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  • 1
    Electronic Resource
    Electronic Resource
    Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 47-55 
    Details
    ISSN: 1432-1041
    Keywords: Key words Tolcapone ; Elderly; levodopa ; pharmacokinetics ; pharmacodynamics ; multiple-dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. 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 ratio1:1) 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 half-life 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050068
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  • 2
    Electronic Resource
    Electronic Resource
    Tyramine pressor sensitivity in healthy subjects during combined treatment with moclobemide and selegiline (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 273-278 
    Details
    ISSN: 1432-1041
    Keywords: Moclobemide ; Selegiline ; interaction ; pharmacodyamics ; tyramine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00226327
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  • 3
    Electronic Resource
    Electronic Resource
    Influence of food on the tyramine pressor effect during chronic moclobemide treatment of healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 507-512 
    Details
    ISSN: 1432-1041
    Keywords: Moclobemide ; food interaction ; tyramine pressor test ; exercise ; monoamine oxidase inhibitor ; blood pressure ; dietary interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 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 〉 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). The administration of the same dose of tyramine both during a protein-rich (75 g proteins, 85 g lipids, 90 g carbohydrates) and lipid-rich (110 g lipids, 55 g proteins, 100 g carbohydrates) meal significantly reduced the average increase in SBP to 21 mmHg, but did not significantly modify the time of appearance of the peak SBP In the exercise test, an increase in SBP of 30 mmHg was produced by the low load of about 100 W. During moclobemide treatment, oral doses of tyramine considerably larger than the amounts present in normal meals did not increase SBP by more than the effort exerted during every day life. Concomitant administration of a large quantity of lipids significantly reduced the pressor response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02285092
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  • 4
    Electronic Resource
    Electronic Resource
    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 (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 169-173 
    Details
    ISSN: 1432-1041
    Keywords: Monoamine oxidase type B ; Positron emission tomography ; Ro 19-6327 ; Pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 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 〉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 〉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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280072
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  • 5
    Electronic Resource
    Electronic Resource
    Tyramine pressor sensitivity in healthy subjects during combined treatment with moclobemide and selegiline (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 273-278 
    Details
    ISSN: 1432-1041
    Keywords: Key words Moclobemide ; Selegiline; interaction ; pharmacodyamics ; tyramine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00226327
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  • 6
    Electronic Resource
    Electronic Resource
    Percutaneous absorption of amorolfine following a single topical application of an amorolfine cream formulation (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental dermatology 17 (1992), S. 0 
    Details
    ISSN: 1365-2230
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 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 (α= 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-2230.1992.tb00275.x
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  • 7
    Electronic Resource
    Electronic Resource
    Multiple dose pharmacokinetics of tiludronate in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 175-181 
    Details
    ISSN: 1432-1041
    Keywords: Key words Tiludronate; healthy volunteers ; bisphosphonates ; pharmacokinetics ; calcium metabolism ; bone resorption ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 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 ⋅ l−1, and maximal plasma concentrations (Cmax) between 1.1 and 7.8 mg⋅l−1 for the lowest and highest doses, respectively. A supra-proportional increase in Cmax, AUC24 and Ae 24 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050181
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  • 8
    Electronic Resource
    Electronic Resource
    Clinical pharmacology of moclobemide during chronic administration of high doses to healthy subjects (1998)
    Springer
    Psychopharmacology 140 (1998), S. 164-172 
    Details
    ISSN: 1432-2072
    Keywords: Key words Moclobemide ; High dose ; Tolerability ; Pharmacodynamics ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The objectives of this study were to assess the tolerability, safety, pharmacodynamics and pharmacokinetics of high-dose moclobemide in healthy subjects. Two sequential groups of six male and six female subjects (eight on active treatment, four on placebo) received for 8 days moclobemide 450 mg b.i.d. and 600 mg b.i.d., respectively. Intravenous tyramine pressor tests were conducted at baseline, at the beginning of treatment and at steady state. Oral tyramine pressor tests with 50, 100 and 150 mg tyramine were conducted under steady-state conditions. Pharmacokinetic parameters of moclobemide and two of its metabolites in plasma and urine were determined after the first and last dose of moclobemide. The incidence and intensity of adverse events was dose-dependent. The most frequently reported adverse events were insomnia, headache, dizziness and dry mouth. The IV tyramine pressor sensitivity during both moclobemide dosing regimens was enhanced 3 to 4-fold. Intake of tyramine 50 mg did not result in systolic blood pressure increases greater than 30 mmHg. With regard to blood pressure increases, tyramine 100 mg is still compatible with moclobemide 450 mg b.i.d. but not with 600 mg b.i.d. The clearance of moclobemide decreased by about 60% on multiple dosing, but no differences were found between both dosing regimens. The urinary excretion of the N-oxide metabolite doubled during multiple dosing. In conclusion, the maximum tolerated dose of moclobemide in healthy subjects is 600 mg b.i.d. provided the tyramine content in a meal is not higher than 50 mg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050754
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  • 9
    Electronic Resource
    Electronic Resource
    Interactions of moclobemide with concomitantly administered medication: evidence from pharmacological and clinical studies (1992)
    Springer
    Psychopharmacology 106 (1992), S. S24 
    Details
    ISSN: 1432-2072
    Keywords: Moclobemide ; Interactions ; Pharmacokinetics ; Pharmacological data
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02246229
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  • 10
    Electronic Resource
    Electronic Resource
    Chronic treatment with Ro 15-1788 distinguishes between its benzodiazepine antagonist, agonist and inverse agonist properties (1986)
    Springer
    Psychopharmacology 89 (1986), S. 113-117 
    Details
    ISSN: 1432-2072
    Keywords: Benzodiazepine antagonist ; Inverse agonist ; Agonist ; Ro 15-1788 ; Tolerance ; Exploration ; Motor activity ; Social interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 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 β-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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00175201
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