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Biomedical subjects

J M Wierda

Publications and source records attributed to J M Wierda.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pharmacokinetics of rocuronium bromide in patients with and without renal failure.

We studied the onset and duration of action and pharmacokinetics of rocuronium bromide during anaesthesia with nitrous oxide, fentanyl and isoflurane after a single bolus dose of rocuronium (0.6 mg kg-1) in nine patients with chronic renal failure requiring regular haemodialysis, and in nine healthy control patients. Blood samples were collected over 390 min and concentrations of rocuronium and its putative metabolites measured using HPLC. Onset time for maximum block and duration of clinical relaxation (DUR25) were 61 (SD 25.0) s and 65 (16.4) s, 55 (26.9) min and 42 (9.3) min, respectively, for patients with and without renal failure. The time for train-of-four ratio to return spontaneously to 0.7 was 99 (41.1) min and 73 (24.2) min, respectively, in the two groups. None of these differences was significant. The pharmacokinetic data were best described by a three-exponential equation. There were significant differences between patients with and without renal failure in the rates of clearance (2.5 (1.1) mL kg-1 min-1 and 3.7 (1.4) mL kg-1 min-1, respectively) and the mean residence times (97.1 (48.7) min and 58.3 (9.6) min) (P < 0.05). The differences in other kinetic parameters were not significant.

Androstanols↗
PubMed1995

Structure-pharmacodynamic-pharmacokinetic relationships of steroidal neuromuscular blocking agents.

Several new steroidal non-depolarizing muscle relaxants have been synthesized and tested in humans recently. Results from these studies suggest that the differences in time-course of action between these compounds are mainly, if not totally, related to differences in biodisposition. Biodisposition, in turn, is determined largely by the physico-chemical characteristics of the drug, such as degree of lipophilicity and protein binding. The various pharmacodynamic and pharmacokinetic variables of a series of structurally related steroidal relaxants, varying in the ester substituent at the 17th position of the androstane skeleton, have been related to the degree of lipophilicity. Significant positive relationships could be shown between lipophilicity (logP at pH 7.4) and, among other things, potency (ED90), effective concentration (EC50), unbound plasma clearance (CLupl) and rate constant of transport between plasma and biophase (ke0). The aforementioned relationships between lipophilicity and pharmacokinetic variables resulted in significant inverse relationships between lipophilicity and time course parameters, such as onset time and duration of neuromuscular blocking effects. It is concluded that changes in the molecular structure of steroidal relaxants which enhance lipophilicity coincide with a decrease of (intrinsic) potency and a shorter time course of action. Protein binding appears to be of minor importance for the biodisposition and time course characteristics, since there were only small differences in degree of protein binding between most of the investigated compounds. However, the surprisingly fast initial rate of block development observed with rocuronium may in part result from its relatively high unbound fraction in plasma.

Adolescent↗
PubMed1995

Hypothermic cardiopulmonary bypass influences the concentration-response relationship and the biodisposition of rocuronium.

In 10 patients scheduled for elective coronary artery bypass grafting under midazolam-sufentanil anaesthesia, the influence of hypothermia on the plasma concentration-response and biodisposition of rocuronium were investigated. Neuromuscular function was monitored mechanomyographically. Plasma and urine concentrations of rocuronium were determined by high performance liquid chromatography. Hypothermic cardiopulmonary bypass prolonged the duration of action of maintenance doses and altered the plasma concentration-response relationship. The elimination and distribution half-lives, following the last maintenance dose after rewarming, and the urinary excretion of rocuronium were similar to values obtained during normothermia. A diminished hepatic uptake and storage in the liver of rocuronium during hypothermia may explain the more pronounced prolongation of the duration compared to that of other steroidal neuromuscular blocking agents.

Adjuvants, Anesthesia↗
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

Pharmacodynamic behaviour of vecuronium in primary hyperparathyroidism.

This study evaluated the potency and time course of action of vecuronium in patients with primary hyperparathyroidism (HPT) and marked hypercalcaemia during nitrous oxide-opioid anaesthesia. Twenty ASA physical status I and II patients were studied by measuring the force of contraction of the adductor pollicis in response to stimulation of the ulnar nerve: ten control patients and ten patients with HPT and ionized calcium concentration over 2.80 mEq.L-1. After induction of anaesthesia with thiopentone and maintenance with N2O/O2 and fentanyl, vecuronium was administered to determine cumulative dose-response curves. When maximum block had been obtained, twitch height was maintained at 10% of baseline value over 20 min by adjusting the infusion rate of a syringe-pump containing vecuronium and vecuronium plasma concentration (EC90ss) was determined. During spontaneous recovery, after termination of infusion, the recovery index, the time from 25 to 75% recovery, was measured. The dose to produce 90% block was greater in the HPT than in control group: 69 (24) vs 54 (18) micrograms.kg-1 (P < 0.02). The calculated ED50 was also greater in HPT: 42 (4) vs 31 (5) micrograms.kg-1 in controls (P < 0.001). (Values are given as mean and coefficient of variation). The slope of the dose-response curve, the dose necessary to maintain 90% block, and the EC90ss did not differ. The RI25-75 was slower in the HPT group although the difference did not reach statistical significance. It is concluded that hyperparathyroidism with hypercalcaemia increases vecuronium requirement; only during the onset of neuromuscular blockade.

Adolescent↗
PubMed1994

Pharmacodynamics and pharmacokinetics of an infusion of Org 9487, a new short-acting steroidal neuromuscular blocking agent.

We have evaluated in 10 anaesthetized patients the time course of action, infusion requirements, reversibility and pharmacokinetics of Org 9487. Org 9487 was administered as a bolus dose of 1.5 mg kg-1, followed by an infusion to maintain a block of 75-85% for 60 min. After recovery from the bolus dose, a mean dose of Org 9487 3.4 (SD 1.0) mg kg-1 h-1 was administered to maintain a mean neuromuscular block of 83 (3)%. During the final 15 min of infusion, the infusion requirements were 2.5 (1.1) mg kg-1 h-1. In the five patients who were allowed to recover spontaneously, a TOF ratio of 0.7 was reached 37.9 (12.4) min after stopping the infusion of Org 9487. In the five patients who received neostigmine, a TOF ratio of 0.7 was reached after 14.5 (6.1) min. Plasma clearance was 8.5 (30%) ml kg-1 min-1. Volume of distribution at steady state was 293 (55%) ml kg-1. Terminal half-life and mean residence time were 71.7 (34%) and 33.4 (31%) min, respectively. The concentration of the 3-OH metabolite remained relatively low. Urinary excretion of Org 9487 and its metabolites was 22% in 24 h. In conclusion, a 1-h infusion of the short-acting drug Org 9487 changed its time course characteristics gradually from that of a short-acting neuromuscular blocking agent to that of a neuromuscular blocker with an intermediate duration of action.

Adolescent↗
PubMed1994

Neuromuscular and cardiovascular effects of neostigmine and methyl-atropine administered at different degrees of rocuronium-induced neuromuscular block.

The neuromuscular and cardiovascular effects of neostigmine, 40 micrograms kg-1, and methyl-atropine, 7 micrograms kg-1, administered at different degrees of rocuronium-induced (600 micrograms kg-1) neuromuscular block were evaluated. In one group of patients spontaneous recovery was awaited (Group A; n = 20). Neostigmine and methyl-atropine were administered 2 minutes after rocuronium (Group B; n = 20) or at 25% twitch recovery (Group C; n = 20). Neuromuscular transmission was monitored mechanomyographically. Data are presented as mean (SD) [95%-CI]. The initial rate of recovery (time until a TOF ratio of 0.2) in group B, i.e. 14.2 (4.5) [12.1-16.3] min, was significantly faster than in group C, i.e. 28.7 (5.3) [26.3-31.1] min. However, the time until clinically sufficient recovery (time until a TOF ratio of 0.7) was similar for groups B, i.e. 29.3 (9.5) [24.9-33.7] min and group C, i.e. 31.8 (5.6) [29.2-34.4] min, both significantly different from that of group A, i.e. 53.2 (14.5) [46.5-59.9] min. The increase in heart rate following neostigmine/methyl-atropine was more pronounced in the group reversed at 2 min after rocuronium (P < 0.01).

Adult↗
PubMed1994

Early and late reversibility of rocuronium bromide.

A computer simulation has been developed based on pharmacodynamic-pharmacokinetic modelling of the effect of neostigmine on rocuronium-induced neuromuscular blockade. The results of a previous study involving 60 patients were used as a test of the model. The model predicts that administration of neostigmine 40 micrograms kg-1 within 20 min of the administration of rocuronium does not decrease the duration of the block until 90% recovery has taken place. The optimum dose of neostigmine depends on the degree of block at the time of administration: for a more intense block the optimum dose is 80 micrograms kg-1 and for a less intense block is about 30 micrograms kg-1. The pharmacokinetic behaviour rather than the potency of the relaxant determines its reversibility.

Androstanols↗
PubMed1994

Pharmacokinetics and pharmacokinetic/dynamic relationship of rocuronium bromide in humans.

The existing human pharmacokinetic studies have been reviewed and compared with data derived from animals. The earliest study confirms the similarity of rocuronium to vecuronium with respect to the variables derived from the plasma concentration decay curves and the proportion excreted renally. Other studies led to the conclusion that concurrent administration of volatile anaesthetics did not significantly influence rocuronium pharmacokinetics and that the potentiation must be due to an increased sensitivity of the neuromuscular junction. These studies do not provide an explanation for the clinical observation of a more rapid onset of action. One possible explanation was the finding of a more rapid onset of block in the laryngeal muscles than in the adductor pollicis. However, no pharmacokinetic explanation for this observation has emerged. Alternative concepts need to be modelled. There is a need for comparative pharmacokinetic studies which focus on the period immediately following administration of rocuronium and vecuronium.

Age Factors↗
PubMed1993

Determination of rocuronium and its putative metabolites in body fluids and tissue homogenates.

A sensitive and selective HPLC method was developed for the quantification of the neuromuscular blocking agent rocuronium and its putative metabolites (the 17-desacetyl derivative and the N-desallyl derivative of rocuronium) in plasma, urine, bile, tissue homogenates and stoma fluid. Samples were prepared by extraction of the biological matrix with dichloromethane, after mixing with a KI-glycine buffer. After evaporation of the organic solvent the samples were chromatographed on a reversed-phase HPLC column, using an aqueous buffer-dioxane (84:16, v/v) as the mobile phase. The aqueous buffer consisting of 0.1 M sodium dihydrogen phosphate, 0.11 mM 9,10-dimethoxyanthracene-2-sulphonate (DAS), 0.11 mM 1-heptane-sulfonic acid, was adjusted to pH 3 with orthophosphoric acid. After separation, the eluent was extracted with dichloroethane, and the organic phase was led to a fluorimetric detector, operating at 385 nm (excitation) and 452 nm (emission). The method was validated for the assay in plasma, urine, bile, tissue homogenates and stoma fluid, by determination of the repeatability, reproducibility, accuracy, lower limit of quantification, lower limit of detection, extraction recovery, effect of sample volume, and stability in the biological matrix. The method was found to be sensitive (lower limit of quantification for rocuronium in plasma is 10 ng/ml) and accurate. The interference of concomitant drugs with the assay of rocuronium and its putative metabolites has been studied extensively. In order to confirm the identity of rocuronium and its putative metabolites, a TLC method was developed. The method has been applied successfully in several pharmacokinetic studies with rocuronium.

Androstanols↗
PubMed1993

The Relaxometer: a complete and comprehensive computer-controlled neuromuscular transmission measurement system developed for clinical research on muscle relaxants.

The Relaxometer is a computer-controlled system developed for reliable clinical experimental measurements on neuromuscular block. This system is based on an adapted personal computer (Atari 1040 ST) with a monochrome monitor (Atari SM 124), and a microcomputer-driven slave unit (stimulator). There are several stimulation patterns available: single twitch at 0.1 and 1 Hz, single train-of-four, continuous train-of-four every 12 seconds, and tetanic stimulation at 50 Hz for 5 seconds followed by posttetanic count. The system is equipped with a temperature module for continuous monitoring of the skin/muscle temperature and a rechargeable battery to allow uninterrupted measurements if the apparatus is disconnected from the line power. All acquired data, computer-calculated parameters (onset time, duration time, recovery index, train-of-four ratio, tetanic fade, and posttetanic count), and the mechanomyogram are presented on screen continuously, are stored on floppy disk, and can be printed in a well-organized format.

Algorithms↗
PubMed1993

The isolated heart-lung preparation in the cat. An in situ model to study the role of the lungs in the disposition of drugs.

In the search for drugs with an extreme short time course of action, compounds should be developed that are rapidly distributed to and temporarily stored in well-perfused organs. Since the lungs receive the complete cardiac output and have the ability to temporarily store drugs, we have developed an in situ, isolated lung preparation in the cat to study the contribution of the lungs to the disposition of drugs. The cat's own heart perfuses the lung in situ with autologous blood. The circulation between the left ventricle and the right atrium is short-circuited via an aorta-caval shunt. The right forelimb is added to study pharmacodynamics simultaneously (only for muscle relaxants). Validation of the model for 180 min of perfusion showed complete isolation of the organs without major biochemical changes or edema and a stable muscle response. In pilot experiments with two structurally related muscle relaxants, initial muscle relaxation was followed by spontaneous recovery of neuromuscular function and a gradually decreasing plasma concentration, indicating partial disposition by the lungs. This was confirmed by direct concentration measurements in the lung. The present model may provide a powerful experimental tool to elucidate the role of the lungs in the disposition of drugs.

Albumins↗
PubMed1993

Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide (Org 9426) during isoflurane anaesthesia in patients with and without renal failure.

We have studied the onset and duration of action and pharmacokinetics of rocuronium bromide (Org 9426) during anaesthesia with nitrous oxide, fentanyl and isoflurane after a single bolus dose of rocuronium 0.6 mg kg-1 in nine patients with chronic renal failure requiring regular haemodialysis, and in nine healthy control patients. Blood samples were collected over 390 min and concentrations of rocuronium and its putative metabolites measured using HPLC. Onset time for maximum block, duration of clinical relaxation (T1(25)) and recovery index, were 61 (SD 25.0) s and 65 (16.4) s, 55 (26.9) min and 42 (9.3) min and 28 (12.3) min and 19 (8.8) min, respectively, for patients with and without renal failure. The time for TOF ratio to return spontaneously to 0.7 was 99 (41.1) min and 73 (24.2) min, respectively, in the two groups. None of these differences was significant. The pharmacokinetic data were best described by a three-exponential equation. There were significant differences between patients with and without renal failure in the rates of clearance (2.5 (1.1) ml kg-1 min-1 and 3.7 (1.4) ml kg-1 min-1, respectively) and the mean residence times (97.1 (48.7) min and 58.3 (9.6) min) P < 0.05). The differences in other kinetic parameters were not significant. We conclude that the effects of rocuronium may be prolonged in patients with renal disease, because of a decreased clearance of the drug.

Adult↗
PubMed1993

Pharmacokinetics of cyclosporine A after intravenous and oral administration in liver transplant patients measured with high-performance liquid chromatography.

Cyclosporine A (CsA) bioavailability after i.v. and oral administration was studied in six stable liver transplant patients with open and clamped bile drain. CsA levels were determined by the high-performance liquid chromatography method (HPLC). External bile drainage decreased CsA absorption considerably. Clamping the bile drain resulted in higher and earlier peak CsA levels. Clamping the bile drain increased the bioavailability (9.6% vs. 7%, p < 0.05), but even then it was considerably lower than the value of approximately 30% generally reported in literature. It is recommended to continue i.v. CsA administration to obtain therapeutic plasma concentrations. Early bile drain clamping or bile refeeding will improve CsA absorption and may also result in continuously therapeutic CsA levels.

Absorption↗