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B Oosterhuis

Publications and source records attributed to B Oosterhuis.

At least 55 records · Page 3Linked to original sources
PubMed1989

Omeprazole: pharmacology, pharmacokinetics and interactions.

Omeprazole is a prodrug which is converted to its active form only at the site of action, namely the parietal cell. There it binds irreversibly with H+-K+-ATPase (the gastric proton pump), which causes an effective and long-lasting inhibition of gastric acid secretion. The pharmacokinetic profile of omeprazole is rather complicated, showing concentration-dependent elimination kinetics and an oral bioavailability which increases with the dose and during repeated administration. For the choice of dosage regimens this has minor consequences, in view of the wide therapeutic range of omeprazole and because an almost continuous maximum effect is obtained with once daily oral administration of 20-40 mg. Omeprazole may influence the pharmacokinetics of concurrently administered drugs by an inhibition of their oxidative metabolism. For most drugs studied thus far, the influence is less or even negligible in comparison with the influence of cimetidine, with the exception of diazepam. For every new combination of omeprazole with a drug that has a critical therapeutic range the consequences of a possible interaction should be studied.

Biological Availability↗
PubMed1989

A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone.

A phase I study of mitoxantrone given as a continuous infusion for 21 days using a venous access port and a portable pump was performed. The first dose step was 0.3 mg/m2/d for 21 days. Courses were repeated every 6 weeks. Dose increment per step was 0.1 mg/m2/d in the first three dose steps and 0.2 mg/m2/d in the latter dose steps. Twenty-five patients entered the study and received a total of 50 courses, with a median of two courses (range, one to five). Up to 0.5 mg/m2/d, no toxicity (according to the World Health Organization [WHO] criteria) occurred. At 0.7 mg/m2/d, one patient experienced grade 2 leukocytopenia and at the 0.9 mg/m2/d dose step, one patient experienced grade 2 leukocytopenia, grade 1 thrombocytopenia, and grade 1 hair loss. At 1.1 mg/m2/d, two of six patients had grade 3 leukocytopenia, and in one patient treatment was discontinued after two days because of myocardial infarction. In both patients receiving 1.3 mg/m2/d, treatment was discontinued after 2 weeks because of grade 3 leukocytopenia. Three patients at the 1.1 mg/m2/d, dose step and two patients at the 1.3 mg/m2/d dose step experienced some nausea in the last week of the infusion period. One patient developed subclavian vein thrombosis. No infectious complications occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Plasma steady-state was reached after 35 hours. During steady-state there was a linear relationship between the mitoxantrone dose administered and the level of mitoxantrone in plasma (r = .93, P less than .005). The mitoxantrone level in leukocytes increased significantly during the infusion period at the 0.9 mg/m2, the 1.1 mg/m2, and the 1.3 mg/m2 dose steps. The area under the curve (AUC) in leukocytes was higher with continuous infusion of 1.1 mg/m2/d for 21 days compared with bolus injection of 12 mg/m2. Mitoxantrone could be detected in plasma for at least five days after the end of the 21-day infusion period and in leukocytes for at least 14 days. Continuous infusion mitoxantrone may increase intracellular drug uptake as expressed by intracellular AUC. We recommend a dose of 1.1 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.

Adult↗
PubMed1989

A nonsteady-state agonist antagonist interaction model using plasma potassium concentrations to quantify the beta-2 selectivity of beta blockers.

We studied the competitive interaction of terbutaline and two beta blockers, metoprolol and oxprenolol, with different cardioselectivity for the beta-2 adrenoceptor. Using pharmacokinetic-dynamic modeling in nonsteady-state conditions, of the antagonism by the beta blockers of the terbutaline-induced hypokalemia, the beta blocker beta-2 selectivity was quantitated in the terms of IC50 values representing plasma concentrations resulting in half-receptor occupancy. Six healthy subjects were given an 0.5-mg s.c. dose of terbutaline on three occasions: 1) 1 hr after p.o. administration of a placebo; 2) 1 hr after 150 mg of metoprolol p.o.; and 3) 1 hr after 80 mg of oxprenolol p.o. During 7 hr after terbutaline administration drug concentrations and effects were monitored. Oxprenolol decreased both terbutaline volume of distribution (-69%) and clearance (-63%) and increased its area under plasma concentrations vs. time curve (+157%). Such effects of metoprolol on terbutaline pharmacokinetics were not observed. The dynamic model offered a good description of the observed effects. The apparent IC50 values varied between 42 and 68 ng/ml (mean, 54 ng/ml) for metoprolol and between 3.6 and 4.7 ng/ml (mean, 4.1 ng/ml) for oxprenolol. In view of these results, and comparing them with apparent beta-1 IC50 values as reported in the literature, metoprolol can be considered a relatively beta-1 selective agent. Pharmacokinetic-dynamic modeling of the interaction of beta-2 sympathicomimetics and beta blocking agents after single dosing, seems to be a suitable method for the determination of the relative beta-2 selectivity of the antagonist.

Adrenergic beta-Antagonists↗
PubMed1988

Pharmacokinetic-pharmacodynamic modelling of oxprenolol in man using continuous non-invasive blood pressure monitoring.

The relationship between the plasma concentration of oxprenolol and its haemodynamic effects during physical exercise was studied in 6 healthy volunteers, in whom BP and heart rate (HR) were continuously monitored by non-invasive techniques (Fin-A-Press-Tonometer) during repeated three-minute exercise periods for 8 h after treatment. Using the fitted pharmacokinetic curve, the drug effect was related to its plasma concentration using the Emax model. The mean EC50 for the relationship between drug concentration and heart rate during exercise (HRex) was 73.1 ng/ml, and for systolic blood pressure during exercise (SBPex) it was 112.7 ng/ml. Emax was 29.0% for HRex, and 33.2% for SBPex. There were no consistent differences between the parameters for the effects on HRex and SPBex. Thus, using a new, non-invasive technique for continuous measurement of blood pressure, the effect of a beta-adrenoceptor blocking drug on SBPex was described with similar accuracy as its effect on HRex.

Adult↗
PubMed1988

Pharmacokinetic and pharmacodynamic comparison of a new controlled-release formulation of metoprolol with a traditional slow-release formulation.

The plasma concentration-time profile and haemodynamic effects of metoprolol after the administration of metoprolol CR (a new multiple-unit controlled-release formulation) and metoprolol SR (a traditional slow-release formulation) once daily, were investigated in 12 healthy men. Data were collected over one 24-h dose interval at steady state after five days of treatment. The study was a randomized, three-way, cross-over comparison of metoprolol CR, 100 mg, metoprolol SR, 100 mg, and placebo. The reduction in exercise heart rate in relation to placebo treatment was used as a measure of beta 1-blockade. The metoprolol plasma concentration-time profile during treatment with metoprolol CR was smooth and uniform, showing a more controlled release profile than that obtained with metoprolol SR. This was demonstrated by the significantly longer time period during which the plasma concentration exceeded 75% of the maximum concentration (T75), for metoprolol CR compared with metoprolol SR (p less than 0.05). The percentage peak-trough fluctuation in plasma metoprolol concentration was significantly smaller for metoprolol CR than for metoprolol SR (p less than 0.001). These pharmacokinetic differences between metoprolol CR and metoprolol SR produced a different duration of clinically relevant beta 1-blockade, defined as a reduction in exercise heart rate of greater than 10%. By this definition metoprolol CR was still effective in seven subjects and metoprolol SR in two subjects 24 h after dosing. The percentage peak-trough fluctuation in exercise heart rate over the dose interval was significantly smaller for metoprolol CR than for metoprolol SR (p less than 0.001), thus demonstrating a more even beta 1-blockade with metoprolol CR.

Adult↗
PubMed1988

Kinetics of drug effects in man.

This review describes general principles that contribute to the understanding of the relationship between drug concentrations and pharmacological effects. In particular, attention is given to drugs that exert direct and reversible pharmacological responses. First of all, the relationship between measured (total) concentration and effective concentration should be considered. The effect kinetics can often be described by rather simple principles, giving important information for interpretation of drug-monitoring data. In other situations, the application of new approaches in pharmacokinetic--pharmacodynamic modeling turns out to provide valuable insight for the interpretation of more complicated concentration--effect relationships that would not otherwise have been recognized.

Humans↗
PubMed1988

No effect of influenza vaccination on theophylline pharmacokinetics as studied by ultraviolet spectrophotometry, HPLC, and EMIT assay methods.

The effect of influenza vaccination on steady-state pharmacokinetics of theophylline was studied in six healthy young adults by comparing pharmacokinetic parameters found on days 4 and 5 during a 5-day course of theophylline alone with those obtained after influenza vaccination on day 4 of a second study phase. Theophylline plasma concentrations were measured by means of high-pressure liquid chromatography (HPLC) analysis and, in part, with a manual ultraviolet spectrophotometric method and with an EMIT assay. On the fourth and fifth days of each of the two periods of drug administration, theophylline plasma concentration-time curves were evaluated, and the following pharmacokinetic parameters were compared: trough plasma concentration (cmin), peak plasma concentration (cmax), time to peak (tmax), and the area under the curve during a dosing interval (AUC). None of these pharmacokinetic parameters of theophylline before and after vaccination were found to be significantly different with any of the analytical methods.

Adult↗
PubMed1987

Beta-2-adrenoceptor-mediated hypokalemia and its abolishment by oxprenolol.

The time course and concentration-effect relationship of terbutaline-induced hypokalemia was studied, using computer-aided pharmacokinetic-dynamic modeling. Subsequently we investigated the efficacy of oxprenolol in antagonizing such hypokalemia, together with the pharmacokinetic interaction between both drugs. Six healthy subjects were given a 0.5 mg subcutaneous dose of terbutaline on two occasions: 1 hour after oral administration of a placebo and 1 hour after 80 mg oxprenolol orally. In the 7-hour period after terbutaline administration, plasma samples were taken for determination of plasma potassium levels and drug concentrations. The sigmoid Emax model offered a good description of the relation between terbutaline concentrations and potassium effects. Oxprenolol caused decreases of 65% and 56% of terbutaline volume of distribution and clearance, respectively, and an increase of 130% of its AUC. In spite of higher terbutaline concentrations after oxprenolol pretreatment, the hypokalemia was almost completely antagonized by the beta 2-blocking action.

Adult↗
PubMed1987

Concentration-dependent effects of prednisolone on lymphocyte subsets and mixed lymphocyte culture in humans.

In a previous study the feasibility of pharmacokinetic-pharmacodynamic modeling for a quantitative description of the lymphocytopenic effect of prednisolone was demonstrated. We now applied this technique to compare the lymphocytopenia of T-lymphocyte subsets, namely CD8 and CD4. The finding of similar rate constants for the delay of the effect on different T-lymphocyte categories supports the explanation of this delay on the basis of pharmacokinetics rather than cellkinetics. The time course of the responsiveness of remaining lymphocytes in mixed lymphocyte culture after prednisolone administration could be described with the same model as the lymphocytopenia. The concurrence of both effects suggests that total lymphocyte counts, if considered intraindividually, could be used as a measure for monitoring the indirect immunosuppressive effect of prednisolone. The inhibitory effect on mixed lymphocyte culture of plasma from subjects who received prednisolone was directly related with the prednisolone concentrations in plasma. Just as for the indirect effect, a threshold concentration could be observed in the concerning concentration-effect relation. This is attributed to the decrease of endogenous hydrocortisone levels under the influence of prednisolone. Possible consequences of our results and those from related studies for the use of prednisolone as an immunosuppressive drug are discussed.

Adult↗
PubMed1986

Twenty-four hour effects of oxprenolol Oros and atenolol on heart rate, blood pressure, exercise tolerance and perceived exertion.

The effects of oxprenolol, a non-selective beta-blocker with moderate intrinsic sympathomimetic activity (ISA), given by the Oros delivery system, on resting and exercise heart rate and blood pressure have been compared over a 24-h period with those of atenolol, a beta 1-selective blocker without ISA. The effects on maximal and submaximal exercise tolerance and perceived exertion were studied in relation to the level of beta-blockade. 9 healthy subjects were treated with placebo, atenolol, 100 mg/day and oxprenolol Oros, 16/260 mg/day in random order, each for 5 days. Progressive maximal exercise tests and submaximal endurance tests at 80% of maximum aerobic exercise capacity were performed 2, 5 and 24 h after intake of the drugs. The reduction of blood pressure 2 and 5 h after drug intake was less pronounced after oxprenolol Oros than after atenolol, but by 24 h after the last dose the effects were similar. The peak level of beta-blockade (i.e. reduction in maximal exercise heart rate) was similar after oxprenolol Oros and atenolol. The minimal level of beta-blockade 24 h after the last dose was greater after oxprenolol Oros than after atenolol. Maximal exercise capacity and submaximal exercise tolerance were impaired after both beta-blockers. The subjective feeling of exertion did not differ between placebo, atenolol and oxprenolol Oros when related to the relative work load, except after the first minute of exercise, when the rating of perceived exertion was higher after atenolol.

Adult↗
PubMed1986

Pharmacokinetic-pharmacodynamic modeling of terbutaline bronchodilation in asthma.

The study of terbutaline pharmacodynamics in patients with asthma is hampered by interfering stimuli when steady-state methods are employed. With pharmacokinetic-dynamic modeling, many of these interferences can be avoided. Using this technique, we studied the effect of terbutaline on lung function in 10 asthmatic patients with greater than 15% lung function reversibility. Terbutaline plasma concentrations, forced expiratory volume in 1 second (FEV1) airway resistance (Raw), and specific airway conductance (sGaw) were measured before and during 7 hours after subcutaneous dosing with 0.75 mg terbutaline. A hyperbolic concentration-effect relation was found. Fitting the time course of the effects required an effect compartment in the integrated model. Thus the delay between plasma concentration and effect time course was characterized by the rate constant ke0. Essentially the same ke0 was found for FEv1, Raw, and sGaw, indicating that the concerning receptors are "localized" in the same pharmacokinetic compartment. Of the lung function measures, sGaw was less sensitive to terbutaline than Raw and FEV1, whereas the latter tended to be the most sensitive one.

Adolescent↗
PubMed1986

Prednisolone concentration-effect relations in humans and the influence of plasma hydrocortisone.

Recently we applied pharmacokinetic-pharmacodynamic modeling to study the relation between the time course of prednisolone concentration and lymphocytopenic effects. A threshold concentration parameter (Cth) was incorporated in the pharmacodynamic model. In the present study the influence of the initial endogenous hydrocortisone (HC) level (HCt = O) was investigated, particularly on Cth estimates. Five healthy subjects received a single p.o. dose of 30 mg of prednisolone on two separate occasions. One dose was given at 8:00 A.M. (data set A), the other at 8:00 P.M. (data set B). A second group of five subjects received 30 mg of prednisolone at 8:00 A.M. on 3 consecutive days, measurements being made after the third dose (data set C). Results from a previous experiment in five subjects who received 30 mg of prednisolone at 8:00 A.M. were reanalyzed in the present study (data set D). Blood samples were taken over a period of 12 hr after dosing for determination of corticosteroid levels and OKT4 positive lymphocyte counts. For data sets B and C, HCt = O tended to be lower and OKT4 counts at t = O tended to be higher in comparison with data sets A and D. Pharmacokinetic parameters of prednisolone were similar in the four experiments. The time course of the OKT4 counts after dosing could be fitted irrespective of the initial counts and HCt = O. The results support the postulate that Cth represents prednisolone replacing lost HC and the conclusion that HC and prednisolone are about equipotent with respect to the lymphocytopenic effect. On the basis of our results and literature data, suggestions are made for optimal immunosuppression with prednisolone.

Adult↗
PubMed1985

Red blood cell electrolytes for monitoring digoxin therapy in adults.

Red blood cell (RBC) electrolyte concentrations were determined, with a method that can be applied easily in any clinical chemistry laboratory, in 18 patients not on digoxin therapy and 37 patients on maintenance digoxin therapy for various diagnoses. Of the digoxin-treated patients, 11 had electrocardiographic changes and other clinical evidence of digoxin toxicity. Mean RBC sodium was higher and mean RBC potassium was lower in patients on prolonged digoxin therapy than in controls, and these changes were more pronounced in patients with toxic symptoms. In the group of 11 patients with toxicity, a positive correlation was found between the ratio of RBC sodium to potassium and plasma digoxin levels (r = 0.8234, p less than 0.05). Plasma digoxin concentrations did not clearly distinguish between toxic and nontoxic patients. The RBC sodium/potassium ratio, however, identified 35 of 37 patients correctly, with two patients from the toxic and two patients from the nontoxic group giving the same results. Changes in intracellular erythrocyte electrolytes in adults appear to correlate closely with clinical signs of digoxin toxicity.

Adult↗
PubMed1984

Liquid chromatography with electrochemical detection for monitoring mebendazole and hydroxymebendazole in echinococcosis patients.

A sensitive method is described for the simultaneous determination of mebendazole and hydroxymebendazole using flubendazole as an internal standard. The analytes were isolated with a single chloroform extraction from 1.0 ml of alkalinized plasma or cyst liquid samples. Separation and quantitation were performed with high-performance liquid chromatography with electrochemical detection. The limit of detection for mebendazole and hydroxymebendazole was approximately 5 and 2.5 ng/ml, respectively. The accuracy of the method was confirmed for mebendazole by a good correlation with an existing radioimmunoassay method. The method was applied for monitoring mebendazole therapy in echinococcosis patients. The results presented support the necessity of such monitoring, as most of the observed peak plasma concentrations did not reach the level regarded as minimal for therapeutic effect.

Benzimidazoles↗
PubMed1984

Pharmacokinetic-pharmacodynamic modeling of prednisolone-induced lymphocytopenia in man.

The lymphocytopenic effect of prednisolone as quantified by OKT3- and OKT4-positive lymphocyte counts in peripheral blood was studied. Single oral prednisolone doses of 10, 30 and 60 mg, respectively, were given to three groups of five subjects. The time courses of prednisolone concentration and lymphocytopenic effects were related by a pharmacokinetic-pharmacodynamic model. The computer program NONLIN was used for parameter estimation. The pharmacodynamic component of the model was a hyperbolic function in which a threshold concentration parameter had to be incorporated. Apparently, this parameter represents depletion of endogenous hydrocortisone after the administration of prednisolone. The results of this study suggest that the prednisolone-induced lymphocytopenia is not related to mRNA transcription and protein synthesis. Furthermore, prednisolone and hydrocortisone seem to be equipotent in man with respect to the studied effect. Smaller doses of prednisolone are relatively more effective due to saturation of the effect and increasing depletion of endogenous hydrocortisone by higher doses.

Adult↗
PubMed1982

Analysis of 6-mercaptopurine in human plasma with a high-performance liquid chromatographic method including post-column derivatization and fluorimetric detection.

A relatively simple assay with improved reliability and sensitivity for measuring levels of 6-mercaptopurine in human plasma is presented. After extraction of the compound and the added internal standard with phenyl mercury acetate, samples were separated by ion-pair reversed-phase high-performance liquid chromatography. On-line the analytes were oxidized to fluorescent products and detected in a flow-fluorimeter. The within-day coefficient of variation was 3.8% at a concentration of 25 ng/ml. The lower detection limit was 2 ng/ml when 1.0 ml of plasma was used. Mercaptopurine concentration versus time curves of two subjects after a single oral dose of azathioprine are shown.

Azathioprine↗
PubMed1982

Determination of salbutamol in human plasma with bimodal high-performance liquid chromatography and a rotated disc amperometric detector.

The sensitivity of electrochemical detection was combined with the selectivity of a bimodal high-performance liquid chromatographic system for the successful determination of salbutamol in human plasma. Following initial sample clean-up using Sep-Pak cartridges, analytes were passed first through a cation-exchange column, and then, after column switching, through a reversed-phase column. An amperometric detector with a rotated disc working electrode was used for detection. The detection limit was 0.5 ng/ml when 1.0 ml of plasma was used. The coefficient of variation was 9.8% at an average concentration of 4.7 ng/ml. The method was adequate for pharmacokinetic studies and for clinical applications.

Albuterol↗