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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 52 (1997), S. 289-292 
    ISSN: 1432-1041
    Keywords: Key words Nicardipine; enantiomers ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. Methods: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a cross-over fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. Results and conclusions: Serum concentration of (+)-nicardipine was approximately 2–3 times higher than that of (−)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3–2.8 times greater than that of the (−)-nicardipine (P 〈 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (−)-nicardipine, respectively, for the 40-mg dose.
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  • 2
    ISSN: 1432-1041
    Keywords: Key words Angiotensin II ; Valsartan; AT1 receptor antagonist ; healthy volunteers ; pharmacokinetics ; renin-angiotensin system ; blood pressure ; passive tilting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet. Methods: This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8. Results: Absorption and distribution of valsartan were rapid (Cmax, 2 h; t½λ1 〈 1 h), followed by a slower terminal elimination phase (t½λ2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of −3.6 and −2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (−2.0 mmHg) and day 8 (−4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats · min−1 on day 1 and by 2.9 beats · min−1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion. Conclusions: Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.
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  • 3
    ISSN: 1432-1041
    Keywords: Key words Felodipine ; metoprolol; combined extended release formulation ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding Cmax of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 52 (1997), S. 115-120 
    ISSN: 1432-1041
    Keywords: Key words Valsartan; pharmacokinetics ; deconvolu‐tion ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of orally and intravenously administered valsartan were determined in two studies. In a first pilot study, three i.v. doses of valsartan were given in an ascending manner (5, 10 and 20 mg) to evaluate tolerability and basic pharmacokinetics of the i.v. formulation. In a second study, the absolute bioavailability of 80 mg valsartan from a capsule and a buffered solution was compared with a 20 mg i.v. dose. Methods: The concentrations of valsartan in plasma and urine were measured using HPLC. The disposition of valsartan after an i.v. dose was characterized by biphasic decay kinetics, with a distribution phase (half-life 1.0 h), followed by a longer elimination phase (half-life 9.5 h). The volume of distribution at steady state was 16.9 l, and the total body clearance 2.2 l · h−1. 29% of the i.v. dose was recovered unchanged in the urine. Results: Plasma levels peaked 2 h after oral administration of the 80 mg capsule. Thereafter, plasma levels declined biexponentially with a terminal t1/2 of 7.0 h. Cmax was reached 1 h after administration of the solution, and t1/2 was 7.5 h. On average 7.3% (capsule) and 12.6% (solution) of the dose was excreted in the urine as the unchanged drug. The fraction of dose absorbed and systemically available after oral administration was 0.23 for the capsule and 0.39 for the solution, based on AUC. Absorption appeared to follow two first-order processes. The first phase was rapid, with a half-life of 0.5 h and 0.9 h for solution and capsule, respectively. The slower absorption phase was characterized by a half-life of 6.5 h for the solution and 3.5 h for the capsule. Most of the drug was absorbed during the period 0.4 h to 3 h post-dosing, and 90% of the fraction absorbed from the capsule was absorbed within 5 h.
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  • 5
    ISSN: 1432-1041
    Keywords: Key words Nebivolol ; Cardiovascular effects; pharma-cokinetics ; healthy volunteers ; obese subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of a single i.v. dose of the new racemic β-adrenoceptor-blocker nebivolol [0.073 mg base · kg–1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). Methods: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4–5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. Results: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (Vss) 673 l; volume corrected by real body weight (Vss · kg–1) 11.2 l ·  kg–1; total clearance (CL) 51.6 h–1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l · h–1) were significantly higher in obese patients. But Vss · kg–1 (9.4 l · kg–1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15–18 l · h–1) and the t1/2 prolonged (32–34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. Conclusion: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.
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  • 6
    ISSN: 1432-1041
    Keywords: Prazosin ; Urapidil ; Vasoconstrictor response ; laser Doppler flow ; finger tip blood flow ; cold stimulation ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of α-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different α1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these α1-adrenoceptor antagonists in human subjects. Method: In thirteen healthy male subjects (20–42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg). Results: Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The α1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil. Conclusion: These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative α1-adrenoceptor blocking potency of drugs.
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  • 7
    ISSN: 1432-1041
    Keywords: Key words Corticosteroids; systemic effects ; plasma cortisol suppression ; white blood cell count ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The systemic effects of single and multiple doses of inhaled fluticasone propionate (FP) and budesonide were examined in 24 healthy male volunteers (age range 18–29 years). The study was of an open, placebo-controlled, randomized, three-way crossover design. On each study day, multiple blood samples were taken over a 20 h period after drug administration (after a single dose and after the last of seven doses) and area under the curve (AUC0–20) for plasma cortisol and white blood cell (WBC) counts was calculated. Results: The present study shows that multiple dosing with FP 1.0 mg b.i.d. for 3.5 days (seven doses) resulted in a marked cortisol suppression from placebo which, at 55%, was more than double that seen with a single dose (25% suppression). Multiple dosing with budesonide 0.8 mg b.i.d. resulted in a 34% suppression in plasma cortisol compared with a suppression of 26% with a single dose. The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts. Conclusion: The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose. This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 49 (1996), S. 411-415 
    ISSN: 1432-1041
    Keywords: Moxisylyte ; pharmacokinetics ; intracavernous administration ; healthy volunteers ; adverse events ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The concentration-time profiles of specific metabolites of moxisylyte, an α-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). Results: Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. Conclusion: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.
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  • 9
    ISSN: 1432-1041
    Keywords: Key words Mefloquine; mefloquine enantiomers ; carboxylic acid metabolite ; blood concentrations ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To compare concentrations of the separate enantiomers of mefloquine (MQ), total racemic MQ and the carboxylic acid metabolite in different blood fractions at steady state. Setting: Human volunteer laboratory, Unit of Clinical Pharmacology, Karolinska Institute. Volunteers: Ten healthy adult Caucasian volunteers. Methods: Drug concentrations were determined by high-performance liquid chromatography (HPLC). Results: Trough concentrations of the (+)RS enantiomer were higher in venous whole blood than in plasma and serum (mean ratios, 1.41 and 1.38). For the other enantiomer, (−)SR, concentrations were lower in whole blood than in plasma (mean ratio 0.89) and for the metabolite this ratio was 0.5. Conclusion: Stereoselective distribution might be important for antimalarial activity and should be considered when pharmacokinetic studies are performed.
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  • 10
    ISSN: 1432-1041
    Keywords: Corticosteroids ; systemic effects ; plasma cortisol suppression ; white blood cell count ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The systemic effects of single and multiple doses of inhaled fluticasone propionate (FP) and budesonide were examined in 24 healthy male volunteers (age range 18–29 years). The study was of an open, placebo-controlled, randomized, three-way crossover design. On each study day, multiple blood samples were taken over a 20 h period after drug administration (after a single dose and after the last of seven doses) and area under the curve (AUC0–20) for plasma cortisol and white blood cell (WBC) counts was calculated. Results: The present study shows that multiple dosing with FP 1.0 mg b.i.d. for 3.5 days (seven doses) resulted in a marked cortisol suppression from placebo which, at 55%, was more than double that seen with a single dose (25% suppression). Multiple dosing with budesonide 0.8 mg b.i.d. resulted in a 34% suppression in plasma cortisol compared with a suppression of 26% with a single dose. The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts. Conclusion: The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose. This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide.
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 50 (1996), S. 381-384 
    ISSN: 1432-1041
    Keywords: Key words Cicletanine ; Tolbutamide; drug interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To determine the possible interaction between the antihypertensive agent cicletanine and the hypoglycaemic drug tolbutamide. Methods: Time-courses of glycaemia and serum immunoreactive insulin (IRI) were followed in 10 healthy subjects after two tolbutamide infusions in each volunteer: initially alone and 9 days later concomitantly with repeated oral cicletanine. Any drug interaction was quantified on the basis of a decrease or increase in the AUC with time of glycaemia and IRI by subtraction of baseline concentration (AUC0 240-GLY and AUC0 60-IRI). Peak glycaemia and peak IRI, and the corresponding time to peaks, were also assessed. Results: Following tolbutamide, mean AUC0 240-GLY values were 97.7 and 98.8 mmol⋅l−1⋅min, without or with cicletanine, respectively; the corresponding AUC0 60-IRI were 485 and 321 mU⋅l−1⋅min. Mean peak glycaemia values were 0.996 and 1.071 mmol⋅l−1. Regarding the peak IRI, a decrease was observed after tolbutamide and cicletanine: median values were 29.2 and 17.4 mU⋅l−1. The corresponding median time to peak of glycaemia and IRI values were 30 and 30 min, and 5 (all subjects) and 5 min. Conclusion: No clinically relevant interaction was shown after the concomitant administration of repeated oral doses of cicletanine and acute intravenous tolbutamide to healthy volunteers.
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  • 12
    ISSN: 1432-1041
    Keywords: Key words Orlistat ; Furosemide ; Atenolol ; Captopril ; Nifedipine; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To study the influence of the lipase inhibitor orlistat on the pharmacokinetics of the antihypertensive drugs atenolol, furosemide, captopril and nifedipine. Methods: Four open-label, crossover studies were performed on six to eight healthy male volunteers. Orlistat was given in doses of 50 mg 3 times daily mid-meal for 7 (nifedipine and captopril) or 8 days (atenolol and furosemide). The four antihypertensive drugs (atenolol 100-mg tablet, furosemide 40-mg tablet, captopril 50-mg tablet and nifedipine 20-mg slow-release tablet) were administered in single doses twice, once before and once together, with orlistat at the end of the orlistat treatment period. Results: The plasma concentration time profiles and the pharmacokinetic parameters estimated for these drugs were in the expected range, except for furosemide, whose bioavailability was lower than reported in the literature. This was probably due to the fact that furosemide was given during a meal. There were minor, but statistically significant, differences in one of the pharmacokinetic parameters of furosemide and nifedipine (no difference for captopril and atenolol) when these drugs were given alone and in combination with orlistat: the half-life of furosemide was slightly longer, the time to peak plasma concentrations of nifedipine was slightly longer. None of these are considered to be clinically significant changes. Conclusions: The lipase inhibitor orlistat given 50 mg 3 times daily does not alter the pharmacokinetics of atenolol, furosemide, nifedipine and captopril to a clinically significant extent.
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  • 13
    ISSN: 1432-1041
    Keywords: Key words Prazosin ; Urapidil; Vasoconstrictor response ; laser Doppler flow ; finger tip blood flow ; cold stimulation ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of α-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different α1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these α1-adrenoceptor antagonists in human subjects. Method: In thirteen healthy male subjects (20–42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg). Results: Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The α1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil. Conclusion: These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative α1-adrenoceptor blocking potency of drugs.
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  • 14
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 49 (1996), S. 411-415 
    ISSN: 1432-1041
    Keywords: Key words Moxisylyte; pharmacokinetics ; intracavernous administration ; healthy volunteers ; adverse events ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The concentration-time profiles of specific metabolites of moxisylyte, an α-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). Results: Four metabolites, unconjugated desacetylmoxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. Conclusion: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 50 (1996), S. 513-514 
    ISSN: 1432-1041
    Keywords: Key words Thioctic acid; enantiomers ; food interaction ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 16
    ISSN: 1436-6215
    Keywords: Strontium ; oraler Strontium-Test ; Calcium ; Absorption ; gesunde Probanden ; Strontium ; oral strontium test ; calcium ; absorption ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Summary Intestinal strontium absorption has been discussed recently as an indirect measure for calcium uptake. Prerequisite for the clinical use of an oral strontium test is the availability of a reliable procedure including controlled strontium supply, sample pretreatment and analysis as well as the assessment of normal values. In the present study, a group of young females (n=33; 24.0 ± 2.7 y; BMI 21.5 ± 1.9) received an oral dose of 2.27 mmol strontium in a standardized breakfast that contained 0.625 mmol calcium. Before and 220 min after the bolus serum strontium concentrations were determined by means of atomic absorption spectrophotometry (coefficient of variation: within day 4.8 %, n=10; day-to-day 9.5 %, n=8). The error of the method was 2.7 %. Calculation of the fractional strontium absorption rate considered the respective distribution volume (extracellular fluid; either estimated using body weight or determined by means of bioimpedance analysis [BIA]). Average absorption rates were 13.3 ± 3.1 % and, considering BIA measurement 13.6 ± 2.6 %, respectively. Smoking, exercise and, use of oral contraceptives showed no effects. Our oral strontium test is characterized by excellent reliability, easy handling and low costs and, thus, is suitable for routine use.
    Notes: Zusammenfassung Die Erfassung der Strontiumabsorption wird heute als indirektes Verfahren zur Beurteilung der intestinalen Calciumabsorption diskutiert. Voraussetzung für die klinische Anwendung ist ein vertrauenswürdiges Testverfahren inclusive kontrollierter Strontiumgabe, Probenaufarbeitung und -analyse sowie die Erfassung von Normalwerten. Für unsere Studien wurde ein Kollektiv junger Frauen (n=33, 24,0 ± 2,7 Jahre; BMI 21,5 ± 1,9) herangezogen. Die Probandinnen erhielten eine Bolusgabe von 2,27 mmol Strontium zusammen mit einem Standardfrühstück (ca. 0,625 mmol Calcium). Vor und 220 min nach der Bolusgabe erfolgte die Bestimmung des Serum-Strontiumgehaltes mittels Atomabsorptionsspektrometrie. Der Variationskoeffizient der Methode lag innerhalb eines Tages bei 4,8 % (n=10) und von Tag zu Tag 9,5 % (n=8). Der Fehler der Methode betrug 2,7 %. Die Berechnung der fraktionellen Strontiumabsorptionsrate erfolgte unter Berücksichtigung des entsprechenden Verteilungsraumes (Extrazellulärflüssigkeit; Schätzverfahren über Körpergewicht bzw. Bioimpedanz-Analyse [BIA]). Die Strontiumabsorptionsrate lag im Mittel bei 13,3 ± 3,1 %, unter Berücksichtigung der BIA-Werte bei 13,6 ± 2,6 %. Rauchen, sportliche Aktivität bzw. Einnahme oraler Kontrazeptiva zeigten keinen Einfluß. Das hier vorgestellte Testverfahren ist aufgrund seiner hohen Vertrauenswürdigkeit und relativ einfacher Handhabung für Routine-untersuchungen geeignet.
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  • 17
    ISSN: 1432-1041
    Keywords: Ramipril ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15 %, by ramiprilat plasma AUC, 44 %. Ramiprilat formation from intravenous ramipril was 53 % and from oral ramipril 28 %. Urinary recovery of oral ramipril was 23 %, i. v. ramipril 49 %, and i. v. ramiprilat 68 % of the given dose. Maximum ACE inhibition was highest (100 %) after i. v. ramiprilat; it was 99 % after i. v. ramipril and 84 % following oral ramipril. ACE inhibition over 24 h was highest after i. v. ramipril, 2 % less with i. v. ramiprilat and 34 % less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44–66 %.
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  • 18
    ISSN: 1432-1041
    Keywords: Piroxicam ; β-Cyclodextrin ; pharmacokinetics ; healthy volunteers ; multiple dose ; adverse event
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract CHF1194 is an inclusion complex of β-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, β-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-β-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of β-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5′-hydroxypiroxicam and β-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80–125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5′-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with β-cyclodextrin. This may be of therapeutic interest as it might accelerate the onset of pain relief. The pharmacokinetics of piroxicam was linear after the doses used here, suggesting that long term treatment with CHF1194 should not require any change in dosing regimen. Even after 14 days of repeated administration of CHF1194, β-cyclodextrin could not be detected in plasma or urine, suggesting that in man the unchanged oligosaccharide was absorbed to a very small extent.
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  • 19
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    European journal of clinical pharmacology 48 (1995), S. 203-208 
    ISSN: 1432-1041
    Keywords: Moxonidine ; Renal haemodynamics ; imidazoline receptors ; natriuresis ; blood pressure ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Moxonidine and related compounds have been recently introduced into antihypertensive therapy. It is thought that these drugs exert their blood pressure lowering effect through interaction with nonadrenergic receptors in the central nervous system, i.e. imidazoline receptors, although the contribution of specific interaction with α2-receptors is still under debate. Imidazoline receptors have recently been documented in the renal proximal tubule. In experimental studies, interaction of imidazolines with these receptors decreased the activity of the Na+/H+ antiporter and induced natriuresis. To quantitate the effect of the imidazoline receptor agonist moxonidine on renal sodium handling and renal haemodynamics in man, we examined ten healthy normotensive males (aged 25 ± 4 years) in a double blind placebo-controlled study using a crossover design. Subjects were studied on a standardized salt intake (50 mmol per day). On the 7th and 10th study day they were randomly allocated to receive either i.v. placebo or i.v. 0.2 mg moxonidine. Urinary electrolyte excretion, lithium clearance (as an index of proximal tubular sodium handling), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), mean arterial blood pressure (MAP), plasma renin activity (PRA) and plasma noradrenaline (NA) levels were assessed. Injection of moxonidine did not increase fractional sodium excretion or lithium clearance. Specifically, antinatriuresis was not observed after injection of moxonidine despite a significant decrease in MAP from 91 to 85 mmHg and a significant increase in PRA. MAP and PRA did not change with administration of placebo. Injection of moxonidine did not affect GFR and RVR; ERPF decreased slightly but not significantly. Acute administration of 0.2 mg i.v. moxonidine decreased blood pressure in healthy volunteers on standardized salt intake, but did not affect natriuresis, proximal tubular sodium reabsorption or glomerular filtration rate. The absence of an antinatriuretic response despite a decrease in blood pressure suggests a direct facilitation of natriuresis by moxonidine.
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  • 20
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    European journal of clinical pharmacology 49 (1995), S. 193-201 
    ISSN: 1432-1041
    Keywords: Renal function ; Prostaglandins ; Flosulide ; non-steroidal anti-inflammatory drug ; renin-angiotensin-aldosterone ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Two double-blind, placebo-controlled, balanced cross-over studies were carried out successively in 8 male normotensive volunteers to investigate the acute and chronic effects of two doses of a novel non-steroidal anti-inflammatory drug flosulide (5 mg b.d. and 25 mg b.d.), on the renin-angiotensin-aldosterone system, linking this to changes in the urinary excretion of prostaglandins. Plasma renin and aldosterone were determined on Days 2 and 9, with the subject supine, after 1 h of rest in the sitting position following 1 h of walking, and 3 h after oral intake of 40 mg furosemide, also in the sitting position. Twenty-four hour urine samples were collected on Days 1 and 8 for the measurement of the electrolytes, aldosterone pH1 and the urinary prostaglandins PGE2, PGF2α, 6-keto-PGF1α and TxB2. Results: After the first day of treatment with 25 mg b.d. flosulide, the increase in body weight was close to significance (0.86 vs -0.08 kg with placebo). A dose-and time-dependent decrease in both active and inactive plasma renin were observed, whereas the fall in plasma and urinary aldosterone was statistically significant only after the higher dose of flosulide. These changes in the renin-angiotensin-aldosterone system were observed in the absence of oedema. Two out of eight volunteers experienced a strong and immediate reduction in the excretion of prostaglandins but overall the two doses tested did not produce a statistically significant inhibition in renal prostaglandins, especially following repeated dosing. The inhibitory effect of flosulide on renal prostaglandin synthesis was found to be less pronounced after repeated treatment, as documented on Day 9 by the lower inhibition of 6-keto-PGF1α and TxB2. Conclusion: These two studies in normal volunteers, in spite of some methodological limitations, were helpful in order to select doses of flosulide which should be effective and safe in patients during Phase II trials, by examining the inhibitory effect of the drug on renin synthesis and renal prostaglandin synthesis.
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  • 21
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    European journal of clinical pharmacology 47 (1995), S. 543-548 
    ISSN: 1432-1041
    Keywords: Sumatriptan ; pharmacokinetics ; single dose ; bioavailability ; dose proportionality ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Sumatriptan is classified as a vascular 5HT1 receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration. The mean subcutaneous bioavilability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 1) and an elimination half-life of 2 h. Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.
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  • 22
    ISSN: 1432-1041
    Keywords: Metoprolol ; Denopamine ; exercise ; heart rate response ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of a combination regimen of metoprolol and β1-adrenoceptor agonist denopamine on resting and exercise heart rate have been studied in 10 normal volunteers. Maximal ramp upright bicycle exercise was performed three times at 1-week intervals. Two hours before each exercise test, 5 mg metoprolol plus 20 mg denopamine, 5 mg metoprolol plus a denopamine placebo, or two placebos were orally administered in a double-blind fashion. During exercise after placebo administration, heart rate increased in parallel with the exercise intensity. Compared to the placebo values, resting heart rate was significantly decreased by an average of 10 beats · min−1 by 5 mg metoprolol, whereas it was not altered by the combination regimen. During exercise, however, both the combination regimen and metoprolol alone showed a significant negative chronotropic effect, decreasing peak exercise heart rate by an average of 14 and 21 beats · min−1, respectively. Peak oxygen uptake was also significantly decreased by both regimens. We conclude that concomitant administration of 5 mg metoprolol and 20 mg denopamine exerts an effective β-adrenoceptor blocking action during exercise but a minimal effect at rest in normal subjects. The combination regimen appears to have a favourable pharmacological profile for β-adrenoceptor blocker therapy in patients with chronic heart failure.
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  • 23
    ISSN: 1432-1041
    Keywords: Atropine ; M2-cholinoceptors ; effect kinetics ; radioreceptor assay ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of an oral dose of atropine (0.03 mg/kg body weight) and an IM (0.02 mg/kg) dose on the heart rate and salivary flow in seven healthy adult volunteers were compared to see whether the oral dose was sufficient to inhibit vagal reflexes of the heart. Atropine concentrations in plasma were determined by an M2-selective radioreceptor assay, and the in vitro occupancy of porcine cardiac M2-cholinoceptors was measured in parallel. In ligand-binding studies, atropine has been shown to have a comparable affinity for human and porcine cardiac M2-cholinoceptors (Ki 4.0 and 5.9, respectively). Slight changes in heart rate after oral administration were not significant. After IM administration, however, the heart rate increased significantly, by a maximum of 22 beats·min−1 after 45 min. The slight increase in heart rate after the oral dose corresponded to a receptor occupancy in vitro near the lower limit of detection, whereas the significant increase in heart rate after the IM dose corresponded to a receptor occupancy of up to 47%. The maximum reduction in salivary flow was similar after the oral and IM doses (84.3 and 87.5%, respectively). The almost complete inhibition of salivary flow could be explained by the lower vagal tone in the salivary glands compared with to the heart. The difference in the effect on heart rate was probably due to lower absorption of the oral dose. Thus, an oral dose greater than 0.03 mg atropine/kilogram body weight is required to compensate for low gastrointestinal absorption and to overcome the high vagal tone of the heart.
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  • 24
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    European journal of clinical pharmacology 49 (1995), S. 237-242 
    ISSN: 1432-1041
    Keywords: Intravenous immunoglobulin G ; Antihepatitis B ; pharmacokinetic parameters ; tolerability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In two independent trials 10 and 12 healthy volunteers received the novel intravenous immunoglobulin (IVIG) preparations BT 511 and BT 507, respectively. BT 511 contains 5 g human plasma proteins per 100 ml, more than 95% of which are immunoglobulins of the G class (IgG). BT 507 contains in addition 61 IU antibody against hepatitis B surface antigen (anti-HBs)·ml−1. In trial I volunteers received 4.0 ml/kg (n+4) and 8.0 ml·kg−1 (n+6) BT 511 to study the tolerability and the magnitude of the increase in immunoglobulins in plasma as well as their decline over 1 month. After administration of the lower dose, plasma IgG increased from 10.7 to 14.7 g·l−1 directly after the infusion. Following the 8.0 ml·kg−1 dose a more pronounced increase from 12.4 to 21.2 g·l−1 was observed. No adverse events occurred. After 1 month IgG concentrations had almost reached baseline values at 12.2 g·l−1 in the 4.0 ml·kg−1 group, but were still significantly increased at 15.2 g·l−1 after the high dose. There was a linear correlation between the maximal IgG plasma concentration and the subsequent decline of IgG during the 29-day observation period. After administration of BT 507 maximal anti-HBs concentrations of 1778 mU·ml−1 occurred 1.4 h after termination of the infusion. The terminal elimination half-life was 22.4 days, and total clearance and volume of distribution were determined to be 0.122 ml·min−1 and 5.41, respectively. The pharmacokinetic parameters calculated for anti-HBs as an indicator of IgG were in accordance with the pharmacokinetic behaviour of native IgG.
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  • 25
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    European journal of clinical pharmacology 47 (1995), S. 395-400 
    ISSN: 1432-1041
    Keywords: Felodipine ; Hydrochlorothiazide ; calcium antagonists ; diuretics ; diuresis ; natriuresis ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of the calcium antagonist, felodipine, and hydrochlorothiazide (HCTZ) on natriuresis/diuresis and blood pressure were evaluated in 12 healthy subjects. The investigation was designed as a double-blind, three-way, randomised, crossover study, and all comparisons were performed against placebo. Urine volume, urine sodium excretion, heart rate and blood pressure were measured after a single dose of felodipine 10 mg, HCTZ 12.5 mg or placebo as well as during steady-state conditions (6 days of treatment with felodipine 10 mg b.i.d., HCTZ 12.5 mg b.i.d. or placebo). A significant increase in natriuresis was seen in the first 4 h after a single dose of felodipine and HCTZ, and the effect of felodipine was approximately 40% that of HCTZ. When the entire 24-h period after a single dose was studied, there was a significant increase in natriuresis after HCTZ, but not after felodipine, compared with placebo. A significant increase in diuresis was found in the first 4 h after a single dose of HCTZ, but not after felodipine, compared with placebo. Under steady-state conditions, there were no statistically significant differences between felodipine and placebo or HCTZ and placebo when the 24-h period, as a whole was considered. Potassium excretion was not affected by any of the drugs. Felodipine caused a significant decrease in diastolic blood pressure in this study. This was not the case for HCTZ or placebo.
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  • 26
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    European journal of clinical pharmacology 47 (1995), S. 417-421 
    ISSN: 1432-1041
    Keywords: Phase I trials ; Alanine amino transferase ; healthy volunteers ; adverse experience ; normal range ; liver function test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In Phase I clinical studies, the maximum tolerated dose has to be determined by a case by case analysis sometimes using a laboratory adverse effect, e.g. an increase in alanine amino transferase (ALT). For this reason a threshold to discriminate between significant or non significant adverse changes in ALT is required particularly in Phase I studies, in order to deal with the very common “close to the limit values”. Previous methods (limit of normal range or normal range plus an arbitrary margin) do not solve this problem. The authors propose a new method taking into account the threshold used as inclusion criteria for ALT (R) and the range of spontaneous variations measured under identical Phase I study conditions (V). The (R) and (V) thresholds, respectively, are defined as 50 IU·1−1 and a 50% increase, from baseline. Thus an ALT value is recognized as a “significant adverse experience” if it exceeds 50 IU·1−1 above an increase from baseline exceeding 50% of the baseline value. To highlight the value of the method, it was implemented in a one year period including 8 studies and 134 subjects. The sensitivity, specificity and positive predictive value of various methods were compared. The results showed the following: Six out of 134 subjects had significant adverse changes in ALT (4%); and all these 6 subjects were detected by the proposed new method without error. Eight subjects including two false positives, were detected by an use of the normal range limit, and only 4 were detected using, the 10% margin. Thus, use of the new method showed 1. keeping the normal range limit as the detection threshold led to preserved sensitivity; 2. it reduced the background noise of false positive results related to chance variation around the upper limit, mainly in subjects with a baseline value close to the limit; 3. it allowed better judgment of the significance of a value which lay just beyond the limit when variation from the baseline exceeding the normal range. The new method produced the best combination of sensitivity, specificity and positive predictive value. Given the small number of subjects in the study, further evaluation with a larger population is required. Finally, the proposed new method seems to be a tool easy to use determining the significance of adverse changes in ALT when the values are close to the limit that is common in Phase I studies.
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  • 27
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    European journal of clinical pharmacology 48 (1995), S. 123-125 
    ISSN: 1432-1041
    Keywords: Hydrocortisone-17-butyrate ; Mometasone furoate ; plasma cortisol ; ACTH concentration ; Synacthen test ; healthy volunteers ; adrenal suppression ; fatty cream
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract To compare the effect of multiple dose treatment with fatty cream 0.1% hydrocortisone-17-butyrate (LLFC) and fatty cream 0.1% mometasone furoate (EFC), under occlusion on adrenal function, we performed an open label, randomised, two-period crossover study, lasting 30 days, in 12 healthy, male volunteers (age 18–45 y). Morning plasma cortisol and ACTH concentrations were determined before, during, and after the treatments, and a Synacthen test was performed before and during the treatments. Both agents suppressed plasma cortisol concentrations, EFC significantly more than LLFC. ACTH concentrations were normal and were comparable between the two treatments throughout the studies, while the Synacthen tests showed normal rises in cortisol levels. Both treatments were well tolerated. We conclude that EFC has a stronger suppressive effect on plasma cortisol values than LLFC, although for short duration treatments both suppressive effects are transient.
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  • 28
    ISSN: 1432-1041
    Keywords: Ramipril ; Piretanide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0–4 h) and ramiprilat (0–24 h) (from 15.8 to 19.8 ng·ml−1·h, and from 63.4 to 74.6 ng·ml−1·h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73 % of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide. The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril. Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.
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  • 29
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    European journal of clinical pharmacology 46 (1994), S. 469-472 
    ISSN: 1432-1041
    Keywords: Amiloride ; Insulin sensitivity ; hyperinsulinemic euglycemic clamp ; glucose utilization ; glucose production ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have evaluated the short-term effects of amiloride on insulin action in vivo, since amiloride is known to impair insulin action in vitro. Seven healthy subjects were treated according to a randomized, double-blind, cross-over protocol. The treatment periods were 3 days each with amiloride 15 mg daily and placebo. Insulin action on glucose turnover was assessed directly after each treatment period with the hyper-insulinaemic euglycaemic glucose clamp technique. At the two insulin concentrations studied (∼ 30 mU·l−1 and ∼ 200 mU·l−1), the glucose infusion rate required to maintain constant euglycaemia did not differ after either amiloride or placebo. The rates of glucose production and utilization were also similar, whereas the so-called insulin sensitivity index at the lower insulin concentration was significantly reduced (by about 15 %) after amiloride. Moreover, amiloride produced significantly higher fasting insulin and C-peptide concentrations, whereas fasting glucose and NEFA concentrations were unaltered. In conclusion, these data suggest that short-term amiloride slightly impairs insulin sensitivity with respect to glucose uptake. However, overall glucose homoeostasis does not appear to be affected, probably due to a compensatory rise in plasma insulin.
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  • 30
    ISSN: 1432-1041
    Keywords: Dilevalol ; Propranolol ; intrinsic sympathomimetic activity ; healthy volunteers ; pulsed Doppler ; regional haemodynamics ; plasma renin activity ; plasma atrial natriuretic factor ; plasma norepinephrine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers. At rest, as compared to placebo, neither dilevalol nor propranolol significantly affected arterial pressure and heart rate but, whereas propranolol decreased cardiac output (−27% at 2 h) and tended to increase total peripheral resistance, dilevalol tended to increase cardiac output and decreased total peripheral resistance (−7% at 2 h). Neither dilevalol nor propranolol affected brachial artery diameter. Propranolol tended to decrease brachial artery flow (−20% at 2 h) and to increase brachial vascular resistance (+25% at 2 h), but dilevalol did not and the brachial irrigation ratios did not change. Neither of the drugs affected carotid haemodynamics or plasma atrial natriuretic factor. Both drugs tended to decrease plasma renin activity, and dilevalol (+82% at 2 h) increased norepinephrine more than propranolol (+19% at 2 h). After exercise, dilevalol and propranolol produced similar falls in the induced increases in arterial pressure, heart rate and cardiac output, and had the same effects on regional haemodynamics, plasma renin activity and atrial natriuretic factor. Finally, dilevalol greatly increased plasma norepinephrine. We conclude that the β2-adrenoceptor agonist activity of dilevalol was clearly expressed at rest, thus inducing vasodilation and counteracting the β-adrenoceptor blockade-induced negative chronotropic and inotropic effects. However, during sub-maximal exercise, only the β-adrenoceptor antagonist activity of dilevalol was apparent.
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  • 31
    ISSN: 1432-1041
    Keywords: Buspirone ; pharmacokinetics ; renal impairment ; hepatic impairment ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (Cmax) and area under the curves (AUC) of buspirone and 1-PP on Days D 5 and 10 were higher than on Day D 1. The trough levels (Cmin) and AUCs (D 5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher Cmax and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers. There was no correlation between the average plasma concentrations of buspirone ( $$\bar C$$ ) and the degree of renal impairment judged by creatinine clearance. An excellent correlation was observed between $$\bar C$$ of buspirone and serum albumin (r=0.862, and P〈0.0001) as well as between $$\bar C$$ and bromsulphalein clearance (r=0.678, P〈0.0003). In view of high intra-and inter-subject variability in buspirone concentrations, definitive dosing recommendations for patients with compromised renal or hepatic function could not be made, but such patients should initially be dosed cautiously with buspirone.
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  • 32
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    European journal of clinical pharmacology 46 (1994), S. 23-28 
    ISSN: 1432-1041
    Keywords: Atenolol ; Captopril ; Central effects ; short term administration ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The central effects of atenolol (50 mg tds) and captopril (50 mg tds) ingested for a period of seven days were studied in ten healthy volunteers. A placebo and two active control drugs, methyldopa (250 mg tds) and oxazepam (10 mg), were included in the design. Oxazepam was ingested on the seventh day only, with a placebo being taken on the preceding six days. On the seventh day, central effects of the drugs were tested at 10.00–11.00 h (session 1), immediately before the subjects' last dose of each drug and at 2.5–3.5 h after the final dose of each drug (1330–1430 h, session 2). Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, critical flicker fusion and two flash fusion. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. Recordings of the EEG and body sway were carried out. Neither atenolol nor captopril altered performance at any of the skills tested. There were no effects on subjectively assessed alertness or mood with captopril, while atenolol significantly increased wakefulness in session 2 and when the two sessions were meaned. Similarly, captopril did not modify body sway, while with atenolol there was a significant decrease in activity in the frequency range 1.0–2.75 Hz from session 1 to session 2. Both captopril and atenolol modified the electrical activity of the brain, with captopril increasing delta and theta activity and atenolol reducing delta, alpha and beta activity. Methyldopa significantly increased the number of involuntary rest pauses in the finger tapping task, and the choice reaction time from session 1 to session 2. There was a decrease in passivity during the first session and an increase in wakefulness in session 2 with methyldopa. This drug also decreased body sway in the frequency range 1.0–2.75 Hz activity in session 2, while oxazepam decreased bodys was at 1.0 to 2.75 Hz and increased activity at 2.5–3.0 Hz in session 2. Oxazepam reduced delta, theta and alpha content of the EEG. The present study has been unable to demonstrate any development of adverse central effects with captopril over a period of 7 days of drug ingestion. With atenolol adverse effects were present following short term dosing but were not more pronounced than with acute ingestion seen in previous studies. However effects on the electrical activity of the brain with atenolol remained after 7 days suggesting that the changes reported previously with single ingestions do not disappear.
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  • 33
    ISSN: 1432-1041
    Keywords: Entacapone ; catechol-O-methyltransferase ; pharmacokinetics ; healthy volunteers ; adverse effects ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) by entacapone, and the pharmacokinetics of entacapone after single oral (5–800 mg) and IV (25 mg) doses have been examined in an open study in 12 healthy young male volunteers. Oral entacapone dose-dependently decreased the activity of S-COMT in RBCs with a maximum inhibition of 82% after the highest dose (800 mg). The inhibition of S-COMT in RBCs was reversible and the activity recovered within 4–8 h. Entacapone showed linear pharmacokinetics over the dose range studied: Cmax and AUC were correlated with the dose of the drug. Oral absorption of entacapone was fast, with a tmax ranging from 0.4 to 0.9 h, depending on the dose. Systemic availability of entacapone varied between 30 and 46%. Entacapone was rapidly eliminated by metabolism with a half-life of 0.27–0.30 h after oral doses of 5 to 50 mg. After doses from 100 to 800 mg the disposition was best described by two phases with a t1/2α of 0.27–0.37 h and t1/2β of 1.59–3.44 h. Over the dose range studied, the single oral and IV doses of entacapone were well tolerated. No haematological, biochemical or haemodynamic adverse effects were seen. The results show that entacapone is an orally effective and reversible COMT inhibitor in man and has simple, linear pharmacokinetics.
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  • 34
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    European journal of clinical pharmacology 46 (1994), S. 339-343 
    ISSN: 1432-1041
    Keywords: Iopromide ; X-ray contrast medium ; pharmacokinetics ; tolerability ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Twelve healthy male volunteers participated in a single-blind, randomised, placebo-controlled cross-over study of IV iopromide in doses of 15 g iodine or 80 g iodine infused over a period of 15 min. The volunteers were observed for three days during which time blood samples, urine and faeces were collected. The terminal disposition phase half-life of iopromide was 2 h and 1.9 h, and the total clearance was 110 and 103 ml·min-1 at the lower and at the higher dose levels, respectively. The steady state volume of distribution was 16 and 17 l, indicating predominantly extracellular distribution of iopromide. Statistical analysis (one-sided t-test) showed that all the target parameters (AUC, half-life and urinary excretion) were equivalent at both dose levels, indicating dose proportionate, first order kinetics of iopromide over the large dose range tested. Iopromide was well tolerated after both doses.
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  • 35
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    European journal of clinical pharmacology 47 (1994), S. 49-52 
    ISSN: 1432-1041
    Keywords: Azithromycin ; Erythromycin ; Midazolam ; drug interaction ; healthy volunteers ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Since macrolide antibiotics inhibit the oxidative hepatic metabolism of various drugs, including midazolam, the present double blind studies were conducted to find out if azithromycin, a new macrolide of the azalide type, would inhibit the metabolism of midazolam and enhance the effects of midazolam on human performance. In Study I, 64 healthy medical students, divided in four parallel groups received placebo, midazolam (10 mg or 15 mg), and midazolam 10 mg combined with azithromycin (500mg+250mg). In Study II, three males received oral midazolam 10 mg in combination with placebo, azithromycin or erythromycin 750 mg (as a positive control) in a cross-over trial. Objective and subjective tests were done before the intake of midazolam and 30 and 90 min after it, and venous blood was sampled for the assay of midazolam. In the placebo group in Study I, the mean numbers of letters cancelled (LC) at baseline, 30 min and 90 min were 21, 20 and 20, respectively, and the corresponding mean numbers of correct digit symbol substitutions (DSS) were 126, 137 and 140, indicating a practice effect. Midazolam 10 mg impaired these performances (21, 13 and 12 for LC, and 127, 113 and 111 for DSS). Either dose of midazolam produced clumsiness, mental slowness and poor subjective performance, midazolam 15 mg being slightly more active. The corresponding, scores in the azithromycin + midazolam group were 21, 16, 16 for LC, and 132, 121 and 119 for DSS, the only significant difference from placebo being the impairment of DSS at 90 min. The combination differed from midazolam 15 mg in producing less drowsiness and mental slowness. In Study II, mean plasma midazolam concentrations (μg·1-1) after erythromycin + midazolam 10 mg were 0 (baseline), 168 (30 min) and 113 (90 min), which were higher than the values (0, 79 and 41) after placebo + midazolam. The corresponding concentrations (μg·1-1) after azithromycin + midazolam (0, 85 and 46) were similar to those found after placebo + midazolam. Erythromycin but not azithromycin enhanced the objective and subjective effects of midazolam. Our results suggest that as azithromycin, unlike erythromycin, does not interfere with midazolam metabolism, it also does not enhance the effects of midazolam.
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  • 36
    ISSN: 1432-1041
    Keywords: Ofloxacin ; sucralfate ; food ; drug interaction ; absorption ; healthy volunteers ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have studied the effect of food on the interaction of ofloxacin with sucralfate. Six healthy men took a single oral dose of ofloxacin (200 mg) on 4 occasions: alone after overnight fasting or after breakfast (non-fasting), and with sucralfate fasting or non-fasting. There were no significant differences in the plasma concentration-time profiles of ofloxacin after ofloxacin alone between fasting and non-fasting conditions. On the other hand, the peak plasma concentration and AUC of ofloxacin after co-administration with sucralfate while fasting fell by 70 and 61 % compared with ofloxacin alone; the changes non-fasting were 39 and 31 % respectively. The interaction of ofloxacin with sucralfate was markedly reduced by food, but still could not be disregarded.
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  • 37
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    European journal of clinical pharmacology 46 (1994), S. 29-33 
    ISSN: 1432-1041
    Keywords: Israpidine ; haemodynamics ; pharmacokinetics ; healthy volunteers ; drug input rate
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Since the magnitude of the response to a drug may depend upon the drug input rate, the concentration-effect relationship of the new dihydropyridine (±)-isradipine was investigated using different administration modalities. Ten normotensive healthy volunteers were given, double-blind and in a crossover fashion, isradipine as a 1 mg iv infusion, 5 mg oral solution, 5 mg standard tablet, 10 mg slow release formulation, and a placebo. Blood pressure, heart rate, and plasma isradipine concentrations were recorded for 24 h. The maximal fall in diastolic blood pressure was similar after the infusion (-11.40 mmHg), the oral solution (-15.20 mmHg), and the standard tablet (-12.50 mmHg). In healthy volunteers the slow release form had no significant effect on blood pressure. The concentration-effect plots showed an increasing slope in the order infusion, solution, and tablet, and anticlockwise hysteresis. This was partly due to marked heart rate counter-regulation, the corresponding mean maximal heart rate increases being 24, 19, and 17 beats·min−1. The pronounced counter-regulation of the heart rate implies that a slow isradipine input rate would be more effective in decreasing blood pressure.
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  • 38
    ISSN: 1432-1041
    Keywords: Colchicine ; pharmacokinetics ; healthy volunteers ; elderly subjects ; absolute bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of colchicine were studied in six healthy male and four elderly female volunteers after i. v. and oral administration. Plasma samples were collected over 72 h and assayed for colchicine by a specific and sensitive radioimmunoassay. Plasma concentration-time curves were fitted using a three-compartmental model after i. v. administration of 0.5 mg (healthy volunteers) and 1 mg (elderly group) colchicine. The first distribution half-life (t1/2 λ1) was short: 9.2 min in healthy volunteers and 3.0 min in the elderly group; the second distribution half-life (t1/2 λ2) was of the same order for both groups, 1.2 h. Plasma elimination half-lives were also in the same range: 30 h for healthy volunteers versus 34 h for the elderly subjects. Mean residence time was also in the same range in the two groups: 27 h in healthy volunteers and 21 h for elderly subjects. The volume of distribution (Vz) was 6.71·kg-1 for the healthy group and 6.31·kg-1 for the elderly group, while Vss was smaller: 4.21·kg-1 for healthy volunteers and 2.91·kg-1 for elderly subjects. Total body clearance was 10.51·h-1 for healthy and 5.51·h-1 for elderly subjects. After oral administration of 1 mg, lag-time was 14 min in healthy volunteers and 11 min in elderly subjects. Maximal plasma concentration was 5.5 ng·ml-1 at 62 min in the healthy group, while in the elderly group Cmax was 12 ng·ml-1 at 87 min. Mean absolute bioavailability of the tablet was the same in both groups, 44% for healthy volunteers and 45% for elderly subjects.
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  • 39
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    European journal of clinical pharmacology 46 (1994), S. 361-365 
    ISSN: 1432-1041
    Keywords: Flosequinan ; Xamoterol ; pharmacodynamic interactions ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The possible cardiovascular pharmacodynamic interactions at rest and during exercise of combining oral flosequinan (100 mg) with xamoterol (200 mg) was investigated in a four-way randomised double-blind placebo-controlled crossover trial in eight healthy male volunteers. Xamoterol was better tolerated than flosequinan. The most common adverse events were mild to moderate headache and facial flushing. One volunteer developed headache and vomiting following flosequinan treatment and was replaced. Compared to placebo, at supine rest, flosequinan significantly increased heart rate (HR) by 5 beats·minv1, but had no effect on cardiac output (CO), stroke volume (SV) and mean blood pressure (MBP). Xamoterol significantly increased CO by 1.5 l·min-1, HR (5 beats·min-1) and MBP (6 mmHg) but not SV. The combined treatment (flosequinan + xamoterol) significantly increased CO (1.71·min-1) and HR (10 beats·min-1), but had no effect on SV and MBP. During exercise, flosequinan had no significant effect on any variable compared to placebo. Both xamoterol and combined treatment reduced the increase in CO (-4.61·min-1 after xamoterol and -3.41·min-1 after combined treatment vs. 0.1 l·min-1 after placebo), but had no effect on other variables. The effect of the combined treatment on each haemodynamic variable were no more than the anticipated additive effects of the two drugs. Thus, no cardiovascular pharmacodynamic interaction was found between flosequinan and xamoterol in healthy volunteers.
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  • 40
    ISSN: 1432-1041
    Keywords: dDAVP ; bioavailability ; gastrointestinal tract ; healthy volunteers ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP) from different regions of the gastrointestinal (GI) tract (stomach, duodenum, jejunum, ileum, colon, rectum) has been studied in 6 healthy, male volunteers aged 24 to 35 years, followed for 12 h after each drug administration. For i. v. administration the subjects received 4 μg dDAVP. For intestinal administration 400 μg dDAVP was directly applied to six distinct sites in the GI tract via two or four channel tubes with or without a distal occlusive balloon. Biological effects were assessed and plasma and urinary levels of dDAVP were measured using a specific, sensitive RIA. Urine osmolality remained elevated and diuresis decreased for 12 h following dDAVP administration irrespective of the site of application. After i. v. administration, the half-life of elimination of dDAVP was 60.0 min, plasma clearance 1.7 ml·min−1·kg−1, amount excreted in urine 2.0 μg and renal clearance was 0.8 ml·min−1·kg−1. The mean bioavailability (f) after gastric application was 0.19% (range 0.02–0.35%). f was 0.24% after duodenal application (range 0.04–0.62%), 0.19% after jejunal (range 0.01–0.41%), 0.03% after distal ileal (range 0.01–0.08%), 0.04% after proximal colonic (range 0.01–0.12%) and 0.04% after rectal (0.01–0.10%) application. The bioavailability was significantly higher in the three upper GI regions in comparison to the three lower regions. The bioavailability of dDAVP after gastric, duodenal and jejunal application was similar to that after swallowing a tablet in a previous study. Absorption from the ileum was lower than expected and no preferential site of absorption was found.
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  • 41
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    European journal of clinical pharmacology 45 (1993), S. 265-269 
    ISSN: 1432-1041
    Keywords: Brofaromine ; Debrisoquine oxidation ; MAO-A inhibitor ; polymorphism ; quinidine ; healthy volunteers ; cytochrome P450 ; drug metabolism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0−∞) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0–72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.
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  • 42
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    European journal of clinical pharmacology 45 (1993), S. 313-320 
    ISSN: 1432-1041
    Keywords: Lorazepam ; CL284,846 ; Psychomotor performance ; memory function ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of single doses of CL284,846 (20 mg), lorazepam (2 mg) and placebo on psychomotor performance, memory function and subjective feelings were assessed in 12 normal, healthy male volunteers. Each subject received each treatment in balanced order and a minimum of 6 days was left between treatments. The subjects performance on a comprehensive battery of tests of psychomotor performance, memory function and subjective ratings was assessed pre-treatment and at 1, 3 and 5 h post-treatment. In general, the effects of CL284,846 on memory were similar to those of lorazepam at 1 h post-treatment but, recovery was rapid with CL284,846. Impairments induced by lorazepam persisted throughout the post-drug testing sessions. This pattern of effects was repeated across most of the variables tested. However, at 1 h, CL284,846 produced less marked psychomotor impairment than lorazepam. The results of this study suggest that CL284,846 is a safe, rapid acting and effective sedative with some clear advantages over lorazepam with respect to unwanted cognitive and psychomotor impairments.
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  • 43
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    European journal of clinical pharmacology 44 (1993), S. 27-33 
    ISSN: 1432-1041
    Keywords: Nicorandil ; vasodilator ; tolerance study ; blood pressure ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 μg·kg−1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electro-cardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing. All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 μg·kg−1). Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (〈20%) systemic clearances and larger values of Cmax and AUC. Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 μg·kg−1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 μg·kg−1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h. Heart rate increased transiently (mean peak increase of 17–24 bpm at the end of the 144 and 200 μg·kg−1 infusions). Blood pressure and heart rate changes over time were statistically significantly correlated with plasma nicorandil concentrations. Individual areas under the blood pressure and heart rate change curves likewise correlated with plasma concentration curve areas.
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  • 44
    ISSN: 1432-1041
    Keywords: Oxprenolol ; β-adrenoceptor blockade ; circadian rhythm ; haemodynamics ; pharmacokinetics ; exercise ; healthy volunteers ; kinetic-dynamic model
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effect of dosage time of oxprenolol (Trasicor®) on its pharmacokinetics and pharmacodynamics in six healthy volunteers. The drug effects measured were heart rate and systolic blood pressure during exercise. Oxprenolol was taken orally at 08.00 h, 14.00 h, 20.00 h, and 02.00 h in randomized order, with 1 week between successive doses. There were differences in the pharmacokinetics of oxprenolol for the ratio between the apparent volume of distribution and systemic availability (P=0.04) and for elimination half-life (P=0.006). Both were lowest after administration at 14.00 h (163 (77) l and 1.2 (0.6) h; mean (SD)) and highest after administration at 02.00 h (229 (100) l, and 1.7 (0.6) h). The systolic blood pressure during exercise before oxprenolol did not vary with dosage time, but heart rate during exercise before intake was lowest before dosage time 08.00 h and highest before dosage time 20.00 h (P=0.03). The time-course of heart rate during exercise after oxprenolol was described by a model that incorporated the factors drug concentration and spontaneous diurnal variation. EC50 and Emax did not vary between dosage times. The spontaneous diurnal variation in heart rate during exercise was unaffected by oxprenolol, leading to an apparently greater effect of oxprenolol during the night than during the day.
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  • 45
    ISSN: 1432-1041
    Keywords: Metoprolol ; controlled-release formulation ; hydrochlorothiazide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers ; efficacy
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied a controlled-release formulation containing metoprolol 100 mg and hydrochlorothiazide 12.5 mg. We compared the pharmacokinetics of both substances and the pharmacodynamics of metoprolol with those of a conventional combination tablet. The controlled-release formulation gave less variable plasma metoprolol concentrations, Cmax 138 nmol·l−1 and Cmin 74 nmol·l−1, whereas for the conventional formulation the mean Cmax of metoprolol was 629 nmol·l−1 and the Cmin 20 nmol·l−1. Despite lower relative systemic availability (68%) for metoprolol from the controlled-release formulation and a smaller AUC, metoprolol from the controlled-release formulation produced a greater total effect, calculated as the area under the curve of the effect on exercise heart rate vs. time (303 vs. 259%·h; P〈0.05). Hydrochlorothiazide was rapidly absorbed from both formulations and the plasma concentration profiles were almost superimposable. Controlled-release metoprolol with hydrochlorothiazide combines effective β1-adrenoceptor blockade for 24 h without affecting the pharmacokinetics of hydrochlorothiazide.
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  • 46
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    European journal of clinical pharmacology 45 (1993), S. 195-196 
    ISSN: 1432-1041
    Keywords: Digoxin ; Amiloride ; Canrenoate ; inotropism ; healthy volunteers ; potassium sparing diuretics
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  • 47
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    European journal of clinical pharmacology 44 (1993), S. 57-62 
    ISSN: 1432-1041
    Keywords: Amoxapine ; Amitriptyline ; antidepressants ; cholinergic functions ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effects of single oral doses of amoxapine (100 mg and 200 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced double-blind crossover design. Amitriptyline significantly reduced salivation and it significantly attenuated both miosis evoked by locally applied pilocarpine and sweat secretion evoked by locally applied carbachol. Amoxapine did not significantly alter any of these measures. Neither treatment significantly altered the pupillary light reflex (latency, amplitude, or 75% recovery time). Resting pupil diameter was significantly reduced by the higher dose of amoxapine but was not affected by the other treatments. The higher dose of amoxapine significantly increased supine systolic blood pressure, but did not affect heart rate or diastolic blood pressure; amitriptyline had no effect on any of these cardiovascular measures. These results confirm the antimuscarinic effects of amitriptyline in man, but provide no evidence for antimuscarinic effects of amoxapine.
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  • 48
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    European journal of clinical pharmacology 44 (1993), S. 79-84 
    ISSN: 1432-1041
    Keywords: Methylphenidate enantiomers ; Narcoleptic patient ; oral administration ; healthy volunteers ; plasma concentration ; nonlinear kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of methylphenidate enantiomers after the oral administration of different doses of racemic methylphenidate to one patient with narcolepsy and to four healthy volunteers. The plasma concentrations of (+)-methylphenidate were much higher than those of (−)-methylphenidate after each dose in all subjects. In the patient the oral clearance (CL/f) of (+)-methylphenidate fell 3-fold and the area under the concentration-time curve (AUC) rose 7-fold when the dose was increased from 20 to 40 mg (from 0.27 to 0.53 mg·kg−1), in spite of the relatively constant terminal half-life of 2.6–2.7 h. Similar dose-dependency was also observed in the healthy volunteers in the dose range of 10–60 mg (0.12–0.77 mg·kg−1). The mean value of CL/f for the 40 mg dose was significantly lower than that for the 20 mg dose. The mean AUC of the (+)-isomer corrected to a dose of 10 mg increased significantly between the 20 mg and 40 mg doses. In the urine (+)- and (−)-ritalinic acid were excreted for 48 h after each dose as 32–37% and 34–40% of the dose respectively. The mean total recoveries (sum of enantiomers of methylphenidate and its metabolite, ritalinic acid) in the urine were relatively constant (63–78% of the doses), suggesting that the changes in AUC with dose may not be due to a change in the intestinal absorption of racemic methylphenidate. We conclude that the nonlinear kinetics of (+)-methylphenidate may be due to saturation of its presystemic elimination.
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  • 49
    ISSN: 1432-1041
    Keywords: Ibopamine ; adrenoceptor function ; chronic treatments ; healthy volunteers ; haemodynamics ; epinine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 18 healthy volunteers, in a double-blind placebo-controlled study, we investigated of whether 14 days treatment with a therapeutic dose of ibopamine (3×100 mg/day p.o.), respectively its active metabolite epinine, would desensitize lymphocyte β2- or platelet α2-adrenoceptors, or α1- and β-adrenoceptor mediated (phenylephrine-and isoprenaline infusions, respectively), changes in systolic and diastolic blood pressure and heart rate. Ibopamine-treatment, which resulted in peak plasma epinine concentrations of 4–5 nmol·l−1, neither affected resting heart rate or blood pressure, nor any of the α- or β-adrenoceptor parameters measured. Since in man in general long-term administration of α- and β-adrenoceptor agonists desensitizes α- and β-adrenoceptors, the lack of any α- and β-adrenoceptor desensitizing effect of ibopamine suggests that, in the dose employed (3×100 mg per day), ibopamine does not exert α- or β-adrenoceptor agonistic effect in humans.
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  • 50
    ISSN: 1432-1041
    Keywords: Nicorandil ; vasodilator ; continuous infusion ; blood pressure ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics and haemodynamic effects of nicorandil after a 12-h infusion. Nicorandil is a mixed vasodilator combining the actions of a nitrate and a potassium channel opener. Nicorandil was infused for 12 h in 21 healthy volunteers at rates of 0.05, 0.10, and 0.20 μg·kg−1·min−1 using a placebo controlled, crossover design. Systemic blood pressure, heart rate, electrocardiographic (ECG) intervals, and cardiac output (impedance cardiography) were measured supine and standing. Dose-related, steady-state plasma nicorandil concentrations occurred within 3 to 4 h. Nicorandil's pharmacokinetics were linear with dose. Four 0.20 μg·kg−1·min−1 nicorandil infusions were terminated early primarily because of moderate or severe headaches. There were no safety concerns (ECG intervals, laboratory assays). Blood pressure fell versus placebo only in the standing position and heart rate increased slightly (not significant). That is, standing blood pressure in the 6 to 12 h interval fell from baseline 8.0*/6.8, 1.6/5.1, and 9.8*/7.9* mmHg (systolic/diastolic, *=P〈0.05 versus placebo) at 0.05, 0.10, and 0.20 μg·kg−1·min−1 respectively. Cardiac output increased slightly above placebo at lower doses. Haemodynamic changes correlated poorly with plasma nicorandil concentrations. Similar total doses were less well-tolerated when extended over 12 h. We saw no evidence of pharmacodynamic tolerance to nicorandil within 12 h.
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  • 51
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    European journal of clinical pharmacology 44 (1993), S. 505-507 
    ISSN: 1432-1041
    Keywords: Adenosine ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 μg·kg−1 respectively) and after infusion of 200 μg·kg−1 in 10 min followed by 400 μg·kg−1 in 10 min. As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min−1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l). After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 μg·ml−1), but the mean clearance and half-life were significantly different (12.1 l·min−1 and 0.63 min respectively). In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.
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  • 52
    ISSN: 1432-1041
    Keywords: Savoxepine ; Neuroleptic drug ; dopamine D2 receptor antagonist ; positron emission tomography ; striatal receptor binding ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The extent and duration of striatal dopamine-D2 receptor occupancy by savoxepine in humans has been studied using positron emission tomography with [11C]-raclopride, in order to investigate why the anticipated favourable ratio between its extrapyramidal and antipsychotic effects was not achieved in practice. After 0.25 mg savoxepine, striatal D2 receptor occupancy peaked at 50–60% after 24–36 h and disappeared within 6 days. After doses of 0.1 mg to 0.5 mg, D2 receptor occupancy in the putamen and caudate nucleus increased from 20 to 70% 3–7 h after administration and amounted to 40 to 75% at the peak time (20–29 h). This suggests that cumulative D2 receptor blockade would occur if equal or increasing doses of savoxepine were given repeatedly. Extrapyramidal adverse-effects would be likely to occur under such circumstances. An adequate test of the theory that preference for hippocampal dopamine D2 receptors with afford a good therapeutic ratio requires an alternative dosing regimen.
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  • 53
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    European journal of clinical pharmacology 45 (1993), S. 37-39 
    ISSN: 1432-1041
    Keywords: Hexoprenaline ; Salbutamol ; extrapulmonary effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have investigated the cardiovascular and metabolic effects of multiple inhaled doses of salbutamol and hexoprenaline in 12 healthy volunteers. They inhaled 200 μg of salbutamol or hexoprenaline at 15 min intervals for 60 min from a metered dose inhaler (total dose 1000 μg). We measured heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval on the ECG, and plasma potassium at baseline, 10 min after each inhalation, and 30 and 60 min after the last inhalation. There was no difference in the effects of the two drugs on blood pressure, total electromechanical systole, or QTc interval. Salbutamol significantly increased heart rate compared with hexoprenaline. Hexoprenaline caused a significantly greater fall in plasma potassium compared with salbutamol.
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  • 54
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    European journal of clinical pharmacology 45 (1993), S. 539-543 
    ISSN: 1432-1041
    Keywords: Atenolol ; Bendrofluazide ; Psychomotor performance ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve normal male subjects received single oral doses of atenolol 100 mg (AT), bendrofluazide 5 mg (BFZ), combined atenolol 100 mg and bendrofluazide 5 mg (AT/BFZ), diazepam 5 mg (Dz), or one of two matching placebos, on each of 6 study days. Tests of psychomotor performance [digit symbol substitution (DSST), letter cancellation (LCT), continuous attention, choice reaction time (CRT), finger tapping, short-term memory, body sway], physiological measurements [critical flicker fusion (CFF), two-flash fusion (2FF)] and subjective assessments using visual analogue scales (VAS), were performed at 2 and 4 hours post-ingestion. Dz (active control) significantly worsened VAS scores at 2 h (+0.68) and reduced DSST scores at both 2 h (−15.0) and 4 h (−11.0). AT and BFZ given alone, each produced significant worsening of VAS at 2 h [AT +1.0; BFZ +1.38], but had no significant effects on performance. In combination however, AT/BFZ at 4 h produced significant impairment of DSST scores (−10.4), reduced finger tapping (−16.5) and increased involuntary rest pauses (+16.5). Despite these effects, no change in VAS scores occurred. In summary, we have demonstrated significant impairment of psychomotor performance in normal subjects with the AT/BFZ combination, which was not evident with the single agents and which occurred in the absence of a change in subjective awareness. These central effects may have important clinical implications for patients taking combined antihypertensive medication.
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  • 55
    ISSN: 1432-1041
    Keywords: Felodipine ; Nitrendipine ; Nifedipine ; enantiomers ; blood pressure ; heart rate ; concentration-effect relationship ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all 20 mg solution p.o.) on non-invasively measured blood pressure and heart rate were investigated in a randomised, double-blind, cross-over study in 12 normotensive, young, healthy males. Compared to baseline values, heart rate increased more after rac-felodipine treatment (+47% at maximum) than rac-nitrendipine (+40%) and nifedipine (+38%); only small and variable changes in blood pressure were observed with any of the drugs. The baseline-corrected area under the heart rate-time curve up to 4 h after the administration of rac-felodipine was 197% and 180% larger than after nifedipine and rac-nitrendipine treatment, respectively. The effects on heart rate could be fitted individually to a sigmoidal Emax-model without hysteresis for all drugs under investigation. The relative potencies of the unbound drugs for their indirect effects on heart rate were 1:7:43 for nifedipine, rac-nitrendipine and rac-felodipine, respectively. The active (S)-enantiomers of felodipine and nitrendipine appeared to be 9-and 60-times as potent as nifedipine in this respect, assuming no (inter)activity of the (R)-enantiomers. Individual and mean changes in blood pressure were small, they were not related to plasma concentrations, and did not differ between treatments.
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  • 56
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    European journal of clinical pharmacology 45 (1993), S. 303-305 
    ISSN: 1432-1041
    Keywords: Bambuterol ; Terbutaline ; Tremor ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bambuterol tablets, 10 and 20 mg, and terbutaline CR-tablets, 5 and 7.5 mg, have been compared for their capacity to produce subjectively determined tremor in a randomised, double-blind, cross-over study in 40 healthy volunteers. The duration of each treatment was one week, with an intervening washout period of at least 2 weeks. On the second and the last treatment days in each period, tremor was subjectively assessed on six occasions. In addition, an overall assessment of night and day tremor was made each morning and evening. Analyses were made for the second and last treatment days and during the treatment week. Paired comparisons for tremor during daytime showed a significant difference between the treatments, with the exception of bambuterol 20 mg and terbutaline 5 mg. Bambuterol 10 mg caused less tremor and terbutaline 7.5 mg caused more tremor than the other treatments. At the end of the week, the differences were smaller and were only significant when comparing bambuterol 10 mg with the 20 mg dose and with high dose terbutaline. Terbutaline 7.5 mg caused more tremor at night than the other treatments. The tremor experienced was generally mild, and after bambuterol 10 mg it was almost negligible (mean 0.13 after the first dose). Two subjects recorded a score of 3 after terbutaline 7.5 mg. The results indicate that, in doses equipotent with regard to bronchodilation, tremor is less pronounced after bambuterol as compared to controlled release tablets of terbutaline.
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  • 57
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    European journal of clinical pharmacology 42 (1992), S. 529-533 
    ISSN: 1432-1041
    Keywords: Fluvoxamine ; Amitriptyline ; antidepressants ; cholinergic functions ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have compared the effects of single oral doses of fluvoxamine (50 mg and 100 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced, double-blind, crossover design. Amitriptyline significantly reduced salivation, the miosis evoked by locally applied pilocarpine, and the sweat secretion evoked by locally applied carbachol. Fluvoxamine also significantly attenuated carbachol-evoked sweat gland activity, although to a smaller degree than amitriptyline; fluvoxamine did not significantly alter salivation or pilocarpine-evoked miosis. Neither treatment significantly altered the miotic responses evoked by brief light stimuli. Heart rate and blood pressure were not greatly affected by either treatment, although the fall in heart rate (erect posture) with placebo was significantly reduced by amitriptyline (100 mg). The results suggest that fluvoxamine has some antimuscarinic activity in man, but is considerably less potent in this respect than amitriptyline.
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  • 58
    ISSN: 1432-1041
    Keywords: NSAID ; Gastrotoxicity ; gastroscopy ; healthy volunteers ; ibuprofen ; ketoprofen ; aspirin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Endoscopic lesions of the gastric mucosa were evaluated in 12 healthy volunteers after administration of single doses of ketoprofen (25 mg), ibuprofen (200 mg) and aspirin (500 mg) in a randomized, double-blind, crossover study. The grades of the lesions (according to Lanza's scale) were lower after the administration of ketoprofen than aspirin and were comparable to ibuprofen. An endoscopic score 〉1 was observed in 3 cases after ibuprofen or ketoprofen, and in 8 cases after aspirin. At a time when low, single doses of NSAIDs are widely used as analgesics, gastroscopy makes it possible directly to assess the local agressivity of these molecules. In this way it was possible to demonstrate that the local toxicity of NSAIDs was lower than that of aspirin.
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  • 59
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    European journal of clinical pharmacology 42 (1992), S. 675-679 
    ISSN: 1432-1041
    Keywords: Tolbutamide ; Magnesium hydroxide ; chlorpropamide ; gastrointestinal absorption ; drug interaction ; healthy volunteers ; plasma glucose ; plasma insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide was examined in a total of 32 healthy volunteers in two separate, randomized parallel-group studies, with 16 subjects in each study. After an overnight fast, the first group of 8 volunteers ingested 500 mg tolbutamide or 250 mg chlorpropamide with 150 ml water, and the second group the same doses of the active drugs with 150 ml water containing 850 mg magnesium hydroxide. Magnesium hydroxide increased the area under the plasma tolbutamide concentration-time curve (AUC) from 0 to 1 h and from 0 to 2 h by 5-fold and 2.5-fold, respectively. The peak plasma concentration, peak time and total AUC were not significantly altered. The incremental insulin area and the decremental glucose area from 0 to 1.5 h were significantly larger in the magnesium hydroxide group than in the controls. The maximum insulin response to tolbutamide was increased fourfold by coadministration of magnesium hydroxide, and it occurred about 1 h earlier than in the control group. In addition, the maximum fall in plasma glucose concentration was attained about 1 h earlier in the antacid group. A tendency to an increased rate of chlorpropamide absorption was observed after magnesium hydroxide, but it did not appear to affect the insulin and glucose responses to chlorpropamide. It is concluded that magnesium hydroxide increased the early bioavailability of tolbutamide, resulting in enhanced insulin and glucose responses. A tendency toward accelerated chlorpropamide absorption by magnesium hydroxide was also observed, but the efficacy of chlorpropamide was unaffected.
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  • 60
    ISSN: 1432-1041
    Keywords: Atenolol ; Propranolol ; Pindolol ; transthoracic electrical bioimpedance ; cardiac output ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have evaluated Sramek's method of impedance cardiography as a non-invasive way of detecting the cardiovascular effects of drugs. We made cardiovascular measurements using the method during passive tilting and exercise 2 h after the oral administration of atenolol (50 and 100 mg), propranolol (40 and 80 mg), pindolol (5 and 10 mg), and placebo in seven separate studies involving eight healthy male volunteers. Equivalent doses of the pure antagonists atenolol (β1) and propranolol (β1, β2) produced similar reductions in heart rate, systolic blood pressure, and cardiac index, and increases in stroke volume and total peripheral resistance, particularly during exercise. In contrast the partial agonist pindolol produced increases in heart rate and cardiac index, and reductions in peripheral resistance at rest. During passive tilting and exercise pindolol reduced heart rate, but cardiac output and total peripheral resistance were unchanged except at the highest levels of exercise. The similar cardiovascular effects of atenolol and propranolol, but differing effects of pindolol, are consistent with reports using other methods of measurement. This suggests that impedance cardiography may have a place in the non-invasive assessment of the cardiovascular effects of drugs.
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  • 61
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    European journal of clinical pharmacology 42 (1992), S. 453-455 
    ISSN: 1432-1041
    Keywords: Insulin ; Atrial natriuretic factor ; natriuresis ; healthy volunteers ; renal function ; sodium metabolism ; water metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Changes in plasma insulin in response to a physiological or pathophysiological elevation in circulating atrial natriuretic factor (ANF) have been investigated. Plasma insulin, glucose, immunoreactive (ir) ANF, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), absolute and fractional excretion of sodium (FENa), have been measured in 14 volunteers before and during infusion of low doses of ANF or vehicle (V). Each subject received single-blind in a randomized sequence at 2 week-intervals: V alone, or ANF 4, 8 and 16 ng·kg−1·min−1, indused over 90 min. Plasma irANF was increased 2.5- to 11-fold during the ANF infusion as compared to the test with the vehicle. Plasma insulin did not change during V administration (baseline vs V: 22 vs 21 μU·ml−1) and was unchanged during ANF at 4, 8 and 16 ng·kg−1·min−1 (19, 19, 21 μU·ml−1, respectively). Blood pressure, ERPF and GFR were not affected, and diuresis, FENa and urinary Na excretion were increased significantly and dose-dependently during ANF, but not V infusion. Compared to baseline, ANF 4, 8 and 16 ng·kg−1·min−1 increased urinary Na excretion by 147, 241 and 446 μmol·min−1, respectively. The findings indicate that, in normal humans, an acute increase in irANF within or slightly above the physiological range, which modified natriuresis and diuresis, did not alter circulating plasma insulin.
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  • 62
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    European journal of clinical pharmacology 42 (1992), S. 55-59 
    ISSN: 1432-1041
    Keywords: Ebastine ; Clemastine ; H1-receptor antagonist ; psychomotor performance ; healthy volunteers ; vigilance ; cognitive performance adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of single oral doses of 10 and 20 mg ebastine were compared with placebo and 2 mg clemastine in a double-blind cross-over study in 16 healthy male volunteers. Clemastine produced the known pattern of changes, namely impairment of psychomotor performance, drowsiness, and a selective effect on cognitive processes. Earlier encoding in a perceptual stage was slowed whereas abstract classification processes were not affected. Electrophysiological measures of vigilance showed a general decrease in vigilance especially 2.5 and 4.5 h after dosing. In contrast at no time was any effect of ebastine different from that of the placebo. Ebastine 10 and 20 mg differed positively from clemastine in its effect on pursuit tracking, subjective rating of drowsiness and general discomfort. Ebastine 10 mg also differed positively from clemastine in the EEG features of vigilance. It is concluded that 10 and 20 mg ebastine were free from sedative adverse effects.
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  • 63
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    European journal of clinical pharmacology 42 (1992), S. 219-222 
    ISSN: 1432-1041
    Keywords: Thiamine ; pharmacokinetics ; analytical method ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A novel liquid chromatographic method for the determination of thiamine in plasma has been developed and has been used to study plasma thiamine concentrations after multiple dosage regimens for 11 days. The method involves purification, concentration and analytical separation of thiochrome on-line, using a switching column system. Ten healthy men were given 500 mg thiamine i.m. once a day (Group 1) and ten were given 250 mg p.o. every 12 h (Group 2). The times to reach steady state (7 and 5.6 days for Groups 1 and 2, respectively) were not different (P〉0.05). The mean elimination half-life was 1.8 days. The mean minimum steady-state concentration after the oral regimen (23 μg·l−1) was 78% of that after the intramuscular regime (29 μg·l−1).
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  • 64
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    European journal of clinical pharmacology 42 (1992), S. 235-236 
    ISSN: 1432-1041
    Keywords: Cisapride ; Paracetamol absorption ; gastric emptying ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have measured the effect of oral cisapride on paracetamol absorption in 12 healthy volunteers in a double-blind placebo-controlled study. Volunteers received paracetamol plus placebo, paracetamol plus cisapride 10 mg and paracetamol plus cisapride 20 mg. Mean plasma paracetamol AUC at 60 min were 1070, 1051 and 1031 μg·min·ml−1 and maximum paracetamol concentrations were 31.5, 29.3 and 27.4 μg·ml−1 respectively (no significant differences). There was no difference also in time to maximum paracetamol concentration [median (range) 30 (15–120), 30 (15–90) and 30 (15–60) min, respectively].
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  • 65
    ISSN: 1432-1041
    Keywords: Ibopamine ; Isosorbide-5-mononitrate ; pharmacokinetics ; drug interaction ; healthy volunteers ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between isosorbide-5-mononitrate (5-ISMN) and epinine, the active metabolite of ibopamine, has been investigated in 8 healthy male subjects given single doses of 200 mg ibopamine and 20 mg 5-ISMN, separately and together. The plasma 5-ISMN concentration-time profile was the same whether 5-ISMN was administered concomitantly with ibopamine or alone [AUC(o-t): 2.24 μg·ml−1·h after 5-ISMN alone, 2.16 μg·ml−1·h after 5-ISMN + ibopamine]. The plasma concentrations of total and free epinine and the urinary recovery of total epinine, homovanillic acid and dihydroxyphenylacetic acid, too, were not different when ibopamine was administered alone or concomitantly with 5-ISMN. The intake of ibopamine did not change the blood pressure and heart rate. The decrease in diastolic blood pressure induced by 5-ISMN was not influenced by concomitant intake of ibopamine. The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between 5-ISMN and ibopamine.
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  • 66
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    European journal of clinical pharmacology 43 (1992), S. 35-38 
    ISSN: 1432-1041
    Keywords: Theophylline ; Verapamil ; drug interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Results of previous studies suggest that the theophylline-verapamil drug interaction may be dependent on verapamil dose. Therefore, in a randomized four-way cross over study, 12 healthy males received theophylline, as a single intravenous dose of aminophylline, alone (phase I) and after a four day regimen of oral verapamil 40 mg (phase II), 80 mg (phase III), and 120 mg (phase IV) every 8 h. Serial blood samples were collected over a 24 hour period for determination of serum theophylline concentration and subsequent pharmacokinetic analysis. Mean theophylline AUC for phase I–IV was 93.6, 105.6, 110.8, 120.1 mg · h · l−1, respectively. Mean theophylline clearance for phase I–IV was 3.89, 3.59, 3.35, and 3.20 l · h−1, respectively. The changes in AUC, clearance, andλ z were linearly correlated to verapamil dose. These results suggest that the inhibitory effect of verapamil on the pharmacokinetic disposition of theophylline is directly related to verapamil dose.
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  • 67
    ISSN: 1432-1041
    Keywords: Tiopronin ; 2-mercaptopropionic acid ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of tiopronin and its principal metabolite, 2-mercaptopropionic acid (2-MPA) in healthy volunteers after the oral administration of 500 mg (2 Acadione® tablets), followed by simultaneous assay of the two compounds in plasma over a period of 48 h using a new method (emission of fluorescence after HPLC and post-column derivatization by pyrene-maleimide). The absorption of tiopronin was slow (tmax between 4 and 6 h) and the plasma concentrations subsequently fell biexponentially. The principal metabolite 2-MPA appeared later in the plasma (tmax between 10 and 12 h after a lag-time of 3 h) then disappeared monoexponentially. About 15% of the tiopronin was metabolized to 2-MPA.
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  • 68
    ISSN: 1432-1041
    Keywords: Noradrenaline ; Adrenaline ; catecholamines ; pharmacokinetics ; healthy volunteers ; IV infusion
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Noradrenaline and adrenaline were infused IV at 5 different rates (0.01–0.2 μg · kg · min− for 30 min to volunteers. The plasma catecholamine concentrations were determined by HPLC and electro-chemical detection. At the highest infusion rate, the arterial and venous plasma concentrations of noradrenaline increased from 1.18 to 44.1 nmol · l−1and from 1.14 to 31.9 nmol · l−1, respectively, and of adrenaline from 0.29 to 23.9 nmol · l−1 and from 0.28 to 19.3 nmol · l−1 respectively. The peripheral venous plasma concentration of noradrenaline averaged 76% of the arterial concentration, and of adrenaline it was 73%. There was a linear relationship between the peripheral venous and arterial plasma noradrenaline and adrenaline concentrations at therapeutic doses.
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  • 69
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    European journal of clinical pharmacology 43 (1992), S. 273-276 
    ISSN: 1432-1041
    Keywords: Molsidomine ; slow release ; pharmacokinetics ; in vitro/in vivo correlation ; pharmacokinetics ; healthy volunteers ; dissolution profile
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (〉 5 ng · ml−1 were not maintained over 24 h by this slow release formulation.
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  • 70
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    European journal of clinical pharmacology 43 (1992), S. 445-447 
    ISSN: 1432-1041
    Keywords: Captopril ; Digitoxin ; impedance cardiography ; drug interaction ; healthy volunteers ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chronic oral administration of 0.07 mg digitoxin o. d. for up to 58 days to 12 healthy volunteers caused a small drop in mean heart rate HR (95 % CI: −7.9 to −1.6 beats · min−1), in mean diastolic blood pressure (95 % CI: −8.3 to −0.4 mm Hg), shortening of the QTc-interval (95 % CI: −42 to −19 ms), shortening of the HR-corrected pre-ejection period PEPc (95 % CI: −16 to −1 ms) and electromechanical systole QS2c (95 % CI: −25 to −1 ms), and an increase in the impedance cardiographic Heather index (dZ/dtmax/RZ, 95 % CI: 0.3 to 4.3) relative to the baseline measurements before digitalisation. The concomitant administration of 25 mg oral captopril b. d. did not significantly alter these responses relative to the concomitant double-blind administration of placebo, nor did it alter the pharmacokinetic characteristics of plasma digitoxin at steady state. Thus, no relevant change in the pharmacokinetic and pharmacodynamic characteristics of chronically administered digitoxin were induced by concomitant treatment with captopril.
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  • 71
    ISSN: 1432-1041
    Keywords: Adinazolam ; Triazolobenzodiazepines ; N-desmethyladinazolam ; psychomotor performance ; uricosuric activity ; active metabolite ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design. No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST. These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.
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  • 72
    ISSN: 1432-1041
    Keywords: Nimodipine ; Cimetidine ; Ranitidine ; pharmacokinetic interaction ; cytochrome P-450 ; healthy volunteers ; haemodynamics ; drug interation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A possible interaction between the calcium antagonist nimodipine and the H2-receptor antagonists cimetidine and ranitidine has been investigated in two separate studies in healthy subjects. In eight young volunteers the concomitant administration of nimodipine 30 mg t.i.d. and cimetidine 1000 mg/d for 7 days led to a significant increase of the relative bioavailability of nimodipine. The changes in the pharmacokinetic parameters were not accompanied by discernible haemodynamic effects or any change in the tolerability of nimodipine. There was no evidence of any significant change in the steady-state pharmacokinetics of nimodipine during five days of combined treatment with 30 mg t.i.d. nimodipine and ranitidine 300 mg/d given as single morning dose to twelve healthy, elderly subjects. Analysis of haemodynamics, clinical chemistry and tolerance also did not reveal any difference between the two treatment periods.
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  • 73
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    European journal of clinical pharmacology 42 (1992), S. 333-335 
    ISSN: 1432-1041
    Keywords: DuP-753 ; Uricosuria ; angiotensin II receptor antagonist ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The uricosuric effect of DuP-753, a novel, specific angiotensin II receptor antagonist, has been explored in a healthy male Japanese volunteers, given single oral doses of 25, 50, 100 or 200 mg (n=6), or 100 mg (n=6) or placebo (n=3) once daily for 7 consecutive days. In the single-dose study, serum uric acid measured at 4 h after dosing showed a dose dependent decrease; the reductions from the corresponding pre-dose values were: 0.32 (25 mg), 0.77 (50 mg), 1.25 (100 mg) and 1.33 mg dl−1 (200 mg). The urinary excretion of uric acid within the first 4 h after treatment was also increased in a dose-dependent manner, whereas the urinary excretion of creatinine remained unchanged. In the multiple-dose study, DuP-753 significantly decreased the serum uric acid concentration measured 4 h both after the first (pre-dose value: 5.68 vs 4 h after: 4.48 mg·dl−1) and last administrations (4.42 mg·dl−1). Simultaneously, the ratio of urinary uric acid to creatinine excretion was significantly increased within the first 4 h both after the first (DuP-753: 1.190 vs placebo: 0.576) and last administrations (1.02 vs 0.576). The findings suggest that DuP-753 posesses a uricosuric effect both after single and multiple doses in healthy subjects. The effect should be further examined in hypertensive patients.
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  • 74
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    European journal of clinical pharmacology 42 (1992), S. 389-393 
    ISSN: 1432-1041
    Keywords: Adverse events ; Phase I studies ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary All the clinical, laboratory and electrocardiographic adverse events detected during 24 Phase I studies in the same unit over a 5 y period are reported here. 430 healthy male volunteers were involved, corresponding to 5488 days of follow-up. The overall incidence of adverse events was 13.5%, with a significant difference between active drug (15.3%) and placebo (7.4%) treatments. There were 69 distinct types of adverse events. Headache was the most frequent symptom (2%). There were severe adverse events in 20 cases (0.36%), with an incidence of 20/430 per subject (4.6%). There were no deaths or life-threatening events. Although the main objective of Phase I studies is to determine the maximum dose tolerated, cause-effect relationships with adverse events are hard to establish, because of the frequency of adverse events with placebo, and because of the limited number of subjects included such studies.
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  • 75
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    European journal of clinical pharmacology 42 (1992), S. 499-505 
    ISSN: 1432-1041
    Keywords: Suriclone ; Diazepam ; Ethanol ; psychomotor performance ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of diazepam (5 mg t.i.d.), suriclone (0.2 and 0.4 mg t.i.d.) and placebo (t.i.d.) were assessed in 12 normal, healthy volunteer subjects after a single dose and after treatment for a period of 8 days. A battery of physiological, psychomotor and subjective tests was administered on days 1 and 8 both before and after drug and after a measured dose of ethanol. The effects of diazepam on the EEG were characteristic of benzodiazepines — a decrease in the slow frequency wave-bands, an increase in fast frequency wave-band and diminished evoked response amplitude. Suriclone had similar effects on fast frequency activity and evoked response amplitude but, in contrast to diazepam, also increased the slow frequency wave-bands after 7 days treatment. Some improvements in performance were seen with suriclone on critical flicker fusion, tapping speed, spiral maze and digit cancellation. In contrast, suriclone impaired performance to a greater extent than diazepam on digit symbol substitution and symbol copying. Body sway was also enhanced by suriclone to a greater extent than diazepam. Subjective ratings for mood and adverse-effects showed few differences between suriclone or diazepam. However, suriclone caused greater gastro-intestinal disturbances than diazepam, especially after ethanol, and subjects rated themselves as more antagonistic and more irritable on suriclone. Ratings for calmness suggested that in contrast to diazepam, suriclone had no anxiolytic effect. Several of the parameters tested showed a build up of effect with diazepam over the treatment period which was not seen with suriclone. It is suggested that this difference may be due to differences in elimination rate. There was little evidence of interaction with ethanol with any of the treatments, most effects being simply additive. The profile of effects of suriclone was similar to that of diazepam but with some differences. The effects of suriclone were usually dose-related, the 0.4 mg dose having equivalent or greater effects than diazepam.
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  • 76
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    European journal of clinical pharmacology 43 (1992), S. 209-210 
    ISSN: 1432-1041
    Keywords: Moxonidine ; Hydrochlorothiazide ; pharmacokinetics ; drug interaction ; steady-state ; healthy volunteers ; adverse effects
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  • 77
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    European journal of clinical pharmacology 41 (1991), S. 201-206 
    ISSN: 1432-1041
    Keywords: Nifedipine ; Nicardipine ; Atenolol ; cardiac output ; impedance cardiography ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A placebo controlled double blind crossover study was performed in 12 healthy volunteers to compare the cardiovascular effects of single oral doses of nifedipine (5, 10 and 15 mg) and nicardipine (20 and 30 mg) in the presence of atenolol 100 mg. Haemodynamic measurements were made by transthoracic electrical bioimpedance cardiography (TEBC) 2 h following drug administration during passive tilting, graded bicycle exercise (30–150 W), and recovery from exercise. In the absence of calcium channel blockade, atenolol reduced mean blood pressure, heart rate, and cardiac index, and increased stroke volume, peripheral resistance, pre-ejection period, and ventricular ejection time, particularly during and after exercise. In comparison with atenolol alone, addition of nifedipine or nicardipine reduced peripheral resistance but did not produce significant changes in stroke volume, cardiac output, dZ/dt[max], pre-ejection period (PEP), Ventricular ejection time (VET), PEP/VET, or Heather index at any point in the experiment. Similar reductions in peripheral resistance were produced by nifedipine 10 mg and nicardipine 20 and 30 mg. These apparently equivalent doses of nifedipine and nicardipine had similar effects on stroke volume, cardiac index, PEP/VET and Heather index. Thus the increases in ventricular performance previously demonstrated in association with nifedipine and nicardipine therapy were not observed in the presence of β-adrenoceptor blockade. Under these conditions no important differences have been observed in the cardiovascular effects of these two calcium channel blockers.
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  • 78
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    Keywords: Loperamide ; Intestinal perfusion ; absorption ; transit time ; healthy volunteers ; intestinal transport
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Jejunal perfusion was performed in 12 healthy volunteers to evaluate the dose dependent effects of loperamide on intestinal absorption, stimulated secretion and transit. In 6 volunteers intestinal perfusion of the jejunal segment with isotonic NaCl solution was followed by addition of loperamide in increasing doses (2–8 mg·l−1). The volunteers were pretreated with 1 mg·l−1 prostaglandin E2 (PgE2) in the perfusate before addition of 4 mg·l−1 loperamide. Phenolsulphonphtalein (PSP) boluses (2 ml) were given to measure mean transit time (MTT). Loperamide 2 mg·l−1 converted the minor secretion after perfusion with the standard solution (water −1.45 ml·min−1, Na −0.09 and Cl −0.04 mmol·min−1) to absorption (water 0.93 ml·min−1, Na 0.23, Cl 0.25 mmol·min−1) within 15 min. Higher doses of loperamide did not increase absorption. The addition of PgE2 induced net secretion of water (−4.48 ml·min−1) and electrolytes (Na −0.57, Cl −0.51 mmol·min−1). Loperamide 4 mg·l−1 significantly diminished the PgE2-induced net secretion by approximately 50%. Loperamide dose dependently increased the MTT from 6 (2 mg·l−1) to 13.3 min (8 mg·l−1). MTT was still delayed 60 min after a wash out period (10.5 min). It is concluded that loperamide had a dual effect or intestinal activities stimulating absorption and prolonging intestinal transit time with rising doses.
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  • 79
    ISSN: 1432-1041
    Keywords: Calciumantagonists ; Oesophageal motility ; oesophageal pharmaco-manometry ; lower oesophageal sphincter pressure ; healthy volunteers ; dihydropyridines ; nifedipine ; nifedipine ; nisoldipine ; nitrendipine ; nimodipine ; side ; effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies. Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30 min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline (−15 min) and in parallel with the manometric measurements. Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24% by nifedipine and 17% by nimodipine, whereas the effects of nitrendipine (decrease of 15%) and nisoldipine (9%) were not significant. Nifedipine significantly decreased by 17% the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r=0.92, nitrendipine r=0.80 and nisoldipine r=0.79. Nimodipine showed no such correlation. It is concluded that among the calcium antagonists studied, nifedipine exerted the strongest effect on oesophageal smooth muscle function, so it appears to be the most suitable compound for the treatment of primary motor abnormalities of the oesophagus.
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  • 80
    ISSN: 1432-1041
    Keywords: Calcium antagonist ; Doppler techniques ; regional haemodynamics ; cardiac effects ; healthy volunteers ; SR 33 557 ; heart rate
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic and regional haemodynamic and cardiac effects of two oral doses (100 and 300 mg) of a new sulphone-indolizine calcium antagonist SR 33 557 (SR) and a placebo were non invasively investigated in a double-blind, cross-over study in 6 healthy male volunteers. Arterial pressure, heart rate, cardiac output, brachial and carotid artery diameters and flows and PR and QT intervals were studied. Stroke volume, total peripheral and forearm vascular resistance, regional cardiac output distribution indices and corrected QT intervals were calculated. SR did not produce any significant modification in systemic haemodynamics, although arterial pressure and cardiac output tended to decrease slightly after 300 mg. In contrast, at the regional level, ST produced strong vasodilatation and significantly increased brachial and carotid blood flow. SR-induced vasodilation affected only the arterioles, as shown by a significant decrease in forearm vascular resistance, but not the large arteries, as shown by lack of change in the brachial and carotid artery diameters. SR-induced vasodilation preferentially affected the brachial rather than the carotid vascular bed, resulting in a redistribution of cardiac output towards the musculo-cutaneous territories. SR caused a marked and long-lasting decrease in heart rate, but it did not affect the auriculo-ventricular conduction time.
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  • 81
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    European journal of clinical pharmacology 41 (1991), S. 11-16 
    ISSN: 1432-1041
    Keywords: Budesonide ; Prednisolone ; calcium ; phosphate ; healthy volunteers ; osteoporosis ; mineral metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomized, double-blind crossover study, the effects of 0.8, 1.6 and 3.2 mg/day inhaled budesonide and 5, 10 and 20 mg/day oral prednisolone on mineral metabolism were compared. Twelve healthy subjects (4 m, 8 f) were treated for 1 week at each dosage level, the graduated dosages being given in ascending order. Budesonide and prednisolone were given twice daily and once daily, respectively, which reflects the schedules common in clinical practice. Serum calcium and the regulatory hormones of calcium metabolism (parathyroid hormone, vitamin D metabolites and calcitonin) were not changed either by prednisolone or budesonide. Prednisolone significantly increased 24 h and 08.00 h fasting urinary calcium excretion and decreased renal calcium reabsorption, while budesonide had little or no effect on urinary calcium loss and increased renal reabsorption at the highest dose level. Both drugs significantly increased renal phosphate reabsorption and serum phosphate levels, but prednisolone caused greater increases than budesonide. In conclusion, during short-term treatment with the dosages used, inhaled budesonide had less effect on calcium and phosphate metabolism than oral prednisolone, and so it may have a lesser action on the skeleton of the type contributing to osteoporosis during long-term treatment.
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  • 82
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    European journal of clinical pharmacology 40 (1991), S. 71-75 
    ISSN: 1432-1041
    Keywords: Isosorbide-5-mononitrate ; sustained-release formulation ; pharmacokinetics ; cardiovascular effects ; chronopharmacology ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 healthy male subjects the pharmacokinetics and haemodynamic effects of sustained-release isosorbide-5-mononitrate 60 mg (IS-5-MN) were studied after oral administration at two different times in the day (08.00 h and 20.00 h). Effects on blood pressure and heart rate after 3 min standing upright were measured in relation to the individual circadian control values. The pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) did not differ after morning and after evening dosing, tmax being 5.2 h and 4.9 h, respectively. In contrast, the cardiovascular effects of IS-5-MN were clearly circadian phase-dependent. The maximum decrease in blood pressure decrease and increase in heart rate occurred significantly earlier after the evening (BPsys 2.8 h; BPdia 2.9 h; HR 3.8 h) than after the morning dose (BPsys 5.0 h; BPdia 6.0 h; HR 5.2 h). Thus, the peak haemodynamic effects coincided with the peak drug concentration after the morning dose, whereas the peak effect was in advance of the peak drug concentration after the evening dose of IS-5-MN. The data provide evidence of circadian phase-dependency in the dose-response relationship of oral IS-5-MN.
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  • 83
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    European journal of clinical pharmacology 40 (1991), S. 135-139 
    ISSN: 1432-1041
    Keywords: Atenolol ; bisoprolol ; β-adrenoceptor ; cardioselectivity ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A dose-ranging study was performed to compare the β1-adrenoceptor selectivity of bisoprolol with that of atenolol and nadolol. Seven normal subjects (mean age 26 y) were given single oral doses of bisoprolol 5 mg (B5), 10 mg (B10), 20 mg (B20); atenolol 50 mg (A50), 100 mg (A100); nadolol 40 mg (N40); and placebo (PL), in a single blind randomised cross-over design. β2-adrenoceptor responses were assessed by attenuation of finger tremor and cardiovascular responses to graded isoprenaline infusions. Dose-response curves were constructed, and doses of isoprenaline required to increase finger tremor by 100% (IT100), heart rate by 25 beats/min (IH25), SBP by 25 mm Hg (IS25), cardiac output by 35% (IC35), and decrease DBP by 10 mm Hg (ID10), after each treatment were calculated. These indices were compared with placebo response and expressed as dose-ratios. Exercise heart rate (EHR) was used to assess β1-adrenoceptor blockade. There were dose-related increases in plasma concentrations of bisoprolol and atenolol. Reduction of EHR was significantly less with B5 (16.8%) in comparison with all other treatments: B10 21.9%, B20 23.1%; A50 22.5%, A100 22.6%; N40 22.9%. There were small but significant reductions in isoprenaline-induced tachycardia with bisoprolol and atenolol, although mean dose-ratios were considerably less in comparison with N40 (IH25 dose-ratios): B5 2.55, B10 3.18, B20 3.93, A50 2.91, A100 4.89, N40 17.23. There were similar patterns for the other isoprenaline responses. These results show that conventional doses of bisoprolol (10 mg) and atenolol (50 mg) produced equal antagonism of β1 and β2-adrenoceptors, and therefore possess equal degrees of β1-adrenoceptor selectivity. Increasing doses of bisoprolol and atenolol were associated with partial loss of selective β1-adrenoceptor blockade, although antagonism of β2-adrenoceptors was significantly less compared with the effects of nadolol.
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  • 84
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    European journal of clinical pharmacology 40 (1991), S. 221-223 
    ISSN: 1432-1041
    Keywords: Digoxin ; digitoxin ; pharmacodynamic differences ; colour vision ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Animal studies suggest that for the same inotropism hydrophilic cardiac glycosides produce greater depression of atrioventricular (AV) conduction than lipophilic ones. This has been explained on the basis of a greater vagomimetic effect with hydrophilic agents and a greater sympathomimetic effect with lipophilic agents. In this randomized, cross-over study we investigated the effects of placebo, digoxin (relatively hydrophilic), and digitoxin (relatively lipophilic) in twelve healthy volunteers. For both drugs steady-state serum concentrations in the mid-therapeutic range were achieved. Both drugs produced the same positive inotropic effect as measured by systolic time intervals (QS2c). There was a trend for digoxin to have a greater effect on AV conduction than digitoxin. After atropine or propranolol there was no difference between the effect of the two cardiac glycosides on AV conduction. No significant effects on colour vision were seen. We conclude that, there do not seem to be pharmacodynamic differences between digoxin and digitoxin at mid-therapeutic serum concentrations.
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  • 85
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    European journal of clinical pharmacology 40 (1991), S. 317-318 
    ISSN: 1432-1041
    Keywords: Verapamil ; atropine ; calcium antagonists ; anticholinergic ; heart-rate ; atrio-ventricular conduction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The calcium antagonist falipamil, a chemical congener of verapamil, has anticholinergic properties. It was decided to study the interaction of verapamil with the anticholinergic drugs, atropine and pirenzepine, using healthy male volunteers. After atropine alone a significant tachycardia developed at 2 min and remained significant up to 90 min. Verapamil pretreatment followed by atropine administration resulted in a significantly greater tachycardia. Pirenzepine alone caused a bradycardic response which was accentuated after verapamil pretreatment. It is postulated that short term verapamil administration is accompanied by reflex activation of the sympathetic nervous system which does not manifest with a tachycardia owing to combined influence of verapamil and vagus on the sino-atrial node. Reduction of vagal tone with atropine treatment results in sympathetic overriding of the sino-atrial suppression, thus causing an additive tachycardia. The clinical use of atropine for prolonged verapamil-induced atrio-ventricular conduction is supported by these results.
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  • 86
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    European journal of clinical pharmacology 41 (1991), S. 109-113 
    ISSN: 1432-1041
    Keywords: Amlodipine ; Insulin sensitivity ; serum lipids ; insulin secretion ; healthy volunteers ; blood pressure ; adverse events
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The sensitivity of peripheral tissues to insulin is of pathophysiological, therapeutic and possibly also of prognostic relevance. Calcium channel blockers are widely used in the treatment of cardiovascular disorders that are commonly associated with decreased insulin sensitivity (SI). To evaluate the effects of calcium channel blokkade on SI, glucose homoeostasis and lipid profiles, studies were made of SI (determined by the Minimal Model Method of Bergman), basal glucose and insulin levels, serum total triglyceride (Tg) and lipoprotein cholesterol (C) fractions and certain other variables in 38 healthy young men (24 y) during placebo and after 3 weeks of calcium channel blockade with amlodipine 5 mg once daily. Measurements were made after 3 days on a standard diet (2200 kcal · day−1, 45% carbohydrates, 40% fat and 15% proteins) and after an overnight fast. Compared to placebo, amlodipine decreased supine systolic blood pressure (P〈0.01). Heart rate, body weight and 24 h urinary sodium excretion were unaltered, and so were fasting plasma glucose (placebo vs amlodipine: 4.86 vs 4.83 mmol·1−1, respectively) and insulin levels (7.7 vs 7.9 μU·ml−1), SI (10.5 vs 9.6·10−4 × min−1 pro μU·ml−1), serum total Tg, C and lipoprotein C fractions. The findings demonstrate unchanged insulin sensitivity and secretion, as well as lipoprotein regulation, during maintenance administration of 5 mg amlodipine daily to healthy young men.
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  • 87
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    Keywords: Atrial natriuretic peptide ; P-ANP ; Hormonal effects ; Angiotensin II ; aldosterone ; arginine vasopressin ; PgE2 ; cGMP ; renal plasma flow ; urinary sodium excretion ; healthy volunteers ; blood pressure ; renal tubular function ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of an analogue of atrial natriuretic peptide (P-ANP) on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary flow rate, urinary sodium excretion, tubular function estimated by the lithium clearance technique, and plasma levels of sodium and water homeostatic hormones, has been studied in 40 healthy males. Placebo or P-ANP 0.3, 1.5, or 3.0 μg·kg−1 bwt were given as an intravenous bolus injection to different groups. P-ANP did not cause any immediate change in GFR or RPF, but significant dose-dependent increases in filtration fraction, urinary flow rate and urinary excretion rate of sodium were detected during the first 30 min after administration. Proximal absolute and fractional tubular reabsorption and distal absolute tubular reabsorption of sodium did not change after injection of P-ANP, while the distal fractional reabsorption of sodium was reduced in a dose dependent manner during the first 30 min. Plasma angiotensin II and aldosterone were significantly increased 30 and 150 min after dosage, whereas plasma atrial natriuretic peptide, plasma arginine vasopressin, and urinary excretion of prostaglandin E2 were unchanged. Cyclic guanosine monophosphate both in plasma and urine were increased in a dose-dependent manner. P-ANP cause a significant reduction in diastolic blood pressure and an increase in pulse rate. Two subjects had vasovagal syncope 30–60 min after injection of P-ANP. It is concluded that P-ANP has natriuretic, diuretic and hypotensive properties in healthy man.
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  • 88
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    European journal of clinical pharmacology 40 (1991), S. 355-362 
    ISSN: 1432-1041
    Keywords: Clomipramine ; alprazolam ; psychomotor performance ; cognitive effects ; adverse effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of a 10 day administration of clomipramine (25–50 mg t.i.d.), alprazolam (0.25–0.75 mg t.i.d.) and placebo were assessed in normal volunteers in a double-blind cross-over study. A battery of physiological, psychomotor and cognitive tests was administered both before and 3 h after drug on days 1, 5 and 10. The effects of alprazolam on EEG and evoked potentials were characteristic of benzodiazepines; clomipramine had little effect. In contrast, reaction speed was markedly slowed by clomipramine but little affected by alprazolam. Neither drug produced any accumulation of effect on a verbal recall task but neither did tolerance develop to the acute impairments produced by active treatments. Alprazolam produced an increase in levels of forgetting, especially on day 5. Subjective ratings for mood and bodily symptoms were adversely affected by clomipramine but little altered by alprazolam. It is suggested that some of the differences between drug treatments may be due to differences in the speed of onset of tolerance.
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  • 89
    ISSN: 1432-1041
    Keywords: Lisuride ; pharmacokinetics ; prolactin concentrations ; healthy volunteers ; adverse effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 μg lisuride hydrogen maleate as an aqueous solution. After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml·min−1·kg−1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration. The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.
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  • 90
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    European journal of clinical pharmacology 41 (1991), S. 147-152 
    ISSN: 1432-1041
    Keywords: Propoxyphene-Ethanol Interaction ; bioavailability ; healthy volunteers ; psychomotor performance drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between a single oral dose of 130 mg propoxyphene and 0.5 g/kg body weight ethanol was investigated in 12 healthy male volunteers by 9 objective performance tests, 8 visual analogue self-rating scales and the measurement of plasma propoxyphene, norpropoxyphene and ethanol concentrations, using a double-blind threeway crossover design. Volunteers were each given one of three treatments, propoxyphene + ethanol, placebo + ethanol and propoxyphene alone, separated by a two week interval. The performance tests were completed before and 1.25 and 4 h after drug intake, and the self-rating scales before and 1.25, 4 and 10 h after it. Ethanol was shown to enhance the bioavailability of propoxyphene by 25% probably by reducing its first-pass metabolism. However, despite this pharmacokinetic effect no pharmacodynamic interaction was found. Subjective ratings disclosed that the effect of ethanol on physical and mental sedation predominated over the effects of propoxyphene.
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  • 91
    ISSN: 1432-1041
    Keywords: Trandolapril ; ACE inhibition ; pharmacodynamics ; duration ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacological activity and safety of the new angiotensin converting enzyme (ACE) inhibitor trandolapril (RU 44570) has been evaluated in ten healthy male volunteers given 2 mg once daily for seven days. Assessment criteria included evaluation of plasma ACE and renin activity and aldosterone levels in the supine and standing positions, monitoring of blood pressure, heart rate and electrocardiogram, routine blood and urine laboratory tests, and evaluation of adverse effects. Plasma ACE activity (both in the supine and standing positions) was significantly lower after the first dose and was almost completely suppressed after 7 days of treatment. Plasma renin activity with the subjects in both positions was significantly increased at the end of treatment. Plasma aldosterone did not vary significantly, except for an increase in the standing position after 7 days of washout. No significant changes occurred in blood pressure, heart rate, electrocardiogram, blood or urine laboratory tests. No adverse effects were reported, in particular, no orthostatic hypotension, cough or episodes of bronchospasm occurred. It is concluded that oral trandolapril 2 mg o.d. is an effective and long-lasting ACE inhibitor with a good safety profile on repeated dosing. Further studies are warranted to investigate its therapeutic application as well as its safety profile after long-term administration.
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  • 92
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    European journal of clinical pharmacology 40 (1991), S. 83-85 
    ISSN: 1432-1041
    Keywords: Noberastine ; antihistamine ; H1-antagonist ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihistaminic effects of 7 days treatment with each of three doses of noberastine (10, 20 and 30 mg) were compared to placebo in 12 healthy male volunteers. The antihistaminic activity was assessed from the inhibition of weal and flare formation after intradermal histamine injections. For both weal and flare there was a highly significant effect of treatment with each of the three doses of noberastine, compared to placebo. The 30 mg daily dose produced the maximum inhibition of weal and flare. The daily mean values for the assessment of sedation by visual analogue scales at 09.00 h, 15.00 h and 21.00 h showed no significant treatment, or order, effect for any of the three doses of noberastine compared to placebo. The mean steady-state plasma concentrations of noberastine were significantly higher with increasing daily doses of noberastine (trough concentrations: 1.0, 1.6 and 2.2 ng·ml−1; peak concentrations: 3.5, 13.4 and 20.9 ng·ml−1 for 10, 20 and 30 mg daily dose, respectively). The percentage weal inhibition correlated (r=0.77) with steady-state noberastine plasma trough levels. The percentage flare inhibition showed a weaker correlation (r=0.35) with steady-state noberastine plasma trough levels.
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  • 93
    ISSN: 1432-1041
    Keywords: Glucocorticosteroids ; cortisol ; androgens ; osteocalcin ; alkaline phosphatase ; hydroxyproline ; budesonide ; prednisolone ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of inhaled budesonide (BUD) and oral prednisolone (PRED) on markers of bone turnover and adrenal function were compared in a randomized, double-blind, double-dummy, crossover study. Twelve healthy subjects were treated for one week with 0.8, 1.6 and 3.2 mg/day BUD and 5, 10 and 20 mg/day PRED, the three doses being given in ascending order. Plasma cortisol and adrenal cortical androgens showed a significantly decreasing trend with the increasing doses of both drugs, although PRED caused a significantly greater decrease than BUD. Osteoblast function, reflected by serum osteocalcin and alkaline phosphatase was significantly reduced by PRED, but BUD had a significantly different effect as it affected only osteocalcin. Urinary hydroxyproline/creatinine, a marker of bone resorption, was not changed by either drug. The average potency ratio for equivalent systemic effects was PRED:BUD 3.9:1. During short-term treatment at equivalent anti-asthmatic doses, BUD has significantly less effect on adrenal function and bone turnover than PRED, and it may carry less risk of bone complications during long-term treatment.
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  • 94
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    European journal of clinical pharmacology 40 (1991), S. 383-386 
    ISSN: 1432-1041
    Keywords: Glipizide ; gastrointestinal absorption ; sodium bicarbonate ; aluminium hydroxide ; glucose ; drug interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of sodium bicarbonate and aluminium hydroxide on the absorption and activity of glipizide have been studied in healthy volunteers in two randomized cross-over trials. After an overnight fast, 5 mg glipizide was given either with 150 ml water or with water containing 3.0 g sodium bicarbonate or 1.0 g aluminium hydroxide. Sodium bicarbonate significantly increased the AUC of plasma glipizide from 0 to 0.5 h, 0 to 1 h, and from 0 to 2 h (six-, four- and twofold, respectively). The time to peak concentration (tmax) fell from 2.5 h during the control phase to 1.0 h during the sodium bicarbonate phase. The absorption half-life (t1/2a), lag time and mean residence time (MRT) were also significantly decreased. No significant change in peak plasma concentration (Cmax), total AUC or elimination half-life (t1/2) was noted. The decremental plasma glucose areas from 0 to 1 h and 0 to 2 h were significantly larger (80% and 50%, respectively) than during the control phase. The maximal decrease in glucose was 50% greater during the sodium bicarbonate phase, and the time to reach it was reduced by 35 min. Aluminium hydroxide had no significant effects on the rate or extent of absorption of glipizide, and the glucose response also remained unaffected. It is concluded that the concomitant ingestion of sodium bicarbonate and glipizide may result in accelerated absorption of glipizide and an increased effect on glucose. A common dose of aluminium hydroxide did not appear to affect the absorption of glipizide.
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  • 95
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    European journal of clinical pharmacology 39 (1990), S. 395-397 
    ISSN: 1432-1041
    Keywords: atropine ; exercise ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the mean volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t1/2, 4.2 vs 3.5 h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 ml·min−1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml−1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml−1). In T5, Ex significantly decreased the t1/2 (3.4 h), Vz (182 l) and CL (575 ml·min−1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min−1), elimination rate constant (ke, 0.0012 vs 0.0015 min−1), Cp (14 ng·ml−1) and AUC (53.3 ng·h·ml−1). These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.
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  • 96
    ISSN: 1432-1041
    Keywords: activated charcoal ; antidotal efficacy ; healthy volunteers ; formulation ; paracetamol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy of several formulations of activated charcoal (AC) was compared by measuring the intestinal absorption of a solution of 1 g paracetamol administered 2 min before administration of 5 g AC as suspension (200 ml), tablets (40 of 125 mg) or capsules (25 of 200 mg). The suspension medium without AC was used as the control treatment. Based on the results of a pilot experiment, an 8 subject panel was used in a two 4×4 Latin square design. All treatments with AC resulted in a statistically significant decrease in paracetamol absorption compared to the control treatment. The suspension was considerably and significantly more effective than the tablets or capsules. Treatment with tablets was slightly but significantly more effective than capsules. The intake of large numbers of tablets and capsules was difficult. In the hospital AC suspensions are available. For first aid elsewhere, at home, at the working place or in the general practitioner's surgery a preservable and easily redispersible AC formulation would be preferable to the present solid forms.
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  • 97
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    European journal of clinical pharmacology 38 (1990), S. 529-533 
    ISSN: 1432-1041
    Keywords: felodipine ; nifedipine ; calcium antagonists ; hepatic blood flow ; forearm blood flow ; healthy volunteers ; haemodynamic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute effects of oral administration of felodipine 10 mg and nifedipine 10 mg on heart rate, blood pressure, forearm blood flow and hepatic blood flow were studied in nine healthy men. Both drugs caused an increase in heart rate of 16 and 7 beats · min−1, respectively. Hepatic blood flow was significantly increased by 1.2 and 0.41 · min−1 after felodipine and nifedipine. There was also a decrease in diastolic blood pressure, 10 and 5 mm Hg, respectively, after felodipine and nifedipine. The forearm blood flow was increased by about 30 ml · 100 ml−1 · min−1 after felodipine, but nifedipine had no effect. The haemodynamic effects were most pronounced 50 min after drug administration.
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  • 98
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    European journal of clinical pharmacology 39 (1990), S. 583-586 
    ISSN: 1432-1041
    Keywords: ranitidine ; piroxicam ; interaction ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng·ml−1 for ranitidine alone and 466 ng·ml−1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml−1 and 2551 h·ng ml−1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 μ·ml−1 in the presence of placebo and 2.0 μg·ml−1 in the presence of ranitidine respectively; mean AUC was 133 h·μg ml−1 and 137 h·μg ml−1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.
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  • 99
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    European journal of clinical pharmacology 39 (1990), S. 491-494 
    ISSN: 1432-1041
    Keywords: blood flow ; calcitonin ; calcitonin gene-related peptide ; duplex-scan ; laser Doppler ; healthy volunteers ; cerebral blood flow ; skin blood flow ; intestinal blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In normal human subjects (n=6), blood flow in the common carotid artery, assessed with an ultrasonic duplex-scanning unit, was increased up to 152% of basal levels by 60-min infusions of human calcintonin gene-related peptide I (αCGRP) 80 pmol·kg−1·h−1, but it was not affected by 20 pmol·kg−1·h−1 CGRP or 88 pmol·kg1·h−1 human calcitonin. In the superior mesenteric artery, on the other hand, blood flow was reduced by 80 pmol·kg−1·h−1 CGRP to 58% of the basal level, but not by 20 pmol·kg−1·h−1 CGRP or with 88 pmol·kg−1·h−1 calcitonin. Blood flow in the abdominal aorta remained largely unchanged under the same conditions. Skin blood flow, assessed by a laser Doppler unit, was increased up to 682% of the basal level by 80 pmol·kg−1·h−1 CGRP, but not by 20 pmol·kg−1·h−1 CGRP or calcitonin. Thus CGRP increased regional blood flow to the brain and the skin at the expense of the gastrointestinal tract.
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  • 100
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    European journal of clinical pharmacology 39 (1990), S. 291-293 
    ISSN: 1432-1041
    Keywords: Platelet aggregation verapamil ; nifedipine ; platelet release products ; calcium channel blockers ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of 1 week of treatment with low and moderate doses of verapamil or nifedipine upon platelet function has been studied in 12 healthy volunteers. The ex vivo platelet aggregation threshold for ADP or adrenaline was not altered by verapamil or nifedipine. The plasma concentrations of β-thromboglobulin and platelet factor 4 were significantly reduced by low but not by moderate doses of verapamil and nifedipine. Low doses of verapamil and nifedipine inhibit in vivo platelet activity in healthy volunteers.
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