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Biomedical subjects

S Agoston

Publications and source records attributed to S Agoston.

At least 19 recordsLinked to original sources
PubMed1997

Extended duration of action of rocuronium in postpartum patients.

We studied the time course of action of a single bolus of 600 micrograms/kg rocuronium given during anesthesia with propofol, fentanyl, and nitrous oxide was studied in 12 nonpregnant and 12 postpartum patients. Neuromuscular effects were quantified by recording the indirectly evoked twitch response of the adductor pollicis muscle after ulnar nerve stimulation. In all patients, the trachea was intubated 60 s after administration of rocuronium. Onset time was similar in both groups (nonpregnant: 91 +/- 28 s vs. postpartum: 95 +/- 30 s), with the time to 25% twitch recovery being significantly longer (P < 0.001) in the postpartum patients (31.1 +/- 3.6 min) compared with the nonpregnant group (24.9 +/- 4.0 min). The time required for recovery from 25% to 75% of the control twitch response after reversal with neostigmine and atropine was significantly longer (P = 0.003) in postpartum (4.8 +/- 0.9 min) than in nonpregnant patients (3.2 +/- 0.6 min). These data suggest that pregnancy-induced changes result in prolonged effects of rocuronium in postpartum patients.

Adolescent↗
PubMed1995

Onset time and evaluation of intubating conditions: rocuronium in perspective.

The customary methods for assessment of intubating conditions, namely the onset time in the adductor pollicis muscle and qualitative rating scales of the conditions at intubation, are unsatisfactory. The onset time of neuromuscular block in the adductor pollicis is not a meaningful, quantifiable endpoint, defining optimal intubating conditions. Consequently, its meticulous recording in all studies is probably obsolete. Qualitative rating scales are very subjective and a single standardized qualitative rating scale for the assessment of intubating conditions is required in order to improve the comparability of data from various studies. Clinical studies simulating rapid sequence induction in elective patients indicate that rocuronium 0.9 mg kg-1 may be suitable for crash intubation. This, however, needs to be confirmed in emergency cases.

Androstanols↗
PubMed1995

Rocuronium bromide in the ICU: dose finding and pharmacokinetics.

Thirty patients requiring elective ventilation in the ICU received either intermittent boluses (25 patients) or a continuous infusion (five patients) of rocuronium. Degree of block was monitored by train-of-four stimuli and maintained at one twitch either observed or palpated. All patients were sedated with intermittent doses or an infusion of 0.14-0.4 microgram kg-1 h-1 of midazolam and received a continuous infusion of either sufentanil or fentanyl (0.25-2.0 micrograms kg-1 h-1). Control of ventilation was better with the continuous infusion of rocuronium, but these patients also had a more intense block receiving 9.9 +/- 1.3 micrograms kg-1 min-1 as compared to 6.4 +/- 2.3 micrograms kg-1 min-1 in the bolus group. Elimination half-time, volume of distribution at steady-state, and mean residence time were significantly greater than in surgical patients receiving comparable infusions, but plasma clearance was similar.

Adolescent↗
PubMed1995

The influence of hypothermia (surface cooling) on the time-course of action and on the pharmacokinetics of rocuronium in humans.

Hypothermia prolongs the time-course of action of non-depolarizing neuromuscular blocking agents. The mechanism, however, is unknown. We studied the influence of hypothermia (by surface cooling, nasopharyngeal temperature < or = 31 degrees C) on the time-course of action and on the pharmacokinetics of rocuronium in humans. Nineteen neurosurgical patients were divided into hypothermic and normothermic groups. Hypothermia (30.4 +/- 0.8 degrees C (mean +/- SD)) increased the duration of action, temperature dependently, and delayed the recovery. Hypothermia reduced the plasma clearance significantly (2.17 +/- 0.62 vs. 4.26 +/- 0.50 mL kg-1 min-1, P = 0.004), did not change the volume of distribution (224 +/- 64 vs. 232 +/- 60 mL kg-1 min-1, P = 1.0), and prolonged the mean residence time (108 +/- 39 vs. 56 +/- 19 mL kg-1 min-1, P = 0.01). We conclude that hypothermia prolongs the duration of action of rocuronium and delays spontaneous recovery and that altered pharmacokinetics, such as a decreased clearance, play an important role in this.

Androstanols↗
PubMed1994

Clinical pharmacology of ORG 7617, a short-acting non-depolarizing neuromuscular blocking agent.

The dose-response relationship and the time course of action of Org 7617, a short acting non-depolarizing neuromuscular blocking agent, were evaluated during thiopentone, fentanyl, halothane and N2O anaesthesia. Neuromuscular transmission was monitored mechanomyographically. The ED50 and ED90 were calculated after single bolus doses of the drug. Twelve, seven and three patients received 2.5, 3.75 or 5.0 mg.kg-1 Org 7617, respectively. Neuromuscular block was characterized by a short lag time (average 30 s) and rapid development of neuromuscular block (69-84 s). Maximum block approximated to 66%, 91% and 95%, and the duration until clinically adequate recovery (TOF ratio of 0.7) to 7.4, 12.1 and 12.2 min after 2.5, 3.75, 5 mg.kg-1 of Org 7617, respectively. The calculated ED50 and ED90 were 1.8 and 3.4 mg.kg-1. Adverse effects, including a moderate fall in systolic and diastolic arterial blood pressure and a concomitant increase in heart rate appeared to be dose-dependent. Some patients showed flushing. One patient given 5 mg/kg Org 7617 had serious adverse effects suggestive of histamine release, i.e. flushing, urticaria, tachycardia, hypotension and bronchospasm. Therefore further clinical investigations were terminated. Although its low potency and the adverse effects observed will prevent further clinical development of ORG 7617, the results do support the contention that it is feasible to develop short-acting non-depolarizing neuromuscular blocking agents from the steroidal series.

Adolescent↗
PubMed1994

Preliminary investigations of the clinical pharmacology of three short-acting non-depolarizing neuromuscular blocking agents, Org 9453, Org 9489 and Org 9487.

Three muscle relaxants, Org 9453, Org 9489 and Org 9487, short-acting in animals, were investigated to establish their profiles in humans. Potency, time course of action, and pharmacokinetic behaviour were studied in 90 healthy patients during fentanyl/halothane/N2O anaesthesia. Neuromuscular function was monitored mechanomyographically. Plasma and urine concentrations (three patients per compound) were measured by HPLC, and these data were analyzed by iterative linear least square regression analysis. The ED90 values for Org 9453, Org 9489 and Org 9487 were 1.4, 0.45 and 1.15 mg.kg-1 respectively. The onset times of Org 9453 (1.5 mg.kg-1, 1.1 X ED90), Org 9489 (0.9 mg.kg-1, 2 X ED90) and Org 9487 (1.5 mg.kg-1, 1.3 X ED90) were 1.2, 1.6 and 1.5 min, and the durations until 25% twitch recovery were 8.6, 22.0 and 8.9 min, respectively. Clearances of these doses were 6.9, 5.8, and 11.1 ml.kg-1.min-1, and mean residence times 26, 79, and 41 min, respectively. Mean renal excretion (parent compound and metabolites) within 24 hr amounted to 5, 11.3 and 12.2% respectively. No side effects other than a moderate short-lasting decrease of blood pressure and a concomittant increase in heart rate were noted. It is concluded that Org 9453 and Org 9487 are short-acting muscle relaxants in humans.

Adolescent↗
PubMed1994

Long-term administration of pancuronium and pipecuronium in the intensive care unit.

This study was performed to determine the optimum dose of pancuronium (n = 30) and pipecuronium (n = 30) under continuous sedation and analgesia in the intensive care unit (ICU). This was an open clinical investigation in 60 critically ill patients with head injury, multiple trauma (in some complicated with sepsis and multi-organ failure), requiring neuromuscular block for ventilation for at least 48 h. Emphasis was placed on the neuromuscular monitoring with a peripheral nerve stimulator and adequate sedation and analgesia. Satisfactory block was achieved in all cases with an average dose of 3 mg/h with either compound. None of the patients experienced prolonged paralysis, muscle weakness, or other neuromuscular dysfunctions in the postventilatory period. We suggest that adequate use of sedative hypnotics and opioids plus neuromuscular monitoring allowed us to optimize the dose of muscle relaxants according to the need of individual patients.

Adolescent↗
PubMed1994

Interactions of volatile anaesthetics with rocuronium bromide in perspective.

A review of several publications shows that there is general agreement that inhalational anaesthetic agents potentiate the neuromuscular effects of rocuronium in the same order as other similar agents, namely; enflurane and isoflurane > halothane > intravenous anaesthetics. However, such potentiation is not evident during induction and only becomes significant as anaesthesia becomes more prolonged. It is manifest as a prolongation in the duration of action of maintenance doses and a decrease in the recovery rate. During long-lasting procedures in which enflurane or isoflurane are used, smaller than usual maintenance doses or lower infusion rates should be employed.

Androstanols↗
PubMed1993

Prolonged paralysis after long-term, high-dose infusion of pancuronium in anaesthetized cats.

We have studied the neuromuscular effects of a 48-h infusion of high-dose pancuronium (400 micrograms kg-1 h-1) in four cats anaesthetized with pentobarbitone, using contraction of tibialis anterior muscles after direct and indirect stimulation. After cessation of the pancuronium infusion, prolonged paralysis existed. The first twitch in the train-of-four stimuli (TOF) reappeared 8-12 h after termination of the pancuronium infusion. Twenty-four hours after termination of the infusion, TOF ratios were less than 0.08 and twitch contraction averaged 39 (SE 8)% of initial values. Twitch contraction after direct stimulation did not differ from initial values. Antagonism of paralysis was accomplished with neostigmine 60 micrograms kg-1 in two animals and neostigmine 90 micrograms kg-1 and 4-aminopyridine 500 micrograms kg-1 in the others. Steady-state plasma concentration of pancuronium (2000 ng ml-1) decreased rapidly after termination of the infusion, but then stabilized at about 130 ng ml-1. These results indicate that prolonged paralysis after long-term administration of high-dose pancuronium is caused primarily by failure of neuromuscular transmission, most likely caused by the persistent plasma concentrations of the drug in the pharmacologically active range.

4-Aminopyridine↗
PubMed1993

Reversal by suramin of neuromuscular block produced by pancuronium in the anaesthetized rat.

1. Rats were anaesthetized with sodium pentobarbitone and maximal twitches of a tibialis anterior muscle were evoked by stimulation of the motor nerve. 2. Suramin, injected intravenously in a series of cumulative bolus doses, each 15 mg kg-1, completely reversed a 90% depression of twitches maintained by a continuous intravenous infusion of pancuronium. The cumulated dose necessary to restore twitches to 50% of their control amplitude was 35 mg kg-1. Suramin did not modify a similar degree of block produced by suxamethonium, nor did it affect the amplitude of control maximal twitches, even in cumulative doses up to 150 mg kg-1. 3. The effects of bolus doses of suramin (85 mg kg-1), neostigmine (0.03 mg kg-1) and 4-aminopyridine (1.2 mg kg-1), calculated to restore pancuronium-blocked twitches to 95% of control amplitude, were compared. Suramin produced the most rapid reversal (1.1 +/- 0.5 min), but its duration of action was the shortest (9.4 +/- 1.6 min). Suramin was without effect on heart rate or blood pressure in the doses used. 4. The results showed that suramin reversed neuromuscular block produced by nondepolarizing blocking drug, pancuronium, but was without effect on a block produced by the depolarizing blocking drug, suxamethonium. Its short duration of action suggests that suramin would probably not be of value clinically as a reversal agent. However, it is possible that it might serve as a starter compound for the synthesis and development of a new class of reversal agents for use in anaesthetic practice.

4-Aminopyridine↗
PubMed1992

Suramin reverses non-depolarizing neuromuscular blockade in rat diaphragm.

Unexpectedly, it was observed that the P2-purinoceptor antagonist, suramin (10 microM to 1 mM), reversed the muscle paralysis caused by structurally unrelated non-depolarizing relaxants. Suramin competitively reversed the blocking action of pancuronium. Both the pre- and postsynaptic blockade of nicotinic receptors by pancuronium was counteracted, as shown by the action of suramin, using train-of-four stimulation. Suramin did not affect the paralysis caused by the depolarizing relaxant, succinylcholine. The reversal action of suramin was not due to an increase in the acetylcholine concentration in the synaptic cleft, since neither the contraction of preparations partially paralysed by diminished acetylcholine release in the presence of low Ca2+ or high Mg2+ nor acetylcholinesterase activity were affected. Suramin did not affect the reduction in twitch tension caused by adenosine and potentiated the ATP-induced reduction in twitch, indicating that ATP-sensitive receptors are not involved in the reversal action of suramin. Consequently, these results suggest that the action of suramin is due to binding with a site on the acetylcholine receptor also occupied by non-depolarizing relaxants, but different from the site occupied by succinylcholine.

Acetylcholine↗
PubMed1992

Porcine model for studying the passage of non-depolarizing neuromuscular blockers through the blood-brain barrier.

A method has been developed for blood-brain barrier disruption to provide reproducible access to the cerebrospinal fluid of the cerebello-medullary cistern. The technique was used successfully to investigate transfer of pancuronium to the cerebral CSF compartment in pigs. After osmotic disruption of the blood-brain barrier, pancuronium concentrations increased significantly in the cerebrospinal fluid.

Animals↗
PubMed1992

Interaction of ORG 9426 and some of the clinically used intravenous anaesthetic agents in the cat.

The interaction of ORG 9426, a new non-depolarizing neuromuscular blocking agent, with intravenous anaesthetic drugs (fentanyl, thiopental, midazolam, droperidol and etomidate) has been investigated in cats. During an infusion of one of the above anaesthetics, the ED95 dose was determined by titration, and thereafter muscle relaxation was maintained with four subsequent doses of ORG 9426. Neither the potency nor the duration of action of the first dose nor that of the maintenance doses of ORG 9426 differed from those observed in a control group of cats anaesthetized with intraperitoneally administered pentobarbital. The recovery rates were similar in all groups. The authors conclude that, under the conditions of this study, commonly used intravenous anaesthetic drugs are not likely to influence the neuromuscular blocking potency and time course of action of ORG 9426 to any appreciable degree.

Androstanols↗
PubMed1992

Atracurium-induced neuromuscular block in the isolated arm.

A modification of the isolated arm technique was applied in 10 females under opioid-based i.v. anaesthesia for comparison of the offset of an atracurium-induced neuromuscular block in an isolated arm to an arm with maintained circulation. The neuromuscular blocking effect of a bolus dose of atracurium 0.5 mg.kg-1 was measured bilaterally using the integrated adductor pollicis EMG response (integrated T1 EMG response in % of baseline value and T4/T1 ratio) after bilateral ulnar nerve train-of-four (TOF) stimulation. At 10% T1 recovery, one arm was isolated from the general circulation for 20 min by means of a tourniquet cuff (isolated arm), while normal circulation was maintained in the other arm (control arm). In both arms, the TOF response, peripheral skin temperature, mixed peripheral venous pH and plasma concentrations of atracurium and laudanosine were then measured and compared. Core and peripheral skin temperatures in both arms remained stable and normal throughout the study, and mixed peripheral venous pH stayed within physiological limits in both arms in all subjects. In the isolated arm, recovery of the neuromuscular block was markedly delayed compared to the control arm, the integrated EMG T1 response and TOF ratio being significantly reduced in the isolated arm after 20 min of isolation. The decline in plasma concentration of atracurium was less in the isolated arm than in the control arm, whereas laudanosine levels increased in the isolated and decreased in the control arm. Normal peripheral circulation is of major importance for termination of an atracurium-induced neuromuscular block.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia Recovery Period↗
PubMed1992

Clinical pharmacokinetics of neuromuscular blocking drugs.

Neuromuscular blocking agents provide muscle relaxation for a great variety of surgical procedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharmacological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. However, the use of relaxants constitutes a deliberate encroachment on respiration, one of the most important physiological mechanisms. The pharmacokinetic behaviour of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures. In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium, rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.

Acute Kidney Injury↗
PubMed1991

The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl.

The pharmacodynamics and pharmacokinetics of a new non-depolarizing neuromuscular blocking agent, Org 9426, were investigated. Ten patients undergoing elective head and neck surgery and anaesthetized with nitrous oxide, halothane and fentanyl, received a bolus dose of Org 9426 (1 mg.kg-1, 3 x ED90). The isometric contractions of the adductor pollicis muscle following ulnar nerve stimulation (0.1 Hz and intermittent TOF) were measured. Blood and urine were sampled over 8 and 24 hr, respectively. Concentrations of Org 9426 and its possible metabolites in plasma and urine were determined using HPLC. Pharmacokinetic variables were calculated by iterative linear least square regression analysis. Intubation conditions were excellent one minute after administration at a neuromuscular block of 88 (13)% (Mean (CV]. Onset time until maximum block, duration until 25% recovery of twitch height, and recovery from 25 until 75% of twitch height were 1.7 (32), 53 (19) and 20 (37) min, respectively. The TOF reached a ratio of 0.7 after 87 (19) min. Half lives were 1.8 (33), 19 (34), 131 (62) min, respectively, in a three exponential decay; distribution volume at steady-state and plasma clearance were 0.264 (56) L.kg-1 and 4.0 (21) ml.kg-1.min-1, respectively. Plasma concentration at 25% recovery of the twitch height was 1.0 mg.L-1. Within 24 h, 33 (37)% of Org 9426 was excreted unchanged in the urine. Metabolites were absent both in plasma and urine. We conclude that the difference in potency between Org 9426 and vecuronium is similar to the difference between their effective concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Pharmacokinetics, neuromuscular effects, and biodisposition of 3-desacetylvecuronium (Org 7268) in cats.

The pharmacokinetics, biodisposition, and neuromuscular blocking properties of 3-desacetylvecuronium were studied in 17 adult cats. Animals were divided into three groups: five cats with kidney failure induced by bilateral ligation of the renal pedicles, six cats with galactosamine-induced fulminant hepatitis, and six control cats. An intravenous bolus of 300 micrograms.kg-1 of 3-desacetylvecuronium was rapidly injected into the jugular vein. Arterial blood, urine, and bile samples were collected at regular intervals for 6 h in control cats and for 8 h in cats with kidney or liver failure. The liver was excised for analysis at the end of the experiment. In cats with renal failure, 3-desacetylvecuronium pharmacokinetic and pharmacodynamic variables did not differ from those in control cats. In cats with liver failure, plasma clearance was significantly less and mean residence time greater than in control cats (2.8 +/- 0.6 vs. 14.1 +/- 6.5 ml.kg-1.min-1 and 334 +/- 225 vs. 49 +/- 29 min, mean +/- SD, respectively). Volume of distribution at steady state in cats with liver failure and in control cats was not different. Also, in cats with liver failure, the duration of action and recovery index of 3-desacetylvecuronium was significantly greater than in control cats (168 +/- 62 vs. 82 +/- 32 min, and 39 +/- 19 vs. 10 +/- 4 min, respectively). Onset time of neuromuscular blockade was similar in all three groups. Total recovery of 3-desacetylvecuronium, for all three groups, in urine, bile, and liver was 90 +/- 11% (mean +/- SD). In control cats, 70 +/- 18% of 3-desacetylvecuronium was recovered in bile and liver and 19 +/- 14% in urine. No 3,17-bidesacetylvecuronium (a putative 3-desacetylvecuronium metabolite) was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗