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  • 1990-1994  (128)
  • 1980-1984
  • 1993  (128)
  • pharmacokinetics
  • Nuclear reactions
  • 1
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315286
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  • 2
    Electronic Resource
    Electronic Resource
    Minor and clinically non-significant interaction between toloxatone and amitriptyline (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 97-99 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315289
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  • 3
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315478
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  • 4
    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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  • 5
    Electronic Resource
    Electronic Resource
    A clinical pharmacological study of subcutaneous nicotine (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 225-230 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271362
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  • 6
    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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  • 7
    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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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of nocloprost in human volunteers and its relation to dose (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 497-500 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315552
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  • 9
    Electronic Resource
    Electronic Resource
    Absorption of zidovudine in patients with diarrhoea (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 501-503 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315553
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  • 10
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of exogenous adenosine in man after infusion (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 505-507 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315554
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  • 11
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02440864
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  • 12
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315351
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  • 13
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of oral tiopronin (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 79-84 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315354
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  • 14
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315499
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  • 15
    Electronic Resource
    Electronic Resource
    Decreased chloramphenicol clearance in malnourished Ethiopian children (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 181-186 
    Details
    ISSN: 1432-1041
    Keywords: Malnutrition ; Chloramphenicol ; children ; pharmacokinetics ; kwashiorkor ; marasmus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of chloramphenicol and chloramphenicol monosuccinate has been studied in thirty-four Ethiopian children of varying nutritional status. After a single intravenous dose corresponding to chloramphenicol 25 mg per kg bodyweight, the plasma clearance of chloramphenicol monosuccinate was decreased only in severely malnourished children with kwashiorkor. Seventeen % of the dose (range 0–51%) was recovered in urine as intact prodrug, indicating incomplete and variable bioavailability of chloramphenicol. Compared to underweight children, on average marasmic and kwashiorkor subjects exhibited a 2- and 3-fold increase, respectively, in the AUC of chloramphenicol. Elevated AUCs could be traced to reduced hepatic clearance of the drug. The unbound fraction both of chloramphenicol and its prodrug were slightly elevated in serum from kwashiorkor subjects. The possibility of using a single point measurement of plasma chloramphenicol as a guide to individualized dosage are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315503
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  • 16
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315284
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  • 17
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315475
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  • 18
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315476
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  • 19
    Electronic Resource
    Electronic Resource
    The pharmacodynamics and pharmacokinetics of the combination of nifedipine and doxazosin (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 279-282 
    Details
    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).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271372
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  • 20
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and β-blocking effects of transdermal timolol (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 493-495 
    Details
    ISSN: 1432-1041
    Keywords: Timolol ; β-adrenoceptor antagonist ; transdermal ; percutaneous absorption ; skin ; pharmacokinetics ; bioavailability ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic profiles of transdermal timolol 6 and 24 mg (as 5 and 20% w/v patches) was studied in four healthy young volunteers. To assess its bioavailability, the pharmacokinetics of an IV infusion of timolol maleate 5 mg was also determined in the same subjects. When the 20% (w/v) timolol patch was applied, the mean bioavailability was 74.4%. Plasma timolol concentrations were below the detection limit when a 5% patch was applied to the same skin area in all four subjects, except for one in whom the bioavailability was 23.6%. Weak erythema developed at the application site in all of the volunteers after application of the 20% (w/v) patch. However, erythema did not develop in any volunteer when the 5% patch was applied. The β-blocking effect was determined by exercise testing. Similar plasma levels generated similar changes in exercise-induced heart rate after the transdermal and intravenous administration of timolol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315551
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  • 21
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02440860
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  • 22
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01428395
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  • 23
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315348
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  • 24
    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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  • 25
    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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  • 26
    Electronic Resource
    Electronic Resource
    Investigation of nimodipine pharmacokinetics in Chinese patients with acute subarachnoid haemorrhage (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 363-366 
    Details
    ISSN: 1432-1041
    Keywords: Nimodipine ; pharmacokinetics ; Chinese patients ; acute subarachnoid haemorrhage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nimodipine pharmacokinetics was investigated in 12 Chinese patients with acute subarachnoid haemorrhage receiving an IV infusion of 1.6 or 2 mg/h (based on estimated body weight) for 10 days. Peripheral venous blood samples were collected for up to 4 days and plasma nimodipine was assayed by GC/ECD. The mean value was taken as the steady state concentration (Css) and Clearance (CL) (hourly dose/Css) was calculated. Eight survivors were given oral nimodipine (60 or 90 mg) every 6h (based on body weight), blood was sampled over 6 h and the plasma nimodipine level determined. The values for Css, CL and CL·kg−1 were 33.5 μg·l−1, 58 l·h−1 and 1.0 l·h−1·kg−1 respectively; in survivors receiving the drug orally, bioavailability of the 30 mg tablet was 9%. In one very sick patient given crushed tablets by naso-gastric tube, the AUC was very low; in vitro studies indicated that adsorption of nimodipine by the tubing was unlikely to have been the cause. The pharmacokinetic findings in Chinese patients are comparable to previously reported values in Caucasians.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265956
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  • 27
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265959
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  • 28
    Electronic Resource
    Electronic Resource
    On the question of interindividual variations in chloroquine concentrations (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 383-385 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265960
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  • 29
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316473
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  • 30
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316474
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  • 31
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316479
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  • 32
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of diphemanil methylsulphate in infants (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 89-91 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315356
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  • 33
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315491
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  • 34
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 367-371 
    Details
    ISSN: 1432-1041
    Keywords: Lansoprazole ; pharmacokinetics ; hepatic failure ; renal failure ; metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of lansoprazole (L) after a single oral dose of 30 mg was determined in 18 healthy volunteers, 17 renal failure patients and 24 hepatic failure patients; 8 hepatitis and 16 with compensated (CC) or uncompensated (UCC) cirrhosis. In renal failure, the absorption of L was unchanged, its half-life being similar to that in healthy subjects; a small change seen in mild renal failure patients (creatinine clearance between 40 and 60 ml/min) was attributed to the age of the patients. Urinary elimination, essentially as metabolites of lansoprazole, was decreased, in relation to the degree of renal impairment. In hepatitis patients, the AUC and t1/2 of L were doubled, without any change in Cmax. In cirrhotics tmax was prolonged, the AUC was increased (P〈0.001) and there was prolongation of t1/2 (6.1 h in CC and 7.2 h in UCC compared to 1.4 h in healthy subjects). These changes resulted from a decrease in the clearance of L. There was also an increase in its sulphone metabolite (Cmax, Rm) and a decrease in the hydroxylated metabolite (Cmax, Rm) in relation to the degree of liver disease, and reflecting a decrease in hydroxylation and biliary elimination. Thus, renal failure had no effect on the pharmacokinetics of L, but severe hepatic failure caused marked changes. A repeated dosing study would be necessary to evaluate the repercussions of the possible accumulation in cirrhotic patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265957
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  • 35
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    Electronic Resource
    The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 27-33 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315276
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  • 36
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 431-436 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315514
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  • 37
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and haemodynamic effects of continuous nicorandil infusion in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 437-443 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315515
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  • 38
    Electronic Resource
    Electronic Resource
    Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 469-475 
    Details
    ISSN: 1432-1041
    Keywords: Cerebrospinal fluid ; Antibiotics ; Osmotic diuretics ; pharmacokinetics ; AUC ratio ; intercompartmental rate constants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Various parameters which may be useful in quantification of drug transit from blood into CSF and vice versa after a short duration infusion are compared here by recalculating previously published data from our group. Due to the slower entry into and elimination from the CSF compartment as compared to the central compartment, the ratio of drug concentrations in CSF and serum sampled at the same time increase with time after an infusion. Therefore, concentration quotients of simultaneously drawn blood and CSF are inadequate to characterise CSF penetration. The ratio of the areas under the concentration-time curves in a body fluid and serum (AUCbody fluid/AUCS) is an established measure to quantify overall penetration from the central into a peripheral compartment. AUCCSF/AUCS is closely correlated with the quotient of the maximum CSF and serum concentrations (CmaxCSF/ CmaxS) (rS=0.87, n=42, P〈0.001) and with the rate constant of distribution in CSF (CLin/VCSF) (rS=0.80, n=42, P〈0.001). Since CmaxCSF/CmaxS depends on the mode of drug administration, it is suggested that AUCCSF/AUCS be used to quantify overall drug transit into CSF. CLin/VCSF is of use when CSF can only be sampled once, or when the velocity of the transit of a drug into CSF is to be described. The CSF exit rate constant (CLout/VCSF) characterises elimination from CSF independent of the elimination from serum and may be applied to estimate the formation rate of CSF; in the present study it averaged 20 ml/h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315520
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  • 39
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315306
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  • 40
    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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  • 41
    Electronic Resource
    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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  • 42
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316478
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  • 43
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316480
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  • 44
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of clonidine in high dosage (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 165-167 
    Details
    ISSN: 1432-1041
    Keywords: Clonidine ; pharmacokinetics ; alcohol withdrawal syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have evaluated the pharmacokinetics of high doses of clonidine, as used in the prophylactic treatment of alcohol withdrawal syndrome, in 11 alcohol-dependent patients undergoing surgery for oesophagogastrectomy. Clonidine was given in a bolus of 150 μg followed by a continuous infusion. After a mean period of treatment of 9.2 (range 3 to 26) days and a mean dose of 0.72 (range 0.29 to 2.37) mg per day of clonidine the mean terminal half-life was 15.8 (range 9.9 to 23) h (n=7). In order to compare initial and terminal half-lives of clonidine intraindividually, four patients were given a bolus of 150 μg followed 24 h later by a continuous infusion. The pharmacokinetics of clonidine were described by two exponentials, with a distribution half-life of 1.2 h and a terminal half-life of 14.6 h. After a mean period of 8.3 (range 2 to 15) days and a mean dose of 0.62 (range 0.15 to 1.82) mg per day the terminal half-life in these four patients was 15.6 (range 14.0 to 17.9) h. The relation between dosage and plasma concentration was linear.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315500
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  • 45
    Electronic Resource
    Electronic Resource
    Single dose pharmacokinetics of fenspiride hydrochloride: phase I clinical trial (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 169-172 
    Details
    ISSN: 1432-1041
    Keywords: Fenspiride ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absolute bioavailability of fenspiride has been studied in twelve healthy volunteers. It was administered IV and orally in single doses of 80 mg fenspiride hydrochloride according to a randomised crossover pattern. Following IV administration, the plasma clearance of fenspiride was about 184 ml·min−1, and its apparent volume of distribution was moderately large (2151). When given orally as a tablet, fenspiride exhibited fairly slow ab- sorption; the maximum plasma concentration (206 ng·ml−1) was achieved 6 h after administration. The absolute bioavailability was almost complete (90%). The tablet had slow release characteristics. The elimination half-life obtained from the plasma data was 14 to 16 h independent of the route of administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315501
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  • 46
    Electronic Resource
    Electronic Resource
    Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 191-193 
    Details
    ISSN: 1432-1041
    Keywords: Torsades de pointes ; Terfenadine ; Itraconazole ; QT-interval ; drug-interaction ; pharmacokinetics ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Terfenadine, a nonsedating H1-selective antihistamine, is widely used in many countries. We report pharmacokinetic results in a patient who developed a prolonged QT-interval in ECG and symptomatic torsades de pointes ventricular tachycardia as a consequence of the interaction of itraconazole and terfenadine. Both drugs were taken in the recommended doses: terfenadine 60 mg b.d. and itraconazole 100 mg b.d. Terfenadine metabolism was delayed by itraconazole, leading to an increased level of unmetabolised terfenadine. Seven weeks after the cessation of itraconazole treatment, terfenadine was rapidly metabolized to its active metabolite and did not prolong the QT-interval when given as a single provocation dose (120 mg). The findings suggest that intraconazole in therapeutic doses inhibits terfenadine metabolism. It is also possible that unmetabolised terfenadine alone, without an increased level of its active metabolite, may cause torsades de pointes. The concomitant use of terfenadine and itraconazole (and ketoconazole) should be avoided.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315505
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  • 47
    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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  • 48
    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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  • 49
    Electronic Resource
    Electronic Resource
    A comparative assessment of amlodipine and felodipine ER: pharmacokinetic and pharmacodynamic indices (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 425-430 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315513
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  • 50
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and pharmacodynamics of 12 weeks of glyburide therapy in obese diabetics (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 459-463 
    Details
    ISSN: 1432-1041
    Keywords: Glyburide ; Diabetes mellitus ; pharmacokinetics ; pharmacodynamics ; obesity ; type II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics and pharmacodynamics of glyburide during long-term therapy in 20 patients with type II diabetes mellitus. The patients were divided according to body mass index (BMI) into an obese group [n=12, age 55(13) y, BMI 36.2(9.2) kg·m−2, total body weight (TBW) 100(23) kg], and a non-obese group [n=8, age 61(13) y, BMI 24.5(2.1) kg·m−2, TBW 73(7) kg]. The dosages of glyburide were titrated to achieve specified therapeutic goals based upon serum glucose concentrations or to a maximum dosage of 20 mg per day. The pharmacokinetics of glyburide were determined at week 12 of treatment. On the study day, the patients took a 2.5 mg liquid test dose of glyburide with a Sustacal meal challenge. The elimination rate constant (λz), clearance (CL), and apparent volume of distribution (Vz) were 0.08 h−1, 3.3 l·h−1, and 47.0 l in the obese group, and 0.07 h−1, 3.1 l·h−1, and 56.8 l in the non-obese group. These values were not statistically significantly different. However, there were differences between the groups when the volume and clearance were corrected by TBW or BMI but not by ideal body weight (IBW) or fat-free mass (FFM). Regression analysis between the pharmacokinetic variables and body weight status revealed statistically significant correlations between volume or clearance and body weight. However, due to large inter-patient variability, these relations were relatively weak and were considered to be non-predictive. In regard to the pharmacodynamic effects of glyburide, there were greater C-peptide and insulin responses at baseline and after 12 weeks of therapy in the obese than in the non-obese patients. However, there were no significant differences in glucose responses between the two groups. More non-obese patients needed the maximum dose (20 mg) of glyburide (7/8) compared with obese patients (6/12). These findings suggest that obese patients may be more sensitive to the effects of glyburide. Alternatively, our obese patients may have had less serious disease than our non-obese patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315518
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  • 51
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    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315314
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  • 52
    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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  • 53
    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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  • 54
    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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  • 55
    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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  • 56
    Electronic Resource
    Electronic Resource
    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%).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02440862
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  • 57
    Electronic Resource
    Electronic Resource
    Pharmacodynamics and pharmacokinetics of eptastigmine in elderly subjects (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 373-376 
    Details
    ISSN: 1432-1041
    Keywords: Eptastigmine ; Cholinesterase inhibition ; Elderly subjects ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eptastigmine is a new cholinesterase inhibitor, which may be potentially useful for the symptomatic treatment of Alzheimer's disease. A preliminary evaluation of its pharmacodynamic and pharmacokinetic profiles in the elderly has now been made in 6 healthy subjects (63–84 years of age) given 30 mg eptastigmine as a single oral dose. Blood was collected prior to and 1, 2, 3, 4, 6, 8, and 12 h after eptastigmine administration for measurement of cholinesterase inhibition in plasma and red blood cells and the plasma drug concentrations. The maximum plasma cholinesterase inhibition was 17%, which was reached 2.7 h after treatment. In red cells the maximum inhibition of the enzyme was 29% after 3.8 h. The estimated half-time of cholinesterase recovery was 12.4 h in plasma and 13.6 h in red blood cells. The peak plasma concentration of eptastigmine of 0.86 ng·ml−1 was reached after 1.4 h. Following absorption the drug was rapidly distributed into tissues (t1/2α = 0.44 h) and then eliminated with a half-life of 12.1 h. The drug was well tolerated in all but one subject, who showed bradycardia with hypertension and nausea for about 2 h after the dose. The results indicate that oral administration of eptastigmine to elderly subjects produces long lasting inhibition of cholinesterase activity in plasma and in red blood cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265958
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  • 58
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265961
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  • 59
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315511
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  • 60
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315510
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  • 61
    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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  • 62
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02440863
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  • 63
    Electronic Resource
    Electronic Resource
    Elimination of cefmenoxime during continuous haemofiltration (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. S31 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01428389
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  • 64
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315494
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  • 65
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    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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  • 66
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    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315399
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  • 67
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    Electronic Resource
    Moexipril does not alter the pharmacokinetics or pharmacodynamics of warfarin (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 291-293 
    Details
    ISSN: 1432-1041
    Keywords: Moexipril ; Warfarin ; pharmacokinetics ; pharmacodynamics ; drug-interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The potential effect of moexipril, a new converting enzyme inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of warfarin has been investigated. Ten healthy male volunteers received in a randomised crossover fashion a single oral dose of 50 mg warfarin sodium alone and together with the first dose of 6 days of oral treatment with moexipril 15 mg o.d. Mean oral plasma clearance of (R)-warfarin was 175 ml·h−1 in the absence and 181 ml·h−1 in the presence of moexipril, and the corresponding values for (S)-warfarin were 248 ml·h−1 and 249 ml·h−1. Apparent volume of distribution, peak plasma concentration, time to reach peak concentration and area under the plasma concentration-time curve both of (R)- and (S)-warfarin were not significantly affected. Moexipril did not alter the maximum prothrombin time (20.3 versus 20.1 s, respectively in the absence and presence of moexipril), time to maximum response (48.0 versus 50 h) and area under the prothrombin time versus time curve. The results suggest that a clinically important interaction between moexipril and warfarin is unlikely to occur in patients treated with both drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315400
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  • 68
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    Electronic Resource
    Zero and first moment area estimation from microdialysis data (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 477-481 
    Details
    ISSN: 1432-1041
    Keywords: Microdialysis ; mean time parameters ; pharmacokinetics ; simulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The calculation of classical pharmacokinetic parameters from microdialysis data has been described in a previous paper. In this paper I have derived methods for calculating AUMC and AUC from the time-integral type of data that are generated in microdialysis pharmacokinetics experiments. The method derived to estimate AUC is elementary, but is given a theoretical basis using principles of mathematical real analysis, clearly stating the assumptions. The method derived to estimate AUMC is a numerical approximation method based on the linear trapezoidal method. A simulation study was performed to evaluate the precision of the methods and to compare them with corresponding methods for analysis of blood sample data. The estimates from the presently derived methods have a small bias and a small variance. In the simulation study I investigated the influence of model parameters, number of samples, size of statistical error, and the size of the AUC beyond the last sample. Finally, I have given numerical examples from real data to illustrate the use of the method.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315521
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  • 69
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    Stereoselective analysis of the disposition of tosufloxacin enantiomers in man (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 489-491 
    Details
    ISSN: 1432-1041
    Keywords: Tosufloxacin ; Enantiomer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tosufloxacin enantiomers after oral administration of racemic tosufloxacin were examined in healthy volunteers. Only small differences were observed in time to peak concentration (2.6±0.3 [mean ± SEM] h for (+)-tosufloxacin vs 2.4±0.2 h for (−)-tosufloxacin), elimination half-life (3.61±0.24 h vs 3.49±0.23 h), and area under the curve (2.78±0.19 h·μg/ml vs 2.87±0.19 h·μg/ml); however, peak concentration (0.40±0.03 μg/ml vs 0.44±0.03 μg/ml), renal clearance (226±10 ml/min vs 202±10 ml/min), and urinary recovery (35.4±2.2% vs 32.4±1.9%) differed significantly between enantiomers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315523
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  • 70
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    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315309
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  • 71
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    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315316
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  • 72
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    Electronic Resource
    Pharmacodynamic modeling of cortisol suppression from fluocortolone (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 581-583 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315319
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  • 73
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    Electronic Resource
    Flumazenil kinetics in the elderly (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 585-587 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315320
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  • 74
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    Electronic Resource
    Plasma concentrations of bupivacaine after wound infiltration of an 0.5% solution after inguinal herniorrhaphy: a preliminary study (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 555-557 
    Details
    ISSN: 1432-1041
    Keywords: Bupivacaine ; wound infiltration ; postoperative ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After routine inguinal herniorrhaphy we gave 12 patients a wound infiltration regimen of bolus doses of 20 ml of 0.5% bupivacaine via a catheter within the wound and rectally administered indomethacin (100 mg). Peak venous plasma bupivacaine concentrations ranged from 0.07 mg·l−1 to 1.14mg·l−1 (mean (SD) 0.47 (0.33) mg·l−1), and occurred at between 0.25 and 2 h after the first dose. Plasma concentrations were well below the toxic threshold of 4 mg·l−1 and there was no accumulation. The regimen provided satisfactory analgesia. There were no wound infections nor signs of toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02440858
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  • 75
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    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315493
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  • 76
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    Electronic Resource
    Effects of acute hypoxia on antipyrine and isoniazid pharmacokinetics in rats with low and high resistance to oxygen deficiency (1993)
    Springer
    Bulletin of experimental biology and medicine 116 (1993), S. 835-837 
    Details
    ISSN: 1573-8221
    Keywords: hypoxia ; pharmacokinetics ; antipyrine ; isoniazid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00786166
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  • 77
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    Electronic Resource
    Observations on the effects of long-term withdrawal on carcass composition and residue concentrations in clenbuterol-medicated cattle (1993)
    Springer
    Veterinary research communications 17 (1993), S. 459-468 
    Details
    ISSN: 1573-7446
    Keywords: β-agonists ; clenbuterol ; immunoassay ; pharmacokinetics ; residues ; ultrasound ; withdrawal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The detection of the illegal use of clenbuterol (CBL) as a growth promoter has relied on detecting residual concentrations of the drug in body fluids or tissues. Analysis of retinal extracts has recently been shown to considerably extend the detection period following withdrawal. The withdrawal periods required to eliminate residues from the liver and retina were investigated by medicating 20 cattle with CBL for 30 days; 6 control animals remained unmedicated. Residual concentrations were monitored throughout this period and for the subsequent 140 days. Concurrent changes in muscle areas and backfat thicknesses were recorded by ultrasound. CBL was detectable in liver up to the 56th day of withdrawal (0.35 ng/g, SD=0.5), but retinal concentrations remained well above detectable concentrations throughout the withdrawal period (22.5 ng/g, SD=6.5). There were small gains (3–4%) in the muscle areas of treated cattle during medication as compared to controls (p〉0.05). These comparative gains remained during withdrawal. Backfat thicknesses in treated animals were 40% lower than in controls at the end of medication (p〈0.01). However, by 70 days after withdrawal this difference had disappeared (p〉0.05) owing to accelerated fat deposition in the treated group. The retina has been shown to be a highly effective target matrix for detecting CBL administration after long withdrawal periods.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839213
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    Electronic Resource
    The pharmacokinetics of thiamphenicol in lactating cows (1993)
    Springer
    Veterinary research communications 17 (1993), S. 295-303 
    Details
    ISSN: 1573-7446
    Keywords: cows ; intramuscular ; intravenous ; lactation ; milk ; pharmacokinetics ; serum ; thiamphenicol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of thiamphenicol were studied after intravenous and intramuscular administration of 25 mg/kg body weight in lactating cows. Distribution (t 1/2α) and elimination (t 1/2β) half-lives of 6.10±1.39 min and 1.60±0.30 h, respectively, were obtained after intravenous administration. The body clearance was 3.9±0.077 ml/kg per min and the apparent volume of distribution was 1220.79±256.67 ml/kg. The rate at which thiamphenicol appeared in the milk, as indicated by the penetration half-life (t 1/2P) (serum to quarters), was found to be 36.89±11.14 min. The equivalent elimination half-life (t 1/2E) (quarters to serum) from the milk was 3.62±1.06 h and the peak thiamphenicol concentration in the milk was 23.09±3.42 µg/ml at 2.5±0.32 h. After intramuscular injection, the elimination half-life was 2.2±0.40 h, the absorption half-life was 4.02±1.72 min and the peak concentration in the serum was 30.90±5.24 µg/ml at 23±8.4 min. The bioavailability after intramuscular administration approached 100%. The penetration half-life was 50.59±6.87 min, the elimination half-life was 5.91±4.97 h and the mean peak concentration in the milk was 17.37±2.20 µg/ml at 3.4±0.22 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839220
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  • 79
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    Electronic Resource
    Pharmacokinetics of benzydamine in dairy cows following intravenous or intramuscular administration (1993)
    Springer
    Veterinary research communications 17 (1993), S. 313-323 
    Details
    ISSN: 1573-7446
    Keywords: benzydamine ; bioavailability ; cattle ; milk ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Five lactating cows were given benzydamine hydrochloride by rapid intravenous (0.45 mg/kg) and by intramuscular (0.45 and 1.2 mg/kg) injection in a crossover design. The bioavailability, pharmacokinetic parameters and excretion in milk of benzydamine were evaluated. After intravenous administration, the disposition kinetics of benzydamine was best described using a two-compartment open model. Drug disposition and elimination were fast (t 1/2α: 11.13±3.76 min;t 1/2β: 71.98±24.75 min; MRT 70.69±11.97 min). Benzydamine was widely distributed in the body fluids and tissues (V d(area): 3.549±1.301 L/kg) and characterized by a high value for body clearance (33.00±5.54 ml/kg per min). After intramuscular administration the serum concentration-time curves fitted a one-compartment open model. Following a dose of 0.45 mg/kg, theC max value was 38.13±4.2 ng/ml at at max of 67.13±4.00 min; MAT and MRT were 207.33±22.64 min and 278.01±12.22 min, respectively. Benzydamine bioavailability was very high (92.07%±7.08%). An increased intramuscular dose (1.2 mg/kg) resulted in longer serum persistence (MRT 420.34±86.39 min) of the drug, which was also detectable in milk samples collected from both the first and second milking after treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839222
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  • 80
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    Electronic Resource
    Disposition kinetics, urinary excretion and dosage regimen of kanamycin in buffalo calves following single intravenous administration (1993)
    Springer
    Veterinary research communications 17 (1993), S. 219-225 
    Details
    ISSN: 1573-7446
    Keywords: buffalo ; disposition ; dose ; kanamycin ; pharmacokinetics ; serum ; urine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The disposition kinetics and appropriate dosage regimen for kanamycin were investigated in buffalo calves following a single intravenous dose of 10 mg/kg body weight. The distribution and elimination half-lives were 0.12±0.01 h and 1.94±0.11 h, respectively. The apparent volume of distribution and total body clearance were 0.2±0.01 L/kg and 92.9±3.69 ml/kg/h, respectively. About 74% of the administered dose was excreted in urine in 24 h. A suitable dosage regimen for the intravenous administration of kanamycin was also calculated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839170
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  • 81
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    Electronic Resource
    The pharmacokinetics of primaquine in calves after subcutaneous and intravenous administration (1993)
    Springer
    Veterinary research communications 17 (1993), S. 129-136 
    Details
    ISSN: 1573-7446
    Keywords: calves ; carboxyprimaquine ; pharmacokinetics ; plasma ; primaquine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of primaquine was studied in calves of 180–300 kg live weight. Primaquine was injected at 0.29 mg/kg (0.51 mg/kg as primaquine diphosphate) intravenously (IV) or subcutaneously (SC) and the plasma concentrations of primaquine and its metabolite carboxyprimaquine were determined by high-performance liquid chromatography. The extrapolated concentration of primaquine at zero time after IV administration was 0.50±0.48 µg/ml (mean ±SD) which decreased with an elimination half-life of 0.16±0.07 h. Primaquine was rapidly converted to carboxyprimaquine after either route of administration. The peak concentration of carboxyprimaquine was 0.50±0.08 µg/ml at 1.67±0.15 h after IV administration. The corresponding value was 0.47±0.07 µg/ml at 5.05±1.20 h after SC administration. The elimination half-lives of carboxyprimaquine after IV and SC administration were 15.06±0.99 and 12.26±3.06 h, respectively. The areas under the concentration-time curve for carboxyprimaquine were similar following either IV or SC administration of primaquine; the values were 11.85±2.62 µg.h/ml after the former and 10.95±2.65 µg.h/ml after the latter. The mean area under the concentration-time curve for primaquine was less than 0.1 µg.h/ml after either route of administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839241
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  • 82
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    Electronic Resource
    Enhancement of anti-tumor activity of recombinant interleukin-2 (rIL-2) by immunocomplexing with a monoclonal antibody against rIL-2 (1993)
    Springer
    Biotherapy 6 (1993), S. 225-231 
    Details
    ISSN: 1573-8280
    Keywords: recombinant interleukin-2 ; monoclonal antibody ; immune complex ; drug delivery system ; pharmacokinetics ; natural killer cell ; anti-tumor effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have investigated biological properties of an immune complex of recombinant interleukin-2 (rIL-2) and a monoclonal antibody against rIL-2 in mice for induction of killer cells and for anti-tumor activity. We have also examined the clearance of subcutaneously-injected immune complex in mice and compared it with that of rIL-2 alone. Plasma rIL-2 levels were sustained longer in mice given the immune complex than in mice given rIL-2 alone at a dose of 10μg/mouse, and they were detectable even at 24 hours after the administration of the immune complex, while they fell to undetectable levels by 6 hours after the administration of rIL-2 alone. A more significant portion of rIL-2 was detected in lymph nodes after subcutaneous injection of the immune complex than that of rIL-2 alone. Splenic lymphocytes from mice given the immune complex demonstrated a higher killer cell activity against YAC-1 cells than those from mice given rIL-2 alone. The immune complex also exerted more significant anti-tumor effect in a dose-dependent manner in Meth-A fibrosarcoma-bearing mice than rIL-2 alone. Our results indicate that immunocomplexing of rIL-2 with an antibody against rIL-2 provides a useful tool as the drug delivery system for cancer therapy using rIL-2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01878084
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  • 83
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    Electronic Resource
    Pulmonary Absorption of Recombinant Methionyl Human Granulocyte Colony Stimulating Factor (r-huG-CSF) After Intratracheal Instillation to the Hamster (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1604-1610 
    Details
    ISSN: 1573-904X
    Keywords: aerosol ; cytokine ; drug delivery ; granulocyte colony stimulating factor (G-CSF) ; recombinant methionyl human G-CSF ; intratracheal instillation ; proteins ; pharmacokinetics ; pulmonary absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Recombinant methionyl human granulocyte colony stimulating factor (G-CSF), a molecule of 18.8 kDa, has been shown to induce a systemic response after delivery by aerosol. In this work, rate and extent of absorption as well as the response were determined after bolus administration of solutions by intratracheal instillation (IT). The protein was quantified using a specific ELISA and the biological response was assessed by monitoring the increase in numbers of circulating white blood cells (WBC). A dose–response curve was obtained after IT, subcutaneous injection (SC), and intracardiac injection (IC) of 100 µL of a nominal dose ranging from 1 to 1000 µg/kg G-CSF (n = 5). WBC numbers were determined 24 hr postadministration. Absorption and clearance kinetics were determined after IT and IC of 500 µg/kg protein over a 24-hr time period (n = 5). The response of the lung to G-CSF was monitored by WBC counts and differentials in lung lavage fluid. 73.6 ± 10.5% (n = 7) of the IT dose reached the lung lobes. The response to single doses of G-CSF by IT or SC was similar, with WBC numbers increasing over 4× baseline at the higher doses. Absorption from the lung was rapid and did not follow first-order kinetics. Clearance after the IC dose was described by a biexponential equation (α = 1.41, β = 0.24 hr−1). Peak serum levels were obtained ≈1–2 hr after IT. The bioavailability was 45.9% of the administered dose and 62.0% of the dose reaching the lung lobes. These results indicate that G-CSF is rapidly absorbed from the lung. Pulmonary delivery via the airways has promise as an alternative to parenteral injection.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018920619424
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  • 84
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    Pharmacokinetic Analysis and Cellular Distribution of the Anti-HIV Compound Succinylated Human Serum Albumin (Suc-HSA) in Vivo and in the Isolated Perfused Rat Liver (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1611-1614 
    Details
    ISSN: 1573-904X
    Keywords: succinylated human serum albumin ; anti-HIV compound ; pharmacokinetics ; perfused rat liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract After intravenous injection of a low dose (25 µg/kg) in rats, the anti HIV-1 compound succinylated human serum albumin (Suc-HSA) is taken up mainly in the liver and spleen and is proteolytically degraded. Ten minutes after injection of 125I-Suc-HSA, 72 and 14% of the dose were found in the liver and spleen, respectively. With immunohistochemistry we demonstrated that in both organs, Suc-HSA was specifically endocytosed in endothelial cells. In the isolated perfused rat liver preparation, liver uptake was shown to be saturable, with a K m of 2.9 10−8 M and a V max of 2.4 µg/inin/100 g body weight. The apparent K m and V max in vivo were 2.2 10−7 M and 10.3 µg/min/100 g, respectively. Uptake in liver and spleen was inhibited by preadministration of an excess of formaldehyde-treated albumin and with polyinosinic acid, indicating the involvement of the scavenger receptor, as anticipated for such polyanionic compounds. Suc-HSA is not absorbed intact from the colon and the ileum. After injecting (i.v.) rats with a high dose of Suc-HSA (10 mg/kg), the elimination t 1/2 was 3 hr, and therefore, sustained plasma levels above the concentration needed for in vitro anti-HIV-1 activity can be achieved.
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    URL: http://dx.doi.org/10.1023/A:1018972603494
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  • 85
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    Electronic Resource
    Absorption and Disposition of a New Antiarrhythmic Agent Bidisomide in Man (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1675-1682 
    Details
    ISSN: 1573-904X
    Keywords: bidisomide ; absorption sites ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Absorption and disposition of bidisomide were studied in 12 healthy male subjects after a 20-min iv (1 mg/kg; N = 6) infusion and oral (2 mg/kg; N = 6) administration of the 14C-labeled drug. The oral absorption profile of unlabeled bidisomide was also studied after administration of a solution by a nasoenteric tube to different sites of the gastrointestinal tract (stomach, duodenum, jejunum, and ileum). The systemic availability was 61%. Absorption was slow initially and then rapid, achieving peak plasma concentrations between 2 and 4 hr. Less than complete systemic availability was attributed to incomplete absorption rather than first-pass metabolism. When the drug solution was delivered directly to the stomach, two distinct peak plasma levels were found. This was attributed to the more rapid absorption of bidisomide in the duodenum and ileum (and/or possibly colon). Following an iv dose, plasma levels of the drug declined with mean half-lives of 0.11, 2.0, and 12 hr for α, β, and γ phases, respectively, and a plasma clearance of 380 mL/min. The percentages of the dose recovered as bidisomide in urine and feces were 19 ± 1 and 29 ± 4 for the iv dose and 9.1 ± 0.9 and 48 ± 5 for the oral dose. Bidisomide did not exhibit substantial enantioselective pharmacokinetics in plasma regardless of the route of administration. The mean urinary excretion of the (–) enantiomer was, however, slightly higher than that of the (+) enantiomer, with (–)/(+) enantiomeric ratios of 1.2 and 1.3 after iv and oral administration, respectively. The enantiomeric ratio of bidisomide recovered in the feces was approximately 1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018945324876
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  • 86
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Diltiazem and Its Metabolites in Dogs After Oral Administration of a Multiparticulate Sustained-Release Preparation (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1165-1168 
    Details
    ISSN: 1573-904X
    Keywords: diltiazem ; sustained-release preparation ; pharmacokinetics ; metabolism ; colon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacokinetics of diltiazem and its six metabolites were compared after oral administration in dogs of a multiparticulate sustained-release diltiazem preparation (HER-SR, QD) and a conventional diltiazem preparation (HER, TID). The plasma concentration of diltiazem, its two active basic metabolites (Ml, N-monodesmethyl diltiazem; M2, deacetyl diltiazem), and four acidic metabolites [Al, ( + )-(2S,3S)-2-(4-methoxyphenyl)-3-acetoxy-4-oxo-2,3,4,5,-tetrahydro-l,5-benzothiazepin-5-acetic acid; A2, 3-deacetyl-Al; A3, O-demethyl-Al; A4, O-demethyl-3-deacetyl-Al] following several administration routes were determined using high-performance liquid chromatography with UV detector (UV-HPLC). Following the oral administration of HER to dogs, plasma concentrations were in the descending order of A2, diltiazem, Ml, and M2. The absolute bioavailability of diltiazem was about 30%. Diltiazem conversion to its metabolites (Ml, M2, A2) was 31.0, 2.1, and 14.6%, respectively. Following intraduodenal and mesenteric venous administration of diltiazem, Ml and A2 were produced mainly in the intestine and liver. Oral administration of HER-SR and HER to dogs resulted in almost-identical plasma concentrations of A2, diltiazem, Ml, and M2 (descending order). Supported evidence was the effective absorption of diltiazem from all gastrointestinal tract regions and similar formation ratios of diltiazem basic metabolites (Ml, M2) from the duodenum, ileum, and colon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018916201735
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  • 87
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Stereomeric 1,4:3,6-Dianhydrohexitol Mononitrates in Rats (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 22-27 
    Details
    ISSN: 1573-904X
    Keywords: organic mononitrates ; pharmacokinetics ; urinary recoveries ; urinary conjugation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and urinary recoveries of four isomeric mononitrates, L-isoidide mononitrate (L-IIMN), isosorbide-2-mononitrate (IS-2-MN), isomannide mononitrate (IMMN), and isosorbide-5-mononitrate (IS-5-MN), were investigated at an intravenous dose of 2 mg/kg in rats. All four compounds exhibited monoexponential kinetics at this dose. The volumes of distribution were similar for all four isomers and were estimated at about 1.0 liter/kg. The systemic clearances of L-IIMN, IMMN, IS-2-MN, and IS-5-MN were 65.1 ± 13.0, 32.7 ± 12.0, 11.0 ± 2.3, and 8.23 ± 1.82 ml/min/kg, respectively (P 〈 0.05, all pairwise comparisons). Free mononitrate in the urine accounted for 0.306 to 4.56% of the administered dose, while the recovery in conjugated forms (after glusulase hydrolysis) accounted for 42.8% of the IMMN dose and 7.70 to 14.5% of the dose of the remaining three isomers. The dose-dependent pharmacokinetics of three of the mononitrates were explored at selected higher doses which cause equivalent vasodilator responses, L-IIMN (22 mg/kg), IS-2-MN (100 mg/kg), and IS-5-MN (300 mg/kg). The clearances of L-IIMN, IS-2-MN, and IS-5-MN at these higher doses were 42.3 ± 5.7, 6.38 ± 0.59, and 3.33 ± 0.62 ml/min/kg, respectively, all significantly less than those found at the 2 mg/kg dose. Typical Michaelis–Menten-type curvatures were observed in the concentration–time curves after IS-2-MN and IS-5-MN dosing. The pharmacokinetics of L-IIMN were also dose dependent, but they could not be described by simple Michaelis–Menten kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018908610086
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  • 88
    Electronic Resource
    Electronic Resource
    Regional Gastrointestinal Absorption of the Beta-Blocker Pafenolol in the Rat and Intestinal Transit Rate Determined by Movement of 14C-Polyethylene Glycol (PEG) 4000 (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 130-135 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; oral absorption ; intestinal permeability ; bioavailability ; double-peaks ; dose dependency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The gastrointestinal absorption characteristics of pafenolol following oral administration as a solution in man and rat has previously been found to be a double-peak phenomenon and exhibited dose-dependent bioavailability, despite negligible presystemic metabolism. In both man and rat the first peak appeared approximately 0.5–1 hr postdose and the second, more pronounced peak 3–4 hr postdose. In rat more than 90% of the available dose was absorbed during the second peak. In the present study we investigated the absorption of a solution of pafenolol in rats after intrajejunal and intraileal administration. The resulting blood concentration–time profile of pafenolol exhibited one peak only; the extent of absorption was similar to that observed when the same dose was given orally. The small intestinal transit time of the 14C-PEG 4000 solution was found to be more than 3 hr. The transit rate was higher in the proximal part of the small intestine compared to the more distal part, where the transit of the solution was staggered. In conclusion, the results of the intestinal transit time investigation and the administrations of pafenolol at different levels of the alimentary tract indicate that pafenolol is a drug with a specific absorption site located in the ileocolonic region.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018993501426
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  • 89
    Electronic Resource
    Electronic Resource
    Enhancement of Tissue Delivery and Receptor Occupancy of Methylprednisolone in Rats by a Liposomal Formulation (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1402-1410 
    Details
    ISSN: 1573-904X
    Keywords: liposomes ; methylprednisolone ; pharmacokinetics ; tissue distribution ; pharmacodynamics ; glucocorticoid receptors ; drug delivery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A liposomal formulation of methylprednisolone (L-MPL) was developed to improve localization of this immunosuppressant in lymphatic tissues. Liposomes containing MPL were formulated from a mixture of phosphatydylcholine and phosphatydylglycerol (molar ratio, 9:1) and sized by extrusion through a 0.1-µm membrane. Male Sprague–Dawley rats received a bolus dose of 2 mg/kg of L-MPL or free MPL in solution (control). Samples of blood, spleen, liver, thymus, and bone marrow were collected at intervals over a 66-hr period. Concentrations of MPL in plasma and organs and free cytosolic glucocorticoid receptors (GCR) in spleen and liver were determined. The plasma MPL profiles for free and L-MPL were bi- and triexponential. Although the alpha phase kinetics of both dosage forms were similar, L-MPL showed a substantially slower elimination phase than did free drug. Incorporation of MPL into liposomes caused the following increases: terminal half-life, from 0.48 (MPL) to 30.13 hr (L-MPL); MRT, from 0.42 to 11.95 hr, V ss, from 2.10 to 21.87 L/kg; and AUC, from 339 to 1093 ng · hr/mL. Uptake of liposomes enhanced significantly the delivery of drug to lymphatic tissues and liver; AUC tissue:plasma ratios for spleen increased 77-fold; for liver, 9-fold; and for thymus, 27-fold. The duration of GCR occupancy was extended 10-fold in spleen and 13-fold in liver by the liposomal formulation. Lymphatic tissue selectivity and extended receptor binding of liposome-delivered MPL offer promise for enhanced immunosuppression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018954704886
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  • 90
    Electronic Resource
    Electronic Resource
    Plasma Pharmacokinetics of the Lactone and Carboxylate Forms of 20(S)-Camptothecin in Anesthetized Rats (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1451-1457 
    Details
    ISSN: 1573-904X
    Keywords: camptothecin ; reversible metabolism ; pharmacokinetics ; hydrolysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract 20(S)-Camptothecin exists in equilibrium between its lactone (CPT) and its carboxylate forms (Na-CPT) under simulated physiological conditions, with the equilibrium favoring the carboxylate form. The rates of lactone hydrolysis were studied in plasma, serum albumin, and blood and were found to be faster than in aqueous buffers at equivalent pH values. From mechanistic information and in vivo activity data, the lactone appears to be the active form of the drug. It has been argued, therefore, that if an equilibrium existed between the lactone and the carboxylate, Na-CPT could be used to deliver the lactone effectively. In the present study, plasma pharmacokinetics were performed in sodium pentobarbital-anesthetized rats treated with both CPT (lactone) and the sodium salt of camptothecin (carboxylate, Na-CPT) and the lactone and carboxylate, as well as the total drug, concentration versus time profiles were assessed. It was found that plasma concentrations and AUC values for the lactone were significantly higher after dosing with CPT than after dosing with Na-CPT. After i.v. administration, the ratio of plasma lactone to carboxylate was skewed by the apparent rapid and extensive uptake of the lactone into tissues and the rapid clearance of both species. From our results, it appears that the lower in vivo activity of Na-CPT compared to that from CPT administration might be attributed to the altered conversion of carboxylate into lactone in vivo compared to that predicted from in vitro data.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018919224450
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  • 91
    Electronic Resource
    Electronic Resource
    The Pharmacokinetics of Recombinant Human Relaxin in Nonpregnant Women After Intravenous, Intravaginal, and Intracervical Administration (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 834-838 
    Details
    ISSN: 1573-904X
    Keywords: relaxin ; pharmacokinetics ; absorption ; intravenous ; intracervical ; intravaginal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of recombinant human relaxin (rhRlx) after intravenous (iv) bolus administration and the absorption of rhRlx after intracervical or intravaginal administration were determined in nonpregnant women. The study was conducted in two parts. In part I, 25 women received 0.01 mg/kg rhRlx iv. After a minimum 7-day washout period, these women were dosed intracervically (n = 10) or intravaginally (n = 15) with 0.75 or 1.5 mg rhRlx, respectively, in 3% methylcellulose gel. Part II was a double-blind, randomized, three-way crossover study in 26 women. At 1-month intervals, each woman received one of three intravaginal treatments consisting of 0 (placebo), 1, or 6 mg rhRlx in 3% methylcellulose gel. The serum concentrations of relaxin following iv administration were described as the sum of three exponentials. The mean (±SD) initial, intermediate, and terminal half-lives were 0.09 ± 0.04, 0.72 ± 0.11, and 4.6 ± 1.2 hr, respectively. Most of the area under the curve was associated with the intermediate half-life. The weight-normalized clearance was 170 ± 50 mL/hr/kg. The observed peak concentration was 98 ± 29 ng/mL, and the weight-normalized initial volume of distribution was 78 ± 40 mL/kg, which is approximately equivalent to the serum volume. If central compartment elimination was assumed, the volume of distribution at steady state (V ss/W) was 280 ± 100 mL/kg, which is approximately equivalent to extracellular fluid volume. V ss/W could be as large as 1300 ± 400 mL/kg without this assumption. After intravaginal administration of the placebo gel, endogenous relaxin concentrations were evident (i.e., ≥20 pg/mL) in 9 of the 26 women (maximum concentrations, 23–234 pg/mL). A similar proportion of women (approximately 35–40%) exhibited measurable serum concentrations of relaxin following intravaginal rhRlx treatment; this proportion increased to 90% following intracervical rhRlx treatment. For both routes of administration, the maximum serum concentrations of relaxin were usually within the range of values observed for endogenous relaxin, suggesting that the absorption of rhRlx was minimal.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018901009062
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  • 92
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    Electronic Resource
    The Impact of Lag Time on the Estimation of Pharmacokinetic Parameters. I. One-Compartment Open Model (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1031-1036 
    Details
    ISSN: 1573-904X
    Keywords: lag time ; pharmacokinetics ; PCNONLIN ; absorption rate constant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Lag time in pharmacokinetics corresponds to the finite time taken for a drug to appear in systemic circulation following extravascular administration. Lag time is a reflection of the processes associated with the absorption phase such as drug dissolution and/or release from the delivery system and drug migration to the absorbing surface. Failure to specify the lag time can lead to inappropriate or erroneous estimates of pharmacokinetic parameters. This has been demonstrated in the case of a one-compartment open model by the pharmacokinetic analysis of bioequivalence data from a study involving the administration of propoxyphene napsylate to human volunteers. Subsequently, pharmacokinetic and statistical analyses of data obtained from a series of 49 simulations involving a wide range of absorption and elimination rate constants (0.05 to 5.00 and 0.01 to 0.95 hr−1, respectively) showed that lag time has a substantial effect on several primary and secondary pharmacokinetic parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018970924508
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  • 93
    Electronic Resource
    Electronic Resource
    Intranasal Absorption of a Kappa Agonist Analgesic (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1083-1086 
    Details
    ISSN: 1573-904X
    Keywords: kappa agonist analgesic ; nasal absorption ; bioavailability ; pharmacokinetics ; ED50.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018987328143
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  • 94
    Electronic Resource
    Electronic Resource
    Mean Residence Time of Oral Drugs Undergoing First-Pass and Linear Reversible Metabolism (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 8-13 
    Details
    ISSN: 1573-904X
    Keywords: oral administration ; mean residence time ; reversible metabolism ; first-pass metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Equations for the mean residence times in the body (MRT) and AUMC/AUC of a drug and its metabolite have been derived for an oral drug undergoing first-pass and linear reversible metabolism. The mean residence times of the drug or interconversion metabolite in the body after oral drug are described by equations which include the mean absorption time (MAT), the mean residence times of the drug or metabolite in the body after intravenous administration of the drug, the fractions of the dose entering the systemic circulation as the parent drug and metabolite, and the systemically available fractions of the drug (F p p) or metabolite (F m p). Similarly, the AUMC/AUC of the drug and metabolite after oral drug can be related to the MAT, ratios of the fraction of the dose entering the systemic circulation to the systemically available fraction, the first-time fractional conversion of each compound, and AUMC/AUC ratios after separate intravenous administration of each compound. The F p p and F m p values, in turn, are related to the first-pass availabilities of both drug and metabolite and the first-time fractional conversion fractions. The application of these equations to a dual reversible two-compartment model is illustrated by computer simulations.
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    URL: http://dx.doi.org/10.1023/A:1018904509178
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  • 95
    Electronic Resource
    Electronic Resource
    Pharmacokinetics, Mass Balance, and Induction Potential of a Novel GABA Uptake Inhibitor, CI-966 HC1, in Laboratory Animals (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1442-1445 
    Details
    ISSN: 1573-904X
    Keywords: GABA uptake inhibitor ; anticonvulsant ; pharmacokinetics ; dose proportionality ; mass balance ; enzyme induction/ inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract CI-966 exhibits anticonvulsant properties in various animal models. The drug acts by inhibiting synaptic uptake of γ-aminobutyric acid (GABA). Oral absorption of CI-966 in dogs given 1.39 mg/kg is rapid with a tmax of 0.7 hr. In rats given 5 mg/kg oral, a mean t max of 4.0 hr was observed. Following iv administration of the same respective doses, elimination t 1/2 in dogs and rats averaged 1.2 and 4.5 hr. Absolute oral bioavailability of CI-966 was 100% in both species. Following oral dosing of [14C]CI-966 HC1 to dogs, fecal, and urinary excretion accounted for 89% and 2.3% of the 14C dose, respectively. In bile-duct cannulated rats, biliary excretion is the major elimination pathway of radioactivity (75%). Urinary and fecal excretion accounted for 4.1 and 12%, respectively. CI-966 does not induce or inhibit mouse hepatic mixed function oxidases, as determined by hexobarbital sleeping time.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018915123542
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  • 96
    Electronic Resource
    Electronic Resource
    Influence of Dose Range on Degree of Nonlinearity Detected in Dose-Proportionality Studies for Drugs with Saturable Elimination: Single-Dose and Steady-State Studies (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 289-293 
    Details
    ISSN: 1573-904X
    Keywords: dose proportionality ; Michaelis–Menten ; nonlinearity ; data analysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Deviation from proportionality occurs when the ratio of area under the curve (AUC) values is not equal to the ratio of administered doses. The degree of nonlinearity (f NL) can be quantitated as the ratio of AUCs divided by the ratio of doses. We explore positive deviation from proportionality (f NL 〉 1) using the classical Michaelis–Menten model of nonlinear elimination after a single dose (n = 1) or at steady state (ss). The degree of nonlinearity is related to the ratio of the highest dose to the lowest dose (Rd = D H/D L): f NL n=1 = (2 + Rd · ε)/(2 + ε), f NL ss= (Rd · Ω −1) /(Rd · Ω −Rd), where ε is the ratio of the initial concentration after the lowest dose to the K m (ε = D L/K m · V) and Ω is the ratio of the V max to the average rate of input for the highest dose (Ω = V maxτ/F · D H). From these relationships, we find that (1) for single-dose studies, K m is the important Michaelis–Menten parameter, while V max is important at steady state; (2) the degree of nonlinearity cannot exceed the ratio of doses in single-dose studies, and when doses in extreme excess of K m· V are chosen, the degree of nonlinearity is equal to the dose range; and (3) at steady state, the degree of nonlinearity can exceed the ratio of doses and approaches infinity as the average input rate approaches V max. Literature data (phenytoin and ethanol) support these findings. We conclude that the degree of nonlinearity is not a useful measure of nonlinearity in and of itself and propose percentage saturation as being more informative.
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    URL: http://dx.doi.org/10.1023/A:1018955315055
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  • 97
    Electronic Resource
    Electronic Resource
    Feasibility of Developing a Neural Network for Prediction of Human Pharmacokinetic Parameters from Animal Data (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 466-469 
    Details
    ISSN: 1573-904X
    Keywords: neural computing ; prediction ; pharmacokinetics ; humans ; animals ; allometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018917128684
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  • 98
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Recombinant Human Interferon-βser in Healthy Volunteers and Its Effect on Serum Neopterin (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 567-572 
    Details
    ISSN: 1573-904X
    Keywords: interferon-β ; pharmacokinetics ; biological response modification ; neopterin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of and biologic response modification by recombinant human interferon-βser (rIFN-βser) were evaluated in 12 healthy male volunteers. Subjects received a single intravenous (iv) injection of 90 × 106 IU of rIFN-βser followed by a single or eight consecutive daily 90 × 106 IU subcutaneous (sc) doses. Blood samples collected after the iv, first sc, and last sc doses and prior to each sc dose were assayed for interferon antiviral activity and the inter-feron-inducible marker neopterin. Following iv administration, serum interferon concentrations generally declined biexponentially, with a mean serum clearance of 0.76 ± 0.28 L/hr-kg, a mean steady-state volume of distribution of 2.88 ± 1.81 L/kg, and a mean terminal half-life of 4.29 ± 2.29 hr as determined by noncompartmental analysis. Following sc administration, absorption of rIFN-βser was prolonged, with serum concentrations generally below 100 IU/mL. No accumulation of rIFN-βser in serum was noted after eight daily sc injections. In contrast, serum neopterin levels did not increase above baseline levels until 12 hr after iv dosing and 24 hr after sc dosing. The mean increase in serum neopterin at 24 hr post iv injection was significantly greater than that at 24 hr post sc dosing.
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    URL: http://dx.doi.org/10.1023/A:1018902120023
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  • 99
    Electronic Resource
    Electronic Resource
    Development of a Sensitive Radioimmunoassay for Fab Fragments: Application to Fab Pharmacokinetics in Humans (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 692-696 
    Details
    ISSN: 1573-904X
    Keywords: Fab fragment ; radioimmunoassay ; pharmacokinetics ; urinary metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Anti-sheep Fab fragment antisera were produced in rabbits using sheep digoxin-specific Fab fragments (Digidot) as immunogen. These antisera were used for the development of a radioimmunoassay (RIA) of sheep Fab fragments in human plasma and urine using 125I-labeled Fab fragments. Interference in the assays by digoxin, human proteins, and antibodies from different species was insignificant, but cross-reactivity between anti-sheep Fab antisera and goat IgG or Fab fragments was 22 to 67%. The limit of detection was 0.1 µg/mL and the assay was linear over a 0.6–28 µg/mL range of Fab fragments. Intra- and interassay coefficients of variation were less than 6.9 and 10.5%, respectively. Accuracy of plasma and urine assays at various Fab fragment levels ranged from 96 to 106%. RIA was applied to the pharmacokinetic study of sheep digoxin-specific Fab fragments in one patient acutely intoxicated by digitoxin and treated with Digidot. The Fab elimination half-life was 12.1 hr. Steady-state volume of distribution and total-body clearance were 10.8 L and 23.4 mL/min, respectively. Unchanged Fab fragments (50 kD) and degradation products (25 kD) isolated by gel filtration chromatography of a urine sample cross-reacted with the anti-Fab antiserum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018903614997
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  • 100
    Electronic Resource
    Electronic Resource
    Prolongation of the Circulation Time of Doxorubicin Encapsulated in Liposomes Containing a Polyethylene Glycol-Derivatized Phospholipid: Pharmacokinetic Studies in Rodents and Dogs (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 703-708 
    Details
    ISSN: 1573-904X
    Keywords: liposome ; doxorubicin ; pharmacokinetics ; polyethylene glycol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of doxorubicin (DOX) encapsulated in liposomes containing polyethylene glycol-derivatized distearoylphosphatidylethanolamine (PEG/DSPE) were investigated in rodents and dogs. The plasma levels of DOX obtained with PEG/DSPE-containing liposomes were consistently higher than those without PEG/DSPE or when PEG/DSPE was replaced with hydrogenated phosphatidylinositol (HPI). Despite the inclusion of PEG/DSPE in liposomes, there was a significant drop in the plasma levels of DOX when the main phospholipid component, hydrogenated phosphatidylcholine, was replaced with lipids of lower phase transition temperature (dipalmitoylphosphatidylcholine, egg phosphatidylcholine), indicating that phase transition temperature affects the pharmacokinetics of liposome-encapsulated DOX. In beagle dogs, clearance was significantly slower for DOX encapsulated in PEG/ DSPE-containing liposomes than in HPI-containing liposomes, with distribution half-lives of 29 and 13 hr, respectively. In both instances, almost 100% of the drug measured in plasma was liposome-associated. The apparent volume of distribution was only slightly above the estimated plasma volume of the dogs, indicating that drug leakage from circulating liposomes is insignificant and that the distribution of liposomal drug is limited mostly to the intravascular compartment in healthy animals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018907715905
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