Biomedical subjects
Publications and source records attributed to R Koopmans.
Magnetic resonance imaging (MRI) provides an objective method of evaluating multiple sclerosis clinical trials and is at least five times more sensitive to disease activity. In a recent clinical trial, MRI was also approximately twice as sensitive as clinical measurements to the treatment effect of a drug.
1. Tumour necrosis factor-alpha is considered an important mediator in the pathophysiology of several diseases. Although much information is available about the serum concentrations of this cytokine in these illnesses, little is known about the production of tumour necrosis factor-alpha in disease in vivo. 2. In the present study we aimed to estimate the extent and the kinetics of whole body tumour necrosis factor-alpha synthesis in experimental endotoxaemia in six healthy humans. For this purpose we first examined the pharmacokinetic behaviour of an intravenously injected bolus of recombinant human tumour necrosis factor-alpha (50 micrograms/m2) in another group of six normal subjects. We then calculated the total amount of tumour necrosis factor-alpha produced after intravenous injection of endotoxin (2 ng/kg) as the product of the systemic clearance of recombinant human tumour necrosis factor-alpha (9.5 +/- 5.0 ml min-1 kg-1) and the area under the tumour necrosis factor-alpha concentration-time curves in the endotoxaemic subjects. 3. Recombinant human tumour necrosis factor-alpha showed evident two-compartment kinetics with an initial rapid disappearance (t1/2 5.1 +/- 2.2 min) and a terminal slower elimination (t1/2 49 +/- 5 min). Tumour necrosis factor-alpha synthesis after endotoxin varied markedly between individuals, ranging from 11.8 to 114.1 micrograms (52.7 +/- 34.7 micrograms). The changes in time of the serum concentrations of tumour necrosis factor-alpha after administration of endotoxin could be accurately described with an adapted two-compartment open model that incorporated both rapid tumour necrosis factor-alpha production (74% of the total amount) and slow tumour necrosis factor-alpha production (26%).(ABSTRACT TRUNCATED AT 250 WORDS)
Juvenile ossifying fibroma (JOF) is a maxillofacial fibro-osseous lesion that may show cell-rich osteoid strands or psammoma-like ossicles. Whether both types are variants of a single entity or different lesions under the same diagnostic label is a subject of debate. This problem was investigated by analyzing a series of 33 patients with lesions having one or both of the above histological appearances. It was concluded that osteoid strands define a unique fibro-osseous lesion but that lesions with psammoma-like ossicles fall within the morphological spectrum of cemento-ossifying fibroma. Therefore the term juvenile ossifying fibroma should be reserved for the lesion with the osteoid strands.
We have studied the effect of dosage time of oxprenolol (Trasicor) on its pharmacokinetics and pharmacodynamics in six healthy volunteers. The drug effects measured were heart rate and systolic blood pressure during exercise. Oxprenolol was taken orally at 08.00 h, 14.00 h, 20.00 h, and 02.00 h in randomized order, with 1 week between successive doses. There were differences in the pharmacokinetics of oxprenolol for the ratio between the apparent volume of distribution and systemic availability (P = 0.04) and for elimination half-life (P = 0.006). Both were lowest after administration at 14.00 h (163 (77) l and 1.2 (0.6) h; mean (SD)) and highest after administration at 02.00 h (229 (100) l, and 1.7 (0.6) h). The systolic blood pressure during exercise before oxprenolol did not vary with dosage time, but heart rate during exercise before intake was lowest before dosage time 08.00 h and highest before dosage time 20.00 h (P = 0.03). The time-course of heart rate during exercise after oxprenolol was described by a model that incorporated the factors drug concentration and spontaneous diurnal variation. EC50 and Emax did not vary between dosage times. The spontaneous diurnal variation in heart rate during exercise was unaffected by oxprenolol, leading to an apparently greater effect of oxprenolol during the night than during the day.
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The influence of dosage time of midazolam on its pharmacokinetics and effects on the central nervous system were investigated in six healthy volunteers, with pharmacokinetic-pharmacodynamic modeling. Each volunteer received single oral doses of 15 mg midazolam on four separate occasions: 8 AM, 2 PM, 8 PM, and 2 AM. An almost significant circadian variation was found in elimination half-life, shortest at 2 PM (1.26 +/- 0.47 hours, mean +/- SD) and longest at 2 AM (1.57 +/- 0.44 hours) (p = 0.05). Drug effects measured were alpha activity of the electroencepalograph and P100 latency of the visual-evoked response. The maximum drug effect (Emax) model described the concentration-effect relationship, extended with either a threshold drug concentration or a sigmoidicity parameter. A significant circadian variation was found in baseline alpha activity: highest at 8 AM (109% +/- 19% of the 24-hour mean) and lowest at 2 AM (80% +/- 12%). For alpha activity the drug concentration at half-maximum effect of both threshold Emax model and sigmoid Emax model showed lower values at 8 AM and 2 AM and higher values at 2 PM and 8 PM. However, these differences were either not significant (p = 0.10, threshold model) or on the verge of statistical significance (p = 0.05, sigmoid model). No circadian variation was found in the parameters describing the effect on the visual-evoked response. We conclude that the sensitivity of the central nervous system to midazolam, as reflected in alpha activity, possibly shows a circadian variation.
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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.
The effect of midazolam on alpha-activity of the EEG and latency of the P-100 of the visual evoked response (VER) was studied in six healthy subjects. Drug concentration was related to effect with the Emax model that was used with either a threshold drug concentration or a sigmoid exponent. An effect compartment was included in the pharmacokinetic-pharmacodynamic model. Four subjects showed hysteresis, and mean values of half-lives-k(eo) ranged from 0.26 to 0.60 hour. Mean values of EC50 ranged from 42.0 to 48.1 ng/ml. Goodness of fit did not differ significantly between the sigmoid Emax model and the threshold Emax model. The sigmoid exponent estimated was 3.7 +/- 1.8 (EEG, mean +/- SD) and 2.9 +/- 1.4 (VER); the threshold concentration was estimated at 15.7 +/- 11.1 ng/ml (EEG) and 11.3 +/- 7.0 ng/ml (VER). We conclude that the Emax model adequately describes the relationship between midazolam concentration and effect and that the sigmoid exponent can be substituted by a threshold drug concentration, with a comparable fit of the model to the data.
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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.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.