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  • 1
    ISSN: 1432-1041
    Keywords: Key words Repaglinide ; Insulin secretagogue ; Type-2 diabetes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The present study was designed to assess the disposition of 14C-repaglinide in whole blood, plasma, urine and faeces, and to measure the total recovery of drug-related material in urine and faeces after a single 2-mg oral dose of 14C-repaglinide during multiple dosing. Methods: In this single-centre, open-label, phase-I trial, six healthy male volunteers received 2 mg of the prandial glucose regulator, repaglinide, four times daily for 13 days, 15 min before meals. On the morning of day 7, breakfast was omitted and the dose was given as an oral solution containing 2 mg of 14C-repaglinide. Results: After oral dosing, a mean peak plasma concentration of repaglinide of 27.74 ng · ml−1 (range: 16.84–36.65 ng · ml−1) was observed with a time to peak concentration of 0.5 h. Approximately 20% of repaglinide and its associated metabolites were distributed into red blood cells. No measurable 14C-radioactivity was present in whole blood samples 6 h after dosing. Within 96 h of dosing with 14C-repaglinide, 90% of the administered dose appeared in the faeces and 8% was excreted in urine. In the plasma, the major compound was repaglinide (61%). In the urine, the major metabolites were unidentified polar compounds, the aromatic amine (M1) (24%), and the dicarboxylic acid (M2) (22%). In the faeces, the major metabolite was M2 (66% of administered dose). Therefore, repaglinide was excreted predominantly as metabolites and the major in vivo metabolite of repaglinide in humans was M2. During regular dosing for 6 days, the morning plasma trough levels of repaglinide were, with very few exceptions, almost always too low to measure, indicating the absence of accumulation at this dose of 2 mg four times daily. Repaglinide was well tolerated, and there were no episodes of hypoglycaemia. Conclusion: After oral dosing with repaglinide, the mean peak plasma concentration was rapidly attained and, thereafter, plasma concentrations decreased promptly. The major route of excretion was via the faeces. These properties make repaglinide a suitable insulin secretagogue for all patients with type-2 diabetes who retain sufficient β-cell function.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 54 (1998), S. 355-357 
    ISSN: 1432-1041
    Keywords: Key words Tiagabine ; Digoxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To assess the possibility of any clinically relevant pharmacokinetic interactions between tiagabine, a novel antiepileptic drug, and digoxin. Methods: Potential pharmacokinetic interactions between tiagabine and digoxin were investigated in an open-label, two-period cross-over study in healthy male volunteers. Thirteen volunteers, aged between 18 and 43 years, were randomised to receive digoxin (0.5 mg twice a day for 1 day, then 0.25 mg once a day for 8 days) either alone or co-administered with tiagabine (4 mg three times daily for 9 days). Following a 7-day wash-out period, volunteers crossed over to the other dosing regimen. Peak serum concentration, time to maximum serum concentration, area under the serum concentration–time curve from zero to 24 h and steady state serum concentration were calculated for digoxin and compared between treatment groups. Results: No statistically significant differences between treatment groups were observed for any of the derived digoxin pharmacokinetic parameters. The most common adverse events reported during digoxin alone and in combination with tiagabine were somnolence and headache; an overall greater frequency of adverse events was reported during combined treatment. Adverse events were generally mild in nature; no serious adverse events were reported. Conclusions: At the doses administered, there is no evidence of a pharmacokinetic interaction between digoxin and tiagabine in healthy male volunteers.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 55 (1999), S. 101-104 
    ISSN: 1432-1041
    Keywords: Key words Troglitazone ; Erythropoietic ; parameters ; Plasma volume
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Troglitazone is a new anti-diabetic agent for the treatment of type 2 diabetes. In placebo-controlled trials troglitazone improves glycaemic control, reduces hyperinsulinaemia and has beneficial effects on blood lipids. However, minor, reversible reductions in erythrocyte count, haemoglobin and haematocrit with no associated clinical symptoms have been observed in some troglitazone-treated patients. The primary objective of the present study was to determine if these changes could be explained by a decrease in red cell mass or change in plasma volume. Methods: Twenty-four healthy males were randomized in a double-blind manner to troglitazone (200 or 600 mg per day) or placebo for 6 weeks. Blood samples for the measurement of red cell mass and plasma volume were obtained in the 2 weeks prior to treatment and after 6 weeks of treatment. Reticulocyte and erythrocyte counts, haemoglobin and haematocrit were also measured. Results: At the end of the treatment period there were no statistically significant changes in red cell mass. Similarly there were no changes in reticulocyte count, erythropoietin or soluble transferrin receptors. These data indicate that troglitazone does not affect erythropoiesis. In addition, troglitazone was not associated with increased red blood cell destruction or haemolysis. There was a trend towards increased plasma volume in the troglitazone groups: increases of 2.5 ml · kg−1 (5.7% increase) in the troglitazone 200 mg group and 3.4 ml · kg−1 (7.8% increase) in the troglitazone 600 mg group were observed compared with placebo. Conclusion: These data suggest that dilutional effects related to a modest increase in plasma volume may explain the haematological changes seen in other clinical trials with high doses of troglitazone, although this study has shown that the changes in plasma volume are not statistically significant.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 24 (1983), S. 761-767 
    ISSN: 1432-1041
    Keywords: theophylline ; bioavailability ; sustained release tablet ; pharmacokinetics ; Theograd-250
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of theophylline after oral administration of a new sustained release tablet Theograd®-250 mg was studied in 7 healthy volunteers, under fasting and non-fasting conditions. Whilst fasting the bioavailability was moderate at 64±22% (mean±SD), whereas in the non-fasting state the relatively high bioavailability of 90±13% was found. The drug appeared to be significantly more slowly absorbed when a tablet was taken after a meal, than when it was ingested on an empty stomach. In the former case, the peak level was reached after 6.9±1.0 h, whereas in the fasting state the maximum serum concentration occurred 4.0±1.7 h after administration of the drug. Despite the slow absorption, the peak non-fasting level of 4.4±1.4 mg·l−1 was significantly higher than the 3.1±1.0 mg·l−1 observed in the fasting state. The profiles of the serum concentration-time curves showed that the concentration remained above 75% of Cmax for 8.7±1.3 h in the fasting and 9.0±1.1 h in the non-fasting state. It was concluded that to define the optimal dosage regime for sustained release oral dosage forms of theophylline, the influence of food on absorption from these preparations should be taken into account. Based on the present results, Theograd®-250 mg tablets have predictable absorption and a high (90%) bioavailability if taken after a meal.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1041
    Keywords: metoprolol ; plasma concentration profile ; controlled-release formulation ; slow-release formulation ; exercise heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration-time profile and haemodynamic effects of metoprolol after the administration of metoprolol CR1 (a new multiple-unit controlled-release formulation) and metoprolol SR2 (a traditional slow-release formulation) once daily, were investigated in 12 healthy men. Data were collected over one 24-h dose interval at steady state after five days of treament. The study was a randomized, three-way, crossover comparison of metoprolol CR, 100 mg, metoprolol SR, 100 mg, and placebo. The reduction in exercise heart rate in relation to placebo treatment was used as a measure of β1-blockade. The metoprolol plasma concentration-time profile during treatment with metoprolol CR was smooth and uniform, showing a more controlled release profile than that obtained with metoprolol SR. This was demonstrated by the significantly longer time period during which the plasma concentration exceeded 75% of the maximum concentration (T75), for metoprolol CR compared with metoprolol SR (p〈0.05). The percentage peak-trough fluctuation in plasma metoprolol concentration was significantly smaller for metoprolol CR than for metoprolol SR (p〈0.001). These pharmacokinetic differences between metoprolol CR and metoprolol SR produced a different duration of clinically relevant β1-blockade, defined as a reduction in exercise heart rate of 〉10%. By this definition metoprolol CR was still effective in seven subjects and metoprolol SR in two subjects 24 h after dosing. The percentage peak-trough fluctuation in exercise heart rate over the dose interval was significantly smaller for metoprolol CR than for metoprolol SR (p〈0.001), thus demonstrating a more even β1-blockade with metoprolol CR.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 44 (1993), S. 237-241 
    ISSN: 1432-1041
    Keywords: Ambroxol ; Uricosuric effect ; uric acid clearance ; creatinine clearance ; hypoxanthine ; diurnal rhythm ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ambroxol is known to promote bronchial secretion and is used as an expectorant. Previous studies had suggested that high doses of ambroxol could reduce the plasma uric acid concentration. The present study was undertaken to confirm this finding, to determine its dose-response relationship and to identify the underlying mechanism of action. Using a placebo-controlled, double-blind parallel group design, 48 healthy male volunteers were randomly allocated to receive placebo b.d. and ambroxol 125 mg b.d., 250 mg b.d. or 500 mg b.d. (12 subjects per group). The subjects were hospitalised during a dietary run-in period of 3 days (Days -3 to -1) and a treatment period of 5 days (Days 1 to 5). On Day -1 (baseline) and Days 1 to 5, all urine was collected and blood samples were taken for the analysis of uric acid, creatinine, xanthine and ambroxol. The measurements were repeated four days after treatment had closed. Steady state plasma concentrations of ambroxol (trough levels) were reached after 2 or 3 days and were linearly related to dose. Ambroxol induced a significant, dose-dependent, reduction in plasma uric acid (250 mg b.d. about 20%; and at 500 mg b.d. about 30%). The diurnally fluctuating uric acid clearance was dose dependently increased and there was no notable effect on creatinine clearance. Plasma hypoxanthine levels were not affected by ambroxol. No severe adverse events were reported and no drug induced changes in the clinical laboratory values were observed. It is concluded that ambroxol has an uricosuric action following oral administration of higher doses (250 mg-500 mg b.d.) and it is well tolerated.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 47 (1994), S. 361-366 
    ISSN: 1432-1041
    Keywords: Ketoprofen ; diet ; bioavailability ; pharmacokinetics ; sustained release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The indirect effect of diet on the single-and multiple-dose pharmacokinetics of sustained-release ketoprofen was studied in 16 healthy male volunteers. In an open, cross-over design, 200 mg ketoprofen was administered as a gastric-juice-resistant, sustained-release tablet once daily during two periods of 5 days. A low-calorie/low-fat diet (LCFD) was given in the first period and a high-calorie/high-fat diet (HCFD) in the second period. The first meal on each day was given 4 h after drug intake. Ketoprofen plasma concentrations were measured over 24 h after the first dose on day 1 and over 36 h after the final dose on day 5 of each period. On average, plasma concentrations of ketoprofen were higher with the LCFD than with the HCFD. With the HCFD there was a tendency to longer absorption-lag times on day 5. The maximum concentration and the area under the curve over one 24-h dosage period (AUC0–24) were significantly higher with the LCFD, both on day 1 and on day 5. For AUC0–24 the differences were on average 15% (day 1) and 24% (day 5). The same tendency was observed for the amount excreted in urine over 24 h (Ae), but the difference was only significant on day 1 (14%). The elimination rate constant (Kβ) and the mean residence time were similar for the two diets, both on day 1 and on day 5. From these results, we conclude that there was an acute indirect effect of diet when a meal was had 4 h after intake of the medication. This resulted in a greater extent of ketoprofen absorption with the LCFD than with the HCFD. The absorption rate was apparently not influenced by this acute effect. The longer gastric residence time of ketoprofen with the HCFD may be the result of a long-term indirect effect on gastric emptying rate. If the extreme difference between the diets in this study is taken into account, it seems unlikely that the observed indirect effects have implications for clinical practice.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1041
    Keywords: Key words CYP2D6 ; CYP2C19 ; Dutch population
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We examined a large database containing results on CYP2D6 and CYP2C19 activity of 4301 Dutch volunteers phenotyped in the context of various clinical pharmacology studies. Methods: The subjects were given 22 mg dextromethorphan, 100 mg mephenytoin and 200 mg caffeine. For CYP2D6, the dextromethorphan/dextrorphan metabolic ratios in urine samples taken for a subsequent 8 h were used. Dextromethorphan and dextrorphan were quantified by reversed-phase high performance liquid chromatography. For CYP2C19 similarly obtained (R)-mephenytoin and (S)-mephenytoin ratios were used. (S)-mephenytoin and (R)-mephenytoin were analysed and quantified by enantioselective capillary gas chromatography. In addition, CYP2C19 poor metabolizer (PM) subjects were reanalysed after acidic pre-treatment of urine samples to confirm the PM status. Results: The investigated population mainly comprised Caucasian (98.9%) males (68%). The age ranged from 18 to 82 years. For CYP2D6, it was found that 8.0% of the subjects were PMs. The average metabolic ratio was 0.014 (0.033) for subjects who showed extensive metabolizing activity (EM) and 5.4 (7.6) for PM subjects. For CYP2C19, it was found that 1.8% of the subjects were PMs. The metabolic ratio was 0.162 (0.124) for EM subjects and 1.076 (0.040) for PM subjects. Within the EM group the metabolic ratio in females was significantly lower for CYP2D6 (−20%) and significantly higher for CYP2C19 (+40%) compared with males. For PMs there was no such difference for CYP2D6 (P = 0.79) or CYP2C19 (P = 0.20). Oral contraceptive (OC) use significantly decreased the CYP2C19 activity by 68% for mephenytoin as compared to non-OC using females. Conclusions: For CYP2D6, the PM incidence (8.0%) is in accordance with literature data. The CYP2C19, PM incidence (1.8%) is low compared to reports from other European countries. For mephenytoin, the acidification procedure has been shown to be very important for the confirmation of CYP2C19 PMs. In EM females compared to EM males, CYP2D6 activity is increased and CYP2C19 activity is reduced. For CYP2C19 in particular this reduction is substantial and most pronounced in the age range from 18 to 40 years. For CYP2C19, the reduced activity is associated with the use of oral contraceptives.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 17 (1980), S. 379-384 
    ISSN: 1432-1041
    Keywords: theophylline ; aminophylline ; obstructive lung disease ; microcrystalline ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Variation in the systemic disposition of theophylline after ingestion of a new microcrystalline product (Theolair®) has been investigated in 7 hospitalized patients with generalized obstructive lung disease. Disposition (absolute bioavailability) was determined by comparing in the same patients the areas under the serum concentration-time curves after a single oral dose of microcrystalline theophylline and after an intravenous infusion of aminophylline. Oral absorption appeared to be fast. The half-life of absorption was 19±9 min (mean±SD). Maximal serum concentrations reached after 100±30 min were found to be in a rather narrow range: 9.8±2.5 mg · 1−1. The absolute bioavailability of the microcrystalline preparation was high and it showed only small variation: 102.7±10.2% of the dose. Relevant pharmacokinetic parameters (half-life of elimination, volume of distribution and total body clearance) were determined after both routes of administration. Individual dosage regimens required to obtain a therapeutic serum concentration were calculated for each individual patient on the basis of the observed pharmacokinetic parameters.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1041
    Keywords: theophylline ; sustained release preparation ; serum level ; saliva level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The correlation between serum and saliva levels of theophylline was investigated in seven healthy volunteers after multiple dose administration of a low dose (300 mg/day) and a high dose (900 mg/day) of a sustained release theophylline preparation (Theo-Dur®). Tablets were taken for five days, at 8 a.m. and 8 p.m. and a last dose was taken on Day 6 at 8 a. m. Fourteen serum and saliva samples were collected simultaneously during the dosing period and for up to 32 h after the last dose. On the 300 mg/day regimen the level in saliva was 55.3% of the serum level, with an overall variability of 6.7% and an intrasubject variability of 10.5%. After 900 mg/day, the saliva concentration was 55.5% of the serum concentration, with an overall variability of 7.6% and an intrasubject variability of 12.7%. A good correlation was found between both determinations (r=0.99), which suggests that saliva levels could be used to monitor theophylline after administration of a sustained release tablet.
    Type of Medium: Electronic Resource
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