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J Dingemanse

Publications and source records attributed to J Dingemanse.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa.

1. Single oral doses of the catechol-O-methyltransferase (COMT) inhibitor tolcapone (10-800 mg) or placebo were administered simultaneously with a dose of levodopa/benserazide 100/25 mg to seven sequential groups of six healthy male subjects in a two-way crossover study. 2. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa (3-OMD) were determined in conjunction with COMT activity in erythrocytes. 3. The drug combination was well tolerated at all dose levels and there were no signs indicative of an increase in dopaminergic stimulation. 4. Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes in parallel with a dose-dependent decrease in the formation of 3-OMD. Tolcapone increased the area under the concentration-time curve and elimination half-life of levodopa. The maximum effects were obtained at a dose of about 200 mg when both parameters increased approximately twofold. The drug had no influence on the maximum concentration of levodopa. 5. Tolcapone was rapidly absorbed and eliminated with, on average, a tmax of 1.5 h and a t1/2 of 2.3 h. The drug showed dose-proportional pharmacokinetics, in contrast to 3-O-methyltolcapone whose formation was relatively decreased at higher doses. 6. Plasma concentrations of tolcapone correlated with inhibition of COMT activity in erythrocytes and suppression of 3-OMD levels, but not with changes in levodopa pharmacokinetics.

Adult↗
PubMed1994

Mixed linear and non-linear disposition of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. Single oral doses (100-300 mg) and multiple oral doses (100-350 mg 12 hourly for 7 days) of lazabemide were administered to 35 young and 40 elderly healthy subjects. Plasma concentrations of unchanged drug were determined to study the dose-concentration relationship. 2. The elimination phase time course of lazabemide concentrations indicated concentration-dependent elimination after both single and multiple dosing. Nevertheless, maximum concentrations and areas under concentration-time curves increased almost proportionally with dose and accumulation after chronic dosing was less than a factor of 2; steady-state concentrations were achieved by the third day of dosing. The apparent half-life determining accumulation was approximately 8-9 h. 3. Drug absorption commenced rapidly after a dose; two components to the absorption process were detectable in young subjects possibly due to simultaneous administration of multiple tablets at the higher doses. 4. Observations after single and multiple dosing were described with a compartmental model allowing for parallel saturable (population mean +/- s.d.: maximum elimination rate Vmax/F: 2.8 +/- 1.4 mg h-1; concentration at half-maximum elimination Km: 36 +/- 19 micrograms l-1) and first-order (CL/F 16 +/- 3.8 l h-1) elimination pathways. No important difference between the young and the elderly subjects was noted in absorption or disposition parameters of lazabemide.

Adult↗
PubMed1994

Pharmacodynamics of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. The inhibition of monoamine oxidase B (MAO-B) by lazabemide was measured in platelets collected from 35 young (19-36 years) and 40 older (60-78 years) healthy volunteers after single (100-300 mg) and multiple (100-350 mg twice daily) oral doses respectively. 2. The relationship of the effect with plasma concentrations of the MAO-B inhibitor was defined by a sigmoid Imax-model using either a parametric or semi-parametric method for predicting plasma drug concentrations. Population parameter estimates were obtained by the expectation maximization method and a standard two-stage method. 3. At the lowest dose platelet MAO-B activity was almost completely inhibited for around 20 h. No time delay between plasma drug concentration and resulting inhibition of platelet MAO-B occurred. Low concentrations of the inhibitor produced 50% of maximum inhibition (IC50, estimates for population mean +/- s.d.: 0.48 +/- 0.89 microgram l-1 for young and 1.5 +/- 2.3 micrograms l-1 for elderly subjects). The maximum extent of enzyme inhibition attributable to lazabemide (Imax) was 94 +/- 5.1% and 96 +/- 4.5% in the young and older populations. There was no correlation between age and either Imax or IC50. 4. Model parameters describing the interaction of lazabemide with the enzyme did not change over the treatment period of 7 days.

Adult↗
PubMed1994

Monoamine oxidase-A: pharmacodynamics in humans of moclobemide, a reversible and selective inhibitor.

1. Single oral doses of 300, 450 and 600 mg moclobemide, a monoamine oxidase type A inhibitor, were administered in a cross-over design to eight healthy male volunteers. Plasma concentrations of the parent drug and of two monoamine metabolites (3,4-dihydroxyphenylglycol DHPG from noradrenaline; 5-hydroxy-indoleacetic acid 5HIAA from serotonin) were measured over time. 2. A physiological pharmacokinetic-pharmacodynamic model was used to describe MAO-A inhibition as reflected in the alterations of monoamine metabolites. Population values for the model parameters were obtained by a two-stage method allowing for repeated dosing per subject. 3. Even at the lowest dose an effect of moclobemide on plasma DHPG and 5HIAA concentrations was detectable in most subjects for up to 24 h. In contrast to DHPG, 5HIAA formation was only partially suppressed by moclobemide (maximum fractional extent of enzyme inhibition Imax: 0.57, CV 26%) suggesting the existence of 5HIAA formation pathways independent of those inhibitable by moclobemide. 4. Plasma moclobemide concentrations associated with 50% of maximum enzyme inhibition (IC50) were in the range of 100 (IC50,5HIAA at 300 mg) to 400 micrograms l-1 (IC50,DHPG at 600 mg).

Administration, Oral↗
PubMed1994

Effects of bretazenil vs. zolpidem and placebo on experimentally induced sleep disturbance in healthy volunteers.

The effects of bretazenil 0.25 and 0.5 mg, a partial agonist at the benzodiazepine receptor, on sleep electroencephalogram (EEG), subjective sleep quality and morning psychomotor performance were compared to zolpidem 10 mg and placebo using noise as an experimental sleep disturbing factor in a single dose, double-blind, crossover study. Twelve healthy volunteers were subjected to prerecorded traffic noise with a mean sound level of 52 dB(A) during eight hours in bed. Significant effects of noise were found on sleep electroencephalogram (EEG) parameters (rapid eye movement [REM] sleep, stage 2 sleep and number of arousals), and subjective sleep quality assessments, but not on psychomotor performance (choice reaction time, digit span memory, and symbol digit substitution). Both drugs reduced the number of shifts between sleep stages and the number of arousals and increased REM sleep latency. Only after 0.5 mg bretazenil, stage 2 sleep increased and REM sleep decreased. Both doses of bretazenil significantly affected performance in the symbol digit substitution test. Sleep quality improved under drug treatments compared to placebo. The results suggest that experimental sleep disturbance can be a valuable tool in the investigation of potential sleep promoting compounds.

Adult↗
PubMed1993

An update of recent moclobemide interaction data.

The classical monoamine oxidase inhibitors (MAOIs) are believed to have serious risks because of interactions with other drugs and foodstuffs, although not with a sound scientific basis in all cases. However, moclobemide, a selective reversible inhibitor of MAO-A, has a low propensity for producing drug interactions. Interaction studies have been carried out in healthy volunteers in an attempt to answer some relevant practical questions related to therapy with moclobemide. In combination with therapeutic doses of either fluvoxamine or fluoxetine, moclobemide did not provide any indication of a serotoninergic syndrome, so that no wash-out period is needed when switching from a selective serotonin re-uptake inhibitor to moclobemide or vice versa. Since concomitant treatment with moclobemide and selegiline had a supra-additive effect on the sensitivity to intravenously administered tyramine, that combination therapy should only be considered when accompanied by dietary restrictions. Concomitant treatment with moclobemide and levodopa/benserazide, however, was well tolerated. When oral ephedrine was added to steady-state moclobemide treatment, the cardiovascular effects of the former were increased to about the same extent as for oral tyramine, i.e. a potentiation of 2-4.

Adult↗
PubMed1992

Interactions of moclobemide with concomitantly administered medication: evidence from pharmacological and clinical studies.

Interactions may occur on pharmacological or pharmacokinetic grounds. Both types of interactions are discussed in relationship with the pharmacological and pharmacokinetic data of moclobemide, a reversible MAO-inhibitor. A variety of interaction studies either designed more specifically as kinetic or as dynamic studies have been performed with moclobemide. The results of these studies are presented. In view of these results as well as in view of data stemming from clinical trials it can be concluded that apart from interactions with cimetidine and pethidine, moclobemide has been shown to be devoid of relevant interactions.

Animals↗
PubMed1992

Influence of moclobemide on ibuprofen-induced faecal blood loss.

In a pharmacological screen on drug-drug interactions performed in laboratory animals moclobemide potentiated at high doses the antiphlogistic/anti-inflammatory activity of ibuprofen. Therefore, a study was undertaken to determine in healthy volunteers the faecal blood loss induced by multiple doses of ibuprofen (600 mg t.i.d.) in presence and absence of steady-state concentrations of concomitantly administered moclobemide (150 mg t.i.d.). The results show that multiple doses of moclobemide do not change faecal blood loss induced by ibuprofen. Furthermore, no clinically relevant pharmacokinetic interaction between the two drugs studied was detected.

Benzamides↗
PubMed1992

Biochemical effects of high single doses of moclobemide in man: correlation with plasma concentrations.

The effects of high single doses of moclobemide (300, 450 and 600 mg given at the end of a standardized meal) on plasma levels of several catecholamines and their deaminated metabolites, and on plasma levels of pituitary hormones were determined in eight healthy young male volunteers in a randomized, double-blind, placebo-controlled study. Assessment of the i.v. tyramine potentiation and determination of the plasma levels of moclobemide were also performed. The tyramine sensitivity factor at 2 h after dosing was about 2.1, with no significant differences between the doses used. The inhibitory activity of moclobemide on MAO-A was reflected in significant reductions of plasma concentrations of DHPG and 5-HIAA. No clear differences were detected between the moclobemide doses. Prolactin plasma concentrations were only slightly increased after the two higher doses. The plasma concentrations of moclobemide were very much in agreement with those found in previous studies under similar experimental conditions. Thus, single oral doses of 300, 450 and 600 mg moclobemide demonstrated marked inhibition of MAO-A activity, whereas a single dose of 300 mg induced a near-maximum effect.

Adult↗
PubMed1992

Comparative investigation of the effect of moclobemide and toloxatone on monoamine oxidase activity and psychometric performance in healthy subjects.

The effects of moclobemide and toloxatone, two reversible monoamine oxidase-A inhibitors, on biochemical parameters that reflect monoamine metabolism and on psychomotor performance parameters were investigated in a study in 12 healthy volunteers. Treatments were given double-blind in a randomized, placebo-controlled cross-over design, with 1 week wash-out between the treatments. Drugs were given thrice daily in the following doses: moclobemide 150-150-150 mg and toloxatone 400-200-400 mg. All assessments were performed on day 8 under standardized conditions. There was no difference with regard to adverse events between moclobemide and toloxatone: both drugs induced a slight decrease in both supine and standing heart rate. Judged on the basis of the area under the curve, the two MAO-inhibitors reduced the plasma levels of DHPG and HVA, with more pronounced effects for moclobemide than for toloxatone. After moclobemide MAO-A inhibition was almost constant over 24 h, whereas the effect of toloxatone was short lasting after each dose. The same differences were reflected in plasma 5-HIAA concentrations and urinary excretion of 3-methoxytyramine and normetanephine. Neither of the compounds tested had any influence on the memory, vigilance, mood, or sleeping habits of the subjects.

Adult↗
PubMed1992

Influence of food on the tyramine pressor effect during chronic moclobemide treatment of healthy volunteers.

An open study was carried out to examine the effect of moclobemide, a new antidepressant reversible inhibitor of MAO-A, on the pressor response induced by oral tyramine added to meals of different lipid and protein composition, and to correlate the blood pressure increase in the tyramine test with that obtained during an exercise test. Eight healthy volunteers of both sexes participated in the study. A tyramine sensitivity and an exercise test were performed beforehand. Subjects were included if, under fasting condition, their systolic blood pressure (SBP) increased by more than 30 mmHg after administration of 400 or 600 mg tyramine. Exercise tests were performed to determine the grade of effort that corresponded to a rise in SBP of 30 mmHg. Subjects received moclobemide 600 mg/d. Starting on Day 7, each subject consumed a standardized meal (52 g lipids, 43 g proteins, 86 g carbohydrates) just before taking moclobemide. Tyramine was added to these meals in daily increasing doses of 50, 100, 150...mg until an increase in SBP > or = 30 mmHg was obtained. On moclobemide treatment, an average dose of 250 mg tyramine (range 150-400 mg) increased SBP by 36.6 mmHg. The time to reach peak SBP was longer (175 min) than in the fasting condition before the trial (40.6 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Percutaneous absorption of amorolfine following a single topical application of an amorolfine cream formulation.

In an open-label, parallel-group, randomized study percutaneous absorption of 14C-labelled amorolfine incorporated into a cream formulation was assessed in healthy male volunteers (n = 12). A single dose of 0.5 g of the 0.25% cream formulation was applied to 100 cm2 of intact (n = 6) and stripped (n = 6) skin for 24 h using occlusive dressing. The remaining drug was removed and the treated skin area of both groups was stripped with adhesive tape. Total urine and faeces were collected in portions up to 3 weeks after the experiment and blood samples were taken at intervals for 3 weeks. Radioactivity was measured in the skin strippings and in the urine, faeces and plasma samples. The intact drug was assessed in the plasma samples. Using mass balance techniques it could be shown that a mean of 92% (range: 84-101%) of the applied radioactivity could be recovered. Small differences in the absorption and elimination of the radioactivity were observed between the two groups but they were not statistically significant (alpha = 0.05). Therefore data from the two groups were pooled. Elimination of drug and drug-related material from the body was very slow. During the 3-week collection period, a mean of 7% (range: 3.8-10.2%) of the dose was excreted in urine and faeces. Another 0.9-3.3% of the dose was retained in the upper layers of the skin as shown by the skin strippings after treatment. Levels of radioactivity and of intact drug in plasma were below the detection limit of 0.5 ng-equiv./ml, respectively. Present data suggest that mean percutaneous absorption of amorolfine following topical application of the 0.25% cream formulation should not exceed 8-10% of the dose applied.

Administration, Cutaneous↗
PubMed1992

Unaltered ibuprofen-induced faecal blood loss upon coadministration of moclobemide.

The influence of moclobemide on ibuprofen-induced faecal blood loss was investigated in 24 volunteers. The subjects were randomly assigned to one of two groups and received from day 1 until day 14 either moclobemide 150 mg t.i.d. (group A) or placebo t.i.d. (group B). On days 8-14, when moclobemide concentrations in group A were at steady state, all volunteers additionally received ibuprofen (600 mg t.i.d). From day 15 to 21, all subjects received placebo alone. Faecal blood loss (FBL) was quantified daily by the 51Cr-labelled erythrocyte method. As expected for ibuprofen, a significant increase in FBL during the second week of the study was observed. There was no difference in FBL between the two treatment groups (moclobemide or placebo). Similar FBL values were observed in both groups (group A vs B): during the first week the FBL values were (mean +/- SD) 0.40 +/- 0.23 ml/day vs 0.55 +/- 0.53 ml/day on days 1-3 and 0.40 +/- 0.21 ml/day vs 0.37 +/- 0.13 ml/day on days 4-7. The increase in FBL during the second week was comparable in both groups, with and without moclobemide (days 8-10: 0.78 +/- 0.59 ml/day vs 0.80 +/- 0.58 ml/day; days 11-14: 1.49 +/- 0.95 ml/day vs 1.28 +/- 0.62 ml/day). A decline in FBL was observed during the third week under placebo in both groups, but baseline values were not reached during the observation period. Again there was no difference between the two groups (days 15-17: 0.91 +/- 0.52 ml/day vs 0.92 +/- 0.47 ml/day; days 18-21: 0.74 +/- 0.30 ml/day vs 0.68 +/- 0.48 ml/day). No statistically significant interaction was found between week and type of treatment, indicating that no significant influence of moclobemide on the ibuprofen-induced faecal blood loss occurred. No notable pharmacokinetic interaction between moclobemide and ibuprofen was observed. Moclobemide plasma concentration-time profiles with and without concomitantly administered ibuprofen were superimposable. The results demonstrate that the concomitant administration of ibuprofen and moclobemide to healthy volunteers does not result in a clinically significant interaction, either at the pharmacodynamic (faecal blood loss) or at the pharmacokinetic level.

Adult↗
PubMed1991

Measurement of human cerebral monoamine oxidase type B (MAO-B) activity with positron emission tomography (PET): a dose ranging study with the reversible inhibitor Ro 19-6327.

Eight normal subjects (3 females and 5 males) were studied using intravenous L-[11C] deprenyl and positron emission tomography. In a single blind study one subject received tracer alone, one subject received an oral pre-dose of 20 mg of L-deprenyl and 6 subjects received oral pre-doses of 10 to 50 mg of a novel reversible MAO-B inhibitor (Ro 19-6327). Dynamic PET scans beginning 12 h after the oral dose were collected over 90 min and arterial blood was continuously sampled. Data analysis was modelled for two tissue compartments and using an iterative curve fitting technique the value of the rate constant for irreversible binding of L-[11C] deprenyl to MAO-B (k3) in whole brain was obtained for each subject. The dose response curves obtained indicated that a dose of at least 0.48 mg.kg-1 of Ro 19-6327 was necessary for greater than 90% decrease in whole brain k3. Inhibition of MAO-B in platelets isolated from blood samples taken at the time of scanning correlated strongly with decrease in whole brain k3 (r = 0.949). The results indicate that PET can be used to determine the dose of Ro 19-6327 necessary to inhibit greater than 90% of brain MAO-B. This technique is an attractive alternative to traditional large scale patient-based dose-finding studies. Moreover it is shown that inhibition of platelet MAO-B can be used as a marker for central MAO-B inhibition with Ro 19-6327.

Aged↗
PubMed1991

The influence of dosage time of midazolam on its pharmacokinetics and effects in humans.

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.

Administration, Oral↗
PubMed1990

Pharmacodynamics of tolerance development to the anesthetic and anticonvulsant effects of phenobarbital in rats.

In this study, the potential development of tolerance towards the anesthetic and anticonvulsant effects of phenobarbital after chronic administration to rats was investigated, differentiating between dispositional and functional tolerance. Chronic exposure to phenobarbital by daily ip injections of 20 or 100 mg/kg for 14 days caused a 30% increase in clearance within 1 week. No changes occurred in the total amounts of phenobarbital and para-hydroxyphenobarbital excreted into urine and feces. Pharmacodynamic effects were quantitated after 2 weeks of treatment. The anesthetic effect was measured by slow iv infusion of phenobarbital until onset of loss of righting reflex (LRR), followed by measurement of drug concentrations in serum (both total and free), brain, and cerebrospinal fluid (CSF). With a phenobarbital dose of 100 mg/kg daily, CSF concentrations at the onset of LRR significantly increased from 136 +/- 12 to 176 +/- 21 mg/L (p less than 0.001), indicating that functional tolerance developed for the anesthetic effect. Protection of phenobarbital against convulsions induced by pentylenetetrazol (PTZ), as measured by the elevation of the PTZ plasma threshold concentration necessary to elicit seizures at the EC50 of phenobarbital, was not altered. The discrepancy observed in the development of functional adaptation of the CNS demonstrates that different mechanisms of action are reflected in the different measures of the anesthetic and anticonvulsant effects of phenobarbital that were utilized.

Anesthetics↗
PubMed1990

MAO-B inhibition in rabbit tissues and in human platelets by Ro 19-6327 shows similar time-course.

In rabbits, 3 mg/kg Ro 19-6327 p.o., induced complete monoamine oxidase type B (MAO-B) inhibition in striatum, cerebral cortex, liver and platelets for about 12 h. In healthy human volunteers complete inhibition of platelet MAO was obtained with only 5 mg Ro 19-6327. After 40 and 200 mg Ro 19-6327 the duration of complete MAO-B inhibition was prolonged to 12 and 24 hours, respectively. Changes in brain MAO-B in humans after Ro 19-6327 are likely to be faithfully reflected by platelet MAO activity.

Animals↗