been in clinical use for almost 40 years, there is still considerable controversy in the literature regarding its neuromuscular blocking potency, the time course of the drug action and the side effects. The aim of this study was to investigate the dose-response relationship of alcuronium and to compare the time course of its neuromuscular effects with vecuronium following intubation doses of both compounds. METHODS. The study was carried out in two parts. In the first part 60 patients and in the second part 30 consenting ASA class I or II patients 20-60 years of age were included. The patients were undergoing elective gynecological or intra-abdominal operations. In the first part the patients received six different doses of alcuronium (60, 90, 120, 150, 180 or 210 micrograms/kg) in order to establish its dose-response relationship. Each dose was administered to ten patients. In the second part patients received either 300 micrograms/kg alcuronium (n = 15) or 100 micrograms/kg vecuronium (n = 15), and the time course of these two compounds (onset time, duration 25%, duration 75% and the recovery index) were compared. To test the reversibility, ten patients in each group received 30 micrograms/kg neostigmine at 25% recovery of T1. The neuromuscular effects of alcuronium and vecuronium were quantitated by EMG using the DATEX relaxograph. RESULTS. The log-logit analysis of the dose response data revealed an ED50 of 111 micrograms/kg and an ED95 of 250 micrograms/kg, which is in reasonable agreement with the measured effects following 120 micrograms/kg and 210 micrograms/kg alcuronium, resulting in 52 +/- 21% and 96 +/- 4% T1 depression, respectively. The onset time, duration 25%, duration 75% and spontaneous recovery index following 300 micrograms/kg alcuronium (5.0 +/- 3.4 min, 62 +/- 25 min, 119 +/- 38 min and 58 +/- 34 min) appeared to be significantly longer (P less than 0.05) than those observed after 100 micrograms/kg vecuronium (3.2 +/- 1.2 min, 33 +/- 7 min, 49 +/- 9 min and 18 +/- 7 min), respectively. The most striking finding of this study is the enormous individual variations observed in both neuromuscular potency and the time course of action of alcuronium. Following 150 micrograms/kg (routinely employed in daily clinical practice), the magnitude of T1 depression ranged between 19% and 100%. The same vast individual variations were observed in the time course of action following 300 micrograms/kg of alcuronium. The onset time, duration 25%, duration 75% and spontaneous recovery index ranged between 1.3 and 14 min, 22 and 110 min, 93 and 186 min and 32 and 116 min, respectively. CONCLUSIONS. The ED50 and ED95 values for alcuronium found in this study are in the same order of magnitude as 106.8 micrograms/kg and 135 micrograms/kg for ED50 and with 280 micrograms/kg for ED95, respectively, as reported by others. The long duration with slow recovery and the wide individual variation in the neuromuscular effects observed in our study have been reported earlier. Based on the above observations and because of the availability of better alternatives with fewer side effects, we conclude that alcuronium should be added to the list of obsolete neuromuscular blocking agents, together with gallamine and d-tubocurarine.

Adult↗

PubMed1989

[Adult prognosis of infantile obstructive bronchitis].

The authors made a followup study of 0-36 months old patients admitted with the diagnosis of obstructive bronchitis to the Komárom City Hospital's Pediatric Department. Eighty eight patients were explored at the age of 23-26 years with the use of questionnaires. Four of these (4,54%) are still under active treatment because of bronchial asthma. This--taking into consideration the prevalence of adult asthma--shows the connection of these disease entities.

Adult↗

PubMed1989

Haemodynamic effects of vecuronium.

Three hundred and twenty adults (ASA grade I, both sexes), received diazepam 10 mg by mouth (50% received atropine 7 micrograms kg-1 in addition) i.m. 45 min before operation. Patients were then allocated randomly to undergo general anaesthesia with either a nitrous oxide-neurolept technique or nitrous oxide-halothane. Vecuronium was administered to 50% of the patients in each anaesthetic group and heart rate and arterial pressure were monitored. Vecuronium did not influence heart rate, or systolic or diastolic arterial pressures.

Adult↗

PubMed1989

A model for determining the influence of hepatic uptake of nondepolarizing muscle relaxants in the pig.

Hepatic uptake and distribution of nondepolarizing muscle relaxants in pigs was investigated. A portocaval shunt preparation enabled the determination of the pharmacodynamics of nondepolarizing muscle relaxants both during temporary liver exclusion and intraportal injection in the same animal. To demonstrate the validity of the model in pigs, in a pilot study the influence of hepatic uptake on neuromuscular blockade by pancuronium (n = 3) and its congener Org 6368 (n = 3) was determined. Thereafter, the influence of hepatic uptake on neuromuscular blockade by gallamine (3.4 mg/kg, n = 5), Org 6368 (0.3 mg/kg, n = 5), and vecuronium (0.1 mg/kg, n = 4 and 0.15 mg/kg, n = 5) was studied in pigs anesthetized with pentobarbital. Each pig received one relaxant, which was injected four consecutive times under different conditions. The first injection was into the jugular vein (iv) the second into the portal vein, the third was iv while the liver was excluded for 10 min and the fourth was iv (control). After each injection the onset time, intensity, recovery rate, and total duration of neuromuscular blockade were measured. These variables were compared between the four injections for each relaxant. In the pilot study the influence of hepatic uptake on neuromuscular blockade was similar for pancuronium and Org 6368. For gallamine the onset time, intensity, recovery rate, and duration of action were similar after all four injections. For Org 6368 the variables of neuromuscular blockade were similar after iv and intraportal injection, but exclusion of the liver prolonged the neuromuscular block.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Pharmacokinetics and disposition of pipecuronium bromide in dogs with and without ligated renal pedicles.

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)

Androstane-3,17-diol↗

PubMed1989

Dose-response relation and time course of action of pipecuronium bromide in humans anesthetized with nitrous oxide and isoflurane, halothane, or droperidol and fentanyl.

The dose-response of pipecuronium bromide, the time course of its neuromuscular blocking effects, and the reversibility of the residual block by neostigmine and edrophonium have been investigated in patients undergoing various types of anesthesia. The estimated doses of pipecuronium required for 95% depression of the twitch height were 44.6, 46.9, and 48.7 micrograms.kg-1 during anesthesia with nitrous oxide (65%) and isoflurane (group 1), halothane (group 2), or droperidol/fentanyl (group 3), respectively. The potentiating effects of the volatile anesthetics were reflected by the significant prolongation of the duration of both initial (50.0 +/- 4.3, 36.0 +/- 3.3, and 29.0 +/- 2.0 minutes) and maintenance doses (56.0 +/- 2.5, 49.5 +/- 3.3, and 41.2 +/- 1.6 minutes) of pipecuronium during anesthesia with nitrous oxide and isoflurane, halothane, or droperidol/fentanyl, respectively. Both edrophonium chloride (0.5 mg.kg-1) and neostigmine methylsulphate (40 micrograms.kg-1) promptly reversed the residual block induced by pipecuronium. No side effects attributable to pipecuronium were seen in this study.

Adult↗

PubMed1989

Interaction between nondepolarizing neuromuscular blocking agents and inhalational anesthetics.

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.

Adult↗

PubMed1988

Uptake and excretion of vecuronium bromide and pancuronium bromide in the isolated perfused rat liver.

Using the isolated perfused rat liver preparation, the disappearance from the perfusate and the excretion in the bile of vecuronium bromide and pancuronium bromide and their metabolites were followed for 2 h after the addition of 1 mg of either drug to the perfusate. In addition, the rate of change of the hepatic content of these two compounds was calculated by serially subtracting the amount of the compound and the metabolites in the bile and in the perfusate from the dose of drug added to the perfusate. It was found that, whereas the concentration of pancuronium in the perfusate declined slowly and monoexponentially, vercuronium concentration in the perfusate declined rapidly in a biexponential manner. No metabolites of either drug were detected in the perfusate. Approximately 40% of the injected dose of vecuronium was excreted in the bile as unchanged vecuronium and another 30% as the 3-hydroxy metabolite. No other metabolites of vecuronium were found in the bile. In total only about 7% of pancuronium (unchanged) was collected in the bile by the end of the experiment. It is concluded that, in comparison to pancuronium, the rat liver takes up large amounts of vecuronium rapidly, half of which is eliminated as unchanged vecuronium and half as the 3-hydroxy derivative. A small amount of vecuronium or its 3-hydroxy metabolite is returned to the perfusate from the liver. Some possible mechanisms underlying these differences are discussed.

Animals↗

PubMed1988

Pharmacokinetics and pharmacodynamics of 2,4-diaminopyridine in the cat.

The pharmacokinetics, antagonistic effects, and cardiovascular effects of 2,4-diaminopyridine (2,4-DAP) were studied in 7 anaesthetized cats. Cats received a pancuronium infusion at a constant rate to cause a 90% block of contraction of the anterior tibialis muscle, stimulated through the sciatic nerve. After steady state was reached, 2,4-DAP (750 micrograms/kg IV) was administered. Plasma, urine, and bile were collected over 8 h and analyzed by means of an HPLC assay. Plasma concentrations decreased biexponentially with half-lives of 9.0 +/- 5.7 min and 140 +/- 36 min, respectively. The volume of the central compartment was 0.85 +/- 0.27 L/kg, and the volume of distribution in the steady state was 3.1 +/- 1.1 L/kg. Total plasma clearance was 18 +/- 5 ml/kg/min. Ninety percent of the administered dose was recovered in the urine and 0.1 percent in the bile in 8 h. The antagonism of the pancuronium-induced steady-state block was 98% +/- 5%, with onset and duration of 3.5 +/- 2 min and 165 +/- 40 min, respectively.

4-Aminopyridine↗