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M Danhof

Publications and source records attributed to M Danhof.

206 records · Page 12Linked to original sources
PubMed1979

Assay of 3-carboxy-antipyrine in urine by capillary gas chromatography with nitrogen selective detection. Some preliminary results in man.

An assay procedure is described for 3-carboxy-antipyrine in urine using gas chromatography with a support coated open tubular capillary column (Carbowax 20M), a solid injection system and nitrogen selective detection. 3-Carboxy-antipyrine was analyzed after derivatization with diazomethane and using 4-bromo-antipyrine as internal standard. Following extraction of the urine samples with a mixture of organic solvents linear calibration curves were obtained in the concentration range of 1--50 microgram/ml. The precision was established as +/- 5.0% (n = 5), and the lowest measurable concentration was 1 microgram/ml at a signal-to-noise ratio of 10:1. Preliminary results in 5 human volunteers showed that after orl administration of 500 mg antipyrine, 3.3 +/- 0.8% of the dose was excreted as 3-carboxy-antipyrine in 52 hours' urine. The compound was excreted completely in the unconjugated form.

Administration, Oral↗
PubMed1979

Studies on the different metabolic pathways of antipyrine in rats: influence of phenobarbital and 3-methylcholanthrene treatment.

1. The amounts of antipyrine and its metabolites excreted in 24 h urine after i.v. injection of 10 mg antipyrine into male Wistar rats were quantified after enzymic hydrolysis with beta-glucuronidase/aryl sulphatase. In 24 h 2.7% of the administered dose was excreted as unchanged antipyrine, 13.3% as 4-hydroxyantipyrine, 7.4% as norantipyrine, 28.9% as 3-hydroxymethylantipyrine and 1.1% as 3-carboxyantipyrine. 2. Treatment with phenobarbital decreased the antipyrine half-life from 65 to 30 min, but did not significantly change the urinary metabolite profile. Only the amount of 3-carboxyantipyrine was significantly different and increased from 1.1 to 2.6% dose. 3. 3-Methylcholanthrene treatment resulted in a decrease of antipyrine half-life from 72 to 37 min. After treatment 4-hydroxyantipyrine was increased from 13.4% to 25.6% dose, whereas 3-hydroxymethylantipyrine was decreased from 26.8% to 8.5% and 3-carboxyantipyrine from 1.3% to 0.2% of the dose respectively; norantipyrine was unchanged. 4. It is concluded that different types of hepatic cytochrome P-450 may be involved in the formation of 4-hydroxyantipyrine on one hand and the formation of 6-hydroxymethylantipyrine on the other. Another possibility is that in methylcholanthrene-treated animals another haemoprotein is formed that results in the formation of more 4-hydroxyantipyrine and less 3-hydroxymethylantipyrine. In any case, the urinary metabolite profile of antipyrine can be used to study changes in the activity of different cytochromes in drug metabolism studies.

Animals↗
PubMedDate not supplied

Pharmacokinetic-pharmacodynamic modelling in pre-clinical investigations: principles and perspectives.

A new approach to preclinical pharmacodynamic investigations is presented which allows, in addition to information on the nature of the pharmacological properties of new chemical entities, also important quantitative pharmacodynamic information to be derived. A single intravenous dose is administered to chronically instrumented rats and the time course of the pharmacological effect is determined in conjunction with plasma or serum concentrations. Datasets obtained in this way are subjected to simultaneous pharmacokinetic/pharmacodynamic modelling to obtain estimates of pharmacodynamic parameters such as EC50, Emax, Hill factor and the rate of biophase equilibration. The new approach was applied in studies with benzodiazepines, baclofen, antiepileptic drugs and adenosine receptor agonists and antagonists. In these studies quantitative EEG parameters, the threshold for convulsion as determined by direct cortical stimulation and various haemodynamic variables were used as a pharmacodynamic endpoint. For drugs exhibiting agonistic or inverse agonistic properties, realistic estimates of the potency and intrinsic efficacy could be obtained by modelling of the direct effects in the various effect models. Estimates of the potency of competitive antagonists (e.g. flumazenil, cyclopentyl-theophylline) could be obtained on the basis of modelling of the pharmacodynamic interaction with a full agonist. For baclofen finally also the rate of biophase equilibration could be estimated. The results of these studies show that by implementation of pharmacokinetic-pharmacodynamic modelling in pre-clinical investigations, useful quantitative information on the pharmacodynamics of new drugs in vivo can be obtained. It is suggested that this information may be of value in the early phases of pre-clinical drug development and that it may facilitate the subsequent clinical development process.

Animals↗
PubMedDate not supplied

Radioimmunoassay of desglycinamide-arginine vasopressin and its application in a pharmacokinetic study in the rat.

The purpose of this investigation was to develop a sensitive and selective radioimmunoassay for Desglycinamide-Arginine Vasopressin (DGAVP). DGAVP was extracted from rat plasma after protein precipitation, using Sep-Pak C18 cartridges and 50 mM glycine buffer/methanol (10:90) solution. Extraction recovery was 73 +/- 14% (mean +/- S.D.; n = 11) and good linearity was achieved in the concentration range of 0.25-128 pg/tube. Instantaneous tracer addition resulted in a detection limit of 250 fg/tube, whereas 24 hours preincubation and delayed tracer addition resulted in a detection limit of 100 fg/tube. Intra-assay variation ranged between 7.4% and 10.0% depending on the peptide concentration and inter-assay variation was 13.2%. Using this procedure, plasma pharmacokinetics of DGAVP in the rat were determined after IV administration. DGAVP plasma concentration showed a rapid distribution phase (t1/2 = 1.0 +/- 0.2 min) and a somewhat slower elimination phase (t1/2 = 7.2 +/- 2.1 min). High clearance values (CLss = 97 +/- 30 ml.min-1) suggest rapid metabolism by amino- and carboxy-peptidases.

Animals↗
PubMedDate not supplied

Determination of the threshold for convulsions by direct cortical stimulation.

In this study we investigated whether determination of the convulsion threshold by electrical stimulation of the cortex could be used as a simple test for measuring anticonvulsant drug activity in unrestrained, unanaesthetized rats. Pulse trains delivered to electrodes implanted in the frontoparietal cortex elicited convulsions, similar to those seen in the classical electroshock tests. The threshold could be determined rapidly with pulse trains which increased in strength in a ramp-shaped fashion (bipolar pulses of 2 msec, 50 pulses/sec, increment 1.3 microA/pulse). The threshold was defined as the current needed to elicit forelimb clonus. Upon repeated stimulation the threshold declined from a value of about 600 microA to about 350 microA in 20 sessions. Thereafter, continued testing did not result in considerable changes in threshold. After stabilization, the convulsion threshold could be determined repeatedly with intervals as short as 5 min. Following i.p. injection of 5 mg/kg of diazepam an elevation of the threshold of 30% was observed 0.5 h after injection. After 5 daily injections, evidence for the development of complete tolerance was obtained. After i.v. injection of 8 mg/kg oxazepam, the threshold increase reached a peak level of 75% after 20 min. The changes in threshold followed arterial blood concentration of oxazepam, which was maximally 4.8 micrograms/ml immediately after injection. The threshold returned to baseline in approximately 6 h. The results of the present study show that with our procedure anticonvulsant drug activity can be accurately, rapidly and repeatedly determined in individual animals, both in acute and chronic experiments.

Animals↗
PubMedDate not supplied

Stepwise intravenous infusion of apomorphine to determine the therapeutic window in patients with Parkinson's disease.

A new experimental strategy was applied to determine the concentration-effect relation and the therapeutic window of apomorphine in individual patients with Parkinson's disease. Apomorphine was administered by a stepwise intravenous infusion. The infusion rate was increased by 10 micrograms/kg/h every 20 minutes, up to 100 micrograms/kg/h or less when adverse effects occurred. Thereafter, the infusion rate was decreased in a stepwise fashion until zero. Plasma apomorphine concentrations were measured every 20 minutes. Clinical efficacy (tapping score and tremor), dyskinesia, and adverse effects were monitored at the same time. The mean clearance of apomorphine was 4.5 L/min (2.2 to 6.6 L/min). Of the 10 patients, 8 responded to apomorphine. The effects were quantal rather than continuous. Within each patient, the concentrations at onset and offset of effect generally were similar. Significant interpatient variability was observed with respect to minimal concentration for each of the effects. Clinical efficacy occurred at a mean minimal effective concentration (MEC) of 4.7 ng/mL (range 1.4 to 10.7 ng/mL). Dyskinesia was observed at a mean concentration of 8.5 ng/mL (range 2.7 to 20 ng/mL). This value was not significantly different from the MEC. The mean minimal toxic concentration was 16.7 ng/mL (8.5 to 24.5 ng/mL) and was significantly different from the mean MEC. In conclusion, the stepwise increase and decrease of the intravenous infusion rate is a suitable tool for the establishment of the concentration-effect relation of apomorphine in individual patients. The finding of a narrow therapeutic window, in which the onset concentrations vary from patient to patient, underlines the need for accurate and individualized dosing.

Adult↗
PubMedDate not supplied

Pharmacokinetics, enantiomer interconversion, and metabolism of R-apomorphine in patients with idiopathic Parkinson's disease.

The pharmacokinetics and metabolism of R-apomorphine were determined in 10 patients with idiopathic Parkinson's disease after intravenous infusion of 30 micrograms.kg-1 in 15 min. Specifically, emphasis was on enantiomeric interconversion into S-apomorphine and on the formation of apocodeine and isoapocodeine, since these metabolites may interfere with the pharmacodynamics of R-apomorphine. The pharmacokinetics of R-apomorphine in plasma were determined using an enantioselective high-performance liquid chromatography assay. In most patients, the plasma concentration versus time profile was characterized by a biexponential function. The values of relevant pharmacokinetic parameters were as follows: clearance 40 +/- 15 ml.min-1.kg-1, volume of distribution at steady state 1.6 +/- 0.5 l.kg-1, and terminal half-life 41 +/- 13 min. No measurable concentrations of S-apomorphine were detected in plasma, indicating that enantiomeric interconversion does not occur in vivo. Furthermore, no measurable concentrations of the methylated metabolites apocodeine and isoapocodeine could be detected in plasma. The metabolism of apomorphine was characterized on basis of the excretion of unchanged R-apomorphine, S-apomorphine, apocodeine, isoapocodeine, and their respective sulfate and glucuronide conjugates in urine. The total excretion of unconjugated S-apomorphine, apocodeine, and isoapocodeine was less than 0.1% of the administered dose. The total excretion of unchanged apomorphine, apomorphine sulfate, and apomorphine glucuronide amounted to 0.3 +/- 0.4%, 3.8 +/- 1% and 6.0 +/- 2.2% of the administered dose, respectively. The findings of this study show that on intravenous administration, S-apomorphine and the metabolites apocodeine and isoapocodeine are unlikely to interfere with the pharmacologic actions of R-apomorphine in patients with idiopathic Parkinson's disease. Furthermore, no pharmacokinetic interaction between R-apomorphine and catechol-O-methyl transferase inhibitors is expected.

Adult↗