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J Dingemanse

Publications and source records attributed to J Dingemanse.

69 records · Page 4Linked to original sources
PubMed1990

Pharmacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats.

1. The purpose of this investigation was to examine in vivo drug-concentration anticonvulsant effect relationships of oxazepam in individual rats following administration of a single dose. 2. Whole blood concentration vs time profiles of oxazepam were determined following administration of doses of 4, 8 and 12 mg kg-1. The pharmacokinetics could be described by an open 2-compartment pharmacokinetic model. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of clearance and volume of distribution were 28 +/- 2 ml min-1 kg-1 and 2.6 +/- 0.31 kg-1, respectively, and were not significantly different from the values obtained at the other doses. 3. The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within one rat. Significant dose-dependent elevations of the seizure threshold were observed. 4. By pharmacokinetic-pharmacodynamic modelling, a log-linear relationship was found between concentration and anticonvulsant effect. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of the pharmacodynamic parameters slope and minimal effective concentration (Cmin) were 243 +/- 27 microA and 0.11 +/- 0.02 mg l-1, respectively and not significantly different from the values obtained at the other doses. 5. In a repeatability study the pharmacodynamic parameters were determined twice on two different occasions with an interval of two weeks in the same group of 11 rats. The inter-animal variability in the pharmacodynamic parameter slope was 46%, whereas the intra-animal variability was 24 +/- 18%. The value of the minimal effective concentration was in each animal and on each occasion close to zero within the relatively narrow range of 0.01-0.30mgI. 6. The results of this study showed that it is possible to determine in vivo concentration-anticonvulsant effect relationships of oxazepam under non-steady-state conditions in individual rats. The anti-convulsant effect of oxazepam appeared to be a rapidly reversible direct effect and acute tolerance did not develop within the time frame of the experiments.

Animals↗
PubMed1989

Diazepam reverses the effects of pentylenetetrazole in rat pups by acting at type 2 benzodiazepine receptors.

Pentylenetetrazole (75 mg/kg) induced a characteristic coarse body tremor (accompanied by limb extension) and hyperactivity in 4-day-old rat pups. These effects were reversed by diazepam (0.5 and 2 mg/kg) but not by CL 218,872 (10 and 20 mg/kg) which is selective for type 1 benzodiazepine receptors. Diazepam did not affect the brain concentrations of pentylenetrazole, indicating that the reversal was not based on a pharmacokinetic interaction. Neither diazepam nor CL 218,872 had significant effects on the behavior of the rat pups, although diazepam (2 mg/kg) tended to increase locomotor activity. The results suggest that diazepam displays an anticonvulsant effect in the neonatal rat which is mediated by type 2 receptors.

Animals↗
PubMed1989

Relationship between receptor occupancy at 37 degrees C and the anticonvulsant effect of flunitrazepam in rats.

In this investigation an attempt was made to evaluate quantitatively the relationship between benzodiazepine receptor occupancy and the anticonvulsant effect of flunitrazepam in rats. A graded measure of anticonvulsant effect was obtained on the basis of an elevation of pentylenetetrazol (PTZ) threshold concentrations. The concentration-anticonvulsant effect relationship could be described by the Emax model with an EC50 in cerebrospinal fluid of 2.9 +/- 0.8 micrograms/liter and an Emax of 227 +/- 22 mg/liter PTZ (mean +/- SE). In vitro receptor occupancy was determined in a crude brain homogenate at 0 and 37 degrees C, which yielded KD values of 2.2 +/- 0.2 and 26 +/- 2 micrograms/liter, respectively. The results obtained in both experiments were combined by focusing on free flunitrazepam concentrations. This strategy resulted in a nonlinear relationship between receptor occupancy and anticonvulsant effect of flunitrazepam, with 90% of the maximum response achieved at a degree of receptor occupancy of approximately 50% at 37 degrees C.

Animals↗
PubMed1989

Pharmacokinetic modeling of the anticonvulsant action of phenobarbital in rats.

The aim of this study was to develop a model for the relationship between concentration and anticonvulsant effect of phenobarbital in the rat. The method of quantitating the anticonvulsant response on the basis of plasma pentylenetetrazol threshold concentrations, was optimized by application of a longitudinal study design. The pharmacokinetics of phenobarbital were studied in a separate set of rats (elimination half-life 11 +/- 2 hr). The anticonvulsant effect was measured 1 hr after i.v. administration. Concentration-effect relationships were assessed for serum (total and free), cerebrospinal fluid and brain concentrations on the basis of the sigmoid maximum effect model. The EC50 for total serum was 76 +/- 9 mg/l and for free serum, cerebrospinal fluid and brain 44 +/- 5, 43 +/- 7 and 50 +/- 8 mg/l and mg/kg, respectively (means +/- S.E.). The maximum effect was about 120 mg/l of pentylenetrazol. The respective EC50 ratios corresponded closely with the concentration ratios between the different compartments as determined by orthogonal regression analysis. For the greater part of the concentration range the concentration-effect relationship also could be fitted accurately to a simple linear model. Such relationships were not perturbed by the occurrence of seizures as these did not alter the distribution profile of phenobarbital. The pharmacokinetics and pharmacodynamics of p-hydroxyphenobarbital, the main metabolite of phenobarbital, also were investigated. This compound is eliminated very rapidly and has neither anticonvulsant activity of its own nor influences the anticonvulsant effect of phenobarbital at serum concentrations up to 30 mg/l. The described experimental strategies allow the study of factors influencing the concentration-anticonvulsant effect relationship of phenobarbital.

Animals↗
PubMed1988

Pharmacokinetic modeling of the anticonvulsant response of oxazepam in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure.

This investigation developed strategies along which the anticonvulsant effect of oxazepam in the rat could be pharmacokinetically modeled. After determination of the pharmacokinetics of oxazepam, which could be described with a two-compartment model (half-lives of distribution and elimination 6 and 52 min, respectively), the drug was administered iv to groups of animals to achieve a serum concentration range of 0.1-2.5 mg/L at 10, 45, and 120 min after administration. At these time points pentylenetetrazol (PTZ) was infused slowly until the first myoclonic jerk occurred. The anticonvulsant response, expressed as the elevation of the serum or brain threshold concentration of PTZ, was modeled versus the serum (both total and free) and brain oxazepam concentration, according to the sigmoid Emax model. The total serum and brain oxazepam EC50 values are about 0.5 mg/L and 1.1 mg/kg, respectively, and Emax 120 mg/L PTZ. No marked differences in pharmacodynamic parameters between the three time groups were found, which indicates that serum and brain are pharmacokinetically indistinguishable from the effect compartment, that there is no (inter)activity of oxazepam metabolites and absence of development of acute tolerance during the investigated time frame. An interfering role of metabolites was also excluded by a direct radioreceptor assay of oxazepam, yielding very similar results as the specific chromatographic assay. It is concluded that the conception-anticonvulsant effect relationship of oxazepam can satisfactorily be described by the sigmoid Emax model, when utilizing the employed experimental strategies.

Animals↗
PubMed1988

Application of serial sampling of cerebrospinal fluid in pharmacodynamic studies with a drug active in the CNS: heptabarbital concentrations at onset and offset of loss of righting reflex in rats.

As cerebrospinal fluid (CSF) possesses unique characteristics in order to explore concentration-pharmacological response relationships of drugs active in the CNS, the practicability of serial sampling of CSF was tested in a study with heptabarbital. Concentrations in CSF and plasma were measured simultaneously in individual rats during and after an intravenous infusion for 30 min. At the end of the infusion, the distribution equilibrium was attained with a CSF/plasma concentration ratio of 0.38, roughly equal to the fraction unbound to protein. When concentrations in blood and CSF were determined at the onset and offset of loss of righting reflex concentrations in blood were significantly greater at onset (146 +/- 19 mg/l) than at offset (108 +/- 16 mg/l, n = 6), whereas concentrations in CSF were identical (39 +/- 5 and 38 +/- 5 mg/l, respectively). This confirmed the earlier observation that the CSF is pharmacokinetically indistinguishable from the site of action. When the duration of the loss of righting reflex was varied, concentrations of heptabarbital in CSF at onset and offset were similar, independent of the duration of the loss of righting reflex (1-5 hr). These findings demonstrate the absence of the development of acute tolerance and confirmed that no (inter)active metabolites interfered with the pharmacological response. In a total number of 26 rats the concentrations in CSF at onset and offset of loss of the righting reflex were compared. The interindividual variation was 13-15% and the intra-individual variation was only 4-6%. The results demonstrate the usefulness of serial sampling of CSF in pharmacodynamic studies with centrally acting drugs.

Animals↗
PubMed1988

Pharmacokinetic-pharmacodynamic modeling of midazolam effects on the human central nervous system.

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.

Central Nervous System↗
PubMed1988

Strategy to assess the role of (inter)active metabolites in pharmacodynamic studies in-vivo: a model study with heptabarbital.

The purpose of this investigation was to develop a universal experimental strategy by which the role of (inter)active metabolites in in-vivo pharmacodynamic studies can be examined. Heptabarbital was chosen as a model drug and several pharmacokinetic variables which may affect in-vivo concentration-pharmacological response relationships were examined. Adult female rats received an i.v. infusion of the drug at one of three different rates (0.225-1.50 mg min-1) until the animals lost their righting reflex (after 11 +/- 1 to 88 +/- 8 min of infusion). The serum concentration of the drug at onset of loss of righting reflex (LRR) increased slightly with increasing infusion rate. The drug concentrations in brain tissue and cerebrospinal fluid (CSF), (mean +/- s.d.: 67 +/- 5 mg kg-1 and 24 +/- 4 mg L-1, respectively, for the lowest infusion rate) were not affected by the infusion rate. The possible contribution of (inter)active metabolites to the pharmacological response of heptabarbital was determined by administration of different i.v. bolus doses (14.1-22.5 mg) resulting in widely differing sleeping-times (7 +/- 3 to 119 +/- 20 min). The concentrations of heptabarbital in serum, brain tissue and CSF at offset of LRR (mean +/- s.d.: 77 +/- 8 mg L-1, 76 +/- 7 mg kg-1 and 29 +/- 5 mg L-1, respectively, for the highest dose) were not affected by the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Altered pharmacokinetic-pharmacodynamic relationship of heptabarbital in experimental renal failure in rats.

The purpose of this investigation was to determine whether renal dysfunction is associated with an alteration in the concentration-anesthetic effect relationship of heptabarbital (HB). Adult female rats were pretreated with uranyl nitrate (5 mg/kg i.v.) to produce renal dysfunction. Saline-injected rats served as controls. The concentration-effect relationship of HB was determined both at onset of loss of righting reflex (LRR) during an i.v. infusion (0.563 mg/min) and at offset of LRR after administration of a bolus dose (82 and 111 mg/kg in renal failure and controls, respectively, inducing similar durations of effect). In renal failure HB concentrations in serum (total and free) and in brain and cerebrospinal fluid (CSF) both at onset and offset of LRR were reduced significantly. When HB was infused at different rates (0.225, 0.563 and 1.50 mg/min) rats with renal impairment had slightly increasing HB concentrations at onset of LRR with increasing infusion rate, not only in serum and brain but also in CSF. When HB was administered in different bolus doses (71, 77, 80 and 96 mg/kg i.v.) the duration of effect increased linearly with the logarithm of the dose, but HB concentrations in serum (both total and free), brain and CSF at offset of LRR were similar, indicating the absence of (inter)active metabolites. The results indicate that renal dysfunction is associated with an increased sensitivity of the brain to HB, which is unrelated to changes in the disposition of HB.

Acute Kidney Injury↗
PubMed1986

Chronic treatment with Ro 15-1788 distinguishes between its benzodiazepine antagonist, agonist and inverse agonist properties.

Ro 15-1788 (flumazepil) is an imidazodiazepine that is able to antagonise most of the behavioural actions of the benzodiazepines, as well as having some intrinsic effects. Acute administration of Ro 15-1788 (10 mg/kg) decreases social interaction between male rats and elevates exploratory head-dipping. After 5 days of pretreatment there was tolerance to the former effect, although Ro 15-1788 retained its ability to antagonise the effects on social interaction of the beta-carboline, FG 7142. Ro 15-1788 also retained its ability to elevate head-dipping: additionally, the chronically-treated rats had elevated motor activity and rearing scores. The acute effects of lorazepam in the holeboard were unchanged by chronic pretreatment with Ro-15-1788. The plasma and brain concentrations after acute administration of lorazepam were unchanged following chronic administration of Ro 15-1788. After chronic treatment the brain concentrations of Ro 15-1788 were unchanged. It is unlikely that pharmacokinetic factors could underlie the different behavioural changes following chronic treatment.

Animals↗
PubMedDate not supplied

Assessment of catechol-O-methyltransferase activity and its inhibition in erythrocytes of animals and humans.

A non-radiometric method to measure the catechol-O-methyltransferase (COMT) activity in erythrocytes was modified to increase its sensitivity four-fold as well as its reproducibility and applicability. The method is based on the COMT-mediated O-methylation of 4-(naphtho [1,2-d] thiazol-2-yl) pyrocatechol, the product of which was determined fluorometrically. COMT activities down to less than 1% of those present at baseline could be measured precisely and accurately. The intra- and inter-assay coefficients were below 3 and 5.3%, respectively. Basal COMT activity and the distribution between soluble and membrane-bound COMT was shown to be variable among different species (ten species tested). The applicability of the method was demonstrated by the characterization of COMT activity-time courses in human erythrocytes after oral administration of the COMT inhibitor tolcapone. The assay developed will be useful in the rapid screening and clinical development of new COMT inhibitors.

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

Multiple-dose tolerability, pharmacodynamics, and pharmacokinetics of the quinolizinone hypnotic Ro 41-3696 in elderly subjects.

The objectives of this double-blind, placebo-controlled study were to assess the multiple-dose tolerability, pharmacodynamics, and pharmacokinetics of the hypnotic agent Ro 41-3696 in elderly men and women (55-75 y of age). On day 1 and days 3-8, doses of 1, 3, 5, and 10 mg were administered sequentially to 4 groups of 10 subjects, 2 of whom received placebo. Psychomotor performance tests (tracking and attention) were conducted just before and at 1.5, 4, and 8 hours after drug intake on days 1, 4, 6, and 8. Memory was assessed at 24 hours after drug intake on days 1 and 8 by recall of a list of 10 words, which had been learned at 2 hours after intake. Ro 41-3696 was well tolerated at all dose levels. One subject dropped out of the study because of a hypersensitive skin reaction during treatment with 10 mg. Performance in both a tracking test and a memory search test was significantly affected by a dose of 10 mg and moderately affected by doses of 3 and 5 mg. The results of the 1-mg dose were indistinguishable from those of placebo. Long-term memory, as assessed by a word learning and recall test, showed the same pattern. Partial tolerance to the impairing effects in the psychometric tests developed over the course of treatment. Pharmacokinetics of both Ro 41-3696 and its O-desethyl metabolite Ro 41-3290 were dose proportional and time independent. Ro 41-3696 was absorbed and eliminated rapidly (time of maximum plasma concentration, approximately 1 hour; elimination half-life, approximately 2 hours). Plasma levels of Ro 41-3290 were higher than those of the parent drug, and it was more slowly eliminated (values for time of maximum plasma concentration and elimination half-life, approximately 2 and approximately 7 hours, respectively).

Aged↗