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  • pharmacokinetics  (70)
  • Springer  (70)
  • MDPI Publishing
  • PANGAEA
  • 1995-1999  (70)
  • 1975-1979
  • 1996  (70)
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  • 1995-1999  (70)
  • 1975-1979
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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of dexamethasone in premature neonates (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 477-483 
    Details
    ISSN: 1432-1041
    Keywords: Dexamethasone ; Premature neonates ; pharmacokinetics ; bronchopulmonary dysplasia ; infant ; newborn
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population. Methods: We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days. Results: There was a strong relationship between clearance (4.96 ml·min−1·kg−1) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min−1·kg−1, respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg−1, respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects. Conclusion: The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195934
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  • 2
    Electronic Resource
    Electronic Resource
    Influence of food on the bioavailability and some pharmacokinetic parameters of diprafenone – a novel antiarrhythmic agent (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 315-319 
    Details
    ISSN: 1432-1041
    Keywords: Key words Diprafenone; antiarrhythmics ; bioavailability ; human ; foods ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The present study was done to investigate the effect of food on the bioavailability of diprafenone. Methods: The most important pharmacokinetic parameters (Cmax, t1/2, AUC) and the relative oral availability of a solid oral preparation of racemic diprafenone were investigated when administered to fasting subjects and 10 min after a standard meal, in an open, randomised, crossover trial. Single oral doses of 100 mg were given on two different occasions, at least 1 week apart. The serum concentrations of diprafenone and its hydroxy-metabolite were determined up to 24 hours after administration by a sensitive, specific HPLC method. Fifteen healthy, male volunteers were enrolled in the trial. Their mean height, weight and age were 183 cm, 80 kg and 22 years, respectively. Fourteen volunteers were found to be rapid hydroxylators and one was a slow hydroxylator of debrisoquine. Only data from the rapid hydroxylators were used in the statistical analysis. Results: Food increased the oral bioavailability of diprafenone by approximately 50%. This effect was similar in rapid and in slow hydroxylators. The only slow hydroxylator in this trial had an AUC0–last ratio (with food/fasting) of 1.54. These findings suggest that diprafenone should be administered in a constant temporal relationship to food.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050115
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  • 3
    Electronic Resource
    Electronic Resource
    A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 335-337 
    Details
    ISSN: 1432-1041
    Keywords: Key words Cyclosporine ; Ursodiol; ursodeoxycholic acid ; absorption ; pharmacokinetics ; liver transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. Methods: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. Results: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml–1, Cmax was 832 vs 871 ng⋅ml–1 and tmax was 2 vs 2 h, after ursodiol and placebo, respectively. Conclusion: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050118
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  • 4
    Electronic Resource
    Electronic Resource
    Absolute bioavailability of fluoride from disodium monofluorophosphate and enteric-coated sodium fluoride tablets (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 321-326 
    Details
    ISSN: 1432-1041
    Keywords: Key words Sodium fluoride ; Disodium monofluorophosphate; absolute bioavailability ; pharmacokinetics ; elderly population
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The absolute bioavailability and other pharmacokinetic parameters of two fluoride formulations were investigated in 13 healthy volunteers, aged 61–70 years. Methods: The following formulations were administered, under fasting conditions, in a single-dose three-way cross-over design: tablets of 76 mg disodium monofluoro phosphate (MFP, equivalent to 10.0 mg F− ion), enteric-coated (e.c.) tablets of 25 mg sodium fluoride (NaFor, equivalent of 11.3 mg F− ion), and an isoosmotic aqueous injection solution (4 ml) of 22.1 mg sodium fluoride (NaFiv, equivalent of 10.0 mg F− ion). There was a wash-out period of at least one week between each administration. Blood was sampled before and during a 24-hour period after administration. For F− excretion urine was sampled 48 hours before (baseline) and over the 48 hours after the adminstration. Results: The mean t1/2 values of the three formulations were 8.3, 8.7 and 8.3 h for MFP, NaFor and NaFiv respectively, and were not significant different. Mean Cmax after MFP was significantly higher than after NaFor [344 vs 142 μg⋅l−1]. Mean tmax for MFP was shorter than for NaFor [1.1 vs 4.6 h]. MFP had significantly higher bioavailability [102.8%] than NaFor [64.2%]. Conclusion: The MFP formulation showed higher bioavailability with smaller variation than the NaFor formulation. MFP is preferable, therefore, for fluoride therapy in clinical practice, and changing from NaFor to MFP will require adjustment of the dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050116
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  • 5
    Electronic Resource
    Electronic Resource
    Single oral doses of amisulpride do not enhance the effects of alcohol on the performance and memory of healthy subjects (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 161-166 
    Details
    ISSN: 1432-1041
    Keywords: Key words Amisulpride; ethanol vector ; performance ; memory ; cognitive function ; interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: Amisulpride is a benzamide antipsychotic that binds selectively to dopamine D2- and D3-receptors, preferentially in limbic and hippocampal structures. Since other substituted benzamides have a limited or negligible interaction with alcohol on human performance, amisulpride was studied for this potential. Methods: In a randomised double-blind crossover study, 18 young, non-smoking men took single oral doses of placebo and amisulpride 50 mg and 200 mg, without and with ethanol (0.8 g ⋅kg−1) taken 30 min later. Objective performance tests and self-ratings were done at baseline and 1.5, 3.5 and 6.5 h after drug intake. Memory (immediate and delayed recall) was tested 2 h after dosing. Breath ethanol and the plasma concentrations of amisulpride and prolactin were measured. Three-way ANOVA + Newman-Keul tests were used for statistical analyses; interactions were confirmed by factorial contrast ANOVA. Results: Mean blood ethanol was 0.94, 0.62 and 0.26 g ⋅l−1 at the three test times. It produced significant impairment in all performance tests (symbol digit substitution, simulated driving, body sway, flicker fusion, tapping, nystagmus), reduced both immediate and delayed recall in memory tests, and caused subjective clumsiness, muzziness and mental slowness, mainly between 1.5 to 4.5 h after dosing. Amisulpride, 50 and 200 mg elevated plasma prolactin but had minimal or no effect on performance, attention and memory. The decreases in immediate free recall after the 50 mg dose and in delayed free recall after the 200 mg dose were slight. Amisulpride neither modified blood ethanol concentrations nor enhanced the detrimental effect of ethanol on skilled and cognitive performance; it slightly antagonised ethanol in the digit copying test. Ethanol did not modify the effect of amisulpride on plasma prolactin, and the plasma concentrations of amisulpride were little changed by ethanol. Conclusions: Amisulpride in single oral doses of 50 and 200 mg did not interact significantly with the effects of high, moderate or low concentrations of ethanol on human skilled and cognitive performance. The drugs did interact pharmacokinetically.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050178
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  • 6
    Electronic Resource
    Electronic Resource
    Comparison between concentrations of racemic mefloquine, its separate enantiomers and the carboxylic acid metabolite in whole blood serum and plasma (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 171-173 
    Details
    ISSN: 1432-1041
    Keywords: Key words Mefloquine; mefloquine enantiomers ; carboxylic acid metabolite ; blood concentrations ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To compare concentrations of the separate enantiomers of mefloquine (MQ), total racemic MQ and the carboxylic acid metabolite in different blood fractions at steady state. Setting: Human volunteer laboratory, Unit of Clinical Pharmacology, Karolinska Institute. Volunteers: Ten healthy adult Caucasian volunteers. Methods: Drug concentrations were determined by high-performance liquid chromatography (HPLC). Results: Trough concentrations of the (+)RS enantiomer were higher in venous whole blood than in plasma and serum (mean ratios, 1.41 and 1.38). For the other enantiomer, (−)SR, concentrations were lower in whole blood than in plasma (mean ratio 0.89) and for the metabolite this ratio was 0.5. Conclusion: Stereoselective distribution might be important for antimalarial activity and should be considered when pharmacokinetic studies are performed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050180
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  • 7
    Electronic Resource
    Electronic Resource
    Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 189-193 
    Details
    ISSN: 1432-1041
    Keywords: Key words Dihydropyridine ; Amlodipine ; Grapefruit juice; flavonoids ; interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Objective: This study was performed to assess whether coadminstration with grapefruit juice significantly affects the pharmacokinetics of amlodipine, a dihydropyridine class calcium antagonist with slow absorption, distribution and low plasma clearance. The primary objective was to evaluate whether short exposure to grapefruit juice could affect the metabolism of amlodipine to an extent similar to that previously demonstrated for other dihydropyridines (e.g. felodipine, nisoldipine, nitrendipine). Methods: Twelve healthy male volunteers followed a randomised, open crossover study design, comparing the effect of a single oral dose of amlodipine (5 mg) taken together with a glass of grapefruit juice (250 ml) vs water. Blood samples to determine plasma concentration were taken and blood pressure (BP) and heart rate (HR) were measured throughout the study. Results: When amlodipine was coadministered with grapefruit juice, Cmax was 115% and AUC(0–72 h) was 116% compared with water, but tmax was not significantly changed. There were no significant differences in BP and HR between the two treatments. A small decrease in diastolic BP, however, was observed in both treatments 4–8 h after drug administration, coinciding with Cmax, but this was normalised after 12 h. The BP reduction seen was compensated by a slight increase in HR, which remained throughout the study. Conclusion: An interaction between grapefruit juice and amlodipine was demonstrated. The haemodynamic data showed that a dose of 5 mg was sufficient to achieve a BP reduction in healthy subjects, but the increase in amlodipine plasma concentration seen after intake of grapefruit juice was too small to significantly affect BP or HR. The clinical significance of this food/drug interaction, however, cannot be ignored since there is considerable variation between individuals and a more extensive intake of grapefruit juice might give more pronounced effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050183
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  • 8
    Electronic Resource
    Electronic Resource
    Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 335-338 
    Details
    ISSN: 1432-1041
    Keywords: Key words Midazolam ; Sauna; metabolism ; pharmacokinetics ; heat ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of short-term heat exposure in a Finnish sauna on hepatic first-pass metabolism and the capacity to metabolize midazolam were studied in a crossover trial. Midazolam oral (15 mg) and intravenous (0.05 mg ⋅ kg−1) was given to 6 healthy young male volunteers, in random order, during a control session and a sauna bathing session (temperature 85–100° C, relative humidity 25–30%). Blood samples for the determination of plasma midazolam and α-hydroxy midazolam concentrations were taken for 6 h after drug administration. Results: After oral administration, the bioavailability and clearance of midazolam were not affected by sauna bathing, nor was there a significant difference in α-hydroxy midazolam plasma concentration or the α-hydroxy midazolam/midazolam AUC-ratio between the sessions. Midazolam Cmax was increased and its t1/2β was prolonged during the sauna session, but the clinical relevance of the findings appears to be modest. The pharmacokinetics of intravenous midazolam were not affected by sauna bathing. Conclusions: Short-term heat exposure may not affect the first-pass metabolism or hepatic capacity to metabolize midazolam.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050208
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  • 9
    Electronic Resource
    Electronic Resource
    Therapeutic monitoring of nalbuphine: transplacental transfer and estimated pharmacokinetics in the neonate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: Key words Nalbuphine ; Neonate; therapeutic drug monitoring ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Nalbuphine, a mixed agonist-antagonist opiate, is commonly used as a systemic analgesic during labour. Recent reports of perinatal adverse effects prompted us to carry out therapeutic nalbuphine monitoring in obstetric analgesia. Because data on fetomaternal transfer are scarce and the pharmacokinetics of this drug in the neonate are largely unknown, we report data obtained from 28 parturients treated with nalbuphine either intramuscularly and/or intravenously during labour. Plasma nalbuphine levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. At delivery, 30–150 min after maternal administration, nalbuphine concentrations ranged from 5.0 to 79.2 ng ⋅ ml−1 in mother plasma samples and from 3.0 to 46.6 ng ⋅ ml−1 in umbilical cord plasma samples. Nalbuphine concentrations were highly correlated to dose. The fetomaternal ratio was high: 0.74 and not correlated to the administered dose of nalbuphine. An estimated plasma half-life of 4.1 h was calculated from two determinations in the neonate based on the assumption of a monoexponential decay of nalbuphine concentrations. Apart from a flattening of the fetal heart rate tracing in 54% of the cases, only one neonate had a low Apgar score at birth. The apparent prolonged half-life of nalbuphine in the neonate indicates the usefulness of an intramuscular injection of naloxone to prevent recurrence of cardiorespiratory depression due to nalbuphine administration to the mother.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050054
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  • 10
    Electronic Resource
    Electronic Resource
    Bioavailability of 1-deamino-8-D-arginine vasopressin with an enzyme inhibitor (aprotinin) from the small intestine in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 491-495 
    Details
    ISSN: 1432-1041
    Keywords: Key words Aprotinin ; Arginine vasopressin; bioavailability ; dDAVP ; enzyme inhibitor ; gastrointestinal tract ; healthy volunteer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP), with and without an enzyme inhibitor, was studied in six healthy, male volunteers aged 19–34 years, followed for 8 h after each drug administration. Methods: For i.v. administration the subjects received 4 μg dDAVP. For intestinal administration 500 μg dDAVP was administered directly, in two separate sessions, in the first part of the duodenum via a triple-lumen channel tube. In one session a solution of isotonic polyethylene glycol (PEG) was given as a continuous enteral perfusion. In the other session a solution of PEG and aprotinin was administered enterally at the constant rate of 5 ml⋅min−1 for 4 h. Plasma dDAVP was measured using a specific, sensitive radioimmunoassay and intestinal juice was collected for measurement of lipase, chymotrypsin and pH every 30 min for 5 h. Results: The intestinal chymotrypsin activity was decreased after perfusion of aprotinin while the lipase activity was not modified. After i.v. administration, the half-life of elimination of dDAVP was 1.56 h and plasma clearance 1.24 ml⋅min⋅kg−1. The mean bioavailability after duodenal administration of dDAVP + aprotinin was 0.46% compared with 0.09% after duodenal administration of dDAVP alone. The bioavailability of dDAVP after direct duodenal administration of an aqueous solution was similar to that after swallowing a tablet in a previous study and increased 5 times when given together with a perfusion of an enzyme inhibitor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050146
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  • 11
    Electronic Resource
    Electronic Resource
    Multiple dose pharmacokinetics of tiludronate in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 175-181 
    Details
    ISSN: 1432-1041
    Keywords: Key words Tiludronate; healthy volunteers ; bisphosphonates ; pharmacokinetics ; calcium metabolism ; bone resorption ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 400, 600 and 800 mg for 12 days. Four groups of ten subjects participated in the study, with a drug to placebo ratio of 4:1. Methods: Pre-dose blood samples were taken on alternate days, starting on Day 1 and additional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices of calcium homeostasis and biochemical markers of bone turnover were assessed during the study as pharmacodynamic parameters. Tolerability was evaluated with special emphasis on renal function and gastrointestinal irritation. Adverse experiences were assessed at regular time intervals. Results and conclusions: Steady state was attained from Day 4 (200 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose on Day 12, minimal plasma concentrations (Cmin) ranged between 0.19 and 1.5 mg ⋅ l−1, and maximal plasma concentrations (Cmax) between 1.1 and 7.8 mg⋅l−1 for the lowest and highest doses, respectively. A supra-proportional increase in Cmax, AUC24 and Ae 24 with dose was observed. There was a linear relationship between the plasma tiludronic acid and its urinary excretion rate, so, the disproportional rise in Cmax and AUC24 with increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only prominent at the highest dose level of 800 mg. Total serum calcium and the urinary calcium/creatinine clearance ratio fell, indicating depression of osteoclastic bone resorption, which was not revealed by serum osteocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydroxyvitamin D3 and intact PTH (1–84) levels increased. None of the safety parameters raised any concerns about the safety of sodium tiludronate administered in this way.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050181
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  • 12
    Electronic Resource
    Electronic Resource
    Haemodynamic effects and pharmacokinetics of oral d-and l-nebivolol in hypertensive patients (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 259-264 
    Details
    ISSN: 1432-1041
    Keywords: Key words Nebivolol ; Hypertension; d ; l-enantiomers ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Nebivolol is a selective β1-adrenergic receptor blocker possessing an ancillary vasodilating effect. The objective of the present study was to study the haemodynamic and pharmacokinetic properties of nebivolol 5 mg once daily in a double-blind, placebo-controlled cross-over study. Methods: Fifteen patients, 12 men and 3 women, with essential hypertension were investigated. Blood pressure and peripheral circulation were determined after acute oral nebivolol administration, 5 mg daily, and after 4 weeks treatment. Results: The acute effect on blood pressure upon single-dosing was weak and non-significant. After 4 weeks both systolic blood pressure (152 vs 163 mmHg) and diastolic blood pressure (89 vs 97 mmHg) were significantly reduced after nebivolol treatment as compared to placebo. Following the first dose the venous volume was higher on placebo (5.88 ml ⋅ 100 ml−1 tissue) as compared to active nebivolol treatment (5.17 ml ⋅ 100 ml−1 tissue), while there were no statistically significant differences with regard to venous plethysmographic findings after 1 month on placebo (5.53 ml ⋅ 100 ml−1 tissue) or on active treatment (5.97 ml ⋅ 100 ml−1 tissue). Calculated peripheral resistance did not differ between active treatment (617 units) or placebo (548 units) after the first dose, whereas it was significantly lowered after 4 weeks of nebivolol treatment (483 units) as compared to placebo (593 units). Conclusions: Oral nebivolol 5 mg once daily lowered blood pressure and heart rate during steady state compared to placebo. Moreover, venous volume was reduced during acute but not steady-state dosing, while peripheral resistance was unaffected in the acute phase but reduced during steady state. Plasma concentrations of the separate enantiomers plus hydroxylated metabolites after the first and last dose in hypertensive patients were similar to those in healthy subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050194
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  • 13
    Electronic Resource
    Electronic Resource
    Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 277-281 
    Details
    ISSN: 1432-1041
    Keywords: Key words Pantoprazole; Proton pump inhibitor drug interaction ; oral anticoagulant phenprocoumon ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pantoprazole is a selective proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzymes in man. Due to the clinical importance of an interaction with anticoagulants, this study was carried out to investigate the possible influence of pantoprazole on the pharmacodynamics and pharmacokinetics of phenprocoumon. Methods: Sixteen healthy male subjects were given individually adjusted doses of phenprocoumon to reduce prothrombin time ratio (Quick method) to about 30–40% of normal within the first 5–9 days and to maintain this level. The individual maintenance doses remained unaltered from day 9 on and were administered until day 15. Additionally, on study days 11–15, pantoprazole 40 mg was given per once daily. As a pharmacodynamic parameter, the prothrombin time ratio was determined on days 9 and 10 (reference value) and on days 14 and 15 (test value), and the ratio test/reference was evaluated according to equivalence criteria. Results: The equivalence ratio (test/reference) for prothrombin time ratio was 1.02 (90% confidence interval 0.95–1.09), thus fulfilling predetermined bioequivalence criteria (0.70–1.43). The pharmacokinetic characteristics AUC0–24h and Cmax of S(−)-and R(+)-phenprocoumon were also investigated using equivalence criteria. Equivalence ratios and confidence limits of AUC0–24h and of Cmax of S(−)-phenprocoumon (0.93, 0.87–1.00 for AUC0–24h; 0.95, 0.88–1.03 for Cmax) and of R(+)-phenprocoumon (0.89, 0.82–0.96; 0.9, 0.83–0.98) were within the accepted range of 0.8–1.25. Conclusion: Pantoprazole does not interact with the anticoagulant phenprocoumon on a pharmacodynamic or pharmacokinetic level. Concomitant treatment was well tolerated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050198
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  • 14
    Electronic Resource
    Electronic Resource
    Bioavailability of estradiol from a new matrix and a conventional reservoir-type transdermal therapeutic system (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 327-330 
    Details
    ISSN: 1432-1041
    Keywords: Key words Hormone replacement therapy; estradiol ; pharmacokinetics ; bioequivalence ; postmenopausal volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Bioavailability of estradiol delivered from a newly developed matrix-type transdermal therapeutic system (MTTS) was compared with that of the conventional reservoir-type system (RTTS). Both formulations have a nominal delivery rate of 50 μg per day of 17β-estradiol (E2). Plasma concentrations of E2 and estrone (E1) were determined at steady state during a 96-h application of each formulation to 34 postmenopausal volunteers, using a two-stage randomized two-period crossover design. Results: The MTTS proved to be equivalent to the RTTS with respect to the extent of E2 absorption. Due to differences in patch design and composition, the rate of absorption was different between the two systems, with less fluctuating E2 plasma levels during application of the matrix system. Local tolerability and adhesion of MTTS appeared to be better than those of the reservoir system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050206
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  • 15
    Electronic Resource
    Electronic Resource
    Rectal pharmacokinetics of budesonide (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 293-298 
    Details
    ISSN: 1432-1041
    Keywords: Key words Budesonide; enema ; pharmacokinetics ; healthy subjects ; hepatic bypass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and systemic availability of budesonide after rectal administration of two single enema doses (2 mg in 100 ml fluid of almost identical composition) were compared in 15 healthy volunteers. In 11 of these subjects, 2 mg oral budesonide in a gelatine capsule was given on a separate occasion. An intravenous administration (0.5 mg) was given as reference. With this design, individual hepatic bypass of the rectally administered budesonide dose could be estimated. The pharmacokinetics of the two enema formulations were similar, although not bioequivalent. Mean systemic availability was 16% (range 4.2–43%) and 15% (3.2–50%) after rectal administration and 6.3% (2.4–10%) after oral administration. The rectal data revealed a small intra- but a substantial inter-subject variability in systemic availability. Cmax was 3.3 nmol ⋅ l−1 (0.95–8.2), 3.0 nmol ⋅ l−1 (0.64–8.9) and 1.3 nmol ⋅ l−1 (0.61–3.0), respectively, for the three formulations. Absorption was rapid and essentially terminated within 3 h after rectal dosing [tmax = 1.3 h for both formulations (range 0.5–2.0)], but was slower after oral dosing [tmax = 2.1 h (1.0–6.0)]. If a complete absorption after oral and rectal dosing is assumed, the fraction of the rectal dose entering the liver at first pass can be calculated to be 88% (55–99%). The higher systemic availability and intersubject variability after rectal dosing does not seem to be caused by differences in first-pass liver metabolism but rather by hepatic bypass of a varying portion of administered drug. This portion seems to be typical for an individual and might be explained by anatomical differences between subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00226330
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    Design of a suitable formulation of FK613, a novel antiallergic agent, based on its pharmacokinetic and pharmacodynamic properties in healthy subjects (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 279-284 
    Details
    ISSN: 1432-1041
    Keywords: Antiallergic drug ; FK613 ; pharmacokinetics ; histamine skin-test ; drug formulation ; urinary excretion ; safety
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetic and pharmacodynamic properties of FK613, a novel indolyl piperidine derivative, were investigated after oral administrations of 5, 10 and 20 mg in hard gelatin capsules to healthy male volunteers. FK613 was rapidly and almost completely absorbed, and 〉89% was recovered in the urine as the unchanged form. The urinary excretion of FK613 was linearly correlated with plasma concentration and its low water solubility was the main concern regarding the safety. In another experiment using a double-blind crossover design, in which 0 (placebo), 5 and 20 mg FK613 were administered to determine the plasma concentration-effect relationship, suppression of the intradermal histamine-induced skin reaction by FK613 was observed. Thus, the maintenance of a plasma concentration of FK613 in the range of 80–250 ng · ml-1 was recommended to ensure the suppression of histamine-induced wheal by 〉50% and not to exceed the solubility in urine. To achieve this, a new hydrogel-type formulation of FK613 was developed, with the aim both of delaying its absorption, so as to suppress the sharp rise in plasma concentration, and of maintaining the effective concentration for a longer period of time. This formulation was administered after meals at the doses of 20, 30, 40, 50 and 60 mg, and at repeated doses of 40 mg twice daily for 6.5 days to evaluate the pharmacokinetics and safety in healthy subjects. The area under the plasma concentration curve increased linearly with dose, whereas maximum plasma concentration (Cmax) tended to peak as dose increased, indicating the desirable properties of this formulation. Although Cmax exceeded 250 ng/ml at doses of 30 mg or more, no urinary crystal formation was observed on careful inspection of urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00226328
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    Rectal pharmacokinetics of budesonide (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 293-298 
    Details
    ISSN: 1432-1041
    Keywords: Budesonide ; enema ; pharmacokinetics ; healthy subjects ; hepatic bypass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and systemic availability of budesonide after rectal administration of two single enema doses (2 mg in 100 ml fluid of almost identical composition) were compared in 15 healthy volunteers. In 11 of these subjects, 2 mg oral budesonide in a gelatine capsule was given on a separate occasion. An intravenous administration (0.5 mg) was given as reference. With this design, individual hepatic bypass of the rectally administered budesonide dose could be estimated. The pharmacokinetics of the two enema formulations were similar, although not bioequivalent. Mean systemic availability was 16% (range 4.2–43%) and 15% (3.2–50%) after rectal administration and 6.3% (2.4–10%) after oral administration. The rectal data revealed a small intra- but a substantial inter-subject variability in systemic availability. Cmax was 3.3 nmol·l-1 (0.95–8.2), 3.0 nmol·l-1 (0.64–8.9) and 1.3 nmol·l-1 (0.61–3.0), respectively, for the three formulations. Absorption was rapid and essentially terminated within 3 h after rectal dosing [tmax=1.3 h for both formulations (range 0.5–2.0)], but was slower after oral dosing [tmax=2.1 h (1.0–6.0)]. If a complete absorption after oral and rectal dosing is assumed, the fraction of the rectal dose entering the liver at first pass can be calculated to be 88% (55–99%). The higher systemic availability and intersubject variability after rectal dosing does not seem to be caused by differences in first-pass liver metabolism but rather by hepatic bypass of a varying portion of administered drug. This portion seems to be typical for an individual and might be explained by anatomical differences between subjects.
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    URL: http://dx.doi.org/10.1007/BF00226330
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    Electronic Resource
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    Increase in magnesium plasma level after orally administered trimagnesium dicitrate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 317-323 
    Details
    ISSN: 1432-1041
    Keywords: Magnesium ; Plasma level ; pharmacokinetics ; bioavailability ; circadian fluctuation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Magnesium plasma concentrations were measured in healthy probands before and after administration of trimagnesium dicitrate by the oral and intravenous routes. There was a notable circadian fluctuation of the plasma concentration with a peak in the evening hours. After oral administration of 12 and 24 mmol magnesium, a long-lasting, statistically significant increase in plasma magnesium concentration measured as the increase in area under the curve (AUC) between 0 and 12 h, of 3.1% and 4.6%, respectively, was found. After intravenous administration of 4 and 8 mmol magnesium, AUCs increased by 9.5% and 16.1%, respectively. The decline in the plasma magnesium concentration after i.v. administration was compatible with a three-compartment model with a terminal half-time of about 8 h. Although no absolute value of the oral bioavailability of trimagnesium dicitrate could be determined from the data, our results may be important in helping to elucidate the influence of magnesium preparations on the plasma magnesium concentration. By comparing the effects of different preparations, it should be possible to estimate the relative oral bioavailability and the bioequivalence of these preparations.
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    URL: http://dx.doi.org/10.1007/BF00226334
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  • 19
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    Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 47-55 
    Details
    ISSN: 1432-1041
    Keywords: Key words Tolcapone ; Elderly; levodopa ; pharmacokinetics ; pharmacodynamics ; multiple-dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Objective: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects. Methods: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes. Results: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased Cmax and AUC values. Despite the long half-life of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory Emax model with constant EC50 values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics. Conclusion: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson’s disease.
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    URL: http://dx.doi.org/10.1007/s002280050068
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  • 20
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    A comparison of the pharmacokinetics and pharmacodynamics of cilazapril between Chinese and Caucasian healthy, normotensive volunteers (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 57-62 
    Details
    ISSN: 1432-1041
    Keywords: Key words Cilazapril ; Caucasians ; Chinese; cilazaprilat ; pharmacokinetics ; pharmacodynamics ; ACE inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Methods: The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 12 Chinese and 13 Caucasian, healthy, normotensive volunteers on their normal diet. Cilazapril was given orally as a single 2.5 mg capsule. Plasma was sampled for assay of the active metabolite, cilazaprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE-activity. Plasma concentrations of the active drug were measured by radioimmunoassay. Blood pressure and heart rate were measured at regular intervals. Results: The pharmacokinetic parameters of cilazaprilat were similar in the two ethnic groups. No significant difference in plasma concentrations was found at any of the time points. However, the weight-adjusted plasma clearance was significantly higher in the Chinese group, which is compatible with their lower body weight. The effects on plasma hormones were also comparable, although there was a somewhat greater rise in PRA and greater fall in aldosterone levels in Chinese than in Caucasians. The effect of cilazapril on blood pressure and heart rate was greater than was previously reported in healthy volunteers. Systolic (SBP) and diastolic (DBP) blood pressure were significantly reduced in both groups, but there was a more prolonged reduction in DBP in Caucasians. In addition, heart rate (HR) was significantly increased from baseline from 5 h onwards in Chinese subjects and significantly higher in comparison with Caucasians at most time points from 1.5 h onwards. The pharmacokinetic parameters of cilazapril were essentially the same in healthy, normotensive Chinese and Caucasians. Cilazapril reduced blood pressure acutely in both groups, with good tolerance. The inhibition of ACE in relationship to time and the plasma concentrations of cilazaprilat were similar in the two groups, although the changes in PRA and aldosterone suggest an ethnic difference in the responses of the renin-angiotensin-aldosterone system.
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    URL: http://dx.doi.org/10.1007/s002280050069
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  • 21
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    Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 203-208 
    Details
    ISSN: 1432-1041
    Keywords: Key words Cyclosporine ; Felodipine; dehydrofelodi-pine ; pharmacokinetics ; blood pressure ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine, and cyclosporine, and 24-hour blood pressure measurements. Methods: Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were given at a 1–2 week interval. Plasma drug concentrations were followed for 2 days after drug intake. Results: For cyclosporine, Cmax was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and Cmax (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite dehydrofelodipine, too, AUC and Cmax were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine (122/68 mmHg) compared to cyclosporine alone (127/73 mmHg). Conclusion: A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and Cmax of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine was only slightly increased by felodipine.
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    URL: http://dx.doi.org/10.1007/s002280050093
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  • 22
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    Effect of food on the bioavailability of oxybutynin from a controlled release tablet (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 221-223 
    Details
    ISSN: 1432-1041
    Keywords: Key words Oxybutynin; effect of food ; N-desethyl oxybutynin ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, Cmax, tmax, t1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined. Results: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20% . The Cmax of oxybutynin and N-desethyl oxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state. Conclusion: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.
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    URL: http://dx.doi.org/10.1007/s002280050096
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    Stereoselective pharmacokinetics of mefloquine in young children (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 241-244 
    Details
    ISSN: 1432-1041
    Keywords: Key words Mefloquine ; Children; enantiomer ; pharmacokinetics ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: the stereospecificity of mefloquine pharmacokinetics in children has been investigated. Patients: Twelve children aged 6 to 24 months were treated for uncomplicated falciparum malaria with a single oral dose of 25 mg⋅kg−1 racemic mefloquine in combination with sulfadoxine and pyrimethamine. Methods: concentrations of mefloquine enantiomers were determined using a coupled achiral-chiral chromatographic system. Pharmacokinetic parameters were calculated using model-independent analysis. Results: Maximum plasma concentrations, areas under the curve and apparent plasma elimination half-lives were higher for the (−) enantiomer than its antipode. In contrast, the apparent volume of distribution (V/f) and total clearance (Cl/f) values were higher for the (+) enantiomer. Conclusion: the stereoselectivity of mefloquine pharmacokinetics is similar to that observed in adults.
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    Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 331-334 
    Details
    ISSN: 1432-1041
    Keywords: Key words Zopiclone ; Itraconazole; drug interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic. Methods: A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 h. Results: Itraconazole significantly increased the Cmax of zopiclone from 49 to 63 ng ⋅ ml−1. The t1/2 of zopiclone was prolonged from 5.0 to 7.0 h. The AUC(0–∞) of zopiclone was increased from 415 to 719 ng ⋅ ml−1 h by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups. Conclusion: Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults.
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    URL: http://dx.doi.org/10.1007/s002280050207
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    Influence of age, frailty and liver function on the pharmacokinetics of brofaromine (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 387-391 
    Details
    ISSN: 1432-1041
    Keywords: Key words Liver function tests; elderly ; pharmacokinetics ; geriatrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y). Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 μmol*h⋅l−1, clearance was reduced (5.0 vs. 11.8 l⋅h−1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r = 0.41, P = 0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r = 0.94, P 〈 0.0001). Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.
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    URL: http://dx.doi.org/10.1007/s002280050037
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    Influence of age, frailty and liver function on the pharmacokinetics of brofaromine (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 387-391 
    Details
    ISSN: 1432-1041
    Keywords: Liver function tests ; elderly ; pharmacokinetics ; geriatrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y). Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 μmol*h·l−1, clearance was reduced (5.0 vs. 11.8 l·h−1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r=0.41, P=0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r=0.94, P〈0.0001). Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.
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    URL: http://dx.doi.org/10.1007/BF00203783
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    Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 411-415 
    Details
    ISSN: 1432-1041
    Keywords: Moxisylyte ; pharmacokinetics ; intracavernous administration ; healthy volunteers ; adverse events ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The concentration-time profiles of specific metabolites of moxisylyte, an α-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). Results: Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. Conclusion: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.
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    URL: http://dx.doi.org/10.1007/BF00203788
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    Therapeutic monitoring of nalbuphine: transplacental transfer and estimated pharmacokinetics in the neonate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: Nalbuphine ; Neonate ; therapeutic drug monitoring ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Nalbuphine, a mixed agonist-antagonist opiate, is commonly used as a systemic analgesic during labour. Recent reports of perinatal adverse effects prompted us to carry out therapeutic nalbuphine monitoring in obstetric analgesia. Because data on fetomaternal transfer are scarce and the pharmacokinetics of this drug in the neonate are largely unknown, we report data obtained from 28 parturients treated with nalbuphine either intramuscularly and/or intravenously during labour. Plasma nalbuphine levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. At delivery, 30–150 min after maternal administration, nalbuphine concentrations ranged from 5.0 to 79.2 ng·ml−1 in mother plasma samples and from 3.0 to 46.6 ng·ml−1 in umbilical cord plasma samples. Nalbuphine concentrations were highly correlated to dose. The fetomaternal ratio was high: 0.74 and not correlated to the administered dose of nalbuphine. An estimated plasma half-life of 4.1 h was calculated from two determinations in the neonate based on the assumption of a monoexponential decay of nalbuphine concentrations. Apart from a flattening of the fetal heart rate tracing in 54% of the cases, only one neonate had a low Apgar score at birth. The apparent prolonged half-life of nalbuphine in the neonate indicates the usefulness of an intramuscular injection of naloxone to prevent recurrence of cardiorespiratory depression due to nalbuphine administration to the mother.
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    URL: http://dx.doi.org/10.1007/BF00195935
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    Pharmacokinetics of quinine in patients with chronic renal failure (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 497-501 
    Details
    ISSN: 1432-1041
    Keywords: Quinine ; Malaria ; pharmacokinetics ; chronic renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (tmax 4.5 vs 1.6 h, Cmax 6.17 vs 3.45 μg·ml−1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min−1·kg−1, whereas Vz/f remained unchanged (1.82 vs 2.78 1·kg−1). This resulted in the increased values of AUC and prolongation of the t1/2z and MRT in the patients (AUC 181.5 vs 61.8 μg·min−1·ml−1, t1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.
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    URL: http://dx.doi.org/10.1007/BF00195937
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    Evaluation of plasma and urinary salbutamol levels in COPD (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 91-93 
    Details
    ISSN: 1432-1041
    Keywords: Key words Salbutamol; nebulised ; pharmacokinetics ; COPD ; overnight urinary salbutamol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To evaluate the use of trough plasma salbutamol and overnight urinary salbutamol excretion in the assessment of nebulised salbutamol delivery in patients with chronic obstructive pulmonary disease (COPD). Methods: Twenty in-patients with COPD receiving nebulised salbutamol, age 69.7 years, FEV1 38.1% predicted, were studied on two consecutive days, receiving four 2.5 mg doses of nebulised salbutamol on day 1 and four 5 mg doses of nebulised salbutamol on day 2, the first dose at 8.00 h the last dose at 22.00 h. Salbutamol delivery was assessed after the last dose by trough plasma salbutamol 8.00 h and overnight urinary excretion of salbutamol (22.00–8.00 h). Results: Levels of urinary salbutamol were detectable in all 20 patients at both doses, whereas for plasma salbutamol detectable levels were only found in 16/20 cases at the 2.5 mg dose and in all cases at the 5 mg dose. For overnight urinary salbutamol (μg⋅10 h−1  n = 20) the results were 141 for 2.5 mg and 249 for 5 mg. The dose ratio for urinary salbutamol between 2.5 mg and 5 mg doses was 1.83. Results for plasma salbutamol (ng/ml, n = 16) were 1.58 at 2.5 mg and 2.43 at 5 mg: dose ratio (geometric mean) 1.49. Conclusion: Overnight urinary salbutamol provides a simple and effective measure of nebulised salbutamol delivery in patients with COPD, which would be suitable for studying nebuliser performance and compliance.
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    URL: http://dx.doi.org/10.1007/s002280050166
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    Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 167-169 
    Details
    ISSN: 1432-1041
    Keywords: Key words Idebenone; mitochondrial encephalomyopathy ; young patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and tolerance of idebenone after single or repeated doses have been studied in young patients with mitochondrial encephalomyopathy. Results: No significant adverse effects were noted. In 3 out of 7 patients idebenone induced overall stimulation and improvement in arousal. Plasma concentrations of idebenone and its main metabolites were determined and the pharmacokinetic parameters of idebenone after single and repeated doses were estimated. During the single dose study, the mean plasma concentrations of idebenone and its main metabolites and mean pharmacokinetic parameters were comparable to published results (Cmax = 452.2 ng ⋅ ml−1, tmax = 2.3 h, AUC = 26 μg ⋅ ml−1 ⋅ h, t1/2β = 16.5 h). During the repeated doses study, no significant difference was found between mean residual plasma concentrations of idebenone on Day 2 (47 ng ⋅ ml−1) and Day 5 (70.6 ng ⋅ ml−1), and mean t1/2β of idebenone after the single and after repeated dose studies, i.e., there was no evidence of accumulation. Although idebenone did not appear to accumulate during this study, the coadministration of anticonvulsants, often prescribed during mitochondrial encephalomyopathy, can affect its pharmacokinetics.
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    URL: http://dx.doi.org/10.1007/s002280050179
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    Macromolecular Carrier Systems for Targeted Drug Delivery: Pharmacokinetic Considerations on Biodistribution (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 820-831 
    Details
    ISSN: 1573-904X
    Keywords: macromolecular carrier ; pharmacokinetics ; targeting ; protein drugs ; gene medicines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This review article describes the current status and future perspectives of site-specific drug delivery by means of macromolecular carrier systems. Basic aspects and recent advances of targeted delivery of 1) conventional drugs, 2) protein drugs, and 3) gene medicines including antisense oligonucleotides and plasmid DNA, are reviewed from a pharmacokintic perspective. Successful in vivo application of macromolecular carrier systems requires pharmacokinetic considerations at whole body, organ, cellular and subcellular levels. The integration of simultaneous research progress in the multidisciplinary fields such as biochemistry, cell and molecular biology, pharmacology, and pharmacokinetics will accelerate the emergence of marketed drugs with macromolecular carrier systems.
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    URL: http://dx.doi.org/10.1023/A:1016084508097
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    Targeted Delivery of Doxorubicin via Sterically Stabilized Immunoliposomes: Pharmacokinetics and Biodistribution in Tumor-bearing Mice (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 861-868 
    Details
    ISSN: 1573-904X
    Keywords: sterically stabilized immunoliposomes ; targeting ; doxorubicin ; lung metastases ; pharmacokinetics ; biodistribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate benefits in tumor localization, availability, and noncancerous organ distribution of doxorubicin (DOX) delivered via small (≤120 nm) sterically stabilized immunoliposomes targeted against a tumor-associated antigen in fibrosarcoma-bearing mice. Methods. DOX-loaded liposomes were prepared with (i) specific monoclonal IgG3 antibody (32/2, D-SSIL-32/2); (ii) non-specific IgG3 (D-SSIL-IgG); or (iii) no IgG (D-SSL) on their surface. Equal DOX amounts were injected intravenously via each type of liposome into BALB/c mice carrying experimental lung metastases of a polyoma virus-induced fibrosarcoma (A9 etc 220) expressing a polyoma virus-induced tumor-associated antigen (PAA) on their surface. Metastases occurred mainly in lung. Mice were treated at 3 stages of tumor development (micrometastases, medium-size metastases, and large, necrotic metastases). Performance evaluation was based on time-dependent quantification of DOX and DOX metabolites (DOX-M) in lung tumor, noncancerous organs, and plasma. Results. (i) DOX delivered via both SSIL retained the prolonged circulation time typical of DOX delivered via D-SSL. (ii) DOX accumulation in noncancerous organs was similar for all preparations. Low levels of DOX-M were obtained for all three preparations in all organs except liver, suggesting a similar processing, (iii) Preparations differed in behavior in lung tumor depending on tumor size and microanatomy. Only at the micrometastases stage were the specifically targeted D-SSIL-32/2 superior to D-SSL and D-SSIL-IgG, delivering 2–4 times more drug into the tumor, (iv) DOX-M level in all three tumor stages was in the following order: D-SSIL-32/2 〉〉 D-SSL 〉〉 D-SSIL-IgG, suggesting that DOX delivered as D-SSIL-32/2 is most available to tumor cells. Conclusions. The advantage of specific targeting of sterically stabilized liposomes is expressed mainly in increasing availability of DOX to tumor cells in a way which is dependent on tumor microanatomy. The impact of this advantage to therapeutic efficacy remains to be determined.
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    Bioequivalence assessment of etoposide phosphate and etoposide using pharmacodynamic and traditional pharmacokinetic parameters (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 313-325 
    Details
    ISSN: 1573-8744
    Keywords: etoposide ; etoposide phosphate ; bioequivalence ; pharmacokinetics ; pharmacodynamics ; humans ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioequivalence of etoposide phosphate, a prodrug of etoposide, to etoposide was assessed in a randomized, crossover study in 29 patients with histologically established solid tumors that had failed conventional treatment. Cohorts of patients received one treatment course each of etoposide and etoposide phosphate which consisted of a 100 mg/m2 per day etoposide equivalent dose infused iv over 1 hr on a Day 1 to 5 schedule of treatment. The second course was administered 21 days later or on recovery of blood cell counts. Plasma and urine samples were collected over 24 hr on Day 1 of each course and assayed for etoposide content by a validated HPLC/UV method. Resulting data were subjected to noncompartmental pharmacokinetic analysis. Hematology profiles were obtained by collecting blood samples prior to the first course and twice a week after each course. The pharmacodynamics and pharmacokinetics of etoposide were virtually identical after the two treatments. The point estimates (90% confidence intervals) for nadir WBC, granulocytes, hemoglobin, and platelets expressed as % decrease from the baseline, and for the pharmacokinetic parameters, Cmax, and AUC0-∞, after intravenous etoposide phosphate relative to etoposide were 100% (96%, 105%), 97% (91%, 103%), 95% (82%, 109%), 95% (84%, 106%), 107% (101%, 113%), and 113% (107%, 119%), respectively. Therefore, etoposide phosphate is bioequivalent to etoposide based on pharmacokinetic and pharmacodynamic assessments.
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    Interspecies Pharmacokinetics of a Novel Hematoregulatory Peptide (SK&F 107647) in Rats, Dogs, and Oncologic Patients (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 794-797 
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    ISSN: 1573-904X
    Keywords: allometric scaling ; peptide ; pharmacokinetics ; hematology ; infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. Methods. Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 ng/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). Results. In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vdss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a·Wb), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vdss, and T1/2 of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. Conclusions. Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.
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    Evaluation of Pharmacokinetic Studies: Is It Useful to Take into Account Concentrations Below the Limit of Quantification? (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 839-845 
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    ISSN: 1573-904X
    Keywords: pharmacokinetics ; precision ; accuracy ; limit of quantification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Based on real data, to evaluate the usefulness of taking into account samples with values below the limit of quantification (LOQ) for the evaluation of pharmacokinetic studies. Methods. To compare for two drugs, after single dose administration the pharmacokinetic parameters obtained by using a poorly sensitive assay (PSA) and a highly sensitive assay (HSA), acting as reference; To evaluate the results of pharmacokinetic studies in the light of different values for the LOQ. Results. Under certain conditions, such as homogeneous population, sufficient subject number, sufficient sampling times and acceptable accuracy (CV 〈 20%) for the concentrations, it is possible to get valuable and more reliable kinetic information by using concentrations obtained with a poor precision (CV 〉 20%). This is especially true for the parameters associated with the terminal phase, such as t1/2β and AUC, but also for parameters depending to a lesser extent on the terminal phase, such as tl/2α and AUCtn. Moreover, the mean concentration time curve is by far best defined by using all the concentrations. Conclusions. In some situations, it is preferable to use concentrations with values below the LOQ to evaluate the results of pharmacokinetic studies. However, this should not be the rule, especially when this does not bring any additional information, or when it is possible to increase the sensitivity of the bioanalytical assay.
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    Effects on the Pharmacokinetics and Pharmacodynamics in the Elderly of Coadministering Ramipril with Water, Apple Juice, and Applesauce (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 639-642 
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    ISSN: 1573-904X
    Keywords: ramipril ; ACE inhibitor ; capsules ; pharmacokinetics ; pharmacodynamics ; elderly patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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    URL: http://dx.doi.org/10.1023/A:1016022827235
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    A Pharmacokinetic Approach for Evaluating Cytokine Binding Macromolecules as Antagonists (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 84-90 
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    ISSN: 1573-904X
    Keywords: antibodies ; soluble receptors ; immunoadhesins, cytokines ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Cytokine binding macromolecules such as antibodies and soluble receptors sometimes produce undesirable agonist-like activities instead of the expected antagonist-like effects when the cytokine binding macromolecule extends the half-life of a short-lived cytokine. The purpose of this paper is to identify the pharmacokinetic and physicochemical properties that can cause these agonist-like activities. Methods. A simple pharmacokinetic model was used to determine whether a given cytokine binding macromolecule will function effectively as an antagonist in therapeutic situations in which cytokine is released chronically. Results. The model proposed satisfactorily fits experimental data for soluble interleukin-4 receptor and for an anti-interleukin-4 monoclonal antibody under conditions in which agonist-like and antagonist activity are observed. Conclusions. We show that the unexpected agonist-like activities result only when there is nonlinearity in the cytokine-cytokine receptor interaction and the cytokine binding macromolecule prolongs the half-life of the cytokine.
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    Development and Pharmacokinetics of Galactosylated Poly-L-Glutamic Acid as a Biodegradable Carrier for Liver-Specific Drug Delivery (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 880-884 
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    ISSN: 1573-904X
    Keywords: drug carrier ; hepatic targeting ; poly-L-glutamic acid ; galactosylation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A biodegradable carrier for the liver-specific delivery of drugs was developed using poly-L-glutamic acid (PLGA) modified with galactose (galactosylated PLGA or Gal-PLGA), and its feasibility was investigated in mice. Methods. 111In-PLGA and 111In-Gal-PLGAs were injected in mice and their distribution and biodegradation properties were studied. Results. After intravenous injection, 111In-PLGA was rapidly eliminated from the plasma and recovered mainly in the kidneys and urine. Approximately 15% of the dose was recovered in the liver, predominantly in the nonparenchymal cells. 111In-Gal-PLGAs were taken up by the liver parenchymal cells. Derivatives having 16 or more galactose residues were taken up by the liver to a higher extent (〉60% of the dose). The hepatic clearance of 111n-Gal-PLGAs correlated with their number of galactose residues. 111In-Gal18-PLGA was degraded into low-molecular weight products in the liver. Conclusions. The advantageous in vivo properties of Gal-PLGA as a liver-specific biodegradable carrier of drugs were demonstrated in mice.
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    Clinical phase I and pharmacokinetic trial of vinorelbine administered as single intravenous bolus every 21 days in cancer patients (1996)
    Springer
    Investigational new drugs 14 (1996), S. 371-378 
    Details
    ISSN: 1573-0646
    Keywords: vinorelbine ; phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have performed a high-dose clinical and pharmacokinetic trial with vinorelbine administered as a bolus injection every 21 days. The aim was to evaluate a schedule with longer treatment intervals than one week and to determine the toxicity pattern of such a schedule. A total of 13 patients (pts) with solid tumors (non-small-cell lung [3 pts], unknown primary [3 pts], mesothelioma [2 pts], colon/rectum, sarcoma, thyroid, head/neck and cervix [1 pt each]) were entered [9 male, 4 female, median age: 56 years (range: 37–69)]. Dose levels were 35, 40 and 45 mg/m2 with a total of 26 cycles administered. At 40 mg/m2, 2/6 pts developed grade 4 granulocytopenia. 1/1 pt at 45 mg/m2 developed a grade 4 leuko- and granulocytopenia. Non-hematological toxicities were mild to moderate. Neurologic toxicity except for constipation was mild. Constipation occurred at 35 mg/m2 in 1/6 pts WHO grade 4, at 40 mg/m2 in 2/6 pts WHO grade 3 and at 45 mg/m2 in 1/1 pt WHO grade 4 and was due to neurotoxicity. No objective antitumor response was observed. Vinorelbine pharmacokinetics were analysed in whole blood and plasma and were similar to previously published studies using ≤30 mg/m2. Our results confirm a high affinity of vinorelbine to corpuscular blood elements. We conclude that the MTD of vinorelbine administered once every 21 days as bolus injection is 40 mg/m2, the dose-limiting toxicities are constipation and granulocytopenia and the recommended dose for subsequent Phase II trials is 35 mg/m2.
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    URL: http://dx.doi.org/10.1007/BF00180813
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    Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma (1996)
    Springer
    Investigational new drugs 14 (1996), S. 227-234 
    Details
    ISSN: 1573-0646
    Keywords: Mitoguazone ; MGBG ; pharmacokinetics ; AIDS related non-Hodgkin's lymphoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m2 of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 μg/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m2 with a relatively large apparent volume of distribution at steady-state of 1012 l/m2 indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.
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    Clinical and pharmacokinetic phase I trial of oral dimethylaminoetoposide (NK611) administered for 21 days every 35 days (1996)
    Springer
    Investigational new drugs 14 (1996), S. 379-386 
    Details
    ISSN: 1573-0646
    Keywords: NK611 ; dimethylaminoetoposide ; phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have conducted a clinical and pharmacokinetic trial of the novel podophyllotoxin derivative NK611 administered orally for 21 consecutive days. The treatment was repeated every 35 days. Eighteen patients were included into the study, all of whom were eligible. Due to early progression of tumor disease in two patients, 16 patients were évaluable for toxicity [7 female, 9 male, median age 64 years (range: 44 to 73)]. Dose escalation steps were 5 mg/day [105 mg per cycle (pc)], 10 mg/day (210 mg pc), 12.5 mg/day (265 mg pc) and 15 mg/day (315 mg pc). A total of 37 courses was administered. Toxicity was evaluated using NCI-CTC criteria. Granulocytopenia was the main hematologic toxicity. Other hematologic toxicities were sporadic. Non-hematologic toxicities were mild and consisted of grade 1 nausea and grade 2 alopecia. Pharmacokinetic analyses were performed in six patients each treated with 10 mg/day and 12.5 mg per day, and in one patient treated with 15 mg/day. Using a two-compartment model, t1/2α ranged from 0.47 to 1.54 h and t1/2β from 2.0–11.6 h. Mean values for C max and AUC were 1.47 ± 0.331 μg/ml and 13.67±3.81 μg/ml·h. No objective tumor responses were observed. However, one patient with metastatic breast cancer had stable disease for twelve months. We conclude that the Maximum Tolerated Dose of NK611 administered daily for 21 consecutive days is 12.5 mg/day. The Dose-Limiting Toxicity is granulocytopenia. The recommended dose for further clinical Phase II studies is 10 mg/day.
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    Determination of plasma concentration of the cardioprotective preparation histochrome (1996)
    Springer
    Bulletin of experimental biology and medicine 122 (1996), S. 1222-1224 
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    ISSN: 1573-8221
    Keywords: free-radical pathology ; antioxidants ; polyhydroxynaphthoquinones ; histochrome ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract A method for measuring the plasma concentration of histochrome is described. Echinochrome, a naturally occurring polyhydroxynaphthoquinone with antioxidant and cardioprotective activities, is the active ingredient of histochrome. Plasma histochrome concentration is measured in patients with acute myocardial infarction. This method can be used for pharmacokinetic analysis.
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    Pharmacokinetics of prednisolone and its impact on cortisol kinetics in the blood serum of apparently healthy human subjects (1996)
    Springer
    Bulletin of experimental biology and medicine 122 (1996), S. 695-697 
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    ISSN: 1573-8221
    Keywords: prednisolone ; cortisol ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Individual characteristics of prednisolone and cortisol pharmacokinetics in five young healthy subjects administered prednisolone in a single oral dose of 25 mg are described. The results suggests that prednisolone inhibits the glucocorticoid function of the adrenal cortex. It is concluded that the pharmacokinetics of prednisolone can be assessed from the reductions in serum cortisol concentration which it causes.
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    In vivo relationships between the cerebral pharmacokinetics and pharmacodynamics of thiopentone in sheep after short-term administration (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 1-18 
    Details
    ISSN: 1573-8744
    Keywords: thiopentone ; pharmacokinetics ; pharmacodynamics ; brain ; cerebral blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The cerebral kinetics and dynamics of thiopentone after infusions of 250, 500, and 750 mg over 2 min were examined in chronically instrumented sheep (6, 6, and 5 sheep per dose, respectively). The cerebral kinetics were studied by rapid sampling of arterial and dorsal sagittal sinus blood (afferent and efferent blood for the brain, respectively) for 40 min, and could be described by a single flow-limited compartment when arterial concentrations and cerebral blood flow were used as forcing input functions. The half-lives of equilibration between blood and the brain were estimated to be 0.67 (SEM=0.07), 0.57 (0.03) and 0.74 (0.05) min for the 250-, 500- and 750-mg doses, respectively, showing that the cerebral concentrations of thiopentone rapidly equilibrate with the afferent blood concentration. Simultaneous pharmacodynamic measurements included cerebral blood flow via a Doppler flowmeter on the sagittal sinus, and an index of the depth of anesthesia based on an algesimetry method. Thiopentone transiently reduced cerebral blood flow to 82 (SEM=3), 80% (7), and 74% (10) of baseline for the 250−, 500−, and 750-mg doses, respectively, and failure to account for drug-induced changes in cerebral bloof flow in the model overestimated the apparent volume of the brain by 12% for the 500-mg dose. For the 500-mg dose, the changes in cerebral blood flow could be accounted for by an effect compartment with a half-life of 0.82 min for arterial blood, and 0.00 min for sagittal sinus blood, showing the effluent brain concentrations were in equilibrium with this drug effect. The time course of the depth of anesthesia for the 250-mg dose could be accounted for by an effect compartment with a half-life of 1.33 min for arterial blood, and 0.41 min for sagittal sinus blood. Thus, the rate of equilibration between blood and brain could not account for all of this delay. It is concluded that after short-term administration thiopentone equilibrated rapidly with the brain, and that this is consistent with the observation that the magnitude of its clinically relevant effects closely follow the time course of the arterial blood concentrations.
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    Pharmacokinetics of eltanolone following bolus injection and constant rate infusion (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 535-549 
    Details
    ISSN: 1573-8744
    Keywords: eltanolone ; pregnanolone ; Kabi 2213 ; context sensitive time ; anaesthesia ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Disposition of intravenous anaesthetic eltanolone was studied when administered as a bolus injection (B) of 0.75 mg/kg and constant rate intravenous infusion at 2 mg/kg/hr (I2) and 3.5 mg/kg/hr (I3.5) for 2 hr in healthy male volunteers. Venous blood samples were collected for 12 hr and 20 hr following bolus injection and intravenous infusion, respectively. Serum eltanolone concentrations were determined by a specific gas chromatographic mass spectrometric assay. Using a nonlinear regression analysis, the individual data sets were best fitted by a three-compartment mamillary model with central elimination. Derived pharmacokinetic parameters expressed as median and 95% confidence intervals indicated an initial fast distribution with a half-life of 1.80 (0.23–5.47) min (B), 1.44 (0.97–2.06) min (I2) and 1.44 (0.95–2.39) min (I3.5), an intermediate phase with a half-life of 35.4 (28.7–45.2) min (B), 39.6 (31.0–47.9) min (I2) and 35.4 (33.3–44.9) min (I3.5) and a moderately short terminal phase with a half-life of 3.8 (2.7–5.9) hr (B), 5.0 (4.2–6.1) hr (I2) and 4.6 (4.0–4.8) hr (I3.5). The serum clearance after bolus injection was 1.37 (1.23–1.67) L/hr/kg and after infusion was 1.36 (1.25–1.52) L/hr/kg (I2) and 1.17 (1.11–1.31) L/hr/kg (I3.5). The pharmacokinetics of eltanolone appear to be linear over the dosage range studied. Pharmacokinetic parameters obtained after bolus injection were very much similar to the parameters obtained after infusion with the exception of t1/2β which was longer after the infusion (significant) and the volume of central compartment which was lower after infusion (not significant). Context sensitive times were estimated for a 30%, 50% and 80% drop in the concentration of eltanolone after different infusion times. A 30% drop in concentration is estimated to take about 2 to 3 min. A 50% drop in concentration, is estimated to take about 8 min when duration of infusion is 3 hr and reaches a value of about 10 min by a duration of infusion of 10 hr. A 80% drop in concentration is estimated to take about 55 min following an infusion of 1 hr and it reaches a value of 70–80 min following an infusion of 10 hr.
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    Multiple solutions, illegal parameter values, local minima of the sum of squares, and anomalous parameter estimates in least-squares fitting of the two-compartment pharmacokinetic model with absorption (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 79-101 
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    ISSN: 1573-8744
    Keywords: two-compartment model ; parameter estimation ; least squares ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract When the two-compartment model with absorption is fitted to data by nonlinear least squares, in general six different outcomes can be obtained, arising from permutation of the three exponential rate constants. The existence of multiple solutions in this sense is analogous to the flip-flop phenomenon in the one-compartment model. It is possible for parameter estimates to be inconsistent with the underlying physical model. Methods for recognizing such illegal estimates are described. Other common difficulties are that estimated values for two of the rate constants are almost identical with very large standard deviations, or that the parameter estimation algorithm converges poorly. Such unwanted outcomes usually signal a local (false) minimum of the sum of squares. They can be recognized from the ratio of largest to smallest singular value of the Jacobian matrix, and are, in principle, avoidable by starting the estimation algorithm with different initial values. There also exists a class of data sets for which all outcomes of fitting the usual equations are anomalous. A better fit to these data sets (smaller sum of squares) is obtained if two of the relevant rate constants are allowed to take complex conjugate values. Such data sets have usually been described as having “equal rate constants.” A special form of the model equation is available for parameter estimation in this case. Precautions relating to its use are discussed.
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    Pharmacokinetics and pharmacodynamics of azosemide after intravenous and oral administration to rats: Absorption from various GI segments (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 551-568 
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    ISSN: 1573-8744
    Keywords: azosemide ; pharmacokinetics ; pharmacodynamics ; multiple peaks ; absorption from various segments of GI tract
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Azosemide, 5, 10, 20, and 30 mg/kg, was administered both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of azosemide in rats (n=7–12). The absorption of azosemide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of azosemide after oral administration were also investigated. After intravenous (iv) dose, the pharmacokinetic parameters of azosemide such ast 1/2, MRT, VSS, CL, CLR, and CLNR were found to be dose-dependent in the dose ranges studied. The percentages of the iv dose excreted in 8-hr urine as azosemide, MI (a metabolite of azosemide), glucuronide of azosemide, and glucuronide of MI—expressed in terms of azosemide—were also dose-dependent in the dose ranges studied. The data above suggest saturable metabolism of azosemide in rats. The measurements taken after the iv administrations such as the 8 hr urine output, the total amount of sodium and chloride excreted in 8-hr urine per 100 g body weight, and diuretic, natriuretic, kaluretic, and chloruretic efficiencies were also shown to be dose-dependent. However, the total amount of potassium excreted in 8-hr urine per 100 g body weight was dose-independent. Similar dose-dependency was also observed following oral administration. Azosemide was absorbed from all regions of GI tract studied and approximately 93.5, 79.1, 86.1, and 71.5% of the doses (5, 10, 20, and 30 mg/kg, respectively) were absorbed between 1 and 24 hr after oral administration. The appearance of multiple peaks after oral administration is suspected to be due mainly to the gastric emptying pattern. The percentages of azosemide absorbed from the GI tract as unchanged azosemide for up to 24 hr after oral doses of 5, 10, 20, and 30 mg/kg were significantly different with doses (decreased with increasing doses), suggesting that the problem of azosemide precipitating in acidic gastric juices or dissolution may have at least partially influenced the absorption of azosemide after oral administration.
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    URL: http://dx.doi.org/10.1007/BF02353480
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    Interspecies Scaling of Bosentan, A New Endothelin Receptor Antagonist and Integration of in Vitro Data into Allometric Scaling (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 97-101 
    Details
    ISSN: 1573-904X
    Keywords: allometric scaling ; interspecies scaling ; pharmacokinetics ; clearance ; in vitro models ; bosentan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The goal of this study was to find a rational and reliable method of using animal data to predict the clearance of metabolised drugs in humans. Methods. One such approach is to use in vitro liver models (e.g. hepatocytes and microsomes) to determine the relative capacities of the various animal species and humans to metabolise the test compound. These data can then be combined with the in vivo clearances in animals, to calculate the in vivo clearance in humans using allometric scaling techniques. In this study, this approach was evaluated with a new endothelin receptor antagonist, bosentan, which is eliminated mainly through metabolism and is characterized by very large interspecies differences in clearance. Therefore, this compound provided a stringent test of our new extrapolation method for allometric scaling. Results. The results obtained with bosentan showed that adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro gave a far better prediction of human clearance than an empirical correcting factor (brain weight). Conclusions. This approach provided a more rational basis for predicting the clearance of metabolised compounds in humans.
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    URL: http://dx.doi.org/10.1023/A:1016037519116
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    Percutaneous Absorption of Ketoprofen from Different Anatomical Sites in Man (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 168-172 
    Details
    ISSN: 1573-904X
    Keywords: ketoprofen ; nonsteroidal anti-inflammatory agent ; topical application ; percutaneous absorption ; regional variation ; pharmacokinetics ; urinary excretion ; enantiomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to investigate the percutaneous absorption of ketoprofen applied topically to different anatomical sites on the body. Methods. The study design was a randomized, four-way crossover in 24 healthy male subjects. One gram of ketoprofen 3% gel (30 mg dose) was applied every six hours for 25 doses over a 100 cm2 of the back, arm, and knee. A 0.5 ml of ketoprofen solution (60 mg/ml) was applied to the back as a reference treatment. Plasma and urine samples were obtained for the assay of racemic ketoprofen and ketoprofen enantiomers (S and R), respectively. Results. The relative bioavailabilities of ketoprofen gel were 0.90 ± 0.50, 1.08 ± 0.63, and 0.74 ± 0.38 when applied to the back, arm, and knee, respectively. The plasma ketoprofen Cmax for gel applied to the back and arm were similar (p 〉 0.05) but Cmax was lower when applied to the knee (p 〈 0.05). The time to Cmax ranged from 2.7 to 4.0 hours and was similar for gel treatments on the back and arm, but longer for the knee treatment. The fraction of dose excreted in urine as total S and R enantiomers ranged from 5.41 to 9.10%. Conclusions. The percutaneous absorption of ketoprofen was similar when applied to either the back or arm but was lower when applied to the knee.
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    Fluconazole Distribution to the Brain: A Crossover Study in Freely-moving Rats Using In Vivo Microdialysis (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1570-1575 
    Details
    ISSN: 1573-904X
    Keywords: microdialysis ; fluconazole ; pharmacokinetics ; brain distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to determine if the microdialysis sampling technique is feasible to study the central nervous system distributional kinetics of a novel triazole antifungal agent, fluconazole, in an awake, freely-moving rat model, and to determine fluconazole distribution to the extracellular fluid (ECF) of the brain. Methods. The relative recovery of the microdialysis probes (CMA-12) was determined in vitro and in vivo by retrodialysis using UK-54,373, a fluorinated analog of fluconazole. Sprague-Dawley rats received 10 mg/kg and 20 mg/kg fluconazole IV bolus doses in a crossover design, and brain extracellular fluid fluconazole concentrations were monitored using microdialysis and on-line HPLC analysis. The plasma fluconazole concentration vs. time data were determined using sequential blood sampling and HPLC analysis. Results. There was no statistical difference between relative probe recoveries for both fluconazole and UK-54,373, either in vitro or in vivo, and probe recoveries did not change during the course of the in vivo crossover experiment. Fluconazole rapidly distributes into in the brain ECF and the average brain distribution coefficient (brain/plasma AUC ratio) was 0.60 ± 0.18 and was independent of dose. Plasma pharmacokinetic parameters were linear in the dose range studied. Conclusions. Fluconazole rapidly reaches a distributional equilibrium between brain extracellular fluid and plasma, and the distribution to the brain is substantial and not dependent on dose over a two-fold range. Furthermore, the results indicate that microdialysis utilizing UK-54,373 as the in vivo retrodialysis probe calibrator is a feasible method to study the transport of fluconazole into the central nervous system.
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    URL: http://dx.doi.org/10.1023/A:1016048100712
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    Enhanced Tumor Delivery and Antitumor Activity of Palmitoyl Rhizoxin Using Stable Lipid Emulsions in Mice (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 305-310 
    Details
    ISSN: 1573-904X
    Keywords: RS-1541(palmitoyl rhizoxin) ; emulsions ; pharmacokinetics ; toxicity ; antitumor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A highly lipophilic antitumor agent, 13-O-palmitoyl-rhizoxin (RS-1541), was incorporated into lipid emulsions of various sizes consisting of triglyceride ODO and surfactant HCO-60. Pharmacokinetics, toxicities, and antitumor activities were evaluated after intravenous administration to mice bearing subcutaneously inoculated M5076 sarcoma cells. Methods. The levels of RS-1541 in the plasma and tissues including tumor, were determined by HPLC. The maximum tolerated dose (MTD) was estimated by toxic death and change in body weight. The decrease in tumor diameter was measured for antitumor activity. Results. There existed large variations in pharmacokinetics of RS-1541, depending on the size of emulsion particles. Compared with a colloidal solution (reference solution), the small (110nm) and medium (230nm) size emulsions showed high concentrations of RS-1541 in the tumor, while the large emulsions (350nm–630nm) exhibited low concentrations. The MTD of RS-1541 was reduced, when incorporated in the emulsions larger than 220nm in size. At MTD, each size of emulsions (70nm–380nm) effectively retarded the tumor growth and increased survival time. The maximum effect was achieved for the 220 nm emulsions. Conclusions. When particle size is properly selected, these emulsions could be promising and effective as an injectable carrier for lipophilic antitumor agents in order to enhance the tumor delivery and efficacies while reducing toxicities.
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    URL: http://dx.doi.org/10.1023/A:1016063719541
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    A Fractal Approach to Heterogeneous Drug Distribution: Calcium Pharmacokinetics (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 663-670 
    Details
    ISSN: 1573-904X
    Keywords: fractal ; fractal kinetics ; calcium kinetics ; heterogeneity ; drug distribution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To point out the importance of heterogeneity in drug distribution processes and develop a noncompartmental approach for the description of the distribution of drug in the body. Methods. A dichotomous branching network of vessels for the arterial tree connected to a similar venous network was used to describe the heterogeneity of blood flow in the successive generations of the networks. The relevant kinetics of drug distribution in the well perfused and the deep tissues was considered to take place under well stirred (homogeneous) and understirred (heterogeneous) conditions, respectively. Results. A “homogeneous model” with classical kinetics (which is mathematically equivalent with the one-compartment model) was developed for these drugs which are confined to well perfused (“well stirred”) spaces. A “heterogeneous model” was proposed for the drugs reaching understirred spaces using a decreasing with time rate coefficient (fractal kinetics) to model the diffusion of drug under heterogeneous conditions. The analysis of the model equations revealed that the homogeneous model can be considered as a special case of the heterogeneous model. Concentration-time plots of multiexponential type were generated using the heterogeneous model equation. The empirically used power functions of time for the analysis of calcium clearance curves, were found to be similar to the equation adhering to the heterogeneous model. Fittings comparable to multiexponential models were obtained when the heterogeneous model equation with only one adjustable parameter was applied to six sets of long period calcium data. Conclusions. The heterogeneous processes of drug distribution in the body can obey the principles of fractal kinetics. Calcium clearance curves were analysed with the heterogeneous model. The validity of multicompartmental models which are based on the concept of homogeneity to describe drug distribution should be reconsidered.
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    URL: http://dx.doi.org/10.1023/A:1016031129053
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    In Vivo ESR Studies on Pharmacokinetics and Metabolism of Parenteral Lipid Emulsion in Living Mice (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 729-733 
    Details
    ISSN: 1573-904X
    Keywords: in vivo ESR ; spin-label ; lipid emulsion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. We applied non-invasive and real-time method with in vivo ESR spectroscopy to determining pharmacokinetics and metabolism of lipid emulsion as a drug carrier in living mice. Methods. A spin-labeled triglyceride (SL-TG) was newly synthesized and lipid emulsion containing SL-TG was prepared. In vivo ESR spectra in mice were observed after intravenous administration of the lipid emulsion. Results. In vivo ESR spectra consisted of three components, coinciding with the in vitro spectra of SL-TG particles, free and immobilized fatty acids. The amount of the components depended on both the observing domain and the period after administration. In the chest, all three components were observed, while SL-TG particle was lacking in the abdomen. The half-life of the lipid particles in the chest was 2 hr. Conclusions. Non-invasive and real-time analysis of drug carriers in living animal is successfully accomplished using an in vivo ESR method.
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    URL: http://dx.doi.org/10.1023/A:1016047532687
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    Species Difference in the Disposition of Liposomes Among Mice, Rats, and Rabbits: Allometric Relationship and Species Dependent Hepatic Uptake Mechanism (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1049-1054 
    Details
    ISSN: 1573-904X
    Keywords: liposome ; species difference ; pharmacokinetics ; drug delivery system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The species difference in the pharmacokinetics of liposomes was investigated in mice, rats and rabbits. Methods. Liposomes were intravenously injected at doses of 1, 10 and 100 (nmol/g body weight), and the time courses of liposomes in blood, liver and spleen were measured. Pharmacokinetic parameters were regressed as a function of body weight (BW) and dose of liposomes (D). The uptake mechanism of liposomes was also examined with the isolated perfused liver between rats and mice. Results. Mean residence time increased with the increase of BW and D of liposomes. This increase of mean residence time resulted from the decreased total body clearance, which was principally explained by the species difference in the hepatic uptake clearance (CLh) of liposomes. The parameter CLh was regressed well by a multiple regression as a function of BW and D. In this analysis, an exponent for BW was around 0.5, which clearly indicates that smaller animals have higher uptake clearance per unit BW. Immunohistochemical analysis revealed that there was no significant difference in the density of Kupffer cells among these species. This suggest that the species difference in CLh resulted not from the density of Kupffer cells but from the uptake ability of Kupffer cells amoung species. In the isolated perfused liver, the hepatic uptake of liposomes was mainly explained by opsonin dependent uptake in rats, while opsonin independent uptake in mice. Conclusions. These quantitative and qualitative information on the species difference of liposome disposition will provide an useful information for constructing a drug delivery system using liposomes.
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    URL: http://dx.doi.org/10.1023/A:1016058724452
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    Bioequivalence of a Highly Variable Drug: An Experience with Nadolol (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1109-1115 
    Details
    ISSN: 1573-904X
    Keywords: nadolol ; pharmacokinetics ; bioequivalence ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard® 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC∞, and Cmax in bioequivalence determinations. Methods. Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax. Results. Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUCt and AUC∞. However, Cmax criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. Conclusions. Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the Cmax of nadolol is only slightly sensitive to absorption rate and the relatively large variability of Cmax reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.
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    URL: http://dx.doi.org/10.1023/A:1016031313065
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    Characterization of AUCs from Sparsely Sampled Populations in Toxicology Studies (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1283-1290 
    Details
    ISSN: 1573-904X
    Keywords: toxicokinetics ; sparse sampling ; pharmacokinetics ; toxicology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this work was to develop and validate blood sampling schemes for accurate AUC determination from a few samples (sparse sampling). This will enable AUC determination directly in toxicology studies, without the need to utilize a large number of animals. Methods. Sparse sampling schemes were developed using plasma concentration-time (Cp-t) data in rats from toxicokinetic (TK) studies with the antiepileptic felbamate (F) and the antihistamine loratadine (L); Cp-t data at 13–16 time-points (N = 4 or 5 rats/time-point) were available for F, L and its active circulating metabolite descarboethoxyloratadine (DCL). AUCs were determined using the full profile and from 5 investigator designated time-points termed “critical” time-points. Using the bootstrap (re-sampling) technique, 1000 AUCs were computed by sampling (N = 2 rats/point, with replacement) from the 4 or 5 rats at each “critical” point. The data were subsequently modeled using PCNONLIN, and the parameters (ka, ke, and Vd) were perturbed by different degrees to simulate pharmacokinetic (PK) changes that may occur during a toxicology study due to enzyme induction/inhibition, etc. Finally, Monte Carlo simulations were performed with random noise (10 to 40%) applied to Cp-t and/or PK parameters to examine its impact on AUCs from sparse sampling. Results. The 5 time-points with 2 rats/point accurately and precisely estimated the AUC for F, L and DCL; the deviation from the full profile was ~10%, with a precision (%CV) of ~15%. Further, altered kinetics and random noise had minimal impact on AUCs from sparse sampling. Conclusions. Sparse sampling can accurately estimate AUCs and can be implemented in rodent toxicology studies to significantly reduce the number of animals for TK evaluations. The same principle is applicable to sparse sampling designs in other species used in safety assessments.
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    URL: http://dx.doi.org/10.1023/A:1016097227603
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    Comparison of Pharmacokinetic Parameters of a Polypeptide, the Bowman-Birk Protease Inhibitor (BBI), and Its Palmitic Acid Conjugate (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1373-1377 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; polypeptide ; BBI ; palmitic acid ; conjugation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The alteration of the pharmacokinetic parameters of the poly-peptide BBI through conjugation with palmitic acid was examined. Methods. 125I-BBI or l25I-Pal-BBI was administered iv to 6 week old CF-1 mice at a dose of 3mg/kg. The mice were sacrificed at 5, 10, 20, 60, 120, 240, 360, and 480 min and the total radioactivity was determined for blood and each organ. The blood was analyzed on a Sephadex G-50 size-exclusion column to determine the amount of intact polypeptide present in the blood. From the amount of intact polypeptide at each time point, the pharmacokinetic parameters were determined. Results. By conjugating three palmitic acids to each BBI molecule, the area under the curve (AUC) and mean residence time (MRT) increase by a factor of 10.8 and 2.8, respectively. There was also a difference in the organ distribution between the two treatments; while 125I-BBI was rapidly cleared from the kidneys, l25I-Pal-BBI was predominantly to the liver. Subsequent studies suggested that the binding of the conjugate to non-albumin serum proteins was most likely the cause of the altered pharmacokinetics. Conclusions. The residence time in the blood and the lipophilicity of BBI were increased upon conjugation with palmitic acid through a reversible disulfide linkage. Pharmacokinetic studies showed an increase in the AUC and a decrease in kidney clearance in palmitic acid conjugates, indicating a potential increase of the therapeutic efficacy of the polypeptide drug.
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    URL: http://dx.doi.org/10.1023/A:1016078118033
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    Intravenous Microdialysis in the Mouse and the Rat: Development and Pharmacokinetic Application of a New Probe (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 12-17 
    Details
    ISSN: 1573-904X
    Keywords: intravenous microdialysis sampling ; flurbiprofen ; pharmacokinetics ; rat ; mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A flexible microdialysis probe was designed for intravenous sampling in small laboratory animals. Methods. Surgical techniques were developed to implant this probe via the femoral vein in the vena cava of the mouse and the rat. The in- and outlet of the probe were exteriorized above the tail of the animal and were directly connected to the microsyringe pump for perfusate delivery and to the injection valve for on-line HPLC analysis of the microdialysate samples. Results. The in vitro recoveries of flurbiprofen and naproxen for these probes were 68.2 ± 6.9% (mean ± S.D., n= 12) and 66.5 ± 7.3%, respectively. The relative loss by in vivo retrodialysis, measured the day after the implantation of the probes, was 66.1 ± 8.8% for flurbiprofen and 60.9 ± 9.9% for naproxen. The pharmacokinetics of unbound flurbiprofen were studied following i.v. bolus administration of flurbiprofen to the mouse (n = 4) and the rat (n = 6) with on-line HPLC analysis of microdialysates every 10 minutes during 6 to 8 hours. Flurbiprofen microdialysate concentrations were converted to unbound concentrations using the in vivo loss of flurbiprofen by retrodialysis carried out just before the start of the pharmacokinetic experiment. The integrity of the probe throughout the experiment was monitored by continuous retrodialysis of naproxen. Conclusions. The developed techniques can be used to carry out routine pharmacokinetic studies in the mouse and the rat as illustrated by our experiments with flurbiprofen, a compound with very high plasma protein binding.
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    URL: http://dx.doi.org/10.1023/A:1016056628685
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    Pharmacokinetics and Biodistribution of Oligonucleotide Adsorbed onto Poly(isobutylcyanoacrylate) Nanoparticles After Intravenous Administration in Mice (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 38-43 
    Details
    ISSN: 1573-904X
    Keywords: oligonucleotides ; nanoparticles ; pharmacokinetics ; poly(isobutylcyanoacrylate) ; tissue distribution ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The goal of this study was to evaluate the ability of nanoparticles to be used as a targeted delivery system for oligonucleotides. Methods. Pharmacokinetic and tissue distribution were carried out in mice by measuring the radioactivity associated to the model oligothymidylate 33P-pdT16 loaded to poly(isobutylcyanoacryrate) (PIBCA) nanoparticles. In addition, we have used a TLC linear analyzer to measure quantitatively on a polyacrylamide gel electrophoresis, the amount of non degraded pdT16 Results. Organ distribution study has shown that nanoparticles deliver 33P-pdT16 specifically to the liver reducing its distribution in the kidney and in the bone marrow. Nanoparticles could partially protect pdT16 against degradation in the plasma and in the liver 5 min after administration, whereas free oligonucleotide was totally degraded at the same time. Conclusions. Nanoparticles protect oligonucleotides in vivo against degradation and deliver them to the liver.
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    URL: http://dx.doi.org/10.1023/A:1016017014573
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    Liposomal Methylprednisolone in Rats: Dose-Proportionality and Chronic-Dose Pharmacokinetics/Pharmacodynamics (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 141-145 
    Details
    ISSN: 1573-904X
    Keywords: liposomes ; methylprednisolone ; pharmacokinetics ; dose dependence ; multiple doses ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Methylprednisolone (MPL) encapsulated in liposomes (L-MPL) targets the immune system and enhances immunosuppressive activity of the steroid. We performed dose-dependent and chronic dose studies of L-MPL versus MPL. Methods. Male Lewis rats received 10 mg/kg IV bolus doses of L-MPL (Solu-Medrol). Plasma samples were obtained over an 8 day period and MPL concentrations were assayed by HPLC. Immunosuppressive effects were measured as inhibition of ex vivo splenocyte proliferation induced with PHA. Results. Drug concentrations declined in a similar manner over the first few hours following MPL or L-MPL. Free MPL was cleared from plasma by 6 hr, while the same dose of L-MPL resulted in persistance over an 8-day period. Dose-dependent changes in pharmacokinetic parameters were observed for both free and liposomal drug. Increasing the dose from 2 to 10 mg/kg led to increased clearance from 5.9 to 10.5 (MPL) and from 1.8 to 2.3 L/hr/kg (L-MPL). Blastogenesis was suppressed over 5 days with return to the baseline at day 8 (L-MPL); free MPL produced immunosuppression only over 10 hr. Multiple 2 mg/kg IV doses of L-MPL versus MPL twice a week produce plasma drug profiles similar to those obtained after single doses, indicating that neither free nor liposomal steroid accumulates in tissues. Liposomes without drug simultaneously administered with MPL caused partial prolongation of plasma steroid half-life (8.4 hr). Conclusions. These studies clarify factors causing prolonged drug persistence and immunosuppression with L-MPL. Nonlinear disposition, irregular pharmacokinetics, and secondary effects of the liposomes are complicating factors in use of L-MPL.
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    URL: http://dx.doi.org/10.1023/A:1016054022750
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    Design of Biological Equivalence Programs for Therapeutic Biotechnology Products in Clinical Development: A Perspective (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1427-1437 
    Details
    ISSN: 1573-904X
    Keywords: bioequivalence ; biotechnology products ; recombinant proteins ; pharmacokinetics ; pharmacodynamics ; efficacy ; immunogenicity ; safety
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The determination of biological equivalence requires that studies are conducted to establish that two molecules, two formulations, or two dosing regimens, for example, are indistinguishable with respect to safety and efficacy profiles that have been previously established. The criteria that are used to establish biological equivalence will depend on the nature of the change (e.g., molecular, process, formulation), the stage of the development program, the duration of treatment, and the intended clinical indications. Key components of an equivalence program include chemical characterization, in vitro and in vivo bioactivity against reference material, pharmacokinetics, and safety. Special considerations for patient populations, endogenous concentrations, environmental factors, immunogenicity, assay methodology, biochemical identity, pharmacodynamic equivalence, and statistical methodology are discussed. In addition, the role of preclinical in vivo assessments is addressed. Specific case studies provide insight into the varied nature of approaches that are currently employed.
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    Pharmacokinetic Analysis of Drug Disposition After Intratumoral Injection in a Tissue-Isolated Tumor Perfusion System (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1438-1444 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; tissue-isolated tumor ; intratumoral injection ; drug disposition ; perfusion experiment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to establish an experimental system for evaluation of the intratumoral behavior of drugs after intratumoral injection using perfused tissue-isolated tumor preparations of Walker 256 carcinoma (3.46–9.73g, n = 16). Methods. We quantified the recovery of Phenol Red (model drug) in the tumor, leakage from the tumor surface and the venous outflow after intratumoral injection using perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model in which the tumor tissue was assumed to be divided into two compartments, i.e., well- and poorly-perfused regions. Results. In small tumors (Type 1, 5.42 ± 0.39 g), the drug appeared immediately in the venous outflow, and the amount remaining in the tumor tissue at 2 hr after injection was small. In contrast, the venous appearance rate reached a significantly lower peak a few minutes after injection, and a large amount of injected drug remained in some large tumors (Type 2, 8.17 ± 0.51 g). Pharmacokinetic analysis revealed that there was a correlation between tumor weight and the rate constants of transfer from the poorly-perfused region to the well-perfused region, and between the rate constants of transfer from the well-perfused region to the venous outflow and dosing ratios into the well-perfused region. Conclusions. An experimental system and analytical method were established for the evaluation of the intratumoral behavior of drugs after intratumoral injection using a tissue-isolated tumor perfusion system. This experimental system will be useful in analyzing the antitumor drug disposition after intratumoral injection.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016054807555
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    Absorption and Presystemic Metabolism of Selegiline Hydrochloride at Different Regions in the Gastrointestinal Tract in Healthy Males (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1535-1540 
    Details
    ISSN: 1573-904X
    Keywords: selegiline ; site-specific ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability. Methods. An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS. Results. Selegiline exposure was greatest following administration to the stomach (~150% 〉 duodenum or jejunum) and least in the terminal ileum (~33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (~18%) at the terminal ileum. Conclusions. The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.
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    URL: http://dx.doi.org/10.1023/A:1016035730754
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    A Novel Extravascular Input Function for the Assessment of Drug Absorption in Bioavailability Studies (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1547-1553 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; input model ; bioavailability ; absorption rate ; extended release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Flexible parametric models describing the input process after extravascular drug administration are needed for the assessment of absorption rate and the use of population methods in bioavailability and bioequivalence studies. Methods. The oral concentration-time curve modeled as the product of the input and disposition function in the Laplace domain was obtained by numerical inversion methods for parameter estimation. The utility of the inverse Gaussian input density was examined using bioavailability data of an extended-release dosage form. Measures of rate of absorption and the cumulative absorbed amount profile were defined in terms of the estimated model parameters. Results. Accurate estimation of absorption parameters was achieved by simultaneous fitting of the extravascular and intravascular data (describing the latter by a triexponential function). The new input function allowed a direct estimation of both extent of absorption and mean absorption time. Conclusions. The findings suggest that the inverse Gaussian density is a useful input function. Its flexibility may reduce the effect of model misspecification in parameter estimation. All parameters can be readily interpreted in terms of the absorption process.
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    URL: http://dx.doi.org/10.1023/A:1016039931663
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    Uptake Is the Rate-limiting Step in the Overall Hepatic Elimination of Pravastatin at Steady-state in Rats (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1559-1564 
    Details
    ISSN: 1573-904X
    Keywords: carrier-mediated active transport ; well-stirred model ; parallel-tube model ; dispersion model ; nonlinearity ; pharmacokinetics ; tissue-distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Of the HMG-CoA reductase inhibitors, the hydrophilic pravastatin has been shown to exhibit relatively specific inhibition of cholesterol synthesis in the liver. As one of the reasons for this relatively specific pharmacological activity, we demonstrated that the tissue distribution of pravastatin is limited because of its high hydrophilicity, while hepatic uptake by active transport takes place at the liver surface via a multispecific anion transporter (M. Yamazaki et al., Am. J. Physiol., 264, G36-44, 1993). In this study, we examined the hepatic elimination of pravastatin at steady-state. Methods. After i.v. infusion, the plasma concentrations of pravastatin in both arterial and hepatic venous blood were measured. Results. The hepatic availability at steady-state exhibited a clear increase on increasing the infusion rate of pravastatin. The total hepatic elimination rate at steady-state exhibited Michaelis-Menten type saturation with the drug concentration in the capillary defined by typical mathematical models (i.e., well-stirred, parallel-tube and dispersion models), Km and Vmax values being comparable with those obtained from analysis of the initial uptake velocity using in vitro isolated hepatocytes. Conclusions. These results indicate that overall hepatic intrinsic clearance of pravastatin at steady-state is regulated by the uptake process, followed by rapid metabolism and/or biliary excretion with minimal efflux to the circulating blood.
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    URL: http://dx.doi.org/10.1023/A:1016044032571
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    Pharmacokinetic Analysis and Antiepileptic Activity of Tetra-Methylcyclopropane Analogues of Valpromide (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 284-289 
    Details
    ISSN: 1573-904X
    Keywords: valproic acid ; valpromide ; tetramethylcyclopropane derivatives ; pharmacokinetics ; antiepileptic activity ; structural requirements
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the β position to the carbonyl, such as in the case of TMCD, or a substitution in the α and in the β positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.
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    URL: http://dx.doi.org/10.1023/A:1016055517724
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    Disposition Characteristics of Plasmid DNA in the Single-pass Rat Liver Perfusion System (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 599-603 
    Details
    ISSN: 1573-904X
    Keywords: plasmid DNA ; liver perfusion ; pharmacokinetics ; gene therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To define the hepatic uptake mechanism of a plasmid DNA, we quantitated the uptake of pCAT (plasmid DNA encoding chloramphenicol acetyltransferase reporter gene fused to simian virus 40 promoter), a model plasmid, after a single pass through the perfused rat liver using albumin- and erythrocyte-free Krebs-Ringer bicarbonate buffer (pH 7.4). Methods. [32P]pCAT was introduced momentarily into this system from the portal vein as a bolus input or constant infusion mode, and the outflow patterns and hepatic uptake were evaluated using statistical moment analysis. Results. The venous outflow samples had electrophoretic bands similar to that of the standard pCAT, suggesting that the plasmid is fairly stable in the perfusate during liver perfusion. In bolus experiments, pCAT was largely taken up by the liver and the uptake was decreased with increase in injected dose. Statistical moment analysis against outflow patterns demonstrated that the apparent volume of distribution of pCAT was greater than that of human serum albumin, indicating a significant reversible interaction with the tissues. The results of collagenase perfusion experiments suggest that the hepatic accumulation of pCAT occurred preferentially in the nonparenchymal cells (NPC). The amount of total recovery in the liver decreased substantially by preceding administration of polyinosinic acid, dextran sulfate, succinylated bovine serum albumin, but not by polycytidylic acid. This suggests that pC AT is taken up by the liver via scavenger receptors for polyanions on the NPC. In constant infusion experiments, the presence of 2,4-dinitrophenol and NH4C1 caused a significant increase in the outflow concentration of [32P]pCAT and decrease by half in the total hepatic recovery than that of plasmid DNA administered alone, suggesting that plasmid DNA may undergo internalization by the NPC. Conclusions. The liver plays an important role in the elimination of plasmid DNA and a successful delivery system will be required to avoid its recognition by the scavenger receptors on the liver NPC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016058407671
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    The Effect of Probenecid on the Pharmacokinetics of Zalcitabine in HIV-Positive Patients (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 449-452 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; zalcitabine ; probenecid ; interaction ; HIV-infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to determine the potential effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients. Methods. Twelve patients received single oral 1.5 mg doses of zalcitabine alone and during probenecid treatment (500 mg at 8 and 2 hours before and 4 hours after zalcitabine dosing) in an open-label, randomized two-way crossover study with a one-week washout period between treatments. Serial blood and urine samples were collected over a 24 hour period and assayed for zalcitabine by a modified GC/MS method. Results. Coadministration of probenecid with zalcitabine resulted in a decrease in mean (%CV) renal clearance of zalcitabine from 310 (28%) ml/min when zalcitabine was given alone to 180 (22%) ml/min with probenecid and a prolonged half-life from 1.7 hours to 2.5 hours. Mean AUCs increased from 59 ng·h/ml when zalcitabine was given alone to 91 ng·h/ml when given with probenecid. Considering the short half-life of zalcitabine (1–3 hours) relative to its dosing schedule, the pharmacokinetic changes observed in this study are not expected to result in significant accumulation during chronic dosing. Conclusions. The results of this study show that co-administration of probenecid with zalcitabine results in a moderate decrease in renal clearance of zalcitabine due to inhibition of renal tubular secretion and a 50% increase in drug exposure. Although well tolerated in this single-dose study, patients taking this combination should be monitored closely for signs of toxicity and dosage reduction should be considered if warranted.
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    URL: http://dx.doi.org/10.1023/A:1016009029536
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    Pharmacokinetics, Bioavailability, and Safety of Montelukast Sodium (MK-0476) in Healthy Males and Females (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 445-448 
    Details
    ISSN: 1573-904X
    Keywords: montelukast sodium ; Singulair™ ; MK-0476 ; pharmacokinetics ; bioavailability ; gender effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The safety, tolerability, and pharmacokinetics of intravenous (i.v.) montelukast sodium (Singulair™, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied. Methods. This was a two-part study. Part I was a four-period study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant-rate i.v. infusions (Periods 1–3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively) or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC. Results. In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg, the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity (AUC) increased proportionately. The mean values of plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/12), and mean residence time in the body (MRTi.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg tablet of montelukast sodium, the AUC, maximum plasma concentration (Cmax), time when Cmax occurred (Tmax), apparent t1/12, mean absorption time (MAT), and bioavailability (F) of montelukast sodium averaged 2441 ng · hr/ml, 385 ng/ml, 3.7 hr, 4.9 hr, 3.4 hr, and 66%, respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the values of CL, Vss, t1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively. Following oral administration of a 10-mg tablet to females, the mean AUC, Cmax, Tmax, apparent t1/2, MAT and F were 2270 ng·hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These parameter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses. Conclusions. The disposition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated.
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    URL: http://dx.doi.org/10.1023/A:1016056912698
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