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  • pharmacokinetics  (209)
  • Immunohistochemistry
  • Springer  (246)
  • Annual Reviews
  • Blackwell Publishing Ltd
  • 2020-2024
  • 2005-2009
  • 1990-1994  (142)
  • 1980-1984  (104)
  • 1975-1979
  • 1993  (142)
  • 1984  (104)
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  • 2020-2024
  • 2005-2009
  • 1990-1994  (142)
  • 1980-1984  (104)
  • 1975-1979
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  • 1
    Electronic Resource
    Electronic Resource
    Occurrence of Chaperonin 60 and Chaperonin 10 in primary and secondary bacterial symbionts of aphids: Implications for the evolution of an endosymbiotic system in aphids (1993)
    Springer
    Journal of molecular evolution 36 (1993), S. 568-577 
    Details
    ISSN: 1432-1432
    Keywords: Aphids ; Endosymbiosis ; Symbionin ; Chaperonin 60 ; Chaperonin 10 ; Immunoblotting ; Immunohistochemistry ; Primary symbiont ; Secondary symbiont ; Endosymbiotic evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary All aphids harbor symbiotrophic prokaryotes (“primary symbionts”) in a specialized-abdominal cell, the bacteriocyte. Chaperonin 60 (Cpn60, symbionin) and chaperonin 10 (Cpn10), which are high and low molecular weight heatshock proteins, were sought in tissues of more than 60 aphid species. The endosymbionts were compared immunologically and histologically. It was demonstrated that (1) there are two types of aphids in terms of the endosymbiotic system: some with only primary symbionts and others with, in addition, secondary symbionts; (2) the primary symbionts of various aphids are quite similar in morphology whereas the secondary symbionts vary; and (3) irrespective of the aphid species, Cpn60 is abundant in both the primary and secondary symbionts, while Cpn10 is abundant in the secondary symbionts but present in small amounts in the primary ones. Based on these results, we suggest that the primary symbionts have been derived from a prokaryote that was acquired by the common ancestor of aphids whereas the secondary symbionts have been acquired by various aphids independently after divergence of the aphid species. In addition, we point out the possibility that the prokaryotes under intracellular conditions have been subject to some common evolutionary pressures, and as a result, have come to resemble cell organelles.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556361
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 247-253 
    Details
    ISSN: 1432-1041
    Keywords: Liver cirrhosis ; Spirapril ; ACE inhibitor ; pharmacokinetics ; haemodynamic effects ; liver function tests
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensinconverting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n=10), in patients with chronic, non-cirrhotic liver disease (n=8) and in a control group of healthy subjects (n=16). The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 μg·h·l−1, 923 μg·h·l−1 and 1300 μg·h·l−1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively. Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h−1 in patients vs. 2.00 h−1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315391
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  • 3
    Electronic Resource
    Electronic Resource
    Modelling circadian variation in the pharmacokinetics of non-steroidal anti-inflammatory drugs (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 357-361 
    Details
    ISSN: 1432-1041
    Keywords: Circadian rhythms ; Indomethacin ; Ketoprofen ; pharmacokinetics ; time-varying models ; nonsteroidal anti-inflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A one-compartment model with first-order absorption has provided good fits to five sets of indomethacin data and four sets of ketoprofen data taken at different times of day. There was substantial variation in the model parameters with time of administration and most of the features of this variation applied equally to both drugs. From the data examined, the source of variation appears to be mainly in the absorption phase and this was confirmed using a chronokinetic analysis, in which simultaneous fits were obtained with time-variant rate parameters. However, there may also be circadian variation in protein binding. The danger of quoting parameter values for either of these two drugs based on administration at a single time of day has been illustrated, and this may well be true for other drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265955
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  • 4
    Electronic Resource
    Electronic Resource
    Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 353-356 
    Details
    ISSN: 1432-1041
    Keywords: Gamma-hydroxybutyric acid ; pharmacokinetics ; dose-proportionality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Gamma-hydroxybutyric acid (GHB) is effective in treatment of the alcohol and opiate withdrawal syndromes. Its absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg kg−1. The AUC increased disproportionately with the dose and so the apparent oral clearance decreased significantly as the dose was increased, whereas the terminal half-life and mean residence time increased. The peak plasma concentrations normalised to the lowest dose fell significantly with increasing doses, whilst the corresponding peak times increased. These findings suggest that both the oral absorption and the elimination of GHB are capacity-limited processes. GHB did not bind to significant extent to plasma proteins over the therapeutic concentration range. The pharmacokinetic parameters in healthy volunteers were not significantly different from those previously observed in alcohol-dependent patients with compensated alcoholic liver disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265954
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  • 5
    Electronic Resource
    Electronic Resource
    Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 451-456 
    Details
    ISSN: 1432-1041
    Keywords: Glyceryl trinitrate spray ; pharmacokinetics ; a/b-ratio ; pulmonary artery diastolic pressure ; finger pulse curve ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time course and the magnitude of the effect of glyceryl trinitrate (GTN) on central venous (pulmonary artery diastolic pressure-PAPd) and peripheral arterial (a/b-ratio of the finger pulse wave) haemodynamics were compared in a randomized double-blind cross-over study in 12 patients suffering from congestive heart failure (NYHA II–III) with elevated PADd at rest (≥15 mm Hg). The data were obtained in a bioavailability study of two sprays of glyceryl trinitrate, which differed in their galenical characteristics and in the dose of GTN (0.4 mg vs. 0.8 mg). Following sublingual administration of each spray, PAPd, a/b-ratio and the plasma concentrations of GTN and its metabolites were measured up to 30 min. The relative bioavailability of GTN of the test preparation was estimated to be 157%, 161% and 147%, when calculated from the plasma concentration-time data or the integrated effect of GTN on a/b-ratio or PAPd, respectively. The mean time courses of the decrease in PAPd and the increase in the a/b-ratio of the finger pulse curve were mirror images. Thus, there was a strong correlation between the mean values of PAPd and a/b-ratio following the administration of glyceryl trinitrate. Since the slope of the relationship differed considerably between the patients, the magnitude of effect of GTN on PAPd in the individual patient could not be predicted from the changes in a/b-ratio.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315542
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of benazepril hydrochloride in patients with major proteinuria (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 463-466 
    Details
    ISSN: 1432-1041
    Keywords: Benazepril ; Proteinuria ; benazeprilat ; ACE inhibitor ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o. The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients. Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42 %. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients. In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315544
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  • 7
    Electronic Resource
    Electronic Resource
    Absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in man (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 473-476 
    Details
    ISSN: 1432-1041
    Keywords: dDAVP ; bioavailability ; gastrointestinal tract ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315546
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  • 8
    Electronic Resource
    Electronic Resource
    Single dose pharmacokinetics of proguanil and its metabolites in pregnancy (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 247-251 
    Details
    ISSN: 1432-1041
    Keywords: Proguanil ; Pregnancy ; Malaria ; cycloguanil ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and whole blood concentrations of proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl-biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of proguanil. Four of these women were restudied 2 months after delivery. The pharmacokinetic properties of proguanil were similar during and after pregnancy. Median peak plasma concentrations of proguanil during pregnancy and following delivery were 212 and 215 ng·ml−1, and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for proguanil during and following pregnancy were 94 and 98 ng·h·ml−1·kg−1, respectively. Corresponding whole blood AUC values were 361 and 396 ng·h·ml−1·kg−1. The mean elimination half lives and mean residence times of proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively. Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng·ml−1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml−1, respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of proguanil. The mean ratio of proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies. The concentrations of 4-chlorophenylbiguanide in both plasma and whole blood in pregnant subjects were also lower than those after pregnancy. These data show that blood concentrations of the active antimalarial metabolite cycloguanil are reduced in late pregnancy and that the currently recommended dose of proguanil could be inadequate for antimalarial prophylaxis in pregnant women.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271366
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  • 9
    Electronic Resource
    Electronic Resource
    On the intraindividual variability and chronobiology of cyclosporine pharmacokinetics in renal transplantation (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 265-269 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporine ; Renal transplantation ; pharmacokinetics ; intraindividual variation ; circadian variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period. The absolute percentage intraindividual difference in daytime AUC (0–12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0–12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t1/2, tmax and Cmax were more variable than the AUC (0–12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng · ml−1 versus 223 ng · ml−1. This, together with a significantly longer t1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA. In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime. It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271369
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  • 10
    Electronic Resource
    Electronic Resource
    Delayed disposition of adriamycin and its active metabolite in haemodialysis patients (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 301-302 
    Details
    ISSN: 1432-1041
    Keywords: Adriamycin ; Haemodialysis ; adriamycinol ; pharmacokinetics ; moment analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271378
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  • 11
    Electronic Resource
    Electronic Resource
    Dose proportional absorption of 25–150 mg atenolol (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 305-306 
    Details
    ISSN: 1432-1041
    Keywords: Atenolol ; bioavailability ; intestinal absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We investigated the dose proportionality after the intake of oral atenolol 25, 50, 100 and 150 mg. Standard tablets were taken by 8 healthy volunteers in randomised order of doses. The area under the curve divided by dose did not differ between the doses, indicating that the absorption of this hydrophilic compound, with known incomplete bioavailability, was constant over the range tested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271380
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  • 12
    Electronic Resource
    Electronic Resource
    The pharmacokinetic and pharmacodynamic interactions of ramipril with propranolol (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 255-260 
    Details
    ISSN: 1432-1041
    Keywords: Ramipril ; Propranolol ; interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacodynamic effects of ramipril, propranolol, and their combination, as well as the effect of propranolol on the pharmacokinetics of ramipril in 12 healthy men (age 24 (SD 6) y, weight 72 (7) kg). Propranolol and placebo, ramipril and placebo, or propranolol and ramipril were given orally for four days in a crossover, double-blind fashion. The pharmacokinetics of ramipril and ramiprilat were investigated on day 4. Effects on plasma renin activity, ACE activity, and heart rate and blood pressure both before and after a standardized exercise test were measured on days 1 and 4. On day 4 the combination reduced the mean arterial pressure by 2.8 mmHg compared with propranolol alone and by 3.7 mmHg compared with ramipril alone. Ramipril had no effect on the bradycardia induced by propranolol. Propranolol reduced exercise mean arterial pressure by 9 mmHg (day 4) and heart rate by 7 beats.min−1 (day 4) compared with ramipril; this was not affected by co-administration of ramipril. On day 4 the average plasma renin activity was not significantly higher than after the combination. ACE activity was not affected by propranolol. The pharmacokinetics of ramipril and ramiprilat were not influenced by propranolol. The combination of ramipril and propranolol has additive pharmacodynamic effects that may be useful in the treatment of hypertension.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315392
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  • 13
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of fenoterol in pregnant and nonpregnant women (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 275-277 
    Details
    ISSN: 1432-1041
    Keywords: Fenoterol ; Pregnancy ; pharmacokinetics ; premature labour
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the β2-adrenergic drug fenoterol, which is used as a tocolytic agent in pregnancy, has been investigated in pregnant (n=9) and nonpregnant (n=5) women during a constant rate intravenous infusion. Clearance and mean residence time were found to be 1990 (1879/2220; Median, Q25/Q75) ml/min and 9.2 (8.0/14.0) min in the pregnant and 2126 (1915/2130) ml/min and 16.6 (16.5/32.1) min in the nonpregnant women, respectively. In addition, fenoterol clearance was estimated in 88 women from a single blood sample collected at steady state during IV therapy and the effect of gestational age on clearance was studied. Clearance displayed large inter-individual variation. There was no apparent correlation between clearance and gestational age. We conclude that there is no need to adjust the dose on pharmacokinetic grounds in the course of pregnancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315396
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  • 14
    Electronic Resource
    Electronic Resource
    The relation between type of renal disease and renal drug clearance in children (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 195-197 
    Details
    ISSN: 1432-1041
    Keywords: Cefotaxime ; Renal insufficiency ; desacetylcefotaxime ; pharmacokinetics ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is generally assumed that the renal clearance of drugs in patients with renal impairment are affected to a similar extent regardless of the type of renal disease (intact nephron hypothesis). We have studied the effect of underlying renal disease on the pharmacokinetics of cefotaxime and desacetylcefotaxime in two groups of children (ages 7 to 16 y) with varying degrees of renal dysfunction. Patients in group 1 (n=5) had intrinsic renal disease and those in group 2 (n=5) had extrinsic renal disease, as identified by the primary renal lesion. After a single intravenous dose of cefotaxime timed blood and urine samples were collected for 24 h; cefotaxime and desacetylcefotaxime were measured by HPLC. There were no significant differences between the groups in age, body surface area, urine output, creatinine clearance, total body clearance, nonrenal clearance, renal clearance, and volume of distribution at steady state of cefotaxime, and renal clearance of desacetylcefotaxime. However, the renal clearance: creatinine clearance (CLR:CLCR) ratios for both cefotaxime [1.34 in group 1 vs. 0.51 in group 2] and desacetylcefotaxime [1.58 in group 1 vs. 0.75 in group 2] were statistically significant between the two groups. Group 1 patients had an average CLR:CLCR ratio greater than 1 for both the parent compound and the metabolite, suggesting that net tubular secretion was still intact, despite a diminished glomerular filtration rate (CLCR=24 ml·min−1·1.73 m−2). In contrast, patients in group 2 (CLCR=49) ml·min−1·1.73 m−2) had an average CLR:CLCR ratio less than 1 for both cefotaxime and desacetylcefotaxime, suggesting that renal tubular transport mechanisms did not remain functional in these patients. Our findings suggest that the effect of renal insufficiency on the renal elimination of cefotaxime and its metabolite desacetylcefotaxime may depend on the cause of renal insufficiency.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315480
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  • 15
    Electronic Resource
    Electronic Resource
    Assessment of bioelectrical impedance for individualising gentamicin therapy in neonates (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 253-258 
    Details
    ISSN: 1432-1041
    Keywords: Bioelectrical impedance ; Gentamicin ; non-invasive technique ; neonates ; predictive models ; pharmacokinetics ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The use of bioelectrical impedance (BI) analysis as a non-invasive approach for individualising gentamicin therapy in newborn infants has been investigated in a two phase study. In Phase I, 1/impedance and length2 were identified as statistically significant predictors of the distribution volume of gentamicin (Adj R2=0.78, CV=12.42%), and length2/impedance and post-conceptual age were predictors of total systemic clearance (Adj R2=0.83, CV=14.5%), following the administration of 2.5 mg·kg−1 gentamicin to 17 neonates (gestational age (GA) 27 to 36 weeks). In a prospective validation of these relationships in an independent (Phase II) group of 27 infants (GA 26 to 41 weeks), predicted serum gentamicin concentrations were close to those achieved. Several instances of high prediction errors (predicted minus achieved levels) were observed in infants with known or suspected renal impairment and they caused significant (P〈0.05) perturbation in the bias and accuracy of the models. Daily BI measures over a four to five day period were able to detect individual changes in the fat-free body compartments, which were translated into alterations in gentamicin regimens. This simple, non-invasive and relatively inexpensive bedside technique provides a potentially valuable means to individualise gentamicin therapy without relying on the measurement of serum gentamicin concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271367
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  • 16
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    Electronic Resource
    Pharmacokinetics and pharmacodynamics of famotidine in patients with reflux oesophagitis (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 357-360 
    Details
    ISSN: 1432-1041
    Keywords: Famotidine ; Reflux oesophagitis ; intraoesophageal long-term pH-metry ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics, pharmacodynamic effect and clinical efficacy of famotidine were studied in 10 patients with reflux oesophagitis Grades I and II. For the pharmacokinetic studies the patients received 20 mg famotidine i. v. The half-life of famotidine was 3.8 h, the total plasma clearance was 297 ml·min−1, and a steady state volume of distribution of 1.21·kg−1 was found. For pharmacodynamic assessment, intraoesophageal pH-metry was performed without and after acute treatment with famotidine 20 mg i. v. and following 3 weeks of oral famotidine 80 mg b. d. The resultant percentage total acid exposure time (pH〈4 within 24 h) were 23.9%, 19.0% and 19.2% (median), respectively (NS). At the end of 6 weeks of oral therapy, symptomatic and endoscopic improvement had occurred in 9 and 5 patients, respectively. Our study shows that the pharmacokinetics of famotidine in patients with reflux oesophagitis is comparable to that in healthy volunteers and peptic ulcer patients. The clinical response to the treatment appeared comparable to that found after other H2-receptor antagonists.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316472
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  • 17
    Electronic Resource
    Electronic Resource
    The influence of steady-state ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of diazepam in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 365-367 
    Details
    ISSN: 1432-1041
    Keywords: Ciprofloxacin ; Diazepam ; quinolone ; benzodiazepine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study. Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml·h−1kg−1; with ciprofloxacin: 12.3 ml·h−1kg−1). Diazepam t1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l·kg−1; with ciprofloxacin: 1.1 l·kg−1). However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.
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    URL: http://dx.doi.org/10.1007/BF00316474
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  • 18
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    Pharmacokinetics of temocapril, an ACE inhibitor with preferential biliary excretion, in patients with impaired liver function (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 383-385 
    Details
    ISSN: 1432-1041
    Keywords: Temocapril ; Liver dysfunction ; angiotensin converting enzyme inhibitor ; diacid ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six subjects with normal liver function (Group 1) and 7 patients with liver dysfunction (Group 2; mean ICGR15 value 30.5 (5.2) %; range 16 to 56) received a single oral dose of 1 mg temocapril, a prodrug-type ACE inhibitor, with preferentially excreted by the biliary route. The plasma temocapril concentrations in Group 2 at 30 min and 1 h postdose were significantly higher than in Group 1, but the difference had disappeared 2 h postdosing. Although the half life of temocapril diacid in Group 2 was significantly longer than in Group 1, there was no significant difference between the two groups in AUC, Cmax or tmax. In Group 2, urinary recovery of temocapril was significantly increased, suggesting a possible delay in the bioactivation of temocapril into the diacid, but recovery of the diacid itself was not abnormal. ACE inhibitory action in Group 2 remained unchanged. Temocapril is regarded as an ACE inhibitor the disposition and efficacy of which are little affected in patients with impaired liver function.
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    Effects of diclofenac on isradipine pharmacokinetics and platelet aggregation in volunteers (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 391-393 
    Details
    ISSN: 1432-1041
    Keywords: Isradipine ; Diclofenac ; pharmacokinetics ; platelet aggregation ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In this open, two-period crossover study in 18 healthy male volunteers, a single oral dose of 50 mg diclofenac was administered alone and on day 7 of multiple oral dosing of 5 mg b.i.d. isradipine to assess a possible pharmacokinetic interaction. The effect of these drugs on ex vivo platelet function was also determined. Serial blood samples were obtained over 12-hour periods on three occasions: after the single diclofenac dose; after the morning dose of isradipine on day 6 and after co-administration of both drugs on day 7 of steady-state isradipine administration. Additional samples were taken at 2 h post dose for determination of ex vivo platelet aggregation. Isradipine plasma concentrations were determined by a gas chromatographic method and diclofenac plasma concentrations by an HPLC method. The pharmacokinetic characteristics of diclofenac were unaltered during co-administration. The maximum plasma concentration of isradipine was increased 19.6% during co-administration from 5.06 to 6.05 ng·ml−1. This is not expected to be of clinical importance. Isradipine's apparent total body clearance and steady-state AUC remained unchanged. Ex vivo induced platelet aggregation was not affected by any of the treatments.
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    URL: http://dx.doi.org/10.1007/BF00316480
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  • 20
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    Pharmacokinetics of intranasal, intramuscular and intravenous glucagon in healthy subjects and diabetic patients (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 555-558 
    Details
    ISSN: 1432-1041
    Keywords: Glucagon ; pharmacokinetics ; i.v. infusion ; intranasal spray ; intramuscular administration ; insulin-dependent diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intranasal, an intravenous infusion, and intramuscular glucagon has been studied in 5 healthy subjects and 11 patients with insulin-dependent diabetes mellitus. After infusion the elimination half-life was significantly longer in diabetics (11.9 vs 6.6 min) and the apparent volume of distribution was twice as high in diabetics (0.19 vs 0.37 l·kg−1). The metabolic clearance rates were the same in the two groups (18.9 and 21.3 ml·min−1·kg−1 in controls and in diabetics) and were about twice those previously reported. After 1 mg intranasally the Cmax of immunoractive glucagon (IRG) was similar in diabetic and in healthy subjects. Administration of a higher dose (2 mg) to diabetic patients produced a higher plasma level, although not proportionately so. The AUC after 1 mg was also similar in controls and in diabetics. The elimination half-life in both groups was similar to the value found after IV infusion; it was significantly shorter in controls (5.5 min) than in diabetics (13.8 min). In both groups, mean Cmax was significantly lower than after IM glucagon, the relative bioavailability of 1 mg intranasally vs IM injection being less than 30%. After IM administration, the Cmax and AUC of IRG in controls and in diabetic patients, were identical. The apparent elimination half-life was also similar in the two groups, and was three- to four-times longer (28.6 and 31.4 min) than after infusion or intranasal administration, possibly because estimation of the t1/2 was affected by slow release of the hormone from the site of injection.
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    URL: http://dx.doi.org/10.1007/BF00315314
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  • 21
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    Pharmacokinetics of chlorpromazine and key metabolites (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 563-569 
    Details
    ISSN: 1432-1041
    Keywords: Chlorpromazine ; metabolites ; N-oxide ; sulfoxide ; 7-hydroxy ; conjugates ; pharmacokinetics ; first pass metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A study was carried out in 11 healthy young men to investigate the pharmacokinetics of chlorpromazine (CPZ) after a bolus intravenous (IV) dose (10 mg) and three single oral doses (25, 50 and 100 mg), with a washout period of two weeks between doses. Plasma levels of CPZ, CPZ N-oxide (CPZNO), CPZ sulfoxide (CPZSO) and both free and conjugated 7-hydroxy-CPZ (7-HOCPZ) were measured by extraction radioimmunoassays. CPZ exhibited multicompartmental pharmacokinetics in most subjects. There was wide between-subject variability in half life (11.05 h), volume of distribution (1215 l), volume of distribution at steady state (642 l) and mean residence time (8.88 h), whereas systemic clearance was somewhat less variable (76.6 l·h−1). All metabolites were present in measurable concentrations in the plasma of 9 of 11 subjects after IV CPZ, whereas free 7-HOCPZ was not detected in the other 2 individuals. With the exception of CPZNO, the biological half lives of the primary metabolites were longer than the half life of CPZ. After oral administration, the percentage of CPZ reaching the systemic circulation intact (F%) was very low (4–38%) and dose dependant. Moreover, both within-subject and between-subject variances were very high. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinite time (AUC) showed evidence of nonlinearity, whereas half life did not appear to be dose dependant. These data suggest that the high degree of variability in the pharmacokinetics of CPZ is a result of extensive first pass metabolism rather than variation in half life. The mean AUC for the total conjugates of 7-HOCPZ was about two fold higher than that of the parent drug or any other metabolite. This shows that phase II metabolism plays a very significant role in the disposition of CPZ. As a result, the role of CYP2D6 in the 7-hydroxylation of CPZ cannot be fully assessed without taking phase II metabolism into account.
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    URL: http://dx.doi.org/10.1007/BF00315316
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  • 22
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    Flumazenil kinetics in the elderly (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 585-587 
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    ISSN: 1432-1041
    Keywords: Flumazenil ; benzodiazepine ; absorption ; disposition ; elderly volunteers ; pharmacokinetics ; aging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open design, randomised, two-way cross-over study, a single 2 mg i.v. dose and a single 30 mg oral dose of flumazenil were each administered to a group of healthy young (n=6) and elderly (n=12) volunteers (male: female 2/1). Plasma samples were collected at intervals and intact drug was assayed. Both the IV and oral doses of flumazenil were very well tolerated by both age groups and no severe or unexpected adverse effects were observed. The main complaints were dizziness and headache, mainly after oral dosing, probably due to the higher Cmax and AUC following this route of administration. After 2 mg i. v. the disposition parameters in the two age groups (elderly/young) were very similar: volume of distribution (Vss): 0.88/0.901·kg−1; total body clearance (ClPL): 0.86/0.99 l·min−1; terminal elimination half-life (t1/2β): 1.02/0.91 h. After the 30 mg oral dose the mean Cmax of 87.6 ng·ml−1 (elderly) and 78.4 ng·ml−1 (young) were generally reached within 0.5 to 1 h. In 26% (elderly) and 23% (young), the absolute bioavailability of flumazenil was very similar. It is concluded that the absorption and disposition paramters of flumazenil were not significantly affected by aging.
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    The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 27-33 
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    ISSN: 1432-1041
    Keywords: Nicorandil ; vasodilator ; tolerance study ; blood pressure ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    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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    Elimination of cefmenoxime during continuous haemofiltration (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. S31 
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    ISSN: 1432-1041
    Keywords: Cefmenoxime ; Renal failure ; continuous haemofiltration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elimination of cefmenoxime after single and repeated i. v. dosing was studied in 12 patients with severe renal failure and sepsis during continuous haemofiltration. More than 30 % of the drug was found in the filtrate. The sieving coefficient (S) was 0.54. Vss % was unchanged 0.311 · kg−1 in comparison with patients with normal renal function, whereas the mean t/12ß was prolonged to about 16 h, and total clearance was reduced 20.8 ml · min−1 · 1.73 m−2. Once daily administration of 1 g cefmenoxime is suggested as the appropriate dose under such circumstances.
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    The effect of oxprenolol dosage time on its pharmacokinetics and haemodynamic effects during exercise in man (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 171-176 
    Details
    ISSN: 1432-1041
    Keywords: Oxprenolol ; β-adrenoceptor blockade ; circadian rhythm ; haemodynamics ; pharmacokinetics ; exercise ; healthy volunteers ; kinetic-dynamic model
    Source: Springer Online Journal Archives 1860-2000
    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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    Pharmacokinetics and pharmacodynamics of quinaprilat after low dose quinapril in patients with terminal renal failure (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. S53 
    Details
    ISSN: 1432-1041
    Keywords: Quinapril ; Renal failure ; quinaprilat ; haemodialysis ; ACE inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of the ACE inhibitor quinaprilat have been studied in six chronic haemodialysis (HD) patients and in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD) after a single oral dose of 2.5 mg quinapril. Mean tmax and Cmax values (SEM) for quinaprilat in interdialytic HD patients were 4.0 (0) h and 84 (8.4) ng · ml−1 respectively, and they did not differ significantly from those in CAPD patients (4.7 (0.7) h and 64 (5.7) ng · ml−1). Elimination half lives were 30 (10.1) h (HD) and 34 (7.3) h (CAPD). Cmax, tmax, t/12, and AUC were increased and CL was decreased compared to data reported previously after giving 2.5 mg to healthy subjects. Peritoneal clearance was calculated as 0.1 (0.1) ml · min−1, thus less than 0.5 % of the dose were removed within 24 h by CAPD. ACE activity was suppressed by more than 93 % between 4 and 24 h postdose (P 〈 0.001). It decreased in both groups with increasing plasma quinaprilat levels. Angiotensin II concentration compared to baseline was significantly decreased at 4 hours (−30.4±10 %) and 24 h (−30±9.9 %) (P 〈 0.05,n=11), while active plasma renin concentration was still significantly increased at 48 h postdose (+60.2±14.5 %,P 〈 0.01). Mean arterial pressure 24 h postdose was significantly (P 〈 0.05) decreased in HD (−12 mm Hg) and CAPD patients (− 20 mm Hg). Only two patients reported unwanted effects (fatigue, dizziness, nausea, and weakness). In conclusion, due to its long lasting effect on ACE activity and on blood pressure in terminal renal failure a starting dose of quinapril 2.5 mg o. d. may be used in hypertensive HD and CAPD patients.
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    The pharmacokinetics of the β2-adrenoceptor agonist, tulobuterol, given transdermally and by inhalation (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 361-364 
    Details
    ISSN: 1432-1041
    Keywords: Tulobuterol ; β2-adrenoceptor agonist ; aerosol inhalation ; transdermal delivery ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of tulobuterol given transdermally or by aerosol inhalation in healthy male volunteers. Tulobuterol was rapidly absorbed after inhalation, with a tmax of 0.8–1.5 h. The Cmax and the AUC increased linearly with dose. Tulobuterol was well absorbed after transdermal administration, with an absorption lag-time of about 4 h. The Cmax and AUC increased linearly with dose and the tmax was about 9–12 h. The mean percentage of drug absorbed during the application of a patch for 24 h was 82–90% after a single dose and 82–85% during repeated dosing. The mean urinary recoveries as unchanged drug after a single inhalation and patch application were 3–4% and 5–6% respectively. Tulobuterol did not accumulate during repeated inhalation or transdermal application. It was well tolerated, except for an increase in heart rate of 10–20 beats · min−1 after five repeated applications of a 4 mg patch.
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    Pharmacokinetics of flosequinan in elderly patients with chronic congestive heart failure (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 387-389 
    Details
    ISSN: 1432-1041
    Keywords: Flosequinan ; Congestive heart failure ; elderly ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have investigated the pharmacokinetics of the direct vasodilator flosequinan in elderly patients with congestive heart failure. Eight patients received a single dose of 50 mg, and 8 patients received once-daily treatment with 25 mg for two weeks. In the single dose study, the tmax of flosequinan was 2.5 h, Cmax was 1.17 μg · ml−1 and t1/2 was 5.63 h. The tmax of the metabolite BTS 53554 was 20.3 h, Cmax was 1.44 μg · ml−1 and t1/2 was 62.0 h. BTS 53554 accumulated gradually in the 14-day repeated dose study and steady-state was reached after approximately 2 weeks. Flosequinan was not found to accumulate. Adverse reactions were not observed in either the single or repeated dose study. It is advisable to consider renal function and body weight when flosequinan is to be administered to elderly patients with congestive heart failure. The initial dose should be 25 mg.
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  • 29
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    The pharmacokinetics and pharmacodynamics of metoprolol after conventional and controlled-release administration in combination with hydrochlorothiazide in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 161-163 
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    ISSN: 1432-1041
    Keywords: Metoprolol ; controlled-release formulation ; hydrochlorothiazide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers ; efficacy
    Source: Springer Online Journal Archives 1860-2000
    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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    Assessment of drug metabolism in hepatic disease: Comparison of plasma kinetics of oral cyclobarbital and the intravenous aminopyrine breath test (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 95-101 
    Details
    ISSN: 1432-1041
    Keywords: cyclobarbital ; aminopyrine ; liver disease ; 14CO2 breath test ; barbiturate ; pharmacokinetics ; hepatic drug metabolism ; cirrhosis ; alcoholic liver disease ; viral hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The exhalation of 14CO2 derived from an i.v. tracer dose of [dimethylamine-14C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled 14CO2 occurred 0.5–2 h after 14C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of 14CO2 exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests.
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    Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 121-124 
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    ISSN: 1432-1041
    Keywords: methotrexate ; psoriasis ; pharmacokinetics ; plasma levels ; urinary excretion ; renal clearance ; tubular absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500–800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52–102 ml/min (mean±SD, 83±19.4 ml/min).
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    Pharmacokinetics of enprofylline in patients with impaired renal function after a single intravenous dose (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 87-93 
    Details
    ISSN: 1432-1041
    Keywords: enprofylline ; pharmacokinetics ; renal elimination ; renal insufficiency ; healthy subjects ; creatinine clearance ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Enprofylline, a new bronchodilating drug, was given i.v. at 1.0 mg/kg to 7 healthy subjects and to 14 patients with differing degrees of chronic renal insufficiency. Plasma and urine concentrations of unchanged drug were followed by HPLC. In the patients the plasma half-life was prolonged and the total and renal clearances were reduced in direct proportion to the degree of renal insufficiency as determined by creatinine clearance. The unbound fraction of enprofylline in plasma increased from 55% in the healthy subjects to 66% in the group of patients with the highest degree of renal impairment. The volume of distribution terms, Vβ and Vss, both tended to decrease with decreasing creatinine clearance. When the volume term calculations were based on the unbound drug level in plasma, this tendency was enhanced. Side-effects were noted in 4 subjects, and to some extent were related to the plasma level of the drug.
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    Comparative pharmacokinetics of sulphasalazine and sulphapyridine after rectal and oral administration to patients with ulcerative colitis (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 275-277 
    Details
    ISSN: 1432-1041
    Keywords: sulphapyridine ; sulphasalazine ; pharmacokinetics ; rectal administration ; oral administration ; plasma levels ; ulcerative colitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Rectal administration of sulphasalazine to patients with ulcerative colitis has recently been shown to have similar therapeutic activity but fewer side effects than oral treatment. The present study is a comparison of the pharmacokinetics of sulphasalazine (SASP) and its metabolite sulphapyridine (SP) after rectal and oral administration of SASP to 6 patients with ulcerative colitis. The areas under the concentration-time curves (AUC) and the maximum concentrations (Cmax) of SASP and SP were significantly lower after rectal than oral administration of SASP (p〈0.05). These findings support the view that the lower frequency of side effects after rectal administration of SASP may result from the lower plasma levels of SASP and SP.
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    Relationship between the cardiovascular effects and steady-state kinetics of clonidine in hypertension (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 309-313 
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    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; therapeutic window ; steady state concentration ; pharmacokinetics ; cardiovascular effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonidine was given orally as monotherapy in increasing daily doses from 3.1 to 25.7 µg/kg to patients with essential hypertension (n=6). When a steady state concentration in plasma was reached at each dose level, the blood pressure (BP) and heart rate were measured during a dosage interval. Effect time — plasma concentration data were submitted to nonlinear regression analysis, which showed that the observed BP effects could be dissociated into depressor and pressor components. A window for the antihypertensive effect was established. At a plasma clonidine concentration of 0.65±0.07 ng/ml 50% of the maximal depressor effect was found, and it was only separated by a factor of 2 from the half maximal pure pressor concentration in plasma. No relationship between the change in heart rate and the plasma clonidine was observed. The findings strengthen the importance of close monitoring of clonidine therapy.
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    Pharmacokinetics of midazolam in the aged (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 381-388 
    Details
    ISSN: 1432-1041
    Keywords: midazolam ; hypnotic drug ; benzodiazepine ; pharmacokinetics ; aged patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of midazolam, an imidazo-benzodiazepine derivative, have been studied in 13 subjects over the age of 60 years who received the drug intravenously (0.07 mg kg−1) as an induction agent for endoscopy. Two to three days later, 6 of these subjects received 5 mg of midazolam intramuscularly, and another 6 of the subjects received 10 mg of the drug orally. The plasma concentration-time curves were again studied pharmacokinetically. After intravenous dosing, the mean (± SD) elimination half-life (2.14±1.24 h) showed a statistically significant trend to increase with age in the subjects older than 60 years. While the mean (± SD) clearance value (0.30±0.19 l kg−1h−1) tended to fall with age in the elderly subjects, this trend was not statistically significant. Apparent volume of distribution did not appear to be related to advancing age beyond 60 years, and this parameter (mean ± SD) did not differ to a statistically significant extent between the aged subjects (0.77±0.47 l kg−1) and the young subjects studied previously (1.09±0.58 l kg−1). Atropine premedication did not appear to alter the dispositional parameters of the intravenously administered drug. Intramuscularly administered midazolam was absorbed rapidly. Bioavailability appeared incomplete (F=0.59±0.15, mean ± SD), possibly due to saturable elimination of the drug at the higher plasma levels which were obtained after intravenous midazolam. Oral bioavailability, relative to intravenous, was 0.34±0.17, (mean ± SD), with an appreciable but variable lag time (0.74±0.40 h, mean ± SD). Orally, in the dose used, the drug was an inefficient hypnotic with four of the six subjects failing to attain the plasma drug level of 44–50 µg l−1, which appeared to be the approximate threshold for sleep. It is impossible to know whether this failure represents an age related effect on drug absorption, or is a consequence of the upper alimentary tract abnormalities for which the endoscopies were done.
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    Pharmacokinetics of cefoxitin administered by i.v. infusion to patients with a pleural effusion (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 389-392 
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    ISSN: 1432-1041
    Keywords: cefoxitin ; beta-lactam antibiotics ; pharmacokinetics ; serum concentration ; pleural fluid concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin was studied in 6 healthy volunteers and in 5 patients with a pleural effusion after administration of a single dose of 30 mg/kg i.v. infusion. The serum and pleural fluid concentrations of cefoxitin were determined microbiologically. The elimination half-life of the antibiotic from pleural fluid in all cases was 2–3fold longer than from serum, which shows a difference between the kinetic elimination processes of the antibiotic from the two fluids. The slow elimination of cefoxitin from pleural fluid facilitates its accumulation in this compartment during a multiple dosage regimen.
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    Pharmacokinetics of cefoperazone in patients undergoing chronic ambulatory peritoneal dialysis: Clinical and pathophysiological implications (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 609-612 
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    ISSN: 1432-1041
    Keywords: cefoperazone ; peritoneal dialysis ; pharmacokinetics ; terminal renal failure ; peritonitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoperazone after i.p. and/or i.v. administration were studied in 12 CAPD patients. After i.v. injection, the plasma half-life was 2.65±0.4 h, the total clearance amounting to 70.1±19.2 ml/min. Peritoneal clearance was calculated to be 6.9±1 ml/min. After peritoneal instillation, the bioavailability was 63.9±5%. After repeated i.p. administration, no accumulation of the drug in the body was observed. Thus, cefoperazone can be safely administered for the treatment of peritonitis in CAPD patients.
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  • 38
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    Intra-individual consistency of prednisolone kinetics during long-term prednisone treatment (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 651-653 
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    ISSN: 1432-1041
    Keywords: prednisolone ; prednisone treatment ; pharmacokinetics ; individual variation ; microsomal enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eleven patients on long-term prednisone treatment were studied on two occasions separated by 45 to 325 days. In 10 patients the total body clearance of prednisolone only changed about 10%. In one case a 78.5% decrease was observed after stopping treatment with rifampicin and isoniazide. No association was found between the prednisone dose rate (mg/kg per month), patient age or mean endogenous plasma hydrocortisone level and prednisolone clearance/kg. The results indicate considerable intra-individual consistency of prednisolone kinetics if other conditions are not changed.
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  • 39
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    D-propoxyphene kinetics in man: Significance of a deep third compartment (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 749-752 
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    ISSN: 1432-1041
    Keywords: dextropropoxyphene ; pharmacokinetics ; half-life ; 3-compartment model ; steady state prediction ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Data from a previously published single dose study of d-propoxyphene 65 mg given i.v. to 8 healthy subjects have been subjected to non linear regression analysis by a curve-fitting program to test the applicability of a 2- and a 3-compartment open model. Analysis of residuals (difference between observed and computed concentrations) revealed similar systematic deviations in all 8 subjects when the 2-compartment model was used (5–10 h negative residuals, after 13 h positive residuals). In contrast, curve-fit by a 3-compartment model (with two parallel peripheral compartments) was good with no systematic deviations. The data show that a terminal monoexponential decline in d-propoxyphene concentrations cannot be expected until 15–30 h after single dose administration, and that the determination of the corresponding half-life is rather inaccurate. Accordingly, precise steady state level predictions may be difficult to obtain from conventional single dose studies with d-propoxyphene.
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  • 40
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    Bioavailability and pharmacokinetics of phenytoin during pregnancy (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 105-110 
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    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
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  • 41
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    Clinical pharmacological studies with the vasodilator endralazine in patients with renal impairment (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 159-163 
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    ISSN: 1432-1041
    Keywords: endralazine ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of renal impairment on the pharmacokinetics of endralazine was studied in 12 patients; 4 patients on regular haemodialysis therapy (creatinine clearance less than 5 ml/min) and 8 patients with varying degrees of renal impairment (creatinine clearance 11–52 ml/min). Following an oral dose of 10 mg endralazine the mean terminal elimination half-life (βt1/2) in the dialysis sub-group was prolonged at 7.1 h (range 3.3 to 14 h), compared to 3.6 h in the other renal patients (and compared to 2.3 h in hypertensive patients with normal renal function). After one week's therapy with 10 mg B.D. endralazine in the 8 patients with moderate renal impairment there was a significant increase in βt1/2 to 8.6 h but there was no significant change in the area under the drug concentration-time curve and no evidence of drug accumulation. In this study those patients with the poorest renal function had the longest βt1/2 after acute dosing. There was a significant correlation between creatinine clearance and acute βt1/2 but there was considerable variability in individual patients and, even with severe degrees of renal impairment, major dose adjustments do not appear necessary.
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  • 42
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    Pharmacokinetics of a fixed combination of sotalol and hydrochlorothiazide in hypertensive patients with moderate renal insufficiency (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 361-362 
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    ISSN: 1432-1041
    Keywords: sotalol ; hydrochlorothiazide ; pharmacokinetics ; moderate renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.
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  • 43
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    Pharmacokinetics of propranolol during pregnancy (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 583-587 
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    ISSN: 1432-1041
    Keywords: propranolol ; pregnancy ; beta-adrenoceptor antagonist ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Propranolol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32 and 36 weeks gestation and when at least 6 weeks postparum. On both occasions, subjects were given propranolol 120 mg orally or 10 mg intravenously in randomised order with a minimum washout period of 1 week. Propranolol was assayed in plasma by gas-liquid chromatography with electron-capture detection and the pharmacokinetic parameters were investigated. There were no significant alterations in elimination half-life, clearance or apparent volume of distribution per kilogram antenatally compared with postnatally: bioavailability was also unchanged. It is concluded that the disposition of propranolol is not altered during pregnancy.
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    Pharmacokinetics of the oral narcotic analgesic bezitramide and preliminary observations on its effect on experimentally induced pain (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 615-618 
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    ISSN: 1432-1041
    Keywords: Bezitramide ; oral absorption profile ; pharmacokinetics ; male volunteers ; experimental pain ; biliary excretion in rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oral absorption of bezitramide 5 mg was studied in 7 human volunteers, using a specific radioimmuno-assay which measured both bezitramide and its active metabolite R-4618. A lag time of 0.5–1.0 h and a Cmax of 5.4 ng/ml plasma were found, the latter occurring 2.5–3.5 h after administration. The apparent elimination half-life varied from 11 to 24 h. Less than 0.3% of the dose was excreted unchanged in the urine. High concentrations in the faeces of some individuals indicate incomplete absorption and/or biliary secretion. The analgesic effect, using a standardized superficial electrical stimulation method, reached its maximum between 2.5 and 3.5 h after dosing, in accordance with the absorption phase. The duration of the effect was highly variable. Experiments in rats (n=6,3H-bezitramide 2.5 µg), demonstrated extensive biliary excretion (up to 70% of total radioactivity) and less than 3% of the label was removed by urinary excretion.
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  • 45
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    Pharmacokinetics of cimetidine in critically ill patients (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 341-346 
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    ISSN: 1432-1041
    Keywords: cimetidine ; pharmacokinetics ; critically ill patients ; intravenous administration ; dose individualization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cimetidine disposition was studied after rapid (1 min) intravenous infusion in eight critically ill patients aged between 20 years and 77 years; one patient was studied on two occasions. Cimetidine dose was 300 mg in seven patients and 400 mg in the remaining patient. Arterial plasma cimetidine concentrations at the end of the infusion were very high and ranged from approximately 15–35 mg/l. Pharmacokinetic parameters displayed wide interpatient variability (coefficients of variation of 30–50%) and significant relationships emerged between some of these parameters and certain patient characteristics. Most notable, total systemic plasma clearance of cimetidine was directly related to estimated creatinine clearance (p〈0.01). This relationship might prove to be a useful method of individualizing cimetidine dosage in critically ill patients.
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  • 46
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    Effect of liver failure on the pharmacokinetics of cyclophosphamide (1984)
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    European journal of clinical pharmacology 26 (1984), S. 591-593 
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    ISSN: 1432-1041
    Keywords: cyclophosphamide ; liver failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cyclophosphamide was investigated in 7 patients in severe liver failure. The pharmacokinetic data were compared with those derived from a matched control group of patients with normal liver function. The half-life (t1/2) of cyclophosphamide following intravenous administration in patients with liver failure was 12.5±1.0 h (m±SD), which was significantly longer than in the normal controls in whom it was 7.6±1.4 h (p〈0.001). The mean total body clearance (Clt) was significantly smaller in liver failure at 44.8+8.6l·kg−1 than in the controls in whom it was 63.0±7.6l·kg−1 (p〈0.01). It is concluded that severe liver disease has a significant effect on the disposition of cyclophosphamide, and that it could lead to accumulation of the drug in the body.
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  • 47
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    Intrapatient variation in tobramycin kinetics in low birth weight infants during first postnatal week (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 647-649 
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    ISSN: 1432-1041
    Keywords: tobramycin ; newborn infants ; intrapatient variations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nineteen newborn infants receiving tobramycin, 2.5 mg/kg every 12 h were studied on two occasions at steady-state during the first week of postnatal age. The two studies were separated by two to four days. Total body clearance of tobramycin averaged 1.15 and 1.14 ml/min/kg (p〉0.05), apparent volume of distribution averaged 0.82 and 0.68 l/kg (p〉0.05), and elimination half-life averaged 8.6 and 7.1 h (p〉0.05), during the first and second study, respectively. When the data were further analyzed based on the birth weight, tobramycin kinetics changed during the second study compared to the first study in very low birth weight infants. In eight infants ⩽1.5 kg birth weight, although total clearance of tobramycin was similar, the average apparent volume of distribution decreased from 1.04 l/kg during the first study to 0.73 l/kg during the second study (p〈0.05) and elimination half-life from 11.1 h during the first study to 8.7 h during the second study (p〈0.05). These data indicate that these infants may require a change in dosing interval with continued tobramycin therapy during the first week of postnatal age. Intrapatient variation in tobramycin kinetics should be considered, in addition to the interpatient variation reported previously, when monitoring the serum concentration to individualize tobramycin therapy in newborn infants ⩽1.5 kg birth weight.
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    Acetaminophen accumulation in pediatric patients after repeated therapeutic doses (1984)
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    European journal of clinical pharmacology 27 (1984), S. 57-59 
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    ISSN: 1432-1041
    Keywords: acetaminophen ; pediatric patients ; fever therapy ; accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetaminophen serum concentrations were studied in 21 infants and children with fever. The maximum serum concentrations ranged from 9.96 to 19.6 µg/ml after a single dose of 12–14 mg/kg and 13.9 to 40.1 µg/ml after a single dose of 22–27 mg/kg. Ten patients were restudied at steadystate after repeat doses had been given every 4 or 8 h for 1 to 3 days. Total area under the acetaminophen serum concentration-time curve normalized for dose averaged 0.181 (ml/min/kg)−1 after the first dose and 0.202 (ml/min/kg)−1 at steady-state (p〈0.05). Five patients showed a 13 to 44% increase in the AUC; one had a 10% decrease in the AUC; and four had less than 6% change in the AUC. There was no evidence of hepatotoxicity. These data suggest that acetaminophen may accumulate after repeated therapeutic doses in children with fever.
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  • 49
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    Effect of food on pharmacokinetics of chlorambucil and its main metabolite, phenylacetic acid mustard (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 111-114 
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    ISSN: 1432-1041
    Keywords: chlorambucil ; chronic lymphocytic leukaemia ; phenylacetic acid mustard ; food intake ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the pharmacokinetics of chlorambucil (C) and its cytotoxic metabolite, phenylacetic acid mustard (PAM), has been studied in man after oral doses of chlorambucil. The administration of chlorambucil with food resulted in slower absorption than when fasting. However, the area under the plasma concentration-time curve (AUC) was unaffected. The mean ratio AUCPAM/AUCC was 2.8 (range 1.4–7.1) under fasting and 3.3 (range 1.3–7.4) under nonfasting conditions. The metabolite very probably plays an important role in the cytotoxic effects observed after administration of C, since calculations show that a major fraction of the metabolite is eliminated by alkylation reactions.
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  • 50
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    Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 115-117 
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    ISSN: 1432-1041
    Keywords: benzodiazepine antagonist ; Ro 15-1788 ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40±8%, mean±SD). A negligible amount (〈0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9±0.2 h, and high total plasma and blood clearances of 691±216 ml/min and 716±199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.
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    Absorption of enprofylline from the gastrointestinal tract in healthy subjects (1984)
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    European journal of clinical pharmacology 27 (1984), S. 329-333 
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    ISSN: 1432-1041
    Keywords: enprofylline ; healthy subjects ; absorption ; pharmacokinetics ; oral- ; duodenal- ; colonic administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1–4 mg/l, i.e. in the assumed “therapeutic interval” according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean±SEM) were 32.5±8.7, 13.3±2.5, and 157±23 min.
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    Pharmacokinetic study of the new sulfamethopyrazine-trimethoprim combination (kelfiprim) in renal insufficiency (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 345-348 
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    ISSN: 1432-1041
    Keywords: kelfiprim ; trimethoprim combination ; sulfamethopyrazine combination ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The combination of trimethoprim (TMP) and sulfamethopyrazine (SMP) has been successfully used to treat chronic urinary tract infections. Since parenchymal involvement associated with renal insufficiency of varying degree is not infrequent in these patients, it was considered important to study the pharmacokinetics of TMP and SMP in a fixed dose combination. Four groups of patients were studied: 1) 4 patients with endogenous creatinine clearance (CLcR) between 80 and 40 ml/min; 2) 3 patients with CLcR between 40 and 10 ml/min; 3) 3 patients on chronic peritoneal dialysis (CAPD); and 4) 3 patients on haemodialysis. A single oral dose of 250 mg TMP and 200 mg SMP was given to each patient. Multiple samples were collected over 9 days and the following pharmacokinetic parameters were calculated: total area under the plasma level curve, slow disposition rate constant β and the corresponding t1/2β, plasma clearance and the apparent volume of distribution. The results show that the two moieties of the TMP-SMP combination behaved differently in uraemic patients as fas as elimination rate was concerned. TMP was eliminated more slowly both in patients with diminished renal function and in those subjected to haemo- or peritoneal dialysis. The reduction in the rate of elimination of TMP was significantly correlated with the degree of renal impairment. The elimination of SMP, however, was not significantly affected by the reduced renal function; indeed a tendency to increase was noted, at least in dialyzed patients. However, as in patients with mild renal insufficiency (CLcR〉40 ml/min) no substantial change in plasma clearance rate need be expected, the TMP-SMP combination could be given to them in the same dose schedule as in people with normal renal function.
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    Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 441-446 
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    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; metabolites ; pharmacokinetics ; single/multiple oral doses ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of canrenone and ‘total metabolites’ after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and ‘total metabolites’ were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2α) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2β) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of ‘total metabolites’ after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of ‘total metabolites’ was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and ‘total metabolites’ were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.
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    Pharmacokinetics of mepindolol in patients with chronic renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 429-433 
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    ISSN: 1432-1041
    Keywords: mepindolol ; renal failure ; haemodialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with a creatinine clearance of 14 to 37 ml/min/1.73 m2 were each given an oral dose of 10 mg of the beta-blocker mepindolol sulphate (Corindolan). In addition, two dialysis patients received the same dose either during hemodialysis or on a dialysis-free day. Plasma levels of mepindolol were measured by a sensitive, specific HPLC method. Mepindolol was rapidly absorbed in all the patients. The maximum plasma level of 35±8 ng/ml was reached after 1.4±0.5 h. The half-life of disposition was 4.0±1.5 h. The area under the plasma concentration-time curve was 237±84 ng × h/ml. The data obtained were no different from those found in normal healthy volunteers.
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    Tolerance and pharmacokinetics of A515U, an acyclovir analogue, in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 471-475 
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    ISSN: 1432-1041
    Keywords: acyclovir ; A515U ; 6-deoxyacyclovir ; pharmacokinetics ; prodrug ; antiviral chemotherapy ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A515U (6-deoxyacyclovir) is an analogue of acyclovir devoid of antiviral activity in vitro but which is well absorbed and undergoes conversion to acyclovir after oral administration to rats. The tolerance and pharmacokinetics of various doses of A515U have been studied in 8 healthy volunteers. Single oral doses of 25, 50, 100, 200 and 400 mg A515U and 400 mg acyclovir for comparison were administered to the volunteers at weekly intervals. Concentrations of the parent drug and acyclovir were determined in plasma and urine. The prodrug was well tolerated and did not cause adverse reactions or changes in haematological or biochemical variables. It was well absorbed and conversion to acyclovir was rapid and extensive at all doses. Plasma concentrations of acyclovir achieved with 50 mg A515U orally were comparable to and less variable than those produced by 400 mg acyclovir. A515U was rapidly cleared with a short plasma elimination half life of approximately 0.5 h. The attainment of high plasma concentrations of acyclovir by oral administration of a prodrug may represent an important advance in antiviral chemotherapy.
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    Biperiden effects and plasma levels in volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 619-621 
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    ISSN: 1432-1041
    Keywords: biperiden ; pharmacokinetics ; pharmacodynamics ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of biperiden was studied and compared with pharmacodynamics (pupil size, accomodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 h, biperiden was rapidly absorbed with a half-life of 0.3 h, plasma peak levels of 5 ng/ml being reached after 1.5 h. Biperiden showed good tissue penetration (distribution half-life 0.6 h; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 h, and the oral clearance was 146 l/h. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 h (accommodation).
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    URL: http://dx.doi.org/10.1007/BF00556903
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    Kinetics of thiamin and thiamin phosphate esters in human blood, plasma and urine after 50 mg intravenously or orally (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 73-78 
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    ISSN: 1432-1041
    Keywords: Thiamin ; thiamin monophosphate ; thiamin diphosphate ; distribution ; thiamin elimination ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentrations of thiamin and thiamin monophosphate and diphosphate in plasma and whole blood samples were assessed in six healthy subjects for 12 h and in urine for 24 h following an IV and PO bolus dose of 50 mg thiamin HCl. Unphosphorylated thiamin increased rapidly in plasma after IV administration and then decreased to its initial value within 12 h in all but one subject; the half-life was 96 min. Thiamin mono and -diphosphate increased moderately (56%), and decreased slowly; the half-life of diphosphate was 664 min. Within 24 h, 53% of the administered dose was recovered in the urine, indicating a restricted distribution. After oral administration, the peak thiamin concentration in plasma was reached after 53 min and the concentration then had increased to 179% of its initial value. The elimination half-life was 154 min, and only 2.5% of the given dose was recovered in the urine. The relative bioavailability of thiamin was 5.3%. A moderate amount of the administered thiamin was stored in blood. Other body tissues must play an important part, therefore, in the distribution of thiamin.
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    URL: http://dx.doi.org/10.1007/BF00315284
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    Lack of effect of magnesium-aluminium hydroxide on the absorption of theophylline given as a pH-dependent sustained release preparation (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 85-88 
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    ISSN: 1432-1041
    Keywords: Theophylline ; Antacids ; Asthma ; slow-release formulations ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Antacids can modify the pharmacokinetic parameters of sustained-release preparations of theophylline by changing the gastric pH. Though this has been studied with various theophylline/antacid combinations, the specific preparations investigated here have not previously been tested. The objective of the study was to assess any change in the availability of theophylline from a sustained-release preparation (SR), induced by the coadministration with an antacid. The study was designed as a double-blind randomized crossover trial in the Pneumology Departments of three general hospitals. Fifteen patients were studied. They all had stable asthma treated with theophylline and no major organ failure or gastro-intestinal lesions requiring the use of antacids. The antacide (aluminium hydroxide 800 mg and magnesium hydroxide 800 mg), or placebo, tid, was added to a stable regimen of theophylline SR bid, for 4 days, in crossover fashion. Plasma theophylline concentrations were measured before and 1,2,3,4,6,8,10,12,16 and 24 h after the morning dose of Armophylline on the fourth day of each treatment period; the maximum plasma concentration (Cmax), and time to Cmax (tmax) were noted, and the area under the 24-h time-concentration curve (AUC0–24) and mean plasma concentration (Cmean) were computed. Peak expiratory flows on the same day, before and 3, 6 and 12 h after the morning dose of Armophylline were also measured. There was no change in any of the parameters studied. The addition of the antacide to theophylline, each given according to standard clinical practice, did not modify the pharmacokinetics of the latter. This result probably can not be generalized to all pairs of sustained-release theophylline-antacid preparations.
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    URL: http://dx.doi.org/10.1007/BF00315286
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    Time course of the changes in prednisolone pharmacokinetics after co-administration or discontinuation of rifampin (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 287-289 
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    ISSN: 1432-1041
    Keywords: Prednisolone ; Rifampin ; drug-interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have investigated changes in the pharmacokinetics of prednisolone caused by co-administration or discontinuation of rifampin. Serial IV pharmacokinetic studies of prednisolone (1 mg/kg) in groups of 3 patients over a 1 month period of rifampin co-treatment or after its withdrawal, revealed significant changes in the area under the curve, the total clearance, the non-renal clearance and the half-life. The changes in the pharmacokinetic parameters reached a 1.5 to 2-fold plateau after 2 weeks and the half maximal effect was attained within 5 days. Neither the volume of distribution nor the protein binding of prednisolone were significantly altered.
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    The pharmacodynamics and pharmacokinetics of the combination of nifedipine and doxazosin (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 279-282 
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    ISSN: 1432-1041
    Keywords: Nifedipine ; Doxazosin ; combination ; pharmacokinetics ; liver blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a single-blind study 12 normotensive men took nifedipine 20 mg (Group 1, n=6) or doxazosin 2 mg (Group 2, n=6), followed by the combination. Each subject attended on four 9-h study days for evaluation of the effects of single and multiple doses of the monotherapy and the effects of adding single and multiple doses of the second drug. Measurements of BP, HR, plasma drug concentrations, and apparent liver blood flow were recorded. The combination was generally well tolerated. BP was consistently lower with the combination than with either monotherapy: for example, average erect BP was 108/61 (Group 1) and 112/62 mmHg (Group 2) compared with 122/66 and 116/68 during steady-state monotherapy. The introduction of nifedipine in Group 2 was associated with a significant increase in liver blood flow at 1.5 h: 1560 vs 1050 ml · min−1 during monotherapy with doxazosin. There was no significant kinetic interaction. In particular, the steady-state AUC of doxazosin was unaffected by the addition of nifedipine: 257, 307, 301, and 256 ng · ml−1 · h for the 4 study days (Group 2).
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    On the question of interindividual variations in chloroquine concentrations (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 383-385 
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    ISSN: 1432-1041
    Keywords: Chloroquine ; Desethylchloroquine ; Blood levels ; Steady state concentrations ; pharmacokinetics ; rheumatic diseases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a review of studies using appropriate methods for drug determinations and controlled intake, an interindividual variation in chloroquine concentrations of 2.3 to 5.6-fold was found. In our department, steady-state concentrations were evaluated in 40 patients with rheumatic diseases. The variation in whole blood concentrations was 11-fold for chloroquine and 10-fold for the desethylchloroquine metabolite. The mean ratio between desethylchloroquine and chloroquine concentrations was 0.53 and the Spearman-Rank correlation 0.92. The correlation between age and the ratio of chloroquine concentration/dose was 0.36 (P〈0.05) and the corresponding correlation for body weight was −0.43 (P〈0.05). Our data indicate that body weight and age are important independent factors for the disposition of chloroquine. However, when extensive 100-fold variations in concentrations are found between individuals we suggest that the reliability of the dose intake should be questioned.
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    Effect of iron deficiency anaemia and its treatment on single dose phenytoin bioavailability (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 387-388 
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    ISSN: 1432-1041
    Keywords: Iron deficiency anaemia ; Phenytoin ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Iron deficiency is a common nutritional deficiency, which leads to structural functional and enzymatic changes in the body that may affect the pharmacokinetics of drugs. The present study in 7 normal volunteers and 8 adult male patients with irondeficiency anaemia (IDA) was done to investigate the effect of iron deficiency and its treatment with total dose iron (TDI) on the bioavailability of a single dose of phenytoin. Phenytoin bioavailability was investigated before and 3 and 28 days after TDI. The bioavailability parameters Cmax, tmax, AUC and 2 h phenytoin concentrations were not significantly different in anaemic patients as compared to normal volunteers before or after treatment, except for an increase in tmax 28 days after TDI treatment.
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    Effects of a sauna on the pharmacokinetics and pharmacodynamics of midazolam and ephedrine in healthy young women (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 377-381 
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    ISSN: 1432-1041
    Keywords: Midazolam ; Ephedrine ; Sauna ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of a sauna on the pharmacokinetics and pharmacodynamics of single doses of ephedrine 50 mg and midazolam 15 mg have been studied in 6 young healthy women in a placebo-controlled, double-blind study. The sauna (3 × 10 min; temperature 80–100°C; relative humidity 30–50%) modified the pharmacokinetics of both drugs: it retarded the absorption of midazolam estimated as Ka values, and it reduced the mean plasma midazolam concentrations at 2 h; ephedrine, was absorbed more rapidly and the maximum plasma concentration occurred earlier than in the control sessions. Changes in the pharmacodynamics due to the sauna were consistent with the pharmacokinetic findings: midazolam decreased flicker recognition and induced exophoria significantly less during the early sauna period than in the control session, whereas ephedrine made the volunteers subjectively more alert at that time. Later, at 2.5 and 3.5 h (1 h 20 min and 2 h 20 min after cessation of the sauna), and despite the equalisation of the plasma levels, midazolam caused significantly more exophoria after the sauna than in the control situation. This indicates an influence of a sauna on drug pharmacodynamics in the post-sauna adaptive phase. The results suggest that exposure to a sauna may alter both drug pharmacokinetics and pharmacodynamics.
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    Minimal biliary excretion and enterohepatic recirculation of metoclopramide in patients with extrahepatic cholestasis (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 415-418 
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    ISSN: 1432-1041
    Keywords: Metoclopramide ; Biliary excretion ; enterohepatic recirculation ; Nasobiliary drainages ; pharmacokinetics ; biliary obstruction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The biliary excretion and apparent oral clearance of metoclopramide (MCL) were determined after oral administration of 1 mg MCL/kg body weight to 10 patients suffering from extrahepatic cholestasis with nasobiliary tube for drainage of the common bile duct. A bilioduodenal endoprosthesis was subsequently fitted in 6 of these patients, i.e. the enterohepatic circulation was restored, and the apparent oral clearance was re-determined. Biliary excretion, comprising free MCL and the products of conjugation, accounted for less than 1% of the administered dose. In accordance with this, the median areas under the plasma concentration-time-curves AUC(0–15 h) in patients with intact and interrupted enterohepatic recirculation were of similar size. The pharmacokinetic values in patients with cholestasis (median apparent oral clearance 0.5 l·kg−1·h−1; median t1/2 4.5 h) were similar to those previously reported in patients with healthy liver function. We conclude that it is not necessary to adjust single doses of MCL in patients recovering from obstructive jaundice.
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    A comparative assessment of amlodipine and felodipine ER: pharmacokinetic and pharmacodynamic indices (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 425-430 
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    ISSN: 1432-1041
    Keywords: Amlodipine ; Felodipine ER ; pharmacokinetics ; blood pressure response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This study investigated potential therapeutic differences between Amlodipine 5 mg and Felodipine ER 10 mg in 12 normotensive/borderline hypertensive subjects by comparison of the plasma drug concentration-time profiles and the blood pressure and heart rate responses. There was significantly less trough-to-peak variability in plasma drug concentrations with amlodipine with a ratio of 67%, compared to 37% for felodipine. Correspondingly there was less variability with amlodipine in the blood pressure reductions across the dosage interval. Overall, amlodipine displayed a more consistent hypotensive effect across 24 hours and lower blood pressure values at trough, i. e. 24 hours post-dose.
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    Effect of metoclopramide and loperamide on the pharmacokinetics of didanosine in HIV seropositive asymptomatic male and female patients (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 409-413 
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    ISSN: 1432-1041
    Keywords: Didanosine ; Metoclopramide ; Loperamide ; HIV patients ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of orally-administered didanosine were evaluated in 6 male and 6 female HIV seropositive patients to determine the effect of pretreatment with metoclopramide, an inducer of gastrointestinal motility, and loperamide, which retards motility. Using a randomized, balanced, crossover design, each patient received the following three treatments under fasting conditions: didanosine as a single agent, didanosine 5 min after a single 10 mg intravenous dose of metoclopramide, and didanosine 1 h after the final of 4 doses, 4 mg each, of loperamide. Serial blood and urine samples were collected for up to 12 h after each dose. Plasma and urine aliquots were analysed for intact didanosine using HPLC with UV detection. Pharmacokinetic parameter values were calculated using noncompartmental methods. The mean Cmax values were significantly greater for the didanosine single agent (2.04 μg·ml−1) and didanosine with metoclopramide (2.30 μg·ml−1) treatments than for the combination of didanosine with loperamide (1.57 μg·ml−1). The t1/2 in males was significantly greater than in females for the didanosine (1.75 vs 1.12 h, respectively) and didanosine with metoclopramide treatments (1.74 vs 1.20 h, respectively). No significant treatment or gender effects were observed for AUC or UR (urinary recovery). The pharmacokinetics of didanosine were not altered appreciably by dosing with metoclopramide. Administration with loperamide affected the rate but not the extent of absorption. There were no clinically relevant differences between males and females in the disposition of didanosine.
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    The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 431-436 
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    ISSN: 1432-1041
    Keywords: Fosinopril ; ACE inhibitors ; haemodialysis ; pharmacokinetics ; pharmacokinetics-pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous 14C-fosinoprilat (7.5 mg), oral 14C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study. Mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vss), mean residence time (MRTiv), and t1/2 values after IV administration of 14C-fosinoprilat were 2,042 μg·ml−1, 11.3 ml·min−1, 11.01, 16.3 h and 28.3 h, respectively. Following oral administration of 14C-fosinopril, mean Cmax, time to maximum plasma concentration (tmax), and fosinoprilat bioavailability values were 197 ng·ml−1, 5.2 h and 29.2 %. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15 % and 2 % of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5 % of the administered dose. The maximum effect (Emax) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. Emax ranged from 95.3 to 102.5 %, and IC50 (the fosinoprilat concentration required to produce 50 % of Emax) ranged from 2.6 to 4.2 ng·ml−1. Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.
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    The pharmacokinetics and haemodynamic effects of continuous nicorandil infusion in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 437-443 
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    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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    Plasma levels of piperacillin and vancomycin used as prophylaxis in liver transplant patients (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 529-534 
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    ISSN: 1432-1041
    Keywords: Piperacillin ; Vancomycin ; liver transplantation ; antibioprophylaxis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of piperacillin and vancomycin used intravenously as antibioprophylaxis were measured in the plasma and bile during orthotopic liver transplantation. Piperacillin (4 g and then 2 g every 4 h) and vancomycin (1 g and then 0.5 g every 6 h) were infused in 10 patients. During vascular clamping without venovenous bypass, clearance of both antibiotics decreased in relation to renal insufficiency. During the surgical procedure, volume of distribution of both drugs increased because of fluid redistribution. The peaks of piperacillin after first, second and third administrations were respectively 314, 265 and 210 mg·l−1, while trough levels were 46.5, 55.2 and 54.5 mg·l−1. The peaks of vancomycin were 54.4, 49.6 and 40.9 mg·l−1, while first and second trough levels were 9.5 and 12 mg·l−1. These plasma concentrations were quite similar to levels reported in healthy subjects despite large blood loss and fluid replacement. However, piperacillin trough concentrations (〈64 mg/l) were too low in relation to its concentration-dependent antibacterial activity and vancomycin peak concentrations (≥40 mg/l) were slightly too high in relation to its toxicity.
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    The consequences of H2 receptor antagonist — piroxicam coadministration in patients with joint disorders (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 507-512 
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    ISSN: 1432-1041
    Keywords: Piroxicam ; H2 receptor antagonists ; Arthritis ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A randomised crossover study was performed in subjects with rheumatoid arthritis (or other arthropathies) to investigate if any alteration in the steady pharmacokinetics of the NSAID piroxicam (a drug which is extensively metabolised via cytochrome P450) or its major metabolites occurred as a result of coadministering either cimetidine or nizatidine. Twelve females and 2 males with mean age, weight, and albumin concentrations of 58 years, 61 kg, and 40 g·L−1 respectively, completed the study. Comparisons were made between the following parameters: plasma piroxicam AUCs [AUC0-24(P)], plasma 5-hydroxypiroxicam AUCs [AUC0-24(5-OHP)], the ratio of these i.e. AUC0-24(5-OHP):AUC0-24(p), the % piroxicam daily dose excreted in urine as 5-hydroxypiroxicam (before and after glucuronidase incubation); and the mean of the steady state trough piroxicam, and 5-hydroxypiroxicam concentrations (obtained during each study phase in addition to the wash-out period). A statistically significant difference as a result of initiating either cimetidine or nizatidine was obtained only for the ratio AUC0-23(5-OHP):AUC0-24(P). This was indicative of a weak potential to inhibit piroxicam hydroxylation. No clinically significant alteration in the steady state pharmacokinetics of piroxicam occurred in these subjects as a result of cimetidine or nizatidine coadministration. Consequently it is unlikely that any adverse events would arise from these combinations.
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    Absorption of zidovudine in patients with diarrhoea (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 501-503 
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    ISSN: 1432-1041
    Keywords: Zidovudine ; Diarrhoea ; HIV ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Many patients with AIDS have gastrointestinal complaints, including the major clinical disorder of chronic diarrhoea. The pharmacokinetics of zidovudine was studied in 9 male patients with HIV infection and diarrhoea to establish whether drug absorption was impaired in them. The peak plasma concentration and AUC after a single oral dose of 200 mg, were the same as those reported in 6 healthy male volunteers (3.1 vs 4.0 μmol·l−1 and 7.2 vs 5.2 μmol·h·l−1, respectively). Since the bioavailability of zidovudine is not particularly impaired, oral zidovudine therapy can be maintained in patients with diarrhoea.
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    Pharmacokinetics of nocloprost in human volunteers and its relation to dose (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 497-500 
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    ISSN: 1432-1041
    Keywords: Nocloprost ; PGE2-analoga ; clearance ; half life ; absolute bioavailability ; pharmacokinetics ; i. v. dose ; oral dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and absolute bioavailability of nocloprost, a synthetic PGE2-analogue with cytoprotective properties, was investigated in human volunteers as a function of the dose. Ten young male volunteers received nocloprost 5 μg i. v. and 100, 200 and 400 μg p.o. in random order at weekly intervals. Serum nocloprost levels were monitored for up to 12 h after each dose, using a specific, validated assay. After nocloprost 5 μg i. v. the highest serum level of 373 pg·ml−1 was found in the first sample 5 min after injection, and the subsequent decline showed one or two phases, with half-lives of 4 and 49 min. The AUC was 89 pg·h·ml−1, the total plasma clearance was 13.2 ml·min−1·kg−1, and the volume of distribution at steady state was 0.16 l·kg−1. After oral administration the maximum serum level and AUC increased in proportion to the dose. tmax showed a wide scatter, with an average value of about 30 min independent of the dose. Although not detectable in every subject, post maximum serum levels declined biphasically, with half-lives of ca 10 and 35–40 min. The absolute bioavailability after oral administration averaged about 2% and was independent of the dose.
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    Pharmacokinetics of exogenous adenosine in man after infusion (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 505-507 
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    ISSN: 1432-1041
    Keywords: Adenosine ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    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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    Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 575-578 
    Details
    ISSN: 1432-1041
    Keywords: Pantoprazole ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma pharmacokinetics of pantoprazole have been investigated following single intravenous infusion and single oral administration at a dose of 40 mg to 12 healthy male subjects in a randomised cross-over study. Both treatments were generally well tolerated and no relevant compound-related adverse events were noted. The plasma pharmacokinetics of pantoprazole following intravenous infusion in this group of subjects were characterised by a total plasma clearance of 0.13 l·h−1·kg−1 and apparent terminal elimination half-life 1.9 h. The apparent volume of distribution estimated at steady state (0.171·kg−1) was compatible with the localization of a major fraction of the compound in extracellular water. Following oral administration as an enteric-coated tablet formulation, a variable onset of absorption was followed by rapid attainment of maximum plasma concentrations of pantoprazole. Pantoprazole was well absorbed following oral administration; the absolute systemic bioavailability of the compound was estimated as 77% (95% CI, 67 to 89%).
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    URL: http://dx.doi.org/10.1007/BF02440862
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    Pharmacokinetic evaluation of oral 17β-oestradiol and two different fat soluble analogues in ovariectomized women (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 563-568 
    Details
    ISSN: 1432-1041
    Keywords: Oestradiol analogues ; 17β-oestradiol ; oestrone ; oestriol ; micronised oestradiol ; oestradiol cyclo-octylacetate ; oestradiol decanoate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A randomised, single-blind comparative study was carried out in 9 ovariectomized women to evaluate the kinetics of single doses of three different steroid combinations: 0.150 mg desogestrel +2.0 mg micronized 17β-oestradiol, 0.150 mg desogestrel +0.500 mg 17β-oestradiol cyclo-octyl acetate and 0.150 mg desogestrel +1.0 mg 17β-oestradiol decanoate. Serum levels of 17β-oestradiol and oestrone were measured, as well as the excretion of 17β-oestradiol and its metabolites (oestrone and oestriol) in urine. In relation to the doses given, higher peak serum concentrations of 17β-oestradiol were obtained after the two fat soluble analogues, while the AUCs were similar to that after micronised 17β-oestradiol. However, there was more extensive conversion of the micronised 17β-oestradiol preparation into oestrone compared to 17β-oestradiol cyclo-octyl acetate and 17β-oestradiol decanoate. The oestrone/17β-oestradiol serum concentration ratio was approximately 2.6 before tablet intake and remained essentially unchanged after intake of 17β-oestradiol cyclo-octyl acetate and 17β-oestradiol decanoate. After micronized 17β-oestradiol however, there was a 2–3-fold increase in the ratio at Cmax and slower elimination of 17β-oestradiol from plasma, which may be due to the fact that high serum oestrone levels may serve as a reservoir, since both a metabolite and also a precursor of 17β-oestradiol. The urinary excretion of 17β-oestradiol, oestrone and oestriol was highest after oral administration of micronized 17β-oestradiol compared to 17β-oestradiol cyclo-octyl acetate and 17β-oestradiol decanoate. The time pattern of urinary excretion reflected the serum concentration profiles of the preparations given.
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    URL: http://dx.doi.org/10.1007/BF02440860
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    On the bioavailability of 2-chloro-2′-deoxyadenosine (CdA) (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 579-582 
    Details
    ISSN: 1432-1041
    Keywords: 2-Chloro-2′-deoxyadenosine (CdA) ; omeprazole ; food ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of oral CdA (0.24 mg/kg) was studied in 4 patients (1 with hairy cell leukaemia and 3 with B-cell chronic lymphocytic leukaemia) to determine any effect of food and fasting with and without omeprazole. Food intake did not significantly influence the bioavailability of CdA (42% after food intake vs 46% while fasting) but it did reduce the maximum plasma concentration (Cmax) by 40%; 83 compared to 116 nM while fasting. The time to reach maximum concentration (tmax) was delayed about 0.8 h after food intake. Pretreatment with omeprazole did not significantly influence the bioavailability of CdA (51% vs 46% without), or the interindividual variability in bioavailability in the fasting state (C.V. 0.26 with and C.V. 0.27 without). In conclusion, there was a small, though not statistically significant reduction in the bioavailability of CdA after food intake. Omeprazole did not significantly improve the bioavailability of CdA.
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    URL: http://dx.doi.org/10.1007/BF02440863
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    Lack of a pharmacokinetic interaction between carvedilol and digitoxin or phenprocoumon (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 583-586 
    Details
    ISSN: 1432-1041
    Keywords: Carvedilol ; Drug interaction ; digitoxin ; phenprocoumon ; pharmacokinetic interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between carvedilol and digitoxin (Study I) or phenprocoumon (Study II) has been evaluated in groups of 12 healthy volunteers. The bioavailability (Cmax, tmax, AUC) of digitoxin and phenprocoumon were assessed after a single dose, given once alone and once on day 6 of treatment with carvedilol 25 mg o.d. Cmax, tmax, AUC and Ut of carvedilol and desmethylcarvedilol were also investigated after the fifth dose of carvedilol and after the sixth dose given concomitantly with digitoxin or phenprocoumon. In Study I, the 95% confidence intervals of the ratio test versus the reference findings were; digitoxin Cmax 0.80–1.20, tmax 0.56–1.14, AUC 0.97–1.33, and for carvedilol Cmax 0.81–1.22; tmax 0.66–1.23; AUC 0.91–1.17. Formation of the active metabolite desmethylcarvedilol and the urinary recovery of carvedilol and esmethylcarvedilol were not influenced by digitoxin. In Study II Cmax and AUC of phenprocoumon were not changed after carvedilol. Cmax of carvedilol was decreased after phenprocoumon. The kinetic parameters of phenprocoumon were Cmax 0.80–1.05, tmax 0.47–2.00, AUC 0.78–1.05, and for carvedilol Cmax 0.59–1.06, tmax 0.71–1.73; AUC 0.80–1.08, respectively. The plasma levels of desmethylcarvedilol and the urinary recovery of carvedilol and desmethylcarvedilol were not influenced by phenprocoumon. The blood pressure and heart rate after carvedilol alone were not affected by concomitant administration of digitoxin or phenprocoumon.
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    URL: http://dx.doi.org/10.1007/BF02440864
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    Minor and clinically non-significant interaction between toloxatone and amitriptyline (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 97-99 
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    ISSN: 1432-1041
    Keywords: Amitriptyline ; Toloxatone ; Depression ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between amitriptyline and toloxatone (a new MAOI-A) has been studied in 17 depressed in-patients. Amitriptyline and its demethylated and hydroxylated metabolites in blood and urine were measured at steady state after the administration of amitriptyline with and without toloxatone in steady state. The metabolic status of patients was determined using the dextromethorphan phenotyping test. There was only a minor pharmacokinetic interaction between amitriptyline (AMT) and toloxatone, with a small increase in the AMT/NT (nortriptyline) plasma ratio: 0.68 before and 0.78 after toloxatone. The urinary excretion and plasma levels of AMT and its metabolites were not affected by the co-therapy. Three of the patients were poor metabolisers, but this did not predict the magnitude of the drug interaction. The interaction does not justify plasma level monitoring of amitriptyline as the change in pharmacokinetics was so small.
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    Stereoselective pharmacokinetics of oral felodipine and nitrendipine in healthy subjects: correlation with nifedipine pharmacokinetics (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 163-169 
    Details
    ISSN: 1432-1041
    Keywords: Felodipine ; Nitrendipine ; Nifedipine ; pharmacokinetics ; stereoselectivity ; enantiomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all given as an oral dose of 20 mg in solution) have been investigated in a randomised cross-over study in 12 healthy male subjects using stereoselective assays. Both felodipine and nitrendipine exhibited stereoselective pharmacokinetics. On average, the AUCs of the active (S)-enantiomers of felodipine and nitrendipine were 139% and 104% higher than those of their optical antipodes, but the elimination half-lives of the enantiomers of each racemate were not different. The AUCs of nifedipine, rac-felodipine, rac-nitrendipine and of their enantiomers were highly correlated (all r〉0.83), suggesting closely related rate limiting steps in the in vivo first-pass metabolism of these high-clearance drugs. Stereoselectivity was only a minor contributor to inter-individual variability in the oral pharmacokinetics of these compounds in healthy subjects.
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    The effect of haemodialysis on the pharmacokinetics of perindoprilat after long-term perindopril (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 183-187 
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    ISSN: 1432-1041
    Keywords: Perindopril ; Haemodialysis ; angiotensin-converting enzyme inhibitors ; perindoprilat ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of perindoprilat, the active metabolite of perindopril, in 7 hypertensive patients undergoing haemodialysis after short-term and long-term (1 month) perindopril. We also measured angiotensin-converting enzyme activity. Each subject took 2 mg of perindopril after a 4-hour haemodialysis. Serial blood samples were obtained each hour during dialysis and between dialysis (7 samples over 44 h). Perindoprilat steady state was reached within 5 haemodialysis sessions. There was a high degree of angiotensin converting enzyme inhibition after the first dose. Administration for 1 month did not modify the time to peak perindoprilat concentration but significantly increased the mean maximal concentration: 10.2 versus 26.8 ng · ml−1. The mean accumulation ratio was 3.5. The mean reduction in perindoprilat concentration after dialysis was greater than 50%. Perindoprilat haemodialysis clearance was 62 ml · min−1 after the first administration and 72 ml · min−1 after 1 month. Tolerance of perindopril was good throughout the study. Treatment can be begun with 2 mg of perindopril after haemodialysis in hypertensive patients undergoing haemodialysis.
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    URL: http://dx.doi.org/10.1007/BF00315478
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    A clinical pharmacological study of subcutaneous nicotine (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 225-230 
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    ISSN: 1432-1041
    Keywords: Nicotine ; subcutaneous ; pharmacokinetics ; stable isotopes ; deuterium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The stable isotope-labeled compound 3',-3'-dideuteronicotine (nicotine-d2) was used to investigate the disposition kinetics and effects of nicotine administered subcutaneously to 6 smokers. Plasma nicotine-d2 concentrations were measured for 8 h after subcutaneous injection of 4 doses (0.4, 0.8, 1.2, and 2.4 mg). Peak plasma nicotine concentration correlated well with the dose, averaging 2.8 to 14.8 ng/ml, 19 to 25 min after injection of the 0.4 mg and 2.4 mg doses, respectively. The plasma clearance over bioavailability ratio (CL/f) averaged 12 to 13 ml · min−1 · kg−1, similar to the clearance reported previously for intravenously administered nicotine. Thus, bioavailability appears to be approximately 100%. The heart rate response was more sensitive to the nicotine dose than the blood pressure response. Subjective effects showed large interindividual variability. The results reported herein may be useful in planning future studies. Administration of nicotine by the subcutaneous route appears to be a practical and safe method for studying the human pharmacology of nicotine.
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    URL: http://dx.doi.org/10.1007/BF00271362
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    Effect of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and electrocardiographic effects of terfenadine (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 41-46 
    Details
    ISSN: 1432-1041
    Keywords: Terfenadine metabolism ; cimetidine ; ranitidine ; antihistamines ; Torsades de Pointes ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Terfenadine is a widely prescribed non-sedating antihistamine which undergoes rapid and almost complete first pass biotransformation to an active carboxylic acid metabolite. It is unusual to find unmetabolised terfenadine in the plasma of patients taking the drug. Terfenadine in vitro is a potent blocker of the myocardial potassium channel. Overdose, hepatic compromise and the coadministration of ketoconazole and erythromycin result in the accumulation of terfenadine, which is thought to be responsible of QT prolongation and Torsades de Pointes ventricular arrhythmia in susceptible individuals. Cimetidine and ranitidine are two popular H2 antagonists which are often taken with terfenadine. The effects of cimetidine and ranitidine on terfenadine metabolism were studied in two cohorts of 6 normal volunteers given the recommended dose of terfenadine (60 mg every 12 h) for 1 week prior to initiation of cimetidine 600 mg every 12 h or ranitidine 150 mg every 12 h. Pharmacokinetic profiles and morning pre-dose electrocardiograms were obtained whilst the patients were on terfenadine alone and after the addition of cimetidine or rantidine. One of the subjects in each cohort had a detectable plasma level of parent compound after 1 week of terfenadine therapy alone; it did not accumulate further after addition of the H2 antagonist. The pharmacokinetics of the carboxylic acid metabolite of terfenadine (Cmax, tmax, AUC) were not significantly changed after co-administration of either H2 antagonist. None of the remaining 5 subjects in either cohort demonstrated accumulation of unmetabolised terfenadine after addition of the respective H2 antagonist and electrocardiographic QT intervals and T-U morphology in them was not changed during the course of the study. We conclude that cimetidine and ranitidine in the dosages used in this study did not affect the metabolism of terfenadine, and that patients exposed to these drug combinations are not at increased risk of altered cardiac repolarisation.
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    The disposition and protein binding of batanopride and its metabolites in subjects with renal impairment (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 59-63 
    Details
    ISSN: 1432-1041
    Keywords: Batanopride ; Renal disease ; metabolites ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the disposition of batanopride and its three major metabolites (the erythro-alcohol, threo-alcohol, and N-desethyl metabolites) in 27 subjects with various degrees of renal function after intravenous infusion of a single dose of 3.6·mg·kg−1 of batanopride over 15 min. The subjects were assigned to one of three treatment groups: group 1, normal renal function (creatinine clearance ≥75 ml·min−1·1.73 m−2; n=13); group 2, moderate renal impairment (creatinine clearance 30–60 ml·min−1·1.73 m−2; n=8); group 3, severe renal impairment (creatinine clearance ≤30 ml·min−1·1.73 m−2; n=6). The terminal half-life of batanopride was significantly prolonged from 2.7 h in group 1 to 9.9 h in group 3. The renal clearance of batanopride was significantly lower in group 3 (25 ml·min−1) compared with group 1 (132 ml·min−1). There were no differences in plasma protein binding or steady-state volume of distribution of batanopride among the groups. There were significantly lower renal clearances for all three metabolites in groups 2 and 3 compared with group 1. The half-lives of all three metabolites were significantly prolonged in group 3 compared with group 1. The dose of batanopride may need to be reduced in patients with creatinine clearances less than 30 ml·min−1·1.73 m−2 to prevent drug accumulation and avoid possible dose-related adverse effects.
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    Pharmacokinetics of oral tiopronin (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 79-84 
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    ISSN: 1432-1041
    Keywords: Tiopronin ; 2-Mercaptopropionylglycine ; bioavailability ; urinary excretion ; cystine urolithiasis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten healthy subjects were given 500 mg (3064 μmol) tiopronin, or 2-mercaptopropionylglycine (2-MPG) by mouth. Cmax was reached after 3–6 h, and after a shorter β-phase a long terminal half-life of 53 h of total tiopronin was found. Tiopronin measured as unbound (non-protein-bound) drug disappeared more rapidly from plasma, with a calculated t 1/2 of 1.8 h. Mean residence time was higher (58 h) when calculated as total tiopronin than as unbound tiopronin (6 h), and this was also the case for the volume of distribution (Vλ=4551 vs Vλ,u=41 1). The results indicate extensive protein binding in plasma and a deep pool of tissue bound tiopronin after the first absorption and distribution phases. Absolute bioavailability (f) was 63%, and bioavailability calculated from urinary excretion was 47%, which are well correlated with each other. Urinary excretion was mainly confined to the first 6 h (74%) and was almost complete (98%) within 12 h. We conclude that the maximal absorption of the tiopronin was late, protein and tissue binding of the drug were high and its bioavailability varied. The renal excretion of low molecular weight tiopronin occurred early, which implies that the drug should be given in divided doses, at least twice daily, for optimal efficiency in the treatment of cystinuria.
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    Pharmacokinetics of diphemanil methylsulphate in infants (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 89-91 
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    ISSN: 1432-1041
    Keywords: Diphemanil methylsulphate ; antimuscarinic agent ; pharmacokinetics ; infants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of diphemanil methylsulphate was evaluated after oral administration of a single 3 mg·kg−1 dose to 5 infants being treated for symptomatic bradycardia. The mean pharmacokinetic parameters of oral diphemanil methylsulphate in infants were similar to those in adults. The mean half-life was 8.6 h. This would allow administration three times a day in infants instead of four to six times a day, as currently prescribed. The mean residence time decreases significantly with age (Spearman's r′=−1), and there is a trend for the half-life to decrease with age (r′=−0.9; NS), suggesting an influence of maturation on its elimination.
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    Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson's disease (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 117-122 
    Details
    ISSN: 1432-1041
    Keywords: Parkinson's disease ; Levodopa ; intraduodenal infusion ; PLM-test ; video ratings ; plasma level response ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Motor performance of five patients with advanced Parkinson's disease was investigated during their optimum oral therapy (conventional tablets and/or depot capsules) and during a continuous duodenal infusion of levodopa. Due to the low water solubility of the drug, conventional tablets of levodopa + carbidopa (Sinemet®) were milled and dispersed in a 1.8% aqueous methylcellulose solution. The dispersion was delivered nasoduodenally by a portable pump. The effect of levodopa in the two dosing regimens was estimated optico-electronically every 15 min and was also evaluated from videorecordings every 30 min and plasma levels of levodopa was regularly measured. Each dosage regimen the was studied twice, at a 2–4 day interval. Duodenal infusion improved motor function in all five patients and the fluctuations were reduced when compared to the oral therapy. Variation in plasma levodopa concentrations was 3–10 fold during oral therapy, while during the infusion a stable concentration was obtained. The therapeutic concentration varied from 0.3–3 μg ml−1 between patients. The relative bioavailability of levodopa in the solid preparation compared to the dispersion was in all patients 100%. Our results encourage further development of a duodenal infusion system with a levodopa dispersion for clinical use in parkinsonian patients who show severe fluctuation.
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    Changes in renal clearance of furosemide due to changes in renal blood flow and plasma albumin concentration (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 135-139 
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    ISSN: 1432-1041
    Keywords: Furosemide ; protein binding ; pharmacokinetics ; renal function ; dehydration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have shown that, within therapeutic plasma concentrations, the unbound fraction of furosemide changes in direct proportion to the reciprocal of the plasma albumin concentration (correlation coefficient 0.99). Changes in the albumin concentration were produced by ultrafiltration of human plasma using a haemofiltration filter. Thus, we propose that, when studying changes in the pharmacokinetics of a highly protein bound drug, calculated changes in the unbound fraction offer an alternative to actual measurement of the unbound concentration, which is often difficult. Nine healthy volunteers receiving a continuous furosemide infusion were studied in normovolaemia and after dehydration (−1.4 kg), with and without pretreatment with an angiotensin converting enzyme inhibitor (captopril) or an a1-adrenoceptor blocking agent (prazosin). Significantly larger changes in the renal clearance of furosemide were found that could be explained by changes in the unbound fraction. Following dehydration, the unbound fraction of furosemide was decreased by about 5%, while its renal clearance fell by 27%, 33% and 13% after pretreatment with placebo, captopril and prazosin, respectively. The secretory clearance of the unbound furosemide changed substantially and in parallel with changes in the renal blood flow. It is suggested that changes in the renal clearance and excretion of furosemide and its t1/2 are much more dependent on changes in renal blood flow than on changes in its unbound fraction.
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    Pharmacodynamics and pharmacokinetics of oral nitrendipine solution in hypertensive patients with advanced renal failure (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 129-134 
    Details
    ISSN: 1432-1041
    Keywords: Nitrendipine ; Hypertension ; pharmacokinetics ; renal function ; hypertensive crisis ; pharmacodynamics ; blood pressure ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nitrendipine solution 5 mg·ml−1 in the dose of 5 mg was given orally to 20 patients with chronic renal failure and elevated diastolic blood pressure (≥110 mmHg), of whom 10 were on maintenance haemodialysis (endogenous creatinine clearance 〈5 ml·min−1) and 10 were at the predialysis stage (endogenous creatinine clearance 5–20 ml·min−1). The aim of the study was to investigate the influence of kidney function and/or dialysis treatment on the pharmacokinetic and pharmacodynamic profile of a solution of nitrendipine and to assess its antihypertensive efficacy. After 10 min there was a significant reduction in blood pressure from 188/113 to 173/100 (patients not dependent on dialysis) and from 197/112 to 161/94 mmHg (patients dependent on dialysis). The maximum fall in blood pressure (approximately 30%) was attained after 90 min in the dialysis patients and after 120 min in the non-dialysis group. Blood pressure increased again about 3 h after the administration of nitrendipine but it was still below baseline after 12 h. The terminal elimination half-life (4.1 h in the dialysis patients and 3.6 h in non-dialysis patients) was similar to that observed in patients with normal renal function. The pharmacokinetics of nitrendipine did not differ between the dialysis and non-dialysis groups. There was a correlation between plasma concentration and the blood pressure reduction. The maximum plasma concentration of nitrendipine was reached after 0.5 h (median) and did not differ between the two groups. The mean maximum plasma concentration was 14.8 μg·1−1 in the study population as a whole, with comparable means in the dialysis (17.3 μg·1−1) and non-dialysis (12.4 μg·1−1) groups. The nitrendipine solution proved to be effective in lowering acutely elevated blood pressure in patients with advanced renal failure and renal hypertension, and was well tolerated. The pharmacokinetics was not affected by renal impairment or by dialysis.
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    Pharmacodynamic modeling of cortisol suppression from fluocortolone (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 581-583 
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    ISSN: 1432-1041
    Keywords: Fluocortolone ; cortisol ; pharmacodynamics ; pharmacokinetics ; adrenal suppression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of fluocortolone on cortisol suppression was characterized using a ‘direct suppression pharmacodynamic model’. The model incorporates the physiologic circadian secretion of cortisol under normal and treatment conditions, together with pharmacokinetic data from single fluocortolone doses of 20, 50, and 100 mg. A mean IC50 value (fluocortolone plasma concentration at which the circadian secretion of cortisol is inhibited by 50%) of 15.5 ng·ml−1 was found. This analysis shows how use of pharmacodynamic modeling can characterize dose-proportionality data to provide an in vivo measure of drug potency.
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    Pharmacokinetic and pharmacodynamic interaction study of diazepam and metoprolol (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 223-226 
    Details
    ISSN: 1432-1041
    Keywords: diazepam ; metoprolol ; drug combination ; pharmacodynamics ; pharmacokinetics ; drug metabolism ; sedation ; interaction study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 normotensive, healthy male volunteers the pharmacodynamic responses (blood pressure, heart rate; sedation index, tracking test, reaction time) to metoprolol (100 mg bid orally), diazepam (0.1 mg/kg intravenously) and to their combination were studied. The pharmacokinetics of diazepam were also compared in a cross-over experiment, with and without pretreatment by the β-adrenoceptor antagonist to evaluate the possibility of a drug interaction. The pharmacodynamic and pharmacokinetic investigations indicated that metoprolol only slightly impaired the elimination of diazepam (18% decrease in total clearance, 25% increase in elimination half-life). The pharmacodynamics of metoprolol (17% decrease in heart rate, 17% decrease in diastolic RR) was not significantly altered by the bolus injection of diazepam. The extent of prolongation in choice reaction time (RT2) induced by diazepam was significantly (p=0.001) more pronounced following the co-administration of metoprolol. However, the results of RT1, the tracking test and the sedation index did not indicate any increased effect due to the β-blocking agent. It is concluded that concomitant treatment with metoprolol and diazepam causes only minor and clinically irrelevant changes in drug metabolism and drug response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630289
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    Pharmacokinetics of estramustine phosphate (Estracyt®) in prostatic cancer patients (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 113-119 
    Details
    ISSN: 1432-1041
    Keywords: estramustine phosphate ; prostatic cancer ; pharmacokinetics ; metabolism ; estramustine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of estramustine phosphate (EMP) was studied in five prostatic cancer patients given single i.v. and oral doses of EMP in a cross-over study. Plasma and urinary concentrations of parent drug, estramustine, estromustine (the estrone analogue), estradiol and estrone were followed for 32 h. The elimination of intravenous EMP from plasma was biphasic. The mean volumes of distribution were small, being 43 and 108 ml/kg for the central and peripheral compartments, respectively. The plasma clearance was 64 ml/kg/h, and the half-lives of the two phases were 0.16 and 1.27 h. Metabolism was the major route of elimination of EMP. It was readily dephosphorylated and oxidized to yield the cytotoxic metabolites estramustine and estromustine. Estromustine was the main metabolite in plasma. When given orally EMP underwent extensive presystemic dephosphorylation, which started in the gastrointestinal tract. The relative bioavailability of estromustine after administration of EMP-capsules was 44%, which reflects incomplete absorption of EMP rather than first-pass metabolism of estromustine. The terminal half-life of estromustine was 10–20 h, which suggests that EMP might be given once or twice a day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546718
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    Correlation between the pharmacokinetics and pharmacodynamics of dopamine in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 163-169 
    Details
    ISSN: 1432-1041
    Keywords: dopamine ; pharmacokinetics ; pharmacodynamics ; adrenaline plasma level ; noradrenaline plasma level ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and the pharmacodynamic action of dopamine were investigated in 5 healthy subjects. Dopamine was given in different doses (200, 400 and 800 µg/min) by constant intravenous infusion over 90 min. In order to control the influence of the procedure on the measured parameters the subjects also received a similar infusion of saline. Dopamine, noradrenaline and adrenaline levels in plasma were followed for up to 6 h after the infusion, and arterial pressure and heart rate were monitored. Dopamine reached a steady state level within 15 to 30 min after commencement of the infusion; the steady state levels averaged 36.5 µg/l at 200 µg/min, 73.8 µg/l at 400 µg/min and 207 µg/l at 800 µg/min. The corresponding total clearances were 5.8 l/ min, 5.51/min and 3.9 l/min suggesting non-linear kinetics. The kinetics could not be described by compartmental model. Noradrenaline and adrenaline levels were found to be elevated during infusion of dopamine. Noradrenaline had returned to its pretreatment level within 15 to 30 min after cessation of the infusion, whereas the adrenaline level did not return to the pretreatment value within the observation period. Heart rate was increased by the dose of 400 µg/min, and the systolic and mean arterial pressures were elevated, whereas distolic blood pressure remained unchanged. Elevated systolic blood pressure was better correlated with plasma dopamine than with noradrenaline concentration. This finding, in conjunction with the unchanged diastolic blood pressure, indicates that elevation of the systolic blood pressure is a direct rather than an indirect effect of dopamine. The increased heart rate was not correlated with the dopamine level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630281
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    Bioequivalence studies in humans of indomethacin capsules marketed in India (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 261-264 
    Details
    ISSN: 1432-1041
    Keywords: indomethacin capsules ; bioequivalence ; volunteers ; pharmacokinetics ; statistical significance ; bioavailability ; comparative bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two, separate 6×6 Latin square cross-over bioequivalence studies were performed in adult male volunteers using 10 different indomethacin capsule preparations marketed in India together with the pure drug powder as the standard. The products were evaluated with respect to plasma level at various times up to 8 h following administration of a 50 mg (2 × 25 mg) dose. Plasma samples were analysed by a fluorimetric method. Various pharmacokinetic parameters were calculated according to a two compartment model. Statistical evaluation of the data employed analysis of variance for a cross-over design (ANOVA) and Duncan's multiple range test to ascertain the significance of differences between the products. Of the 10 products studied, two were found to be bioinequivalent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630296
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    Lack of clinically important interaction between erythromycin and theophylline (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; erythromycin ; interaction ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 11 healthy volunteers the kinetics of theophylline and the plasma levels and the urinary excretion of its metabolites were studied before and after treatment with erythromycin for 10 days. Theophylline was administered as an intravenous bolus injection (280 mg) followed by a constant intravenous infusion (23.8±4.1 mg/h) for 6 hours. The total clearance of theophylline at steady-state (63.4±9.9 vs 63.8±14.4 ml/min, before vs after erythromycin treatment) and the elimination half-life after cessation of the infusion (6.7±2.6 vs 7.5±1.8 h, before vs after treatment) did not change during the treatment with erythromycin. No difference in the formation of metabolites before and after treatment with erythromycin was detected; the findings in urine were 40.4±5.0 vs 42.1±5.4% 1,3-dimethyluric acid, 29.6±4.6 vs 30.1±5.9% 1-methyluric acid and 13.4±3.5 vs 12.5±2.2% 3-methylxanthine before and after erythromycin treatment, respectively. It is concluded that a clinically relevant interaction between erythromycin and theophylline does not occur.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542146
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    Single and multiple dose kinetics of clobazam, and clinical effects during multiple dosage (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 499-503 
    Details
    ISSN: 1432-1041
    Keywords: benzodiazepines ; clobazam ; desmethylclobazam ; pharmacokinetics ; sedation ; accumulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sixteen healthy volunteers, aged 19 to 62 years, took a single 20-mg oral dose of clobazam and the serum concentrations of clobazam and desmethylclobazam were measured for the following 7 days. The mean kinetic variables for clobazam were: volume of distribution 1.31/kg, elimination half-life 24 h, total clearance 0.47 ml/min/kg. 13 of the volunteers then took clobazam 5 mg twice daily for 22 consecutive days. Serum concentrations were measured during and after this period. Both clobazam and desmethylclobazam showed slow and extensive accumulation, their steady-state kinetics being entirely consistent with those observed after single doses. Elimination of both compounds after termination of treatment was equally slow. Clinical self-rating of morning sedation indicated a significant increase over baseline in subjective perception of sedation during the treatment period, and this effect persisted into the washout period. However, sedation did not increase in parallel with accumulating levels of clobazam and desmethylclobazam, probably due to functional adaptation or tolerance.
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    URL: http://dx.doi.org/10.1007/BF00542148
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    Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 505-511 
    Details
    ISSN: 1432-1041
    Keywords: prednisolone ; prednisone ; oral contraceptives ; 6β-hydroxylase ; transcortin ; protein-binding ; steroid metabolism ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n=10) had higher mean (±SD) area under the plasma concentration versus time curves of total (428±67 µg/ml/min vs 188±28 µg/ml/min, p〈0.001) and unbound prednisolone (64±10 µg/ml/min vs 41±10 µg/ml/min, p〈0.001) than women not taking oral contraceptive steroids (n=10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p〈0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.
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    URL: http://dx.doi.org/10.1007/BF00542149
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    Acetaminophen accumulation in pediatric patients after repeated therapeutic doses (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 57-59 
    Details
    ISSN: 1432-1041
    Keywords: acetaminophen ; pediatric patients ; fever therapy ; accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetaminophen serum concentrations were studied in 21 infants and children with fever. The maximum serum concentrations ranged from 9.96 to 19.6 µg/ml after a single dose of 12–14 mg/kg and 13.9 to 40.1 µg/ml after a single dose of 22–27 mg/kg. Ten patients were restudied at steadystate after repeat doses had been given every 4 or 8 h for 1 to 3 days. Total area under the acetaminophen serum concentration-time curve normalized for dose averaged 0.181 (ml/min/kg)−1 after the first dose and 0.202 (ml/min/kg)−1 at steady-state (p〈0.05). Five patients showed a 13 to 44% increase in the AUC; one had a 10% decrease in the AUC; and four had less than 6% change in the AUC. There was no evidence of hepatotoxicity. These data suggest that acetaminophen may accumulate after repeated therapeutic doses in children with fever.
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    URL: http://dx.doi.org/10.1007/BF00553155
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    Pharmacokinetics of metoprolol in healthy, elderly, non-smoking individuals after a single dose and two weeks of treatment (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 217-222 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; pharmacokinetics ; age effect ; repeated doses ; pre-systemic elimination ; total body clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of long-term treatment on the absorption and dispsoition of metoprolol has been evaluated in 8 healthy, non-smoking, elderly individuals (mean age 74.5 years) and in a control group of 8 healthy, young individuals. Two trace doses of [3H]metoprolol were given i.v., first concomitantly with a single oral 50 mg dose of cold metoprolol, and second, with the morning dose after 2 weeks of treatment with 50 mg b.d. In the elderly, the mean AUC increased by about 45% (p〈0.05) over the treatment period, while in the control group the mean AUC was 18% greater (p〈0.05) on Day 14 than on Day 1. In the elderly, changes both in pre-systemic elimination and in total body clearance accounted for the elevation of the AUC, whereas reduced first-pass effect appeared to be the major cause of the increased steady-state plasma level in the control group. With the exception of the volume term, V β , the pharmacokinetic parameters were not significantly different between the elderly and the young individuals. For this reason, almost identical steady-state plasma levels were attained in the two groups. The results suggest that age-related physiological changes may have some minor effects on the pharmacokinetics of metoprolol, and also that the changes do not lead to significantly altered plasma concentrations compared to those in young individuals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544048
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    Lack of effect of haemodialysis on mebendazole kinetics: Studies in a patient with echinococcosis and renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 243-245 
    Details
    ISSN: 1432-1041
    Keywords: mebendazole ; haemodialysis ; echinococcosis ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of haemodialysis on mebendazole kinetics has been studied in a patient receiving both mebendazole therapy and haemodialysis. The procedure of haemodialysis did not influence the plasma concentration — time profiles or the mean daily plasma levels. The arterio-venous difference in the dialyser was negligible and no mebendazole could be detected in the dialysate. Protein binding of mebendazole was 90% before dialysis and 88% during dialysis and not significantly different from the binding in patients without renal disease (91.4±1.9%, n=22).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544053
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    Naproxen disposition in patients with alcoholic cirrhosis (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 291-296 
    Details
    ISSN: 1432-1041
    Keywords: naproxen ; cirrhosis ; pharmacokinetics ; protein binding ; nonsteroidal antiinflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chronic liver disease is known to alter the absorption and disposition of many drugs. To assess the influence of chronic alcoholic liver disease on the disposition of naproxen, we administered the drug both as a single dose and to steady state to 10 individuals with alcoholic cirrhosis and to 10 healthy controls. Plasma and serum samples collected after naproxen dosing were assayed for both total and (following equilibrium dialysis) unbound drug concentration. Clearance calculated based on both total and unbound naproxen concentration revealed no change in total plasma clearance of the drug at steady state but a marked reduction of approximately 60% in clearance based on unbound drug. Naproxen volume of distribution changed only minimally. Because clearance based on unbound drug concentration at a given dosing rate determines the plasma or blood free drug concentration, this concentration may increase significantly in patients with alcoholic liver disease given usual doses of naproxen. Unbound drug concentration is thought to determine the pharmacologic effect of a drug. We therefore recommend that naproxen dosing be reduced by at least half in patients with chronic alcoholic liver disease. In the absence of data to the contrary, this recommendation can be extended to individuals with other forms of hepatic disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542162
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