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Biomedical subjects

S Agoston

Publications and source records attributed to S Agoston.

At least 55 records · Page 3Linked to original sources
PubMed1988

Pharmacokinetics and disposition of pipecuronium bromide in the cat.

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.

Androstane-3,17-diol↗
PubMed1987

The action of some new aminopyridines on mammalian non-myelinated nerve fibres.

The effects of a recently synthesized series of aminopyridines 2-methyl-4-AP, 2-chloro-4-AP and 2-(N,N-methyl-benzyl)amino-4-AP (2A-7) on voltage-operated sodium and potassium channels and on the sodium pump activity of non-myelinated fibres of the guinea-pig vagus nerve were studied with the sucrose-gap method. The compound action potential evoked by electrical stimulation and the propagation velocity along the nerve were not affected by 2-methyl-4-AP or 2-chloro-4-AP up to a concentration of 10(-3) M. The post-tetanic potential (PTH) evoked by repetitive stimulation of the nerve and reflecting sodium pumping was also not affected by these agents. The amplitude and duration of the compound action potential were enhanced to some extent by 2-methyl-4-AP at the highest concentration used (3 X 10(-3) M); this action was also observed and was more pronounced with 4-aminopyridine (4-AP). The other aminopyridine 2A-7 (3 X 10(-5) - 3 X 10(-4) M) caused suppression of the compound action potential, a diminished propagation velocity and a reduction of the PTH, an action also observed with lidocaine. These results show that 2-methyl-4-AP and 3-chloro-4-AP did not affect the voltage-operated sodium or potassium channels in non-myelinated fibres of the vagus nerve. Only 2-methyl-4-AP had a small 4-AP-like action at high concentrations. The aminopyridine 2A-7 possesses a local anaesthetic action as reflected by the inhibition of voltage-operated sodium channels.

Action Potentials↗
PubMed1987

A comparison of the pharmacological actions of 4-aminopyridine and two of its derivatives in the monkey.

The neuromuscular, cardiovascular and central nervous system stimulating effects of 4-aminopyridine (4-AP), 2,4-diaminopyridine (2,4-DAP) and LF-14 were investigated in the monkey. All these compounds were shown to reverse the stable neuromuscular blockade produced by the intravenous infusion of pancuronium bromide. The doses producing 50% antagonism (ED50) of the pancuronium-induced neuromuscular block were 0.50, 0.54 and 0.71 mg/kg for LF-14, 2,4-DAP and 4-AP respectively. The compounds had only slight cardiovascular effects. In contrast to 4-AP, LF-14 and 2,4-DAP did not reduce the duration of ketamine/diazepam-induced anesthesia, suggesting minimal if any central nervous system effects of these two compounds.

4-Aminopyridine↗
PubMed1987

Histamine metabolism after adverse reactions due to d-tubocurarine administration.

We investigated histamine release in five female patients, submitted for gynaecological surgery, after intravenous administration of the neuromuscular blocking agent d-tubocurarine. In these patients, we measured the plasma levels of histamine and its metabolites, N tau-methylhistamine and N tau-methylimidazoleacetic acid, making use of mass fragmentographic methods. The newly developed determination of plasma N tau-methylimidazoleacetic acid had a within-day coefficient of variation of 2.7% (n = 10). Normal values of N tau-methylimidazoleacetic acid in plasma ranged from 41.3-75.6 nmol/l (n = 13). All five patients developed anaphylactoid reactions: two patients showed severe systemic reactions, one patient a minor systemic reaction and two had skin reactions only. Plasma histamine and N tau-methylhistamine levels appeared to be the most reliable biochemical parameters for confirming both the occurrence and severity of an anaphylactoid reaction. In comparison with plasma histamine, the determination of plasma N tau-methylhistamine is less hampered by artefacts caused by blood collection and plasma preparation. Together with the fact that the increase in plasma N tau-methylhistamine levels after anaphylactoid reactions lasts much longer than the increase in plasma histamine levels, this leads to the conclusion that the determination of plasma N tau-methylhistamine is a useful retrospective parameter for histamine release in this type of pathological state. The plasma N tau-methylimidazoleacetic acid levels fluctuated considerably, showing only a significant increase after administration of d-tubocurarine in the two patients who had severe anaphylactoid reactions. This parameter is, therefore, less useful in such studies.

Adult↗
PubMed1986

Hepatobiliary disposition of vecuronium bromide in man.

The plasma and bile concentrations, the biliary excretion and the neuromuscular blocking effect of vecuronium bromide were studied during surgery in 13 patients who had received 150 micrograms kg-1 i.v. The amount of vecuronium in liver biopsies taken after i.v injection was measured in a separate group of six patients. Vecuronium appeared early in the bile, in concentrations that were 30-50 times greater than those in the plasma. On the basis of the measured amount of vecuronium excreted in the bile, together with the accepted average daily bile flow, it was estimated that more than 40% of vecuronium was excreted in the bile in 24 h. Liver biopsies indicated that the liver may contain more than 50% of the i.v. dose 30 min after injection. The large distribution of vecuronium into the liver may account for the initial rapid decline in vecuronium plasma concentration and its relatively short duration of action. In this study, neuromuscular blockade was prolonged, possibly as a result of interference, by surgical manipulation, with the rapid hepatic uptake of vecuronium.

Adult↗
PubMed1986

Does intravenous infusion of nitroglycerin potentiate pancuronium- and vecuronium-induced neuromuscular blockade?

The dose requirement for 95% depression of twitch tension and the time course of the neuromuscular blocking effects of the ED95 of pancuronium bromide and vecuronium bromide were studied during intravenous infusion of glucose, 5%, and nitroglycerin, 1 microgram X kg-1 X min-1, in 20 cats anesthetized with pentobarbital. Nitroglycerin administered continuously starting 1 hr before the administration of the ED95 and maintained during at least five maintenance doses of either pancuronium or vecuronium did not significantly potentiate the action of the neuromuscular blocking drugs, nor did it alter their time course of action. A tendency for a decrease (statistically not significant) rather than an increase in the duration of action of maintenance doses of both pancuronium and vecuronium was apparent during the treatment with nitroglycerin. These findings indicate a lack of interaction between pancuronium or vecuronium and nitroglycerin, provided that moderate doses are used.

Animals↗
PubMed1986

Comparative pharmacokinetics and dynamics of vecuronium and pancuronium in anesthetized patients.

Plasma concentrations and the degree of neuromuscular blockade after a 2-min infusion of 0.1 mg/kg of vecuronium bromide or pancuronium bromide (equipotent doses) were studied in 12 gynecologic patients. The plasma concentrations of both drugs declined in a triphasic manner. The difference between the intercepts and rate constants of the two drugs was not significant. Vecuronium was removed faster from the plasma than pancuronium; this was reflected in a significantly larger plasma clearance rate for vecuronium (4 ml X min-1 X kg-1 vs 1.1 ml X min-1 X kg-1 for pancuronium). The effective plasma concentrations at 50% recovery of the twitch height were 0.11 +/- 0.02 (vecuronium) and 0.2 +/- 0.03 microgram/ml (pancuronium). The disposition kinetics were adequately described by a three-compartment model. An effect compartment was added to the model to correlate the neuromuscular effects and plasma concentrations of both drugs. The ratio between concentrations of vecuronium and pancuronium in the effect compartment at 50% twitch height was 0.83. In spite of its greater potency, vecuronium has a shorter duration of action than pancuronium.

Adult↗
PubMed1986

Disposition and urinary excretion of vecuronium bromide in anesthetized patients with normal renal function or renal failure.

The effect and plasma concentrations of vecuronium bromide were measured in normal patients after an intravenous dose of 50, 100, or 150 micrograms/kg and in patients with renal failure after 50 or 100 micrograms/kg. Urinary excretion of vecuronium was studied in normal patients after the 150 micrograms/kg dose. Pharmacokinetic parameters of patients with or without renal failure were similar. No metabolites of vecuronium were found in the plasma. Twenty percent of vecuronium was excreted unchanged in the urine; 5% as the 3-hydroxy derivative. No other metabolites of vecuronium were found in the urine. Increasing doses of vecuronium shortened the onset, but prolonged the duration of action and the recovery rate, to a similar extent in patients with or without renal failure. It was concluded that the disposition of vecuronium was best described by a three compartment model. Both the disposition and the effect of vecuronium are only marginally disturbed by renal failure.

Adult↗
PubMed1986

Pharmacokinetics and pharmacodynamics of vecuronium and pancuronium in anesthetized children.

The pharmacokinetics and pharmacodynamics of vecuronium and pancuronium were determined in 12 children (3-6 yr) undergoing minor surgery under 60% nitrous oxide, 1 MAC halothane anesthesia. When the level of anesthesia and the electromyograph (EMG) recording of the adductor pollicis were stable, an intravenous bolus of vecuronium (100 micrograms/kg) or pancuronium (100 micrograms/kg) was administered. Plasma concentrations of the two muscle relaxants were determined for 6 hr after the administration by means of a fluorimetric assay followed by a thin layer chromatography. Plasma concentrations of vecuronium and pancuronium declined biexponentially in children and no metabolites could be detected in plasma. The elimination half-lives of vecuronium and pancuronium did not differ significantly. The volume of distribution at steady state (Vdss) was greater (P less than 0.05) after vecuronium (320 +/- 181 ml/kg; mean +/- SD) than after pancuronium (203 +/- 36 ml/kg). Plasma clearance of vecuronium (2.8 +/- 0.9 ml X min-1 X kg-1) was greater than that of pancuronium (1.7 +/- 0.2 ml X min-1 X kg-1; P less than 0.05). Plasma concentrations measured at 10%, 50%, or 90% recovery of the EMG response did not differ significantly for vecuronium and pancuronium. Thus the shorter duration of action of vecuronium is probably due to its greater apparent volume of distribution, as well as to its higher plasma clearance. Thus although the elimination half-lives are comparable, the plasma disappearance of vecuronium is more rapid than that of pancuronium.

Anesthesia, General↗
PubMed1985

Interaction between pancuronium bromide and vecuronium bromide.

The interaction between two non-depolarizing neuromuscular blocking agents, pancuronium bromide and vecuronium bromide, has been studied at standardized levels of neuromuscular blockade and alternating the sequence of their administration, in 40 surgical patients. The drug administered first appeared invariably to play a dominant role in influencing both the dose requirements and the duration of action of the subsequent neuromuscular blocker. This resulted in reduced dose requirements and significant prolongation of action of vecuronium administered after pancuronium and increased dose requirements and shortening of neuromuscular blocking action of pancuronium given during vecuronium-induced partial neuromuscular blockade. Possible mechanisms of such interaction are discussed.

Adult↗
PubMed1985

Disposition of vecuronium bromide in the cat.

The disposition of vecuronium bromide has been investigated in six normal cats (group I) and in six cats with ligated renal pedicles (group II). A combined fluorimetric and chromatographic technique was used to determine the concentrations of vecuronium and its metabolites in biological material. After i.v. injection of 0.6 mg kg-1, vecuronium disappeared rapidly from the plasma of the normal cat. Concentrations decreased bi-exponentially with half-lives of 4.6 and 31 min, respectively. The steady state volume of distribution was 0.23 litre kg-1 and the clearance 11 ml min-1 kg-1. Seventy percent of an i.v. dose of vecuronium (or its metabolites) was recovered: 15% in the urine, 40% in the bile and 15% in the liver. Only 3.8% of this consisted of the 3-hydroxy metabolite. There were no significant differences in pharmacokinetic data or in the amounts of vecuronium and its metabolites recovered in cats with ligated renal pedicles. The 15% of vecuronium normally excreted by the kidney was compensated for by increased hepatic and biliary concentration of vecuronium.

Animals↗
PubMed1985

Effects of hepatic uptake of vecuronium bromide and its putative metabolites on their neuromuscular blocking actions in the cat.

The neuromuscular blocking effects of equipotent doses of the three putative metabolites of vecuronium (3-hydroxy vecuronium, 17-hydroxy vecuronium and 3,17-dihydroxy vecuronium) were compared with those of an equipotent dose of vecuronium. Results obtained with the liver excluded from the circulation and after intraportal injection were compared with those following i.v. injection, in the cat. Following injection i.v., and with the liver excluded from the systemic circulation, there was a marked prolongation of duration of action (which averaged 100%) with all four compounds. After intraportal injection the only significant results were shortening of the duration of action and a decrease in the maximum blockade achieved with the 3-hydroxy metabolite. It is concluded that, in the cat, the hepatic removal of these compounds from the circulation is a major determinant of their duration of action. This process seems to be of importance for all four compounds, although the 3-hydroxy derivative appeared the most sensitive.

Animals↗
PubMed1985

Evolution of vecuronium requirements for stable mechanical effect: comparison with or without previous succinylcholine administration.

To evaluate possible interactions between residual succinylcholine and vecuronium, the amount of vecuronium required to maintain the twitch height (TH) at 10% of its initial value was measured over a 90-min period by the on-demand infusion method in two series of 15 adult patients (ASA class I-II). One group, the vecuronium treatment (V) group, received 70 micrograms X kg-1 of vecuronium and the on-demand infusion. The second group, the succinylcholine-vecuronium treatment group (SV), was given 30 micrograms X kg-1 of vecuronium and on-demand infusion 5 min after the complete recovery of TH after administration of 1 mg X kg-1 of succinylcholine. During the first 10 min, the amount of vecuronium required to maintain TH at 10% of its control was significantly greater in the group given V than in the group given SV, 15122 +/- 856 (mean +/- SEM) vs 9851 +/- 486 micrograms X m-2 X hr-1 (P less than 0.001). Thereafter, the amount of vecuronium required to maintain TH at 10% of control was similar: 2808 +/- 275 and 3068 +/- 206 micrograms X m-2 X hr-1. When the infusion of vecuronium was stopped after 90 min, the time required for spontaneous recovery from 25 to 75% of control TH levels was similar: 20.1 +/- 3.3 min in the group given V and 18.9 +/- 2.5 min in the group given SV (not significant). We conclude that after a vecuronium on-demand infusion of long duration (lasting more than 90 min), previous succinylcholine administration does not interfere with late vecuronium requirements and the spontaneous rate of recovery of TH.

Adult↗
PubMed1985

Inhibition of corticosteroidogenesis by etomidate.

The effects of the intravenous anesthetic etomidate have been investigated on ACTH-induced steroidogenesis in vitro, using purified isolated rat adrenal cells. It was found that etomidate almost completely blocked corticosterone production induced by physiological concentrations of ACTH at doses of 200 ng or greater. The mean inhibitory etomidate concentration resulting in 50% inhibition approximated 1.5 X 10(-7)M which is in the range of concentrations measured after clinical doses of etomidate.

Adrenal Cortex↗