Biomedical subjects

J Dingemanse

Publications and source records attributed to J Dingemanse.

At least 37 records · Page 2Linked to original sources

PubMed1997

Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48-6791, compared with midazolam, in healthy subjects during first administration to man studies. METHODS: The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48-6791 was administered as a slow i.v. infusion in doses of 0.1-0.3-1 mg in the first group, and 1-2-3 mg in the second. Midazolam was infused at 0.1 mg kg(-1). The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min(-1)) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (beta-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling. RESULTS: Ro 48-6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (V(SS)) and plasma clearance of Ro 48-6791 were on average markedly larger than those of midazolam (171 +/- 65 vs 41 +/- 10 l and 2.2 +/- 0.9 vs 0.42 +/- 0.11 l min(-1), respectively). The doses of Ro 48-6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48-6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in beta-power than Ro 48-6791 at the highest administered dose. Ro 48-6792, a metabolite of Ro 48-6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48-6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further. CONCLUSIONS: This first study with Ro 48-6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.

Adjuvants, Anesthesia↗

PubMed1997

Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48-8684, compared with midazolam, in healthy subjects during first administration to man. METHODS: The study was double-blind and five-way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48-8684 was infused in doses of 0.1-0.3-1 mg in the first group, and 1-3-10 mg in the second, with different infusion rates (expressed as mg min(-1)) among doses. Midazolam was infused at 0.1 mg(-1) kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article. RESULTS: Ro 48-8684 caused dose-dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48-8684 were larger than of midazolam (337+/-114 vs 50+/-121 and 2.4+/-0.5 vs 0.47+/-0.11 l min(-1), resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48-8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48-8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48-8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration-effect-relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48-8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4-fold (range 1.6, 7.3 times), with doses of Ro 48-8684 increasing from 1 to 10 mg. The metabolite Ro 61-2466 had a longer half-life than the parent compound Ro 48-8684. The influence of this metabolite during prolonged administration should be further investigated. CONCLUSIONS: These results show that Ro 48-8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48-8684 with repeated administration of rising doses due to as yet undetermined factors.

Adult↗

PubMed1997

Pharmacokinetic-pharmacodynamic modelling of the EEG effects of Ro 48-6791, a new short-acting benzodiazepine, in young and elderly subjects.

The objectives of this study were to explore, by a modelling approach, in nine young (24-28 yr) and nine elderly (67-81 yr) male subjects, the pharmacokinetics and pharmacodynamics of Ro 48-6791, a new water soluble benzodiazepine. A microprocessor-controlled i.v. infusion pump generated linearly increasing arterial plasma concentrations until predetermined EEG and clinical end-points were attained. This concentration was maintained for 15 min and thereafter the infusion was discontinued. Haemodynamic and respiratory variables were monitored continuously. At full reorientation of the subject, a second infusion cycle was started under the same conditions to investigate the reproducibility of the concentration-effect relationship. The plasma concentration-time profiles of Ro 48-6791 were fitted accurately to an open three-compartment model. Plasma concentrations of Ro 48-6792, an N-dealkylated metabolite, accumulated during the course of the study. Pharmacokinetic variables of Ro 48-6791 were similar for both groups. The largest differences between young and elderly subjects, respectively, were found for clearance (mean 85 (SD 23) vs 71 (15) litre h-1) and k12 (11 (7) vs 7 (3) h-1). The concentration-median EEG frequency relationship was described with a sigmoid Emax model. Elderly subjects showed slightly increased drug sensitivity compared with young subjects (EC50 72 (25) and 44 (15) micrograms litre-1 in young and elderly subjects, respectively). The concentration-response data of the second infusion cycle deviated from the fitted curve suggesting either development of acute tolerance to the EEG effects of Ro 48-6791 or a role for drug metabolites. Because of the differences in sensitivity and clearance, lower doses of Ro 48-6791 should be administered to elderly compared with young subjects in order to achieve similar effects.

Adult↗

PubMed1997

Pharmacokinetics and pharmacodynamics of single and multiple doses of the MAO-B inhibitor lazabemide in healthy subjects.

AIMS: The objectives of this study were to assess the tolerability, pharmacokinetics and pharmacodynamics of the reversible monoamine oxidase B (MAO-B) inhibitor, lazabemide, in healthy subjects. METHODS: Single and multiple (1 week) twice daily oral doses (100-350 mg) of lazabemide were administered sequentially to five groups of six healthy male subjects in a placebo-controlled, double-blind design. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of lazabemide were determined after single and multiple doses. Pharmacodynamics were assessed by determination of MAO-B activity in blood platelets and intravenous tyramine potentiation tests. RESULTS: Lazabemide was well tolerated at all dose levels, causing no clinically relevant changes in vital signs or laboratory parameters. Headache was the most frequent adverse event at higher doses. Lazabemide was rapidly absorbed and eliminated by mixed linear and non-linear pathway. Only minor accumulation occurred upon multiple dosing and steady-state plasma concentrations were achieved on the third day. Lazabemide caused a rapid and reversible inhibition of MAO-B activity in platelets. The twice daily dosing regimen resulted in complete inhibition at all dose levels. The duration of complete inhibition was dose-dependent and ranged from 16 h with 100 mg to 36 h with 350 mg. The sensitivity to i.v. tyramine did not change to a clinically relevant extent following single and multiple doses of lazabemide. CONCLUSIONS: The clinical pharmacology characteristics of lazabemide did not differ markedly after single and multiple oral doses. A dose regimen of lazebemide 100 mg twice daily is anticipated because it caused full and continuous MAO-B inhibition.

Administration, Oral↗

PubMed1996

Tyramine pressor sensitivity in healthy subjects during combined treatment with moclobemide and selegiline.

OBJECTIVE: The objectives of this double-blind study were to assess the tolerability and i.v. tyramine pressor response during combined treatment with moclobemide and selegiline. SUBJECTS: Two parallel groups of 12 healthy male and female subjects were treated with 200 mg moclobemide or 5 mg selegiline b.d. for 14 days. On Day 7, selegiline or moclobemide was added to the other treatment. IV tyramine pressor tests were conducted at baseline and at steady state during mono- and combined treatment. RESULTS: Treatment with moclobemide and selegiline alone was well tolerated, whereas combined treatment led to a slight increase in adverse events. Tyramine pressor sensitivity during moclobemide, selegiline and moclobemide + selegiline treatment was enhanced, on average, by 2.4-, 1.3- and 8.4-times, respectively. CONCLUSION: Although combined treatment with moclobemide and selegiline was well tolerated, the supra-additive potentiation of the tyramine pressor effects means that dietary restriction of tyramine intake will be necessary during such combination therapy.

Adrenergic Agents↗

PubMed1996

Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects.

OBJECTIVE: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects. METHODS: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio 1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone; its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased Cmax and AUC values. Despite the long halflife of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory Emax model with constant EC50 values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics. CONCLUSION: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson's disease.

Aged↗

PubMed1996

Multiple dose pharmacokinetics of tiludronate in healthy volunteers.

OBJECTIVES: A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 400, 600 and 800 mg for 12 days. Four groups of ten subjects participated in the study, with a drug to placebo ratio of 4:1. METHODS: Pre-dose blood samples were taken on alternate days, starting on Day 1 and additional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices of calcium homeostasis and biochemical markers of bone turnover were assessed during the study as pharmacodynamic parameters. Tolerability was evaluated with special emphasis on renal function and gastrointestinal irritation. Adverse experiences were assessed at regular time intervals. RESULTS AND CONCLUSIONS: Steady state was attained from Day 4 (200 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose on Day 12, minimal plasma concentrations (Cmin) ranged between 0.19 and 1.5 mg.1(-1), and maximal plasma concentrations (Cmax) between 1.1 and 7.8 mg.1(-1) for the lowest and highest doses, respectively. A supra-proportional increase in Cmax, AUC24 and Ae24 with dose was observed. There was a linear relationship between the plasma tiludronic acid and its urinary excretion rate, so, the disproportional rise in Cmax and AUC24 with increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only prominent at the highest dose level of 800 mg. Total serum calcium and the urinary calcium/creatinine clearance ratio fell, indicating depression of osteoclastic bone resorption, which was not revealed by serum osteocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydroxyvitamin D3 and intact PTH (1-84) levels increased. None of the safety parameters raised any concerns about the safety of sodium tiludronate administered in this way.

Adolescent↗

PubMed1996

The role of cytochrome P450 2D6 in the metabolism of moclobemide.

The metabolic fate of moclobemide (Ro 11-1163), a new reversible and selective inhibitor of monoamine oxidase type A (MAO-A), has been assessed in a pilot study in 2 debrisoquine poor metabolizers (PM) and 4 extensive metabolizers (EM) after multiple oral dosings of moclobemide with and without co-medication of dextromethorphan. Absorption and disposition parameters were not different between PM and EM. Concurrent application of dextromethorphan, a selective substrate of CYP2D6, did not affect the pharmacokinetics of moclobemide. These results indicate that the cytochromal isoenzyme CYP2D6 does not play a major role in the metabolic degradation of moclobemide. Limited CYP2D6 activities because of a genetic defect or co-medications with CYP2D6 substrates should therefore not give rise to elevated moclobemide blood levels.

Absorption↗

PubMed1996

Determination of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in human plasma by a simple and rapid high-performance liquid chromatography assay.

In order to study the pharmacodynamic effects of drugs on dopamine and serotonin metabolism, a reversed-phase HPLC assay coupled with electrochemical detection (ECD) for measuring plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) was developed. The system was operated isocratically using a mobile phase of aqueous 0.03 M KH2PO4 buffer containing 0.15 mM EDTA in methanol (8.75:1.25), with a final pH of 4.0. The flow rate was set at 1.5 mL/min, and potentials at +450 mV. Using a signal to noise ratio of > 3, the minimum detection limit assessed by direct on-column injection of a standard solution for DOPAC and 5-HIAA was < 1 pg. The assays were linear from basal concentrations (1-10 ng/mL) to 100 ng/mL. The intra- and interassay variations were < 10% and < 20%, respectively.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Pharmacokinetic-pharmacodynamic interactions between two selective monoamine oxidase inhibitors: moclobemide and selegiline.

The objectives of this study were to assess potential pharmacokinetic and pharmacodynamic interactions between moclobemide and selegiline. Two groups of 12 healthy male and female subjects were treated with 200 mg moclobemide or 5 mg selegiline b.i.d. for 16 days. On study day 8, the alternative active drug or placebo was added to the respective treatments. Concentration-time profiles of moclobemide and two of its main metabolites and 3,4-dihydrox/phenylglycol (DHPG, a norepinephrine metabolite), 5-hydroxy-indoleacetic acid (HIAA, a serotonin metabolite), and 3,4-dihydroxyphenylacetic acid (DOPAC, a dopamine metabolite) in plasma as well as MAO-B activity and serotonin concentration in platelets were determined at steady state during monotreatment and combined treatment. The pharmacokinetic parameters of moclobemide and its metabolites changed on multiple dosing but were not influenced to a relevant extent by concomitant administration of selegiline. The measured pharmacodynamic parameters, expressed as the maximum effect on a study day and the area under the effect-time curve, characterized the drugs' influence on peripheral neurotransmitter metabolism. The most reliable variables to assess inhibition of MAO-A and -B in humans proved to be DHPG in plasma and serotonin in platelets and MAO-B activity in platelets, respectively. Several variables (DHPG, platelet serotonin) suggested that selegiline has some MAO-A inhibitory activity. This became particularly apparent upon addition of selegiline to moclobemide treatment; i.e., the effects of combined moclobemide and selegiline treatment were statistically greater than those of moclobemide monotreatment. Moclobemide alone exerted a slight inhibition of platelet MAO-B activity. The reported pharmacodynamic interactions are not considered to be clinically relevant. However, due to the previously found supraadditive tyramine potentiation upon simultaneous treatment, moclobemide and selegiline should only be combined when applying dietary restrictions with respect to tyramine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide.

Irreversible, nonselective monoamine oxidase (MAO) inhibitors have been reported adversely to interact with indirectly acting sympathomimetic amines present in many cough and cold medicines. This study investigated the safety and tolerability of concomitant administration to 12 healthy subjects of both genders (aged 19-36 years) of ephedrine and moclobemide, a reversible MAO-A inhibitor. A 2-day, randomized, crossover administration of placebo or ephedrine (two doses of 50 mg with a 4-h interval) was followed by 9 days open-label dosing with moclobemide, 300 mg b.i.d.. On the last 2 days of moclobemide dosing, the randomized crossover treatment of ephedrine and placebo was repeated. No subject was withdrawn from the study for tolerability reasons. Moclobemide treatment, however, increased the incidence of adverse events elicited by ephedrine, particularly palpitations and headache. The pharmacodynamic interaction between the two drugs was quantified by calculation of the area under the effect-time course (AUE) for systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR). The difference in AUE between monotreatment with ephedrine and placebo was statistically significant for all three vital signs. Moclobemide potentiated the effect of ephedrine by a median factor of 3.2 for SBP, 3.8 for DBP, and 0.6 for HR. Ephedrine had no significant influence on the plasma concentrations of moclobemide or its metabolites. In conclusion, the combined use of moclobemide and high doses of sympathomimetic drugs should be approached with caution.

Adrenergic Agents↗

PubMed1996

Automated determination of dextromethorphan and its main metabolites in human plasma by high-performance liquid chromatography and column switching.

An automated column-switching technique coupled to isocratic high-performance liquid chromatography (HPLC) with fluorescence detection was developed for simultaneous determination of dextromethorphan and its three major metabolites, dextrorphan, hydroxymorphinan, and methoxymorphinan. After cleavage of conjugates by incubation with glucuronidasearylsulfatase at 37 degrees C for 15 h, plasma samples were injected directly into the HPLC system. Dextromethorphan and metabolites were retained on a cleanup column (10 x 4.6 mm internal diameter [ID]) filled with cyanopropyl (CN) material (Hypersil CPS, 10-microns article size) while interfering proteins and lipids were washed to waste. After column switching, the drugs were eluted from the cleanup column and separated on Spherisorb CN material (5-microns particle size, column size 250 x 4.6 mm ID). Fluorescence detection was carried out with an excitation wavelength of 220 nm and an emission wavelength of 305 nm. Sample cleanup and HPLC separation were completed within 20 min. Regression analyses found linearity (r > 0.99) between drug concentration and detector response over a wide range-5-220 ng/ml for dextromethorphan, 5-550 ng/ml for dextrorphan, 5-500 ng/ml for hydroxymorphinan, and 5-200 ng/ml for methoxymorphinan. The limit of quantification was approximately 5 ng/ml, and the recovery was > 90% for all compounds. At concentrations of 20-500 ng/ml, the intra- and interassay coefficients of variation ranged from 3.5 to 14.6% and from 7.0 to 14.0%, respectively. The method is suitable for in vivo phenotyping of CYP2D6 activity, which catalyzes the O-demethylation of dextromethorphan to dextrorphan, and is also applicable to pharmacokinetic studies in man.

Adult↗

PubMed1996

Tyramine pharmacodynamics during combined administration of lazabemide and moclobemide.

The objective of this study was to assess the tyramine pressor sensitivity during combined administration of selective and reversible inhibitors of monoamine oxidase A and B, viz. moclobemide (300 mg b.i.d.) and lazabemide (100 mg b.i.d.), respectively. In part A, 5 healthy male subjects underwent i.v. tyramine pressor tests before (baseline) and during (day 7) combined treatment with both drugs. The tyramine dose was titrated until an increase in systolic blood pressure of 30 mmHg was attained. Subsequently, lazabemide treatment was discontinued and i.v. tyramine pressor tests were again conducted after 2 - 3 days of moclobemide monotreatment. The tyramine pressor sensitivity factor (mean + or - SD) during combined moclobemide and lazabemide treatment was 4.2 + or - 0.9 and during moclobemide monotreatment 3.1 + or - 1.1. In part B, a separate panel of 8 subjects received combined treatment with moclobemide and lazabemide for up to 10 days. Ascending oral doses of tyramine were administered on days 7 - 10 to determine the threshold dose eliciting a 30 mmHg increase in systolic blood pressure. In comparison to baseline the effects of oral tyramine were potentiated by a factor of 13.5 + or - 6.9. The low amount of oral tyramine needed (51 + or - 20 mg) to induce relevant increases in blood pressure indicates that dietary precautions are needed when both MAO-A and B are inhibited by 2 reversible inhibitors.

Administration, Oral↗

PubMed1995

Pharmacotherapy of insomnia: practice and prospects.

Insomnia is a complex complaint which is often multifactorial in origin. Pharmacotherapy can only be an adjunct in the treatment of insomnia and hypnotics should be given on an intermittent basis for short periods of time. An overview is presented of the currently available hypnotics, of which benzodiazepines are still the most widely prescribed. New drugs which bind to specific receptor subtypes or which are partial benzodiazepine receptor agonists might overcome the disadvantages associated with chronic benzodiazepine use, but more long-term investigations are needed.

Aging↗

PubMed1995

Pharmacokinetics and pharmacodynamics of Ro 41-3696, a novel nonbenzodiazepine hypnotic.

This report describes the first evaluation in humans of Ro 41-3696. Based on its preclinical profile, Ro 41-3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo-controlled, double-blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41-3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41-3696 was absorbed and eliminated rapidly (tmax = approximately 1 hour; t1/2 = approximately 4 hours). At all times plasma levels of Ro 41-3290, the desethylated derivative of Ro 41-3696, were higher than those of the parent drug (tmax and t1/2 values = approximately 2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose-proportional pharmacokinetics for both Ro 41-3696 and Ro 41-3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long-term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41-3696 in doses up to approximately 5 mg and further exploration of the characteristics of Ro 41-3290.

Administration, Oral↗

PubMed1995

Comparative pharmacodynamics of Ro 41-3696, a new hypnotic, and zolpidem after night-time administration to healthy subjects.

In a double-blind, six-way crossover study the effects on psychomotor performance and memory of single doses of Ro 41-3696 (1, 3, 5 and 10 mg), a novel non-benzodiazepine partial agonist at the benzodiazepine receptor, zolpidem (10 mg) and placebo were compared after night-time administration to 12 healthy young male subjects. Psychomotor performance tests (tracking and attention as part of a standardized task battery) were conducted just before and at 1.5 and 8 h after drug intake. The memory test consisted of the recall of a list of 15 words at 8 h after drug intake which had been learned at 1.5 h after intake. At 1.5 h after drug intake 10 mg zolpidem induced markedly larger psychomotor effects than any dose of Ro 41-3696. The effects of 5 and 10 mg Ro 41-3696 and zolpidem were significantly greater than those of placebo (P < 0.05). The following morning, 8 h after drug intake, the slight residual effects of 5 and 10 mg Ro 41-3696 were statistically significantly greater than placebo, whereas zolpidem effects did not differ from placebo. The results of the memory test showed that learning as well as recall were most clearly impaired by zolpidem. An influence of Ro 41-3696 on these variables was not observed for doses up to 5 mg. In conclusion, Ro 41-3696 at all doses tested induced less effects on psychomotor performance and memory than 10 mg zolpidem at 1.5 h after intake. However, the effects of Ro 41-3696 appeared to be of longer duration.

Adult↗

PubMed1995

Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans.

OBJECTIVES: To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers. METHODS: In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity. CONCLUSIONS: The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

Administration, Oral↗

PubMed1995

Switch in treatment from tricyclic antidepressants to moclobemide: a new generation monoamine oxidase inhibitor.

The combination of classic monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressant drugs (TCAs) has been associated with a variety of adverse events. A switch in treatment from TCAs to moclobemide, a reversible and selective inhibitor of MAO-A, was investigated in a double-blind, placebo-controlled study in healthy volunteers. Two groups of 12 subjects were treated with either amitriptyline (75 mg/day) or clomipramine (100 mg/day) until steady-state conditions had been attained (14 days). Treatment with the TCAs was discontinued abruptly and switched to either a therapeutic dose regimen of moclobemide (300 mg/day) or placebo. The tolerability and safety pattern did not reveal any clinically relevant differences between moclobemide and placebo recipients, nor was there any sign of a pharmacokinetic interaction between the TCAs and moclobemide. In conclusion, the findings of this study suggest that therapeutic doses of moclobemide up to 300 mg daily can be given 24 hours after the last dose of treatment with either amitriptyline or clomipramine without major risks.

Adolescent↗