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  • Digitale Medien  (172)
  • 1980-1984  (172)
  • 1982  (172)
  • Gas chromatography  (98)
  • pharmacokinetics
  • Nuclear reactions
Materialart
  • Digitale Medien  (172)
Erscheinungszeitraum
  • 1980-1984  (172)
Jahr
  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Psychopharmacology 78 (1982), S. 170-175 
    ISSN: 1432-2072
    Schlagwort(e): Acetylcholine ; Choline ; Soman ; Organophosphate ; Anticholinesterase ; Toxicity ; Lethality ; CNS ; Brain areas ; Rats ; Gas chromatography ; Mass spectrometry ; Time course ; Cholinergic function
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The time course of changes in rat brain levels of acetylcholine (ACh) and choline (Ch) was investigated following a single SC injection of soman (0.9 LD50, 120 μg/kg) to understand the relationship between central neurotransmitter alteration and soman toxicity. Of the animals exposed to the dose of soman, 46% died within 24 h, with maximum mortality occurring during the first 40 min following soman administration. In a second group, surviving rats were killed at various times after treatment by a beam of focused microwave radiation to the head, and ACh and Ch levels were determined by gas chromatography-mass spectrometry. Soman produced a maximal ACh elevation in the brain stem at 20 min (34.4%), in cerebellum at 40 min (51.9%), in cortex and striatum at 2 h (320.3% and 35.2%, respectively), and in hippocampus and midbrain at 3 h (94.5% and 56.8%, respectively). ACh levels remained above normal approximately 30 min in the brain stem; 2 h in the midbrain, cerebellum, and striatum; 8 h in the cortex; and 16 h in the hippocampus. Ch levels were elevated in all areas except the striatum. Ch maxima occurred at 10–40 min and returned to control levels approximately 3 h after injection. Results suggest that perturbation of ACh levels due to soman was not uniform throughout the brain and that soman toxicity may reflect ACh changes in multiple areas, rather than changes in any given area. These data further suggest a possible relationship between elevated Ch levels and soman toxicity.
    Materialart: Digitale Medien
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  • 2
    Digitale Medien
    Digitale Medien
    Springer
    Research in experimental medicine 181 (1982), S. 19-25 
    ISSN: 1433-8580
    Schlagwort(e): Gas chromatography ; Serum level ; Azathioprine ; 6-Mercaptopurine ; Immunosuppression
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The knowledge of serum levels of azathioprine or its metabolite 6-mercaptopurine is important for the monitoring of the immunosuppressive therapy after kidney transplantation, especially when kidney function is low. For this reason, the work of Bailey et al. was modified. 6-Mercaptopurine was extracted from the serum with a mixture of isopropanol-ethylacetate (1:1 v:v), derivatized with trimethylaniliniumhydroxyde and measured gaschromatographically. Sulfhydryl-protecting reagents were added to prevent loss of substance. Oxyethyltheophylline was used as the internal standard. The extraction and clean-up method recovered 80% of the 6-mercaptopurine present, the lower limit of sensitivity was 20 ng/ml, i.e., ten times lower than that of Bailey et al. The method could be realized on eight patients treated with azathioprine, the half life of the drug was about 20–40 min within the first hour after i.v. application.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1432-0428
    Schlagwort(e): Glibenclamide ; pharmacokinetics ; high performance liquid chromatography ; plasma insulin ; blood glucose
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary A simple high performance liquid Chromatographic assay for the determination of plasma glibenclamide concentrations is described. This resolved glibenclamide from normal plasma constituents. The calibration curve of the assay was linear over the range 10–500 μg/1 and the minimum level of detection was 2 μg/1. Within-assay coefficients of variation were 11.6% (20 μg/1); 5.3% (50 μg/1); 6.8% (100 μg/1); between-assay coefficients of variation were 8.4% (20 μg/1); 4.7% (50 μg/1) and 7.4% (100 μg/1). The assay was used to study the pharmacokinetics of a 1 mg intravenous dose of glibenclamide in eight normal subjects. The mean half-life was found to be 1.47±0.42 h (SD) and no evidence for a non-linear β-phase or slowly equilibrating ‘deep’ compartment was found although this could not be rigorously excluded. The mean systemic drug clearance was 78±29 ml·h-1·kg-1 and the apparent volume of distribution in the β-phase was 155±44 ml/kg. The median time of maximum response of plasma immunoreactive insulin was 25 min and the median time of maximum blood glucose response was 53 min. No correlation could be found between the pharmacokinetics of glibenclamide and these responses in fasted normal individuals.
    Materialart: Digitale Medien
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  • 4
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 321 (1982), S. 293-297 
    ISSN: 1432-1912
    Schlagwort(e): Alcoholism ; Cerebrospinal fluid ; Ethanol ingestion ; Gas chromatography ; Mass spectrometry ; 5-Hydroxytryptophol ; Urine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The serotonin metabolite 5-hydroxytryptophol was determined in cerebrospinal fluid and urine of alcoholics and healthy subjects, by a glass capillary gas chromatographic-mass spectrometric method. The urinary excretion rate (14.6±2.9 pmoles/μmoles creatinine) and urine (109±20 pmoles/ml) and cerebrospinal fluid (4.12±0.21 pmoles/ml) concentrations in healthy subjects were established. Only 1% of the 5-hydroxytryptophol in urine occurred in free form. Ethanol ingestion (80, 120 g) by healthy subjects lead to a 20–100-fold increase in the urinary excretion rate of 5-hydroxytryptophol. In cerebrospinal fluid the increase was about 60%. Alcoholics had increased urinary excretion rates and cerebrospinal fluid levels during intoxication, which were in the same range as in intoxicated healthy subjects. During recovery from intoxication, the 5-hydroxytryptophol level in alcoholics decreased, but the CSF levels were still higher than in healthy subjects.
    Materialart: Digitale Medien
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  • 5
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 287-291 
    ISSN: 1432-1041
    Schlagwort(e): tolmesoxide ; hypertension ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Tolmesoxide is a new, direct-acting vasodilator drug for use in the management of both hypertension and cardiac failure. In 6 essential hypertensives inadequately controlled by combined β-blocker and diuretic therapy (average supine blood pressure 178/103 mm Hg) the addition of tolmesoxide (300–900 mg daily) was associated with a significant improvement in blood pressure control (average supine blood pressure 161/89 mmHg). The effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide have also been studied because, particularly at higher doses, the drug has been associated with upper gastrointestinal upset and it has been empirically recommended that it be taken with food. The blood pressure and heart rate responses were not significantly different when tolmesoxide was taken fasting or with food. Food resulted in a significant reduction in the peak plasma tolmesoxide concentration (2.14 µg/ml compared to 2.97 µg/ml) and a significant increase in the time to reach peak plasma concentration (1.67 h compared to 0.63 h). Although there was no impairment of its hypotensive effect, food significantly altered the pharmacokinetics of tolmesoxide and may therefore be useful in reducing the gastrointestinal disturbance associated with its use. In the treatment of inadequately controlled hypertension, tolmesoxide has a limited role as an alternative vasodilator.
    Materialart: Digitale Medien
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  • 6
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 307-310 
    ISSN: 1432-1041
    Schlagwort(e): piretanide ; renal failure ; high dose ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The kinetics of piretanide was studied in patients with renal failure. After oral administration of a high dose of piretanide (96 mg), the pharmacokinetic parameters were: elimination rate constant 0.346±0.072 h−1, half life 2.00±0.35 h, and total plasma clearance 119.55±35.90 ml · min−1. Compared to the values obtained in adults with normal renal function, these results show a decrease in total plasma clearance, but conservation of the metabolic clearance which amounts to 45% of the total clearance in the healthy adult.
    Materialart: Digitale Medien
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  • 7
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 397-402 
    ISSN: 1432-1041
    Schlagwort(e): ergotamine ; migraine ; radioimmunoassay ; clinical effects ; adverse effects ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The systemic availability of ergotamine after a single therapeutic oral or rectal dose was studied using a radioimmunoassay during the headachefree state in 24 patients suffering from migraine. Plasma concentrations of the drug were compared with anamnestic data about its clinical effects in the same patients. Among 12 patients with a good therapeutic response to medication, the mean plasma ergotamine levels stayed in the range 0.20 to 0.50 ng/ml for 6h. Their mean plasma levels at 30 min (0.33ng/ml) and 1h (0.40ng/ml) were significantly higher than those (0.06 and 0.08ng/ml, respectively) in 9 patients with only a moderate therapeutic response. In 9 patients with a moderate and 3 with a poor therapeutic response, the mean plasma level generally stayed below 0.10ng/ml. The mean peak concentrations in moderate (0.13 ng/ml) and poor (0.11ng/ml) responders appeared later (at 3h) than in good responders (at 1h). Side effects of the medication appeared to be associated with relatively low plasma levels of ergotamine and also with delayed maximum plasma concentrations of the drug. The present results suggest that the time of the maximum plasma drug level is an important determinant of the clinical effects of ergotamine, and that a good therapeutic response may be expected if a plasma ergotamine level of 0.20ng/ml or more is achieved within 1 hour after oral or rectal administration.
    Materialart: Digitale Medien
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  • 8
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 343-350 
    ISSN: 1432-1041
    Schlagwort(e): orphenadrine ; single dose ; multiple doses ; bioavailability ; pharmacokinetics ; N-demethylorphenadrine ; metabolism ; dog ; man
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Plasma concentrations of orphenadrine were measured by a specific gaschromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2–20.1 h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.
    Materialart: Digitale Medien
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  • 9
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 273-279 
    ISSN: 1432-1041
    Schlagwort(e): amoxycillin ; i.v. administration ; pharmacokinetics ; two- and three-compartment models
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetic characteristics of amoxycillin were studied in healthy volunteers after intravenous injection of 250 mg, 500 mg and 1,000 mg, and infusion of 2 g and 5 g. Serum concentrations were fitted using either bi- and tri- exponentional equations. Comparison of the regression curves obtained revealed that the three-compartment model gave a better fit to the serum concentration versus time curve. It was evident that there was a third, slow, dose dependent phase of disposition. This result has been confirmed by the fact that the terminal half life of amoxycillin on cessation of a continuous infusion is significantly greater than after acute administration.
    Materialart: Digitale Medien
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  • 10
    ISSN: 1432-1041
    Schlagwort(e): indapamide ; bioavailability ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Two formulations of indapamide tablets (2.5 mg) were given as a 5.0 mg dose and the subsequent blood levels were compared to those obtained after administration of a 5.0 mg solution. The study was conducted as a randomized three-way crossover design using healthy male volunteers. The drug was well tolerated by all the subjects involved. The area under the blood concentration versus time curve, extrapolated to infinity was essentially the same for all three formulations (4.2, 4.7, and 4.4 µg-h/ml). Statistical comparison of the blood levels from the two tablets showed that one tablet had a significantly greater maximum blood concentration (263 vs 231 ng/ml) and a significantly shorter time of maximum blood concentration (2.3 vs 3.5 h). Cmax (333 ng/ml) and tmax (0.7 h) values for the solution were significantly higher than either tablet. The average half-life (β-phase) for all three formulations was 15 h, while the average systemic clearance was 20 ml/min. Indapamide has a low clearance rate and there was no evidence that the drug undergoes a first-pass effect.
    Materialart: Digitale Medien
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  • 11
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 257-264 
    ISSN: 1432-1041
    Schlagwort(e): TRIS buffer ; metabolic acidosis ; pharmacokinetics ; cellular uptake ; renal excretion ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary To investigate the pharmacokinetics of TRIS, an infusion of the buffer was given to 6 healthy volunteers (121 mg/kg=1 mmol/kg; pH 7.4) and to 20 patients suffering from metabolic acidosis (109–376 mg/kg; pH 10.9). The drug exhibited two-compartment characteristics in volunteers (t0.5,β=5.6 h) and patients with intact renal function (t0.5,β=16.3–45.6 h). The final volume of distribution (Vβ) indicated uptake into tissues, but equilibration between body compartments was slow. Mainly unchanged TRIS was eliminated by the kidney; 82% of the administered dose was recovered from 24 h-urine of healthy subjects. In the patients a linear correlation between creatinine-clearance and TRIS-clearance was observed, the latter always being somewhat greater than the former. Only insignificant amounts of the drug were found in bile and gastric juice. In anuric patients the plasma concentration of TRIS declined monoexponentially, with a half-life between 10 and 58 h. Haemodialysis or haemofiltration did not influence this process. From the data it seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis, but the possibility of drug accumulation must be borne in mind if repeated doses are given to the same patient.
    Materialart: Digitale Medien
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  • 12
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 75-80 
    ISSN: 1432-1041
    Schlagwort(e): psoriasis ; 8-methoxypsoralen ; food influence ; suction blister fluid ; serum ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The influence of food on the kinetics of 8-methoxypsoralen (8-MOP) in serum and suction blister fluid was evaluated in a cross-over study in 19 psoriatic patients under PUVA treatment. The peak serum concentration of 8-MOP was reached 1.5 h after ingestion on an empty stomach, and in suction blister fluid the maximum concentration was already present in the first sample taken after 2 h, the time when UVA radiation was given. The postprandial kinetics of 8-MOP in serum and suction blister fluid differed, the highest levels being reached, respectively, at 2.4 and 3 h after intake, i.e. in both body fluids after irradiation had started. The side effects of 8-MOP, such as nausea and dizziness, in the two groups were similar. The present results indicate that to optimize the therapeutic effect of PUVA in individual patients, 8-MOP should be given on an empty stomach.
    Materialart: Digitale Medien
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  • 13
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 189-195 
    ISSN: 1432-1041
    Schlagwort(e): befunolol ; propranolol ; pharmacokinetics ; pharmacodynamic effects ; beta-adrenoceptor blocking agent
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Repeated doses of a new β-adrenoceptor blocking agent, befunolol, were administered orally to adult male volunteers for a cross-over comparison with propranolol. The β-adrenoceptor blocking activity of befunolol was greater than that of propranolol when assessed by the percentage reduction in exercise-induced tachycardia. The elimination half-life of drug was significantly prolonged on repeated administration of propranolol, but not of befunolol. The percentage reduction in exercise-induced tachycardia was highly correlated with the log plasma level of each drug. Both drugs produced a significant reduction in pre-exercise systolic and diastolic blood pressure, and significant attenuation of exercise-induced rise in systolic blood pressure.
    Materialart: Digitale Medien
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  • 14
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 235-240 
    ISSN: 1432-1041
    Schlagwort(e): ergotamine ; pharmacokinetics ; migraine ; plasma drug levels ; i.v. administration ; i.m. administration ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2–3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with an initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90–155 min). The mean total plasma clearance was 11.0 ml kg−1 min−1, and the volume of distribution (Vdβ ) was 1847.6 ml kg−1. Individual t1/2β showed a positive linear correlation with the individual Vdβ . The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3–60.8%).
    Materialart: Digitale Medien
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  • 15
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 327-330 
    ISSN: 1432-1041
    Schlagwort(e): bendroflumethiazide ; cantharides plasters ; blister fluid ; plasma levels ; pharmacokinetics ; compartmental analysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of bendroflumethiazide (BFT) was investigated following the oral administration of 10 mg to 3 healthy volunteers. Each subject participated twice in the study. BFT was determined in plasma and cantharides blister fluid from 1/2 to 30 h post administration. Blister fluid was obtained from blisters 10–22 h old. Plasma levels were fitted to a tri-exponential equation and the concentration of the drug in the peripheral compartment was calculated from the microscopic rate constants. In 5 of 6 cases investigated, cantharides blister fluid levels paralleled the concentration of the drug in the peripheral compartment. The mean blister fluid levels exceeded the calculated concentration in Compartment 2 1.46 fold. In one case, the blister fluid level paralleled the plasma level. This subject clearly differed from the others as more than 10 h were required for blister formation in her. The results suggest that following the administration of BFT, cantharides blister fluid behaves as part of the peripheral compartment. The possible value of studying blister fluid levels in pharmacokinetic investigations is discussed.
    Materialart: Digitale Medien
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  • 16
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 343-347 
    ISSN: 1432-1041
    Schlagwort(e): valproic acid ; fatty acids ; plasma protein binding ; pharmacokinetics ; drug metabolism
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37°C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34–182% (p〈0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50–87%,p〈0.01) than in fasting samples (10–50%,p〈0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (p〈0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.
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  • 17
    ISSN: 1432-1041
    Schlagwort(e): L-threo-3,4-dihydroxyphenylserine ; familial amyloid polyneuropathy ; pharmacokinetics ; norepinephrine ; pressor response
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of oralL-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) was studied in 7 normal subjects and 7 patients with familial amyloid polyneuropathy. Each person swallowed a single 300 mg dose in the fasting state, andL-threo-DOPS in plasma and urine was determined by high performance liquid chromatography with an electrochemical detector after separation on a boric acid gel column.L-threo-DOPS was slowly absorbed by normal subjects; the maximum plasma concentration occurred 3 h after administration and 20% of the oral dose was recovered unchanged in the urine within 12 h. It induced a substantial elevation of plasma norepinephrine levels, the peak being attained at 5 h, but without any change in blood pressure. In the patients, the absorption and metabolism ofL-threo-DOPS were delayed, and a prolonged pressor response was observed, with a peak after 8 h. It was concluded that the effects on plasma norepinephrine and blood pressure of oralL-threo-DOPS were essentially equal to those of twice as large a dose ofDl-threo-DOPS.
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  • 18
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 501-504 
    ISSN: 1432-1041
    Schlagwort(e): cimetidine ; uraemia ; dosing regimen ; prediction ; computer program ; old age ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Using a recently developed computer program based on a correlation between methods to predict the elimination half-life and apparent volume of distribution of cimetidine and actual data from patients, ideal dosage regimens were generated for patients with renal impairment and for geriatric patients, together with the corresponding maximum and minimum steady state concentrations. Using the ideal dosage regimens, practical regimens with feasible dosing intervals of 6, 8 and 12 h were computed, which should result in therapeutic concentrations of 0.4 to 1.3 µg/ml. For uraemic patients and geriatric patients above the age of 75 years it would be desirable to have an additional oral 100 mg dosage form.
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  • 19
    ISSN: 1432-1041
    Schlagwort(e): amitriptyline ; imipramine ; clomipramine ; antidepressant overdose ; clinical effects ; pharmacokinetics ; cardiotoxicity ; maprotiline ; doxepine ; nortriptyline ; opipramol
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24 h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 µg/l, with concentrations above 500 µg/l in 11 cases. The serum amitriptyline concentration remained high for 3–4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 µg/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidpressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60–500 µg/l) but not high (〉500 µg/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.
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  • 20
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 1-5 
    ISSN: 1432-1041
    Schlagwort(e): clonidine ; noradrenaline ; pharmacokinetics ; arterial blood pressure ; plasma concentration
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of clonidine and its relation to blood pressure response and side effects were studied after single oral doses of 75 µg, 150 µg and 250 µg in normotensive subjects. Following oral administration, the drug was absorbed rapidly after an initial lag time of 19–22 min and peak levels were reached between 2.4 and 2.9 h. Sampling over 48 h was necessary for accurate estimation of pharmacokinetic parameters. Post-peak plasma concentration declined in a monoexponential manner and the half-life of the elimination phase ranged from 9.0 to 15.1 h. Maximum plasma concentration (Cmax) and area under curve (AUC) increased proportionally with increasing doses. Clonidine produced significant reductions in the pulse rate and a dose dependent decrease in blood pressure. Clonidine (150 µg) also produced significant reductions in plasma catecholamine levels.
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  • 21
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 43-47 
    ISSN: 1432-1041
    Schlagwort(e): timolol ; pharmacokinetics ; pharmacodynamics ; healthy subjects ; cardiac infarction patients ; i.v. therapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Disappearance pharmacokinetics, pharmacodynamics and general tolerance of i.v. timolol were compared in 12 healthy volunteers and 10 patients with a definite or proven acute myocardial infarction. The drug was administered to the patients immediately on arrival at the hospital after a median delay time of 4 h. Tolerance to the injections was good in both volunteers and patients. The study revealed disappearance pharmacokinetics that were similar in volunteers and patients.
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  • 22
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 293-301 
    ISSN: 1432-1041
    Schlagwort(e): metipranolol ; deacetyl metipranolol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6–25 mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20 mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40 mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; tmax 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20 mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of β-blocking agents.
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  • 23
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 315-323 
    ISSN: 1432-1041
    Schlagwort(e): bendroflumethiazide ; propranolol ; hydralazine ; pharmacokinetics ; thin-layer chromatography ; fluorimetry ; fixed combination product
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Bendroflumethiazide (Bft) was administered to 6 healthy subjects at 3 different dose levels (2.5, 5 and 10 mg) in a cross-over design, either as capsules (2.5 mg) or as tablets (5 mg). Its pharmacokinetics were evaluated then and following administration of a fixed combination of Bft with propranolol and hydralazine to a further 7 volunteers. Plasma and urinary concentrations of Bft were determined by a new fluorimetric — thin-layer chromotography procedure. Peak plasma levels occurred after 2–3 h and averaged 15, 27 and 45 µg/l in the three dose groups. Areas under the plasma concentration — time curves (AUC0→12), which were 75, 147 and 250 µg l−1 h respectively, and cumulative urinary recovery (20%) were independent of the dose administered and the type of formulation. Thus Bft kinetics proved to be linear within the dose range evaluated. The plasma clearance was calculated to be 505 ml/min, renal clearance 108 ml/min and nonrenal clearance 396 ml/min. Bioavailability of Bft was not altered following administration of the fixed combination. The amount of propranolol found in the circulation did not change, whereas that of hydralazine (determined as apparent hydralazine) increased by 59% when the fixed combination was administered.
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  • 24
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 421-425 
    ISSN: 1432-1041
    Schlagwort(e): benzodiazepine ; lormetazepam ; lormetazepam glucuronide ; transfer to milk ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The concentrations of lormetazepam and its glucuronide in plasma and milk were determined during administration of 10 daily doses of lormetazepam 2 mg (2 tablets of NOCTAMID® - 1) to five mothers delivered by Caesarian section. Their babies were breast-fed throughout the study, and the plasma levels of lormetazepam and its glucuronide were determined three times in the babies. At 12 and 24h after administration, the plasma level of lormetazepam was about 3.5 ng/ml and 1.8 ng/ml in mothers, and below 0.09 ng/ml in the children. In milk the lormetazepam concentration was below 0.2 ng/ml. The plasma level of glucuronide varied between 24 ng/ml at 12h and 11 ng/ml 24h after administration. Almost no accumulation of unchanged lormetazepam was observed (factor: 1.3). The ratio of the levels of lormetazepam in milk and plasma was estimated to be below 0.06, and for the glucuronide the ratio was 0.04. The quantity of free and conjugated active ingredient transferred to the children via breast milk was calculated to be at most 100 ng/kg, corresponding to 0.35% of the maternal dose, which is regarded as tolerable.
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  • 25
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 499-504 
    ISSN: 1432-1041
    Schlagwort(e): gentamicin ; malnutrition ; pharmacokinetics ; infant
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of gentamicin was investigated in normal and malnourished infants aged 4–10 months. Neither mean “elimination” nor “distribution half life” show any difference, but the volume of distribution was higher in malnourished babies, probably due to their larger total body water.
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  • 26
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 423-428 
    ISSN: 1432-1041
    Schlagwort(e): pindolol ; renal failure ; metabolism ; pharmacokinetics ; 14C-pindolol ; blood metabolites ; urinary metabolites
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Increased metabolism of pindolol in renal impairment has previously been suggested by pharmacokinetic calculations. The present study was a pharmacokinetic and metabolic investigation in 7 patients with severe renal impairment (endogeneous creatinine clearance below 5 ml/min). All the patients received pindolol 5 mg t.d.s. 5 days. On the sixth day, after an overnight fast, 14C-pindolol 5 mg was given orally as a solution to drink. Blood samples were taken for up to 72 h and urine was collected at intervals up to 96 h for measurement of unchanged pindolol by a fluorimetric method and total radioactivity by liquid scintillation counting. Metabolites in blood and urine were analysed after separation by HPLC. It was found that the plasma levels following a single dose of 14C-pindolol were similar to those observed in healthy volunteers, but the elimination half-life was slightly increased up to 11.5 h. The observed steady state plasma concentrations of pindolol were twice as high but they are still in the therapeutic range of 10 to 100 ng/ml. Therefore, the dose of pindolol could have been reduced by a factor 2, but the reduction was not essential. No active metabolite of pindolol was found in plasma or urine, but elimination of the metabolites was decreased. The elimination half-life following multiple doses was prolonged compared to normal and it was quite comparable to that found for the pharmacodynamic half-life in renal patients. The discrepancy between the present findings and the previous results for metabolism and pharmacodynamic half-life was probably due to the sensitivity of the fluorimetric assay of pindolol.
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  • 27
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 155-160 
    ISSN: 1432-1041
    Schlagwort(e): amikacin ; pharmacokinetics ; development ; neonate ; infant ; child
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The disposition kinetics of a single i.v. dose of amikacin was studied in 6 neonates (6–25 days old), 10 infants (4–18 months) and 8 young children (3–11 years). There was a progressive change in the distribution and elimination kinetics during development. The distribution coefficient of the antibiotic averaged of 0.429, 0.320 and 0.210 l/kg in the newborns, infants and young children, respectively and serum half-life (t1/2 β) in these three groups averaged 2.812, 1.803 and 1.196 h, respectively. Significant differences in certain pharmacokinetic parameters were found between the values in paediatric patients and in adults receiving the same dose. A linear relationship was established between the distribution volume of the antibiotic and the weight of the patients, as defined by the following equation: $${\text{Vd}}_{{\text{ss}}} \left( 1 \right) = 0.976 + 1.140 \cdot {\text{TBW}}\left( {{\text{kg}}} \right);r = 0.954$$ The results suggest that a regimen of very frequent administrations should be employed in infants and young children in order to maintain a therapeutic level throughout treatment.
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  • 28
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 161-169 
    ISSN: 1432-1041
    Schlagwort(e): mebendazole ; hydatid disease ; Echinococcus granulosus ; hepatic disease ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The plasma concentrations of mebendazole and its metabolites have been monitored in twelve patients after receiving a 10 mg/kg dose for cystic hydatid disease. The mebendazole plasma concentration-time profiles differed considerably between patients; elimination half-lives ranged from 2.8–9.0 h, time to peak plasma concentration after dosing ranged from 1.5–7.25 h and peak plasma concentrations ranged from 17.5 to 500 ng/ml. The mean peak plasma concentration of mebendazole after an initial dose (69.5 ng/ml) was lower than found in patients during chronic therapy (137.4 ng/ml). The plasma AUCTs for the major metabolites of mebendazole (methyl 5-(α-hydroxybenzyl)-2-benzimidazole carbamate and 2-amino-5 benzoylbenzimidazole) were about five times the plasma AUCT found for mebendazole in patients on chronic therapy. It is suggested that the slower clearance of these polar metabolites relative to mebendazole results from enterohepatic recycling. Since mebendazole is also highly plasma protein bound, caution should be observed in administering mebendazole to patients with liver disease. Concentrations of mebendazole found in the tissue and cyst material collected from two patients during surgery ranged from 59.5 to 206.6 ng/g wet weight.
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  • 29
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 173-176 
    ISSN: 1432-1041
    Schlagwort(e): melperone ; neuroleptic drug ; dose dependent kinetics ; i.m. injection ; i.v. injection ; pharmacokinetics ; oral application
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of melperone (Buronil®, Ferrosan, Sweden) was studied after administration of various parenteral and oral doses to man. After parenteral administration, the data could be fitted to a two-compartment model, but after oral dosing the distribution phase could not be separated from the elimination phase, and so an one-compartment model gave the best fit. The half-lives were about 3–4 h, except after intramuscular injection, when the half-life was about 6 h. The bioavailability of oral doses was about 60% of the intravenous injection. After the highest oral dose of 100 mg, the pharmacokinetics, expressed as AUC or Cmax, showed non-linearity, possibly due to saturation of the hepatic elimination system.
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  • 30
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 331-333 
    ISSN: 1432-1041
    Schlagwort(e): ketoconazole ; vaginal candidosis ; oral antimycotic ; distribution ; pharmacokinetics ; vaginal tissue concentrations
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Plasma samples and biopsies of vaginal tissue were obtained from 23 healthy women undergoing operative sterilization, 1 to 6 h after a single oral dose of ketoconazole 200 mg. Drug concentrations in plasma and tissue, were measured by a specific gas chromatographic method. The vaginal tissue concentration averaged 2.4 times less than the corresponding plasma levels. Equilibrium between tissue, and plasma was established within 1 h after dosing, when vaginal tissue levels exceeded 1 µg/g. Ketoconazole concentrations decayed monoexponentially over the time interval studied (1–6 h), with the similar half-lives of 1.2 and 1.4 h in plasma and tissue, respectively. Following an oral 200 mg dose, a tissue concentration not less than 0.01 µg/ml was maintained over a 12 h period. This concentration has been shown to prevent outgrowth of the invasive (pseudo) mycelial form ofCandida albicans. Hence, a b.i.d. or t.i.d. dosage schedule of ketoconazole in vaginal candidosis would give continuously effective levels at the site of infection. Ketoconazole concentrations in vaginal fluid are thought to be much higher than in the tissue because of ion-trapping. The present data may explain the efficacy of oral ketoconazole in the treatment of vaginal candidosis.
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  • 31
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 303-306 
    ISSN: 1432-1041
    Schlagwort(e): furosemide ; renal failure ; haemodialysis ; pharmacokinetics ; children ; dosage schedule
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Furosemide was measured by gas-liquid chromatography in blood and dialysis fluid from 7 children with chronic renal failure, undergoing regular haemodialysis. It was administered chronically, in two or three daily doses (4.2–9.4 mg/kg). Two children received 1 mg/kg intravenously for determination of the pharmacokinetics. The half-life was longer than in adults and in anephric patients on haemodialysis. Systemic and renal clearance were also much lower. Plasma protein binding in 2 out of 6 cases was reduced as campared to normal adults. The data do not suggest any need to modify the present dosage schedule despite the 4–5 fold increase in the half-life of furosemide. The contribution of haemodialysis to drug clearance was minimal, and accounted for less than 10% of the total clearance.
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  • 32
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 331-334 
    ISSN: 1432-1041
    Schlagwort(e): diclofenac sodium ; rheumatoid disease ; healthy subjects ; serum albumin ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Pharmacokinetic data for diclofenac sodium has been well established in healthy volunteers, whereas in patients with rheumatoid arthritis very little information is available in the literature. A single oral dose of enteric-coated diclofenac sodium was given to 10 patients with active rheumatoid disease, adopting the same procedures used for a group of 10 healthy volunteers in whom pharmacokinetic data was already available. Plasma specimens were collected over a period of 8h following administration and concentrations of diclofenac determined by GLC. Resulting plasma concentration curves were similar to those obtained in the healthy subjects in that areas under curves and terminal half-lives were comparable. However, peak concentrations of diclofenac were significantly reduced in the rheumatoid patients. The lower peak concentrations were correlated with the lower serum albumin levels in the patients which are associated with active rheumatoid disease.
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  • 33
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 47-52 
    ISSN: 1432-1041
    Schlagwort(e): apnoea ; caffeine ; premature infants ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of caffeine was examined in 13 premature infants (gestational age 25–34 weeks, birth weight 920–2060 g, postnatal age 1–42 days) who received the drug for treatment of opnoea. Caffeine (1% aqueous solution) was given i.v. in single doses; guided by the clinical response infants received between one and seven (mean 2.6) doses of 15 mg/kg. Mean (± SE; range) Clb was extremely slow − 8.5 ml/kg/h (±0.4; 5.8–12.2), t1/2 was prolonged − 65.0 h (±3.7; 48.2–87.5 h) and Vd was 0.781/kg (±0.04; 0.47–1.01). No significant correlation was found between Clb, t1/2 and postnatal age in the whole group or in individual infants. Effective plasma concentrations varied over a wide range (12–36 µg/ml) and overlapped with subtherapeutic concentrations (⩽24 µg/ml). Single doses of 15 mg/kg i.v. or p.o. prevented apnoea in most cases, if necessary followed by additional doses. Monitoring the blood level of caffeine in infants receiving frequent repeated doses is necessary to prevent toxicity.
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  • 34
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 359-365 
    ISSN: 1432-1041
    Schlagwort(e): chlorpheniramine ; pharmacokinetics ; oral absorption ; half-life ; bioavailability ; volume of distribution
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Plasma and urinary levels of chlorpheniramine (CPM) and its 2 demethylated metabolites were measured by HPLC after i.v. and oral dosing. In 5 mg (maleate) i.v. bolus studies in 2 subjects, plasma CPM levels were fitted to triexponential equations with terminal half-lives (t 1/2) of 23 and 22 h and area of 3.6 and 3.21/kg, respectively. Intravenous data predicted hepatic blood extraction ratios for the 2 subjects to be 0.06 and 0.07, respectively. Absolute bioavailability from oral solution (10 mg) was 59 and 34%, and from tablets (8 mg) 44 and 25%, respectively, indicating extensive gut first-pass metabolism. Mean t 1/2 from 7 oral fasting studies in 5 subjects was 28 h (19–43 h). Mean absorption lag time was 0.7 h (0.4–1.3 h), and mean peak time was 2.8 h (2–4 h). In 2 subjects, 6 mg solutions were given every 12 h for 9 doses; good correlation between single and multiple dose kinetics was found. Significant accumulation was demonstrated in simulation studies with frequent daily dosing. Estimated accumulation ratios vary from 4.1 to 9.4 (mean 6.5). The t 1/2 from urinary data (collected for 12 days) was consistent with plasma data. The above results suggest the need to reexamine the current practice of frequent daily dosing and the use of sustained or controlled release dosage forms of this drug. The possible cause of reduced plasma clearance of CPM in renal patients is discussed.
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  • 35
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 93-97 
    ISSN: 1432-1041
    Schlagwort(e): tolmesoxide ; vasodilator ; hypertension ; pharmacokinetics ; haemodynamics ; plasma renin activity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The haemodynamic response and pharmacokinetics of single dose oral tolmesoxide were studied at various dose levels in 4 patients with severe hypertension. There was a reproducible fall in mean arterial pressure from baseline of 24.2% and a rise in heart rate of 37.6% following administration of tolmesoxide. The onset of antihypertensive action occurred within 1 h, with a peak effect at 3 h after dosing. The mean duration of action was up to 12.0 h. Tolmesoxide had a mean half-life of 3.0 h. It was rapidly absorbed with a mean peak plasma level occurring at 1.0 h. Plasma levels correlated well with the doses administered. Side-effects included mild nausea, facial flushing and postural symptoms.
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  • 36
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 37-42 
    ISSN: 1432-1041
    Schlagwort(e): metoprolol ; propranolol ; oxprenolol ; pharmacokinetics ; acetubolol ; diacetolol ; oral contraceptive
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Plasma concentrations of metoprolol, propranolol oxprenolol, acebutolol and its metabolite diacetolol were measured after single oral doses in young healthy volunteers. In order to assess the inter-and intra-subject variability the following pharmacokinetic parameters were compared: AUC o 24 , Cmax, tmax and t1/2. The smallest variation in inter-subject variability was seen with oxprenolol and acebutolol: intrasubject variability was more uniform. Female volunteers taking an oral contraceptive generally had higher AUC o 24 and Cmax values than those not. This finding reached statistical significance only for metoprolol AUC o 24 .
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  • 37
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 49-57 
    ISSN: 1432-1041
    Schlagwort(e): verapamil ; norverpamil ; pharmacokinetics ; atrial fibrillation ; oral administration ; i.v. administration
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetic parameters and oral bioavailability of the antiarrhythmic drug verapamil were determined in six patients with atrial fibrillation. Plasma samples were taken following i.v. injection of verapamil 10 mg (Isoptin® 2 ml), and oral verapamil 80 mg (Isoptin® 2 tablets of 40 mg). Verapamil and its N-demethylated metabolite, norverapamil, were analyzed to 1 ng/ml plasma by gas chromatography-mass spectrometry using deuterated standards. Following intravenous injection, the disposition of verapamil followed a biexponential pattern with a fast distribution phase and a slower elimination phase (t1/2β=5.79 h), corresponding to a plasma clearance of 0.26 1/kg/h. After oral administration, only an elimination phase was evident, with the same elimination rate (t1/2β=5.53 h). The oral bioavailability was 10.5%±7.5%. The norverapamil formed after i.v. and oral administration of verapamil had plasma half-lives of 5.86 h and 6.77 h, respectively. The elimination of verapamil in patients with atrial fibrillation was decreased compared to that in healthy young volunteers and the oral bioavailability was lower. Very good correlation between the percentage reduction in heart rate and the log plasma concentration of verapamil was found in every patient during the elimination phase, irrespective of the route of administration. There was also a high correlation when the plasma concentration — effect data from all the patients were pooled (r=0.59,n=71;p〈0.0005).
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  • 38
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 123-127 
    ISSN: 1432-1041
    Schlagwort(e): theophylline ; bronchiolitis ; infants ; pharmacokinetics ; single dose ; multiple doses ; HPLC
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Theophylline pharmacokinetics were studied in 12 infants (age 3 weeks–6.5 months) with bronchiolitis. 9 of the 12 patients received a single dose of aminophylline (5.0–8.5 mg/kg) whereas the remainder were at steady-state receiving multiple doses (2.5–5.0 mg/kg) of aminophylline. The dose was administered IV over 0.5–1.0 h. An HPLC method was used to measure theophylline concentrations in serum and urine. Peak serum concentrations of theophylline measured by HPLC ranged from 8.48–21.6 µg/ml. Total, renal and nonrenal clearance of theophylline ranged from 4.66 to 19.25, 1.07 to 5.76 and 3.59 to 16.83 ml/min/m2, respectively. Mean apparent volume of distribution and elimination half-life were 8.75 l/m2 and 11.38 h, respectively. Although no significant correlation was observed between age and theophylline kinetic parameters, clearance appeared to increase and half-life decrease with age. Our patients had a substantially lower clearance and longer half-life as compared to published data in children 〉1 year of age. A five-fold variation in theophylline clearance demonstrates the need for monitoring theophylline serum concentration to minimize the risk of potential toxicity.
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  • 39
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 129-134 
    ISSN: 1432-1041
    Schlagwort(e): theophylline ; ethinylestradiol ; oral contraceptives ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The effect of chronic oral contraceptive (OC) usage on the disposition of theophylline was examined. Aminophylline solution (4 mg/kg) was given orally to 8 healthy female non-OC users and to 8 healthy women who were chronic (〉6 months) OC users. The OC user group had a significantly lower total plasma clearance of theophylline than women not using OC (35.1±5.6 vs. 53.1±14.5 ml/h/kg). The t1/2 was also significantly prolonged in the OC group (9.79±1.43 vs. 7.34±1.75 h) while the volume of distribution was similar between the 2 groups. The serum ethinylestradiol (EE) concentrations after oral OC administration were measured simultaneously. The apparent clearance of EE was about 30% lower in the OC users. A significant positive correlation was found between the apparent clearance of EE and the plasma clearance of theophylline. The effects of OC are predominantly due to chronic use with decreased elimination of both theophylline and EE.
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  • 40
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 167-172 
    ISSN: 1432-1041
    Schlagwort(e): ticarcillin ; probenecid ; excretion ; pharmacokinetics ; automated chemical assay method
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The excretion of radioactivity has been investigated in 3 healthy volunteers following rapid intravenous administration of 5 g of [35S]-ticarcillin. The radioactive dose was rapidly and completely excreted, since within 4 days 98.5% was recovered, 95% in the urine and 3.5% in faeces. All the urine radioactivity was accounted for as ticarcillin and its penicilloic acid. Plasma and urine samples collected from the volunteers at frequent intervals during the first 6 h of the experiment were assayed for penicillin by an automated chemical method and also for radioactivity. The results obtained by the chemical autoanalyser method were in excellent agreement with the plasma levels of radioactivity. From the data it was possible to calculate the renal clearance of the penicillin, a mean value of 104 ml/min was observed in the 3 volunteers. A further three volunteers were dosed intravenously with a 5 g bolus of non-radiolabelled ticarcillin in a cross-over study with and without predosing with probenecid. Serum samples were analysed by the chemical method for penicillin and the data subjected to pharmacokinetic analysis using a two compartment open model. The results indicate a shift of the distribution equilibrium of ticarcillin from the serum into the peripheral compartment after predosing with probenecid. Furthermore, the mean half-life of ticarcillin in the serum of the three volunteers was significantly increased from 1.3 h to 2.1 h by predosing with probenecid.
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  • 41
    ISSN: 1432-1041
    Schlagwort(e): dipyridamole ; platelets ; plasma levels ; pharmacokinetics ; adenosine uptake
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Two preparations of dipyridamole have been studied by oral administration to 11 normal volunteers. The plasma levels of dipyridamole and its glucuronide were determined simultaneously by high performance liquid chromatography. The instant form (I.F., 100 mg) was administered four times daily and the slow release preparation (SRP, 200 mg) twice daily, for 3 days. Multiple blood samples were collected on Days 1–4 to provide plasma for assay, and simulteneously, platelet rich plasma was prepared for ex vivo study of the effect of dipyridamole on platelet uptake of adenosine. The pharmacokinetics of absorption and distribution of dipyridamole were described using a two compartment model with lag time and prolonged absorption. Strong inhibition of the platelet adenosine uptake was observed at therapeutic plasma levels. The inhibition of platelet adenosine uptake may be related to some of the pharmacological properties of dipyridamole.
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  • 42
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 349-351 
    ISSN: 1432-1041
    Schlagwort(e): indomethazine ; rheumatoid arthritis ; pharmacokinetics ; tolerance ; side effects ; slow-release tablets
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics, efficacy and tolerance of a new formulation of slow-release indomethacin tablet were compared with those of a conventional indomethacin capsule in 30 patients with rheumatoid arthritis. The slow-release tablet was absorbed more slowly than the capsule (tmax 3.7 h and 〈 2 h, respectively) and produced more even serum drug levels in 10 subjects. Side-effects, especially dizziness and diarrhoea, were less frequent after the slow-release tablet than during the capsule period.
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  • 43
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 335-341 
    ISSN: 1432-1041
    Schlagwort(e): phenylephrine ; pharmacokinetics ; bioavailability ; first-pass metabolism ; phenolic conjugates ; m-hydroxymandelic acid ; intravenous ; oral
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary 7-3H-phenylephrine was given to 15 volunteers by a short-infusionn=4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. As almost the same3H-activity was excreted in urine after i.v. and p.o. administration, 86% and 80% of the dose respectively, complete enteral absorption can be assumed. A considerable difference was seen in the fraction of free phenylephrine, i.v. 16% of the dose versus p.o. 2.6%, which suggested reduced bioavailability. This was confirmed by comparison of the areas under the serum curve, which showed a bioavailability factor of 0.38. The result for the patient with porto-caval anastomosis was comparable to that in the normal volunteers. The biological half-life of 2 to 3h was comparable to that of structurally related amines, as were the total clearance of 2 1/h, and the volume of distribution of 340l. Metabolism to phenolic conjugates mainly after oral ingestion, and tom-hydroxymandelic acid after i.v. injection, again demonstrated thatm-hydroxylated amines are predominantly conjugated during the “first-pass” metabolism.
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  • 44
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 315-320 
    ISSN: 1432-1041
    Schlagwort(e): furosemide ; cirrhotic patients ; ascitic fluid ; diuretic effect ; pharmacokinetics ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of furosemide was studied in 7 patients with diagnosed liver cirrhosis and in 7 healthy subjects. Furosemide in plasma and ascitic fluid was analyzed spectrofluorometrically. After a single intravenous dose, the cirrhotic patients showed lower initial plasma concentrations of furosemide because of the larger volume of distribution. The mean half-life in cirrhotic patients was significantly greater than in healthy volunteers. The longer half-life was associated with a reduction in the serum clearance of furosemide. Ascitic fluid volume in the patients ranged from 4.6 to 7.71. There was no significant amount of furosemide in the fluid. The diuretic interchange between this fluid and plasma was slow, as peak concentrations ranged from 0.3 to 0.5 µg/ml within 3 to 5 h after bolus administration of furosemide. Diuresis and urinary sodium excretion, 5 h after furosemide injection, were similar in both groups; larger potassium excretion was found in the cirrhotic patients.
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  • 45
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 325-330 
    ISSN: 1432-1041
    Schlagwort(e): cimetidine ; renal failure ; cimetidine sulphoxide ; pharmacokinetics ; haemodialysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary A single intravenous dose of cimetidine 200mg was administered to 6 patients with severe chronic renal failure one hour prior to haemodialysis. The plasma concentrations of cimetidine and its sulphoxide metabolite at the start of haemodialysis were 2.74±0.12 and 0.76±0.08 µg/ml, and after dialysis for 4h 1.08±0.10 and 0.51±0.08 µg/ml, respectively (mean ± SE). The average haemodialysis clearance (ClHDa) of cimetidine during dialysis was 46–92ml/min at a dialysate flow rate of 320ml/min and blood flow rates in the 6 patients between 160–240ml/min. The mean ClHDa of the sulphoxide metabolite was 44% higher than that of cimetidine, and ranged between 49–148ml/min. During haemodialysis the mean plasma elimination half-life (t1/2) of cimetidine was 3.24h (range 2.08–5.08) and of the sulphoxide metabolite 9.49h (range 4.70–14.39). There was a significant relationship between the elimination rate constant (β) and ClHDa of the sulphoxide metabolite (p〈0.01), but no such relationship was found between β and ClHDa of cimetidine. However, there was a tendency to a relationship between β of cimetidine and the capacity to metabolise the drug, expressed as the ratio between the plasma concentrations of the sulphoxide metabolite and cimetidine after dialysis for 4h. These ratios ranged between 0.23–0.76, and the lowest ratio was seen in the patient with the lowest β value of cimetidine. Thus, the large variations in the plained by differences in their capacity to metabolise the drug. The mean total amount of cimetidine eliminated during dialysis was 27.3mg (range 17.9–31.8), which was 9.0–15.9% of the given dose. Between 12.2–21.2mg (mean 15.3) of the sulphoxide metabolite was eliminated in the dialysate. Major adjustment of the dose of cimetidine on days of dialysis is not necessary.
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  • 46
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 351-354 
    ISSN: 1432-1041
    Schlagwort(e): lithium ; plasma level decay curve ; elimination ; pharmacokinetics ; psychiatric patients
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Chronic treatment with conventional lithium carbonate was interrupted in a selected group of 40 psychiatric patients of mixed sex and race. All patients had normal renal function. Serum samples were taken 12, 24, 36 and 48 h after the last dose and lithium was assayed by atomic absorption spectrophotometry. Decay rates calculated for the 12–24 h and 36–48 h periods yielded different values. This was ascribed to the presence of an incomplete redistribution phase during the earlier period. The distribution of elimination rates determined during the later period gave a more symmetrical spread and approximated a normal distribution. The mode, median, mean and standard deviation of the lithium elimination half-lives were 12.5, 14, 18.2 and 7.3 h and 22.5, 24.5, 29.8 and 10.1 h for the two periods, respectively. The results contrast sharply with another report of the distribution spread of elimination half-lives in a much larger sample. The current values have implications for dosage prediction, serum level monitoring and dosage formulation, especially sustained-release preparations. The evidence was against the possibility that some individuals ‘retain’ lithium.
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  • 47
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 373-377 
    ISSN: 1432-1041
    Schlagwort(e): propranolol ; sotalol ; thyrotoxicosis ; bioavailability ; serum tri-iodothyronine ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The elimination and bioavailability of two beta-blocking agents, propranolol and sotalol, were studied in 10 thyrotoxic patients, both before and after treatment with iodine-131. Each subject received in random order propranolol 160 mg and sotalol 160mg as single oral doses both while hyperthyroid and after euthyroidism had been achieved. The pharmacokinetics of sotalol was not affected by hyperthyroidism, whereas serum propranolol concentrations were significantly lower during hyperthyroidism than in the euthyroid state. During hyperthyroidism, the bioavailability of propranolol was significantly reduced (p〈0.05) and its clearance was increased (p〈0.005), whereas there was no difference in its serum t1/2. This indicates that the bioavailability of propranolol in hyperthyroidism is reduced by a mechanism which may depend on increased first-pass metabolism in the liver, or on an increased distribution volume of the drug. Both propranolol and sotalol caused a slight decrease in serum tri-iodothyronine concentration. As the effects of beta-blocking agents on the symptoms of hyperthyroidism are correlated with the serum concentration of the drugs, sotalol, with its long half-life and unaltered elimination in hyperthyroidism, has certain advantages over propranolol in the treatment of thyrotoxicosis.
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  • 48
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 433-441 
    ISSN: 1432-1041
    Schlagwort(e): antipyrine ; antipyrine metabolites ; drug metabolism ; route of administration ; healthy volunteers ; urinary excretion ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8±1.9% of the dose was excreted in urine as unchanged antipyrine in 48h, 24.9±6.3% as 4-hydroxyantipyrine, 16.5±3.2% as norantipyrine, 13.0±2.2% as 3-hydroxymethyl-antipyrine and 5.8±1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.
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  • 49
    ISSN: 1432-1041
    Schlagwort(e): clomipramine ; desmethylclomipramine ; depressive syndrome ; plasma level ; pharmacokinetics ; clinical response ; benzodiazepines
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Thirty one in-patients suffering from depression were treated orally with clomipramine (Cl) at various dosage, for 28 days, after a “wash-out” period of three days. In 17 patients receiving 75 mg per day of Cl, steady state plasma levels of Cl were reached at Day 14, and steady state plasma levels of its active metabolite, desmethylclomipramine (DMCl), were reached at Day 21. In contrast, in 7 other patients receiving a dosage increasing to 150 mg per day at Day 7, mean plasma levels of Cl and DMCl continued to rise during the entire treatment period. At the steady state, a correlation was found between Cl dosage expressed as mg kg body weight and the plasma concentration of Cl and DMCl. Factors such as tobacco and alcohol consumption seem to modify the Cl/DMCl ratio. A comparison of clinical response with plasma levels of Cl, DMCl and Cl + DMCl showed a significant negative linear correlation.
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  • 50
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 77-84 
    ISSN: 1432-1041
    Schlagwort(e): allopurinol ; oxipurinol ; benzbromarone ; hydrochlorothiazide ; pharmacokinetics ; bioavailability ; interaction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary An high-pressure liquid chromatographic method was used to measure allopurinol and oxipurinol in plasma and urine in 6 healthy volunteers after a single intravenous or oral dose of allopurinol. The influence of coadministrated benzbromarone and hydrochlorothiazide on the pharmacokinetics of allopurinol and oxipurinol was also investigated. After intravenous injection of allopurinol 300 mg the plasma disappearance was biexponential, with a mean distribution half-life of 2.32±1.08 min $$(\bar x \pm SD)$$ and an elimination half-life of 47.8±10.6 min. The total clearance of allopurinol was 11.37±2.70 ml/min/kg, whereas its renal clearance was only 1.73±0.79 ml/min/kg. Oxipurinol disappeared monoexponentially from plasma ith a mean half-life of 12.2±2.6 h. Its renal clearance was 0.42±0.091 ml/min/kg. After oral administration of allopurinol 300 mg the peak plasma concentration of 2.1±0.6 µg/ml (1.5×10−5 M) was reached within 30 to 120 min. The peak level of oxipurinol of 5.8±1.5 µg/ml (3.8×10−5 M) was found within 2 to 5 h after intravenous and oral allopurinol. The bioavailability of oral allopurinol computed from plasma data was 90.4±8.7%. The total recovery from urine was 77% (allopurinol 8%, oxipurinol 69%) after oral and 88% after i.v. administration. It was concluded that about 10% of the oral dose was not absorbed and that 12% was eliminated by an unknown mechanism, presumably as riboside. The pharmacokinetics of allopurinol and oxipurinol were not significantly influenced by coadministration of benzbromarone or hydrochlorothiazide.
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  • 51
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 343-349 
    ISSN: 1432-1041
    Schlagwort(e): methadone ; opiate addicts ; pharmacokinetics ; single and multiple doses ; stable isotope technology ; methadone maintenance therapy ; deuterium technique
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Deuterated methadone (M-d30) and GC-MS were used to study the pharmacokinetics of methadone (M) during the induction stage of methadone maintenance treatment (MMT). A pulse dose of M-d3 was given on Days 1 and 25 of two dosage regimens, one with a continuous 30 mg dose (n=6), and the other with 30 mg for 10 days, followed by 60 mg as the maintenance dose (n=6). Plasma and urinary levels of M and M-d3 were measured throughout and plasma half-lives, oral bioavailabilities and volumes of distribution were calculated from the data of Days 1–2 and 24–26. The oral bioavailability of a methadone solution was found to be between 81 and 95%; elimination half-life in the β-phase varied between 19 and 58 h; the volume of distribution was 4.1±0.65 l/kg; and total body clearance of M was 54–195 ml/min and its renal clearance 3.4–34 ml/min. A consistent finding was a lower urinary pH and increased renal clearance during the first days of MMT as compared with after one month. In 4/12 of the patients dispositional tolerance was developed to methadone during the first month of treatment. The shorter elimination half-lives in those patients probably caused unacceptably high fluctuation in the body content of M during the 24 h dosage interval, and may have interfered therefore, with its therapeutic effectiveness
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  • 52
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 515-521 
    ISSN: 1432-1041
    Schlagwort(e): tienilic acid ; uricosuria ; pharmacokinetics ; pharmacodynamics ; uric acid ; diuretic ; plasma level assay
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary A simple and reliable HPLC method for the determination of tienilic acid ((TA) Selacryn®, Selcryn®, Diflurex®, Ticrynafen®) and its alcoholic metabolite in plasma and urine has been developed. In 8 healthy adult volunteers the plasma and urinary levels of tienilic acid and its alcoholic metabolite, and plasma and urinary levels of sodium, creatinine and uric acid were measured after oral administration of tienilic acid 250 mg. The pharmacokinetic parameters found differed only slightly from those reported in the literature, as there was faster absorption and a shorter half-life. TA is probably excreted by a saturable renal tubular transport mechanism. The pharmacodynamic effects of tienilic acid developed quickly, the uricosuric effect being very impressive and the natriuretic effect moderate. These effects disappeared in about 8 h. An inverse relationship was found between the starting plasma uric acid level in an individual and the maximal uric acid clearance — the higher the plasma uric acid level, the lower was the maximum effect. Plasma tienilic acid level and natriuretic effect were correlative within individuals and intra-individually (p〈0.05). Urinary tienilic acid level and natriuretic effect were correlated, too (p〈0.05 top〈0.001), but only intraindividually. No correlation between drug level and uricosuric effect was found.
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  • 53
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 535-539 
    ISSN: 1432-1041
    Schlagwort(e): noscapine ; pharmacokinetics ; absorption ; bioavailability ; intravenous application ; oral application ; ion exchange resin tablet
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Noscapine was administred to five healthy volunteers in a randomized crossover design, as an intravenous infusion of 66 mg, and as an oral 150 mg dose of either rapidly dissolving tablets or a tablet containing ion exchange resin-bound noscapine. After i.v. administration, the disposition of noscapine was bi-exponential with an elimination half-life of 2.6 h; the total plasma clearance was 22 ml/min/kg and the volume of distribution (Vdarea) was 4.7 l/kg. The absolute oral bioavailability was 30%, with a 3.6-fold interindividual variation. There was no pharmacokinetic evidence to support a prolonged action of the ion exchange resin tablet.
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  • 54
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 417-422 
    ISSN: 1432-1041
    Schlagwort(e): theophylline ; aminophylline ; obstructive airways disease ; short-term i.v. infusion ; log-normal distribution ; pharmacokinetics ; serum concentrations
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Serum theophylline concentrations after intravenous administration of a new short-term infusion (Euphyllin® Kurzzeitinfusion) were measured in 50 out-patients with chronic obstructive airways disease (COAD). An intravenous infusion of theophylline ethylenediamine 480 mg (corresponding to approximately 350 mg anhydrous theophylline) in 50 ml isotonic solution was given in 20 min. Blood samples were taken beforehand and 25 to 30 min and 1, 3 and 6 h after starting the infusion. 86% of the patients had a one-hour serum level in the therapeutic range of 8–20 mg/l, and 2 h later, this was true of 64% of the patients. The short-term infusion was well tolerated, even in cases with unknown high pre-infusion serum levels. Pertinent pharmacokinetic parameters were determined, such as total body clearance, apparent volume of distribution, and half-life of elimination. Geometric mean and 95%-confidence limits, derived from the log-normal distribution of these parameters, were: Cl=0.044 (0.018–0.109) l/h/kg ideal body weight, Vd=0.451 (0.258–0.789) l/kg ideal body weight, and t1/2(el)=7.1 (2.6–19.1) h.
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  • 55
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 249-252 
    ISSN: 1432-1041
    Schlagwort(e): mecillinam ; bacmecillinam ; pivmecillinam ; pharmacokinetics ; pro-drug ; healthy volunteers ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (±SD) peak levels of plasma mecillinam were 1.43±0.34, 2.73±0.43, and 4.62±1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38±0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21±0.19, 3.99±0.63, and 7.74±1.38 mg·h·l−1 for bacmecillinam and 5.35±0.93 mg·h·l−1 for pivmecillinam. The elimination half-lives were 0.8–1.1h for bacmecillinam and 0.7h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p〈0.001), AUC (p〈0.001) and urinary recovery (p〈0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p〈0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.
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  • 56
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 267-270 
    ISSN: 1432-1041
    Schlagwort(e): terodiline ; human volunteers ; pharmacokinetics ; serum clearance ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of terodiline HCl was studied in nine healthy volunteers given 12.5 mg i.v. and p.o. or 20 mg i.v. and 25 mg p.o. on two different occasions. The serum concentrations were measured by gas chromatography — mass spectrometry, using deuterated terodiline HCl as the internal standard. After i.v. administration the kinetics could be described by a two-compartment model with a mean distribution half life of 0.3 h and a mean elimination half life of 63 h. The serum clearance and apparent volume of distribution varied about 4-fold with mean values of 4.8 l/h and 417 l, respectively. After oral administration, the mean half life of absorption was 0.7 h and that of elimination 65 h. The absolute bioavailability varied between 64% and 105% with a mean of 92%. The long serum half life of terodiline should permit its once daily administration.
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  • 57
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 369-372 
    ISSN: 1432-1041
    Schlagwort(e): neuromuscular blockade ; pancuronium ; non-depolarizing neuromuscular blocking agent ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Pancuronium in bolus doses of 40 to 350 µg/kg was administered to surgical patients in order to evaluate the linearity of its pharmacokinetics. The profile of the plasma decay curve and of its urinary elimination were compared with reference to the administered dose. It was possible to superimpose the dose-normalized plasma decay-curves. The parameters of the two compartment-open model used to describe the pharmacokinetics of pancuronium were not influenced by the dose. The elimination half-life was 89±20 min and the plasma clearance was 1.84±0.38 ml/min/kg. The profiles of cumulative urinary excretion were also dose-independent. After 6 and 24 h, 57% and 69% of the administered dose, respectively, had been excreted in the urine. The results indicate that the pharmacokinetics of pancuronium is linear.
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  • 58
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 523-527 
    ISSN: 1432-1041
    Schlagwort(e): endralazine ; acetylator phenotype ; hydralazine ; pharmacokinetics ; plasma concentrations
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30±1.08 h for the 5 mg dose and 4.25±1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC 0 ∞ ) was 18.2% lower (p〈0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p〉0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC 0 ∞ of the acetylation metabolite (methyltriazoloendralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p〈0.01).
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  • 59
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 265-272 
    ISSN: 1432-1041
    Schlagwort(e): pharmacokinetics ; variation of absorption ratios ; bioavailability ; dissection of variation due to absorption and intermediate processes ; oral drug application
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Differences in the plasma concentrations of drugs after oral administration are caused by two main factors: variation in absorption ratios and in the distribution processes in the body. A new method for the dissection of both types of factors is discussed. The method uses a reference regression of the AUC-values to the corresponding values after intravenous infusion of graded doses. The reference regression is estimated from an appropriate trial. Deviation of the determined AUC-values from the regression curve afford an estimate of the residual variance due to varying distribution volumes or similar random biological effects. For the estimation of absorption ratios after oral administration the drug is given orally to another sample of subjects and their AUC-values are calculated. The deviation of these AUC values due to the above mentioned random effects are simulated using the residual variance of the reference regression, and are subtracted from the observed AUC-values. Then, the differences in the corresponding absorbed doses are transformed by inverting the reference regression. From these doses the empirical distribution function and statistical parameters (e.g. quantiles) are determined. The method has the advantage that no restrictive assumptions are required, such as first order processes, dose linearity, homogeneity of variance or normal distribution of absorption ratios. Its applicability to substances with qualitative differences in their pharmacokinetics is demonstrated by appropriate examples.
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  • 60
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 337-342 
    ISSN: 1432-1041
    Schlagwort(e): methadone ; pharmacokinetics ; urinary pH ; RBC level ; saliary level ; mass fragmentography
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The influence of urinary pH on the acute disposition of methadone in man was studied in five healthy volunteers. A cross-over experiment was performed in each subject. In the first experiment the subjects were treated with ammonium chloride (urinary pH ≈ 5.2) and in the other the urine was made alkaline (pH ≈ 7.8) by treatment with sodium hydrogen carbonate. d, 1-Methadone-HCl 10 mg (M) was administered intramuscularly on each occasion and blood, saliva and urine levels of M were determined by mass fragmentography. Plasma half-lives, volumes of distribution and body clearances of M were calculated in both experiments. The plasma half-lives in the β-phase were 19.5±3.6 h (acidic urine) and 42.1±8.8 h (alkaline urine), respectively (p〈0.001). The volumes of distribution were increased when the pretreatment was changed from ammonium chloride to sodium bicarbonate, namely from 3.51±0.41 l/kg to 5.24±0.83 l/kg (p〈0.01). The body clearance decreased from 134±21 ml/min (acidic) to 91.9±9.1 ml/min (alkaline urine) (p〈0.01). The ration Mplasma/MRBC was about 2.3 and the elimination of M from RBCs was in good agreement with the plasma kinetics of M under both experimental conditions. The salivary levels of M did not reflect the plasma kinetics and considerable variation was seen in the ratio Msaliva/Mplasma (0.26–2.98). Thus, the present experiments demonstrate that pretreatment either with ammonium chloride or bicarbonate had profound effects on both the distribution and elimination kinetics of methadone.
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  • 61
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 435-440 
    ISSN: 1432-1041
    Schlagwort(e): erythromycin ; haemodialysis ; dosage adjustment ; pharmacokinetics ; protein-binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Erythromycin kinetics were studied in 17 patients with end stage renal failure treated with maintenance haemodialysis and 9 normal volunteers to discover if dialysis patients needed a modified dose. The elimination half life in dialysis patients (on dialysis days) was similar to that reported in normal subjects. Only small amounts of drug appeared in the dialysate, no patient loosing more than 9 mg in one dialysis. Both patients and volunteers had similar plasma concentrations 8 h after the end of a 5-day course. Protein-binding did not change significantly during dialysis and was similar to that reported in normal subjects. We conclude that dialysis patients requiring 1.5 g of erythromycin stearate daily or less can be given normal doses.
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  • 62
    ISSN: 1612-1112
    Schlagwort(e): Teflon capillary columns ; Chemically modified teflon ; Gas chromatography
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The preparation of teflon capillary columns employing direct coating of the stationary phase to the chemically modified teflon surface and the role of the chemically modified teflon in the separation mechanism are described. Two types of contributions from the modified teflon have been observed: nonspecific adsorption of the carbon surface and specific interactions of polar groups in the carbon skeleton. The use of polar liquid phases can eliminate adsorption due to the presence of polar groups in the modified teflon.
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  • 63
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 16 (1982), S. 60-62 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Amines ; Derivatization ; Chloroformate esters
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The gas chromatographic analysis of amines after conversion to electron capture sensitive carbamates in two-phase systems has been studied. Hydrophilic compounds, for instance methylamine, are reacted with 2,2,2-trichloro-tert. butyl chloroformate. Quantitation below 10−7 M can be made by thermionic or electron capture detection. A hydrophobic amine, namely N,N-dimethyl-n-octylamine, was derivatized with 2,4,6-tribromophenyl chloroformate with addition of iodide ion to the aqueous phase. The favorable effect of iodide ion as well as the choice of pH and chloroformate ester is discussed.
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  • 64
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 16 (1982), S. 98-102 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Rectangular channel ; Efficiency ; Capacity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary Gas chromatographic experiments have been performed in a truly rectangular channel with a 60∶1 cross-sectional aspect ratio, constructed according to the field-flow fractionation technology. It is shown that the peak broadening is controlled by the thickness of the channel while the maximum load is determined by the largest cross-sectional dimension. However, even with its elongated configuration, the side walls contribute significantly to the band broadening of solutes with a high diffusivity. Good agreement is found between the experimental plate height data and the recent theoretical calculations of Golay [13] taking into account the side-wall effect.
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  • 65
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 94 (1982), S. 1069-1071 
    ISSN: 1573-8221
    Schlagwort(e): pharmacokinetics ; alcohol ; alcohol abstinence
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Materialart: Digitale Medien
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  • 66
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 94 (1982), S. 1373-1375 
    ISSN: 1573-8221
    Schlagwort(e): pharmacokinetics ; phenazepam ; 3-hydroxyphenazepam ; cats ; blood ; metabolic model
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Materialart: Digitale Medien
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  • 67
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 94 (1982), S. 1689-1692 
    ISSN: 1573-8221
    Schlagwort(e): ethanol preference ; endogenous ethanol ; pharmacokinetics ; estrous cysle
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Materialart: Digitale Medien
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  • 68
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 465-494 
    ISSN: 1573-8744
    Schlagwort(e): disopyramide ; pharmacokinetics ; bioavailability ; metabolite ; half-life ; protein binding ; disease states ; drug-drug interaction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Current information on the pharmacokinetics of disopyramide is reviewed with emphasis on the implications for antiarrhythmic therapy. The absolute bioavailability, the disposition half-life, the plasma clearance, and the renal clearance for normal subjects and patients are discussed. Drug-drug interactions are discussed, and a new flexible intravenous dosing schedule is proposed.
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  • 69
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 335-348 
    ISSN: 1573-8744
    Schlagwort(e): pharmacokinetics ; bioavailability ; growth ; literature growth ; logistic function
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The literature growth in pharmacokinetics and bioavailability between the years 1964 and 1980 is analyzed. During much of this period, the literature doubled approximately every 1.6 years. However, during the period 1978–1980, little or no growth was observed. During the period 1950–1967, the total chemical literature increased exponentially with a half-life of 8.28 years; between 1968 and 1980, the half-life was 12.4 years. Thus, the pharmacokinetic literature increased at a much more rapid pace than did the total chemical literature in general. The subject of growth is considered in a general context, particularly as influenced by psychological, sociological, political, and economic factors. It is concluded that while mathematical functions may adequately describe past literature trends, they have little if any utility in predicting future trends in specific research areas such as pharmacokinetics.
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  • 70
    ISSN: 1573-8744
    Schlagwort(e): chloramphenicol-3-monosuccinate ; chloramphenicol-1-monosuccinate ; chloramphenicol ; bioavailability ; pharmacokinetics ; intravenous administration ; adult patients
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics of chloramphenicol (CAP) and total chloramphenicol succinate (CAPS) were studied in eight hospitalized adult patients with normal renal and hepatic function receiving intravenous chloramphenicol sodium succinate therapy. The steady-state peak concentrations of CAP (8.4–26.0 μg/ml) occurred at an average of 18.0 min (range 5.4–40.2) after cessation of the chloramphenicol sodium succinate infusion. Unhydrolyzed CAPS prodrug, representing 26.0±7.0% of the dose, was recovered unchanged in the urine indicating that the bioavailability of CAP from a dose of intravenous chloramphenicol succinate is not complete. A pharmacokinetic model was developed for simultaneous fitting of CAP and CAPS plasma concentration data. Pharmacokinetic parameters determined by simultaneous fitting were: V, 0.81±0.18 liters/kg; t1/2, 3.20 ±1.02 hr; CLB, 3.21±1.27 ml/min/kg for chloramphenicol; and V, 0.38±0.13 liters/kg; t1/2, 0.57±0.12hr; CLB, 7.72±1.87 ml/min/kg for total chloramphenicol succinate.
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  • 71
    ISSN: 1573-8744
    Schlagwort(e): antiarrhythmic compound ; experimental arrhythmia ; pharmacokinetics ; three compartment model ; pharmacological response ; combined pharmacokinetic pharmacodynamic model
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. ke0, a measure of the lag time of pharmacological response behind changes in plasma concentration, and Ce (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.
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  • 72
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 231-245 
    ISSN: 1573-8744
    Schlagwort(e): nitrazepam ; i.v. ; oral ; rectal administration ; protein binding ; pharmacokinetics ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.
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  • 73
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 27-51 
    ISSN: 1573-8744
    Schlagwort(e): pharmacokinetics ; models ; plasma protein binding ; nonlinear processes ; Sulfaethidole
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Sulfaethidole distribution and elimination in the rat was studied over a 90-fold dose range. This experimental design produced marked nonlinearity in the binding of Sulfaethidole to proteins in both interstitial fluid and plasma. Using a multicompartmental model consisting of binding of Sulfaethidole to plasma and interstitial fluid proteins, Sulfaethidole distribution in the body could be simulated. Urinary and biliary elimination of Sulfaethidole depended on the unbound drug mass in the plasma and urine flow. The results confirm the central role of the unbound species in the distribution and elimination of drugs with marked binding to plasma proteins.
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  • 74
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 559-574 
    ISSN: 1573-8744
    Schlagwort(e): pharmacokinetics ; steady state predictions ; sensitivity analysis ; parameter estimates ; optimum sampling strategies
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The sensitivity theory is applied to derive a linear approximation to the functional dependence of some steady state quantities of therapeutic significance on pharmacokinetic parameters obtained from the biexponential response to a single drug dose. The error of a steady state prediction depends in general on two terms. The first one may be viewed as an approximate sensitivity of the prediction to the parameter errors, and this depends solely on the algebraic relation between the prediction and the parameters. The second term is the relative error in parameters, and this may be affected by experimental design and the method of data analysis. Comparisons are made with Monte Carlo simulations and “a posteriori”estimates of variance of a prediction.
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  • 75
    ISSN: 1573-8744
    Schlagwort(e): theophylline ; pharmacokinetics ; variability ; disposition rate constant ; man
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract After administering a single 300 mg dose of theophylline in oral solution to 12 healthy adults, the dose-normalized area under the plasma concentration-time curve was 97.2±20.1 % (mean±SD) of that after giving a 500 mg dose and statistically indistinguishable. Similarly, these areas multiplied by the individual's terminal disposition rate constant (β) were statistically indistinguishable between 300 and 500mg doses (99.1±10.3%), giving no evidence of dose-dependence for theophylline kinetics at the levels below 15 μg/ml observed in these individuals. After an intravenous dose, a shortlived distribution phase (t1/2α) is sometimes seen. An a phase, however, is hardly discernible in over 250 profiles arising from oral doses administered during five single dose bioavailability studies. Almost all such profiles appear to follow single-compartment model predictions. With precautions to avoid a potential a phase, a terminal log-linear slope can be fitted by least squares analysis with a relative standard error in the slope determination almost always less than 6%. Covariance analysis confirms statistically that 39 of the 60 participating individuals varied in their β on the different occasions each was required to take a dose during the course of a crossover bioavailability trial. In one study, even though each individual was observed on only two occasions, 9 out of 12 showed statistically identifiable variation in β. Fluctuations in β of 60% can be seen. Changes of 30% or greater are common and can occur within 3 or 4 days. Thus real, large, and potentially frequent changes in β of theophylline have been identified in a majority of normal subjects. These changes do not appear to be confined to either sex, to smokers or nonsmokers, or to heavier or lighter individuals. No chronological pattern has, as yet, been recognized in the intraindividual variability in β.
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  • 76
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 147-156 
    ISSN: 1573-8744
    Schlagwort(e): intravenous hydrocortisone ; blood concentrations ; pharmacokinetics ; endogenous hydrocortisone suppression
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics of hydrocortisone were examined following single intravenous doses of 5, 10, 20, and 40 mg hydrocortisone, as the sodium succinate salt, to healthy male volunteers. Endogenous hydrocortisone was suppressed by administration of 2 mg dexamethasone the night before hydrocortisone injection. Plasma samples obtained serially during 8 h after hydrocortisone injection were assayed by reversephase HPLC using a fixed wavelength (254 nm) ultraviolet detector. Initial concentrations of hydrocortisone in plasma were proportional to dose size. The subsequent decline in hydrocortisone concentrations was biphasic, and individual data sets were adequately described in terms of the pharmacokinetic two-compartment open model. Values of pharmacokinetic parameters were similar from the 5, 10, and 20 mg doses. Following the 40 mg dose, the overall elimination rate constant decreased, while the distribution volume, Vdss,and plasma clearance increased, in comparison with the values obtained from lower doses. Changes in the pharmacokinetics of hydrocortisone at high doses may be related to drug concentrationdependent changes in the binding of hydrocortisone to plasma proteins. Previously reported dosedependent changes in some pharmacokinetic parameters following oral hydrocortisone are attributed to absorption rather than distribution or elimination effects.
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  • 77
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 15-26 
    ISSN: 1573-8744
    Schlagwort(e): cefroxadin ; pharmacokinetics ; man
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics of cefroxadin have been studied after the administration of single oral and intravenous doses to healthy volunteers. Cefroxadin was assayed by HPLC. The kinetics in plasma following i.v. administration were described by using a three-compartment model. An additional disposition phase was observed following oral administration that could not be detected after the low i.v. dose. The terminal half-life was 1.03 h. The apparent volume of distribution at the steady state was consistent with a diffusion of the antibiotic in all extracellular fluids. The AUCafter oral administration was linearly related to the dose. The urinary excretion amounted to 95% of the dose with virtually complete absorption of orally administered drug.
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  • 78
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 1-14 
    ISSN: 1573-8744
    Schlagwort(e): disopyramide ; pharmacokinetics ; antiarrhythmic, healthy subjects
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects, the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (α), these are the only parameters which can be reported without qualification as to the concentration. The mean ± SD total body clearance of unbound drug in the eight subjects was 5.40± 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of α, while the renal clearance of total disopyramide is dependent upon α.
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  • 79
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 201-227 
    ISSN: 1573-8744
    Schlagwort(e): interspecies variations ; scaling ; heterogony ; allometry ; pharmacokinetics ; physiological time ; pharmacokinetic time ; maximum lifespan potential
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Interspecies variation in pharmacokinetics is considered and treated as a property and consequence of body size (allometry). Consequently, it is possible to reference (scale) pharmacokinetic parameters to the organism's individual anatomy, biochemistry, and/or physiology in such a manner that differences between species are nullified. Thus, in the mouse, rat, dog, monkey, and human, methotrexate plasma clearance always equals 133% of creatinine clearance and as such becomes invariant. Pharmacokinetic time (a variable in terms of chronological time) is shown to be a form of physiological time in which a pharmacokinetic event becomes the independent variable, e.g., disposition halflife. A relationship between pharmacokinetic time and body size is demonstrated. It is suggested that man's lesser quantitative ability to metabolize many drugs may be correlated with his enhanced longevity.
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  • 80
    ISSN: 1573-8744
    Schlagwort(e): diuretic ; bumetanide ; pharmacokinetics ; pharmacodynamics ; normals
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics and pharmacodynamics of bumetanide (1 mg) administered either orally or intravenously were studied in a group of normal subjects using high-pressure liquid chromatography. A two-compartment model adequately fitted the intravenous data. Renal clearance (85 ml min−1 contributed 65% to the total elimination of bumetanide irrespective of whether a model-dependent or model-independent method was used. Oral administration of bumetanide elicited a greater and a more prolonged pharmacological response than did intravenous bumetanide. An attempt is made to relate the pharmacokinetics of the drug to its pharmacodynamics.
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  • 81
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 704-706 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Isopropyliden-sorboses ; TMS-derivatives ; GC-MS combined technique ; Mass spectra
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary A method has been developed using gas chromatography — electron impact mass spectrometry for the determination of the di-0-isopropylidene-sorbofuranose and mono-0-isopropylidene-sorbofuranose. The compounds are separated as their trimethylsilyl derivatives on a capillary column coated with the stationary phase SE-52. The mass spectra show that the silylation reaction is quantitiative and that the isopropylidene groups does not change.
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  • 82
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 183-185 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Analysis of ethylbenzene hydroperoxide ; Time normalization method
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary A gas chromatographic method, based on the time normalization technique, is described for the analysis of ethylbenzene hydroperoxide in mixtures containing ethylbenzene, acetophenone, 1-phenylethanol, benzaldehyde and phenol. Different liquid phases were tested and the best results were obtained with tricresyl phosphate and neopentyl glycol sebacate. The influence of the support, the liquid loading and the gas velocity are discussed.
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  • 83
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 625-630 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Open-tubular (capillary) columns ; Comparison of liquid phases ; Influence of temperature ; Retention index data
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The influence of temperature and liquid phase film thickness of open-tubular (capillary) columns on the retention index values of hydrocarbons on methylsilicone liquid phases is discussed. Data obtained on methylsilicones and squalane are compared. Retention index values of 43 hydrocarbons between 40 and 70 °C on OV-101 liquid phase are listed.
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  • 84
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 351-354 
    ISSN: 1612-1112
    Schlagwort(e): Supported catalysts ; Reserved-flow GC ; Drying step ; Gas chromatography
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary Application of reversed-flow gas chromatography to study the drying step in the preparation of supported catalysts is proposed. It is demonstrated that this technique can be applied to investigate the kinetic law followed, as well as to obtain kinetic parameters of drying (rate constants, activation energies and frequency factors). Amaterial illustrating this application is γ-Al2O3 impregnated with usual organic solvents (n-C5H12,n-C6H14,n-C7H16, CH3COCH3 and CH3CH2OH). It was found that in all cases above a simple first-order law based onone kind of active site is followed. Moreover, it was observed that the activation energyE a of the drying process increases almost linearly with the relative molecular mass of the solvent, whereas for the same solventE a increases with the amount used. The operation of a kinetic compensation effect suggests “similar” activated complexes of the various solvents used.
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  • 85
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Fused silica capillaries ; New polar phases: OV-1701 and RSL-310 ; Immobilization
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The possibilities of OV-1701 and RSL-310, two new stationary phases, have been evaluated for capillary gas chromatography in fused silica columns. OV-1701 is a cyanopropylphenyldimethyl polysiloxane of moderate polarity possessing excellent chromatographic characteristics. The phase exhibits high coating and chromatographic efficiencies, high temperature stability and is suitable for cross-linking. RSL-310 is a polar liquid stationary phase yet to be permanently bonded in a capillary column. The selectivity of both phases extends the applicability of fused silica columns.
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  • 86
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 241-244 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Monosaccharides ; Polyols ; GC of TMS derivatives
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary This paper describes the gas chromatographic separation of the mixture of isopropylidene monosaccharides, and their trimethylsilyl derivatives. Based on the total analysis time and resolution the best stationary phase was SF-96 using Chromosorb G as the solid support and temperature programming.
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  • 87
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 312-314 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Injection-port modification ; Oxygen and nitrogen traces
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The paper presents a new device modifying normal injection port of a gas chromatograph for eliminating air contamination thus enabling determination of traces of oxygen or nitrogen. Further modification is also proposed which enables the analysis to be carried out with a limited quantity of sample gas. Potential application of this device in the analysis of reactive gases like florine has been indicated.
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  • 88
    ISSN: 1612-1112
    Schlagwort(e): Phthalides ; Gas chromatography ; Chromosorb W ; Isomerization ; Ligustilide
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary During GLC of naturally occurring mixtures of phthalides on packed columns an artefact was sometimes detected that originated from Z-ligustilide. Active sites of Chromosorb W were responsible for the formation of the artefact, that was assumed to be E-ligustilide as GC-MS revealed that its mass spectrum was identical with that of Z-ligustilide. No isomerization was observed when freshly coated Chromosorb W was used or the support was deactivated by benzoyl chloride or melamine. The identity of the artefact was confirmed by UV irradiation experiments.
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  • 89
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 30-32 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Arsenic ; Inorganic materials
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary A method is described for the quantitative chlorination and extraction of arsenic as arsenic trichloride from a number of alloys. The conditions for the quantitative gas chromatographic measurement of the volatile chloride have been studied. The proposed method for inorganic materials is very fast giving results within 10 min; sensitive, 1.5·10−13 g As can be detected, simple and accurate. At the ng level of As the error is about 20% with a standard deviation less than 20%, and at the 10pg level the error is about 36% with a standard deviation of 44%.
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  • 90
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 765-768 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Preparative scale chromatography ; Capacity ; Dual-stage separation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The capacity of different versions of single- and dual-stage separation of mixtures on a preparative scale is considered. It has been shown that dual-stage separation with intermediate condensation considerably enhances the capacity of the installation as compared with a single-stage process.
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  • 91
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 117-124 
    ISSN: 1612-1112
    Schlagwort(e): Various packed GC column ; Gas chromatography ; Porous layer beads ; GC/MS analysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary Theoretical comparisons of various packed GC column types are presented with respect to analysis time, efficiency, sample dilution, and sample capacity for a given maximum inlet pressure. In particular, totally porous particles, porous layer beads, and glass beads are compared with one another. It is shown that 30 μm porous layer beads offer a useful compromise between analysis time and plate count with relatively good sample capacity. Moreover, when using 1 mm i.d. columns (microbore), outlet flow rates that are reasonable for direct coupling to magnetic sector mass spectrometers are achieved making these columns suitable for GC/MS. Using 30 μm Zipax porous layer beads, columns yielding 8,000 to 10,000 plates/meter have been produced with inlet pressures of 13 to 26 atm. A simple modification of the injection port converts the maximum inlet pressure of a commercial gas chromatograph to 26 atm. With such pressures, columns in excess of 20,000 plates can be achieved. Chromatograms are presented illustrating the promise of these microbore columns for GC and GC/MS analysis.
    Materialart: Digitale Medien
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  • 92
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 245-248 
    ISSN: 1612-1112
    Schlagwort(e): Chromatoscopy ; Gas chromatography ; Graphitized carbon black ; Molecular structure and retention ; Aromatic hydrocarbons
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary A molecular-statistical calculation of the retention volumes at zero sample size on graphitized thermal carbon black is carried out for quasi-rigid molecules of fluorene, indene, 1-methylindene, 2-methylindene and three dimethylindenes. A reasonable agreement is observed between the calculated and the available experimental gas chromatographic data. The potential barrier to internal rotation and the torsional angle in styrene molecules are estimated by comparing theoretically calculated and measured retention volumes.
    Materialart: Digitale Medien
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  • 93
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Silicone liquid phases ; Oxidation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The on-column oxidation of apolar and polar silicones used as gas chromatographic stationary phases is investigated. Even at 225° the effects of oxidation are found to be slight. Of the materials investigated the methylphenylsilicones are the most stable.
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  • 94
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 505-508 
    ISSN: 1612-1112
    Schlagwort(e): Glass capillary ; Gas chromatography ; Methyl chloroacetates ; Methyl chloropropanoates ; Methyl chlorobutanoates
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The gas chromatography of all chlorinated methyl acetates, methyl propanoates and methyl mono- and dichlorobutanoates has been studied on Carbowax 20M and SE-30 glass capillary columns under various running conditions. The order of elution on a non-polar column was largely determined by the boiling point of esters, whereas on a polar column it was much influenced by the structure of compounds. Complete separation of the combined mixture of all 27 compounds could not be achieved, however, methyl 3,3-dichlorobutanoate was the only ester overlapped on both columns in spite of the various column temperatures used. The best separation of the mixture was on Carbowax 20M with a temperature program from 50°C at 8°C/min, isothermal running conditions leading either to poor separation of volatile components or long analysis time and broad peaks of higher chlorinated esters. The relative retention times for compounds at the various column temperatures are given and the retention order on a polar and on a non-polar column discussed.
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  • 95
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 517-520 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Carbon-silica adsorbents ; n-Octadecanol film ; Phase transitions
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The properties of the n-octadecanol film on carbon-silica adsorbent (Carbosil) were investigated. It was found that n-octadecanol forms an oriented film on the Carbosil's surface. If the surface of the basic silica gel is not completely covered with carbon, then the phase transition takes place in this film at a temperature higher than the melting temperature of n-octadecanol. One may distinguish two forms of this film, characterised by the different structures and the temperatures of the phase transitions. The first exists on the surface of silica gel unblocked by carbon. This part of the film is a monolayer, in which the alcohol molecules are vertically oriented. The solid compact-liquid expanded type phase transition at the well-defined temperature occurs in this film. In the second part of the film formed on the carbon surface, there is a multilayer of n-octadecanol. Its molecules are probably parallely oriented in relationship to the adsorbent surface. This film desintegrates progressively when the temperature increase. Maximum temperature of this phase transition is lower than the temperature of its analogue on pure silica gel surface.
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  • 96
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 15 (1982), S. 546-558 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Capillary columns ; Quantitative analysis ; Sample inlet systems ; High-speed analysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The attainment of precise quatitative analytical data using open-tubular (capillary) columns in standard, commercially available gas chromatographic instrumentation is demonstrated. Key elements in the design and proper utilization of the instrumentation are discussed. The function of the various sample introduction systems is elaborated and their quantitative performance demonstrated. The extra-column contribution to band-spreading is determined and the resultant data is used assessing the suitability of commercial instrumentation for highspeed capillary gas chromatography. The quantitative analysis of a sample containing some eleven components in less than thirty seconds is shown.
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  • 97
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Crystal hydrates as stationary phases ; Mobile Phases containing water ; Selective retentions
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary The use of crystallohydrates, crystallohydrate solutions and melts as stationary phases in gas chromatography has been proposed. Crystallohydrates have been shown to display high selectivity in the separation of polar organic compounds when use is made of water vapours as the mobile phase. Some aspects of gas-liquid chromatography in water vapours and with the stationary phase comprising crystallohydrates have been studied, and the preliminary results obtained point to the desirability of further progress in this field.
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  • 98
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 16 (1982), S. 201-203 
    ISSN: 1612-1112
    Schlagwort(e): Phenols ; Whisky ; Gas chromatography ; Aroma compounds
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary Twelve volatile phenols were identified in whisky by combined gas chromatography-mass spectrometry. Of these phenols 2,4-dimethylphenol was found for the first time in the aroma of whisky. The content of phenol, o-, m-, and p-cresol, guaiacol, p-ethylphenol, p-ethylguaiacol and eugenol in whiskies originating from different countries was determined by gas chromatography as their 2,4-dinitrophenyl ethers using electron capture detection. The results show that Scotch whiskies differ from others in the content of o-, m-, and p-cresol. The odour threshold values of phenols studied were determined in a 10% (v/v) ethanol-water mixture and in some cases also in the whiskies. Cresols have been found to make contribution to the aroma of Scotch whisky.
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  • 99
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 16 (1982), S. 26-31 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Ionization detectors ; Gaia
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary This paper is an account of the development of the gaia hypothesis as seen through the eyes of a gas chromatographer. Gaia is a radical notion about the Earth which postulates the climate and chemical composition to be regulated at an optimum by and for life. Gas chromatography played an important role in the gathering of evidence for the hypothesis but most significantly the art of inventing detectors lead to the developement of a planetary life detector through which gaia was revealed.
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  • 100
    Digitale Medien
    Digitale Medien
    Springer
    Chromatographia 16 (1982), S. 282-285 
    ISSN: 1612-1112
    Schlagwort(e): Gas chromatography ; Naphtha analysis ; Gasoline analysis ; Hydrocarbon type analysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Summary Two different gas chromatographic methods are used for the determination of hydrocarbon type distribution in naphtha and gasoline samples with final boiling points up to 275 °C. The methods are based either on a single capillary column or on a valve-switched packed column system. Both methods give extensive information on paraffins, olefins, naphthenes and aromatics in total as well as by carbon-number. In each case the analysis is fully automated with a computer controlling the entire analysis from injection to results presentation. The advantages and limitations of both methods are discussed.
    Materialart: Digitale Medien
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