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  • Electronic Resource  (107)
  • 1990-1994  (107)
  • 1985-1989
  • 1992  (107)
  • pharmacokinetics
  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of meropenem in subjects with renal insufficiency (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 535-538 
    Details
    ISSN: 1432-1041
    Keywords: Meropenem ; Carbapenem ; pharmacokinetics ; uraemia ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of IV meropenem (500 mg over 30 min) has been studied in 6 healthy volunteers and 26 patients with various degrees of renal impairment. Blood samples were taken at different times over 24 h in healthy subjects and 36 to 48 h in uraemic patients, and four or five urine samples were collected over 24 or 48 h. Meropenem concentrations in plasma and urine were measured by a microbiological assay. The mean peak plasma concentration of meropenem ranged from 28 to 40 μg·ml−1 and was not affected by the degree of renal impairment. The terminal half-life of meropenem was approximately 1 h in subjects with normal kidney function and it was proportionately increased as renal function decreased. A significant linear relationship between total body clearance and creatinine clearance as well as between renal clearance and creatinine clearance was observed. The mean apparent volume of distribution at steady state was not significantly altered in uraemic patients. The mean cumulative urinary recovery of meropenem in healthy volunteers was 77% of the administered dose and it was significantly decreased in patients with renal impairment. Haemodialysis shortened the elimination half-life, from 9.7 h during the predialysis period to 1.4 h during the dialysis period. The dose of meropenem should be reduced in relation to the decrease in creatinine clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314864
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  • 2
    Electronic Resource
    Electronic Resource
    Disposition of quinine in plasma, red blood cells and saliva after oral and intravenous administration to healthy adult Africans (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 171-174 
    Details
    ISSN: 1432-1041
    Keywords: Quinine ; Malaria ; pharmacokinetics ; red blood cells ; plasma ; saliva ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of quinine has been studied in ten healthy adult Africans after intravenous infusion and oral ingestion of a 500 mg dose. Blood and saliva samples were collected over 48 h and quinine in plasma, red cells and saliva was determined by HPLC. Quinine was rapidly and almost completely absorbed after an oral dose, with absorption half-life of 0.53 h, a tmax of 1–3 h and a bioavailability of 88%. Analysis of the i. v. data gave an apparent volume of distribution of 3.6 1·kg−1 and a plasma clearance of 0.19 l·kg−1·h−1. The concentration-time curves for plasma, red cells and saliva had declining phases were approximately parallel, giving a similar half-life that in all three media. The half-lives after the i. v. infusion also did not different from those after oral administration. The dose was well tolerated by both methods of administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278479
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  • 3
    Electronic Resource
    Electronic Resource
    Binding of a metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid) to serum proteins in rat and man (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 175-179 
    Details
    ISSN: 1432-1041
    Keywords: 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) ; Triflusal ; triflusal metabolite (HTB) ; pharmacokinetics ; protein binding ; ultrafiltration ; binding constant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of the platelet anti-aggregant drug triflusal. Its binding to plasma proteins of rats and healthy volunteers in vitro and in vivo has been studied. Rats were given a single oral dose of 50 mg·kg−1 triflusal and the healthy volunteers received 300 mg as a single oral dose or a multiple dose regimen of 600 mg every 24 h and 300 mg every 8 h, both for 13 days. Protein-free HTB was obtained by ultrafiltration. Unbound and total HTB concentrations were determined by HPLC. HTB was primarily bound to albumin in plasma. The Scatchard plots suggested two types of binding sites for HTB on the albumin molecule. In rats, the binding constants (K=intrinsic affinity constant, n=number of binding sites) were K1=1.4×105 l·mol−1, n1=1.23, and K2=4.1×103 l·mol−1 and n2=3.77. The mean plasma concentration in rats after oral administration was 185 (37) μg·ml−1 (protein-free HTB: 2.44 (0.77)%). The binding constants in human plasma were K1=4.7×105 l·mol−1, n1=1.93, K2=4.3 l·mol−1 and n2=4.28. The plasma HTB concentration in man (n=8) was 35 μg·ml−1 (Cmax) after a single oral dose of triflusal 300 mg, 172.96 μg·ml−1 (Cmax·ss) during the multiple dosage regimen of 300 mg every 8 h, and 131 μg·ml−1 (Cmax·ss) during the multiple oral dose regimen of 600 mg every 24 h. Unbound HTB ranged from 0.27 to 0.43%, depending on dose. HTB had high affinity for plasma albumin, which was not saturable after therapeutic doses. It showed linear elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278480
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  • 4
    Electronic Resource
    Electronic Resource
    Temporary reversal of serum to cerebrospinal fluid glycerol concentration gradient after intravenous infusion of glycerol (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 181-185 
    Details
    ISSN: 1432-1041
    Keywords: Glycerol ; brain oedema ; serum ; cerebrospinal fluid ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Glycerol 50 g infused i. v. over 2 to 6 h is widely used to treat cerebral oedema in patients with acute stroke. Its transit through the blood-cerebrospinal fluid barrier in subjects with uninflamed meninges has now been examined. In 7 patients with an external ventriculostomy for occlusive hydrocephalus, each of whom was given 500 ml of a 10% solution IV over 4 h, serum and CSF were repeatedly sampled during and after the infusion and glycerol was measured enzymatically. The highest serum glycerol level of 191–923 mg/l was observed at the end of the infusion. The maximum CSF glycerol of 18.7–110.8 mg/l was attained 0–1 h after the end of the infusion. Elimination both from serum and CSF approximated a single-exponential decay; the elimination half-life from serum was 0.29–0.56 h compared to 1.03–3.68 h from CSF. In six of the seven cases there was a temporary reversal of the serum/CSF concentration gradient during glycerol elimination. The ratios of the AUCs of CSF and serum, which describe the overall penetration of glycerol into CSF, ranged from 0.09–0.31. In conclusion, the serum level of glycerol produced by giving 50 g IV glycerol over 4 h may not be sufficiently high reliably dehydrate to brain tissue in many patients, and the slow elimination of glycerol from the CSF may be related to the so-called rebound phenomenon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278481
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  • 5
    Electronic Resource
    Electronic Resource
    Formation and excretion of dipyrone metabolites in man (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 187-191 
    Details
    ISSN: 1432-1041
    Keywords: Dipyrone ; Acetylation phenotype ; metabolism ; pharmacokinetics ; urinary excretion ; metabolite clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The formation and urinary excretion of the dipyrone metabolites, methylaminoantipyrine (MAA), aminoantipyrine (AA), formylaminoantipyrine (FAA) and acetylaminoantipyrine (AAA) were determined following administration of a single oral 1.0 g dose of dipyrone to 12 healthy volunteers. The AAA/AA plasma ratio showed that 3 subjects were slow and 9 were rapid acetylators. Pharmacokinetic parameters were determined separately for each group. A good correlation was found between the plasma and urine AAA/AA ratios. The renal clearance of the four metabolites was similar for both phenotypes. A significant difference in the rate of formation of dipyrone metabolites was found for AA, 0.25 (slow) vs 0.1 ml·min−1·kg−1 (rapid), and for AAA 0.75 (slow) vs 7.53 ml·min−1·kg−1 (rapid). There were comparable differences between slow and rapid acetylators in the AUC and the urinary excretion extrapolated to infinity for AA and AAA. The present results show that the kinetics of dipyrone metabolites in plasma and urine can provide a useful measure of the activity of the enzymes involved in their production.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278482
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  • 6
    Electronic Resource
    Electronic Resource
    Rectal bioavailability of 6-mercaptopurine in children with acute lymphoblastic leukaemia: partial avoidance of “first-pass” metabolism (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 619-622 
    Details
    ISSN: 1432-1041
    Keywords: 6-Mercaptopurine ; suppository ; bioavailability ; acute lymphoblastic leukaemia ; children ; interindividual variability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels and the area under the plasma concentration-time curve (AUC) values of 6-mercaptopurine (6-MP) were determined in a balanced crossover study of oral (powder) and rectal (macrogol suppository) administration to 5 children with acute lymphoblastic leukaemia (ALL). The AUC (538.6 ng · h · ml−1) after the rectal dose of 30 mg/m2 was approximately 1.5-times of that (365.5 ng · h · ml−1) after the oral dose of 87.5 mg/m2. The coefficients of variation of interindividual variability of the AUCs were 21.5% and 32.3%, respectively. The relative bioavailability of the macrogol suppository compared to the powder was approximately 4.39. These findings indicate that rectal administration of 6-MP could avoid the first-pass effect of this drug in the alimentary canal and/or liver, resulting in a large AUC of 6-MP, and so could reduce interindividual variability in plasma 6-MP concentrations. Rectal administration of 6-MP may be more effective than empirical oral dosing for the treatment of children with ALL, especially for patients with nausea and/or vomiting.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265925
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  • 7
    Electronic Resource
    Electronic Resource
    Relationship between arterial and peripheral venous catecholamine plasma catecholamine concentrations during infusion of noradrenaline and adrenaline in healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 245-249 
    Details
    ISSN: 1432-1041
    Keywords: Noradrenaline ; Adrenaline ; catecholamines ; pharmacokinetics ; healthy volunteers ; IV infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Noradrenaline and adrenaline were infused IV at 5 different rates (0.01–0.2 μg · kg · min− for 30 min to volunteers. The plasma catecholamine concentrations were determined by HPLC and electro-chemical detection. At the highest infusion rate, the arterial and venous plasma concentrations of noradrenaline increased from 1.18 to 44.1 nmol · l−1and from 1.14 to 31.9 nmol · l−1, respectively, and of adrenaline from 0.29 to 23.9 nmol · l−1 and from 0.28 to 19.3 nmol · l−1 respectively. The peripheral venous plasma concentration of noradrenaline averaged 76% of the arterial concentration, and of adrenaline it was 73%. There was a linear relationship between the peripheral venous and arterial plasma noradrenaline and adrenaline concentrations at therapeutic doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02333017
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  • 8
    Electronic Resource
    Electronic Resource
    The effect of a low dose of quinidine on the disposition of flecainide in healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 441-443 
    Details
    ISSN: 1432-1041
    Keywords: Flecainide ; quinidine ; pharmacokinetics ; metabolism inhibition ; drug interaction ; renal transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effects of quinidine on ECG intervals and on the pharmacokinetics of flecainide and its two metabolites in 6 healthy men in an open randomized crossover study. Flecainide acetate (150 mg) was given as a constant rate i. v. infusion over 30 min. Quinidine (50 mg orally), given the previous evening, did not change the volume of distribution of flecainide (7.9 vs 7.41·kg−1), but significantly increased its half-life (8.8 vs 10.7 h). This was attributable to a reduction in total clearance (10.6 vs 8.1 ml·min−1·kg−1), most of it being accounted for by a reduction in non-renal clearance (7.2 vs 5.2 ml·min−1·kg−1). The excretion of the metabolites of flecainide over 48 h was significantly reduced. These findings suggest that quinidine inhibits the first step of flecainide metabolism, although it may also reduce its renal clearance, but to a lesser extent (3.5 vs 2.9 ml·min−1·kg−1). The effects of flecainide on ECG intervals were not altered by quinidine. Thus, quinidine tends to shift extensive metabolizer status for flecainide towards poor metabolizer status and may also alter its renal excretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02220625
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  • 9
    Electronic Resource
    Electronic Resource
    Lack of effect of omeprazole, cimetidine, and ranitidine on the pharmacokinetics of ethanol in fasting male volunteers (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 209-212 
    Details
    ISSN: 1432-1041
    Keywords: Ethanol ; gastric acid inhibition ; pharmacokinetics ; antisecretory drugs ; omeprazole ; ranitidine ; cimetidine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of three gastric antisecretory drugs on the pharmacokinetics of ethanol have been studied in a randomized crossover experiment. Male medical students (n=12) took ethanol 0.8 g/kg body weight at 08.00 h after an overnight fast. On seven successive days before drinking ethanol they were given omeprazole 20 mg, cimetidine 800 mg, ranitidine 300 mg, or no drug, with a period of at least 7 days between treatments. The peak blood ethanol concentration of 21.9 to 22.8 mmol·l−1 occurred at 64 to 70 min after the end of drinking. The rate of disappearance of ethanol from the blood ranged from 3.0 to 3.3 mmol·l−1·h−1 and the rate of removal from the whole body ranged from 8.0 to 8.5 g·h−1. The apparent volume of distribution of ethanol was almost the same for all four treatments: mean 0.68 l·kg−1, corresponding to a mean total body water of 441 (59% body weight). Mean areas under the concentration-time profiles of ethanol ranged from 83 to 87 mmol·l−1·h for the four treatments. It is concluded that omeprazole, cimetidine and ranitidine do not alter the kinetics of a moderate dose of ethanol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278486
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  • 10
    Electronic Resource
    Electronic Resource
    Absence of interaction between tenoxicam and warfarin (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 227-229 
    Details
    ISSN: 1432-1041
    Keywords: Tenoxicam ; Warfarin ; drug interaction ; pharmacokinetics ; anticoagulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of tenoxicam on plasma warfarin concentrations and on its anticoagulant effect has been studied in healthy volunteers. Tenoxicam did not alter the plasma warfarin concentration versus time profile. Treatment with it for 14 days had no effect on the average dose of warfarin required to maintain the prothrombin time within a specified range. The coumarin dose index, an indicator of warfarin sensitivity, remained unchanged during tenoxicam administration. The results demonstrate the lack of a clinically relevant effect of tenoxicam on warfarin-induced anticoagulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278491
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  • 11
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and dialysability of isradipine in chronic haemodialysis patients (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 231-233 
    Details
    ISSN: 1432-1041
    Keywords: Isradipine ; Haemodialysis ; pharmacokinetics ; dialysability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of isradipine, a calcium-channel blocker, have been studied in eight patients on chronic haemodialysis. A single oral dose of 5 mg was administered on both a non-haemodialysis and a haemodialysis day and the plasma concentrations of isradipine were analyzed. The mean cmax, tmax, AUC, and t1/2 in plasma on the non-haemodialysis day were 5.2 ng·ml−1, 1.4 h, 23.8 ng·h·ml−1, and 3.1 h, respectively. The dialysis clearance of isradipine was negligible (5.0 ml·min−1). The t1/2 values during haemodialysis were not significantly different from those observed during the same period post dose on the non-haemodialysis day. The study demonstrates that supplemental doses of isradipine are not necessary in these patients since isradipine is not significantly removed by haemodialysis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278492
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  • 12
    Electronic Resource
    Electronic Resource
    High dose oral methylprednisolone in patients with rheumatoid arthritis: pharmacokinetics and clinical response (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 85-88 
    Details
    ISSN: 1432-1041
    Keywords: Methylprednisolone ; Rheumatoid arthritis ; bioavailability ; pharmacokinetics ; clinical response ; pulse steroid therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A commercially available 1.0 g intravenous (i.v.) dosage formulation of methylprednisolone, as the sodium hemisuccinate salt (Solu MedrolR, Upjohn) was administered both parenterally and orally (pulse steroid therapy) on separate occasions, to eight elderly (mean 65 y) patients with active rheumatoid arthritis. The relative oral bioavailability of the sterol was 69.2%. Elimination of methylprednisolone was prolonged when given orally; the mean residence times were 7.23 h and 3.94 h for oral and i.v. administrations, respectively. Clinical response to pulse steroid therapy was no different with respect to route of administration. There were no significant differences in standard clinical and laboratory assessments of disease activity when the two therapies were compared. Oral administration of methylprednisolone in patients requiring high-dose pulse steroid therapy is convenient and avoids the discomfort and inconvenience associated with i.v. administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314925
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  • 13
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 89-93 
    Details
    ISSN: 1432-1041
    Keywords: Acetyl-L-carnitine ; Senile Dementia of Alzheimer Type ; pharmacokinetics ; plasma concentration ; cerebrospinal fluid concentration ; carnitine metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetyl-L-carnitine (ALC), a physiological component of the L-carnitine family, has been proposed for treating Alzheimer's disease in pharmacological doses. As this condition requires prolonged therapy, its kinetics has been examined after a multiple dose regimen, involving different routes of administration, in 11 patients suffering from Senile Dementia of Alzheimer Type. The study design comprised a 3-day basal observation period, sham treatment with repeated blood sampling; treatment with 30 mg·kg−1 i.v. given twice for 10 days (plasma kinetics was studied on the 7th day), and 50 days of 2.0 g/day p.o. given in three daily doses. Total acid soluble L-carnitine, L-carnitine and acetyl-L-carnitine in plasma and CSF were evaluated using an enantioselective radioenzyme assay. Short chain L-carnitine esters were calculated as the difference between total and free-L-carnitine. The plasma concentrations of individual components of the L-carnitine family did not change during the three days of the basal period, nor were they affected during the sham therapy period. Following the i.v. bolus injections, the plasma concentrations showed a biphasic curve, with average t1/2 of 0.073 h and 1.73 h, respectively. At the end of oral treatment, plasma acetyl-L-carnitine and L-carnitine short chain esters were significantly higher than during the run-in phase. The CSF concentrations paralleled those in plasma, suggesting that ALC easily crosses the blood-brain barrier. It is concluded that i.v. and oral administration of multiple doses of ALC can increase its plasma and CSF concentration in patients suffering from Alzheimer's disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314926
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  • 14
    Electronic Resource
    Electronic Resource
    Multiple dose kinetics of ofloxacin and ofloxacin metabolites in haemodialysis patients (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 95-99 
    Details
    ISSN: 1432-1041
    Keywords: Ofloxacin ; Haemodialysis ; ofloxacin metabolites ; pharmacokinetics ; multiple doses ; dosage selection ; renal failure ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 7 patients with end-stage renal disease on regular haemodialysis were treated orally with a loading dose of 200 mg ofloxacin and multiple maintenance doses of 100 mg per 24 h for 10 days. The pharmacokinetics of ofloxacin and its metabolites were studied at the end of the treatment period. Plasma and dialysate concentrations of ofloxacin and ofloxacin metabolites were measured by HPLC. Peak (3.1 mg·1−1) and trough levels (1.6 mg·1−1) and the AUC of ofloxacin were comparable to the values in healthy volunteers given 300 to 400 mg ofloxacin p.o. The mean half-life, determined in the dialysis-free interval (t1/2β) and during the haemodialysis session (t1/2HD), was 38.5 h and 9.9 h, respectively. Extrarenal clearance (32.7 ml·min−1) was unchanged as compared to that reported in healthy volunteers after a single dose of ofloxacin. The fractional removal by haemodialysis amounted to 21.5%. Two metabolites, ofloxacin-N-oxide and demethyl-ofloxacin, were detected in plasma. Despite prolonged t1/2β of both metabolites (66.1 and 50.9 h) and multiple doses of ofloxacin the peak concentrations of the metabolites reached only 14% and 5% of that of the parent drug, respectively. It is concluded that in patients on regular haemodialysis treatment the dosage adjustment employed resulted in safe and therapeutically favourable plasma concentrations. The observed accumulation of ofloxacin metabolites does not appear to have any toxic or therapeutic significance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314927
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  • 15
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of rufloxacin in healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 101-105 
    Details
    ISSN: 1432-1041
    Keywords: Rufloxacin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma and urine kinetics of rufloxacin were assessed in healthy volunteers after single (100, 200, 400 and 800 mg) and multiple (300 mg followed by 150 mg daily, Group 1, and 400 mg followed by 200 mg daily, Group 2) oral doses. The kinetics of a single oral dose of 800 mg was assessed in fasting and non-fasting subjects to assess the influence of food intake on drug absorption. The AUCs were 134, 266 and 375 μg · h · ml−1 after 100, 200 and 400 mg, respectively. The AUC after 800 mg p. o. was 715 μg · h · ml −1 in fasting subjects and 614 μg · h · ml−1 in non-fasting subjects. The parameters of the model and the mean renal clearance values indicated some departure from linearity in rufloxacin kinetics. After multiple doses the plasma drug levels during the 6th treatment day were similar to those after the first dose in Group 1 and were about 30–40% higher after the first dose in Group 2. The half-lives after the last dose were much shorter than those estimated in the single dose studies (33–36 h and 50–80 h, respectively).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314928
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  • 16
    Electronic Resource
    Electronic Resource
    The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 121-125 
    Details
    ISSN: 1432-1041
    Keywords: Methotrexate ; non-steroidal anti-inflammatory drugs (NSAIDs) ; interaction ; disposition ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment). The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%. These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278469
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  • 17
    Electronic Resource
    Electronic Resource
    Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 237-256 
    Details
    ISSN: 1432-1041
    Keywords: Non-steroidal anti-inflammatory drugs ; Enantioselective ; Enantiomers ; pharmacodynamics ; pharmacokinetics ; stereoselective
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00266343
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  • 18
    Electronic Resource
    Electronic Resource
    Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics on felodipine — and its potential clinical relevance (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 313-317 
    Details
    ISSN: 1432-1041
    Keywords: Dihydropyridine ; Felodipine ; availability ; flavonoids ; dietary interaction ; pharmacokinetics ; pharmacodynamics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of drinking grapefruit juice on the acute pharmacokinetic and haemodynamic actions of the dihydropyridine calcium antagonist felodipine given as a 5 mg plain tablet has been studied in nine, healthy, middle-aged males. Compared to water, grapefruit juice caused an increase in Cmax from mean 6 to 16 nmol · l−1, and in the AUC from 23 to 65 nmol · h · l−1. The change in AUC corresponded to an increase in the systemic availability of felodipine from 15 to 45%, assuming no change in its clearance. This change was probably caused by inhibition of the oxidation of felodipine to the inactive dehydrofelodipine by flavonoids in grapefruit juice. The interaction with grapefruit juice is believed to be a class effect for the dihydropyridines, as oxidation of the dihydropyridine ring to the corresponding pyridine derivative is a major metabolic route for all these drugs. The higher plasma concentrations of felodipine taken with grapefruit juice resulted in a greater change in blood pressure measured in the morning 3 h after dosing (−9%) than did water (0%).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00266354
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  • 19
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of midazolam during continuous infusion in critically ill neonates (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 329-332 
    Details
    ISSN: 1432-1041
    Keywords: Midazolam ; Fentanyl ; Neonates ; pharmacokinetics ; sedation drug interaction ; hypotension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Midazolam is a water soluble benzodiazepine, with a short elimination half-life in adults and children. An IV bolus (0.2 mg·kg−1) immediately followed by continuous infusion of 0.06 mg·kg−1·h−1 was administered to 15 critically ill neonates at a gestational age of 32.8 weeks, who required sedation for mechanical ventilation. Heart rate and blood pressure were closely monitored. Hypotension occurred in 4 patients after the bolus dose or during the continuous infusion. Three of them had also been given fentanyl. Individual pharmacokinetic parameters were calculated: plasma clearance was 3.9 ml·min−1, elimination half-life was 12.0 h. Because of its short half-life compared to diazepam, midazolam may be used during the neonatal period to achieve rapid, brief sedation. However, it should be administered cautiously to neonates, particularly in premature infants, or if fentanyl is also given.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00266357
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  • 20
    Electronic Resource
    Electronic Resource
    Theophylline steady state pharmacokinetics is not altered by omeprazole (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 343-345 
    Details
    ISSN: 1432-1041
    Keywords: Omeprazole ; Theophylline ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of omeprazole treatment on theophylline pharmacokinetics was studied in eight, non-smoking healthy male volunteers during repeated administration of a slow release formulation of theophylline. In a randomized double-blind cross-over study, the subjects received theophylline 5 mg·kg−1 per day with omeprazole 20 mg per day or identical placebo during two periods, each of 7 days, separated by a washout period of 7 days. The oral clearance of theophylline remained unchanged whether it was administered alone or with omeprazole (54.2 ml·min−1). The average urinary excretion of theophylline and its metabolites, 1,3 dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU) amounted to 9%, 32%, 12% and 22% of the administered dose, respectively, and no significant change occured during concomitant treatment with omeprazole. Thus, the formation and clearance of the metabolites was not altered by omeprazole. Consequently, omeprazole in the recommended dose of 20 mg daily can safely be administered to patients on theophylline therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00266361
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  • 21
    Electronic Resource
    Electronic Resource
    Disposition kinetics and concentration-effect relationship of metipranolol in patients with cirrhosis and healthy subjects (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 337-340 
    Details
    ISSN: 1432-1041
    Keywords: Metipranolol ; Liver cirrhosis ; pharmacokinetics ; pharmacodynamics ; beta-adrenoreceptor blockade
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics and heart rate reducing effect of deacetylmetipranolol (DMP), the active form of the β-adrenoreceptor blocking agent metipranolol (MP), administered as a single 40 mg oral dose have been compared in 6 patients with cirrhosis and 6 healthy volunteers. The mean maximal DMP concentration was significantly higher and the time to reach the peak level shorter in the patients compared to the healthy subjects. There was also a significantly higher AUC of DMP, a shorter half-life of the rapid phase of the decline in DMP concentrations, a smaller central compartment and lower apparent DMP clearance in patients. A correlation with the albumin level was observed in cirrhotics for individual values of apparent DMP clearance (r=0.92) and AUC (r=-0.89). The maximal reduction in heart rate was recorded in patients at plasma DMP levels which were already significantly lower than the peak levels. Median inhibitory concentrations (IC50) and maximum possible heart rate reductions (Δ HRmax), obtained by fitting individual plots of the plasma DMP concentration-effect relationship to the inhibitory Emax model in the postdistributional phase of DMP disposition were significantly higher in cirrhotics than in healthy subjects. It is conjectured that down-regulation of adrenoreceptors due to chronic sympathetic activation in hepatic cirrhosis contributes to decreased sensitivity to the reduction in heart rate following a single dose of the beta-blocker.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00266359
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  • 22
    Electronic Resource
    Electronic Resource
    Influence of food on serum ambenonium concentration in patients with myasthenia gravis (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 371-374 
    Details
    ISSN: 1432-1041
    Keywords: Ambenonium chloride ; Myasthenia gravis ; dietary effect ; serum concentration ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Influence of food on the serum concentration and kinetics ambenonium chloride (AMBC) has been examined in thirteen patients with myasthenia gravis (MG). Mean serum concentrations and Cmax during fasting were higher than those in the non-fasting state. The AUC (0–3 h) was also about four-times larger. The drug effects versus the serum concentration were observed to be anti-clockwise or clockwise. The effective range of the Cmax varied between patients. The unexpected increase in Cmax led to adverse muscarinic actions of AMBC, when the condition was changed from the non-fasting to the fasting state. It is recommended that the dose be changed during non-fasting treatment when adjusting the optimum regimen for patients myasthenia gravis. Patients must be advised to keep to the dosing and dietary schedule in order to avoid unexpected adverse actions to AMBC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280120
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  • 23
    Electronic Resource
    Electronic Resource
    Stereoselective pharmacokinetics of oral nitrendipine in elderly hypertensive patients with normal and impaired renal function (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 423-427 
    Details
    ISSN: 1432-1041
    Keywords: Nitrendipine ; enantiomers ; stereoselectivity ; Renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the enantiomers of nitrendipine has been studied in seven elderly patients with chronic renal failure (CRF) and in six control subjects (mean creatinine clearance 30 and 97 ml·min−1 respectively). Racemic nitrendipine 20 mg was given once daily for seven days and the pharmacokinetics of the enantiomers over the last dosage interval were determined using a stereospecific assay. In both groups nitrendipine exhibited stereoselective pharmacokinetics (AUC, Cmax), but the half-lives of the enantiomers did not differ in individual subjects. As an index of stereoselectivity, the mean S/R ratio of AUCs in control subjects (2.07) was not significantly different from the ratio in patients with CRF (2.68). The mean AUCs of (S)- and (R)-nitrendipine during the last dosage interval were increased in CRF by 132% and 85%, respectively. The observed doubling of the half-lives and the increases in Cmax did not reach significance because of the large variability in each group. Thus, the pharmacokinetics of oral nitrendipine is altered in CRF, but there was no change in the stereoselectivity of its pharmacokinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280129
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  • 24
    Electronic Resource
    Electronic Resource
    Chloroquine levels in blood during chronic treatment of patients with rheumatoid arthritis (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 429-433 
    Details
    ISSN: 1432-1041
    Keywords: Chloroquine ; Rheumatoid arthritis ; desethylchloroquine ; bisdesethylchloroquine ; blood levels ; toxicity ; therapeutic activity ; dose-effect relationship ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Blood levels of racemic chloroquine and its main metabolites desethylchloroquine and bisdesethylchloroquine were measured in 29 patients treated chronically for rheumatoid arthritis. In six patients, the concentrations were followed during a one day dosage interval. There was considerable intersubject variability in the steady state blood concentrations of chloroquine (range 36.6 to 3895 ng·ml−1) and its two main biotransformation products; the latter represented, respectively, 47.7% and 12.9% of the concentration of chloroquine. This finding shows the need for further studies in view of the known toxic effects of chloroquine and the inevitable accumulation due to the exceptionally long residence time of the compound and its metabolites. The main requirement, which has not yet been met, for adding chloroquine to the list of drugs for which therapeutic drug monitoring is useful, is the lack of information about its mechanism of action, and consequently the dose-effect relationships of its therapeutic and toxic actions. Regular ophthalmic examination, in particular, is strongly recommended. The relatively high concentrations of desethylchloroquine and bisdesethylchloroquine found during chronic treatment show the need for more information about the therapeutic value and adverse effects of the metabolites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280130
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  • 25
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 439-443 
    Details
    ISSN: 1432-1041
    Keywords: Alprazolam ; benzodiazepines ; pharmacokinetics ; pharmacodynamics ; sublingual dosage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study. The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes. Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography. Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P〈0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng·ml−1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h·ng·ml−1. Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h. In general the two routes were significantly different from placebo but not from each other.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280132
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  • 26
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of ethanol in plasma and whole blood: estimation of total body water by the dilution principle (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 445-448 
    Details
    ISSN: 1432-1041
    Keywords: Ethanol ; whole blood ; plasma ; total body water ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ethanol in plasma and whole blood have been investigated and the results used to estimate the volume of total body water (TBW) by means of the dilution principle. Fifteen men (mean age 62 y) were given 0.6 g ethanol/kg body weight as an intravenous infusion over 1 h. The peak concentration of ethanol in plasma was 120 mg·dl−1 compared to 108 mg·dl−1 for whole blood. The disappearance rate of ethanol from plasma was 18.6 mg·dl−1·h−1 compared to 17.0 mg·dl−1·h−1 for the whole blood concentration-time data. The apparent volume of distribution of ethanol (Vz) was 0.54 l·kg−1 according to plasma kinetics compared to 0.59 l·kg−1 for the kinetics derived from whole blood. The mean area under the curve (AUC) was 294 mg·dl−1×h for plasma kinetics compared to 266 mg·dl−1×h for whole blood. The TBW was 40.9 l or 50.9% of body weight for the plasma concentration-time data. This agreed well with the 40.3 l or 50.1% of body weight obtained using whole blood.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280133
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  • 27
    Electronic Resource
    Electronic Resource
    Elevated plasma nilvadipine concentration after single and chronic oral administration to patients with chronic liver disease (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 475-479 
    Details
    ISSN: 1432-1041
    Keywords: Calcium channel blocker ; Nilvadipine ; blood pressure ; liver disease ; pharmacokinetics ; pharmacodynamics ; cirrhosis ; hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fourteen normotensive patients with liver disease (6 with cirrhosis and 8 with chronic hepatitis) and 7 healthy volunteers were given a single oral dose of nilvadipine 2 mg. In addition, nilvadipine 4 mg was administered orally twice daily for several months to 6 hypertensive patients with mild liver dysfunction and 18 hypertensives with normal liver function. A significant increase in plasma nilvadipine was found in the patients with cirrhosis as compared both to the normal and chronic hepatitis subjects; the time to peak concentration was similar among the three groups. The peak plasma nilvadipine concentration was closely correlated both with the serum albumin level and the retention of indocyanine green. Changes in blood pressure, pulse rate and various vasoactive hormones following a single oral dose of nilvadipine did not differ between the groups. Thus, an increase in plasma nilvadipine relative to the level in normal subjects was demonstrated in patients with cirrhosis following a single oral dose, as well as in patients with slight liver dysfunction following long-term oral administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314853
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  • 28
    Electronic Resource
    Electronic Resource
    Digoxin-interactions in man: Spironolactone reduces renal but not biliary digoxin clearance (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 481-485 
    Details
    ISSN: 1432-1041
    Keywords: Digoxin ; Spironolactone ; drug interaction ; biliary clearance ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of an inhibitory effect of spironolactone on the biliary clearance of digoxin has been investigated in 6 healthy subjects. Plasma clearance and the renal and biliary clearance of digoxin were determined twice at steady state (digoxin 0.5 to 1 mg·d−1 p.o. for 6 days), alone or in combination with spironolactone 200 mg daily, after an intravenous dose of digoxin (0.7 × oral dose) on Day 7. Plasma and urine were collected for 48 h. Biliary clearance of digoxin was determined on Day 8 by a duodenal perfusion technique. During spironolactone treatment plasma digoxin clearance tended to be lower (255 vs 224 ml/min; P=0.057) and renal clearance significantly lower (166 vs 144 ml/min), while the biliary clearance of digoxin remained unchanged (106 vs 103 ml/min). Thus, spironolactone reduced the renal clearance of digoxin by an average of 13%, without affecting its biliary clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314854
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  • 29
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of vinorelbine in man (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 545-547 
    Details
    ISSN: 1432-1041
    Keywords: Vinorelbine ; anti-neoplastic agents ; vinca alkaloids ; pharmacokinetics ; lung neoplasms ; HPLC ; assay method
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of vinorelbine has been investigated by a new HPLC method in 8 cancer patients receiving 8 weekly doses (30 mg·m−2) administered by brief infusion (15 min). The plasma concentration-time curves showed a tri-exponential decay with a long terminal half-life (44.7 h) and a high volume of distribution (Vz=75.61·kg−1). The concentrations after the 8th infusion were significantly lower than after the 1st infusion, but without significant modification of CL (1.28 l·h−1·kg−1) or AUC (0.80 mg·l−1·h). The pharmacokinetic parameters exhibited wide inter-individual variations. The results are consistent with those of previous RIA studies, although the HPLC method appears to be more specific and more precise.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314866
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  • 30
    Electronic Resource
    Electronic Resource
    Investigation of a possible pharmacokinetic interaction between ibopamine and isosorbide-5-mononitrate (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 549-552 
    Details
    ISSN: 1432-1041
    Keywords: Ibopamine ; Isosorbide-5-mononitrate ; pharmacokinetics ; drug interaction ; healthy volunteers ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between isosorbide-5-mononitrate (5-ISMN) and epinine, the active metabolite of ibopamine, has been investigated in 8 healthy male subjects given single doses of 200 mg ibopamine and 20 mg 5-ISMN, separately and together. The plasma 5-ISMN concentration-time profile was the same whether 5-ISMN was administered concomitantly with ibopamine or alone [AUC(o-t): 2.24 μg·ml−1·h after 5-ISMN alone, 2.16 μg·ml−1·h after 5-ISMN + ibopamine]. The plasma concentrations of total and free epinine and the urinary recovery of total epinine, homovanillic acid and dihydroxyphenylacetic acid, too, were not different when ibopamine was administered alone or concomitantly with 5-ISMN. The intake of ibopamine did not change the blood pressure and heart rate. The decrease in diastolic blood pressure induced by 5-ISMN was not influenced by concomitant intake of ibopamine. The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between 5-ISMN and ibopamine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314867
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  • 31
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of mefloquine in the presence of primaquine (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 559-560 
    Details
    ISSN: 1432-1041
    Keywords: Mefloquine ; Thai subjects ; pharmacokinetics ; Primaquine ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314870
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  • 32
    Electronic Resource
    Electronic Resource
    Metamizole-furosemide interaction study in healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 593-598 
    Details
    ISSN: 1432-1041
    Keywords: Metamizole ; Furosemide ; prostaglandins ; drug interaction ; adverse effects ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and pharmacodynamic interactions between metamizole (dipyrone) and furosemide were investigated in 9 of 12 healthy female subjects able to complete the study. They received oral metamizole 3×1 g for 3 days or placebo (cross-over) and on the last day of both study periods furosemide 20 mg IV. On the last two days a balanced sodium diet (120 mEq) and on Day 3 an oral water load (600 ml) were given. Metamizole significantly inhibited basal urine flow, whereas the fractional excretion of sodium and chloride and the 12 h-GFR remained unchanged. Metamizole significantly reduced furosemide clearance (175 vs 141 ml · min−1), furosemide-stimulated plasma renin activity (1.42 vs 0.79 ng AI · ml−1 · h−1) and the urinary excretion of prostacyclin metabolites and of prostaglandin F2α (by 70–81%). The renal clearance and terminal half-life of furosemide, peak renal chloride and volume excretion were unchanged. Thus, metamizole did not interact with the renal excretion and the diuretic effect of furosemide, although prostaglandin synthesis was significantly reduced.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265921
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  • 33
    Electronic Resource
    Electronic Resource
    Effect of salbutamol on digoxin pharmacokinetics (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 197-201 
    Details
    ISSN: 1432-1041
    Keywords: Digoxin ; Salbutamol ; serum ; skeletal muscle digoxin ; pharmacokinetics ; drug interaction ; serum potassium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single dose of the β2-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a β2-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man. Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 μg·kg−1·h−1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i. v. injection of digoxin 15 μg·kg−1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0–6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this may be secondary to a β2-adrenoceptor-mediated increase in Na-K-ATPase activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278484
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  • 34
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of nicorandil in patients with normal and impaired renal function (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 203-207 
    Details
    ISSN: 1432-1041
    Keywords: Nicorandil ; pharmacokinetics ; angina pectoris ; uraemia ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of oral nicorandil 20 mg 12 hourly for 9 doses was evaluated in 21 hospitalized patients with angina pectoris due to coronary heart disease and with normal and impaired renal function. Patients were divided into 3 groups based on creatinine clearance (CLCr): GROUP I (n=6) 〉 80 ml/min, GROUP II (n=8) 20–80 ml/min, and GROUP III (n=7) 〈 20 ml/min. After the first dose, the total clearance of nicorandil (CL) value did not change with increasing renal failure and so was not dependent on creatinine clearance. After the last dose CL was 51 l·h−1 in Group I, 44 l·h−1 in Group II and 56 l·h−1 in Group III, and it was not related to creatinine clearance. The percentage of the dose excreted in the urine was 0.4%. No significant difference was noted in any of the other pharmacokinetic parameters examined in the three groups, not even on comparing values obtained on the first and last days of treatment. The findings suggest that there is no need to change the dose of nicorandil in subjects with different degrees of renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278485
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  • 35
    Electronic Resource
    Electronic Resource
    Plasma thiamine concentrations after intramuscular and oral multiple dosage regimens in healthy men (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 219-222 
    Details
    ISSN: 1432-1041
    Keywords: Thiamine ; pharmacokinetics ; analytical method ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A novel liquid chromatographic method for the determination of thiamine in plasma has been developed and has been used to study plasma thiamine concentrations after multiple dosage regimens for 11 days. The method involves purification, concentration and analytical separation of thiochrome on-line, using a switching column system. Ten healthy men were given 500 mg thiamine i.m. once a day (Group 1) and ten were given 250 mg p.o. every 12 h (Group 2). The times to reach steady state (7 and 5.6 days for Groups 1 and 2, respectively) were not different (P〉0.05). The mean elimination half-life was 1.8 days. The mean minimum steady-state concentration after the oral regimen (23 μg·l−1) was 78% of that after the intramuscular regime (29 μg·l−1).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00278489
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  • 36
    Electronic Resource
    Electronic Resource
    Effect of treatment at night with S-1452, a thromboxane A2 receptor antagonist, on the morning rise in platelet aggregation (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 501-505 
    Details
    ISSN: 1432-1041
    Keywords: S-1452 ; thromboxane A2 receptor antagonist ; nocturnal dosage ; platelet aggregation ; circadian rhythm ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is well known that platelet aggregation shows a morning rise, which may contribute to the increase in the onset of ischaemic heart diseases during the morning period. The present study was undertaken to determine whether nocturnal dosage with S-1452, a thromboxane AZ receptor antagonist, would blunt the morning rise in platelet aggregability. S-1452 50 mg or placebo were given orally to 8 healthy subjects at 10.00 h (day trial) or 22.00 h (night trial) according to a cross-over design. Plasma concentrations of S-1452 and its metabolites, bisnor-( + )-S-145 and tetranor-(+ )-S-145, and platelet aggregation were determined during the 12-hour period following the dose. Mean plasma concentrations of S-1452, bisnor-( + )-S-145 and tetranor-(+ )-S-145 during the absorption phase were lower after the nocturnal dose than after the morning dose. The maximum plasma concentration and area under the plasma concentration-time curve of the compounds were also lower and the time to the maximum concentration were delayed after the treatment at night. A morning rise in platelet aggregation was observed following placebo treatment. The inhibitory effect of S-1452 on platelet aggregation was observed at 3 hours and persisted for up to 9 h in both trials. The results suggest that S-1452 is absorbed more slowly after the nocturnal dose than after the morning dose. However nocturnal treatment with 50 mg S-1452 may blunt the morning rise in platelet aggregability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02285091
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  • 37
    Electronic Resource
    Electronic Resource
    Intracolonic bioavailability of human calcitonin in man (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 527-531 
    Details
    ISSN: 1432-1041
    Keywords: Calcitonin ; Colonic administration ; Bioavailability ; pharmacokinetics ; pharmacodynamics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Human calcitonin (hCT) injected into the lumen of the descending colon of normal human subjects was absorbed within minutes and could be recognized intact in plasma as shown by RIA in combination with reverse-phase HPLC. The absorption was low and variable, with bioavailabilities ranging from 0.01% to 2.7% relative to intravenously administered hCT (area under the concentrationtime curve). With intravenous hCT serum calcium was lowered and the fractional urinary excretion of calcium, phosphorus, sodium and chloride was significantly stimulated. With the intracolonic hCT, the fractional urinary excretions of calcium, sodium and chloride were also marginally stimulated relative to intracolonic vehicle (placebo). In conclusion, hCT is absorbed intact from the colon, but the bioavailability is low and highly variable.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02285096
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  • 38
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    Electronic Resource
    Pharmacokinetics of diphemanil methylsulphate in healthy subjects (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 689-691 
    Details
    ISSN: 1432-1041
    Keywords: Diphemanil methylsulphate ; pharmacokinetics ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters of oral diphemanil methylsulphate have been evaluated in six healthy male volunteers. Absorption of the drug was slow (tmax=2 to 4 h), the mean half-life was 8.35 h, and the amount of the drug recovered in urine within 48 h ranged from 0.6 to 7.4% of the administered dose. The results suggest low bioavailability, assuming that the drug is poorly metabolized.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265939
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  • 39
    Electronic Resource
    Electronic Resource
    Dose proportionality study of loperamide following oral administration of loperamide oxide (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 693-694 
    Details
    ISSN: 1432-1041
    Keywords: Loperamide ; loperamide oxide ; diarrhoea ; pharmacokinetics ; dose-proportionality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of loperamide, after oral administration of increasing doses (1 to 16 mg) of loperamide oxide, has been investigated in 10 healthy male volunteers, using a randomised cross-over design. Comparison of the maximum plasma loperamide concentration and AUC demonstrated that the bioavailability of loperamide was proportional to the dose of loperamide oxide administered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265940
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  • 40
    Electronic Resource
    Electronic Resource
    Evaluation of the accuracy of a pharmacokinetically-based patient-controlled analgesia system (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 67-75 
    Details
    ISSN: 1432-1041
    Keywords: Morphine ; Patient-controlled analgesia ; opioids ; pharmacokinetics ; bolus-elimination-transfer ; computer-assisted continuous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bone marrow transplant patients having severe, prolonged oral mucositis pain (expected to last for one to three weeks) used a computer-controlled infusion system to self-administer morphine for pain control. Individual patient pharmacokinetic information, derived from a pretreatment bolus morphine dose, was used in a new bolus-elimination transfer algorithm to produce rapid adjustments of steady plasma morphine concentrations when the patient requested more or less drug. We evaluated the performance characteristics (bias and precision) of this pharmacokinetically based patient-controlled analgesic infusion system (PKPCA) in a group of 15 cancer patients over six to 14 days. Although we found a three- to fivefold pharmaco-kinetic variability in the tailoring morphine dose data, the PKPCA system was free of systematic bias (insignificant overall prediction error) during the patient-controlled infusions in this study population. The absolute prediction error was 19.9% for the group on the first study day and 25.6% over the entire study period (aggregate results; 6–14 days of continuous use). Two-thirds of the patients exhibited no bias throughout the study period, and individual bias in the others was symmetrically distributed (three patients with underpredictions and two overpredicted). Magnitude of prediction error during the patient-controlled morphine infusions was not related to the magnitude of pharmacokinetic deviation of individual subjects from group parameters. Our results indicate that this PKPCA system provides accurate control of plasma morphine concentration when used by patients to self-administer opioid for prolonged pain relief continuously over 1 to 2 weeks. Use of individual pharmacokinetic information, instead of population parameters, may account for superior performance characteristic of this computer-assisted continuous drug infusion system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02280757
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  • 41
    Electronic Resource
    Electronic Resource
    Steady state pharmacokinetic profile of indomethacin in elderly patients and young volunteers (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 77-80 
    Details
    ISSN: 1432-1041
    Keywords: Indomethacin ; steady-state ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady-state pharmacokinetic profile of indomethacin was examined in twelve healthy volunteers (4 m, 8 f; 20–34 y) and in 12 elderly subjects (7 m, 5 f; 70–88 y). Two formulations of indomethacin were examined, providing duplicate data for each subject group. The subjects received each formulation of indomethacin (25 mg tid) for 6 days in a single blind crossover fashion. On day 7, after an overnight fast, a final 25 mg dose of indomethacin was given and plasma concentrations measured over the following 12 h. Kinetic parameters Cpmin, tmx and AUC (0–12 h) were determined. There were no differences in the pharmacokinetic parameters between young and elderly subjects or between data for the two formulations of indomethacin. AUC values (μg · ml−1 · h), for example, for the two formulations in the young subjects were 5.85 and 6.85 while the values for the elderly subjects were 6.55 and 6.50 respectively. When each treatment period was considered independently there was a significant difference between young and elderly subjects with regard to compliance. The rates of non compliance (over and under compliance) using a capsule count technique were, however, low with a mean maximum value of 5.8% being recorded for the elderly subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02280758
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  • 42
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and blood pressure effects of carvedilol in patients with chronic renal failure (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 85-88 
    Details
    ISSN: 1432-1041
    Keywords: Hypertension ; Carvedilol ; chronic renal failure ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and acute systemic haemodynamic effects of a single oral dose of 50 mg carvedilol has been studied in 24 hypertensive patients with chronic renal failure. The patients were stratified into 3 groups according to the creatinine clearance: I 51–90 ml · min−1; II 26–50 ml · min−1; III 4–25 ml · min−1. The area under plasma level time curve AUC, the elimination half-life t/12, the maximum plasma concentration Cmax, the time to peak concentration tmax were not significantly different between groups, whereas the amount of unchanged drug or metabolite excreted in urine Ae and the renal clearance CLR of carvedilol and its metabolites M2, M4, M5 were significantly decreased in Group III. Blood pressure and heart rate decreased in all 3 groups of patients after acute administration of 50 mg carvedilol. Mild adverse effects were reported in 6 patients. Despite a decrease in the renal clearance of carvedilol and of its metabolites with decreasing kidney function, its main pharmacokinetic parameters remained unchanged. The present results suggest that the dose of carvedilol need not be reduced in hypertensive patients with chronic renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02280760
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  • 43
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of tiopronin and its principal metabolite (2-mercaptopropionic acid) after oral administration to healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 93-95 
    Details
    ISSN: 1432-1041
    Keywords: Tiopronin ; 2-mercaptopropionic acid ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of tiopronin and its principal metabolite, 2-mercaptopropionic acid (2-MPA) in healthy volunteers after the oral administration of 500 mg (2 Acadione® tablets), followed by simultaneous assay of the two compounds in plasma over a period of 48 h using a new method (emission of fluorescence after HPLC and post-column derivatization by pyrene-maleimide). The absorption of tiopronin was slow (tmax between 4 and 6 h) and the plasma concentrations subsequently fell biexponentially. The principal metabolite 2-MPA appeared later in the plasma (tmax between 10 and 12 h after a lag-time of 3 h) then disappeared monoexponentially. About 15% of the tiopronin was metabolized to 2-MPA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02280762
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  • 44
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of cyclosporine in hyperlipidaemic long-term survivors of heart transplantation (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 161-165 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporine ; Hyperlipidaemia ; heart transplantation ; fenofibrate ; fenofibric acid ; pharmacokinetics ; drug interaction ; nephrotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cyclosporine (Cy) binds to lipoproteins in plasma. In order to test if its pharmacokinetics would be modified when efficient lipid-lowering treatment is introduced, a study has been done of Cy pharmacokinetics and any interaction with the lipid-lowering agent fenofibrate in hyperlipidaemic long-term, survivors of heart transplantation. Fenofibrate 200 mg once daily significantly reduced blood lipids (cholesterol 6.5 vs 7.7 mmol/l; apoprotein B 1.2 vs 1.6 g/l) but did not modify mean whole blood Cy trough levels (113 before fenofibrate vs 103 ng·ml−1), Cmax (812 ng·ml−1 by RIA and 757 ng·ml−1 by HPLC before fenofibrate versus 865 and 741 respectively, during fenofibrate); tmax (1.6 and 1.7 h before fenofibrate versus 1.4 and 1.4 h respectively), and t1/2 (13.9 and 11.1 h versus 9.5 and 10.7 h). The only adverse effect was an increase in creatinine (157 vs 145 mmol/l). Further studies are needed to investigate the mechanism of Cy-fenofibrate nephrotoxicity and to evaluate the long-term efficiency and safety of fenofibrate after heart transplantation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01740664
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  • 45
    Electronic Resource
    Electronic Resource
    Lack of pharmacodynamic and pharmacokinetic interactions of the antihistamine ebastine with ethanol in healthy subjects (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 179-184 
    Details
    ISSN: 1432-1041
    Keywords: Ebastine ; Ethanol interaction ; carebastine ; psychomotor performance ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a double-blind, crossover study for one week each. The subjects were tested for drug effects on Day 6 of each period, and for interactions of ebastine with ethanol (0.8 g·kg−1) on Day 7. On both days, the testing runs were done at baseline and at 2, 4, and 6 h after the drug. Performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, nystagmus, simulated driving, body balance) and subjectively (visual analogue scales) and with questionnaires. Venous blood samples were taken daily during maintenance and during each test run for assay of plasma carebastine. Blood ethanol concentrations were assayed with an Alcolmeter in the breath and directly in the blood. Plasma carebastine concentration reached a steady-state from Day 3 on; the mean concentrations in the morning were 92 µg·l−1 on Day 6 and 104 µg·l−1 on Day 7. The rise in plasma carebastine after an extra 20 mg of ebastine was accelerated but not increased by ethanol. Ebastine did not impair performance objectively or subjectively. It slightly improved body balance and reduced errors during simple tracking at 4 h. Blood ethanol concentrations peaked (mean 0.76 g·l−1) at 1.5 h after ethanol intake. Ethanol impaired performance in most objective tests and produced clumsiness, muzziness, and mental slowness, but little drowsiness. Ebastine neither modified the blood ethanol concentrations nor increased the effects of ethanol. We conclude that treatment with 20 mg ebastine once daily for one week provides steady concentrations of carebastine in plasma without impairment of skilled performance or important interactions with alcohol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01740667
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  • 46
    Electronic Resource
    Electronic Resource
    Altered pharmacokinetics of lignocaine after epidural injection in Type II diabetics (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 269-271 
    Details
    ISSN: 1432-1041
    Keywords: Lignocaine ; diabetes mellitus ; pharmacokinetics ; epidural anaesthesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of lignocaine has been compared after epidural anaesthesia in diabetics and nondiabetic patients. Epidural lignocaine 8 mg · kg−1 was given to 8 well controlled Type II diabetic and 8 nondiabetic patients and the plasma drug concentration in serial blood samples were measured by HPLC. The plasma level of lignocaine was lower in diabetics compared to non-diabetics. The peak level was attained at 20 min in both groups. The clearance of the drug was significantly higher, (39,9 vs 16,7 ml · min− · kg−) associated with a decreased elimination half-life and mean residence time. The study suggests that the rate of absorption of lignocaine is not altered after epidural administration and that its hepatic metabolism is increased in diabetics compared to non-diabetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02333021
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  • 47
    Electronic Resource
    Electronic Resource
    Pharmacokinetic profile of a novel slow release preparation of molsidomine (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 273-276 
    Details
    ISSN: 1432-1041
    Keywords: Molsidomine ; slow release ; pharmacokinetics ; in vitro/in vivo correlation ; pharmacokinetics ; healthy volunteers ; dissolution profile
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (〉 5 ng · ml−1 were not maintained over 24 h by this slow release formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02333022
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  • 48
    Electronic Resource
    Electronic Resource
    Pharmacokinetic estimations from microdialysis data (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 289-294 
    Details
    ISSN: 1432-1041
    Keywords: Microdialysis ; Drug concentration ; parameter estimation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Microdialysis has recently been adapted for sampling the extracellular fluid of various organs in order to measure drug concentrations, and the first clinical application has been published. My aim here is to provide simple rules about how to analyse pharmacokinetic data from such studies. The plotting of data on a time scale and the estimation of C (0) and slopes is not a trivial problem when multicompartmental models are assumed or sampling intervals are unequal. I have developed formulae and algorithms to solve the problem. A simple rule of thumb is given, suggesting when these formulae need to be applied. It is shown that the calculations of half-life and slopes is similar to standard methods for equal sample intervals and that calculation of AUC and clearance may be even more accurate for microdialysis data than for ordinary blood sampling, because of the time-integral character of the dialysis method. I have dealt with both zero-order and first-order kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02333025
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  • 49
    Electronic Resource
    Electronic Resource
    Captopril does not interact with the pharmacodynamics and pharmacokinetics of digitoxin in healthy man (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 445-447 
    Details
    ISSN: 1432-1041
    Keywords: Captopril ; Digitoxin ; impedance cardiography ; drug interaction ; healthy volunteers ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chronic oral administration of 0.07 mg digitoxin o. d. for up to 58 days to 12 healthy volunteers caused a small drop in mean heart rate HR (95 % CI: −7.9 to −1.6 beats · min−1), in mean diastolic blood pressure (95 % CI: −8.3 to −0.4 mm Hg), shortening of the QTc-interval (95 % CI: −42 to −19 ms), shortening of the HR-corrected pre-ejection period PEPc (95 % CI: −16 to −1 ms) and electromechanical systole QS2c (95 % CI: −25 to −1 ms), and an increase in the impedance cardiographic Heather index (dZ/dtmax/RZ, 95 % CI: 0.3 to 4.3) relative to the baseline measurements before digitalisation. The concomitant administration of 25 mg oral captopril b. d. did not significantly alter these responses relative to the concomitant double-blind administration of placebo, nor did it alter the pharmacokinetic characteristics of plasma digitoxin at steady state. Thus, no relevant change in the pharmacokinetic and pharmacodynamic characteristics of chronically administered digitoxin were induced by concomitant treatment with captopril.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02220626
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  • 50
    Electronic Resource
    Electronic Resource
    Rebound of plasma vancomycin levels after haemodialysis with highly permeable membranes (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 635-639 
    Details
    ISSN: 1432-1041
    Keywords: Vancomycin ; Haemodialysis ; highflux membranes ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Vancomycin is usually given only once a week to haemodialysis (HD) patients. If highly permeable dialysis membranes are used, however, high clearance values have been reported, so the aim of the study was to determine whether high clearance of vancomycin resulted in sufficient drug elimination to induce subtherapeutic plasma levels after one week. In 18 chronic HD patients, treated with polysulfone dialyzers (1.2 m2), the pharmacokinetics of vancomycin were studied after administration of 1 g. Concentrations were determined by fluorescence polarisation immunoassay. At a blood flow of 219 ml·min−1, HD clearance of vancomycin was 62.3 ml·min−1. Immediately after dialysis plasma concentrations were 38% lower than predialysis levels. However, marked rebound in the vancomycin level was observed 5 h later, resulting in plasma levels only 16% lower than prior to dialysis. 3 HD treatments in 1 week removed about one third of the initial dose. After one week 15 of 18 patients still had a therapeutic plasma level (〉5 μg·ml−1). In conclusion, polysulfone membranes show high clearance of vancomycin. However, transfer of drug from blood to dialysate appears to be faster than from tissues to blood. Because of a marked rebound in plasma level after treatment, therapeutic drug concentrations will still be present in most patients after one week.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265928
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  • 51
    Electronic Resource
    Electronic Resource
    The postoperative pharmacokinetics of codeine (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 663-666 
    Details
    ISSN: 1432-1041
    Keywords: Morphine ; Codeine ; drug metabolism ; pharmacokinetics ; systemic availability ; individual variability ; post-operative state
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolism and systemic availability of codeine have been studied in 12 patients after cholecystectomy. They were given 20 mg codeine as an IV bolus dose on the first day after surgery and 50 mg codeine as a single oral on the fourth day after surgery. Codeine had a medium to high extraction ratio and a total plasma clearance of 10.8 (4.3) ml·min−1·kg−1. The clearance varied fourfold between subjects. All the patients were extensive metabolizers with regard to the debrisoquine/sparteine polymorphism, as tested using dextromethorphan as the probe drug. Nevertheless, the formation of morphine from codeine was very small and plasma morphine concentrations were below the detection limit of 3.3 nmol·1−1 (1 ng·ml−1). As a corollary, the morphine/codeine ratio in the the concentration-time curves was less than 3% in all the patients. The systemic availability of codeine varied extensively between subjects (range 12–84%). This might partly explain differences in the dose of codeine required as an analgesic.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265933
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  • 52
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of nifurtimox in chronic renal failure (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 671-673 
    Details
    ISSN: 1432-1041
    Keywords: Nifurtimox ; Changas' disease ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of nifurtimox, a drug used in the treatment of Trypanosoma cruzi infections, has been studied in seven patients with chronic renal failure undergoing haemodialysis, and in seven healthy subjects. Each subject took nifurtimox 15 mg·kg−1 orally and blood samples were obtained for 10 h after administration. Nifurtimox in serum was analyzed by HPLC. The patients with chronic renal failure had a higher Cmax than the control subjects due to a change in systemic availability. An alternative explanation would be that both the distribution volume and the clearance had changed. The mean half-life in the patients with chronic renal failure was similar to that in the healthy subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265935
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  • 53
    Electronic Resource
    Electronic Resource
    Effect of tetracycline on mefloquine pharmacokinetics in Thai males (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 567-569 
    Details
    ISSN: 1432-1041
    Keywords: Mefloquine ; Tetracycline ; Thai subjects ; Thai subjects ; drug interaction ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a single oral dose of mefloquine given either alone or with tetracycline has been studied in 20 healthy Thai male volunteers. There was a significantly higher maximum whole blood mefloquine concentration after coadministration with tetracycline (1600 vs 1160 ng · ml−1), as well as a significantly reduced terminal half-life (14.4 vs 19.3 days), mean residence time (11.9 vs 16.0 days) and volume of distribution at steady state (13.3 vs 19.91 · kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 7 days was significantly increased by tetracycline (6.18 vs 4.76 μg · ml−1 · day). The changes in mefloquine disposition after tetracycline treatment are probably due to a reduction in enterohepatic recycling. The initial increase in mefloquine AUC without an apparent increase in side-effects suggests that this combination may have a place in the treatment of multi-drug resistant falciparum malaria.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02285105
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  • 54
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    Electronic Resource
    The influence of hydrochlorothiazide on the pharmacokinetics of enalapril in elderly patients (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 173-177 
    Details
    ISSN: 1432-1041
    Keywords: Enalapril ; Hydrochlorothiazide ; pharmacokinetics ; renal impairment ; old patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomized, cross-over, single-dose study of 19 elderly hypertensive patients (aged 62–84 y, SBP 〉 160 mm Hg, DBP 〉 100 mm Hg, creatinine clearance 11–93 ml·min−1) we have studied the pharmacokinetics of the angiotensin converting enzyme (ACE) inhibitor enalapril after a single oral dose of either 10 mg enalapril or 10 mg enalapril + 25 mg hydrochlorothiazide. The pharmacokinetics of enalapril were unaffected by hydrochlorothiazide, but there was a significant reduction in renal clearance and a significant increase in AUC(0–24 h) of enalaprilat after hydrochlorothiazide, resulting in higher serum concentrations of the active drug. This was independent of the individual degree of renal impairment and might be due either to an initial reduction of GFR by hydrochlorothiazide or to interference with the tubular secretion of enalaprilat. The relationships between serum enalaprilat and serum ACE activity were similar after both treatments, both consistent with a value for Ki of enalaprilat of about 0.1 nmol·l−1. Thus, serum ACE activity was not affected by hydrochlorothiazide but completely reflected the pharmacokinetics of enalaprilat in both treatments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01740666
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  • 55
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    Electronic Resource
    Lack of interaction ofβ-methyldigoxin with ranitidine in patients with chronic congestive heart failure (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 205-206 
    Details
    ISSN: 1432-1041
    Keywords: β-Methyldigoxin ; Ranitidine ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01740673
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  • 56
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    Electronic Resource
    The effect of haemodialysis on the pharmacokinetics of tenoxicam in patients with end-stage renal disease (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 197-199 
    Details
    ISSN: 1432-1041
    Keywords: Tenoxicam ; pharmacokinetics ; haemodialysis ; end-stage renal disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of tenoxicam after single and multiple oral doses of 20 mg in five patients (2 men and 3 women) with end-stage renal disease undergoing haemodialysis. After a single dose, tenoxicam had a half-life (t1/2) of 33 h, an apparent clearance (CL·f−1) of 4.3 ml·min−1, and an apparent volume of distribution (Vz·f−1) of 11.8 l. The maximum tenoxicam concentration (Cmax) was 4.3 mg·l−1 at a median tmax of 1.7 h. There were no significant differences between the values calculated from the pre- or post-dialyser port plasma samples. Tenoxicam plasma concentrations measured during once daily dosing before and after haemodialysis showed that tenoxicam does not accumulate. Our findings suggest that dosage adjustment may not be required in patients with end-stage renal disease on haemodialysis taking tenoxicam.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01740671
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  • 57
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    Electronic Resource
    Lack of pharmacokinetic interaction between moxonidine and hydrochlorothiazide (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 209-210 
    Details
    ISSN: 1432-1041
    Keywords: Moxonidine ; Hydrochlorothiazide ; pharmacokinetics ; drug interaction ; steady-state ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01740675
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  • 58
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    Electronic Resource
    Pharmacokinetics of pirmenol in young and elderly subjects (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 437-439 
    Details
    ISSN: 1432-1041
    Keywords: Pirmenol ; pharmacokinetics ; elderly subjects ; age effect ; adverse effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady state pharmacokinetics of pirmenol was compared in twelve healthy young (aged 18 to 45 y) and 11 elderly subjects (over 65 y) subjects given pirmenol HCl 100 mg every 12 h for a total of 14 doses. In addition, the single-dose pharmacokinetics of pirmenol was determined following a 100 mg oral dose in the young subject group for comparison with the results of repeated administration. In the young subjects, the mean single-dose and steady-state CLR of pirmenol were similar; however, Ae was 29 % higher and CL/f was 22 % lower at steady state than after the single dose. Steady-state (fourteenth dose) Cmin, Cmax, tmax, λz, Ae, CL/f, CLR and V values were similar in the young and elderly subjects. Based on pharmacokinetic considerations, the dosage of pirmenol is unlikely to differ in young and elderly subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02220624
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  • 59
    Electronic Resource
    Electronic Resource
    General Treatment of the Enterohepatic Recirculation of Drugs and Its Influence on the Area Under the Plasma Level Curves, Bioavailability, and Clearance (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1306-1313 
    Details
    ISSN: 1573-904X
    Keywords: enterohepatic recirculation ; pharmacokinetics ; bioavailability ; clearance ; biliary excretion ; first-pass effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A general treatment of enterohepatic recirculation of drugs has been developed based on the fraction of drug in systemic circulation that is excreted in the bile and the fraction of drug reabsorbed from the gut that reaches systemic circulation in each enterohepatic cycle. The deduced equations make it possible to establish mathematical relationships between the areas under the blood level curves (AUC) of a drug when administered to normal and bile duct-cannulated animals and to predict the effect of enterohepatic recycling on bio-availability and clearance. The results were compared with those obtained by other authors using different approaches to enterohepatic recirculation, and some discrepancies were found in the equations describing the effect of enterohepatic recycling on AUC and bioavailability of drugs. The cause of such discrepancies and the problems associated with the prediction of hepatic extraction ratio from in vitro studies are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015861502354
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  • 60
    Electronic Resource
    Electronic Resource
    Effect of Isoflurane Anesthesia on Antipyrine Pharmacokinetics in the Rat (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1515-1517 
    Details
    ISSN: 1573-904X
    Keywords: isoflurane ; anesthesia ; antipyrine ; metabolism ; pharmacokinetics ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015835618709
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  • 61
    Electronic Resource
    Electronic Resource
    Influence of Permanent Cannulation of the Jugular Vein on Pharmacokinetics of Amoxycillin and Antipyrine in the Rat (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1587-1591 
    Details
    ISSN: 1573-904X
    Keywords: permanent cannulation ; pharmacokinetics ; amoxycillin ; antipyrine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effect of chronic cannulation of the rat jugular vein on the pharmacokinetics of amoxycillin and antipyrine administered by the i.v. and oral routes has been evaluated. Animals that received the i.v. dose of amoxycillin on the eighth day after jugular vein cannulation showed decreased clearance (4.0 ± 0.3 ml/min) and steady-state volume of distribution (105 ± 8 ml) compared to animals that received the i.v. dose on the fourth day (5.5 ± 1.1 ml/min and 155 ± 17 ml, respectively). Rats first dosed by the i.v. route showed an oral bioavailability of 54 ± 12%, whereas for those first dosed by the oral route the calculated bioavailability was 31 ± 6%. Antipyrine was administered to rats by the i.v. and oral routes on the first and fourth days after jugular vein cannulation. Animals intravenously dosed on the fourth day showed a decreased clearance (1.9 ± 0.3 ml/min) compared to rats intravenously dosed on the 1st day (2.7 ± 0.6 ml/min). Antipyrine bioavailability was larger in animals first dosed by the i.v. route than in animals first dosed by the oral route (173 ± 43 and 74 ± 15%, respectively). These results argue against the use of crossover studies in rats with permanently implanted cannulas since kinetic changes induced by cannulation can be larger than previously proposed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015864425069
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  • 62
    Electronic Resource
    Electronic Resource
    Effect of Chronic Hypertension on the Blood–Brain Barrier Permeability of Libenzapril (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 236-243 
    Details
    ISSN: 1573-904X
    Keywords: blood–brain barrier (BBB) ; pharmacokinetics ; liben-zapril ; cerebrospinal fluid (CSF) ; chronic hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Very little information is available on the permeability of theblood–brain barrier (BBB) to small polar drugs inchronic hypertension. The blood and cerebrospinal fluid (CSF)pharmacokinetics of liben-zapril (LZP), a potentangiotensin converting enzyme inhibitor, were investigated inhypertensive (SH) and normotensive (SD) rats.Following intravenous bolus administration of this hydrophilic drug, theterminal rate constant for elimination (β),steady-state volume of distribution ( $$V_{d_{ss} }$$ ), and systemic clearance (CL) were similar in these two animalgroups. Other pharmacokinetic parameters (Cp°,α, k l2, and k 21)were significantly (P 〈 0.05) greater in thehypertensive group, except for the volume of the central compartment(Vc) and ratio of Vc to $$V_{d_{ss} }$$ , which were smaller in SH rats. The ratio ofarea under the concentration–time curve (AUC) in CSF toblood was about twofold higher in SH rats compared to normotensive rats,showing increased BBB permeability in hypertensive rats. An acute brainuptake study was also performed in SH, SD, and WK rats by intracarotidadministration of 14C-LZP along with3H2O as a reference marker. Both LZP and watertransport was found to be significantly higher (about two-to five-fold) in six of the seven different brain regions inSH rats as compared to the normotensive (SD and WK) controls.Because of this simultaneous increase in concentrations of both the drugand the reference marker, BUI values were not affected. Regional brainconcentrations in SH rats were also linearly correlated with the meanarterial pressure (MAP) values, providing further evidence ofthe systemic pressure related increase in BBB permeability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018945608888
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  • 63
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and Pharmacodynamic Comparison of Immediate-Release and Sustained-Release Adinazolam Mesylate Tablets After Single- and Multiple-Dose Administration (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 457-463 
    Details
    ISSN: 1573-904X
    Keywords: psychomotor performance ; sedation ; pharmacody-namics ; pharmacokinetics ; active metabolite ; N-desmethyladinazo-lam
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on mulitiple dosing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015875910222
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  • 64
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    Electronic Resource
    The Pharmacokinetics of Pulmonary-Delivered Insulin: A Comparison of Intratracheal and Aerosol Administration to the Rabbit (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 764-768 
    Details
    ISSN: 1573-904X
    Keywords: insulin ; aerosol ; pulmonary ; pharmacokinetics ; gamma scintigraphy ; drug delivery ; rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pulmonary deposition and pharmacokinetics of insulin, administered via an endotracheal tube as an aerosol and instillate, in formulations containing either 113mIn-DTPA or 99mTc-DTPA (for gamma scintigraphic imaging) have been studied in four male New Zealand White rabbits. Using a randomized crossover design, the pharmacokinetics of intravenous insulin were also characterized. Recovery of immunoreactive insulin after nebulization was greater than 90%, indicating that the aerosolisation procedure did not cause appreciable insulin degradation. Gamma scintigraphy demonstrated that the penetration index (peripheral:central deposition) for the aerosolized formulation (1.52) was much greater than that for the instillate (0.32). Gamma scintigraphy also allowed exact quantification of the dose deposited after aerosol administration and thus permitted accurate determination of bioavailabilities. The bioavailable fraction for aerosolized insulin was 10-fold greater than for instilled insulin (57.2 vs 5.6%). Mucociliary clearance was likely to be greater for the instillate since it showed a preferential central deposition; this may account for the lower bioavailability. Insulin pharmacokinetics from both pulmonary formulations were absorption rate limited, resulting in postpeak half-lives which were approximately 20-fold greater than the intravenous elimination half-life (3 min). The apparent absorption rate constants resulting from instillation and aerosolisation were statistically equivalent (0.015 and 0.011 min−1, respectively). Mucociliary clearance of insulin would result in an overestimation of the true absorption rate constant; hence if mucociliary transport were greater for the instillate, then the true airways to blood transfer rate constant will be higher for the aerosolized formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015851521551
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  • 65
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    Electronic Resource
    Multiple Oral Administration of a Ketoprofen–Dextran Ester Prodrug in Pigs: Assessment of Gastrointestinal Unavailability by Deconvolution (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 915-919 
    Details
    ISSN: 1573-904X
    Keywords: ketoprofen ; prodrugs ; pharmacokinetics ; deconvolution ; in vivo dissolution/release profile
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Deconvolution has been applied to estimate the in vivo dissolution/ release process of ketoprofen from a ketoprofen–dextran ester pro-drug in pigs. The prodrug was given to three pigs at intervals of 12 hr and in seven doses corresponding to 4 mg ketoprofen/kg body weight. Frequent blood sampling was carried out at the first, third, and seventh intervals. Plasma steady-state concentrations of ketoprofen following the prodrug administration were between 2 and 4 µg/ml. The reference consisted of a single p.o. dose of parent ketoprofen (4 mg/kg body weight). For each pig the response following the multiple dosing was deconvolved with the reference response using an algebraic deconvolution procedure adopted from the literature. The obtained cumulated in vivo dissolution/release profiles revealed similar release rates for the three pigs and similar extents of release (59, 70, and 65%). The mean in vivo dissolution/release times (MDT) were calculated to be 5.4, 6.1, and 5.7 hr, respectively. In conclusion, following administration of the dextran prodrug the plasma concentration curves and the dissolution/release profiles are uniform, with small interindividual variations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015805000595
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  • 66
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    Electronic Resource
    Pharmacokinetic Analysis of the Structural Requirements for Forming “Stable” Analogues of Valpromide (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1058-1063 
    Details
    ISSN: 1573-904X
    Keywords: valpromide ; stable analogues ; pharmacokinetics ; structural requirements
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The following valpromide (VPD) analogues were synthesized and their structure-pharmacokinetic relationships explored: 3-ethyl pentanamide (EPD), methylneopentylacetamide (MND), 1-methyl cyclohexanecarboxamide (MCD), cycloheptanecarboxamide (CHD), and t-butylacetamide (TBD). Two aliphatic (EPD and MND) and two cyclic amides (MCD and CHD) underwent complete or partial conversion to their corresponding acids. The only amide found in this study to be “stable” to the amide-acid biotransformation was TBD. It also had the lowest clearance and the longest half-life and mean residence time. Unlike the other investigated amides, TBD contained two substitutions of two methyl moieties at the β position of its chemical structure. A “stable” valpromide analogue must have either two substitutions at the β position, such as in the case of TBD, or a substitution in the α and β positions, such as in the case of the VPD isomer valnoctamide (VCD). This paper discusses the antiepileptic potential of stable VPD analogues which may be more potent and less teratogenic than their biotransformed isomers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015862613315
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  • 67
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    Electronic Resource
    Nonlinear Disposition of Intravenous 2′,3′-Dideoxyinosine in Rats (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1070-1075 
    Details
    ISSN: 1573-904X
    Keywords: nonlinear disposition ; 2′,3′-dideoxyinosine ; anti-AIDS drug ; dideoxynucleosides ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of 2′,3′-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively. At the highest dose, a slower third phase with a half-life of 56 min was observed. The total-body clearances were 99, 77, and 37 ml/min-kg for the 8, 40, and 200 mg/kg doses. The steady-state volume of distribution showed a trend for a decrease with increasing doses, but the difference was not statistically significant. Twenty-four-hour urinary recovery of unchanged drug for the three doses was similar at about 20%, suggesting that a major fraction of the dose was metabolized. Urinary excretion of ddI metabolite, hypoxanthine, accounted for less than 5% of the dose. Renal and metabolic clearances decreased with increased doses, ddI was metabolized in blood; the addition of inorganic phosphate, a cosubstrate in phos-phorylase-mediated nucleoside catabolism, enhanced the degradation by about fourfold. In summary, these data indicate equal distribution of ddI in the extracellular and intracellular spaces in blood, its enzymatic degradation in blood, and nonlinear elimination kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015866714224
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  • 68
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    Electronic Resource
    Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer-controlled infusion pump (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 147-169 
    Details
    ISSN: 1573-8744
    Keywords: computers ; pharmacokinetics ; pharmacodynamics ; infusions ; drug delivery ; computer driven ; effect site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Computer-controlled infusion pumps incorporating an internal model of drug pharmacokinetics can rapidly achieve and maintain constant drug concentrations in the plasma. Although these pumps offer more accurate titration of intravenous drugs than is possible with simple boluses or constant rate infusions, the choice of the plasma as the target site is arbitrary. The plasma is not the site of drug effect for most drugs. This manuscript describes two algorithms for calculation of the infusion rates necessary for a computer-controlled infusion pump to rapidly achieve, and then maintain, the desired target concentration at the site of drug effect rather than in the plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01070999
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  • 69
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    Electronic Resource
    Neural networks in pharmacodynamic modeling. Is current modeling practice of complex kinetic systems at a dead end? (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 397-412 
    Details
    ISSN: 1573-8744
    Keywords: neural networks ; pharmacodynamics ; pharmacokinetics ; modeling ; drug effect prediction ; alfentanil ; model testing ; system analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems, in particular the brain. Computational NN are classified as parallel distributed processing systems that for many tasks are recognized to have superior processing capability to the classical sequential Von Neuman computer model. NN are recognized mainly in terms of their adaptive learning and selforganization features and their nonlinear processing capability and are considered most suitable to deal with complex multivariate systems that are poorly understood and difficult to model by classical inductive,logically structured modeling techniques. A NN is applied to demonstrate one of the potentially many applications of NN for modeling complex kinetic systems. The NN was used to predict the effect of alfentanil on the heart rate resulting from a complex infusion scheme applied to six rabbits. Drug input-drug effect data resulting from a repeated, triple infusion rate scheme lasting from 30 to 180 min was used to train the NN to recognize and emulate the input-effect behavior of the system. With the NN memory fixed from the 30- to 180-min learning phase the NN was then tested for its ability to predict the effect resulting from a multiple infusion rate scheme applied in the subsequent 180 to 300 min of the experiment. The NN's ability to emulate the system (30–180 min) was excellent and its predictive extrapolation capability (180–300 min) was very good (mean relative prediction accuracy of 78%). The NN was best in predicting the higher intensity effect and was able to identify and predict an overshoot phenomenon likely caused by a withdrawal effect from acute tolerance. Current modeling philosophy and practice is discussed on the basis of the alternative offered by NN in the modeling of complex kinetic systems. In modeling such systems it is questioned whether traditional modeling practice that insists on structure relevance and conceptually pleasing structures has any practical advantages over the empirical NN approach that largely ignores structure relevance but concentrates on the emulation of the behaviorof the kinetic system. The traditional searching for appropriate models of complex kinetic systems is a painstakingly slow process. In contrast, the search for empirical models using NN will continue to improve, limited only by technological advances supporting the very promising NN developments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062465
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  • 70
    Electronic Resource
    Electronic Resource
    A Sensitive and Specific Procedure for Quantitation of ADR-529 in Biological Fluids by High-Performance Liquid Chromatography (HPLC) with Column Switching and Amperometric Detection (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 101-108 
    Details
    ISSN: 1573-904X
    Keywords: column switching ; high-performance liquid chromatography ; electrochemical detection ; cardioprotectant (ADR-529) ; sensitive ; validation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract An HPLC method using electrochemical detection (ED) has been validated for the determination of ADR-529 in plasma and urine using ICRF-192 as an internal standard (IS). Prior to storage and quantitation, both plasma and urine samples require acid stabilization. Acidified plasma samples were prepared for HPLC using a two column solid-phase extraction (SPE). An aliquot of buffered plasma (i.e., pH 6-7) was first deproteinated and desalted on a C-18 SPE column. The analytes were then eluted onto a C-8 SPE column where retention and selective cleanup were achieved in the cation-exchange mode via silanol interactions. Acidified urine samples were diluted in acetonitrile prior to injection. The HPLC system for plasma and urine samples employed two narrow-bore silica columns used in the weak cation-exchange mode and separated by a switching valve. To prohibit late-eluting peaks from passivating the glassy carbon working electrode, a heart-cut containing ADR-529 and the IS was vented from the first silica column to the second using an automated switching valve. Amperometric detection at an oxidation potential of +1050 mV vs a Ag/AgNO3 reference electrode was used. Linearity was validated between 5 and 500 µg/ml in plasma and between 2 and 100 µg/ml in urine. Imprecision and percentage bias were typically 〈10% for both plasma and urine controls throughout their respective dynamic ranges. The absolute recoveries for ADR-529 and the IS from plasma were 〉95%. This method is being successfully applied to the pharmacokinetic/dynamic evaluation of ADR-529 in animals and humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018992029844
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  • 71
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    Electronic Resource
    Age and the Pharmacokinetic-Pharmacodynamic Relationship of Phenobarbital in Rats: “Pseudo”-Longitudinal vs Cross-Sectional Study Design (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1456-1459 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamics ; aging ; phenobarbital ; cross-sectional ; “pseudo”-longitudinal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In a previous study, an apparent age-related increase in brain sensitivity to the anesthetic effect of phenobarbital was observed in BN/BiRij rats. However, since this study was conducted according to a cross-sectional design, the observed change could, in principle, also have been the result of a cohort effect. The purpose of the present investigation was to exclude the role of such a cohort effect by adopting a “pseudo”-longitudinal study design. In this design 45 animals out of one cohort were reserved, and one subgroup was investigated at five ages (7, 14, 21, 29, and 34 months). A decrease in the anesthetic threshold dose of phenobarbital was found during aging, which appeared to be due mainly to an increase in the brain sensitivity. It is concluded that the previously observed increase in brain sensitivity is indeed the result of the aging process rather than a cohort effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015815014166
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  • 72
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    The Bioinequivalence of Carbamazepine Tablets with a History of Clinical Failures (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1612-1616 
    Details
    ISSN: 1573-904X
    Keywords: carbamazepine ; human ; bioavailability ; pharmacokinetics ; dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioavailability of three lots of a generic 200-mg carbamazepine tablet, which had been withdrawn from the market, was compared to the bioavailability of one lot of the innovator product in 24 healthy volunteers. Fifty-three lots of the generic product had been recalled by the manufacturer because of concerns over reports of clinical failures for several of the lots. The three generic lots tested in this study exhibited a wide range of bioavailability, as well as large differences in the in vitro dissolution rates. The mean maximum carbamazepine plasma concentrations for two of the generic lots were only 61-74% that of the innovator product, while the third lot was 142% of the innovator. The mean areas under the plasma concentration-time curve for the three generic lots ranged from 60 to 113% that of the innovator product. The results clearly indicate a significant difference in the rate and extent of absorption of the generic products compared to the innovator, as well as among the generic lots. A good relationship was found between the in vivo parameters and the in vitro dissolution results for the four dosage forms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015872626887
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  • 73
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    Competitive Inhibition of Zidovudine Clearance by Probenecid During Continuous Coadministration (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 228-235 
    Details
    ISSN: 1573-904X
    Keywords: zidovudine ; probenecid ; competitive inhibition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of zidovudine in the rabbit were studied during coadministration of probenecid at two infusion rates. Each animal (n = 6) served as its own control during an initial 8-hr infusion of zidovudine. In the second 8-hr infusion period, probenecid was coadministered with zidovudine. Urine samples were collected by bladder flush hourly for 19 hr. Plasma samples were taken at the midpoint of the urine collection interval and at predetermined intervals for 3 hr postinfusion. Plasma concentrations of zidovudine reached steady state during control periods but showed incomplete attainment of steady state during the infusions of probenecid at the higher rate. Total and renal clearance of zidovudine were reduced by 24.0 ± 4.0 and 20.7 ± 15%, respectively, during low-dose probenecid treatment and 48.9 ± 7.4 and 55.7 ± 3.4%, respectively, with high-dose probenecid treatment. Plasma probenecid concentrations during low-dose and high-dose infusion were 56.9 ± 12 and 248 ± 42 µg/ml. Postinfusion data showed that the zidovudine terminal half-life during high-dose probenecid treatment was longer than that with low-dose probenecid treatment (58.2 ± 4.6 vs 39.0 ± 9.1 min). The volume of distribution of zidovudine also decreased (1.76 ± 0.27 vs 1.10 ± 0.095 L/kg) as a result of probenecid coadministration. The results are consistent with competitive inhibition of renal and nonrenal clearances. A drug interaction model relating zidovudine clearances to plasma probenecid concentrations was derived. Michaelis-type constants for probenecid inhibition of zidovudine renal and nonrenal clearances were 73 and 55 µg/ml, respectively. The maximum proportion of AZT's renal clearance subject to inhibition is significantly greater (72%) than that of the nonrenal clearance (54%) and agrees closely with the fraction not filtered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018993524818
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  • 74
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    Electronic Resource
    Treatment of gastrointestinal and renal adenocarcinomas with interferon-alpha (1992)
    Springer
    Biotherapy 4 (1992), S. 179-187 
    Details
    ISSN: 1573-8280
    Keywords: interferon-alpha ; 5-fluorouracil ; gastrointestinal cancer ; pyrimidines ; renal cancer ; biochemical modulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Treatment of adenocarcinomas with interferon-alpha as a single agent has been disappointing. Recent efforts have focused on the combination of interferon with cytotoxic drugs such as 5-fluorouracil. A number of postulated mechanisms can explain synergistic interactions between 5-fluorouracil and interferon-alpha, including interaction with pyrimidine pathways, and alteration of drug metabolism. Previous studies in colorectal cancer, using 5-fluorouracil and interferon-alpha are reviewed, suggesting that the combination is more active than 5-fluorouracil alone. In renal cell carcinoma, the literature is reviewed, suggesting that daily interferon is the most efficacious schedule; preliminary data suggest that addition of 5-fluorouracil to interferon-alpha can double the expected response rate of 16% achieved by interferon-alpha alone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02174204
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  • 75
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    Electronic Resource
    Biovailability of ivermectin administered orally to dogs (1992)
    Springer
    Veterinary research communications 16 (1992), S. 125-130 
    Details
    ISSN: 1573-7446
    Keywords: bioavailability ; dogs ; ivermectin ; oral formulations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The bioavailability of three formulations of ivermectin was determined following oral administration to dogs. The average peak plasma level (C max) of ivermectin administered in the standard tablet formulation at 6 and 100 µg/kg of body weight was 2.97 and 44.31 ng/g, respectively. This suggest dose-dependent pharmacokinetics.C max and total ivermectin bioavailability, as assessed from the area under the plasma curve (AUC), were similar between two tablet formulations of ivermectin administered at 100 µg/kg. Furthermore,C max was similar following administration of radiolabelled ivermectin at 6 µg/kg in either a beef-based chewable formulation or in the standard tablet formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839009
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  • 76
    Electronic Resource
    Electronic Resource
    Hemodynamic and antiischemic effects of tedisamil in humans (1992)
    Springer
    Cardiovascular drugs and therapy 6 (1992), S. 353-360 
    Details
    ISSN: 1573-7241
    Keywords: tedisamil ; coronary artery disease ; hemodynamics ; right heart catheterization ; catecholamines ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Twenty-four patients with angiographically documented coronary artery disease, chronic stable angina, and reproducible ST-segment depression took part in this openlabel, baseline-controlled study on the hemodynamic, antiischemic, metabolic, and neurohumoral effects of tedisamil following IV doses of 0.1, 0.2, and 0.3 mg/kg (eight patients in each dose group). Tedisamil produced a dose-dependent decrease in both heart rate [rest: 2.4, 7.5 (p〈.01), and 9.2 beats/min (p〈.001); exercise: 6, 4.6, and 8.9 beats/min (p〈.01), respectively] and the index of myocardial oxygen consumption (exercise: 6–9% in each group) associated with an improvement of ST-segment depression [−12.1%, −10.7%, −41.9% (p〉.01), resp.]. While cardiac output was found decreased due to the heart-rate reduction both at rest [−8.5%, −5.7%, and −10.2% (p〈.05), respectively] and during exercise (2–8%), being significant only at rest in the highest dose group, stroke volume remained unaltered. Pulmonary artery pressure, pulmonary capillary wedge pressure, right-ventricular ejection fraction, and pulmonary vascular resistance were without significant changes. Blood pressure and systemic vascular resistance tended to increase, associated with a decrease in plasma catecholamines (20–40%). Tedisamil produced a dose-dependent prolongation of QTc duration [+2%, +6%, +12% (p〈.05), respectively] with PQ and QRS unaltered. The elimination half-life of tedisamil IV ranges between 6.8 and 7.8 hours. In conclusion, tedisamil, at a dose of 0.3 mg/kg IV, was well tolerated and was found to have favorable hemodynamic and antiischemic effects in patients with ischemic heart disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00051021
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  • 77
    Electronic Resource
    Electronic Resource
    Distribution and Elimination of the Glycosidase Inhibitors 1-Deoxymannojirimycin and N-Methyl-1-Deoxynojirimycin in the Rat in Vivo (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1442-1450 
    Details
    ISSN: 1573-904X
    Keywords: 1-deoxymannojirimycin ; N-methyl-1-deoxynojirimycin ; glycosidase inhibitors ; pharmacokinetics ; in vivo ; intravenous administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We studied the pharmacokinetics of two synthetic derivatives of 1-deoxynojirimycin in the rat after intravenous administration. The mannosidase IA/B inhibitor 1-deoxymannojirimycin and the glucosidase inhibitor N-methyl- 1-deoxynojirimycin exhibited minimal plasma protein binding and showed a rapid biphasic plasma disappearance, with an initial t 1/2 of 3.0 and 4.5 min, respectively, and a terminal t 1/2 of 51 and 32 min, respectively. For both compounds renal excretion is the major route of elimination. After 120 min, 52% of the dose of 1-deoxymannojirimycin and 80% of the dose of N-methyl- 1-deoxymannojirimycin was recovered unchanged from the urine, whereas only 4.9 and 0.2%, respectively, of the dose was excreted in bile. Urinary clearance of 1-deoxymannojirimycin was similar to the glomerular filtration rate. In contrast, urinary clearance of N-methyl- 1-deoxynojirimycin was two to three times higher than the glomerular filtration rate, indicating active tubular secretion. Ligation of the renal vessels decreased the total-body clearance of 1-deoxymannojirimycin and N-methyl- 1-deoxynojirimycin 18- and 24-fold, respectively. Neither alkalinization of the urine by infusion of bicarbonate solutions nor forced diuresis altered the renal excretion rate of these compounds, implying the absence of tubular reabsorption. At 120 min, the amounts of 1-deoxymannojirimycin in liver and kidney were 2.1 and 1.1% of the dose, respectively, while small intestine, stomach, and heart contained only 0.9, 0.6 and 0.1%. Less than 1% of the dose of N-methyl-1-deoxynojirimycin was found in the collected organs 2 hr after injection. At the same time point, the kidney/plasma concentration ratio of N-methyl- 1-deoxynojirimycin was 10-fold higher than in other tissues, whereas for 1-deoxymannojirimycin it was only 2- to 3-fold higher in kidney, indicating a more persistent general tissue retention of 1-deoxymannojirimycin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015810913257
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  • 78
    Electronic Resource
    Electronic Resource
    In Vivo Evaluation of Biodegradable Progesterone Microspheres in Mares (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1502-1506 
    Details
    ISSN: 1573-904X
    Keywords: biodegradable microspheres ; polylactic acid ; progesterone ; pharmacokinetics ; pregnancy maintenance ; mares
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015879400962
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  • 79
    Electronic Resource
    Electronic Resource
    Validation of Different Microdialysis Methods for the Determination of Unbound Steady-State Concentrations of Theophylline in Blood and Brain Tissue (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1592-1598 
    Details
    ISSN: 1573-904X
    Keywords: microdialysis ; methods ; theophylline ; pharmacokinetics ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Three microdialysis methods, the “tritium” method, the “point-of-no-net-flux” method, and a method using the low perfusion rate of 0.1 µl/min, were compared with respect to their ability to generate estimates of unbound steady-state concentrations (Cuss) of the antiasthmatic drug theophylline in blood and brain tissue in anesthetized rats. Concomitantly, the influence of the perfusion flow rate on the estimated extracellular Cuss obtained with the point-of-no-net-flux method was investigated. Theophylline was administered as a rapid intravenous bolus dose followed by constant intravenous infusion. Changes in perfusion flow rate from 2.0 to 0.75 µl/min and, finally, to 0.25 µl/min, using the point-of-no-net-flux method, had no significant effect on the estimated Cuss of theophylline in blood and striatum. This observation, particularly in the case of brain tissue, is not consistent with the theory that the process of dialysis drains a significant amount of substance from the immediate vicinity of the dialysis probe. Similar estimates of Cuss in blood as well as in brain tissue were obtained with all three methods. Their accuracy in estimating Cuss in blood was further strengthened by observations of unbound fractions similar to those reported in the literature. Furthermore, all three methods gave striatum/blood ratios at steady state of approximately 0.5, indicating that there is active transport of theophylline from brain tissue. It is concluded that the tritium method, when validated, can be used to study the time course of unbound drug concentrations in blood and tissues.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015816509140
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  • 80
    Electronic Resource
    Electronic Resource
    An Experimental Design Strategy for Quantitating Complex Pharmacokinetic Models: Enterohepatic Circulation with Time-Varying Gallbladder Emptying as an Example (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 169-177 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; experimental design ; enterohepatic circulation ; intermittent gallbladder emptying ; simulation ; compartmental model ; nonlinear least-squares fitting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A four-step strategy is proposed for determining appropriate experimental designs for investigating the pharmacokinetics of drugs characterized by complex compartmental models and this strategy has been applied to the pharmacokinetics of enterohepatic circulation (EHC). The four steps are (1) to establish an appropriate pharmacokinetic model, (2) to complete an identifiability analysis for the model to determine the route(s) of administration and sampling compartment(s) that are theoretically adequate for the quantitation of model parameters, (3) to carry out nonlinear least-squares fitting for the proposed number and timing of simulated error-free data points, and (4) to complete nonlinear least-squares fits of the model to data obtained by adding random error to the simulated data in step 3. The four-compartment model chosen for EHC of unchanged drug contained central, peripheral, gallbladder, and intestinal compartments and an intermittent gallbladder emptying rate constant. Identifiability analysis demonstrated that three alternative experimental designs for route(s) of administration and sampling compartment(s) are adequate for quantitating all model parameters, when the gallbladder emptying rate constant as a function of time is known (using controlled emptying from an engineered gallbladder in an animal model or quantitation in humans or animals using imaging techniques). Parameter estimates from fitting error-free data matched closely with the known values for all three experimental designs, indicating an adequate number and appropriate timing of data points. Results from fitting simulated data containing ±10% random error indicated unacceptable coefficients of variation and a nonrandom pattern in residual plots for one of the experimental designs. Of the two remaining designs, one was less resilient relative to poor initial estimates and relative to timing of gallbladder emptying simultaneously with the distribution process. It is clear that application of this new strategy permits the elimination of experimental designs that are inadequate (from either a theoretical or an experimental standpoint) prior to initiating in vivo experiments. As such, it represents a major advance in reliability over methods used previously for complex models.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018968819366
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  • 81
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Evaluation of Drug Interactions with Anti-Human Immunotrophic Virus (HIV) Drugs. III. 2′,3′-Dideoxycytidine (ddC) and Zidovudine in Monkeys (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 224-227 
    Details
    ISSN: 1573-904X
    Keywords: anti-human immunotrophic virus (HIV) nucleosides ; drug interactions ; pharmacokinetics ; monkeys
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A pharmacokinetic evaluation of a potential drug interaction between zidovudine (AZT) and dideoxycytidine (ddC) was conducted in monkeys. Each of six animals received 20 mg/kg of AZT intragastrically in the absence and presence of an intravenous steady-state dosage regimen of ddC. The regimen was designed to produce steady-state ddC plasma concentration of 1.77 µg/ml for 30 min. Plasma and urine samples were analyzed for AZT, its major glucuronide metabolite, GAZT, and ddC by HPLC techniques. Pharmacokinetic parameters for AZT and GAZT were calculated by non-compartmental methods. The mean apparent clearance of AZT was 1.40 and 1.78 L/hr/kg in the absence and presence of ddC, respectively. The mean AUC for GAZT was 36.39 µg-hr/ml in the absence of ddC and 28.81 µg-hr/ml in the presence of ddC. No statistical differences were found in these and other pharmacokinetic parameters in the absence and presence of ddC. The absence of an effect on AZT's pharmacokinetics by ddC is attributed to the primary metabolic and renal elimination pathways for AZT and ddC, respectively. The results of this study provide a rational basis to design combined AZT-ddC treatment regimens in AIDS patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018941507979
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  • 82
    Electronic Resource
    Electronic Resource
    The Pharmacokinetics of Trilostane and Ketotrilostane in an Interconverting System in the Rat (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 464-468 
    Details
    ISSN: 1573-904X
    Keywords: trilostane ; ketotrilostane ; reversible metabolism ; pharmacokinetics ; metabolic interconversion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of trilostane and one of its metabolites ketotrilostane are described and characterized in the rat following the separate intravenous administration of trilostane and ketotrilostane. It was noted during these studies that the parent compound and its metabolite undergo metabolic interconversion–trilostane producing ketotrilostane and ketotrilostane generating trilostane. This result means that trilostane is conserved in the body by interconversion-being metabolized to ketotrilostane and then subsequently back to the “parent” drug, trilostane.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015828027060
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  • 83
    Electronic Resource
    Electronic Resource
    Saturable Tissue Binding and Imirestat Pharmacokinetics in Rats (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 469-473 
    Details
    ISSN: 1573-904X
    Keywords: imirestat ; statil ; pharmacokinetics ; tissue binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To investigate the hypothesis that the pharmacokinetics of imirestat, an aldose reductase inhibitor, are influenced by saturable binding to tissues, three experiments were done. (1) The nature of the dose dependence was characterized in rats. Two groups of nine adult male Sprague–Dawley rats received iv 14C-imirestat at doses of 2 or 8 mg/kg. Serial blood samples were obtained over 15 days. Volume of distribution at steady-state was significantly different between the high- and the low-dose groups (0.744 ± 0.103 1 and 1.10 ± 0.228 L, respectively). Clearance was independent of dose over this fourfold range (∼15 ml/hr). (2) The effect of either statil or AL3152, both aldose reductase inhibitors and potential competitors for aldose reductase binding, on the pharmacokinetics of a single 0.2-mg/kg iv dose of imirestat was assessed. A 2.4-mg/kg loading dose of statil was administered and a constant-rate infusion (56 µg/hr/kg) was begun 16 hr before imirestat. A 2-mg/kg loading dose of AL3152 and a constant-rate infusion (115 µg/kg/hr) were also administered 16 hr before imirestat. The infusions were maintained throughout the study. AL3152 administration decreased the imirestat steady-state volume of distribution by a mean of 63%. Statil administration decreased it by a mean of 39%. (3) The dosing regimen of the second study was repeated and, at two sampling times, nine tissues and plasma were obtained from four rats per sampling time for determination of imirestat tissue-to-plasma concentration ratio. The tissue/ plasma imirestat concentration ratio in the adrenals 24 hr after imirestat administration was 56.9 ± 20.0 in the imirestat group, 17.7 ± 1.27 in the statil-coadministered group, and 12.3 ± 2.59 in the AL3152-coadministered group. A similar trend of decrease in the ratios was observed in all tissues at both 24 and 168 hr. The results suggest that a saturable tissue binding phenomenon at least partially accounts for the nonlinear pharmacokinetics of imirestat.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015880011131
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  • 84
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and Metabolic Disposition of p-Chloro-m-xylenol (PCMX) in Dogs (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 677-682 
    Details
    ISSN: 1573-904X
    Keywords: p-chloro-m-xylenol (PCMX) ; metabolism ; pharmacokinetics ; conjugated metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic and metabolic profile of p-chloro-m-xylenol (PCMX) was studied in healthy mongrel dogs after intravenous and oral administration of single doses of 200 and 2000 mg of PCMX, respectively. Calculation of pharmacokinetic parameters was based on compartmental and noncompartmental methods. The mean pharmacokinetic parameters of elimination half-life and mean residence time were 1.84 and 1.69 hr, respectively. The apparent volume of distribution at steady state was estimated to be 22.4 liters, and the plasma clearance was 14.6 liters/hr. The bioavailability of PCMX was 21%, indicating low absorption for this drug. PCMX's metabolite data show that a presystemic elimination process (first-pass effect) is also occurring. PCMX plasma concentrations after intravenous administration of 500-, 200-, and 100-mg doses were found to be proportional to the dose given, demonstrating that the pharmacokinetic profile of PCMX is linear over the dose range studied. Biotransformation studies showed that urinary excretion was not the major route for rapid elimination of unchanged PCMX and almost all material excreted in urine was associated with the conjugated species (glucuronides and sulfates). Statistical significant differences were not found (P 〉 0.05) between the percentages excreted in urine of PCMX and its conjugated metabolites after intravenous and oral administration. The percentages excreted in urine after iv and oral doses of unchanged PCMX were, respectively, 0.45 and 0.37; total conjugates, 46.3 and 43.3; sulfates, 38.1 and 33.2; and glucuronides, 8.2 and 10.2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015814513373
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  • 85
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Droperidol in Healthy Volunteers Following Intravenous Infusion and Rectal Administration from an Osmotic Drug Delivery Module (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 694-696 
    Details
    ISSN: 1573-904X
    Keywords: droperidol ; pharmacokinetics ; rectal absorption ; osmotic pump ; rectal delivery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015822715190
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  • 86
    Electronic Resource
    Electronic Resource
    Plasma Concentration Clamping in the Rat Using a Computer-Controlled Infusion Pump (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 800-807 
    Details
    ISSN: 1573-904X
    Keywords: computers ; infusion pumps ; infusions, intravenous ; pharmacokinetics ; thiopental ; rats ; computer-controlled drug delivery ; nonlinear regression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have developed a computer-controlled infusion pump to achieve rapidly and then maintain stable plasma thiopental concentrations in rats. Initially we derived the parameters of a triexponential pharma-cokinetic model for thiopental, administered as a brief infusion to 10 rats, using nonlinear regression and standard pharmacokinetic equations. These parameters were incorporated into the pharmacokinetic model of a computer-controlled infusion pump. In a second group of animals this device was used to maintain three consecutive target thiopental concentrations ranging from 5 to 100 µg/ml in a stepwise fashion. Arterial blood gases were kept normal through controlled ventilation when necessary. The plasma thiopental concentrations in this second group of animals were generally higher than the target concentrations. The bias in pump performance (median prediction error) was +25%, and the inaccuracy (median absolute prediction error) was 26%. We fit the parameters of a three-compartment model to the plasma thiopental concentrations observed in the second group of animals. This produced a second set of thiopental pharmacokinetic parameters with the unique characteristic of having been derived from a computer controlled infusion study. These parameters were tested prospectively with a computer-controlled infusion pump in a third group of animals. This second set of thiopental pharmacokinetic parameters performed better, with a median prediction error of 0% and a median absolute prediction error of 15%. This study shows that it is possible to achieve rapidly and maintain steady plasma thiopental concentrations in the rat. Our results suggest that it is feasible to derive robust pharmacokinetic parameters from unusual drug dosing approaches, such as employed by a computer-controlled infusion pump. The ability rapidly to clamp plasma drug concentrations at desired targets in small laboratory animals will facilitate research into the relationship of plasma and tissue concentration to drug effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015863824277
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  • 87
    Electronic Resource
    Electronic Resource
    An in Vitro Pharmacodynamic Model to Simulate Antibiotic Behavior of Acute Otitis Media with Effusion (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 920-924 
    Details
    ISSN: 1573-904X
    Keywords: in vitro ; pharmacodynamics ; pharmacokinetics ; amoxicillin ; otitis media
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The purpose of this investigation was to develop an in vitro pharmacodynamic model (IVPM) that would simultaneously simulate in vivo serum and middle ear amoxicillin pharmacokinetic characteristics of acute (purulent) otitis media and then utilize the IVPM to assess amoxicillin-mediated killing of a type 7F Streptococcus pneu-moniae (MIC = 0.002 mg/L). The IVPM consisted of a sterile central compartment and a membrane-bound “infected” peripheral compartment. Peak peripheral compartment amoxicillin concentrations occurred within 2 hr after its introduction into the central compartment and were approximately 30% of peak central compartment concentrations. Amoxicillin elimination from the central compartment was designed to provide a 1-hr t 1/2. Amoxicillin elimination from the peripheral compartment was slower than from the central compartment, with an average half-life of 2.3 hr. Significant concentration-related differences in maximal bacterial kill rates were not detected over the range of amoxicillin concentrations studied (0.26 to 14.6 mg/L). However, at peak central compartment amoxicillin concentrations of ≤2 mg/L, a lag phase in killing was observed. In general, the in vitro pharmacokinetic data derived from this model compare well with published in vivo data.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015857117433
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  • 88
    Electronic Resource
    Electronic Resource
    Pharmacodynamics of Insulin Following Intravenous and Enteral Administrations of Porcine-Zinc Insulin to Rats (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1003-1009 
    Details
    ISSN: 1573-904X
    Keywords: insulin ; intravenous ; enteral ; pharmacokinetics ; bio-availability ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Previous work from this laboratory showed site-dependent variations in the apparent permeability of insulin as measured using the everted rat gut sac technique, with the greatest permeability in the distal jejunum and the lowest in the duodenum (5). To quantify better the rate and extent of insulin absorption from the small intestine, closed-loop in situ experiments were performed in nondiabetic rats. Results correlated with the everted gut sac technique in that the absolute bioavailability determined in situ was higher for insulin solution administered to the more distal region of the intestine (0.133%) than that absorbed from an earlier portion of the intestine (0.059%). While the difference in regional bioavailabilities was not significant (P = 0.08), the blood glucose response showed highly significant differences (P = 0.0015), with severe and prolonged hy-poglycemia resulting from insulin delivered to the distal jejunum/ proximal ileum. Insulin administered iv followed a two-compartment pharmacokinetic model. Whole-body elimination rate constants were similar for both iv and enteral insulin. Although therapeutic quantities of insulin were absorbed from the distal small intestine, absorption enhancers would be necessary to decrease the dose of insulin required.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015894125611
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  • 89
    Electronic Resource
    Electronic Resource
    Pilocarpine Disposition and Salivary Flow Responses Following Intravenous Administration to Dogs (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1064-1069 
    Details
    ISSN: 1573-904X
    Keywords: xerostomia ; pilocarpine ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Oral doses of pilocarpine increase salivary flow rates in patients afflicted with xerostomia (dry mouth). This study examined the pharmacokinetics of and a pharmacodynamic response (salivation) to intravenous pilocarpine nitrate administration in dogs. Disposition was linear over a dose range of 225–600 µg/kg; plasma concentrations were 10–120 µg/L. Elimination was rapid and generally biphasic, with a terminal elimination half-life of approximately 1.3 hr. The systemic clearance of pilocarpine was high (2.22 ± 0.49 L/kg/hr) and its steady-state volume of distribution (2.30 ± 0.64 L/kg) was comparable to that of many other basic drugs. All doses of pilocarpine induced measurable submaxillary and parotid salivary flow rates which could be maintained constant over time. Cumulative submaxillary saliva flow was linearly related to total pilocarpine dose. Plasma pilocarpine concentration was linearly related to both steady-state and postinfusion submaxillary salivary flow rates.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015814730154
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  • 90
    Electronic Resource
    Electronic Resource
    Corticosteroid Pharmacodynamic Modeling: Osteocalcin Suppression by Prednisolone (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1096-1098 
    Details
    ISSN: 1573-904X
    Keywords: pharmacodynamics ; osteocalcin ; prednisolone ; corticosteroids ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015875016041
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  • 91
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    Electronic Resource
    Effect of intra-arterial cisplatin and 1,3-bis(2chloroethyl)-1-nitrosourea (BCNU) dosage on radiographic response and regional toxicity in malignant glioma patients: proposal of a new method of intra-arterial dosage calculation (1992)
    Springer
    Journal of neuro-oncology 13 (1992), S. 291-299 
    Details
    ISSN: 1573-7373
    Keywords: dosage calculation ; intra-arterial chemotherapy ; neurotoxicity ; malignant glioma ; pharmacokinetics ; dosing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The frequency of both neurologic toxicity and therapeutic response due to intra-arterial (IA) chemotherapy is decreased by dose reduction. A method to individualize IA drug dosage is needed to provide each patient with the safest, most effective dose. Most trials of IA chemotherapy for malignant glioma have used body surface area (BSA) to calculate dosage; but brain size and arterial distribution do not correlate well with BSA. Fixed doses of cisplatin and BCNU were used in combination to perform 35 IA infusions in 20 malignant gliomas patients. Doses modified by the number of major intracranial vessels supplied by the infused artery were used in 34 infusions in 19 patients. Patients receiving 150 to 200 mg CP and 300 mg BCNU had an incidence of neurologic deficit of 5.6% if ≥ 3 vessels were supplied by the infused artery compared to 42% for those with only 2 vessels. This crude dose modification maintained efficacy while reducing neurologic toxicity. Further refinement is possible using well established intra-arterial pharmacokinetic principles. Intra-arterial dosing based on volume flow at the site of infusion would yield a more reproducible exposure of the infused capillary bed to a drug than methods currently in use. More consistent drug exposure should reduce toxicity due to over dosing and treatment failure due to under dosing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172483
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  • 92
    Electronic Resource
    Electronic Resource
    The influence of age on the pharmacokinetics of aditoprim in pigs after intravenous and oral administration (1992)
    Springer
    Veterinary research communications 16 (1992), S. 355-364 
    Details
    ISSN: 1573-7446
    Keywords: aditoprim ; age ; bioavailability ; intestinal absorption ; pharmacokinetics ; pigs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Some pharmacokinetic parameters of aditoprim were determined in 3- and 6-month-old pigs. After intravenous administration of 5 mg/kg body weight, the mean total body clearance of the older pigs was smaller than that of the younger pigs. This difference was not reflected in the elimination half-life. After oral administration of 5 mg/kg body weight, the mean absorption rate constant was smaller and the mean absorption half-life was longer in the older pigs. The age-related changes in the pharmacokinetics of aditoprim were not sufficiently pronounced to suggest the necessity of modifying the oral dosage regimen in pigs of this age range. The favourable pharmacokinetics of aditoprim in pigs (large apparent volume of distribution, long elimination half-life and high bioavailability) may permit introduction of this drug into swine practice, after safety and residue depletion studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839185
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  • 93
    Electronic Resource
    Electronic Resource
    The disposition of venlafaxine enantiomers in dogs, rats, and humans receiving venlafaxine (1992)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 4 (1992), S. 84-90 
    Details
    ISSN: 0899-0042
    Keywords: high-performance liquid chromatography (HPLC) ; chiral assay ; naproxen chloride ; pharmacokinetics ; racemate ; stereoselective ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A stereospecific high-performance liquid chromatographic (HPLC) method was developed for the quantitation of the enantiomers of venlafaxine, an antidepressant, in dog, rat, and human plasma. The procedure involves derivatization of venlafaxine with the chiral reagent, (+)-S-naproxen chloride, and a postderivatization procedure. The method was linear in the range of 50 to 5,000 ng of each enantiomer per ml of plasma. No interference by endogenous substances or known metabolites of venlafaxine occurred. Studies to characterize the disposition of the enantiomers of venlafaxine were conducted in dog, rat, and human, following oral administration of venlafaxine. The Cmax, area under the curve (AUC) and (S)/(R) concentration ratios of the (R)- and (S)-enantiomers were compared. In rats, the mean plasma ratio of (S)-venlafaxine to that of (R)-venlafaxine over 0.5 to 6.0 h varied from 2.97 to 8.50 with a mean value of 5.51 ± 2.45. The Cmax, AUC0 - ∞, and t1/2 values of the (R)- and (S)-enantiomers in dogs were not significantly different from one another (P〉0.1). The mean ratios [(S)/(R)] of enantiomers of venlafaxine in human over a 2 to 6 h interval ranged from 1.33 to 1.35 with an overall ratio of 1.34 ± 0.26 (n = 12). These ratios of the enantiomers [(S)/(R)] were not statistically different from unity (P〉0.1) indicating that the disposition of venlafaxine enantiomers in humans is not stereoselective and is more similar to that in dogs than that in rats.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530040204
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  • 94
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    Electronic Resource
    Glutathione conjugation and pharmacokinetics of 2-bromo-3-phenylpropionic acid in vitro and in the rat in vivo (1992)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 4 (1992), S. 407-414 
    Details
    ISSN: 0899-0042
    Keywords: GSH conjugate ; pharmacokinetics ; biliary excretion ; chiral ; 2-bromo-3-phenyl propionic acid ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Glutathione (GSH) conjugation of the chiral compound 2-bromo-3-phenylpropionic acid (BPP) was studied in vitro and in the rat in vivo. GSH conjugation of BPP, catalyzed by a mixture of glutathione-S-transferases (GST's) from rat liver cytosol in vitro, was stereoselective: at a substrate concentration of 250 μM, (R)-BPP was more rapidly conjugated than (S)-BPP (R/S-ratio = 2.6). The blood elimination kinetics of the separate BPP enantiomers and the biliary excretion kinetics of the corresponding GSH conjugates were studied in the rat in vivo after administration of (R)- or (S)-BPP at a dose level of 50 μmol/kg. Elimination of (R)-BPP from blood was faster than that of (S)-BPP: half lives were 9 ± 2 min for (R)-BPP and 13 ± 1 min for (S)-BPP. The biliary excretion rate of the GSH conjugate of (R)-BPP declined monoexponentially, while that of the GSH conjugate of (S)-BPP displayed a biphasic profile. Half lives of excretion were 13 ± 1 for the GSH conjugate of (R)-BPP, and 11 ± 2 for the GSH conjugate of (S)-BPP (second phase). The first phase in the biliary excretion of the GSH conjugate of (S)-BPP could not be attributed to capacity limitation of biliary transport carriers as higher excretion rates were attained upon administration of higher doses (100 and 200 μmol/kg) of ((S)-BPP). The blood elimination profiles of (R)- and (S)-BPP differed greatly from the biliary excretion profiles of the corresponding GSH conjugates. This suggests that the kinetics of BPP conjugate excretion are determined by other processes than hepatic GSH conjugation. © 1992 Wiley-Liss, Inc.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530040702
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  • 95
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    Electronic Resource
    Pharmacokinetics and cytotoxicity of B.3839, a molecular combination of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea, in a mouse model (1992)
    Springer
    Investigational new drugs 10 (1992), S. 149-158 
    Details
    ISSN: 1573-0646
    Keywords: pharmacokinetics ; cytotoxicity ; molecular combination ; fluorouracil ; nitrosourea
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary B.3839 is the prototype compound in a series of novel molecular combinations of chloroethylnitrosoureas and 5-fluorouracil(5-FU) and has been tested against MAC tumours in mice. Previous studies have shown it is moderately active against MAC15A and highly active against MAC13 though this activity is dependent on route of administration. The aim of this study was to determine whether bioavailability could explain this difference in anti-tumour activity. Plasma levels of B.3839 and 5-FU after i.p. and oral administration were measured using HPLC. Non tumour-bearing and MAC26 bearing mice gave almost identical plasma profiles after i.p. administration with the Cmax being 29.8 and 30.4μ gml−1 and t1/2 16 and 15 min. The AUCs were 15.3 and 13.9μg h ml−1 suggesting tumour load had no influence over plasma levels. Oral administration gave a much lower Cmax of 8.0μg ml−1 but an AUC of 15.2μg h ml−1 due to a longer terminal t1/2 (94 min) giving 99% bioavailability. Levels of 5-FU release from B.3839 by either route were considered too small to influence anti-tumour activity. Cytotoxicity assaysin vitro against the MAC lines gave IC70 values of 5.3, 13.8 and 8.6μg ml−1 for MAC 26,13 and 15A respectively after a one hour exposure. Bone marrow toxicity was shown to be less severe than that of TCNU which is currently in clinical trials. The results show bioavailability alone is not enough to explain tumour response. There appears to be a need for a threshold concentration (C) to be maintained for a period of time (t).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00877239
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  • 96
    Electronic Resource
    Electronic Resource
    A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion (1992)
    Springer
    Investigational new drugs 10 (1992), S. 183-190 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; pharmacokinetics ; TNF ; continuous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokinein vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40μg/m2 and was ultimately escalated to 200μg/m2. A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160μg/m2 was defined as the MTD. At 160μg/m2 peak serum levels occurred within 5–20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80μg/m2. This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00877244
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  • 97
    Electronic Resource
    Electronic Resource
    Clinical pharmacology studies of Oltipraz — A potential chemopreventive agent (1992)
    Springer
    Investigational new drugs 10 (1992), S. 289-298 
    Details
    ISSN: 1573-0646
    Keywords: Oltipraz ; chemoprevention ; dithiolethiones ; pharmacokinetics ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacological studies on Oltipraz [4-methyl-5(pyrazinyl-2)-1-2-dithiole-3-thione)] were conducted with normal healthy subjects using various doses and schedules. Administration of single doses (1, 2 and 3 mg/kg) resulted in detectable drug levels in the serum (mean peak serum concentrations 16, 61 and 205 ng, respectively) and urine. The t1/2 was short (4.4, 4.1 and 5.3 hours respectively) and no steady state was achieved after multiple daily doses for 12 days. Introduction of a loading dose during the first day produced a steady state when 1.5 and 2.0 mg/kg/day were used. Daily administration of Oltipraz sustained the steady state with insignificant variations. Consumption of a high fat diet increased the serum and urine concentrations of Oltipraz (30–60%) compared to the low fat diet. Two subjects experienced flatulence during the administration of the drug. One subject developed numbness and pain in the thumbs with occurrence of small purplishblack spots resembling those observed in subacute endocarditis. These changes disappeared 10 days after discontinuation of the drug. No changes in peripheral blood counts, biochemical profile or thyroid function tests were observed after four weeks of Oltipraz. Further studies with a larger number of healthy subjects are needed for clarification of the safety and biological efficacy of small doses of Oltipraz during chronic administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00944183
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  • 98
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    Electronic Resource
    The pharmacokinetics of a slow-release theophylline preparation in horses after intravenous and oral administration (1992)
    Springer
    Veterinary research communications 16 (1992), S. 131-138 
    Details
    ISSN: 1573-7446
    Keywords: horses ; pharmacokinetics ; slow release formulation ; theophylline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of a slow-release theophylline formulation was investigated following intravenous and oral administration at 10 mg/kg in horses. A tricompartmental model was selected to describe the intravenous plasma profile. The elimination half-life (t1/2β) was 16.91 ± 0.93 h, the apparent volume of distribution (V d) was 1.35 ± 0.18 L/kg and the body clearance (ClB) was 0.061 ± 0.009 L kg−1 h. After oral administration the half-life of absorption was 1.24 ± 0.30 h, and the calculated bioavailability was above 100%. Thet1/2β after oral administration was 18.51 ± 1.75 h, only a little longer than that after intravenous administration. The slow release formulation did not exhibit any advantage in prolonging thet1/2β of theophylline in the horse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839010
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  • 99
    Electronic Resource
    Electronic Resource
    The distribution and some pharmacokinetic parameters of ivermectin in pigs (1992)
    Springer
    Veterinary research communications 16 (1992), S. 139-146 
    Details
    ISSN: 1573-7446
    Keywords: ivermectin ; pharmacokinetics ; pigs ; residues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ivermectin was injected subcutaneously into five pigs at the usual dose rate of 300 µg/kg and found to distribute well to all tissues and body fluids which were sampled 24 h post-injection. Ivermectin was detected in the contents and mucus at all levels of the gastrointestinal tract. The drug was excreted in bile, with high concentrations of the drug in the intestines and faeces. High concentrations of ivermectin were measured in skin, ears and ear wax, suggesting that the drug should be effective in the treatment of ectoparasitic infestations, particularly ear mites. The high lipid solubility of the drug may explain the high concentrations found in ear wax and skin. Ivermectin was also detected in the body fluids and tissues of an untreated pig penned with the treated animals. Direct contact appeared to be necessary for transfer of ivermectin from the treated to the untreated pig but coprophagia or urine drinking is a possible explanation. The pharmacokinetics of ivermectin administered subcutaneously at a dose rate of 300 µg/kg to six pigs were studied. There was marked individual variation in the pharmacokinetics of ivermectin. In one pig the area under the plasma concentration-time curve was particularly high. This may reflect individual variation in uptake and excretion of the drug. The mean elimination half-life of the drug was 35.2 h, suggesting that the drug is cleared slowly from pigs with drug detectable in plasma for 6–10 days. This persistence should allow a short period of protection before re-infection with parasites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839011
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  • 100
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    Electronic Resource
    Pharmacokinetics following a single intravenous administration and a dosage regimen for sulfadoxine in buffalo calves (Bubalus bubalis) (1992)
    Springer
    Veterinary research communications 16 (1992), S. 215-219 
    Details
    ISSN: 1573-7446
    Keywords: pharmacokinetics ; dosage regimen ; sulfadoxine ; Bubalus bubalis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839158
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