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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1432-1041
    Keywords: phenylephrine ; pharmacokinetics ; bioavailability ; first-pass metabolism ; phenolic conjugates ; m-hydroxymandelic acid ; intravenous ; oral
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 7-3H-phenylephrine was given to 15 volunteers by a short-infusionn=4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. As almost the same3H-activity was excreted in urine after i.v. and p.o. administration, 86% and 80% of the dose respectively, complete enteral absorption can be assumed. A considerable difference was seen in the fraction of free phenylephrine, i.v. 16% of the dose versus p.o. 2.6%, which suggested reduced bioavailability. This was confirmed by comparison of the areas under the serum curve, which showed a bioavailability factor of 0.38. The result for the patient with porto-caval anastomosis was comparable to that in the normal volunteers. The biological half-life of 2 to 3h was comparable to that of structurally related amines, as were the total clearance of 2 1/h, and the volume of distribution of 340l. Metabolism to phenolic conjugates mainly after oral ingestion, and tom-hydroxymandelic acid after i.v. injection, again demonstrated thatm-hydroxylated amines are predominantly conjugated during the “first-pass” metabolism.
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  • 2
    ISSN: 1432-1041
    Keywords: orthostatic hypotension ; etilefrine ; dihydroergotamine ; bioavailability ; combination therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Etilefrine undergoes considerable first-pass metabolism through conjugation in the gut wall. In six volunteers bioavailability was reduced to 35% for a fast release tablet and to 17% for a sustained release preparation. The addition fo dihydroergotamine (DHE) to the sustained release preparation surprisingly increased bioavailability to 61%. The plasma levels of the main metabolite formed during the passage through the gut wall indicated an increase in the rate of enteric absorption and therefore also in bioavailability by DHE. This might be due to the influence of DHE upon the vascular resistance of the vessels in the gut wall or a change in gastro-intestinal motility with a prolongation of drug contact time within the absorbing gut segment.
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  • 3
    ISSN: 1432-1041
    Keywords: guanethidine ; chronic therapy ; urinary excretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuation of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.
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  • 4
    ISSN: 1432-1041
    Keywords: m-octopamine ; metabolism ; first-pass effect ; man ; enteric absorption ; monohydroxylated phenylalkylamines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The diminished sympathomimetic pressor activity of monohydroxylated phenylalkylamines after oral administration has been attributed to incomplete enteric absorption. Therefore, urinary excretion of the unchanged drug and its metabolites has been compared after intravenous and oral administration of3H-m-octopamine to eight patients. Identical amounts of3H-activity (80% of the dose) were excreted after the two routes of dosing, so enteric absorption has been assumed to be complete. Significant differences were found in the fraction of free urinarym-octopamine, which amounted to 10.5% of the dose after infusion and 0.58% after oral administration. The only metabolic pathways form-octopamine are deamination and conjugation. Following oral administration the percentage of conjugates was considerably higher than after intravenous infusion. This metabolic pattern appears typical of all phenylalkylamines with a hydroxyl group in themeta position. Ring hydroxylation to catecholamines was not observed. The enzymes mainly responsible for conjugation after oral administration are located in the gut wall. The resulting “first pass effect”, i.e. metabolism prior to the access to the central compartment, can account for the diminished pharmacodynamic effect after dosing by this route.
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  • 5
    ISSN: 1432-1041
    Keywords: Etilefrine ; pharmacokinetics ; metabolism ; first-pass effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic and metabolic studies with3H-etilefrine were performed to assess the importance of a first-pass effect on the pharmacodynamic action of this sympathomimetic amine. Identical amounts of3H-activity, ca. 80% of the dose, were excreted in the urine after intravenous or oral administration, which indicates complete enteral absorption of the drug. Comparison of the areas under the plasma curves of unchanged etilefrine after both routes of administration resulted in a bioavailability factor of 0.55, which can be explained by an extensive first-pass effect. The time curve of plasma levels of etilefrine was compatible with an open 2-compartment model characterized by a rather large volume of distribution (Vd, β) of 160 1, and a predominant half life of 2 hours. The pharmacodynamic action corresponded to the amount of drug in the central compartment. The major pathway of metabolism of etilefrine was conjugation to form the phenolic sulphate, and a very minor proportion of the drug was excreted as the corresponding hydroxymandelic acid. This metabolic pattern seems to confirm our hypothesis that phenylalkylamines with the hydroxyl group in the m-position of the benzene ring are predominantly conjugated in contrast to p-hydroxylated compounds which are mainly deaminated.
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  • 6
    ISSN: 1432-0738
    Keywords: Cyclohexylamine ; Pharmacokinetics ; Pharmacodynamics ; Cyclamate ; Cyclohexylamin ; Pharmakokinetik ; Pharmakodynamik ; Cyclamat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Cyclohexylamin — ein Stoffwechselprodukt des künstlichen Süßstoffes Cyclamat — wurde in Dosen von 2,5, 5 und 10 mg/kg KG oral an gesunde Versuchspersonen verabreicht. Die Plasmahalbwertszeit von CHA betrug 3,5 bis 4,8 Std, wobei eine deutliche Abhängigkeit der Halbwertszeit von der applizierten Dosis beobachtet werden konnte. 86 bis 95% der verabfolgten Dosis wurden innerhalb 48 Std als unverändertes CHA im Urin ausgeschieden. Da Cyclohexylamin mit einem pKa von 10.6 eine stark basische Substanz ist, ist die fast vollständige enterale Resorption, ermittelt über die cumulative Urinausscheidung, als unerwartet hoch anzusehen. CHA verursachte einen dosisabhängigen Blutdruckanstieg, wobei eine enge Beziehung zwischen Blutdruckanstieg und den Cyclohexylaminplasmaspiegeln aufgestellt werden konnte. Auf Grund dieser Blutspiegel-Wirkungskurve konnte gezeigt werden, daß für einen signifikanten Blutdruckanstieg der kritische Cyclohexylaminplasmaspiegel zwischen 0,7 bis 0,8 μg/ml liegt. 10 mg/kg K.G. Cyclohexylamin verursachten einen signifikanten Anstieg der unveresterten Plasma-Fettsäuren und der cumulativen Katecholaminausscheidung im Harn, wohingegen Dosen von 2,5 und 5 mg/kg ohne Effekt waren. Diese Ergebnisse zeigen, daß CHA ein indirektes Sympathikomimetikum ist, das allerdings wesentlich weniger wirksam ist als verwandte sympathikomimetische Substanzen.
    Notes: Abstract Cyclohexylamine (CHA) a possible metabolite of the artificial sweetener cyclamate was administered orally in doses of 2.5, 5 and 10 mg/kg b.w. to healthy volunteers. Plasma half lives of CHA ranged from 3.5 to 4.8 h showing a clear dose dependency. 86 to 95 % of the dose administered was excreted in the urine during 48 h as unchanged drug. Since CHA is a fairly strong base with a pKa of 10.6 the almost complete enteral absorption was rather unexpected. Cyclohexylamine caused a dose dependent rise in arterial blood pressure. A close correlation between plasma levels of CHA and increase of mean arterial blood pressure could be established. The analysis of this concentration response curve revealed that plasma levels of CHA of about 0.7 to 0.8 μg/ml are required in order to cause a significant increase in arterial blood pressure. A significant increase in plasma free fatty acids and cumulative urinary excretion of catecholamines was observed only after the administration of 10 mg/kg b.w. CHA. Our findings are consistent with cyclohexylamine being an indirect acting sympathomimetic amine which is some orders of magnitude less potent than related sympathomimetic substances.
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  • 7
    ISSN: 1432-1440
    Keywords: Malignes Phäochromocytom ; Behandlung ; α-Methyl-p-Tyrosin ; Catecholamin-Metabolismus ; Malignant Pheochromocytoma ; Treatment ; α-methyl-p-tyrosine ; Catecholamine Metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary In a patient with malignant pheochromocytoma treated unsuccessfully with propranolol and phenoxybenzamine the additional therapy with α-methyl-p-tyrosine resulted in a substantial decrease of the blood pressure to almost normal values. His general condition improved considerably. During therapy the urinary excretion rates of catecholamines and all their metabolites dropped to about 50% of control values. O-Hydroxylation of α-methyl-p-tyrosine could be demonstrated by the isolation of α-methyldopa and α-methylnormetanephrine. After discontinuation of treatment with α-methyl-p-tyrosine blood pressure and catecholamines returned to control values within two days.
    Notes: Zusammenfassung Bei einem Patienten mit malignem Phäochromocytom führte die Behandlung mit α-methyl-p-Tyrosin zu einer fast vollständigen Normalisierung des Blutdrucks. Propranolol und Phenoxy-benzamin waren vorher ohne großen Erfolg angewendet worden. Das Allgemeinbefinden des Patienten besserte sich beträchtlich. Während der Behandlung fielen die Ausscheidungsraten von Catecholaminen und ihren Metaboliten auf ca. 50% der Werte vor Behandlung ab. Der Nachweis von α-Methyldopa und α-Methylnormetanephrin bewies die Möglichkeit der o-Hydroxylierung von α-methyl-p-Tyrosin. Nach Beendigung der Behandlung stiegen Blutdruckwerte und Ausscheidung von Catecholaminen innerhalb von 2 Tagen wieder in die vor Behandlung gefundenen hochpathologischen Bereiche an.
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  • 8
    ISSN: 1432-1440
    Keywords: “Raynaud's syndrome” ; Phentolamine ; i.a. Injection ; Alpha-adrenoceptor blockade ; “Raynaud-Syndrom” ; Phentolamin ; intraarterielle Injektion ; alpha-Rezeptorenblockade
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Der Effekt steigender Dosen von intraarteriell appliziertem Phentolamin auf die digitale Durchblutung wird an 5 Patienten untersucht, welche an einem “Raynaud-Syndrom” litten. Sie zeigten im Angiogramm mehrere Verschlüsse der Fingerarterien. Venenverschlußplethsymogramme des Unterarmes, Volumenpulsamplitude eines Fingers der behandelten und der unbehandelten Extremität, Blutdruck der a. brachialis und die EKG-Ableitung II wurden registriert. Durch Blockade der alpha-Rezeptoren mittels Phentolamin kann die begleitende funktionelle Komponente günstig beeinflußt werden: Es kommt zu einer erheblichen Zunahme der Volumenpulsamplitude an der behandelten Extremität ohne nennenswerte Veränderungen der anderen haemodynamischen Größen bis zu einer Dosis von 0,5 mg. Eine Dosis von 0,5–1,0 mg Phentolamin wird als optimal angesehen, höhere Dosen ergeben kein wesentlich günstigeres Resultat. Der alpha-Rezeptoren-blockierende Effekt wird durch das Blutdruckverhalten bei Valsalva-Manöver, die venöse Reflexantwort und die verminderte Reaktion auf Noradrenalin dokumentiert.
    Notes: Summary Five patients suffering from “Raynaud's syndrome” were studied as regards the effects of increasing doses of intraarterially administered phentolamine on the blood flow to the digital arteries. Upon angiography they had shown multiple occlusions of their digital arteries. Venous occlusive plethysmography of the forearm, volume pulse amplitude of a finger tip of treated and untreated extremity, respectively, intraarterial pressure in the brachial artery and ECG lead II have been monitored continuously. The blockade of the alpha-adrenoceptors by phentolamine resulted in a favourable effect upon the accompanying functional component: The volume pulse amplitude of and the blood flow to the treated extremity increased considerably, without significant changes in the other hemodynamic parameters upon administration of doses up to 0.5 mg of phentolamine. A dose of 0.5 to 1.0 mg of phentolamine seems to be the optimum, higher doses yielding no better results. The effective blockade of the alpha-adrenoceptors could be demonstrated by the influence on the arterial blood pressure during a Valsalva maneuvre, on the venous reflex response, and the diminished effectiveness of noradrenaline in the treated extremity.
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 63 (1985), S. 1212-1217 
    ISSN: 1432-1440
    Keywords: Methimazole ; Analytical method ; Pharmacokinetics ; Hyperthyroidism ; Bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A newly developed method for extracting and measuring methimazole in biological fluids was used to study the pharmacokinetics of methimazole in two euthyroid and eight hyperthyroid subjects. The volume of distribution approximated total body water; the biological half-life was 2–3 h in euthyroid and about 6 h in hyperthyroid patients. Total clearance was lower in hyperthyroid patients than in euthyroid subjects, and it did not increase after thyroid function was normalized. Bioavailability in euthyroid subjects was greater than 1 but only 0.5 in hyperthyroid subjects. The reasons for these observed differences are not known.
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  • 10
    ISSN: 1439-0973
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Azlocillin, a new semisynthetic penicillin with a wide spectrum of antimicrobial activity and a member of the ureidopenicillin group, was administered to ten adults in a dosage of 2 g by intravenous bolus injection. The determination of antibiotic activity in serum and urine demonstrated an average concentration of 58.9µg/ml after one hour, 28.1µg/ml after two hours, and 6.1µg/ml after four hours. The total urinary excretion was 60% within six hours. The pharmacokinetic parameters were calculated for the one and two compartment models, respectively. Mathematical analysis according to an open two-compartment model resulted in better curve adjustment as judged from the sum of the deviant squares. The resulting parameters for volume of distribution and rate of elimination show only minor differences however. Similar results were seen on comparison with the respective data for ampicillin.
    Notes: Zusammenfassung Azlocillin, ein neues halbsynthetisches Penicillin mit breitem Wirkungsspektrum aus der Gruppe der Ureidobenzyl-Penicilline, wurde in einer Dosis von 2 g 10 Er-wachsenen mit normaler Nierenfunktion intravenös verabreicht. Die Bestimmung der Serum- und Urinkonzentrationen ergab nach 1 Stunde eine mittlere Serumkonzentration von 58,9 mcg/ml, nach 2 Stunden 28,1 mcg/ml und nach 4 Stunden 6,1 mcg/ml, die Gesamtausscheidung über die Niere betrug innerhalb von 6 Stunden 60%. Darüber hinaus wurden Halbwertzeit, Verteilungsvolumen, Fläche unter der Serumkonzentrationskurve sowie renale und totale Clearance ermittelt. Die mathematische Analyse ergibt eine bessere Anpassung der experimentell ermittelten Werte an ein 2-Kompartment-Modell, die Berechnung der entsprechenden Parameter nach dem 1-Kompartment-Modell zeigt jedoch nur geringfügige, kaum ins Gewicht fallende Unterschiede. Ein Vergleich mit den entsprechenden Daten für Ampicillin und Carbenicillin läßt eine ähnliche Kinetik erkennen.
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