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J H Proost

Publications and source records attributed to J H Proost.

54 records · Page 3Linked to original sources
PubMed1995

Adaptive control of drug dosage regimens using maximum a posteriori probability Bayesian fitting.

Optimal drug therapy can only be achieved if a drug is given in the right dosage regimen. Therefore the dosage regimen needs to be optimized, using the available information of the drug, the patient, and his disease. The optimization of drug therapy comprises two major steps: First, the clinician should define explicit therapeutic goals for each patient individually. Second, a strategy to achieve these goals with the greatest possible precision should be chosen. An overview of the optimization of drug therapy is presented, with special reference to maximum a posteriori probability (MAP) Bayesian fitting. Drug dosage optimization requires 1. measurement of a performance index related to the therapeutic goal, generally one or more plasma concentration measurements, 2. population pharmacokinetic parameters, including mean values, standard deviations, covariances and information on the statistical distribution, and 3. reliable software for adaptive control strategy and optimal dosage regimen calculation. The benefit of optimal drug therapy by adaptive control using MAP Bayesian fitting has been proven, resulting in improved patient outcome by improved efficacy of therapy and a reduction of adverse reactions, and in reduced costs, mainly due to a reduction of hospitalization. Newer strategies might replace the MAP Bayesian fitting procedure, if their advantage has been demonstrated convincingly, and if reliable and user-friendly software is available.

Bayes Theorem↗
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

The sinusoidal efflux of dibromosulfophthalein from rat liver is stimulated by albumin, ligandin and fatty acid binding protein but not by other dibromosulfophthalein binding proteins.

Organic anions can be excreted from the liver into the bile or back into the general circulation (sinusoidal efflux). It has previously been shown that the net sinusoidal efflux rate of dibromosulfophthalein from the perfused liver into the perfusate is the result of actual efflux from and reuptake into the liver, and can be strongly influenced by the presence of bovine serum albumin in the perfusion medium. The present study investigated whether the influence of albumin on the net sinusoidal efflux process is albumin-specific or whether other binding proteins could have a similar effect on the sinusoidal efflux. Using a single-pass liver perfusion technique and short-lasting (pulse) protein infusions, the stimulatory effect of a wide range of dibromosulfophthalein binding proteins on the sinusoidal efflux process were determined. These experiments showed that all the serum albumins tested as well as the liver cytosolic binding proteins fatty acid binding protein and ligandin (glutathione S-transferase) stimulated this process. The other proteins tested, bovine beta lactoglobulin-b, human gamma globulin and chicken egg lysozyme showed no stimulatory effect, despite relatively high equilibrium binding of dibromosulfophthalein. No clear-cut relationship was found between the equilibrium unbound ligand concentration as measured in perfusate and the stimulatory effect, suggesting absence of equilibrium binding in the sinusoids. Equilibrium binding of dibromosulfophthalein to chicken serum albumin and ligandin as well as the dissociation rate constants were determined in vitro with rapid filtration techniques.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Disposition of glycosidase inhibitors in the isolated perfused rat liver: hepatobiliary and subcellular concentration gradients of 1-deoxymannojirimycin and N-methyl-1-deoxynojirimycin.

The hepatic disposition of two glycosidase inhibitors was studied in the isolated perfused rat liver and after subcellular fractionation. The mannosidase inhibitor 1-deoxymannojirimycin (dMM) and the glucosidase inhibitor N-methyl-1-deoxynojirimycin (MedNM) exhibited minimal binding to albumin and reached liver concentrations that approximately equaled their medium concentrations, after 30 min (MedNM) or 90 min (dMM). Within 2 hr 0.5% of the dose of MedNM and 2.9% of dMM were excreted in bile. No metabolites were found for MedNM, whereas minor (bio)degradation was inferred for dMM. After subcellular fractionation, dMM and MedNM were found predominantly in the cytosolic fraction. Compared to the other particulate fractions, MedNM was elevated in the microsomal fraction, and both compounds were slightly enriched in the lysosomal fraction. We conclude that dMM and MedNM will likely inhibit liver enzymes when sufficiently high plasma levels are reached.

1-Deoxynojirimycin↗
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

Pharmacokinetic modeling of the sinusoidal efflux of anionic ligands from the isolated perfused rat liver: the influence of albumin.

This study contains a pharmacokinetic analysis on the efflux of organic anions from the liver into the bloodstream (sinusoidal efflux) with specific reference to the influence of albumin. The net sinusoidal efflux rate of dibromosulfophthalein (DBSP) from preloaded livers, being the resultant of sinusoidal efflux and reuptake of ligand by hepatocytes downstream the sinusoid, can be strongly increased by the presence of bovine serum albumin (BSA), a protein having multiple binding sites for DBSP. We previously attributed this effect to a reduction of reuptake through extracellular binding of the organic anion to the protein, rather than to an intrinsic stimulatory effect on the actual membrane transport process from the cells. In the present study we tested this hypothesis using a pharmacokinetic multicompartment liver model. This model resembles the parallel tube model in that the liver is described by several compartments placed in series instead of a single well-stirred compartment and it takes into account rates of dissociation and association in binding to proteins in the sinusoidal space. The model parameters were fitted from the sinusoidal efflux and biliary excretion data from efflux experiments measuring the stimulatory effect of various concentrations of BSA. Equilibrium binding of DBSP to albumin as well as the dissociation rate constant (koff) were determined in vitro with rapid filtration techniques. The experimental data could not be fitted satisfactorily when using the experimentally obtained values of the protein association and dissociation rate constants (kon and koff). However, they could be simulated accurately assuming 16 times higher values for the association and dissociation rate constant compared to those determined in vitro. Time constants of the perfusate flow, liver (re)uptake, and protein association and dissociation indicate that binding equilibrium does not exist within the sinusoids and that, in particular at low protein concentrations, the net sinusoidal efflux rate is association rate-limited: A large fraction of the ligand effluxed from the cell into the median is taken up by the hepatocyte before binding to the proteins occurs. Higher kon and koff values predicted by the model might indicate altered DBSP-albumin binding characteristics upon passage through the liver but alternatively can be explained by an intrinsic effect of albumin on the carrier-mediated efflux process. Efflux experiments showed a marked stimulatory effect of the protein on sinusoidal efflux but only a moderate effect on biliary excretion, despite a strong decrease in liver content. These patterns indicate that sinusoidal efflux and biliary excretion occur from two different intracellular compartments that equilibrate slowly.

Albumins↗
PubMed1993

Time course of action and endotracheal intubating conditions of Org 9487, a new short-acting steroidal muscle relaxant; a comparison with succinylcholine.

In a randomized study, we evaluated lag time (time from the end of injection of muscle relaxant until the first depression of the train-of-four response [TOF]), onset time (time from the end of injection of muscle relaxant until the maximum depression of the first twitch of the TOF [T1]), neuromuscular block, and endotracheal intubating conditions at 1 min after 1 mg/kg succinylcholine (n = 15) and 1.5 mg/kg Org 9487 (n = 30). Two minutes after administration of Org 9487, 15 of the 30 patients received neostigmine for reversal. Recovery of neuromuscular block after succinylcholine, Org 9487 without and Org 9487 with neostigmine were compared using the time until T1 was 90% for the succinylcholine group, and the time until TOF was 70% for the Org 9487 groups. Neuromuscular transmission was monitored mechanomyographically. Onset time was similar (67 [20] and 83 [38] s for succinylcholine and Org 9487, respectively) and endotracheal intubating conditions were also similar after both muscle relaxants. Times until clinically sufficient recovery of neuromuscular block induced by succinylcholine (time until T1 = 90%: 10.6 [3.3] min) and Org 9487 with neostigmine (time until TOF = 70%: 11.6 [1.4] min) were not different. In contrast, in the Org 9487 without neostigmine group, more time was required until complete recovery (24.1 [6.2] min) (P < 0.05). In conclusion, ORg 9487 is a muscle relaxant suitable for endotracheal intubation and short-lasting interventions.

Adult↗
PubMed1992

MW/Pharm, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring.

The pharmacokinetic software package MW/Pharm offers an interactive, user-friendly program which gives rapid answers in clinical practice. It comprises a database with pharmacokinetic parameters of 180 drugs, a medication history database, and procedures for an individual drug dosage regimen calculation. The included curve-fitting facilities allow estimation of pharmacokinetic parameters on the basis of medication history, taking into account a varying status of the patient with respect to body weight and kidney function, optionally using a Bayesian procedure. The module KinBes performs the evaluation of bioavailability studies, including various methods, and an extensive statistical evaluation of bioequivalence.

Algorithms↗
PubMed1990

Decreased ciprofloxacin absorption with concomitant administration of ferrous fumarate.

The effect of ferrous fumarate on the relative bioavailability of ciprofloxacin after a single 500 mg oral dose of ciprofloxacin was studied in eight healthy males. Blood samples were collected at regular intervals 0-24 h post-dose. Urine was collected during 24 h to determine the cumulative urine excretion of ciprofloxacin. Ciprofloxacin concentrations in serum and urine were determined by high pressure liquid chromatography. Mean area under the serum concentration-time curve decreased significantly (P less than 0.001) after ciprofloxacin was taken with 200 mg ferrous fumarate. The relative bioavailability was 30% when ciprofloxacin was given with ferrous fumarate. The maximum blood level decreased from 2.1 +/- 0.9 (control) to 0.6 +/- 0.2 mg/l (with ferrous fumarate). Further studies are needed to determine if chronic treatment with ferrous fumarate further decreases the relative bioavailability. For the moment administration of ciprofloxacin with ferrous fumarate should therefore be avoided.

Adolescent↗
PubMed1990

Absorption kinetics of oral and rectal flecainide in healthy subjects.

UNLABELLED: The absorption kinetics of different pharmaceutical formulations of orally and rectally administered flecainide have been assessed in a cross-over study in 7 healthy volunteers. The subjects received single doses of flecainide after a washout period of at least one week. A tablet, an oral solution, a rectal solution and a 10 min i.v. infusion during 10 min each containing 100 mg flecainide were administered to the subjects in a randomized order. The mean absolute bioavailability was 98%, 78% and 81% for the rectal and oral solutions and the tablet. The lag time after administration of the oral solution was 0.33 h and it was 0.86 h after the tablet and 0.18 h after the rectal solution. The mean time to the peak serum concentration (tmax) after the rectal solution (0.67 h) was shorter than after either the tablet (4 h) or oral solution (1 h). The maximum serum concentration (Cmax) was 0.29 mg.l-1 after the rectal solution, 0.14 mg.l-1 after the tablet and 0.17 mg.l-1 after the oral solution. All the volunteers showed significantly higher serum flecainide concentrations during the first 20 min of the absorption phase after rectal administration of 100 mg flecainide as a solution compared to its oral administration. IN CONCLUSION: based on the absolute bioavailability, Cmax, tmax, and lag times, rectal administration of flecainide solution gave a better absorption profile than after oral tablet or solution.

Administration, Oral↗
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↗
PubMed1983

Plasma levels of acetylsalicylic acid and salicylic acid after oral ingestion of plain and buffered acetylsalicylic acid in relation to bleeding time and thrombocyte function.

Buffered acetylsalicylic acid (Alka Seltzer, B-ASA) and plain aspirin (P-ASA) tablets were compared as to their effects on bleeding time and platelet function in eight healthy male volunteers. Two doses (500 and 1000 mg) of each preparation were investigated in a cross-over design, each volunteer being his own control in each dose group (n=4). Both preparations disturbed platelet aggregation to the same extent. Bleeding time increased after both preparations, though significantly more after the buffered preparation than after plain acetylsalicylic acid, irrespective of the dosage. The 1000 mg dose prolonged bleeding time significantly more than the 500 mg dose, irrespective of the preparation. Kinetic analysis showed that B-ASA gave higher peak plasma levels of acetylsalicylic acid (ASA) and accordingly salicylic acid peak levels were also higher after the buffered preparation. It is concluded that B-ASA in equi-analgesic doses prolongs bleeding time more than the plain preparation. Since it is less agressive on the gastro-intestinal mucosa, its use may be advantageous in situations where acetylsalicylic acid induced loss of platelet aggregation is desired. However, the risk of prolonged bleeding--e.g. after tooth extractions--is probably higher after the buffered preparation.

Adult↗