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  • bioavailability  (74)
  • Immunocytochemistry
  • Springer  (145)
  • American Chemical Society
  • Periodicals Archive Online (PAO)
  • 2000-2004  (11)
  • 1975-1979  (134)
Collection
Publisher
  • Springer  (145)
  • American Chemical Society
  • Periodicals Archive Online (PAO)
Years
Year
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    BioMetals 13 (2000), S. 29-35 
    ISSN: 1572-8773
    Keywords: bioavailability ; inflammation ; iron ; malabsorption ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Inflammatory conditions of the gastrointestinal tract and iron-deficiency anemia are very common in humans. Acute intestinal inflammation was pathologically established in rats by intraluminal administration of acetic acid into the duodenum and the proximal jejunum. The study included two control groups of intact (untreated) rats and sham-operated (saline-treated) rats for each intestinal segment. A third group of rats received acetic acid. The acetic acid-induced inflammatory process was established histopathologically and biochemically. Two days after treatment, iron absorption was measured using ligated 10-cm loops of proximal jejunum or ligated duodenum in which 59Fe was injected intraluminally (n=6 in each group). In another four control groups (intact and sham-operated for each intestinal segment) and two acetic acid-treated groups, serosal-luminal secretion of 59Fe was measured after intravenous injection (n=5 in each group). 59Fe transfer from the lumens of the duodenum and jejunum to the portal system was significantly lower in those rats in whom inflammation was induced by acetic acid. There was no apparent serosal-luminal secretion of intravenously injected 59Fe in any of the studied groups. We conclude that acetic acid-induced intestinal inflammation significantly reduces iron absorption by the duodenum and the proximal jejunum.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Calcified tissue international 24 (1977), S. 223-229 
    ISSN: 1432-0827
    Keywords: Enamel-cementum-morphology ; Immunocytochemistry ; Biochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The continuously erupting rabbit incisor tooth is normally thought of as having an enamel covered “crown” on its labial surface and a cementum covered “root” on its lingual surface. We have examined both surfaces of continuously erupting rabbit incisor teeth taken from near term embryos by a variety of means, including transmission and scanning electron microscopy, biochemical fractionation, and immunohistochemistry. In all cases, we could detect no qualitative difference in the early extracellular matrices taken from the labial and lingual surfaces of the teeth. Both matrices were shown to be composed of dentin and enamel, although the thickness and geometry of the enamel matrix on the lingual surface was somewhat different from that on the labial surface.
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  • 3
    ISSN: 1432-2048
    Keywords: Avena ; Immunocytochemistry ; Phytochrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Phytochrome of oat (Avena sativa L., cv. Garry) coleoptile cells in the red-light-absorbing form, Pr, is diffusely distributed while after conversion to the far-red-light-absorbing form, Pfr, it is observed only in very small areas within the cell. Comparison of phytochrome photoversibility measurements to the distribution of the pigment within the cell indicates that the spectral assay is not influenced by the observed compartmentalization of the chromoprotein. However, the observed compartmentalization of phytochrome is correlated with a loss in spectrophotometrically detectable Pr.
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  • 4
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    Springer
    European journal of clinical pharmacology 8 (1975), S. 293-299 
    ISSN: 1432-1041
    Keywords: Rifampicin ; p-aminosalicylic acid ; bentonite ; drug interaction ; bioavailability ; drug adsorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability (plasma concentrations, AUC and urinary excretion) of an oral solution of rifampicin was investigated in six healthy volunteers. Simultaneous administration of PAS granules produced a significant decrease in the absorption of RMP, whereas Na-PAS tablets had no effect. This indicated that the dosage form of the granules and not PAS itself was responsible for the interaction, and that the dissolution of RMP was not involved. The interaction could be reproduced by giving dummy granules that contained the same excipients but no PAS. The disintegration and dissolution of PAS granulesin vitro correlated well with the disappearance of RMP from the solution. The major excipient of the granules, bentonite (a mineral closely related to kaolin), was found to adsorb rifampicin rapidly and strongly.
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  • 5
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    Springer
    European journal of clinical pharmacology 8 (1975), S. 365-370 
    ISSN: 1432-1041
    Keywords: Particle size ; bioavailability ; digoxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of digoxin in three tablets prepared from materials with different particle sizes was measured in healthy volunteers in a cross-over study using an alcoholic solution of digoxin as a reference standard. Its bioavailability in tablets with particle sizes of 7 µ or 13 µ was 78–97% of that of digoxin in solution. The tablet with largest particle size (102 µ) showed markedly lower bioavailability than the reference solution, namely 39%. It is obvious that particle size is an important determinant of the dissolution rate and bioavailability of digoxin.
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  • 6
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    Springer
    European journal of clinical pharmacology 9 (1975), S. 209-212 
    ISSN: 1432-1041
    Keywords: Anticonvulsants ; phenytoin ; diphenylhydantoin ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma phenytoin levels were measured in 60 patients under steady-state conditions for a period of six weeks. During the trial, the preparation of phenytoin was changed from Phenytoin BP (Regent) to Epanutin Infatabs. A significant increase in plasma phenytoin levels following the change of tablet was matched by a decrease in the number of seizures.
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  • 7
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    European journal of clinical pharmacology 9 (1975), S. 213-218 
    ISSN: 1432-1041
    Keywords: Phenytoin ; diphenylhydantoin ; anticonvulsants ; bioavailability ; drug absorption ; generic inequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to evaluate the bioavailability of four different brands of phenytoin (diphenylhydantoin, DPH) tablets single doses of 600 mg DPH in acid form were given to six volunteers in a cross-over study. A micronized DPH-acid suspension was used as the reference standard. Significant differences between various products were found. The areas under the serum DPH concentration-time curves (AUC) were 26, 59, 68 and 90 per cent of the AUC of the DPH suspension. The peak serum DPH concentrations using the different tablets were 24, 54, 55 and 80 per cent of the peak value of the DPH suspension. It is likely that the differences in bio-availability of the DPH tablets are of clinical significance.
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  • 8
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    European journal of clinical pharmacology 9 (1976), S. 315-317 
    ISSN: 1432-1041
    Keywords: Tolamolol ; bioavailability ; maximum exercise tachycardia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bioavailability of capsule and tablet formulations of tolamolol were compared by measuring plasma concentration of tolamolol and reduction in maximum exercise heart rate over a period of twelve hours in eight healthy subjects in a two-way cross-over study. Tolamol was absorbed more rapidly from capsules than from tablets; this did not result in any significant difference in the reduction in maximum exercise heart rate between the two formulations. There was no significant difference between area under curve of reduction in exercise tachycardia and area under curve of plasma concentration of tolamolol for the two formulations. Reduction in maximum exercise heart rate was related to logarithm of plasma concentration of tolamolol between two and twelve hours after both formulations.
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  • 9
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    European journal of clinical pharmacology 9 (1976), S. 373-379 
    ISSN: 1432-1041
    Keywords: Methyldigoxin ; repetitive doses ; bioavailability ; deep compartments ; oral and i.v. dose ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of β-methyldigoxin 0.3 mg. After oral or intravenous administration of β-methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.
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  • 10
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    European journal of clinical pharmacology 8 (1975), S. 371-376 
    ISSN: 1432-1041
    Keywords: Digoxin ; bioavailability ; plasma levels ; cumulative urinary excretion ; particle size ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Various brands of digoxin tablets, and even different batches of one brand, may differ greatly in bioavailability. Digoxin-Sandoz® tablets have been compared with Lanoxin® manufactured between 1969 and 1972 and after May 1972. Comparisons were also made between and within batches of Digoxin-Sandoz tablets. Three separate cross-over studies were conducted involving a total of 20 volunteers. Digoxin-Sandoz tablets were shown to have a constant bioavailability and to produce plasma concentrations very similar to “new” Lanoxin. Storage for 2 years of one batch of Digoxin-Sandoz did not alter the bioavailability. Particle size was shown to influence bioavailability. Care should be exercised when plasma data alone are interpreted as an index of bioavailability. Measures of bioavailability based on plasma data obtained up to 6 h after administration differed from those based on cumulative urinary excretion data (in this study by a factor of about 2), which can lead to the belief that a difference in bioavailability is much greater than is actually the case. Data from cumulative urinary excretion, collected over a sufficiently long period of time, are likely to be the most reliable method for determining the bioavailability of a substance such as digoxin.
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  • 11
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    Springer
    European journal of clinical pharmacology 16 (1979), S. 211-215 
    ISSN: 1432-1041
    Keywords: fluoride ; bioavailability ; calcium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of milk products on the gastrointestinal absorption of fluoride from sodium fluoride tablets was studied in five healthy subjects. Two different diets were tested: (1) 250 ml standardized milk (3% fat) and (2) 500 ml of milk, 3 pieces of white bread with cheese and 150 ml of yoghurt. The 100% bioavailability of sodium fluoride tablets during fasting was greatly decreased by coadministration of milk products: with Diet 1 the absolute bioavailability calculated from combined plasma and urine data was in the range 50–79% and with Diet 2 it ranged from 50–71%. It is suggested that the decreased bioavailability produced by dairy products should be taken into account when establishing fluoride dosage regimens for prophylaxis of caries.
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  • 12
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    Springer
    European journal of clinical pharmacology 10 (1976), S. 231-236 
    ISSN: 1432-1041
    Keywords: Digoxin ; beta-methyl-digoxin ; capsules ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The intestinal absorption and urinary elimination rate of total cardioactive material was compared following digoxin and beta-methyldigoxin (BMD) administration to twelve healthy volunteers. Significantly more injected digoxin was recovered in urine. Urinary clearance was more rapid for digoxin, mean half-lives of elimination being 35 hours for digoxin and 40 hours for BMD. Calculated percentage intestinal absorption was lowest for digoxin tablets with a dissolution rate of 77% in one hour, intermediate for BMD tablets, and maximal for an experimental soft gelatin formulation of digoxin in solution. Respective mean values were 75%, 87% and 97%. Similar steady state plasma concentrations followed twice daily ingestion of the 0.25 mg digoxin tablets and 0.20 mg BMD tablets. Mean peak plasma concentration and percentage urinary recovery of ingested dose were higher during continued BMD administration. Between-subject variation in absorption was higher for the digoxin tablets. The comparative intestinal absorption of BMD and digoxin depends upon the formulation. Digoxin is virtually completely absorbed from a solution encapsulated in soft gelatin. Relatively more BMD is eliminated by nonrenal routes.
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  • 13
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    European journal of clinical pharmacology 10 (1976), S. 251-256 
    ISSN: 1432-1041
    Keywords: Sisomicin ; pharmacokinetics ; bioavailability ; two-compartment analysis ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sisomicin, a new single component aminoglycoside antibiotic related to gentamicin c1a, were determined in four healthy volunteers after intravenous and intramuscular administration of a 1 mg/kg dose. The elimination profile of this antibiotic follows two-compartment model kinetics after I.V. administration. The fast (α) and slow (β) disposition rate constants averaged 0.072 and 0.004 min−1, respectively. The volume of distribution at the steady-state averaged 0.185 liters/kg which approximately corresponds to the volume of extracellular space. The physiological availability of an intramuscular dose appeared to be complete. A method of administration adapted to the kinetic properties of the drug is proposed.
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  • 14
    ISSN: 1432-1041
    Keywords: Cefoxitin ; lidocaine ; intramuscular ; bioavailability ; pain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The use of lidocaine HCl solution at concentrations of 0.5 and 1.0% to reconstitute sodium cefoxitin relieves the pain associated with intramuscular injections of the antibiotic. Cefoxitin absorption by the intramuscular route is initially rapid and is virtually complete. Peak serum concentrations, corresponding to about one-half those of a comparable intravenous infusion, are achieved in 30 min. Continuing absorption tends to maintain higher serum concentrations for longer times. Renal clearance and serum half-life of cefoxitin do not appear to be affected by lidocaine at its effective anaesthetic concentrations.
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  • 15
    ISSN: 1432-1041
    Keywords: p-Chlorophenoxyisobutyric acid ; clofibrate ; steady-state plasma concentrations ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations and bioavailability of clofibrinic acid have been estimated under conditions approaching the steady-state during a ten-day period of administration as clofibrate or as a calcium clofibrinate-carbonate combination (1:1 w/w) at a dosage interval of 12 h. Formulation — related differences in bioavailability were not significant, and the 95% confidence limits of these differences were within −2% to +8% of the mean for the reference formulation of clofibrate. The mean steadystate plasma concentrations of clofibrinic acid measured on the tenth day of dosing were 116 µg/ml±22 S.D. and 119 µg/ml±23 S.D. after administration of 885 mg as clofibrate and the calcium clofibrinate-carbonate combination respectively. The peaks of mean plasma concentrations were 70 µg/ml±15 S.D., 119 µg/ml±32 S.D. and 131 µg/ml±26 S.D. on the first, fifth and tenth day of dosing with clofibrate, and 62 µg/ml±13 S.D., 127 µg/ml±S.D. and 143 µg/ml±25 S.D. on the corresponding days of dosing with the calcium clofibrinate-carbonate combination. After the last dose on the tenth day of dosing, the mean apparent half-lives of elimination of clofibrinic acid from plasma were 24.2 h±4.4 S.D. and 25.5 h±3.2 S.D. after administration of clofibrate and the calcium clofibrinate-carbonate combination respectively.
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  • 16
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    European journal of clinical pharmacology 13 (1978), S. 125-128 
    ISSN: 1432-1041
    Keywords: bioavailability ; diuretics ; gastrointestinal absorption ; hydrochlorothiazide ; thiazides ; food effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Hydrochlorothiazide (hct) 75 mg was administered orally to eight healthy volunteers without (Study I) or together with a standardized meal (Study II), and plasma and urine concentrations of hct were analyzed by GLC. The plasma levels of hct were higher initially when the tablets were taken on an empty stomach, but after 5 h they were higher in Study II. There was no difference between the two studies in the area under plasma concentration time curves. The urinary recovery of hct totalled 55.6±4.9 mg when the drug was given with food and 47.4±6.0 when it was taken on an empty stomach. The difference is significant (p〈0.01). As the urinary recovery represents the uptake of hct, it appears that the gastrointestinal absorption of hct is enhanced when the drug is given with food.
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  • 17
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    European journal of clinical pharmacology 10 (1976), S. 257-262 
    ISSN: 1432-1041
    Keywords: Anti-inflammatory and analgesic drug ; indoprofen ; pharmacokinetics ; bioavailability ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a pharmacokinetic study of the new analgesic and anti-inflammatory drug indoprofen, plasma levels and urinary excretion were determined in four healthy volunteers after 100 mg and 200 mg iv, and after 100 mg (capsules) and 200 mg (tablets) oral doses. After iv administration, the mean biological half-life (t1/2 β) was about 2 h (range 1.4 to 3.2 h). The apparent volume of distribution Vdβ ranged between 11 to 17 % of body weight, indicating its limited extravascular distribution. Most of the drug was excreted in urine as glucuronide and a smaller proportion as unchanged indoprofen: the 24 h urinary excretion of these compounds accounted for 67 to 95 % of an iv dose. Peak plasma levels occurred between 30 and 120 minutes after oral administration of 100 mg as capsules or 200 mg as tablets. The mean biological half-life was about 2 h, as after iv administration. The bioavailability of oral doses was assessed using both plasma levels and urinary excretion data. The absorption of capsules and tablets was practically complete, that of the former being faster.
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  • 18
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    European journal of clinical pharmacology 10 (1976), S. 101-108 
    ISSN: 1432-1041
    Keywords: Cardiac glycosides ; methyl proscillaridin ; plasma concentrations ; electrocardiogram ; bioavailability ; 86Rb-erythrocyte assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The aim of this study was to obtain data about the pharmacological properties of a new glycoside derivative in man. Plasma concentrations and ECG parameters were measured after oral and intravenous administration of a single dose of 1.2 mg methyl proscillaridin in 16 healthy volunteers, using a strictly randomized, two-period change-over design. Glycoside concentrations were measured using a modified86Rb-erythrocyte-assay. QT-duration, corrected for frequency (QTc), was the principal variable measured in the ECG. By either route, there was a maximum plasma level after 1 hour, which had decreased to a minimum at 3 hours, followed by a second peak at 4 to 10 hours (orally〉iv). From 10 to 72 hours the concentrations decreased with a median t 1/2 of 23.3 hours (iv) and 33.0 hours (orally). Comparison of the ratio of plasma concentrations following oral and iv administration resulted in a bioavailability of 69 % using the 48 hour plasma levels, and 59 % using the areas under the concentration-time curves. The mean QTc was maximally shortened to 28 msec at 1 hour after iv and to 19 msec at 10 hours after the oral dose. A distinct similarity between time-concentration and time-QTc curves was seen after the initial distribution phase, both after oral and intravenous administration. The new derivative shows a rapid elimination. Its bioavailability is reasonably high.
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  • 19
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    European journal of clinical pharmacology 16 (1979), S. 417-421 
    ISSN: 1432-1041
    Keywords: theophylline ; aminophylline ; bioavailability ; rapidly dissolving tablet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of a rapidly dissolving tablet of theophylline and three brands of standard aminophylline tablets was estimated in a four way cross-over study involving 8 healthy adult volunteers. The relative extent of bioavailability as assessed by the measurement of the total area under the plasma concentration time curves showed no difference between the products (P〉0.05). Computed estimates of the rate of drug absorption were similar for all 4 products tested. The results indicate that the rapidly dissolving tablet offers no advantage in respect to rate and extent of absorption over conventional aminophylline tablets.
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  • 20
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    European journal of clinical pharmacology 12 (1977), S. 69-72 
    ISSN: 1432-1041
    Keywords: Metronidazole ; serum concentration ; bioavailability ; food intake ; healthy subjects ; Crohn's disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possible influence of food intake on the bioavailability of metronidazole was examined in ten healthy volunteers by administration of a single dose of metronidazole on an empty stomach, and with a standardized breakfast. Food intake did not significantly alter the bioavailability of metronidazole. The interindividual variation in bioavailability appeared to be slight. In nine patients with Crohn's disease, the absorption of metronidazole appeared to be reduced and to be more variable than in healthy subjects. In both groups there was a clear relationship between the amount absorbed and dose/kg body weight. Thus, from the pharmacokinetic point of view, metronidazole can safely be given either with or between meals. The dose should be related to body weight.
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  • 21
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    European journal of clinical pharmacology 12 (1977), S. 285-290 
    ISSN: 1432-1041
    Keywords: Phenytoin acid ; phenytoin calcium ; bioavailability ; inequivalence of generics ; normal subjects ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum phenytoin concentrations have been studied in epileptic patients and healthy subjects taking tablets of phenytoin calcium (Desitin), A, phenytoin acid (Desitin), B, and phenytoin acid (Nordmark), C. Retrospective data and prospective investigation of hospitalized patients on long-term phenytoin treatment showed that significantly higher serum concentrations of phenytoin were produced by the phenytoin acid preparations B and C than by the phenytoin calcium preparation A. In a cross over study six volunteers received 200 mg/day of preparations A, B, and C for three weeks. In this study, too, higher phenytoin serum concentrations were produced by B and C than by A, although the differences were not statistically significant. The reasons for the discrepancies between the studies in healthy and epileptic subjects are discussed.
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  • 22
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    European journal of clinical pharmacology 12 (1977), S. 383-386 
    ISSN: 1432-1041
    Keywords: Benzodiazepine ; temazepam ; pharmacokinetics ; bioavailability ; hard and soft gelatine capsules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels of temazepam were determined in healthy subjects after single oral administration of soft and hard gelatin capsules, and after 7 consecutive night-time doses in soft capsules. Absorption from soft gelatin capsules was significantly faster and produced earlier and higher peak plasma levels. The two pharmaceutical forms did not show any significant difference in relative availability. The apparent half-life of temazepam after night-time administration was significantly shorter than after morning administration, but no change in half-life was observed between the first and seventh night-time doses.
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  • 23
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    European journal of clinical pharmacology 14 (1978), S. 253-259 
    ISSN: 1432-1041
    Keywords: Pseudoephedrine ; side effects ; bioavailability ; multiple oral dosing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dose tolerance and pharmacokinetic studies of pseudoephedrine sustained action capsules were performed in thirty-three adult male subjects who received either 120 mg or 150 mg capsules every twelve hours for seven consecutive days in a double-blind parallel design study. Although only one subject in the 150 mg group was discontinued prematurely from this study, a large number of side effects typical of CNS stimulation were seen. A placebo effect might account for a portion of these complaints, however symtoms evaluated as being due to drug were significantly more severe and persistent in the 150 mg group. Pulse rates showed a persistent and significant increase while systolic and diastolic blood pressure fell from the baseline values in both groups. A pharmacokinetic analysis of the pseudoephedrine plasma concentration-time data provided estimates of half-life and the volume of distribution/availability ratio. The values obtained were in good agreement with values reported by others. Half-life was not influenced by urine pH probably as a result of the narrow range of urine pHs observed in the subjects. Calculations of relative bioavailability suggest that the 120 mg capsule formulation has a 30% greater bioavailability compared to the 150 mg capsule.
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  • 24
    ISSN: 1432-1041
    Keywords: chlorthalidone ; pharmacokinetics ; oral and i.v. doses ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t1/2 after i.v. dosing was 36.5 h (±10.5 SD), and the mean plasma t1/2 after oral doses was 44.1 h (±9.6 SD). The mean red blood cell concentration t1/2 after i.v. doses was 46.4 h (±9.9 SD), and the mean red blood cell t1/2 after the oral doses was 52.7 h (±9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (±8.6 SD) % of the intravenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (±8.5 SD) %. Faecal excretion ranged from 1.3–8.5% of dose in the i.v. study to 17.5–31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were — a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F=0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.
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  • 25
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    European journal of clinical pharmacology 16 (1979), S. 31-38 
    ISSN: 1432-1041
    Keywords: bezafibrate ; hyperlipoproteinemia ; bioavailability ; pharmacokinetics ; GC-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics of bezafibrate, a newly developed drug of great lipid-lowering potency, were investigated in normal male subjects. Five male volunteers received14C-labelled bezafibrate orally in solution, and a further 10 were given the same dose (300 mg) of un-labelled drug as tablets. The concentration of bezafibrate in serum and urine from the latter was determined by GC, and in the former total radioactivity in serum, urine and feces was followed for 48 h, and urinary excretion products were analysed by TLC and GC-MS. Rapid absorption from the gastrointestinal tract led to peak serum levels 30 min and 2 h after administration of solution and tablets, respectively. Since approximately 95% of the administered14C-bezafibrate was excreted in urine within 48 h, and almost all the remainder was detected in feces, absorption can be regarded as complete after administration in solution. The relative optimal bioavailability from the tablets was also complete, since in both cases approximately 50% of the administered dose was detected as unchanged bezafibrate in urine within 24 h by GC in the tablet study, and by TLC in the solution study. Of the decomposition products, more than 20% of the dose was present as glucuronides and the remainder consisted of several more polar compounds, one of which was identified as a hydroxyderivative of bezafibrate. Since the apparent halflife of bezafibrate in serum was 2.1 h, this new drug possesses favourable pharmacokinetic features: rapid and complete absorption, even from tablets, combined with a conveniently short half-life, and clearance which is half renal (56 ml/min) and half metabolic (43 ml/min), giving a total clearance of 99 ml/min.
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  • 26
    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; single dose ; bioavailability ; pharmacodynamics ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers received single iv and oral doses of 2-[p-(1-oxo-2-isoindolinyl)phenyl] butyric acid 100 mg (indobufen; K 3920), an inhibitor of platelet aggregation. Plasma levels and urinary excretion of the drug were determined by GLC. Collagen-induced platelet aggregation was assessed turbidimetrically at various intervals after administration. The plasma half-life of the drug was 7–8 h and more than 70% of the administered dose was recovered within 48 h in urine, as unchanged drug and as the glucuronide of indobufen. After oral administration of tablets of two different formulations, the drug was completely absorbed, but one formulation showed faster absorption. The maximal inhibitory effect on platelet aggregation was observed 1 to 4 h after iv administration, and it had decreased by 8 h. After tablets, peak effect and the time of the peak were similar, but activity was significantly prolonged, in accordance with the higher plasma levels found at 8 h. The data suggest that the effect of indobufen on platelets is reversible, and that for this drug platelets behave as a compartment that slowly equilibrates with plasma.
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  • 27
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    European journal of clinical pharmacology 16 (1979), S. 45-48 
    ISSN: 1432-1041
    Keywords: quinidine ; slow release formulation ; pharmacokinetics ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of quinidine in two sustained release preparations A and B has been compared in three females and three males with i.v. administration of quinidine. The initial rate of oral absorption did not differ between the two drug preparations; the peak concentration was observed after 4 h both for A and B, but was significantly higher after B. A slower decrease in plasma concentration was observed after preparation A than B. Absolute bioavailability did not differ significantly between A (median value 78.4%) and B (median 87.1%). Drug absorption in vivo was in good agreement with the results of in vitro dissolution tests on both preparations. The slower decrease in plasma concentration found for the new sustained release form of quinidine should be of clinical advantage.
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  • 28
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    European journal of clinical pharmacology 10 (1976), S. 183-187 
    ISSN: 1432-1041
    Keywords: Hydralazine ; bioavailability ; pharmacogenetics ; first pass effect ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After oral administration of a single 50 mg dose of hydralazine (Apresoline®), the serum half-life (T1/2) and bioavailability (AUC0−∞) were assessed in 16 healthy volunteers. The half-life was 2.57±0.14 h (S.E.) in 10 slow acetylators of sulphadimidine, and 2.18±0.15 h in 6 fast acetylators (difference not statistically significant). AUC0−∞ was significantly higher in slow acetylators, at 1.04±0.10 µg·hour·ml−1, compared to 0.66±0.12 µg·hour·ml−1 in the fast acetylators (p〈0.025). Treatment with Apresoline® 25 mg tid produced minimum serum concentrations at steady-state of 57.3±7.3 ng·ml−1 and 33.4±4.2 ng·ml−1 in 8 slow and 5 fast acetylators, respectively (p〈0.05). The corresponding maximum concentrations were 228.8±20.3 ng·ml−1 and 147.6±15.0 ng·ml−1 in slow and fast acetylators, respectively (p〈0.025). First-pass metabolism of hydralazine could explain the difference in bioavailability of the drug between fast and slow acetylators, without any corresponding difference in the elimination rate of the drug in the post-distributive phase.
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  • 29
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    European journal of clinical pharmacology 10 (1976), S. 395-401 
    ISSN: 1432-1041
    Keywords: Hydralazine ; bioavailability ; polymorphic acetylation ; first-pass metabolism ; oral and intravenous dosing
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of orally administered hydralazine was assessed in 4 healthy subjects after separate administration of a single oral or intravenous dose (0.3 mg·kg−1). Comparison of the areas under the serum concentration-time curves showed that 26 – 55 % of the oral dose was available to the systemic circulation as unchanged drug. The O - 24 h excretion of the drug in urine was rapid: 11.4 – 14.1 % of the dose after intravenous administration, and 2.0 – 3.6 % after an oral dose. Acetylation of hydralazine leads to formation of 3-methyl-s-triazolo-3,4,a-phthalazine (MTP) and a gas-liquid-chromatographic method for its measurement in urine was developed. After oral and intravenous administration, 0.8 – 1.2 % and 1.4 – 2.3 % of the dose, respectively, were recovered within 24 hours from urine as MTP. After oral administration there was a relative increase in the amount of MTP in every subject, which indicates route-dependent metabolism. The lower bioavailability of oral hydralazine could be explained in terms of first-pass metabolism.
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  • 30
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    European journal of clinical pharmacology 16 (1979), S. 335-340 
    ISSN: 1432-1041
    Keywords: cimetidine ; enterohepatic circulation ; irregular absorption ; bioavailability ; pharmacokinetics ; volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability and pharmacokinetics of cimetidine have been studied in healthy volunteers after administration of single intravenous (100 mg) and oral doses (100, 400 and 800 mg). After i.v. administration, the kinetics of cimetidine could be described by a linear, two compartment open model. Substantial variation in half-life was observed between subjects, with a mean value of 2.1 h (range 0.9–4.7). Cimetidine had a low hepatic extraction ratio and a high total plasma clearance, due to extensive urinary excretion of unchanged drug. After oral administration, the plasma concentration vs time curves in most subjects exhibited two marked peaks, an observation that seemed to be constant within individuals and was independent of dose. Bioavailability, estimated as the area under the plasma concentration vs time curves (AUC), after oral doses as compared to the intravenous dose, in most cases exceeded 100%. There was no correlation between bioavailability estimated as AUC and as urinary excretion of unchanged drug. These observations may indicate an enterohepatic circulatory mechanism, predominantly after oral administration. Both unchanged drug and its sulphoxide metabolite appear to be excreted in bile. The latter was shown in vitro to be reduced to cimetidine by fecal bacteria.
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  • 31
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    European journal of clinical pharmacology 13 (1978), S. 267-274 
    ISSN: 1432-1041
    Keywords: Chlordiazepoxide ; benzodiazepines ; pharmacokinetics ; bioavailability ; intramuscular injection ; alcohol withdrawal
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of oral and intramuscular (i. m.) chlordiazepoxide hydrochloride (CDX · HCl) was compared in two pharmacokinetic studies. In Study One, single 50-mg doses of CDX · HCl were administered orally and by i. m. injection to 14 healthy volunteers using a crossover design. Whole-blood concentrations of chlordiazepoxide (CDX) and its first active metabolite, desmethylchlordiazepoxide (DMCDX), were determined in multiple samples drawn after the dose. Mean pharmacokinetic variables for CDX following oral and i. m. administration, respectively, were: highest measured blood concentration, 1.65 vs 0.87 µg/ml (p〈0.001); time of highest concentration, 2.3 vs 7.6 h after dosing (p〈0.001); apparent absorption half-life, 0.71 vs 3.39 h (p〈0.001). Biphasic absorption after i. m. injection, consistent with precipitation at the injection site, was observed in 9 of 14 subjects. Based upon comparison with previous intravenous data, the completeness of absorption was 100% for oral vs 86% for i. m. CDX · HCl (p〈0.1). In Study Two, 28 male chronic alcoholics with clinical manifestations of the acute alcohol withdrawal syndrome were randomly assigned to one of four treatment conditions: 50 or 100 mg doses of CDX · HCl, by mouth or by i. m. injection. Concentrations of CDX and DMCDX, determined in plasma samples drawn every 20 min for 5 h following the dose, were significantly higher after oral administration of a given dose than at corresponding points in time after i.m. injection after the same dose. Thus absorption of oral CDX is reasonably rapid and complete, whereas the absorption rate of i. m. CDX is slow.
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  • 32
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    European journal of clinical pharmacology 15 (1979), S. 269-274 
    ISSN: 1432-1041
    Keywords: phenytoin ; food-intake ; bioavailability ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the absorption of phenytoin was examined in eight healthy volunteers, by study of single-dose kinetics following ingestion of phenytoin 300 mg either with a standardized breakfast or on an empty stomach. Blood samples were collected at regular intervals from 0 to 48 h, and serum concentrations of unmetabolized phenytoin were determined by gas chromatography. Serum concentrations of the major metabolite of phenytoin, 4-hydroxyphenytoin, were measured by mass fragmentography. Concurrent intake of food and phenytoin appeared to accelerate absorption of the drug from the formulation used, and the peak concentrations were significantly higher (mean increase 40%) in the postprandial than in the preprandial state. As reflected by the AUC (area under the curve), the amount of drug absorbed was increased during postprandial conditions, although the difference only reached borderline significance. It is suggested that phenytoin should always be taken in a defined relation to meals.
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  • 33
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    European journal of clinical pharmacology 16 (1979), S. 107-112 
    ISSN: 1432-1041
    Keywords: quinidine ; enteric-coated tablets ; bioavailability ; gastric emptying ; pH
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of quinidine from single and multiple doses of an enteric-coated preparation (Systodin®) was studied in seven healthy subjects, and was compared with the pharmacokinetics of intravenously administered quinidine and the results of in vitro dissolution tests of the tablets. Absorption of quinidine began after a variable delay, 2–8 h (mean 4.8) after fasting and 3–10 h (mean 6.1) after food. The rate of absorption varied both in and between individuals. It appeared to be lower when the drug was administered after food. Multiple doses after food gave a pattern of plasma concentration-time curves similar to that found on administration of single doses after food. The delay prior to absorption was prolonged at night. The ratio between the maximum and minimum concentration of quinidine during a dose interval varied from 1.3 to 3.2 (mean 2.0). Bioavailability of quinidine in fasting subjects ranged from 69 to 95% (mean 83); variation was greater when doses were administered after food. The release of quinidine from the enteric-coated preparation was pH dependent and was sustained at low pHs as may be found in the intestines. The results indicate that the absorption of quinidine from the enteric-coated formulation was dependent on the highly variable rate of gastric emptying and the pH of intestinal fluid, and it varied greatly both within and between individuals.
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  • 34
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    European journal of clinical pharmacology 16 (1979), S. 141-147 
    ISSN: 1432-1041
    Keywords: prazepam ; N-desmethyldiazepam ; bioavailability ; pharmokinetics ; electron-capture gasliquid chromatography
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An original electron-capture gas chromatographic assay was developed for simultaneous measurement of plasma levels of the benzodiazepine derivative prazepam and of its principal unconjugated metabolite, N-desmethyldiazepam. The assay was used to study the pharmacokinetics of the drug and its comparative bioavailability from tablets and from a specially prepared solution. Nine healthy adult volunteers were studied. Each volunteer on one occasion took 30 mg of the drug in tablet form, and on another occasion 30 mg of the drug in solution. In all subjects, N-desmethyldiazepam appeared in plasma shortly after prazepam appeared and reached a peak within four hours of prazepam ingestion. Thereafter plasma N-desmethyldiazepam levels were much higher than plasma prazepam levels throughout. Prazepam became undetectable within six hours of intake, whereas its metabolite could still be measured in plasma fourteen days after dosage. Thus much of the pharmacological action of prazepam may be mediated through its metabolite, N-desmethyldiazepam. In five of the nine subjects, areas under the plasma level curves for the metabolite were not markedly different for the tablet and solution formulations studied. In the other four subjects the area under the curve for the tablets was 50% to 80% of the area under the curve for the solution. The time to reach peak plasma level for the metabolite was shorter after the solution formulation (mean 2.0±SD 1.2 h) than after the tablet formulation (mean 4.2±SD 1.7 h).
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  • 35
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    European journal of clinical pharmacology 10 (1976), S. 55-58 
    ISSN: 1432-1041
    Keywords: Penicillin V ; bioavailability ; pharmacokinetics ; dose ranging
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An absorption study was performed in ten healthy volunteers to test the bioavailability of various doses of two penicillin V-K preparations: Isocillin® (Hoechst AG, Federal Republic of Germany), — tablets of 600 000 and 1.2 Mega U; V-Cillin® (Eli Lilly, USA), — tablets of 200 000, 400 000 and 800 000 U. The serum concentrations and elimination of the active substance in urine were measured for six hours after administration. Independently of the source of the preparation, a strict linear relation between the dose and the area under the serum curve (AUC), or between the dose and the urinary elimination, was demonstrated by regression analysis. The dose-dependent increase in the AUC was highly significant (p〈0.01) in the range tested, i.e. between 200 000 and 1.2 Mega U. The relative elimination of active substance in urine lay within narrow limits for all doses (35.7–41.3%). Thus, both compounds proved to have the same bioavailability.
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  • 36
    ISSN: 1432-1041
    Keywords: Ampicillin ; bioavailability ; pharmacokinetics ; branded products ; proprietary preparations ; capsule formulation ; tablet formulation
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of three different brands of ampicillin were studied in 10 volunteers. After intravenous administration ampicillin can be described adequately by a two-compartment open pharmacokinetic model. The half-life during the α-phase was 9 min and the β-half-life was in the range 50–60 min, independent of the mode of administration. Absolute bioavailability was determined from the ratio of the areas under the serum concentration curves obtained after oral and intravenous administration of equal doses. Bioavailability was also estimated by analysis of variance. The results indicated absolute availability of the three products of 39–54%. One of the products, a capsule formulation, showed a significantly lower bioavailability than the others, which were tablet formulations.
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  • 37
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    European journal of clinical pharmacology 11 (1977), S. 277-281 
    ISSN: 1432-1041
    Keywords: Proscillaridin ; oral administration ; portal venous sample ; porto-peripheral concentration difference ; bioavailability ; 86Rb-uptake inhibition assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of proscillaridin A was studied in four patients undergoing catheterization of the portal vein for diagnostic purposes. Proscillaridin 1.5 mg was given as a single oral dose and plasma glycoside activity was analyzed by the86Rb-uptake inhibition technique. Proscillaridin appeared rapidly in the portal blood, peak activity being found after 15 min in three and after 30 min in one patient. In peripheral blood the peak activity occurred after approximately 35 min. Despite rapid passage across the gut wall, porto-peripheral differences in glycoside activity were small; they were zero after 4 h. The mean amount absorbed as active proscillaridin during the first 4 h after the dose was calculated to be only 7.1% of the given amount. Late porto-peripheral differences, probably due to enterohepatic recycling, appeared after 6 h in three patients. The results suggest that proscillaridin undergoes first pass inactivation in the gut wall. Enterohepatic recirculation may contribute to the amounts of active glycoside that reach the systemic circulation.
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  • 38
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    European journal of clinical pharmacology 10 (1976), S. 49-54 
    ISSN: 1432-1041
    Keywords: Three-compartment open model ; intravenous infusion ; apparent volume of distribution ; renal insufficiency ; miconazole ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic profile of miconazole has been studied in normal subjects and in patients suffering from severe renal insufficiency; one group of patients was undergoing intermittent haemodialysis. A three-compartment open model was fitted to the observed plasma concentrations obtained after intravenous infusion of miconazole 522 mg over fifteen minutes. The rate constants of elimination and exchange between compartments computed for the three groups were not significantly different. The apparent volumes of distribution in the cases of renal failure not undergoing haemodialysis were significantly smaller than the corresponding control values. A computational procedure is described which reduces observations obtained after infusion to the case of a single rapid intravenous administration.
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  • 39
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    European journal of clinical pharmacology 11 (1977), S. 207-212 
    ISSN: 1432-1041
    Keywords: Chlorpropamide ; hypoglycaemic agent ; bioavailability ; plasma concentrations ; bioequivalence ; dissolution tests
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of chlorpropamide from two new formulations (Melitase® tablets) has been compared to that from a reference formulation which is currently in clinical use as a hypoglycaemic agent. In both rate and extent of bioavailability, all three formulations may be considered equivalent, providing allowances are made for differences in drug content. With 95% confidence, the mean bioavailability of chlorpropamide from the new formulations was within about 16% of the mean from the reference formulation, and formulation-related differences were not statistically significant. Although all three formulations were shown to have similar dissolution profiles, dissolution of chlorpropamide was pH-dependent in vitro. Dissolution was almost complete during 30 min at pH 7.2, but only 40%–60% had dissolved during 90 min at pH 2.0. A peak mean concentration of 22.7 µg/ml was reached 3 h after administration of 2×100 mg tablets of the new formulation and peak mean concentrations of 26.8 µg/ml and 27.4 µg/ml were reached 3 h and 4 hours after administration of one 250 mg tablet of the new formulation and one 250 mg tablet of the reference formulation respectively. Formulation-related differences of mean plasma concentrations (after scaling for equal doses of 250 mg) were not significant and each formulation provided similar plasma concentrations at corresponding times after administration. Statistically significant subject-related differences in all the parameters of bioavailability were shown by analyses of variance.
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  • 40
    ISSN: 1432-1041
    Keywords: ergotamine ; migraine ; bioavailability ; radioimmunoassay ; plasma level ; CSF level ; continuous dosing
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma ergotamine concentrations were determined by radioimmunoassay in 10 healthy subjects after a 2 mg oral dose of ergotamine, administered at 24 h intervals on three consecutive days. After the first dose the mean peak plasma level of 0.35±0.05 (SEM) ng/ml was found 1–2 h after administration. In the samples obtained 2 h after the second and third doses, plasma ergotamine levels did not exceed the first peak value. On the other hand, after the third and last dose the plasma ergotamine began to rise slowly, reaching maximum of 0.70± 0.10 ng/ml on the 6th day after administration. This supports the concept of accumulation of the drug or of immunoreactive metabolites. CSF ergotamine was determined in 4 patients, who underwent lumbar puncture for other diagnostic purposes, 1 to 2 h after the 2 mg oral dose. A concentration of 0.40± 0.03 ng/ml was observed. In seven out of 18 migraine patients who were taking ergotamine preparations daily (mean 11.7 mg/week), ergotamine could not be detected in plasma 1 h after administration of the dose. In the remaining migraine patients, the pattern of plasma ergotamine after both the daily and the test doses was similar to that of the 10 healthy subjects. The results in volunteers and migraine patients suggest notable variation in bioavailability of the drug. It seems that in most subjects there is accumulation or tissue redistribution of ergotamine or its immunoreactive metabolites, although in a significant number of migraine patients who use the drug daily, ergotamine does not appear to be biologically available.
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  • 41
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    European journal of clinical pharmacology 16 (1979), S. 405-410 
    ISSN: 1432-1041
    Keywords: diclofenac ; plasma levels ; intravenous bolus administration ; oral administration ; enteric coating ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of diclofenac were examined following single rapid intravenous injection and also following single oral doses to healthy female volunteers. After intravenous injection plasma levels of diclofenac fell rapidly and were below the limits of detection at 5.5 h postdosing. Individual drug profiles were described by a triexponential function and mean half-lives of the three exponential phases were 0.05, 0.26 and 1.1 h. After oral doses of enteric-coated tablets, the lag time between dosing and the appearance of drug in plasma varied between 1.0 and 4.5 h. However once drug absorption had commenced similar plasma drug profiles were obtained in different individuals. Peak plasma diclofenac levels ranged from 1.4 to 3.0 µg · ml−1. The mean terminal drug half-life in plasma was 1.8 h after oral doses. This value was not significantly greater than the value of 1.1 h following intravenous doses. Fifty percent of orally dosed diclofenac did not reach the systemic circulation due, predominantly, to first-pass metabolism.
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  • 42
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    European journal of clinical pharmacology 11 (1977), S. 219-224 
    ISSN: 1432-1041
    Keywords: Nortriptyline ; 10-OH-nortriptyline ; bioavailability ; plasma metabolites ; first pass metabolism ; oral dose ; intramuscular dose
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nortriptyline was given orally and intramuscularly to six depressed patients. Plasma concentrations of parent drug and the unconjugated and conjugated principal metabolite, 10-hydroxynortriptyline, were determined by mass fragmentography. There was a significant decrease in the area under the nortriptyline plasma concentration — time curve after the oral route of administration, whilst the elimination rate was unchanged. With the oral dose, plasma concentrations of the metabolites were higher and peaked earlier than after intramuscular administration, whilst the opposite was true for the parent compound. This proves that the difference in bioavailability between the two routes of administration was due to first pass metabolism. As determined from the ratio between corresponding areas, the relative bioavailability of the oral dose was 66±21 S.D. per cent. This fraction is higher than that reported previously when intravenous nortriptyline was used as the reference dosage form.
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  • 43
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    European journal of clinical pharmacology 12 (1977), S. 281-284 
    ISSN: 1432-1041
    Keywords: Tetracycline ; bioavailability ; plasma levels ; nutritional state ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Relative bioavailability after oral administration of a single dose and Cmin levels of tetracycline in plasma after multiple doses were determined in groups of well-nourished and undernourished subjects. The relative bioavailability of tetracycline, assessed by the area under serum concentration time-curves, did not differ in undernourished and well-nourished patients. The plasma levels were not different in the two groups after the conventional dose of tetracycline HCl 250 mg at 6 hour intervals. However, in these studies undernourished subjects received a higher dose per kg body weight, which could have compensated for any effect of a shortened half life of the drug. When the dose per kg body weight was reduced, the Cmin levels were lower. On the other hand, with the same dose per kg body weight at more frequent intervals, the plasma concentrations were similar to those in well-nourished subjects. These studies indicate that the dosage regimen should be based both on body weight and on the nutritional status of the individual.
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  • 44
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    European journal of clinical pharmacology 12 (1977), S. 65-68 
    ISSN: 1432-1041
    Keywords: Indomethacin ; antacids ; drug-drug interactions ; bioavailability ; drug combinations
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The biovailability of indomethacin from two indomethacin-antacid (aluminum hydroxide magnesium carbonate and magnesium hydroxide) combinations was compared with the bioavailability of oral indomethacin. Relative bioavailability was estimated by three methods: comparison of plasma concentrations at various times, comparison of areas under plasma concentration time curves, and comparison of the amount of drug excreted unchanged in the urine. A double blind three-way crossover study was conducted in twelve healthy volunteers. The combination with the slightly smaller amount of antacid (preparation A) showed significantly decreased bioavailability by all three methods in comparison with indomethacin alone (preparation C). The combination with the larger amount of antacid (preparation B) was also less bioavailable than preparation C. This effect was significant only for the comparison of areas under curves and not for plasma levels, although the mean plasma levels produced by preparation B at all times were lower than those for preparation C. These findings suggest that aluminum hydroxide magnesium carbonate and magnesium hydroxide decrease the bioavailability of indomethacin.
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  • 45
    ISSN: 1432-1041
    Keywords: Tolmetin ; pharmacokinetics ; bioavailability ; antacid ; oral dose
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The purpose of this study was to determine whether a concomitant single dose of antacid or multiple doses of antacid administered prior to, and with tolmetin, alter the pharmacokinetics of tolmetin when the drug was administered as a commercially available tablet containing tolmetin sodium. The possible effects of the antacid on plasma concentrations and urinary excretion of tolmetin and its major metabolite were evaluated following administration of: (a) tolmetin sodium alone; (b) antacid four time a day for three days prior to a single dose of tolmetin sodium, with continuation of the antacid during the day tolmetin was given; and (c) co-administration of single doses of tolmetin sodium and antacid. The twenty-four subject study was of the crossover type. There were no significant differences among treatment means for: (i) peak plasma concentrations of both tolmetin and metabolite, (ii) AUC 0–8 h and AUC 0-∞ for both tolmetin and metabolite, (iii) time to peak plasma concentration for both tolmetin and metabolite, (iv) plasma concentrations of both tolmetin and the metabolite at all sampling times (except for tolmetin at 2 h), (v) renal clearance of both tolmetin and its metabolite, and (vi) the amount of metabolite excreted in the 0–24 h urine. There were small, but significant, differences among amounts of tolmetin excreted in the 0–24 h urine. Semilogarithmic plots of both tolmetin and metabolite plasma concentrations past the peak concentrations were curved over the entire 8-h observation period; although the elimination half-life of tolmetin has been reported to be about one hour, the half-life most probably exceeds 2.6 h in most subjects. The results of this study indicate a lack of a significant drug-drug interaction between the non-steroidal anti-inflammatory agent, tolmetin sodium, and a commonly used antacid, which is a mixture of magnesium and aluminium hydroxides.
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  • 46
    ISSN: 1432-1041
    Keywords: Coumarin ; 7-Hydroxycoumarin ; drug disposition ; first-pass effect ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of coumarin (C) upon i.v. and p.o. administration and its metabolites 7-hydroxy-coumarin (7-HC) and 7-hydroxy-coumarin glucuronide (7-HCG) have been studied. Six healthy volunteers were involved in this investigation. Four of the volunteers participated in a crossover study. Coumarin was administered i.v. and p.o. in dose sizes of 0.25 mg/kg and 0.857 mg/kg, respectively. Coumarin is rapidly absorbed p.o., however the availability to systemic circulation is less than 4%. The rest of the dose appears quantitatively as 7-HC and 7-HCG in systemic circulation suggesting an extensive firstpass effect. Coumarin and 7-HCG are best fitted to an open two-compartment model, whereas 7-HC is best fitted to an open one-compartment model. The biological half-life of both C (0.80 vs. 1.02 h) and 7-HCG (1.47 vs. 1.15 h) was not significantly different for the two routes of administration. The large total clearance of C again suggests a first-pass effect; while that of 7-HCG, which is nearly exclusively eliminated into urine, indicates active tubular secretion of the glucuronide.
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  • 47
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    European journal of clinical pharmacology 13 (1978), S. 35-39 
    ISSN: 1432-1041
    Keywords: Norethindrone ; bioavailability ; man ; competitive protein binding ; sex differences ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A competitive protein binding assay for norethindrone was developed to measure plasma levels in human subjects. The plasma levels were considerably higher in women than in men, especially at low dose levels. The plasma levels were directly related to the dose in men; but greater variations in the plasma levels were observed in women. The plasma half-life was about 5 h in both sexes with single oral doses of 5 to 20 mg. A comparative bioavailability study with norethindrone from 2 different manufacturers, formulated in the same manner, showed no significant differences in absorption characteristics and provided sufficient data for pharmacokinetic analysis.
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  • 48
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    European journal of clinical pharmacology 14 (1978), S. 261-265 
    ISSN: 1432-1041
    Keywords: Procainamide ; slow release formulations ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Procainamide was given to 20 patients with normal renal function as an i.v. bolus of 500 mg followed by 1.0 or 1.5 g eight-hourly by mouth in the form of a slow release preparation (Durules). 97.6±27.1 (SD)% of the oral procainamide was absorbed, the absorption half life being 1.54 h. The elimination half life following the oral formulation was 6.0±0.8 h, compared to a mean of 3.4±0.4 h following i.v. administration. Elimination half life following i.v. administration was slightly related to acetylator status, being 2.75±0.9 h in fast acetylators, and 4.4±2.4 h in slow acetylators. This dependence on acetylator status was not seen in half life following oral administration. Total body clearance, steady state plasma procainamide and N-acetylprocainamide were not significantly dependent on acetylator status, although a few patients who are slow acetylators had unexpectedly low clearance and high steady state procainamide concentrations when given the higher dose.
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  • 49
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    European journal of clinical pharmacology 14 (1978), S. 357-360 
    ISSN: 1432-1041
    Keywords: Lanoxin tablets ; Lanoxicaps ; sorbitol ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary (1) The mean cumulative urinary digoxin excretion over 8 days was compared in 8 healthy volunteers after single doses of digoxin administered as 3 Lanoxin tablets of 0.25 mg, 3 digoxin tablets of 0.2 mg, 12 Lanoxicaps without sorbitol of 0.05 mg, 6 Lanoxicaps without sorbitol of 0.1 mg digoxin, 3 Lanoxicaps without sorbitol of 0.2 mg and 3 Lanoxicaps with sorbitol of 0.2 mg. (2) There was no significant difference between the 8 day cumulative urinary excretion for any of the Lanoxicaps treatments. (3) Cumulative urinary excretion after 3 digoxin tablets of 0.2 mg was significantly (P〈0.05) lower than after all other treatments. (4) Cumulative urinary excretion after 3 Lanoxin tablets of 0.25 mg was not significantly different from that after any of the Lanoxicaps treatments except 0.1 mg Lanoxicaps without sorbitol, it was significantly (P〈0.05) lower after the latter. (5) Mean urinary excretion of digoxin was 60% of ingested dose for all Lanoxicaps treatments and was significantly (P〈0.05) higher than the mean value of 50% for both tablet treatments. (6) Enhanced absorption of digoxin from Lanoxicaps was confirmed and shown to be unrelated to the sorbitol content of the capsule shell.
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  • 50
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    Bioscience reports 20 (2000), S. 239-258 
    ISSN: 1573-4935
    Keywords: heavy metals ; phytoremediation ; bioremediation ; bioavailability ; chemical availability ; soil microorganisms ; plant-microbe interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract In this review, chemical and biological parameters are discussed thatstrongly influence the speciation of heavy metals, their availability tobiological systems and, consequently, the possibilities to usebioremediation as a cleanup tool for heavy metal polluted sites. In orderto assess heavy metal availability, a need exists for rapid, cost-effectivesystems that reliably predict this parameter and, based on this, thefeasibility of using biological remediation techniques for site managementand restoration. Special attention is paid to phytoremediation as anemerging technology for stabilization and remediation of heavy metalpollution. In order to improve phytoremediation of heavy metal pollutedsites, several important points relevant to the process have to beelucidated. These include the speciation and bioavailability of the heavymetals in the soil determined by many chemical and biological parameters,the role of plant-associated soil microorganisms and fungi inphytoremediation, and the plants. Several options are described how plant-associated soil microorganisms canbe used to improve heavy metal phytoremediation.
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  • 51
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    Cell & tissue research 200 (1979), S. 223-227 
    ISSN: 1432-0878
    Keywords: Hypothalamus ; Lacertilian reptiles ; Vasotocin neurons ; Mesotocin neurons ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The hypothalamic magnocellular neurosecretory system of lizards was studied with the unlabeled antibody peroxidase-antiperoxidase complex (PAP) technique at the light microscopic level. It was shown that vasotocin and mesotocin are synthesized in separate neurons. The vasotocinergic as well as the mesotocinergic perikarya are of different sizes. Both cell types occur in close juxtaposition, but without a distinct pattern of distribution. The external zone of the lacertilian median eminence contains numerous immunoreactive vasotocinergic fibers and only few immunoreactive mesotocinergic fibers. The general organization of the hypothalamic magnocellular neurosecretory system of lizards, as revealed by immunocytochemistry, is essentially similar to that revealed with unspecific staining methods.
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  • 52
    ISSN: 1432-0878
    Keywords: Immunocytochemistry ; Ecdysteroids ; Prothoracic gland ; Insect hormones ; Galleria mellonella
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    Topics: Biology , Medicine
    Notes: Summary Fixation of prothoracic glands of Galleria mellonella with a solution containing saponin permits immunocytochemical staining of the entire gland. By this means ecdysteroids were demonstrated electron microscopically to be present in the hyaloplasm and microtubules.
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  • 53
    ISSN: 1432-0878
    Keywords: Enkephalin neurons ; Vasotocin neurons ; Isotocin neurons ; Immunocytochemistry ; Goldfish (Carassius)
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    Topics: Biology , Medicine
    Notes: Summary Our immunocytochemical investigation of the magnocellular neuroendocrine system in the goldfish hypothalamus reveals enkephalin (ENK)-containing neurons interspersed among the vasotocin (VT)- and isotocin (IT)-containing neurons of the preoptic nucleus. The perikarya of the ENK, VT, and IT neurons do not show distinct morphological differences at the level of light microscopy and are not located preferentially within the nucleus. Separate ENK, VT and IT fibers course laterally and ventrally through the hypothalamus as they descend toward the pituitary gland. All three fiber types form terminals around blood vessels in the neurohypophysis.
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  • 54
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    Keywords: Pancreatic polypeptide (PP) ; Neurones ; Central nervous system ; Peripheral nervous system, gut ; Immunocytochemistry ; Mammals ; Birds
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Pancreatic polypeptide (PP) is a candidate hormone of unknown physiological significance. It is produced by a population of endocrine cells in the pancreas. In the present study a PP-like peptide was found to occur in the mammalian and avian central and peripheral nervous systems. Immunoreactive nerve fibres and nerve cell bodies were widely distributed in the brain. Dense accumulations of nerve fibres occurred in the following areas: nucleus accumbens, interstitial nucleus of the stria terminalis, para- and periventricular hypothalamic nuclei, and medial preoptic area. In addition, nerve fibres were regularly seen in cortical areas. Immunoreactive perikarya were observed in the following regions: cortex, nucleus accumbens, neostriatum and septum. In the gut, immunoreactive nerve fibers were distributed in the myenteric plexus, in smooth muscle, around blood vessels, and in the core of the villi. Immunoreactive perikarya occurred in the submucosal and myenteric plexus, suggesting that PP immunoreactive nerves are intrinsic to the gut. In the species examined, the neuronal PP-like peptide could be demonstrated with an antiserum raised against avian PP, but not with those raised against bovine or human PP. Thus, neuronal PP is distinct from the PP that occurs in pancreatic endocrine cells.
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  • 55
    ISSN: 1432-0878
    Keywords: Pituitary ; Dexamethasone ; ACTH ; Autoradiography ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary 3H-Dexamethasone (10 μg/kg) was injected intravenously in adrenalectomized rats and after survival times of 5, 30, 60, and 180 min its uptake within the pituitary was studied by autoradiography. Radioactivity was concentrated in cell nuclei in the pars nervosa and pars distalis. Within the pars intermedia, only cells of the marginal zone were labeled. In the pars distalis, some cells showed a weak nuclear accumulation of radioactivity as early as 5 min after injection. The tissue radioactivity was nearly maximal at 5 min, and the proportion of radioactivity in nuclei reached a maximum of 60–70% by 30 min. In competition experiments, non-radioactive steroids (1 mg/kg) were injected 5 min before 3H-dexamethasone and sacrifice was 30 min later. Dexamethasone markedly diminished the nuclear accumulation in the pars distalis, but corticosterone and progesterone did not. In the pars nervosa, corticosterone and progesterone competed for nuclear uptake of 3H-dexamethasone, although less effectively than dexamethasone itself. Different cell types in the pars distalis were characterized by treating autoradiograms with an immuno-peroxidase bridge procedure. Cells treated with anti-ACTH 17–39 had the greatest nuclear concentration of radioactivity, and those stained with anti-TSH were least heavily labeled. Cells treated with antisera to GH, PRL, and hCG were moderately labeled.
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  • 56
    ISSN: 1432-0878
    Keywords: Rat posterior pituitary ; Neurophysin-vasopressinergic and neurophysin-oxytocinergic fibres ; Immunocytochemistry ; Electron microscopy
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    Topics: Biology , Medicine
    Notes: Summary By means of the unlabeled antibody peroxidase-antiperoxidase (PAP) technique at the electron microscopic level, it was demonstrated that the hormones of the neural lobe of the rat hypophysis are located in separate neurophysin-vasopressinergic and neurophysin-oxytocinergic nerve fibres. These observations confirm the results of our previous immunocytochemical studies at the light microscopic level.
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  • 57
    ISSN: 1432-0878
    Keywords: Growth hormone-release inhibiting hormone ; Somatostatin ; Hypothalamus ; Immunocytochemistry
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    Topics: Biology , Medicine
    Notes: Summary Utilizing the unlabeled antibody enzyme method, we investigated the distribution of hypothalamic elements immunoreactive with antibodies to growth hormonerelease inhibiting hormone (GH-RIH). Immunostained elements, resembling neural processes, are distributed along a pathway corresponding to a portion of the tuberoinfundibular tract. However, GH-RIH fibers are caudal, dorsal and medial to LH-RH fibers detected by the same technique. Similar topographic arrangements are noted in coronal and sagittal sections. Comparable results were obtained with two different preparations of antisera to GH-RIH. No cell bodies specifically stained by anti-GH-RIH were detected. Our data agree with those of other investigators using immunohistochemical techniques.
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  • 58
    ISSN: 1432-0878
    Keywords: Pituitary gland ; Cell types ; Estrogen ; Autoradiography ; Immunocytochemistry
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    Topics: Biology , Medicine
    Notes: Summary Dry-mount autoradiography was combined with peroxidase immunocytochemistry to examine estrogen uptake in four pituitary cell types. Quantification by silver grain counts was used to compare 3H-estradiol uptake in nuclei of pituitary cells 60 min after i.v. injection into short-term (control) and long-term ovariectomized and in long-term thyroidectomized rats. Under all three hormonal states, the order of labeling intensity was: gonadotropes 〉 somatotropes 〉 lactotropes 〉 thyrotropes. Long-term ovariectomy caused a significant increase in estrogen uptake of gonadotropes, somatotropes and lactotropes, while uptake in thyrotropes decreased. Long-term thyroidectomy decreased uptake in somatotropes, lactotropes and thyrotropes while gonadotropes remained unchanged.
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  • 59
    ISSN: 1432-0878
    Keywords: Nerve growth factor ; Submandibular gland mice ; Immunocytochemistry
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    Topics: Biology , Medicine
    Notes: Summary Nerve growth factor (NGF) was localized in the submandibular gland of adult male mice by a direct immunocytochemical method using highly purified antibodies against NGF coupled to horseradish peroxidase. In light microscopic sections the reaction product was entirely confined to the cells of the secretory tubules. The acinar part of the gland was free of reaction product. This finding was confirmed by electron microscopy. Within the cells NGF was localized exclusively in the apical secretory granules. No reaction was observed in the rough endoplasmic reticulum, the Golgi region or in the granules of the basal part of the cells. This observation favours the assumption that NGF is derived from a precursor molecule and that the precursor is transformed into immunologically active NGF within the secretory granules during their transport from the basal to the apical part of the tubular cells. Stimulation of the submandibular gland with carbachol (2 mg/kg) led to a massive release of the content of the secretory granules, including NGF, into the salivary duct.
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  • 60
    ISSN: 1432-0878
    Keywords: Luteinizing hormone-releasing hormone ; Median eminence ; Electron microscopy ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary LH-RH was localized at the ultrastructural level in axons and nerve terminals of the median eminence of the male guinea pig. LH-RH positive neuronal profiles were most concentrated in the medial-dorsal aspect of the infundibular stalk and in the post-infundibular median eminence at the level immediately following separation of the stalk from the base of the brain. LH-RH containing axon profiles were most abundant in the palisade zone; nerve terminals in contact with the hypophysial portal vasculature were relatively rare. The hormone was present within granules that measured 900–1,200 Å in axons of the palisade zone and 400–800 Å in nerve terminals abutting on the portal plexus. The differently sized granules represent heterogeneous populations.
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  • 61
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    Cell & tissue research 170 (1976), S. 263-273 
    ISSN: 1432-0878
    Keywords: Fetal pituitary ; Cell differentiation ; Immunocytochemistry ; Tissue culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Adenohypophysial primordia of rat embryos at 13 to 15 days gestation were cultured in Parker 199 synthetic medium for 2 to 11 days. At the end of the culture period their fine structure and the presence of immunoreactive trophic hormones using the peroxidase-labeled antibody technique were investigated. The degree of differentiation in the glands depends largely on the age of the embryos furnishing the explants. Cultured pituitaries explanted on the 13th day of gestation contain only ACTH-positive cells and about 15% of the cells are granular. The granules are 50–100 nm in diameter in some cells, while in other cells they range from 50 to 200 nm. In cultivated adenohypophysial primordia of embryos on the 15th day of intrauterine life ACTH, prolactin, LH and TSH cells are evident, but only the same two kinds of granular cells can be observed with the electron microscope. The extent of cytodifferentiation in the glands explanted on the 14th day of gestation is intermediate between the two other groups. The data suggest that the fetal rat pituitary has the capacity of self-differentiation but to a lesser extent than that of the in situ hypophysis.
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  • 62
    ISSN: 1432-0878
    Keywords: Neurophysin ; Vasopressin ; Median eminence ; Electron microscopy ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary With the use of tissue prepared by freeze-substitution and the unlabelled antibody enzyme technique, neurophysin and vasopressin were localized at the ultrastructural level in the posterior pituitary and median eminence of the guinea pig. In the posterior pituitary neurophysin was found in the large neurosecretory granules (1300–1500 Å) of axons, Herring bodies, and nerve terminals. In some of these axons immunoreactive neurophysin was found outside of granules in the axoplasm. By light microscopy neurophysin was found in both the zona interna and zona externa of the median eminence; this was confirmed by electron microscopy. In the zona interna as in the posterior pituitary, neurophysin was localized both inside and outside the large neurosecretory granules. In the zona externa, immunoreactive deposit was primarily located in granules with a diameter of 900–1100 Å in nerve terminals abutting on the primary portal plexus. The distribution of vasopressin paralleled that of neurophysin except that the hormone was rarely extragranular. These results demonstrate for the first time that both neurophysin and vasopressin are present in granules of axons that are in contact with the hypophysial portal vasculature.
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  • 63
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    Cell & tissue research 164 (1975), S. 543-557 
    ISSN: 1432-0878
    Keywords: Magnocellular hypothalamic nuclei ; Fetal and neonatal pigs ; Anti-porcine neurophysin serum ; Immunocytochemistry ; Slab gradient polyacrylamide gel electrophoresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The immunoperoxidase cytochemical reaction was applied to the localization of neurophysin-containing elements in the fetal and adult pig hypothalamus. In the 60 day fetal pig, cells of the supraoptic nucleus (SON) were the only structures in the hypothalamus in which neurophysin was detected. However, by 87 days the cell bodies in both the SON and paraventricular nucleus (PVN) contained neurophysin-like material. The distribution of immunoreactive material in the 111 day fetal animal was similar to that found in the adult pig. In transverse section of the mature pig the SON exists in two discrete components; an antero-lateral group of cells connected by scattered cells to a smaller postero-medial group. Anteriorly, the PVN appears as a line of cells bordering the third ventricle but as we proceed posteriorly the dorsal aspect expands laterally to give a wedge-shaped group of cells. In mid-sagittal sections, the cells of the PVN are distributed over a wide area of the anterior hypothalamus in a triangular profile. The borders between the SON and PVN became more difficult to define in medial sections than in lateral sections. Continuous gradient polyacrylamide gel electrophoresis was carried out on the neural lobe extracts from fetal, newborn and adult pigs. Proteins with an electrophoretic mobility similar to that of porcine neurophysins-I,-II and -III were present in the newborn and 98 day fetal pig. It is concluded that material immunoreactive with anti-neurophysin serum is present in the hypothalamus of the 60 day fetal pig. Furthermore, at late fetal development and during the postnatal period it is tentatively suggested that the neurophysin present in the pituitaries of these animals is chemically identical with that of adult neurophysin.
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  • 64
    ISSN: 1432-0878
    Keywords: Amphibian hypothalamus ; Vasotocinergic and mesotocinergic neurons ; Neurophysins ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Using the unlabeled antibody peroxidase-antiperoxidase (PAP) technique at the light microscopic level, it was demonstrated that, in the amphibian magnocellular hypothalamo-hypophysial neurosecretory system, vasotocin and mesotocin are synthesized in separate neurons. A tendency to preferential location of the two kinds of neuronal perikarya is described. The neurosecretory perikarya are the origin of separate vasotocinergic and mesotocinergic axons. In the neural lobe, the pattern of distribution of the two types of axons is different. The coarse ventricular “dendrites” of both kinds of neurons are hormone-containing processes. Staining with anti-bovine neurophysin I serum suggested that the vasotocinergic and the mesotocinergic neurons synthesize different neurophysins.
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  • 65
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    Cell & tissue research 178 (1977), S. 17-38 
    ISSN: 1432-0878
    Keywords: Myosin ; Immunocytochemistry ; Adrenal medulla ; Exocytosis ; Secretion
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    Topics: Biology , Medicine
    Notes: Summary Myosin was isolated in high purity from the bovine adrenal medulla by gel filtration and ion exchange chromatography. The purified myosin was analyzed by electrophoresis in gels containing SDS and found to contain a 200,000 molecular weight heavy chain and major light chains of molecular weights 20,000 and 17,000 in a 1∶1∶1 molar ratio. At high ionic strength the myosin had high Ca-ATPase and K-EDTA-ATPase activities and low Mg-ATPase activity. At low ionic strength, the Mg-ATPase was activated to a low level by rabbit muscle actin. The myosin was found to decorate F-actin in the absence, but not the presence of ATP. In low ionic strength solutions, the myosin assembled into characteristic bipolar filaments. The distribution of this myosin in the adrenal medulla and of cross-reacting myosin in several other bovine tissues was determined with the use of antimedullary myosin immunoglobulin G as a specific stain that was detected by direct and indirect immunofluorescence. In the medulla strong staining was seen between the chords of chromaffin cells indicating the presence of a highly muscular vasculature that may perform functions analogous to those of the myoepithelium of exocrine glands. The chromaffin cells showed weak positive staining around the nuclei and in a pattern radiating toward adjacent blood vessels. Cells of the inner zone of the adrenal cortex showed strong staining in the peripheral cytoplasm while cells in the intermediate and outer zones did not stain. In a blood smear, platelets and the cytoplasm of leukocytes stained strongly while erythrocytes did not stain. In striated muscle and the gray and white matter of the cerebrum only the capillaries and larger vessels stained. In the liver the phagocytic cells bordering vascular sinuses stained strongly while the hepatocytes were separated from one another by a 2 micron trilaminar band possibly representing the microfilament web surrounding the bile canaliculi and associated with junctional complexes. The results suggest that myosin is present in several highly differentiated, non-motile tissue cells where it may play a role in secretion or other specialized functions.
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  • 66
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    Cell & tissue research 200 (1979), S. 29-33 
    ISSN: 1432-0878
    Keywords: Magnocellular neurosecretory system ; Activation ; Rat ; Vasopressinergic neurons ; Oxytocinergic neurons ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The activated hypothalamic magnocellular neurosecretory system of the rat was studied in tissue sections, double stained with the unlabeled antibody peroxidase-antiperoxidase complex (PAP) technique. The results indicate that in animals with an activated hypothalamic magnocellular neuroendocrine system, as well as in normal animals, vasopressin and oxytocin are exclusively synthesized in separate vasopressinergic and oxytocinergic neurons.
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  • 67
    ISSN: 1432-0878
    Keywords: Pituitary gland ; Cytology ; Pars tuberalis ; Immunocytochemistry ; Luteinizing hormone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The objective was to acquire evidence regarding the secretory capacity of cells in the pars tuberalis of the rat pituitary by the application of immunocytochemical staining. For this purpose the conjugated antibody and immunoglobulin-enzyme bridge techniques were utilized with antisera to the following hormones of the pars distalis: human somatotropin, human thyrotropin, human β-melanotropin, ovine luteinizing hormone (LH), porcine β17–39-corticotropin, and β1–24-corticotropin. Only LH-containing cells were demonstrated. They were exceedingly rare in the cephalic pars tuberalis beneath the median eminence. The frequency of LH-cells was greater in the pars tuberalis associated with the infundibulum and increased distally. LH-cells were most common ventrolateral to the infundibular stem and occurred singly and in clusters. These results indicate that following hypophysectomy the portion of the pars tuberalis that remains in situ has the capacity to secrete only LH of all the pars distalis hormones.
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  • 68
    ISSN: 1432-0878
    Keywords: Amphibian posterior pituitary ; Vasotocinergic and mesotocinergic fibres ; Immunocytochemistry ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Using the unlabeled antibody peroxidase-antiperoxidase (PAP) technique at the electron microscopic level, it was demonstrated that the hormones of the posterior pituitary of Rana temporaria are located in separate vasotocinergic and mesotocinergic nerve fibres. This observation confirms the results of our previous immunocytochemical studies at the light microscopic level.
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  • 69
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    Cell & tissue research 175 (1976), S. 165-181 
    ISSN: 1432-0878
    Keywords: Pig ; Neurophysin-I ; Neurophysin-II ; Immunocytochemistry ; Specific neurophysin neurosecretory systems
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Antibodies raised against porcine neurophysin-I and porcine neurophysin-II using an injection regime in rabbits over a short time period, were used to localize neurophysin-I and neurophysin-II in hypothalamic neurosecretory elements of the domestic pig. In transverse section, neurophysin-II containing cells were more abundant in the dorsal medial region of the rostral supraoptic nucleus (SON) as compared with the distribution of neurophysin-I neurons. The main bulk of the cells of the SON were heavily stained for neurophysin-I with neurophysin-II containing cells positioned dorsal from the edge of the optic chiasma. Neurosecretory cells of the SON as seen in sagittal section also showed a differential staining for neurophysins-I and -II. Rostral regions of the pig paraventricular nucleus (PVN) contained magnocellular elements near the third ventricle which were stained predominantly for neurophysin-II. In regions corresponding to the caudal PVN there appeared two populations of neurosecretory neurons: (a) an area of cells adjacent to the third ventricle which contained neurophysin-II antigen and (b) a group of densely populated cells in the dorsal-lateral region which was stained for neurophysin-I. The results support the existence in the pig of at least two distinct populations of neurosecretory neurons corresponding to the neurophysin-I and neurophysin-II neurosecretory system.
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  • 70
    ISSN: 1432-0878
    Keywords: Somatostatin ; Somatostatin cells ; Rat stomach ; Paracrine action ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Somatostatin cells in the stomach of the rat have a characteristic shape and distribution. In the antral mucosa they occur together with gastrin cells and enterochromaffin cells at the base of the glands. In the oxyntic mucosa they are scattered along the entire glands with some predominance in the zone of parietal cells. Throughout the gastric mucosa the somatostatin cells possess long and slender processes that emerge from the base of the cell and end in clublike swellings. Such processes appear to contact a certain proportion of neighbouring gastrin cells in the antral mucosa and parietal cells in the oxyntic mucosa. Exogenous somatostatin given by intravenous infusion to conscious rats counteracted the release of gastrin stimulated by feeding, elevated antral pH or vagal excitation. Gastrin causes parietal cells to secrete HCl and endocrine cells in the oxyntic mucosa to mobilise and synthesise histamine. Somatostatin is known to block the response of the parietal cells to gastrin. In contrast, somatostatin did not block the response of the histamine-storing endocrine cells to gastrin, perhaps because these endocrine cells lack receptors to somatostatin. Conceivably, somatostatin in the gastric mucosa has a paracrine mode of action. The observations of the present study suggest that somatostatin may affect some, but not all of the various cell types in the stomach. Under physiological conditions this selectivity may be achieved in the following ways: 1) Communication may be based on direct cell-to-cell contact. 2) Only certain cell types are supplied with somatostatin receptors.
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  • 71
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    Cell & tissue research 186 (1978), S. 399-412 
    ISSN: 1432-0878
    Keywords: Pituitary gland ; Dog ; Pars distalis ; Thyrotropin (TSH) ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Using the immunoperoxidase technique and antisera to the specific beta (β) subunits of bovine and rat TSH1, selective immunocytochemical staining was localized in a specific cell population in the pars distalis of the dog pituitary gland. These TSH cells were found to be positive to aldehyde fuchsin, alcian blue, periodic acid-Schiff (PAS) and aniline blue. With the performic acidalcian blue (pH 0.2) -PAS-orange G procedure these cells stained blue-purple, demonstrating FSH/LH cells (blue or turquoise), ACTH/MSH cells (redpurple) and PRL cells (orange-red). The TSH cells were further differentiated from other functional cell types of the pars distalis on the basis of their typical cytological features, intraglandular distribution and by immunocytochemical double staining. In the pars distalis of adult male dogs the TSH cells were mostly shown to be smaller in size and less numerous than in bitches in the anestrous phase of the sexual cycle. Moreover, cytological alterations in the immunoreactive thyrotrophs in the pituitary of male and female dogs generally paralleled the spontaneous changes in thyroid function associated with thyroid atrophy and/or pituitary insufficiency, and thyroid hyperplasia or goiter. In conclusion, because of their specificity and high potency, the antisera to the β-subunits of bovine and rat TSH represent an effective tool for the selective immunocytochemical localization of TSH in the dog pituitary. This allows the study of the morphology and function of TSH cells under different physiological, pathological and experimental conditions.
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  • 72
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    Cell & tissue research 188 (1978), S. 99-106 
    ISSN: 1432-0878
    Keywords: LHRH-neurosecretion ; Avian hypothalamus ; Vasotocin neurosecretion ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary A fluorescent technique applying specific LHRH and vasotocin antisera was used for the immunocytochemical localization of the respective neurosecretory systems in the hypothalamus of gonadectomized, testosteronetreated and/or serotonin injected male domestic ducks. An immunoreactive (IR) LHRH-producing system, with perikarya located in the preoptic nucleus, could be traced through the ventral hypothalamus down to the external layer of the rostral and caudal ME, in close vicinity to the hypophysial portal system. An IR-vasotocin system originating in the paraventricular and supraoptic nuclei ran through the ventral hypothalamus, but terminated in (i) the external layer of the rostral ME, and (ii) in the posterior lobe of the hypophysis.
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  • 73
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    Cell & tissue research 188 (1978), S. 119-132 
    ISSN: 1432-0878
    Keywords: Neurophysin ; Paraventricular nucleus ; Supraoptic nucleus ; Sheep ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary An antiserum cross-reactive against ovine neurophysins-I-II and -III has been used in conjunction with the immunoperoxidase histochemical procedure to localize the cells of the sheep paraventricular (PVN) and supraoptic nuclei (SON). In order to describe the topographical distribution of the SON and PVN a study was made on the serial sections cut (a) transversely from rostral to caudal positions and (b) sagittally from lateral to medial positions of the hypothalamus. The cells of the SON, when examined in the transverse aspect, extended approximately 1900 μ caudally and when examined in the sagittal plane were contained within a lateral-medial distance of 4830 μ. In each case the SON cells lay adjacent to the optic chiasm. As sections were cut transversely, the cells of the PVN first appeared in a rostral position defined as 0 μ and close to the ventral lining of the third ventricle. This general ventral and ventro-lateral distribution of cells maintained up to a caudal distance of approximately 840 μ. From positions 1260–2310 μ there was a dramatic dorsal shift of the PVN cells which by this time had also extended laterally. The total rostral-caudal distance occupied by the PVN cells was 3150 μ. That the lateral-medial distance occupied by the PVN was small (1050 μ) was determined on examining the magnocellular nuclei in sagittal section.
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  • 74
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    Cell & tissue research 201 (1979), S. 315-325 
    ISSN: 1432-0878
    Keywords: Immunocytochemistry ; Post-natal development ; Neurohypophysial peptides ; Magnocellular and parvocellular neurons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Immunocytochemical localization of vasopressin (VP), oxytocin (OXY) and neurophysins I and II (NI and NII) in the hypothalamus of growing rats revealed several new features. Hormones and neurophysins were present in magnocellular neurons of newborn rats: VP and NII in a first neuronal population, OXY and NI in a second neuronal population. For the first three days after birth, the ratio of detected VP to detected NII increased whereas the ratio of detected OXY to detected NI appeared constant. It was obvious that maturation of the OXY/NI magnocellular system occurred later than maturation of the VP/NII magnocellular system. During the first three weeks of development, VP/NII fibres in the median eminence were separated into two distinct groups: the hypothalamo-neurohypophysial tract in the internal part of the median eminence, and pericapillary endings heavily loaded with VP and NII in the external part of median eminence. OXY/NI fibres did not show this particular distribution. Therefore, during this post-natal period, loading of infundibular VP endings was related to the increase of ACTH synthesis demonstrated by various authors. Therefore, we suppose that simultaneous participation of VP and corticotropin-releasing hormone does not only appear during experimental and chronic stimulation of ACTH synthesis (after adrenalectomy, for example) but that it also exists during physiological stimulation of corticotropic function. At birth, parvocellular suprachiasmatic neurons were devoid of VP and NIL A slight immunological reactivity appeared in 6-to 10-day-old rats and it became equivalent to the immunological staining in the adult rat during the third post-natal week. Thus, the appearance of suprachiasmatic VP preceded the differentiation of the rhythmic activity of the pituitary adrenal axis. These chronological relationships suggest the involvement of the suprachiasmatic VP-related-peptide in the circadian periodicity of the corticotropic function.
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  • 75
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    Cell & tissue research 201 (1979), S. 349-359 
    ISSN: 1432-0878
    Keywords: Hypothalamus ; Rat ; Somatostatin-containing neurons ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The rat hypothalamus was studied at the light microscopic level with the use of single and double immunocytochemical staining methods. It was shown that the rat supraoptic and paraventricular hypothalamic nuclei, and their accessory neurosecretory nuclei, do not contain magnocellular somatostatin neurons. The distribution of the hypothalamic parvocellular somatostatin cells is described. The parvocellular component of the rat hypothalamic paraventricular nucleus is, at least partly, composed of somatostatin cells: they form a fairly well circumscribed periventricular cell mass. The rat suprachiasmatic nuclei contain separate somatostatin neurons and vasopressin neurons. Scattered somatostatin cells are present in the entire arcuate nucleus. In addition to the periventricular somatostatin cells located in the preopticanterior hypothalamic area and in the arcuate nucleus, the rat hypothalamus also contains numerous scattered somatostatin cells located distant from the third ventricle.
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  • 76
    ISSN: 1432-0878
    Keywords: Immunocytochemistry ; Vasopressin ; Oxytocin ; Somatostatin ; Luteining hormone releasing hormone
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    Topics: Biology , Medicine
    Notes: Summary The hypothalamic hormones arginine-vasopressin (AVP), oxytocin (OXT), somatostatin (SOM), and luteinizing hormone-releasing hormone (LHRH) were localized in the rat neurohypophysis by the use of semithin serial sections and the unlabeled antibody enzyme method. Clusters of AVP fibres are present within the central region of the neural lobe, clusters of OXT fibres mainly in the peripheral part. The AVP fibres enter bilaterally into the neural lobe. The results call into question previous reports on the presence of AVP on receptors in the pars intermedia cells, since incubation with anti-AVP resulted in similar staining in the pars intermedia of the Wistar and homozygous Brattleboro rat, a mutant strain deficient in AVP. The same intermediate lobe cells are stained after incubation of serial sections with anti-AVP and anti-α-melanocyte-stimulating hormone (α-MSH). This staining of anti-AVP could be removed by solid phase absorption to α-MSH and is thus most probably due to cross reaction with α-MSH. SOM fibres appear to be present in the peripheral parts of the proximal neurohypophysial stalk and mainly lateral in its more distal parts. In the neural lobe they rapidly decrease in number, although some fibres continue into the distal part of the neural lobe, running bilaterally and situated adjacent to the pars intermedia. The SOM staining within magnocellular elements, which has been reported in the literature, can most probably be explained by cross reaction of anti-SOM with neurophysins. LHRH fibres are very scarce in the neurohypophysial stalk and absent in the neural lobe.
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  • 77
    ISSN: 1432-0878
    Keywords: Immunocytochemistry ; ACTH ; Lymnaea stagnalis ; Neurohormone ; Neurotransmitter
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Two giant neurons (diameter 130 μm) were identified immunocytochemically by means of the unlabeled antibody enzyme technique with anti ACTH 1–39 and 1–24 in the pond snail Lymnaea stagnalis. The cells are located in the visceral and the right parietal ganglion, respectively. They contain moderately electron dense elementary granules (diameter 150–160 nm). By means of the intracellular horseradish peroxidase injection technique it was shown that the cells send fibres into the neuropiles of various ganglia and into nerves. Synapses occur on the fine fibre branches in the neuropile. Synapse-like structures were found on the cell bodies and on the major fibres. The giant neurons are electrotonically coupled. With toluidine blue staining for small peptides it was demonstrated that in the central nervous system of the pond snail numerous peptidergic neurons occur in addition to those identified with the classical staining methods for neurosecretion.
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  • 78
    ISSN: 1432-0878
    Keywords: Isotocinergic neurons ; Immunocytochemistry ; Hypothalamus ; Intracellular recording ; Goldfish (Carassius)
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    Topics: Biology , Medicine
    Notes: Summary Isotocinergic (IT) neurons show physiological and morphological characteristics that are similar to those of other preoptic neuroendocrine cells in the goldfish. Preoptic IT cells show resting membrane potentials of 20–55 mV, action potentials of up to 100mV, and physiological evidence of axonal branching. Dye-marked IT cells measure 14–56 μm, their dendrites projecting to the ependyma and into the hypothalamic neuropil, their multiple beaded axons projecting to the pituitary. Indirect immunofluorescence identifies these dyemarked cells as IT. By combining electrophysiological, dye-marking and immunocytochemical techniques we can now, for the first time, study single, antidromically-identified peptidergic neurons of a specific type in vertebrate and invertebrate species.
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  • 79
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    Cell & tissue research 188 (1978), S. 259-264 
    ISSN: 1432-0878
    Keywords: Hypothalamus ; Human fetus ; Oxytocin ; Neurophysin ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The use of antibodies against oxytocin or neurophysin enabled the detection by immunocytochemistry of oxytocin-neurophysin neurons in the hypothalamus in the human fetus. The perikarya of these neurons are located in the paraventricular and supraoptic nuclei. Immunoreactive neurons occur in the median eminence. The neurophysin immunoreactive neurons were more numerous than the oxytocin immunoreactive neurons. The specificity of the immunocytological reaction was controlled. The first oxytocin-neurophysin neurons are seen as early as the 14th week of gestation.
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  • 80
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    Cell & tissue research 185 (1977), S. 465-479 
    ISSN: 1432-0878
    Keywords: Somatostatin cells ; Pancreas ; Gut ; Immunocytochemistry ; Comparative study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Somatostatin cells are numerous in the pancreas and digestive tract of mammals as well as birds. In the pancreas of chicken, cat and dog they occur in both the exocrine parenchyma and in the islets. In the rat and rabbit, somatostatin cells have a peripheral location in the islets, whereas in the cat, dog and man the cells are usually more randomly distributed. In the stomach of rabbits and pigs, somatostatin cells are more numerous in the oxyntic gland area than in the pyloric gland area, whereas the reverse is true for the cat, dog and man. In the cat, pig and man, somatostatin cells are fairly numerous in the duodenum, whereas in the rat, rabbit and dog they are few in this location. In the remainder of the intestines somatostatin cells are few but regularly observed. Somatostatin cells are numerous in the human fetal pancreas and gut. In the fetal rat, somatostatin cells first appear in the pancreas and duodenum (at about the 16–17th day of gestation) and subsequently in the remainder of the intestine. Somatostatin cells do not appear in the gastric mucosa until after birth. Three weeks after birth, somatostatin cells show the adult frequency of occurrence and pattern of distribution. In the chicken, somatostatin cells are numerous in the proventriculus, absent from the gizzard, abundant in the gizzard-duodenal junction (antrum), infrequent in the duodenum and virtually absent from the remainder of the intestines. No immunoreactive cells can be observed in the thyroid of any species nor in the ultimobranchial gland of the chicken. In the chick embryo, somatostatin cells are first detected in the pancreas and proventriculus (at about the 12th day of incubation). They appear in the remainder of the gut much later, in the duodenum at the 16th day, in the antrum at about the 19th day and still later in the lower small intestine. The ultrastructure of the somatostatin cells was studied in the chicken, rat, cat and man; the cells were identified by the consecutive semithin/ultrathin section technique. The somatostatin cells display the properties of the D cell. There was no difference in granule ultrastructure between somatostatin cells in the gut and the pancreas. The granules, which are the storage site of the peptide, are round, supplied with a tightly fitting membrane and have a moderately electron-dense, fine-granulated core. The mean diameter of the somatostatin granules is smallest in rat (155–170 nm) and largest in the chicken (270–290 nm).
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  • 81
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    Cell & tissue research 202 (1979), S. 251-261 
    ISSN: 1432-0878
    Keywords: Somatostatin ; Growth hormone ; Mouse Fetus ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The objective of the present study was to determine, by means of immunocytochemistry, the age in fetal development at which GH is first detectable in the pituitary gland and somatostatin in the median eminence, and to correlate temporally the development of these two hormones throughout the remainder of pregnancy. Mice were studied at 15–19 days of gestation with the peroxidase-antiperoxidase (PAP) technique of Sternberger. Somatotropes in the pars distalis were initially detected at 16 days of gestation and by 17 days they were a prominent component of the parenchymal cell population of the hypophysis. These cells were ovoid and distributed uniformly throughout the pars distalis; many were located adjacent to sinusoidal capillaries. Their number and staining intensity increased by 19 days. Somatostatin was not consistently observed in the median eminence until 19 days of gestation. Reaction product indicative of the presence of somatostatin in presumptive nerve endings was located on the ventral surface of the median eminence and in the external lamina of the infundibulum in proximity to the superficial portal capillaries. Results of the present investigation support the concept that the potential for neuroendocrine control of GH secretion exists in the mouse by the end of fetal development. Several hypotheses concerning the temporal relationship between the appearance of somatostatin in the hypothalamus and of GH in the anterior pituitary gland are discussed.
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  • 82
    ISSN: 1615-6102
    Keywords: Arabinogalactan proteins ; Fiber ; Linum usitatissimum ; Immunocytochemistry ; Polysaccharide ; Secondary wall
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The deposition and formation of a thick secondary wall is a major event in the differentiation of flax (Linum usitatissimum) fibers. This wall is cellulose-rich; but it also contains significant amounts of other matrix polymers which are noncellulosic such as pectins. We have used immunocytochemical techniques with antibodies specific for various epitopes associated with either pectins or arabinogalactan proteins (AGPs) to investigate the distribution of these polymers within the walls of differentiating young fibers of 1- and 2-week-old plants. Our results show that different epitopes exhibit distinct distribution patterns within fiber walls. Unesterified pectins recognized by polygalacturonic acid-rhamnogalacturonan I (PGA/RG-I) antibodies and rhamnogalacturonan II recognized by anti-RG-II-borate complex antibodies are localized all over the secondary wall of fibers. PGA/RG-I epitopes, but not RG-II epitopes, are also present in the middle lamellae and cell junctions. In marked contrast, β-(1→4) galactans recognized by the LM5 monoclonal antibody and AGP epitopes recognized by anti-β-(1→6) galactan and LM2 antibodies are primarily located in the half of the secondary wall nearest the plasma membrane. LM2 epitopes, present in 1-week-old fibers, are undetectable later in development, suggesting a regulation of the expression of certain AGP epitopes. In addition, localization of cellulose with the cellobiohydrolase I-gold probe reveals distinct subdomains within the secondary walls of young fibers. These findings indicate that, in addition to cellulose, early-developing flax fibers synthesize and secrete different pectin and AGP molecules.
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  • 83
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    Journal of pharmacokinetics and pharmacodynamics 4 (1976), S. 255-280 
    ISSN: 1573-8744
    Keywords: biliary recycling ; bioavailability ; biotransformation ; clearance ; route dependence ; enterohepatic circulation ; indomethacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract There are no discernible quantitative differences in the biotransformation and the excretion of indomethacin following oral, rectal, and intravenous administration of indomethacin-14 C. Approximately 50% (range 24–115% for n=6) of an intravenous dose undergoes enterohepatic circulation. Thus the bioavailability of indomethacin to the systemic circulation may exceed the administered dose. Relative to the intravenous dose, indomethacin is 80 and 100% bioavailable from suppositories and capsules, respectively. Absorption and/or reabsorption appears to be more rapid and uniform by the rectal route. Recognition of the attributes of biliary recycling also helps to explain the observed variability in apparent plasma half-life, while their neglect requires alternative explanations for anomalies between the disappearance rate from plasma and the corresponding appearance rate in urine.
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  • 84
    ISSN: 1573-8744
    Keywords: accelerated convergence method to estimate AUC0-∞ and A e ∞ ; bioavailability ; estimation of total areas ; estimation of total amounts excreted ; blood sampling schemes for digoxin ; elimination half-life of digoxin ; intra- and interindividual variation of renal clearance of digoxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Five methods are compared to estimate the total area under the digoxin plasma or serum concentrationtime curve (AUC0-∞) after a single dose of drug. To obtain accurate estimates of AUC0-∞, data required are concentrations at a sufficient number of sampling times to define adequately the concentration-time curve prior to the log-linear phase, and at least three, but preferably four or more equally spaced points in the terminal loglinear phase. One method (designated Method I) requires a digital computer; another (Method III) is the classical method (these two methods do not require equally spaced points in the loglinear phase). Method IIA is the accelerated convergence method of Amidon et al.; Methods IIB and IIC are modifications of this method, but incorporate usual and orthogonal least squares, respectively, which make them more accurate with real (noisy) data. Methods I and IICgave very comparable estimates of AUC0-∞. Results indicate that digoxin administered orally in aqueous solution was completely (100%) absorbed when bioavailability estimates were based on oral and intravenous AUC0-∞ estimates and the actual doses, whereas formerly only about 80% absorption was reported, based on areas, under plasma concentration curves which were truncated at 96 hr. It is shown that the sampling scheme of blood can produce biased apparent bioavailability estimates when areas under truncated curves are employed, but an appropriate sampling scheme and application of method IIyield accurate bioavailability estimates. This is important particularly in those bioavailability studies where one is attempting to determine the appropriate label dose for a new “fastrelease” digoxin preparation relative to the label dose and bioavailability of currently marketed tablets. It is shown that the magnitudes and variability of apparent elimination rate constants and halflives of digoxin, estimated from urinary excretion data by the σ− method, depend on which value of A e ∞ is used. The formerly reported greater interindividual variability of AUC data compared to At data for digoxin is explained in that the AUCs, but not the Ae,'s, involve the renal clearance, which exhibits considerable inter- and intraindividual variation.
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  • 85
    ISSN: 1573-8744
    Keywords: quinidine ; pharmacokinetic parameters ; assay methods ; assay specificity ; area under the plasma concentration-time curve ; bioavailability ; clearance ; therapeutic window
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Previously published estimates of pharmacokinetic characteristics of quinidine can be shown to be dependent on whether the investigators have used analytical methods which are specific for quinidine. Areas under the plasma concentration-time curve and peak plasma concentrations after administration of the drug were higher and clearance values consequently lower in studies utilizing nonspecific assays unable to distinguish quinidine from its metabolites. The error introduced is larger after oral administration as a result of marked first-pass metabolism of quinidine. The absolute oral bioavailabilities from pharmaceutical preparations might therefore be estimated higher in studies with assays including metabolites in the determination. Although the pharmacodynamic response to quinidine is related to the plasma concentration, the therapeutic window of drug concentrations has been defined only using nonspecific assays. In light of the availability of newly developed specific assays, redefinition of the range of therapeutic plasma concentrations is opportune.
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  • 86
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 265-282 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; linear systems analysis ; in vivo dissolution rates ; absorption rates ; metabolic rates ; bioavailability ; numerical desconvolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The application of certain aspects of linear systems analysis to pharmacokinetic-problems is described. Topics covered include the evaluation of in vivodissolution rates, absorption rates, and metabolic rates, and the use of pharmacological data. Relevant numerical procedures are also discussed.
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  • 87
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    Journal of pharmacokinetics and pharmacodynamics 4 (1976), S. 337-353 
    ISSN: 1573-8744
    Keywords: bioavailability ; pharmacological data ; pharmacokinetics ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The use of data deriving from monitoring the time variation of the intensity of pharmacological effect(s) following dosing can often present an advantageous alternative to the more conventional approach of using chemical or radiological assay of blood and/or urine level data for bioavailability evaluations of drug products: bioavailability studies can be performed with drugs where no assay exists. A relatively simplified discussion of the general theoretical principles on which the use of pharmacological data is based and a stepwise description of the approach for its routine application in bioavailability studies are presented. Approaches for computing rates and extents of drug bioavailability vs. time profiles on analog and digital computers are qualitatively described and quantitatively presented in a subsequent report. The concept of preabsorption (gastrointestinal bioavailability) is introduced and biophasic availability of drugs to local sites of action is discussed.
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  • 88
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    Journal of pharmacokinetics and pharmacodynamics 4 (1976), S. 355-375 
    ISSN: 1573-8744
    Keywords: deconvolution ; bioavailability ; pharmacokinetics ; modeling ; pharmacological data
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Mathematical expressions and approaches to the computation of rates and extents of drug bioavailability for implementation on analog and digital computers are derived. The equivalency of expressions derived on the basis of assuming compartment models to an approach based on using experimentally determined weighting functions is demonstrated. The relative merits of the two techniques are discussed: their application for use with temporal pharmacological data is emphasized. The applicability of the computational techniques to determining the availability of drugs at local sites of action (biophasic availability) and to computing preabsorptive drug release into the gastrointestinal contents (gastrointestinal bioavailability) is pointed out. An approach to computationally predicting in vivo blood level or pharmacological response vs. time profiles from in vitro dissolution testing results is presented and its limitations are discussed.
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  • 89
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    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 429-451 
    ISSN: 1573-8744
    Keywords: ampicillin ; bacampicillin ; pivampicillin ; prodrug ; bioavailability ; zero-order absorption ; two-compartment model ; renal clearance
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    Topics: Chemistry and Pharmacology
    Notes: Abstract Five healthy fasting male subjects were each given single doses of intravenous ampicillin (471 mg), oral ampicillin tablets (495 mg), oral bacampicillin hydrochloride tablets (562 mg ampicillin equivalent), and oral pivampicillin hydrochloride capsules (491 mg ampicillin equivalent) in a crossover experiment. The resulting concentrations of ampicillin were determined in plasma and urine. The pharmacokinetic analysis was made according to a two-compartment open model. The total distribution volume of unbound ampicillin during the disposition phase was 0.247 ± 0.045 (sd) liter/kg, which is only slightly more than the extracellular fluid, suggesting that tissue binding and intracellular distribution of ampicillin are limited. The bioavailability of the esters bacampicillin (86 ± 11%) and pivampicillin (92± 18%) was significantly greater than that of ampicillin (62 ± 17%); however, the difference between the esters was not statistically significant. The absorption for all drugs given orally proceeded at a constant rate, suggesting zero-order release rates from the products. The absorption rate was highest for bacampicillin (0.89 ± 0.39% of dose absorbed per minute), followed by pivampicillin (0.64 ± 0.19) and ampicillin (0.58 ± 0.16). Bacampicillin also had the shortest lag time for the start of absorption (7.0 ± 0.9 min) under the present conditions. Thus, in comparison with ampicillin, the esters have a higher bioavailability, which, in fact, is close to the theoretically highest possible value by clearance concepts. The higher bioavailability in connection with higher absorption rates may be clinically important in ampicillin treatment by the oral route.
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  • 90
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    Journal of pharmacokinetics and pharmacodynamics 4 (1976), S. 327-336 
    ISSN: 1573-8744
    Keywords: bioavailability ; phenytoin ; capacity-limited elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioavailability of phenytoin, a drug subject to capacity-limited disposition, was examined using linear and nonlinear pharmacokinetic techniques. The linear method (comparative areas) underestimates the essentially complete bioavailability of this drug from capsules (Epanutin, Parke-Davis). The error incurred in using area ratios is inversely related to the rate of absorption of the drug. The time course of absorption of phenytoin capsules is irregular and prolonged over nearly 2 days.
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  • 91
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    Journal of pharmacokinetics and pharmacodynamics 4 (1976), S. 521-535 
    ISSN: 1573-8744
    Keywords: carbamazepine ; single and repeated oral doses in healthy humans ; pharmacokinetic profile ; bioavailability ; enzymatic induction ; computer calculation of the elimination rate changes during treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic profile of carbamazepine was studied in six normal humans after single and repeated oral doses. The plasma concentrations following single dose (100, 200, 600 mg) were fitted by a one-compartment open model. Using area as a measure, availability was constant in the dose range studied. The elimination half-life ± SEafter a single dose was 37.7±5.7hr; it decreased during chronic treatment to a calculated value around 21 hr. The steady-state plasma concentration, lower than expected from the single-dose study, was adequately predicted from the single-dose data when a correction was made for the increased elimination rate constant. The present findings contrast with the apparently unpredictable plasma levels reported during carbamazepine therapy.
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  • 92
    ISSN: 1573-8744
    Keywords: aspirin ; dissolution ; bioavailability ; effect of antacids ; acid ; capacity ; consuming ; in vivo ; buffering effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The in vitrodissolution profile, in vitroand in vivobuffering characteristics, and single-dose bioavailability of various buffered aspirin tablet formulations were studied. Buffering agents,such as magnesium and aluminum hydroxides (formulations B and C) or magnesium carbonate and aluminum glycinate (formulation D), significantly increased the rate of aspirin dissolution from solid dosage forms as compared to an unbuffered tablet (formulation A). The extent of aspirin absorption was equivalent with all formulations;however, the faster rate of dissolution (t50 and t90)with buffered formulations resulted in earlier and higher peak concentration of salicylate compared to that with unbuffered formulation, following a two-tablet dose in the fasting state. A comparison of the in vivobuffer capacity of a four-tablet dose of formulations B and D was performed in the postcibal state at the time of maximal meal-induced acid secretion, using a radiotelemetry procedure for determination of pH. Formulation B prolonged the interval of elevation of intragastric pH 〉 3 for 32 min as compared to 12 min for D.
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  • 93
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    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 133-146 
    ISSN: 1573-8744
    Keywords: bioavailability ; phenytoin sodium capsules ; plasma levels ; human studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Eleven single lots of 100-mg phenytoin sodium capsules were evaluated for their relative bioavailability in 12 normal human volunteers. These products were manufactured by eight different companies and met all compendial specifications. The products were evaluated with respect to plasma levels at various times up to 96 hr following administration of single 100-mg doses, times of peak level, peak plasma concentrations, and areas under the plasma level—time curve. Several of the products exhibited statistically significant differences in the various parameters studied.
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  • 94
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    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 183-192 
    ISSN: 1573-8744
    Keywords: propranolol ; kinetics ; volunteers ; bioavailability ; threshold dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of propranolol in blood was studied in healthy volunteers, following intravenous administration of 0.1 mg/kg and increasing oral doses of 10,20, and 40 mg, using a specific and sensitive gas Chromatographie method. The systemic availability of orally administered propranolol varied from 9% to 38% between subjects, but it was constant within each subject. A linear relationship was found between the area under the blood concentration-time curve and the oral dose. At variance with literature data, we could not observe a threshold dose.
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  • 95
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 99-110 
    ISSN: 1573-8744
    Keywords: bioavailability ; tetracycline HCl capsules ; dose dependency ; brand dependency ; water ingestion ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Seven healthy male volunteers were administered, on different occasions, one, two, and three capsules of two commercially available brands (A and B) each containing 250 mg tetracycline HCl. Urinary excretion rates and cumulative amounts of drug excreted in the urine in 4 days were used to assess the bioavailability of the two brands at the different doses studied. The rate constants of absorption and elimination of tetracyline were similar at all dose levels. However, the extent of absorption (F)appears to be dependent on the brand, dose, and volume of water ingested with the drug. Fof Brand B was not significantly different than that of brand A at the 250-mg dose but was decreased by 23.3% (p〈0.01)at the 500-mg dose and by 19.7% (p 〈0.05) at the 750-mg dose. With respect to dose, Fof each brand at the 500-mg dose was not significantly different than its value at the 250-mg dose. However, Fof brand A at the 750-mg dose was reduced by 14.8% (p 〈0.05) and that of brand B by 21.1% (p 〈0.05) relative to their respective values at the single dose. Surprisingly, when the 750-mg dose of brand A was ingested with a small volume of water, Fwas increased by 18.9% (p 〈0.05) compared to the ingestion of the identical dose of the same brand under waterloading conditions.
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  • 96
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 547-558 
    ISSN: 1573-8744
    Keywords: statistical moments ; network theory ; pharmacokinetics ; bioavailability ; deconvolution ; plasma concentration-time curve ; urinary excretion rate-time curve ; compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Statistical moments are parameters that describe the characteristics of the time courses of plasma concentration (area, mean residence time, and variance of residence time) and of the urinary excretion rate that follow administration of a single dose of a drug. The relationship between the moments of a time-course curve and pharmacokinetic profiles of drug disposition, i.e., absorption, distribution, metabolism, and excretion, is described. The moments are related to the extent and rate of bioavailability, and it is shown that they can be effectively applied to the deconvolution operation.
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  • 97
    ISSN: 1573-8744
    Keywords: trapezoidal rule ; area under the curve ; pharmacokinetics ; clearance ; bioavailability ; integration method ; sulfisoxazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The linear trapezoidal rule method is commonly used for the estimation of the area under the plasma level-time curve. Error analyses are performed when the method is used in first-order absorption and first-order elimination kinetics in the one-compartment system. It is found that significant underestimations and overestimations in area during the absorption phase and postabsorption phase, respectively, can occur when the method is improperly used. During the exponential postabsorption phase the relative error is only a function of the ratio (n)of the time interval over the half-life of the two plasma data points in the interval. The error from the linear trapezoidal rule method at n=0.5 is about 1%. The error increases to 15.5% and 57.1 % when nis increased to 2 and 4, respectively. It is recommended that for most absorption studies the linear trapezoidal method be used for prepeak and plateau plasma data and the logarithmic trapezoidal method for postpeak plasma data.
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  • 98
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    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 1-27 
    ISSN: 1573-8744
    Keywords: furosemide ; renal failure ; congestive heart failure ; bioavailability ; diuretic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of furosemide and the attempt to correlate biological fluid measurements with diuretic response have been the subject of a large number of studies since the original reports of HajdÚ, Rupp, and coworkers in the mid-1960s. This article attempts to critically review these studies under seven different sections: furosemide pharmacokinetics in normal volunteers, furosemide pharmacokinetics in patients with decreased renal function, furosemide pharmacokinetics in patients with congestive heart failure, furosemide metabolism and assay methods, furosemide bioavailability, dose-response relationships, and the role of inhibitors and mediators on furosemide effects. The literature is reviewed through August 1978.
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  • 99
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 295-303 
    ISSN: 1573-8744
    Keywords: tetracycline ; antibiotics ; Billroth-II gastrectomy ; gastrectomy ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioavailability of a single 250-mg oral dose of tetracycline hydroghloride was studied in seven patients following Billroth-II gastrectomy in comparison with seven control subjects matched for age and body weight. There were no significant differences between control subjects and gastrectomized patients in the apparent lag time prior to the start of absorption (23.6 vs. 22.8 min), peak serum tetracycline concentration (1.72 vs. 1.75 μg/ml), the time of attainment of peak concentrations (3.35 vs. 3.42 hr), the apparent first-order absorption half-life (1.8 vs. 1.4hr), or the apparent first-order elimination half-life (8.0 vs. 8.7hr). Completeness of tetracycline absorption, as judged by area under the 24-hr serum concentration curve, did not differ significantly between the two groups, nor did 24-hr urinary excretion of tetracycline. Thus the abnormalities of gastrointestinal structure and function produced by Billroth -II gastrectomy do not result in impairment of the rate and completeness of tetracycline absorption.
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  • 100
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    Journal of pharmacokinetics and pharmacodynamics 3 (1975), S. 159-170 
    ISSN: 1573-8744
    Keywords: diphenhydramine ; intravenous infusion ; oral administration ; first-pass effect ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Plasma levels and urinary excretion of diphenhydramine were measured after administration of three single 50-mg doses of diphenhydramine hydrochloride to two healthy male volunteers as an intravenous infusion, an oral solution, and a commercially available capsule. A large first- pass effect was evident from the data, with about 50% of the drug being metabolized by the liver before it reached the general circulation. The drug in solution given orally appeared to be fully available to the hepatoportal system, and the availability of diphenhydramine from the capsule was about 83% relative to the solution in one subject and 100% in the other subject. Cumulative amounts of unchanged diphenhydramine excreted in the urine were less than 4% of the administered dose. Both subjects went to sleep at the end of the 1-hr intravenous infusion, but were only drowsy following the oral treatments.
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