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  • pharmacokinetics  (310)
  • wheat  (88)
  • bioavailability  (80)
  • Coleoptera  (79)
  • Springer  (527)
  • Blackwell Publishing Ltd
  • 2020-2024
  • 2005-2009
  • 1990-1994  (218)
  • 1980-1984  (249)
  • 1975-1979  (60)
  • 1990  (218)
  • 1983  (170)
  • 1980  (79)
  • 1977  (60)
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  • 2020-2024
  • 2005-2009
  • 1990-1994  (218)
  • 1980-1984  (249)
  • 1975-1979  (60)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of nutrition 29 (1990), S. 219-228 
    ISSN: 1436-6215
    Keywords: Vitamin K ; Menadion ; Menadiol ; Bioverfügbarkeit ; Stabilität ; Geflügel ; vitamin K ; menadione ; menadiol ; bioavailability ; stability ; poultry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Summary A bioassay of vitamin K is described, based on the prothrombin clotting time of 3-week-old, vitamin-K-depleted, and cumatetralyl-sensitized male broiler chicks, using a homologous thrombokinase preparation. With this test it could be shown that the diacetate and dibutyrate esters of menadiol are vitamin-K-active. The bioactivity of menadione from these menadiolesters amounted to about 70 % of the standard menadione from a coated menadione sodium bisulfite (Dohyfral). Menadiol seems to be temperature-resistant under such conditions, whereby two uncoated MSB preparations lost about 60 % of their activity.
    Notes: Zusammenfassung In einem biologischen Testverfahren an Cumatetralyl sensibilisierten Küken konnte in 3 Versuchen anhand des Parameters Thromboplastinzeit mit homologer Thrombokinase gezeigt werden, da\ Menadioldiacetat und Menadioldibutyrat Vitamin-K-wirksam sind. Die biologische Wirksamkeit von Menadion aus diesen Menadiolestern betrug ca. 70 % der Menadionaktivität aus gecoatetem Menadionbisulfit (Dohyfral®). Im Gegensatz zu 2 ungeschützten MSB-Präparationen, welche bei Wärmebelastung ca. 60 % ihrer ursprünglichen Wirkung verloren, waren die Menadiolester temperaturstabil.
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  • 2
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    Springer
    European journal of nutrition 22 (1983), S. 14-26 
    ISSN: 1436-6215
    Keywords: branched chain α-keto acids ; 4-methyl-2-oxopentanoate, 3-methyl-2-oxopentanoate ; 3-methyl-2-oxobutyrate ; dehydrogenation ; transamination ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Michaelis-Konstanten und Aktivitäten von Dehydrogenasen und Transaminasen der drei verzweigten α-Ketosäuren Keto-Valin, Keto-Leucin und Keto-Isoleucin in Leber, Niere, Skeletmuskel und Gehirn von Ratten werden mitgeteilt. Nach oraler Zufuhr passieren nur 11–22% der Ketosäuren unverändert die Leber. Aus pharmakokinetischen und Resorptions-Untersuchungen erhaltene Blutspiegel an Ketosäuren werden zu den Michaelis-Konstanten in Beziehung gesetzt. Bei den geringen Konzentrationen an Ketosäuren nach oraler Zufuhr kann angenommen werden, daß die oxidativen Prozesse in den nichthepatischen Geweben über die Transaminierung überwiegen. Daten über die Wachstumseffizienz von verzweigtkettigen α-Ketosäuren im Vergleich zu den entsprechenden Aminosäuren stimmen mit dieser Vorstellung überein. Bei intravenöser Verabreichung müßten die Voraussetzungen für Transaminierung besser sein als nach oraler Zufuhr. Auf der Basis von Daten aus der Literatur werden die Übertragbarkeit unserer Befunde auf den Menschen und die verschiedenen Faktoren, welche die Effizienz der verzweigten α-Ketosäuren durch Einwirkung auf ihren Stoffwechsel beeinflussen können, diskutiert.
    Notes: Summary Miehaelis-constants and enzyme activities for dehydrogenation and transamination of the three branched chainα-keto acids in liver, kidney, skeletal muscle, and brain of rats are reported. After oral load only 11–22 % of the keto acids pass the liver unchanged. Blood levels in pharmacokinetic and absorption studies are related to the Michaelis-constants. At the low keto-acid concentrations after oral application, dehydrogenation in the non-hepatic tissues is supposed to prevail over transamination. Data on feed efficiency of branched chain α-keto acids reported in the literature support this view. The chance for transamination is better after intravenous administration. The transferability of our data to humans, and various factors influencing the efficiency of branched chain α-keto acids are discussed in connection with data reported in the literature.
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  • 3
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    European journal of nutrition 22 (1983), S. 185-194 
    ISSN: 1436-6215
    Keywords: sugar substitutes ; D-glucose ; bioavailability ; D-glucitol (D-sorbitol) ; D-mannitol ; Palatinit® ; D-glucosyl-α(1→1)-D-mannitol ; D-glucosyl-α(1→6)-D-glucitol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Zur Vertiefung des Verständnisses vom Stoffwechsel des Zuckeraustauschstoffes Palatinit® wurden seine zwei Bestandteile D-Glucosyl-α(1→1)-D-mannit und D-Glucosyl-α(1→6)-D-glucit [D-Glucosyl-α(1→6)-D-sorbit] nach dem Verfahren von Karimzadegan et al. auf ihre Glucose-Bioverfügbarkeit an ketotischen Ratten untersucht. Bei Umwandlungsraten in Glucose von 6 bzw. 20 % für Mannit und Glucit (Sorbit) sowie von 39 bzw. 42% für Glucosylmannit und Glucosylglucit erhält demnach der metabolische Glucose-Pool nicht das volle Glucose-Äquivalent aus diesen Verbindungen. Von dem Anteil an präformierter Glucose in den Glucosylhexiten — theoretisches Maximum 50 % — sind nur 36 % aus Glucosylmannit bzw. 32 % aus Glucosylglucit bioverfügbar. Die im Vergleich zur Theorie verminderte Bioverfügbarkeit von Glucose aus Palatinit® wird auf partiellen mikrobiellen Abbau in unteren Darmabschnitten zurückgeführt. Die an Ratten erhaltenen Ergebnisse werden auch für alle anderen Spezies gelten, welche in Caecum und/oder Colon Kohlenhydrate vergären. Die Unterschiede zwischen D-Glucosyl-α(1→1)-D-mannit und D-Glucosyl-α(1→6)-D-glucit werden durch unterschiedliche Verzögerung der Glucoseresorption im Dünndarm, wo auch D-Glucit angreift, bedingt. Die Ermittlung der Glucose-Bioverfügbarkeit gewährt weitgehende Einblicke in das Schicksal von Kohlenhydraten einschließlich der Symbiose zwischen Säugetier und Mikroorganismen im Dickdarm. Da ein ziemlich vollständiger Überblick über die metabolischen Konsequenzen nach ihrer Zufuhr erhalten wird, sollte das Verfahren zur Messung der Bioverfügbarkeit von Glucose daher bei Abschätzungen der Lebensmittelsicherheit anderer Zuckeraustauschstoffe ebenfalls angewandt werden.
    Notes: Summary For the sake of metabolic insight into the fate of the sugar substitute Palatinit®, its two components D-glucosyl-α(1→1)-D-mannitol and D-glucosyl-α(1→6)-D-glucitol [D-glucosyl-α-(1→6)-D-sorbitol] were assayed for glucose bioavailability by the procedure of Karimzadegan et al. using ketotic rats. With conversion rates into glucose of 6 and 20 %, respectively, for free mannitol and glucitol (sorbitol), 39 % for glucosylmannitol and 42 % for glucosylglucitol, the metabolic glucose pool of the rat does not receive the full carbohydrate complement of these compounds. The preformed glucose moiety of the glucosylhexitols is bioavailable by 36 and 32 %, respectively, from glucosylmannitol and glucosylglucitol, with 50 % as theoretical maximum. Less than theoretical bioavailability of glucose from Palatinit® is ascribed to microbial attack in the hindgut. The data on rats are held valid also for other species demonstrating carbohydrate fermentation in the caecum and/or colon. Differences between D-glucosyl-α(1→1)-D-mannitol and D-glucosyl-α(1→6)-D-glucitol are caused by a differential delay of glucose absorption in the small intestine, also exerted by D-glucitol. The deep metabolic insight offered by the glucose bioavailability assay into the fate of carbohydrates includes the mammal-microbial symbiosis in the large bowel. Since a rather complete survey of the metabolic consequences after their intake can be obtained, the assay system should be generally applied in assessments of food safety also of other sugar substitutes.
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  • 4
    ISSN: 1572-8889
    Keywords: Coleoptera ; Scarabaeidae ; Cotinis nitida (L.) ; beetle flight ; pheromone bioassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 5
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    Entomologia experimentalis et applicata 54 (1990), S. 219-224 
    ISSN: 1570-7458
    Keywords: Diabrotica virgifera virgifera ; Coleoptera ; Chrysomelidae ; corn ; life-stage occurrence ; planting date
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Dans les conditions de l'est du Sud Dakota (USA), 3 dates de semailles de maïs et 3 dates de contamination avec des œufs de D. virgifera virgifera LeConte ont servi à imposer ou à empêcher la synchronisation des éclosions des œufs et par conséquent des développements ultérieurs. Les dates médianes d'apparition de chacun des 3 stades larvaires et des imagos ont été déterminées en relation avec les unités de température et le nombre de jours depuis la contamination. Aucune différence significative entre les dates médianes d'apparition n'a été mise en évidence par utilisation des unités de température; par contre, ces différences deviennent significatives lorsque l'on utilise le nombre de jours depuis la contamination. Des paramètres fiables sont nécessaires pour prédire la présence des différentes stades de cet insecte. En dépit des différentes conditions imposées pour cette étude, la méthode la moins capricieuse pour prédire l'apparition d'un stade larvaire et l'émergence des adultes est la somme de températures avec une base de 11°C.
    Notes: Abstract Under field conditions in eastern South Dakota, USA three different planting dates of corn and three times of egg infestation were used to imposed synchronous and asynchronous timing of corn growth and Diabrotica virgifera virgifera LeConte egg hatch and subsequent development. Median occurrence of each of the three larval stages and of the adult stage for each of the infestation-planting treatments was determined by relating occurrence to thermal units and to days after infestation. No significant differences were found among the treatments for median occurrence of each life stage when the thermal unit approach was used. However, significant differences were found among treatments for median occurrence when the day after infestation approach was used. Consistent parameters are needed for prediction of the occurrence of life stages of this insect. Despite the various imposed conditions, this study indicates that the least variable method of predicting life stage occurrence and adult emergence of D. v. virgifera was the use of thermal unit accumulations (base 11°C).
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  • 6
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    Cellular and molecular life sciences 46 (1990), S. 700-704 
    ISSN: 1420-9071
    Keywords: Coleoptera ; Tenebrionidae ; Tribolium confusum ; defesive secretion ; biosynthesis of 1-alkenes ; oxidative decarboxylation ; anti-elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The terminally unsaturated hydrocarbons of the defensive secretion ofTribolium confusum are biosynthesized from fatty acids by oxidative decarboxylation. The process involves an enantiospecific cleavage of the C−H bond of thepro-(S) C(3)−H atom and simultaneous decarboxylation of the acid into an 1-alkene and carbon dioxide via ananti-periplanar transition state geometry (anti-elimination). The stereochemistry of this biotranformation is identical in all respects with the same reaction in higher plants. The mechanism seems to be of general importance for the biosynthesis of many vinylic substructures of natural products from oxygen-containing precursors.
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  • 7
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    Entomologia experimentalis et applicata 34 (1983), S. 291-296 
    ISSN: 1570-7458
    Keywords: Coleoptera ; Curculionidae ; Cyrtobagous ; Salvinia weevil ; Feeding characteristics of larvae ; Development of larvae ; Plant nutrition ; Temperature effects on development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Après leur naissance, les larves de Cyrtobagous sp. passent de 1 à 4 jours à brouter les racines, et de 0 à 9 jours dans les bourgeons de la plante hôte, Salvinia molesta, avant d'y creuser une galerie dans le rhizome. Bien que les larves aient été capables de survivre jusqu'à 38 jours en broutant les racines, quant elles furent privées de rhizome, elle ne purent achever leur développement. Quand les galeries furent commencées, le développement larvaire, entre 21° et 31°, dépendit de la température et de la teneur en azote de l'hôte. Les larves ne se développèrent pas à 17°. Une haute valeur nutritive de l'aliment consommé par les larves réduisit la durée du développement, mais n'influença pas la durée ultérieure de leur développement nymphal. Les lieux de prise de nourriture et les dégâts produits par des larves isolées furent précisés.
    Notes: Abstract Newly-emerged larvae of a salvinia weevil, Cyrtobagous sp. spent from 1–4 days browsing on the roots and from 0–9 days in the buds of the host plant, Salvinia molesta, prior to tunnelling into the rhizome of this aquatic weed. Although larvae were able to survive up to 38 days browsing on roots when rhizomes were withheld, they were unable to complete development. After tunnelling began, larval development between 21° and 31° was dependent on temperature and nitrogen levels in the host. Larvae failed to develop at 17°. High nutritional intake by the larvae reduced larval development time but did not influence duration of their subsequent pupal development. The feeding sites and plant damage produced by individual larvae were assessed.
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  • 8
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    Entomologia experimentalis et applicata 56 (1990), S. 15-21 
    ISSN: 1570-7458
    Keywords: Coleoptera ; Chrysomelidae ; corn rootworms ; age-specific survival ; age-specific fecundity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé D. virgifera virgifera LeConte a été placé sur des régimes nutritifs mimant l'évolution des tissus du maïs disponsibles dans le champ lorsque les insectes éclosent est aux stades suivants du maïs: 1) après émergence de l'épi mâle, mais avant l'apparition des barbes et l'émission du pollen; 2) lors de la présence de barbes et de l'émission de pollen; 3) après la pollinisation et quand les barbes ont bruni. Un quatrième régime a été fourni pendant toute l'expérience comprenant des barbes vertes, du pollen et des feuilles. Les pontes moyennes des femelles pendant les 12 semaines de l'étude on été 125, 235, 179 et 441 pour les régimes 1, 2, 3 et 4. Les dates de mort de la moitié des adultes a été 7,2, 7,2, 6,7 et 8,8 semaines pour respectivement les mêmes régimes. Les femelles du régime 1 pondent à un âge plus avancé que les femelles des régimes 2 et 3. L'influence des changements de la qualité alimentaire du maïs au fur et à mesure du vieillissement des plantes et deDiabrotica, a été déterminée par la survie au bout de 48 heures d'insectes éclos depuis peu et d'autres maintenus en cage sur des lots de maïs à différents stades poussant en serre depuis des temps plus ou moins longs. Plus les plantes sont âgées, plus la survie des 2 groupes deDiabrotica diminue, mais plus vite chez les lots d'insectes âgés.
    Notes: Abstract Adult corn rootworm beetles,Diabrotica virgifera virgifera LeConte, were maintained on three dietary regimes which mimicked the progression of corn tissues that would be available in the field for beetles eclosing when corn was in the following growth stages: (A) after tassels had emerged but prior to silking and pollen shed; (B) while plants were silking and shedding pollen; and (C) after pollination was complete and silks had turned brown. A fourth regime (D) was established in which green corn silks, pollen, and leaves were provided throughout the study. The mean number of eggs laid per female over the 12-week duration of the study was 125, 235, 179, and 441 for regimes A, B, C, and D, respectively. Median length of life was 7.2, 7.2, 6.7, and 8.8 weeks for regimes A, B, C, and D respectively. Beetles in regime A laid a greater proportion of their eggs at an older age than did beetles from regimes B and C. To further investigate the influences on survival of changes in food quality of corn as plants and beetles aged, newly-eclosed beetles and beetles that had been maintained in caged plots of corn growing in a greenhouse for various lengths of time were caged on corn at different stages of growth, and the proportion of beetles surviving for 48 h was determined. Survival decreased as plants aged for both groups of beetles, but decreased at a faster rate for old than for young beetles.
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  • 9
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    Entomologia experimentalis et applicata 34 (1983), S. 124-126 
    ISSN: 1570-7458
    Keywords: Negret ; Melanic mutant ; X-linked mutation ; Flour Beetle ; Tribolium confusum ; Coleoptera
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 10
    ISSN: 1570-7458
    Keywords: Storage pests ; Coleoptera ; Bostrichidae ; Prostephanus truncatus ; (±)-1-methylbutyl (E)-2-methyl-2-pentenoate ; Rhyzopertha dominica ; (±)-1-methyl-butyl (E)-2,4-dimethyl-2-pentenoate ; Dominicalure ; Aggregation pheromone ; Monitoring
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Les réponses de Prostephanus truncatus Horn (Coleoptera: Bostrichidae) à deux constituants de la phéromone d'agrégation de Rhyzopertha dominica Fabricius (Coleoptera: Bostrichidae), le (±)-1-méthylbutyl (E)-2-méthyl-2-penténoate et le (±)-1-méthylbutyl (E)-2,4-diméthyl-2-pentéoate, connus comme “Dominicalure 1” et “Dominicalure 2”, ont été étudiées au laboratoire et au champ. Auslaboratoire ces composés ont été essayés individuellement et en mélange 1:2. Une membrane de caoutchouc imprégnée de phéromone a été utilisée comme émetteur lent, et une courbe de réponse en fonction de la dose a été établie. P. truncatus répondait plus vigoureusement à la Dominicalure 2 seule. Tous ces traitements ont été comparés dans un essai aux champs en Tanzanie, dans lesquels des pièges en carton ondulé contenant des diffuseurs de phéromone étaient placés dans des entrepôts de maïs dans les fermes. La Dominicalure 1 et le mélange de 1 et 2 étaient tous deux efficaces pour piéger R. dominica. La Dominicalure 2 a piégé plus de P. truncatus que les autres traitements et était à peu près aussi efficace que le contrôle visuel pour détecter la présence de cet insecte dans les stocks. On peut envisager que la Dominicalure 2 pourrait servir de base à un programme pour lutter contre P. truncatus en Afrique de l'Est.
    Notes: Abstract Laboratory and field studies have been made of the responses of Prostephanus truncatus (Horn) to two components of the aggregation pheromone of Rhyzopertha dominica (Fabricius) — (±)-1-methylbutyl (E)-2-methyl-2-pentenoate and (±)-1-methylbutyl (E)-2,4-dimethyl-2-pentenoate, known as “Dominicalure 1” and “Dominicalure 2” respectively. In the laboratory, these compounds were tested individually and as a 1:2 mixture; P. truncatus responded most strongly to Dominicalure 2 alone. All three treatments were compared in a field trial in Tanzania to monitor both R. dominica and P. truncatus in farm stores. Dominicalure 1 or a mixture of 1 and 2 were both highly effective for trapping R. dominica. In contrast, Dominicalure 2 trapped more P. truncatus than the other treatments and was about as effective as visual inspection at demonstrating the presence of the beetle in stores. Dominicalure 2 could form the basis of a monitoring programme for P. truncatus in East Africa.
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  • 11
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    European journal of nutrition 22 (1983), S. 27-33 
    ISSN: 1436-6215
    Keywords: wheat ; lysine ; carnitine ; lipids ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung 32 abgesetzte männliche Albinoratten wurden in 4 Gruppen eingeteilt, um die Wirkung einer lysinarmen Weizendiät (AW), einer Weizendiät mit 0,4 % Lysin (LW) oder 0,2 % Carnitin (CW) sowie einer Caseindiät auf den Stoffwechsel von Lipiden in verschiedenen Geweben zu untersuchen. Nach 8 Wochen Fütterung der verschiedenen Diäten unter Anwendung der „paired feeding technique“ wurden Veränderungen in den Gesamtlipiden, den Lipidbestandteilen, den einzelnen Fettsäuren und dem Lipidgehalt der Mitochondrien des Herzens, der Skelettmuskeln, der Lungen und des Fettgewebes der Tiere bestimmt. Die lysinarme Weizendiät (AW) bewirkte eine Lipidanreicherung (vor allem an Acylglyzerinen) im Herzen, in der Leber, den Skelettmuskeln sowie eine Lipidabnahme im Fettgewebe. Die Diäten mit 0,4 % Lysin (LW) oder 0,2 % Carnitin (CW) zeitigten die entgegengesetzte Wirkung, wobei CW wirkungsvoller erschien als LW. LW und CW erhöhten die relativen Anteile von C14∶0-, C16∶0- und C16∶1-Fettsäuren und verkleinerten diejenigen von C18∶1-, C18∶2- und C18∶3-Fettsäuren, während die Anteile unter der AW- und Caseindiät ab- bzw. zunahmen. Die Fettsäurezusammensetzung des Fettgewebes war bei allen Gruppen gleich. Die AW-Diät vergrößerte die relativen Anteile von C14∶0- und C20∶4- und verringerte die von C16∶0-, C16∶1- und C18∶3-Fettsäuren in den Lungen. Die AW-Ergänzungsdiäten verringerten die relativen Anteile von C16∶0-, C16∶1-, C18∶3-sowie auch der C18∶1-Fettsäuren. Der Lipidgehalt der Mitochondrien von Leber, Herz, Skelettmuskeln und Lunge verringerte sich unter der AW-Diät und erhöhte sich unter den LW- und CW-Diäten.
    Notes: Summary 32 weanling male albino rats were divided into 4 groups to study the effects of lysine-deficient wheat diet (AW) and AW supplemented with either 0.4 % lysine (LW) or 0.2 % carnitine (CW) as compared to casein diet on metabolism of lipids in various tissues. LW, CW and casein diet groups were pair-fed with AW group. Changes in total lipids, lipid components, individual fatty acids, mitochondrial content in liver, heart, skeletal muscles, lungs and adipose tissue were determined after 8 weeks of feeding. AW diet resulted in accumulation of lipids (mainly acylglycerols) in heart, liver, skeletal muscles and depletion in adipose tissue. The LW and CW diets reversed the effects of AW diet, the CW being more effective than LW diet. The LW and CW diets increased the relative proportion of C 14∶0, C 16∶0, C 16∶1 and decreased that of C18∶1, C18∶2, C18∶3 fatty acids which were decreased and increased, respectively, on the AW and casein diets. The fatty acids composition of adipose tissue was the same in all the groups. The AW diet increased the relative proportions of C 14∶0, C 20∶4 and decreased that of C 16∶0, C 16∶1, C 18∶3 fatty acids in the lungs. Supplemented AW diet decreased the relative proportions of the former group and increased that of the later group including C 18∶1 fatty acid also. The mitochondrial content of liver, heart, skeletal muscles and lungs was decreased on AW and reversed on LW and CW diets.
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  • 12
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    Mycopathologia 111 (1990), S. 181-189 
    ISSN: 1573-0832
    Keywords: mycotoxin ; ochratoxin ; Penicillium ; storage ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Eleven-kilogram parcels of HY-320 wheat, a cultivar of the new Canada Prairie Spring class, were kept at 15 and 19% initial moisture contents (IMC) in simulated storage in a Manitoba farm granary for 60 weeks to determine biotic and abiotic changes and mycotoxin production. Ochratoxin A reached a maximum of 0.24 ppm by week 20 in the 19% IMC wheat, but was absent in the 15% IMC wheat; no other mycotoxins were detected. Temperature, moisture content, O2 and CO2 levels, fat acidity values, seed germination, microfloral incidence and abundance, and the presence of other mycotoxins were monitored. Principal component analysis of all variables showed that the first principal components accounted for 32–41% of the system variability, and contained the ochratoxin A variable. Ochratoxin A was produced in moist grain that had decreased seed germination andAltermaria activity, and high fungal activity byPenicillium andAspergillus versicolor. Compared to other stored cereals previously studied, HY-320 wheat would be ranked in a low-risk category for mycotoxin formation, based on the ochratoxin A levels observed.
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  • 13
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    Nutrient cycling in agroecosystems 21 (1990), S. 163-166 
    ISSN: 1573-0867
    Keywords: Critical level of Zn ; alkaline soils ; Zn-deficiency ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Field experiments were conducted at 32 locations, chosen for their wide range in DTPA extractable Zn, to determine the critical deficiency level of Zn for predicting response of wheat to Zn application. Soil application of 5.6 kg Zn ha−1 significantly increased the grain yield in deficient soils. Soil extractable Zn was significantly related with per cent grain response and absolute grain yield. Both the graphical and statistical methods of Cate and Nelson indicated the critical level to be 0.75 mg kg−1 soil of DTPA extractable Zn. This level gave a predictability value of 82 per cent.
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  • 14
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    Nutrient cycling in agroecosystems 22 (1990), S. 147-159 
    ISSN: 1573-0867
    Keywords: Sulfate ; elemental sulfur ; leaching ; ryegrass ; wheat ; greenhouse experiments ; split application
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Three factorial experiments with four replications were conducted in a greenhouse to examine the effectiveness of gypsum, elemental sulfur (ES powder) and three S containing N fertilizers, viz., ammonium sulfate (AS), urea + ES, and Ureas (20% AS and 80% urea). All experiments were conducted twice in different years. In the first experiment with uncropped soil, the effects of soil type, leaching rate (2.3 and 6.9 mm water per day) and urea addition on sulfate leaching losses were studied. Leaching losses decreased in the order Ureas 〉 ammonium sulfate (AS) 〉 gypsum ≫ urea + ES. Increasing the leaching rate greatly increased sulfate losses from both soils. Losses were greater in the sandy Typic Hapludoll than in the clayey Oxic Paleustalf. Sulfate adsorption was found to decrease strongly with rising the pH in both soils. Hydrolysis of urea temporarily raised the pH of the soil, thereby increasing the sulfate leaching losses. In the second experiment the effects of S rate (0–65 mg per kg soil), split application and leaching rate (0 and 2.3 mm per day) on sulfate leaching losses and ‘apparent S recovery’ (ASR) by three successive cuts of ryegrass (Lolium perenne L.) were studied. Herbage yield more than doubled when S was applied. The effectiveness of the sulfate fertilizers was greater when S was split-applied than given all at once. With split applications the ASR decreased in the order: Ureas 〉 AS 〉 gypsum 〉 urea + ES 〉 ES powder. ES fertilizers were least effective, because the oxidation rate of ES to sulfate was clearly too slow. In the third experiment the effects of S rate (0–40 mg per kg soil) and split application on sulfate leaching losses and ASR in the grain of wheat (Triticum aestivum L.) were studied under leaching conditions (2.3 mm per day). Grain yield increased strongly due to S application. Split application greatly increased the effectiveness of the sulfate fertilizers and appeared to be an effective tool in satisfying the S need of the crop under leaching conditions. Again, ES fertilizers were least effective, because the oxidation rate of ES was too slow to meet the S demand of the crop. In all experiments leaching losses of sulfate from the ES fertilizers were smaller than from the sulfate fertilizers.
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  • 15
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    Nutrient cycling in agroecosystems 22 (1990), S. 97-107 
    ISSN: 1573-0867
    Keywords: Superphosphate ; placement depth ; banding ; relative effectivenesss ; lupins ; wheat ; field experiment
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    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract In a field experiment on a sandplain soil in a low rainfall (326mm per annum) Mediterranean environment of south-western Australia, seven levels of single superphosphate, 0, 7.5, 10, 14, 19.5, 30 and 39 kg P ha−1, were placed at either 3, 5, 7, 9, 11 or 13 cm depth before sowing wheat (Triticum aestivum) at 3 cm. In a separate treatment, superphosphate was drilled with the seed (the normal practice). In the second year, the plots were sown with lupins (Lupinus angustifolius) at 3 cm depth with no additional superphosphate. In three separate treatments, superphosphate at 0, 14 and 39 kg P ha−1, was drilled with the lupin seed (the normal practice) on plots that had received no superphosphate in the first year. Yields of wheat and lupins were used as a measure of the effectiveness of the superphosphate placement treatments relative to the effectiveness of superphosphate drilled with seed of wheat (year 1) or lupins (year 2), to give relative effectiveness (RE) values in each of the two years. In the first year the RE of superphosphate was increased by about 20% when the fertilizer was placed 5 to 9 cm deep in the soil. In the second year, the RE of superphosphate for producing lupin grain was increased by about 30–60% where the fertilizer had been placed 5–13 cm deep in the previous year compared with freshly drilled 3 cm deep. The yield of wheat or lupins was closely related to the P content of plant tissue; each relationship was independent of the depth or year of superphosphate application.
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  • 16
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    Nutrient cycling in agroecosystems 26 (1990), S. 229-235 
    ISSN: 1573-0867
    Keywords: Grass ; wheat ; nitrogen nutrition ; dilution curve ; mineral content ; mineral removal ; phosphorus ; potassium
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    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The important effect of nitrogen in changing the patterns of mineral content and mineral removal is analysed for grass swards and wheat. Different models are proposed; accumulated dry matter developed throughout a growing period is shown to be an excellent reference for assessing the evolution of the plant mineral content and the mineral removal the growing crop. Applications in diagnosing mineral nutrition status and optimising fertilizer use are proposed and discussed.
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  • 17
    ISSN: 1423-0445
    Keywords: toxin sequestration ; predation ; human dietary hazard ; cantharidin ; Coleoptera ; Meloidae ; Epicauta vittata ; Rana ; Hirudo ; Nerodia
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    Topics: Biology
    Notes: Summary Frogs(Rana pipiens) fed on blister beetles (Meloidae) or cantharidin, retain cantharidin systemically. After cessation of feeding, they void the compound relatively quickly. Systemic cantharidin does not protect frogs against ectoparasitic feeding by leeches(Hirudo medicinalis) or predation by snakes(Nerodia sipedon). As suggested by our data, and from reports in the early literature, ingestion of cantharidin-containing frogs can pose a health threat to humans.
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  • 18
    ISSN: 1423-0445
    Keywords: pheromone ; attractant ; triene ; tetraene ; hydrocarbon ; Insecta ; Coleoptera ; Nitidulidae ; Carpophilus freemani
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    Topics: Biology
    Notes: Summary Males ofCarpophilus freemani Dobson (Coleoptera: Nitidulidae) produce an aggregation pheromone to which both sexes fly in a wind-tunnel bioassay. The major pheromone component (ca. 30 ng per male per day in volatile collections) was identified as (2E,4E,6E)-5-ethyl-3-methyl-2,4,6-nonatriene. A minor component, (2E,4E,6E,8E)-7-ethyl-3,5-dimethyl-2,4,6,8-undecatetraene, was 3–10% as abundant as the major triene and was 5–20% as active when compared at relative doses ranging from natural proportions to 1:1. These compounds act synergistically: a mixture of major and minor components in natural proportions attracted more than twice as many beetles as the major component alone, and the mixture fully accounted for the activity of male-derived volatile collections. Six other male-derived conjugated hydrocarbons, ranging from 2% down to 0.04% as abundant as the major component, were also identified. These are (in order of decreasing bioassay activity when compared on an equal-weight basis): (3E,5E,7E)-6-ethyl-4-methyl-3,5,7-decatriene, (2E,4E,6E)-5-ethyl-3-me-thyl-2,4,6-octatriene, (3E,5E,7E,9E)-8-ethyl-4,6-dimethyl-3, 5,7,9-dodecatetraene, (2E,4E,6E,8E)-3,5,7-trimethyl-2,4,6, 8-undecatetraene, (3E,5E,7E)-5-ethyl-7-methyl-3,5,7-undecatriene, and (2E,4E,6E)-3,5-dimethyl-2,4,6-nonatriene. All structure identifications were confirmed by synthesis. In the wind tunnel, the pheromone acted synergistically with “host”-type volatiles such as propyl acetate, valeric acid, and ethanol. This concept was verified by fields tests in California, in which there was dramatic synergism between the pheromone and fermenting host materials. Pheromone biosynthesis is discussed.
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  • 19
    ISSN: 1423-0445
    Keywords: secretion-grooming ; pygidial glands ; chemical defence against microorganisms ; respiration ; aquatic beetles ; Coleoptera ; Hydradephaga ; Gyrinidae ; Haliplidae ; Noteridae ; Hygrobiidae ; Dytiscidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary All Hydradephaga investigated so far crawl onto land when exposed to an increase in water temperature and light intensity and spread the secretion from their pygidial glands over the body surface (“secretion-grooming”). The secretions have antimicrobial properties and are mainly applied to hydrofuge body regions important for aquatic respiration. Experimental prevention of secretion-grooming leads to the loss of the respiratory air bubble and a significant increase in mortality. These findings support the view that the secretion-grooming of adephagous aquatic beetles, like in some aquatic Heteroptera, inhibits the growth of microor-ganisms, thus preventing the contamination and wetting of the cuticular respiratory structures. Thus it keeps functional the air-retaining hydrophobous body regions essential for aquatic respiration. A model is presented on how secretion-grooming may have evolved in the Hydradephaga. Other possible functions of the pygidial gland secretions are discussed.
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  • 20
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    Cellular and molecular life sciences 46 (1990), S. 1016-1017 
    ISSN: 1420-9071
    Keywords: In vitro absorption ; calcium ; wheat ; Bengal gram
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    Topics: Biology , Medicine
    Notes: Summary The in vitro absorption of calcium from the duodenum was significantly less in a group of rats fed on a wheat diet than in a group fed a wheat and Bengal gram (70∶30) diet.
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  • 21
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    Cellular and molecular life sciences 46 (1990), S. 1209-1211 
    ISSN: 1420-9071
    Keywords: Pheromone ; E-myrcenol ; ipsdienol ; Ips duplicatus ; Coleoptera ; Scolytidae ; Picea abies
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    Topics: Biology , Medicine
    Notes: Summary Males of the Eurasian bark beetleIps duplicatus, when feeding in host Norway spruce (Picea abies (L.) Karst.), produced and released ipsdienol andE-myrcenol, which we show to be aggregation pheromone components. Bioassays using walking beetles indicated thatE-myrcenol in synergistic combination with ipsdienol is essential for attraction. Synergism ofE-myrcenol and ipsdienol released at natural rates in the forest was also demonstrated with a new technique using mechanical slow-rotation of sticky traps.
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  • 22
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    European journal of clinical pharmacology 39 (1990), S. 395-397 
    ISSN: 1432-1041
    Keywords: atropine ; exercise ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the mean volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t1/2, 4.2 vs 3.5 h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 ml·min−1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml−1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml−1). In T5, Ex significantly decreased the t1/2 (3.4 h), Vz (182 l) and CL (575 ml·min−1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min−1), elimination rate constant (ke, 0.0012 vs 0.0015 min−1), Cp (14 ng·ml−1) and AUC (53.3 ng·h·ml−1). These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.
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  • 23
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    European journal of clinical pharmacology 38 (1990), S. 343-346 
    ISSN: 1432-1041
    Keywords: indomethacin ; cerebrospinal fluid ; pharmacokinetics ; protein binding ; analgesic activity
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling. According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7±0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF. The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.
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  • 24
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    European journal of clinical pharmacology 38 (1990), S. 523-524 
    ISSN: 1432-1041
    Keywords: tolbutamide ; hydroxytolbutamide ; carboxytolbutamide ; urinary excretion ; age ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.
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  • 25
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    European journal of clinical pharmacology 38 (1990), S. 499-503 
    ISSN: 1432-1041
    Keywords: 2-mercaptopropionylglycine ; body clearance ; half-life ; pharmacokinetics ; protein binding
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 2-mercaptopropionylglycine (2-MPG) was studied in ten healthy volunteers after a single i. v. injection of 250 mg (1532 μmol). The total and non-protein-bound concentrations versus time curves were best described by a three-exponential function with terminal half-lives of 55 and 59 h respectively. Body clearance based upon the total concentration was estimated to be 105 and 231 ml/min based on the non-protein-bound 2-MPG. The corresponding values for Vss were 99 l and Vss,n 173 l, and for Vγ485 l and Vγ,n 1121 l respectively. 75% of the dose was excreted in the urine, mainly during the first 6 h after injection. The proportion of non-protein-bound 2-MPG diminished exponentially during the first 15 h and then levelled off at about 30%. There was a nonlinear increase in the non-protein-bound fraction of 2-MPG as the total plasma concentration of the drug increased.
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  • 26
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    European journal of clinical pharmacology 38 (1990), S. 526-527 
    ISSN: 1432-1041
    Keywords: phenytoin ; posture ; pharmacokinetics ; plasma levels
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  • 27
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    European journal of clinical pharmacology 39 (1990), S. 487-490 
    ISSN: 1432-1041
    Keywords: sulphadimethoxine ; plasma concentration ; skin blister fluid concentration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-dependent concentration curves of sulphadimethoxine in plasma and cantharidin-induced skin blister fluid have been evatuated following a single oral dose of 1 g. In contrast to other drugs, sulphadimethoxine exhibited two-stage penetration into the blister fluid, the second peak concentration being higher than the first. The maximum plasma concentration of 94.1 mg·l−1 was observed after 4 h, and in skin blister fluid the first peak of 25.6 mg·l−1 was found after 7 h, and the second of 58.0 mg·l−1 occurred after 30 h. The penetration of sulphadimethoxine into skin blister fluid, defined as the ratio of the AUC there to that in plasma was 0.748. The results suggest that sulphadimethoxine penetrates into skin blister fluid to a great extent from plasma and achieves concentrations exceeding the MIC for susceptible pathogens, but it requires a relatively long time to do so.
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  • 28
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    European journal of clinical pharmacology 38 (1990), S. 207-208 
    ISSN: 1432-1041
    Keywords: diclofenac ; oral administration ; bioavailability ; healthy subjects ; diclofenac hydroxyethylpyrrolidine
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A pharmacokinetic study in man has been made of a new dosage form of diclofenac hydroxyethylpyrrolidine (DIEP); soluble salt packed in sachets was compared with diclofenac sodium as enteric coated tablets. Oral DIEP 2×50 mg showed a significant difference in absorption kinetics (ka, lag time and tmax) as compared to oral diclofenac sodium 2×50 mg. A relevant plasma concentration of diclofenac was detected just 15 min after DIEP, while diclofenac sodium produced a measurable plasma concentration only 0.5–1 h after the treatment. Cmax and t1/2 after DIEP and diclofenac sodium were comparable. Comparison of the two AUC values showed that DIEP was bioequivalent to diclofenac sodium (Q=100%).
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  • 29
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    European journal of clinical pharmacology 38 (1990), S. 209-211 
    ISSN: 1432-1041
    Keywords: Isradipine ; hypertension ; pharmacokinetics ; pharmacodynamics ; clinical trial
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In conjunction with a multicentre clinical trial of the calcium antagonist isradipine in hypertension, pharmacokinetic and pharmacodynamic studies were conducted in 9 subjects. An initial dose of 5 mg (capsule formulation) of isradipine was given orally. The mean Cmax, tmax and AUC(0–8) were 6.0 ng · ml−1, 1.5 h and 15.1 h · ng · ml−1 respectively. Seven subjects repeated the study at steady state after 10 week's dose titration with isradipine. Cmax, tmax and AUC(0–8) were 3.7 ng · ml−1, 1.2 h and 12.2 h · ng · ml−1 respectively indicating that the drug does not accumulate over time. Control of blood pressure paralleled plasma isradipine concentrations which suggested that the drug should be given at least twice daily. Pharmacokinetic studies performed in conjunction with clinical trials can provide valuable information about the patterns of drug response.
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  • 30
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    European journal of clinical pharmacology 39 (1990), S. 583-586 
    ISSN: 1432-1041
    Keywords: ranitidine ; piroxicam ; interaction ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng·ml−1 for ranitidine alone and 466 ng·ml−1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml−1 and 2551 h·ng ml−1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 μ·ml−1 in the presence of placebo and 2.0 μg·ml−1 in the presence of ranitidine respectively; mean AUC was 133 h·μg ml−1 and 137 h·μg ml−1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.
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  • 31
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    European journal of clinical pharmacology 39 (1990), S. 613-614 
    ISSN: 1432-1041
    Keywords: Thioridazine ; debrisoquine polymorphism ; pharmacokinetics ; adverse effects
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  • 32
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    European journal of clinical pharmacology 38 (1990), S. 255-258 
    ISSN: 1432-1041
    Keywords: theophylline ; mequitazine ; drug interaction ; pharmacokinetics ; asthma
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of an oral anti-allergic drug, mequitazine, on the pharmacokinetics of theophylline has been investigated in seven asthmatic patients. They received chronic theophylline therapy (a sustained-release theophylline tablet 200–400 mg b.d. at 12 h intervals) and coadministered mequitazine 6 mg for 3 weeks. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of mequitazine were compared. No significant change in the pharmacokinetic parameters of theophylline or in the urinary recovery of unchanged drug and its metabolites was observed. Thus, mequitazine did not influence the pharmacokinetics of theophylline and it should be safe for coadministration to asthmatic patients on chronic theophylline therapy.
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  • 33
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    European journal of clinical pharmacology 38 (1990), S. 259-263 
    ISSN: 1432-1041
    Keywords: tacrine ; amyotrophic lateral sclerosis ; postoperative sedation ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 9-amino-1,2,3,4-tetrahydroacridine; tacrine, THA, was studied after intravenous administration and following the first and last oral doses of a seven week clinical trial involving 8 patients with amyotrophic lateral sclerosis, ALS. Two surgical patients given intravenous THA for reversal of postoperative sedation were also included. Plasma concentration of THA and in some cases the metabolite, 1-hydroxy-THA, were assayed using a selective and sensitive method with high performance liquid chromatography. After an intravenous dose of 30 mg THA, the plasma concentrations were fitted to a two-compartment model. Plasma clearance showed a threefold interindividual variation with a mean of 2.42 l·h−1. Volume of distribution, Vα varied 100–680 l with a mean of 349 l. The plasma half-lives of distribution and elimination were 1.8 and 98.2 min, respectively. Oral bioavailability showed large interindividual differences and ranged 6–36% in the four subjects studied. After seven weeks treatment with oral THA, plasma concentrations immediately prior to medication were below 10 ng/ml in three patients and above 100 ng/ml in two patients. At the same occasion the plasma metabolite concentrations considerably exceeded those of THA. THA medication was associated with side effects in the majority of the patients.
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  • 34
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    European journal of clinical pharmacology 38 (1990), S. 269-273 
    ISSN: 1432-1041
    Keywords: flecainide ; quinine ; pharmacokinetics ; metabolism inhibition ; drug interaction ; renal transport
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of flecainide and its two sequential metabolites, both free and conjugated, its pharmacodynamics, and the influence of simultaneously administered quinine, have been studied in 10 healthy subjects. The study comprised two, 48-h open phases at an interval of 1 week. Flecainide acetate 150 mg was given as a 30-min i.v. infusion and quinine sulphate orally 500 mg×3 over 24 h. Quinine administration did not change the apparent volume of distribution or the renal clearance of flecainide, but it significantly reduced its systemic clearance (9.2 vs 7.6 ml · kg−1 · min−1), thus increasing the elimination half-life (9.6 vs 11.5 h). The amount of flecainide transformed to its first, meta-O-dealkylated metabolite (MODF) fell with no change in the renal excretion of the latter, either in its free or conjugated forms. This finding, in association with a fall in amount of the second, meta-O-dealkylated lactam metabolite (MODLF) recovered in its conjugated forms in the urine, suggests that quinine inhibits both the first and the second steps of the sequential metabolism of flecainide. When the subjects received quinine in addition to flecainide, the PR interval in the ECG was slightly more prolonged than with flecainide alone. Due to the study design, an effect of quinine per se and the consequence of increased serum flecainide levels could not be distinguished.
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  • 35
    ISSN: 1432-1041
    Keywords: celiprolol ; renal failure ; pharmacokinetics ; enantioselective kinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the ß1-selective adrenergic antagonist (R,S)-celiprolol has been studied after oral administration of 200 mg celiprolol-HCl to 8 healthy volunteers and 8 patients with various degrees of impaired renal function. No significant difference was found between the two enantiomers in the control group or in the patients. In healthy volunteers an average of 9.8% of the dose of R-(+)-celiprolol and 9.5% of S-(-)-celiprolol was recovered unchanged in the urine. Renal impairment reduced the urinary excretion of both enantiomers to the same extent according to the severity of the uraemia, producing higher AUCs. Nevertheless, the terminal half-lives of the R- and S-enantiomers were not significantly different between the groups. Dosage reduction in patients with renal impairment does not seem to be necessary.
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  • 36
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    European journal of clinical pharmacology 38 (1990), S. S53 
    ISSN: 1432-1041
    Keywords: nitrates ; pharmacokinetics ; pharmacodynamics ; nitrate tolerance ; isosorbide-5-mononitrate
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Healthy male volunteers received three different dose regimens of a controlled-release form of isosorbide-5-mononitrate (IS-5-MN; 60 mg per tablet). Dose regimen I consisted of a single daily dose of 60 mg given for 5 days. Dose regimen 11 was started with a dose of 60 mg, followed by 30 mg 12 h later and thereafter every 8 h. The last dose, on the 5th day was again 60 mg. In dose regimen III60 mg followed by 30 mg 6 h later were administered every day for 5 days. The peripheral arterial and venous effects of IS-5-MN during the first and last dosing interval were followed by changes in the finger pulse curve, standing systolic blood pressure, heart rate, and venous distensibility. Plasma concentrations of IS-5-MN were measured frequently following the first and the last dose. Following dose regimen I all hemodynamic effects produced by the first dose were maintained during the study. The maximal plasma concentrations were about 400 ng/ml and the trough value, lower than 100 ng/ml. Following dose regimen II the hemodynamic effects of IS-5-MN and sublingual glyceroltrinitrate were completely abolished on the 5th day. Trough plasma concentrations were approximately 300 ng/ml during the entire study period. Following dose regimen III pronounced hemodynamic effects were seen on the 1st day. However, a significant attenuation of the hemodynamic effects was measured on the 5th day, when trough plasma concentrations were between 100 and 230 ng/ml. There was a significant negative correlation between the magnitude of hemodynamic effect remaining on the 5th day (measured by the area under the finger pulse curve) and the trough plasma concentration. Thus, the maintenance of minimum plasma concentrations of IS-5MN of 300 ng/ml or higher produces a rapid development of hemodynamic nitrate tolerance, whereas no tolerance was found when the plasma concentrations were allowed to decline below 100 ng/ml before the next dose was given. A significant attenuation of hemodynamic effects was found when minimum plasma concentrations were between 100 and 230 ng/ml. The degree of attenuation in this concentration range increased with increasing trough plasma concentrations.
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  • 37
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    European journal of clinical pharmacology 12 (1977), S. 137-145 
    ISSN: 1432-1041
    Keywords: Chlormethiazole ; pharmacokinetics ; metabolites ; oral administration ; young and elderly human subjects ; quantitative gas chromatographymass spectrometry ; whole blood distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of chlormethiazole and two of its metabolites has been measured in three young and three aged human subjects following administration of a single oral dose of chlormethiazole. A sensitive analytical method based on gas chromatography-mass spectrometry using the selective ion monitoring mode of operation was developed to permit quantitation of the plasma levels. The time course of the plasma concentration of chlormethiazole and metabolites showed wide inter-subject variation, particularly between the young and elderly subjects. Absorption of chlormethiazole was rapid in the subjects of both groups as assessed by the time taken to reach the peak plasma concentration. The mean peak plasma level of chlormethiazole was more than five times greater in the elderly (2.90±1.56 µg/ml) than in the young (0.55±0.58 µg/ml) subjects. The plasma level of chlormethiazole was consistently higher in the aged subjects and this was reflected by the larger area under the plasma curve in aged (7.62±5.37 µg.h/ml) than in young (0.94±0.66 µg.h/ml) individuals. Decreased pre-systemic elimination by the liver has been suggested as an important factor contributing to the higher plasma level in the elderly. Estimates of absolute systemic availability, calculated by reference to previous intravenous studies, were greater for the elderly subjects. The distribution of chlormethiazole in whole blood from six young and six elderly human subjects was investigated in vitro. The unbound fraction of chlormethiazole in plasma increased significantly from 0.308±0.035 in young subjects to 0.403±0.067 in the elderly. Distribution of the drug in whole blood was different for the two age groups; the fraction of drug distributed to plasma water was significantly greater and the fraction in blood cells was significantly less in the aged.
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  • 38
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    European journal of clinical pharmacology 12 (1977), S. 171-174 
    ISSN: 1432-1041
    Keywords: Tolamolol ; hypertension ; pharmacokinetics ; mean steady-state concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolamolol was administered in a “double-blind” study to fifteen hypertensive patients by dose-titration against arterial blood pressure. Mean steady-state plasma tolamolol concentrations (Css) were determined for each patient from the area under the plasma concentration — time curve during a dosage interval whilst patients were receiving optimal tolamolol doses. No significant correlation was observed between daily tolamolol dose and Css; the relationship between fall in lying mean arterial pressure and Css also failed to reach conventional levels of statistical significance, but Css was observed to be correlated with the fall in standing pressure. The results suggest that plasma concentrations in excess of 200 ng/ml may be required to achieve an effective hypotensive response with the drug.
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  • 39
    ISSN: 1432-1041
    Keywords: sodium valproate ; epileptic patients ; pharmacokinetics ; plasma concentration ; prediction ; maintenance dosage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination (β phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.
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  • 40
    ISSN: 1432-1041
    Keywords: prenalterol ; beta1-adrenoceptor agonist ; metabolic effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective β1-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables — triglycerides, glucose, lactate, pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.
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  • 41
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    European journal of clinical pharmacology 17 (1980), S. 111-116 
    ISSN: 1432-1041
    Keywords: zimelidine ; norzimelidine ; antidepressants ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of a new antidepressant, zimelidine, and of its pharmacologically active metabolite, norzimelidine, was studied in six healthy male volunteers. Three single doses of zimelidine (25 mg and 100 mg orally and 25 mg i.v.) and two single doses of norzimelidine (25 mg orally and i. v.) were given to each volunteer allowing at least seven days between administrations. Plasma concentrations of zimelidine and norzimelidine were determined in serial blood samples by HPLC. Following oral zimelidine peak plasma concentrations of the metabolite were attained about 3 h after dosing. Oral administration of norzimelidine itself resulted in a plasma concentration profile for this compound that was similar to that observed after oral zimelidine. Utilising the plasma concentration data following intravenous infusion of each compound, the elimination half-lives for zimelidine and norzimelidine were calculated to be 5.1 h (range 4.3–6.0) and 15.5 h (range 10.6–22.9) respectively. The total body clearances of the 2 compounds were similar at 0.52 l · min−1 (range 0.26–0.70) for zimelidine and 0.56 l · min−1 (range 0.28–0.83) for norzimelidine. The substantially longer elimination half-life of norzimelidine was apparently the result of a larger volume of distribution (9.4 l · kg−1; range 7.8–11.4) for this metabolite, as compared to zimelidine (3.21 · kg−1; range 1.6–4.9). The calculated bioavailability of zimelidine was 26% (range 9.1–39) after the 25 mg oral dose, and 29% (range 14–46) after the 100 mg dose. The bioavailability of norzimelidine was 66% (range 36–91). However, oral administration of zimelidine resulted in as much or more norzimelidine reaching the systemic circulation, as the oral administration of norzimelidine itself. This is important as a large part of the activity of the drug may be due to the metabolite.
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  • 42
    ISSN: 1432-1041
    Keywords: Muzolimine ; pharmacodynamics ; pharmacokinetics ; furosemide ; saluresis
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a biometrically planned, double-blind study on 12 Oedema-free male patients the saluretic effect of muzolimine 30 mg was compared with furosemide 40 mg. The plasma level of muzolimine was determined and correlated with its pharmacodynamics. In terms of excretion during the 12-hour observation period muzolimine 30 mg had as great a cumulative effect as furosemide 40 mg. There was a significant difference in the time-response curve. During the first two hours furosemide 40 mg had more saluretic effect than muzolimine 30 mg. Between two and four hours there was no significant difference between the two substances. Between four and six hours, however, muzolimine was somewhat more effective than furosemide, although the difference did not reach the level of significance. After 6 h there was no longer any difference between the two compounds. The half-life of the fall in concentration of muzolimine in plasma was 3.7 up to 10 h after its administration. The time-response curve of the increased urine excretion correlated well with the time course of the concentration of muzolimine in plasma.
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  • 43
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    European journal of clinical pharmacology 17 (1980), S. 129-133 
    ISSN: 1432-1041
    Keywords: dapsone ; salivary drug elimination ; pharmacokinetics ; acetylator phenotype
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A high performance thin layer chromatographic assay for dapsone is described with a minimum level of detection of 20 ng ml−1 which is suitable for the study of dapsone pharmacokinetics in plasma and saliva. 100 mg dapsone was administered orally to seven normal adult volunteers, the mean plasma pharmacokinetic parameters were: α=0.23 h−1; β=0.0236 h−1, and t1/2β=30.2 h. Dapsone is also eliminated into the saliva and the t1/2 may be determined via its estimation in saliva. It is 73% bound to plasma protein and the saliva/plasma concentration ratio was found to be 27%. In two subjects the free plasma dapsone concentration was identical to the simultaneous salivary dapsone concentration. Therefore the salivary dapsone concentration is a measure of the free plasma fraction of dapsone. Saliva/plasma dapsone concentration ratios show no time or concentration dependence and little inter-individual variation but are unsuitable for acetylator phenotype determination because monoacetyldapsone is not eliminated in the saliva.
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  • 44
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    European journal of clinical pharmacology 12 (1977), S. 125-132 
    ISSN: 1432-1041
    Keywords: Valproic acid ; pharmacokinetics ; saliva concentration ; urinary excretion ; serum protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9±2.6 h in the single dose and 17.3±3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064±0.0011 l/kg×h. The apparent volume of distribution was small at 0.15±0.2 l/kg. The mean steady state plasma concentration (Css) reached after 4 days was 81.3±13.0 µg/ml. Css observed was lower than Css predicted (99.2±14.7 µg/ml) from single dose kinetics (p〈0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7±0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.
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  • 45
    ISSN: 1432-1041
    Keywords: Cefoxitin ; lidocaine ; intramuscular ; bioavailability ; pain
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    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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  • 46
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    European journal of clinical pharmacology 12 (1977), S. 367-373 
    ISSN: 1432-1041
    Keywords: Sulphamethizole ; tetracycline ; doxycycline ; rest ; exercise ; pharmacokinetics ; excretion ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The serum level and urinary excretion of sulphamethizole, tetracycline and doxycycline were studied in healthy volunteers subjected to intensive exercise and bed rest in a cross-over trial. Each group consisted of 7–8 subjects. The exercise or bed rest began 15 min before oral administration of the drug and was continued for the following 4 hours. During exercise serum drug concentration and the area under the serum concentration-time curve for each agent was significantly higher (p〈0.05) than the corresponding values at rest. Exercise greatly suppressed the renal excretion of tetracycline and doxycycline, but the decrease alone appeared insufficient to account for the pronounced increase in serum drug concentration. Total drug excretion in urine was unchanged. Thus, it seemed most unlikely that overall absorption from the gastrointestinal tract had been altered by exercise. However, the rate of absorption appeared to be more rapid in the exercise than in the rest period. Marked haemoconcentration was not produced by the exercise. In addition to changes in absorption and elimination rates, alteration in the volume of distribution might contribute to the higher serum drug concentration during exercise. Therefore, the level of physical activity should be considered in the interpretation of pharmacokinetic data both in clinical practice and in pharmacokinetic studies.
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  • 47
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    European journal of clinical pharmacology 18 (1980), S. 321-326 
    ISSN: 1432-1041
    Keywords: sotalol ; hypertension ; renal impairment ; chronic administration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten hypertensive patients with moderate to severe impairment of renal function were treated with sotalol for 5 to 10 weeks (average 6.4 weeks). Dosage was individually titrated (range 80 to 480 mg daily). The drug was given once daily in the morning. In eight patients blood pressure was satisfactorily controlled. Higher steady-state levels were observed than have been reported after similar doses in patients with normal renal function. The apparent first-order elimination rate constant and plasma clearance were significantly correlated with glomerular filtration rate. For an anuric patient, serum half-life was calculated to be 69 h. In relation to the raised plasma levels, side effects were uncommon. Since sotalol is excreted predominantly via the kidney, therapy in patients with impaired renal function should start with a low dose and any increase in dosage should be made carefully. As the anti-hypertensive effect does not appear to be correlated with the plasma level or with tolerance, adjustment of dose should be based on clinical response.
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  • 48
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    European journal of clinical pharmacology 18 (1980), S. 517-520 
    ISSN: 1432-1041
    Keywords: desmethyldiazepam ; oxazepam ; cimetidine ; hepatic elimination ; pharmacokinetics ; interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of single oral doses of desmethyldiazepam 20 mg or oxazepam 50 mg were studied in 5 healthy volunteers under controlled conditions, before and following a 24 h pretreatment with cimetidine 200 mg×5. Cimetidine significantly impaired (p=0.03) the elimination of desmethyldiazepam, as shown prolongation of its elimination half-life from 51.7±21.9 h to 72.6±39.4 h (mean ± SD), and a decrease in total plasma clearance from 12.0±2.7 ml/min to 8.6±3.3 ml/min. The disposition of oxazepam was not affected. From these results, and recently published data on diazepam and chlordiazepoxide, it is concluded that cimetidine impairs the hepatic elimination of those benzodiazepines which are metabolized by phase I reactions.
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  • 49
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    European journal of clinical pharmacology 17 (1980), S. 449-457 
    ISSN: 1432-1041
    Keywords: alcuronium ; single dose ; multiple dose ; plasma levels ; neuromuscular response ; pharmacokinetics ; anaesthesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic behaviour of alcuronium is described for nineteen patients undergoing anaesthesia for elective surgery. Eleven patients received a single bolus intravenous dose of 0.25 mg/kg, while 8 patients required additional doses of 0.125 mg/kg. A two-compartment open model was found to describe adequately both the single dose and multiple dose data for the majority of patients. No significant differences were found in the model-independent pharmacokinetic parameters between the single and multiple dose studies. Mean values for the pooled data for the half-life (t1/2β), apparent volume of distribution (Vdβ), volume of distribution at steady-state (Vdss), volume of the central compartment (Vc) and plasma clearance (Clp) were 198.75 min, 24.261, 20.891, 8.181 and 90.22 ml/min respectively. Evoked muscle twitch response was monitored in 17 of the patients to assess the degree of relaxant blockade. The bolus dose of alcuronium produced complete block in 9 patients and between 95 and 99% block in the remainder. The time of onset to maximum block ranged from 3 to 30 min with the concurrently measured plasma levels of alcuronium being 0.79 to 2.25 µg/ml. The time taken following bolus administration to 5% recovery (95% paralysis) was a mean of 42 min and the corresponding mean alcuronium plasma concentration was 0.78 µg/ml.
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  • 50
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    European journal of clinical pharmacology 18 (1980), S. 269-273 
    ISSN: 1432-1041
    Keywords: paracetamol ; thyrotoxicosis ; hypothyroidism ; drug disposition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption, distribution and elimination of oral paracetamol have been studied in patients before and after treatment of thyrotoxicosis (n=7) and hypothyroidism (n=4). Absorption was faster in patients with untreated thyrotoxicosis than when subsequently euthyroid. The peak paracetamol concentration, however, was lower in thyrotoxic patients due to an apparent increase in the total body clearance and a shorter plasma half-life. Both absorption and elimination rates were reduced in hypothyroid patients, but were not significantly different from the euthyroid results. When estimated using a two compartment model the total volume of distribution and the hybrid distribution rate constants were unrelated to thyroid status, but the apparent volume of the central compartment was significantly greater in the thyrotoxic group. These changes in drug disposition may contribute to differences in drug response seen in thyroid disease.
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  • 51
    ISSN: 1432-1041
    Keywords: alminoprofene ; antalgic ; pharmacokinetics ; single dose ; multiple doses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 2-(p-methylallylaminophenyl) propionic acid, alminoprofene (INN), a new antalgic drug, was administered orally to men as a single (300 mg) and multiple doses (300 mg three times daily). Plasma and urine concentrations of alminoprofene were determined by gas-liquid chromatography. After the single oral dose, the peak plasma level (36.2 to 41.5 mg/l) was reached within 0.5–1.5 h. The biological half-life ranged from 2.5 to 3.2 h. During chronic administration of alminoprofene, steady-state equilibrium quilibrium was etablished within 24 h. The urinary excretion of alminoprofene as unchanged product and as glucuronide was very important.
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  • 52
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    European journal of clinical pharmacology 18 (1980), S. 423-428 
    ISSN: 1432-1041
    Keywords: pyridostigmine ; myasthenia gravis ; pharmacokinetics ; bioavailability ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of pyridostigmine was evaluated after intravenous injection in two healthy male volunteers and after oral administration to five subjects. Plasma concentrations of pyridostigmine were determined after ion pair extraction from plasma and analysis by gas chromatography — mass spectrometry with chemical ionization, using d6-pyridostigmine as internal standard. Degradation of pyridostigmine in vitro was compensated for by use of the deuterated internal standard and by rapid cooling and separation of plasma after blood sampling. After intravenous administration of pyridostigmine 2.5 mg the plasma elimination half-life was 1.52 h, the volume of distribution was 1.43 l/kg and the plasma clearance 0.65 l/kg × h. The pharmacokinetic constants were very similar after oral administration of pyridostigmine 120 mg; the elimination half-life was 1.78±0.24 h, the volume of distribution 1.64±0.29 l/kg and the plasma clearance was 0.66±0.22 l/kg × h. The bioavailability was calculated to be 7.6±2.4%. When pyridostigmine was taken together with food, the time to reach the peak plasma concentration was prolonged from 1.7 to 3.2 h. Bioavailability, however, was not influenced by concomitant food intake. “Steady-state” plasma concentrations of pyridostigmine were measured in myasthenic patients on their ordinary dose schedule of cholinesterase inhibitor drugs. More than a seven-fold difference in steady-state plasma concentration was found between patients taking approximately the same daily dose of pyridostigmine.
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  • 53
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    European journal of clinical pharmacology 18 (1980), S. 473-477 
    ISSN: 1432-1041
    Keywords: aminophylline ; asthma ; serum theophylline ; pharmacokinetics ; prediction of serum level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 15 acutely ill asthmatics the steady-state serum theophylline concentration was predicted by the method of Chiou et al. using two serum concentration measurements obtained 1 and 5h after starting a continuous infusion of aminophylline. Two theophylline assays with different precision characteristics were compared. With a precise HPLC-assay the prediction was excellent: prediction error (predicted minus measured concentration)=−0.22±1.97 mg/l (mean ± SD); r=0.922. When the theophylline concentration was determined by a rapid enzyme immunoassay of lower precision, but convenient for clinical use, the prediction was less accurate (prediction error=0.58±3.88, r=0.852). However, it was still clearly superior to dosing recommendations based on the population average of theophylline clearance, even after taking into consideration the effect of smoking, congestive heart failure and cirrhosis (prediction error=3.62±13.36, r=0.560). As employed in this study, the method may be useful in helping the physician to choose the optimal dose in severely ill asthmatics.
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  • 54
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    European journal of clinical pharmacology 17 (1980), S. 459-463 
    ISSN: 1432-1041
    Keywords: colestipol ; fenofibrate ; fenofibric acid ; pharmacokinetics ; interaction ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between two hypolipidemic drugs, colestipol, an ion exchange resin, and fenofibrate, a phenoxyacid derivative, was studied in 6 male volunteers. The investigation followed a four-step protocol during 18 days, and relied on determination of plasma and urinary levels of fenofibric acid, the active metabolite of fenofibrate. The kinetics of a single dose of fenofibrate 300 mg was established over 3 days. Thereafter, from Days 4 to 9 fenofibrate was given daily as 200 mg in the morning and 100 mg in the evening; the plasma fenofibric acid level reached about 10 µg/ml. From Days 9 to 15 the same dose of fenofibrate was administered together with colestipol 10 g in the morning and 5 g in the evening. Plasma fenofibric acid concentrations remained unchanged and the 24 h urinary excretion of fenofibric acid did not fall. On Day 15, a last single dose of fenofibrate 300 mg was given with colestipol 15 g. The pharmacokinetic pattern of fenofibric acid on Days 15 to 18 did not differ significantly from that found previously (Days 1 to 3). From these results, it is likely that there is no pharmacokinetic interaction between the two hypolipidemic drugs.
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  • 55
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    European journal of clinical pharmacology 18 (1980), S. 51-53 
    ISSN: 1432-1041
    Keywords: pethidine ; phenobarbital ; aminoglycoside antibiotics ; pharmacokinetics ; clinical response
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  • 56
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    European journal of clinical pharmacology 18 (1980), S. 55-63 
    ISSN: 1432-1041
    Keywords: diuretics ; furosemide ; caffeine ; theophylline ; neonate ; pharmacokinetics ; disposition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elimination of diuretics and methylxanthines is considerably slower in the neonate than in the adult. Dose guidelines, especially during long term maintenance, must be adjusted to account for this slower drug elimination. Pharmacokinetic studies and the requisite pharmacologic evaluation on diuretics such as hydrochlorothiazide, spironolactone, ethacrynic acid and others should be done. Furosemide undergoes biotransformation in the newborn producing an acid metabolite and a glucuronide conjugate. Methylxanthines are effective in the treatment of neonatal apnea. Plasma elimination of theophylline is exceedingly slow, more so with caffeine. Decreased elimination is partly explained by decreased oxidative biotransformation. Caffeine is excreted in the urine of the newborn mainly unchanged (85%) in contrast to the adult where caffeine is a minor portion of urinary excretion (2%). Theophylline is methylated to caffeine and may possibly exert additive pharmacologic effects.
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  • 57
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    European journal of clinical pharmacology 18 (1980), S. 195-198 
    ISSN: 1432-1041
    Keywords: ampicillin ; age ; oral dose ; i. v. dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ampicillin (500 mg) was administered intravenously (i. v.) and orally to a small panel of young and elderly subjects in a cross-over fashion. Plasma concentrations of ampicillin were measured by a fluorimetric technique for 8 h following dosage. A two compartment-open model was used to characterise the plasma concentration-time data for the intravenous study, and a one compartment-open model incorporating an absorption lag time and a first-order absorption rate constant for the oral data. Plasma clearance after i. v. ampicillin was found to be significantly decreased in the elderly (P〈0.05, 0.08 1 h−1kg−1 versus 0.18 1 h−1kg−1), and half life and area under the plasma level-time curve were significantly increased (P〈0.05, 6.70 h versus 1.68 h, t1/2β; p〈0.01, 176.51 µg·h ml−1 versus 37.88 µg·h ml−1, AUC o ∞ ) as compared to the young. No sigificant differences were observed between the age groups for the volume of distribution terms and the changes in drug handling noted in the elderly were attributed to a decrease in the renal elimination of ampicillin. Following oral administration a significant increase in t1/2β, AUC o ∞ and the maximum plasma concentration (Cpmax P〈0.01, 6.59 µg ml−1 versus 3.42 µg ml−1) of ampicillin was found in the elderly subjects. These findings were similarly attributed to a decrease in drug elimination in the aged, since no apparent age differences were noted in the pharmacokinetic parameters governing both rate and extent of ampicillin absorption.
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  • 58
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    European journal of clinical pharmacology 18 (1980), S. 237-244 
    ISSN: 1432-1041
    Keywords: isosorbide dinitrate ; 2-isosorbide mononitrate ; 5-isosorbide mononitrate ; digital plethysmography ; hypotension ; bradycardia ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 18 subjects were given isosorbide dinitrate (ISDN) 5 mg sublingually and serum concentrations of ISDN, 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) were measured, as well as changes in digital plethysmographic amplitude, heart rate, ECG, blood pressure and Schellong's test. ISDN was rapidly absorbed and metabolized, having an elimination half-life of 29 min. Its metabolites 2-ISMN and 5-ISMN had longer half-lives of 1.75 and 7.6 h respectively. The amplitude of the α-wave of the digital plethysmograph did not change significantly either in the predrug period or after placebo administration. It increased within 4 min of administration of ISDN, and reached a maximum after 14 min; the effect lasted for about 2 h. ISDN lowers blood pressure and increases heart rate in most volunteers, but in 3 of the 18 subjects severe hypotension occurred, accompanied by severe, reversible bradycardia, which was probably due to vagal reflexes initiated by the markedly diminished ventricular enddiastolic volume (LVEDV) and pressure (LVEDP). No correlation could be demonstrated between the serum concentration of ISDN and/or its vasoactive metabolites and changes in plethysmographic amplitude.
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  • 59
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    European journal of clinical pharmacology 24 (1983), S. 127-136 
    ISSN: 1432-1041
    Keywords: statistical analysis ; nonparametric statistical methods ; bioavailability ; confidence interval ; ANOVA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary For a two-way cross-over design, which appears to be the most common experimental design in bioavailability studies, 95%-confidence limits for expected bioavailability can be obtained by classical analysis of variance (ANOVA). If symmetry of the confidence interval is desired about zero (differences) or unity (ratios) rather than about the corresponding point estimator, Westlake's modification can be used. Two nonparametric methods and their adaptations to bioavailability ratios are reviewed, one based on Wilcoxon's signed rank test (Tukey), and the other on Pitman's permutation test. The necessary assumptions and the merits of these procedures are discussed. The methods are illustrated by an example of a comparative bioavailability study. A FORTRAN program facilitating the procedures is available from the authors upon request.
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  • 60
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    European journal of clinical pharmacology 24 (1983), S. 185-190 
    ISSN: 1432-1041
    Keywords: amezinium ; hypotension ; antihypotensive drug ; ECG ; concentration-effect relationship ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Blood pressure, ECG and plasma concentration were determined for up to 12h following single i.v. (10 mg) and oral (20 mg) doses of amezinium (Regulton®) in 8 healthy, male volunteers. The i.v. and oral doses were almost equi-active in significantly increasing systolic blood pressure (SBP) by 14.5 and 15.6 mmHg, respectively. The maximum SBP after the i.v. dose was reached after 45 min, and 105 min after oral administration. The heart rate fell reflexly. The increases in mean and diastolic blood pressures were not significant. Pulse pressure was enhanced after both i.v. and oral administration. The effect on systolic blood pressure lasted for about 4 h. There was a slight shortening of the QTc duration, which could not be explained as a drug effect. Other ECG time intervals were not altered. Multiple regression analysis showed a significant positive correlation between the log plasma concentration and the increase in SBP between 0.5 and 5 h after oral administration (r=0.78,p〈0.001) and between 0.75 and 5 h after i.v. administration (r=0.83,p〈0.001). 30 min after amezinium p.o. the mean SBP began to rise, when a plasma level of about 30 ng/ml was reached.
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  • 61
    ISSN: 1432-1041
    Keywords: sulfinpyrazone ; pharmacokinetics ; metabolites ; inhibition of platelet aggregation
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulfinpyrazone, and the plasma levels of its sulfide and sulfone metabolites, have been determined after a single oral dose (400 mg) and during steady-state conditions (4×200 mg daily for 6 days) in healthy female volunteers. The plasma half-lives of sulfinpyrazone, the sulfone and the sulfide were 3.7, 3.2 and 14.7 h, respectively, during steady-state. After a single dose and during steady state conditions the half-lives of sulfinpyrazone and the sulfone did not differ significantly. The trough plasma levels of the sulfide metabolite exceeded those of the parent compound in four of the six volunteers on the last day of the study. The data suggest that in man the most likely candidate for the prolonged inhibition of platelet aggregation observed after treatment with sulfinpyrazone is its sulfide metabolite, because of its prolonged elimination.
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  • 62
    ISSN: 1432-1041
    Keywords: trimethoprim ; sulphadiazine ; urinary tract infection ; children ; pharmacokinetics ; urinary concentrations
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical effect and pharmacokinetics of the combination trimethoprim (TMP)-sulphadiazine (SD) were studied in 18 children with acute urinary tract infections (UTI), aged 2–56 months. A suspension of TMP-SD (9+41 mg/ml) was taken orally twice daily for 10 days. Various doses of TMP (2.9–3.7 mg/kg/day) and SD (12.9–16.7 mg/kg/day) were also given to children of different ages. After 2–4 days of treatment, bacterial cultures of urine were negative and C-reactive protein in serum, WBC count and ESR in all patients had become normal. Steady state serum levels for both components were reached after 4 or more days of treatment. At steady state, mean peak serum concentrations of TMP and SD of 1.4 µg/ml and 27 µg/ml, respectively, were found within 2–4 h after a fasting morning dose. The biological half-lives of TMP and SD were of the same order of magnitude, but the total clearance of TMP was 5 times greater than that of SD. The concentrations of TMP-SD in urine were invariably more than 10 times the minimum inhibitory concentrations (MIC) for the causative organisms (tested at the ratios 1:20 and 1:4 of TMP and SD). Non-metabolized SD constituted 77% of total SD in urine of infants, and 55% of total SD in children of 1 year or more. The TMP-SD combination showed a satisfactory clinical effect and favourable pharmacokinetic properties in children with UTI.
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  • 63
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    European journal of clinical pharmacology 24 (1983), S. 337-343 
    ISSN: 1432-1041
    Keywords: ketamine ; diazepam ; drug interaction ; pharmacokinetics ; premedication ; clorazepate ; drug metabolism ; enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Anaesthesia with continuous i.v. ketamine and 65% nitrous oxide in oxygen was given to a total of 49 patients undergoing major abdominal surgery. A control group was premedicated with atropine and other groups received in addition rectal diazepam or clorazepate i.v. Four further patients had been on oral diazepam or barbiturates for 1–14 years; as premedication they received atropine alone. The anaesthetic technique gave good operative conditions in the 4 groups of patients. The haemodynamic stimulation of ketamine was significantly reduced in patients premedicated with diazepam. Psychotomimetic side effects were not prominent in any of the groups. Patients premedicated with diazepam required a lower rate of ketamine infusion as compared to controls during the initial 30 min of anaesthesia. The patients in the other groups did not differ from the control group in this respect. There were large differences in metabolic pattern between the groups. As compared to the controls, the patients on long-term diazepam or barbiturates had high concentrations of hydroxylated metabolites, with levels higher than that of norketamine. The patients pretreated with diazepam had very low plasma levels of hydroxylated metabolites. Clorazepate premedication did not significantly affect the metabolism of ketamine. The biological half-life of ketamine was significantly increased in the diazepam-treated group, and it was shortened in those on long term treatment with barbiturates or diazepam.
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  • 64
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    European journal of clinical pharmacology 24 (1983), S. 485-494 
    ISSN: 1432-1041
    Keywords: amiodarone ; pharmacokinetics ; therapeutic serum level ; thyroid function ; antiarrhythmic therapy ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 17 patients on long term therapy with amiodarone, serum drug levels measured by HPLC were related to pharmacological effects. At steady state, serum levels were directly proportional to the dose, 5 mg/kg per day leading to an average serum level of approximately 2.5 µmol/l. The non-amiodarone level of iodine averaged 4-times higher than the level of amiodarone iodine. The elimination half-life of amiodarone ranged from 21 to 78 days, and of non-amiodarone iodine from 24 to 160 days. Control of arrhythmias was satisfactory in all 12 evaluable patients, when the serum amiodarone level exceeded 1.5 µmol/l. Deterioration of vision and polyserositis occurred only at amiodarone levels above 4 µmol/l. Tentatively, a therapeutic range of 1.5 to 4 µmol/l is proposed. In contrast, thyroid dysfunction was observed at any amiodarone level. In view of the narrow therapeutic window, therapy with amiodarone may be optimized by monitoring its serum level and in addition, thyroid function should be regularly checked.
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  • 65
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    European journal of clinical pharmacology 24 (1983), S. 521-524 
    ISSN: 1432-1041
    Keywords: sotalol ; beta-adrenoceptor antagonist ; pregnancy ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32–36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4±0.3 ml/min/kg) than in the post-natal phase (1.5±0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6±0.6h ante-natally and 9.3±0.7h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.
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  • 66
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    European journal of clinical pharmacology 24 (1983), S. 549-556 
    ISSN: 1432-1041
    Keywords: dibromosulfophthalein ; pharmacokinetics ; plasma levels ; urinary excretion ; biliary excretion ; biliary fistula ; enterohepatic circulation ; hepatic transport test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of dibromosulfophthalein (DBSP), the 3,6-dibromo analogue of BSP, was studied in 7 patients with a biliary fistula, 52 h after cholecystectomy, and in 6 gynaecological patients with an indwelling urethral catheter, following extirpation of the uterus i.e. with an intact enterohepatic circulation. Plasma protein binding determined by ultrafiltration was 98–99% up to a concentration of 700 µg/ml. After an intravenous bolus injection of DBSP 5 mg/kg, a biexponential plasma decay was found in both groups, with a rapid initial t1/2 of 2–6 min and a slow secondary phase of 33–109 min (mean 66 min) in the cholecystectomy patients, and 10–30 min (mean 19 min) in the gynaecological patients. The biliary excretion rate varied considerably between the patients and was highly correlated with bile flow. Biliary output amounted to a maximum of 86% of the dose in 24 h. The excretion rate curves showed ascending and descending phases, the mean terminal t1/2 being 65 min. Urinary excretion was 3–11% of the dose in 8 h in the gynaecological patients (mean 6%) and 6–31% in the cholecystectomy group (mean 16%). Renal clearance of unbound DBSP was about ten-times greater than the glomerular filtration rate, which indicates tubular secretion. A two compartment model with elimination from the peripheral and central compartments was selected because of these data. Analysis of the plasma-disappearance curves indicated an initial plasma clearance of 500–600 ml/min, which suggests that hepatic uptake will be very dependent on flow. Steady state (biliary) clearance was about 400 ml/min in the gynaecological group and approximately half that in the cholecystectomy patients; V1 tended to be higher and V2 to be lower in the latter group. It is concluded that biliary excretion rate of DBSP in patients with a biliary fistula is probably depressed by the postoperative bile drainage and the lack of enterohepatic cycling of bile salts.
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  • 67
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    European journal of clinical pharmacology 24 (1983), S. 661-665 
    ISSN: 1432-1041
    Keywords: hydrochlorothiazide ; pharmacokinetics ; renal failure ; dosage adjustment ; excretory mechanism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of hydrochlorothiazide (HCT) was investigated in 23 subjects with normal renal function or widely varying degrees of renal failure. The half-life of elimination increased from 6.4 h in subjects with normal renal function to 11.5 h in patients with mild renal impairment (endogenous creatinine clearance between 30 and 90 ml/min), and to 20.7 h in patients with an endogenous creatinine clearance below 30 ml/min. The cumulative urinary excretion and the renal HCT clearance were correspondingly reduced in patients with impaired kidney function. In normal subjects HCT was mainly excreted by tubular secretion, but as renal HCT clearance in patients with renal impairment did not differ significantly from endogenous creatinine clearance, it was concluded that the secretory mechanism is most markedly impaired. In patients with an endogenous creatinine clearance of 30 to 90 ml/min, the dosage of HCT should be reduced to 1/2 and in patients with a endogenous creatinine clearance below 30 ml/min to 1/4 of the normal daily dose to avoid dose dependant side-effects.
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  • 68
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    European journal of clinical pharmacology 24 (1983), S. 791-796 
    ISSN: 1432-1041
    Keywords: furosemide ; bioavailability ; diuretic effect ; urine sodium ; urine potassium ; power of ANOVA ; tablet formulations ; urinary flow rate ; normal volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The relative bioavailability and diuretic effect of 2 commercially available tablet preparations of furosemide 40 mg was examined in 10 healthy male volunteers. A close linear relationship between the urinary excretion rate of furosemide and the rate of sodium ion excretion in urine and/or flow rate of urine was demonstrated. There were no significant differences in the urinary excretion of furosemide, sodium and potassium ions or urinary volume following the oral doses. The difference in drug content affected the urinary recovery of furosemide over 24 h but had no effect on the pharmacological response. The analytical power of ANOVA using the various parameters of the responses to furosemide was no lower than when the parameters of urinary excretion of furosemide were used.
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  • 69
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    European journal of clinical pharmacology 24 (1983), S. 813-818 
    ISSN: 1432-1041
    Keywords: dihydroergotamine ; dextran 70 ; pharmacokinetics ; radioimmunoassay ; drug interaction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of subcutaneous dihydroergotamine (DHE) with or without dextran 70 infusion was evaluated in a single- and multiple-dose study in 30 patients. Radioimmunoassay was used to measure plasma DHE and the anthrone method to determine the dextran concentration. In the single-dose study no significant interaction between DHE and dextran was noted with respect to their plasma levels. The absorption of s.c. DHE was rapid and the disappearance curve followed a biphasic pattern, t0.5 α being 1.4 and 2.0 h, t0.5 β 22 and 21 h for DHE and DHE/dextran 70, respectively. In the multi-dose study the trough level of DHE initially had a tendency to rise, in accordance with simulated plasma concentration curves. DHE trough levels were about 0.5 ng/ml and were well above the assumed minimum effective value to induce venoconstriction (0.06 ng/ml). Dextran concentrations were significantly higher when DHE was co-administered, possibly, due to changes in plasma volume. It is concluded that DHE 0.5 mg s.c. twice daily will give an adequate plasma concentration and that there was no important interaction between it and infused dextran 70.
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    European journal of clinical pharmacology 25 (1983), S. 77-80 
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; multiple dosing ; plasma protein binding ; analgesic
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of meptazinol (Meptid®) have been studied in nine male volunteers after single and multiple oral administration of 200 mg tablets and also after a single 25 mg intravenous dose. Plasma concentrations of meptazinol were determined by HPLC using fluorescence detection. Drug absorption after oral dosage was rapid, peak plasma concentrations being reached between 0.25 and 2 h after drug administration. Subsequent elimination proceeded in an apparently mono-exponential fashion with a half-life of 2 h, although after intravenous dosage there was evidence of an initial rapid distributive phase. The mean total plasma clearance was 2.21/min and the mean apparent volume of distribution (Vdβ) was 4.99 l/min. The bioavailability ranged from 1.9 to 18.5% (mean=8.7%) and was related to the rate of absorption. Multiple dosing, 6-hourly for 3 days, did not produce any accumulation above that predicted from a single dose. Plasma protein binding of the drug was 27.1% and did not vary over the therapeutic concentration range of 25 to 250 ng/ml.
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  • 71
    ISSN: 1432-1041
    Keywords: carteolol ; pharmacokinetics ; beta-adrenoreceptor blocking drug ; absolute bioavailability ; plasma levels ; urinary excretion ; renal handling
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and absolute bioavailability of a new nonselective β-adrenoreceptor blocking agent, carteolol, were investigated after administration of single intravenous and oral doses to eight normal volunteers. Plasma and urine drug concentrations were measured by an HPLC method. The pharmacokinetic parameters after intravenous dosing were obtained by a two-compartment analysis: elimination or β-phase t1/2 4.7±0.3 h; Vc, 0.74±0.101/kg; Vd, 4.05±0.48 l/kg; Cl, 10.13±0.94 ml/min/kg; ClR, 6.56±0.58 ml/min/kg; and ClNR, 3.57±0.40 ml/min/kg. The absolute bioavailability obtained from plasma data was 83.7±8.0%, which was consistent with that derived from analysis of urine of 82.7±4.2%. The amounts excreted unchanged in urine up to 48 h after the intravenous and oral doses were 65.0±1.5% and 53.8±3.2% of the administered doses, respectively. The t1/2 for removal of the drug derived from plasma and urine findings after intravenous and oral dosing were similar, which indicates that the main route of elimination of carteolol is via the kidneys. As the ClR of carteolol exceeded the Cl of creatinine there may be renal tubular secretion of the drug.
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  • 72
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    European journal of clinical pharmacology 25 (1983), S. 237-241 
    ISSN: 1432-1041
    Keywords: triamterene ; bioavailability ; pharmacokinetics ; metabolism ; hydroxy triamterene sulphate ; urinary excretion ; i.v. administration ; first-pass-effect
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary With a new formulation, which made intravenous infusion of triamterene (TA) possible, plasma levels and urinary excretion rates of TA and its main metabolite (OH-TA-ester) were measured in a randomized, cross-over trial in 6 healthy volunteers given triamterene 10 mg i.v. and 50 mg p.o. TA and OH-TA-ester were determined by densitometric measurement of native fluorescence after thin layer chromatography. Distribution volumes of the central compartment of TA and OH-TA-ester were 1.49 l/kg and 0.11 l/kg, respectively. Terminal half-lives were 255 min for TA and 188 min for OH-TA-ester after i.v. administration. For TA total plasma clearance was 4.5 l/min and renal plasma clearance 0.22 l/kg. The formation of OH-TA-ester was very rapid and the concentration of the metabolite exceeded that of TA at all times. After i.v. administration the urinary recovery of TA and OH-TA-ester was 4.4% and 50.9%, respectively. The bioavailability of TA was 52%, corresponding to absorption of 83%. TA is partly eliminated by a first-pass-effect. The main metabolite of TA is OH-TA-ester, which is pharmacologically active.
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  • 73
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    European journal of clinical pharmacology 25 (1983), S. 369-373 
    ISSN: 1432-1041
    Keywords: pengitoxin ; pharmacokinetics ; 16-acetylgitoxin ; absorption ; urinary excretion ; healthy subjects ; cardiac glycoside
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of pengitoxin has been studied in 28 healthy subjects after intravenous and oral administration. The mean plasma concentration 24 h after 0.5 mg i.v. was 5.2 ng · ml−1. Following an open two-compartment model a mean elimination half-life of 60.5 h (24.9 to 103.5 h) and a mean volume of distribution (Vdarea) of 66.91 (31.8 to 109.61) were calculated. Absorption calculated by comparison of the AUC0-∞-values amounted to 99%. Within 4 days, 16.7% (11.7 to 21.1%) or 27.8% (18.4 to 33.7%) (0.5 mg i.v. or 1.2 mg p.o.) was excreted in urine. After pengitoxin 0.5 mg i.v. total body clearance and renal clearance were 13.3 ml · min−1 (7.0 to 18.6 ml · min−1) and 3.0 ml · min−1 (1.9 to 3.9 ml · min−1) respectively. The elimination half-life of pengitoxin is longer than that of digoxin and distinctly shorter than that of digitoxin, whilst its distribution volume and clearance are closer to those of digitoxin than of digoxin.
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  • 74
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    European journal of clinical pharmacology 25 (1983), S. 399-405 
    ISSN: 1432-1041
    Keywords: ceftriaxone ; pharmacokinetics ; concentration-dependent binding ; volume of distribution
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both Vβ and the model-independent VSS) were inaccurate/invalid; b) V β based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms ( $$\bar f_P $$ and $$\bar V_{SS}^T $$ ) were introduced which provide additional insight concerning the disposition of this type of drug. The $$\bar f_P $$ is the area-weighted average fraction unbound in the plasma and $$\bar V_{SS}^T $$ is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.
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    European journal of clinical pharmacology 25 (1983), S. 455-457 
    ISSN: 1432-1041
    Keywords: digoxin ; concentration plateau ; pharmacokinetics ; systolic time intervals ; optimal infusion scheme ; dose-response data
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a volume-controlled infusion pump, a mean serum plateau level of digoxin of 4–5 ng/ml was rapidly achieved and maintained in 6 healthy volunteers. The infusion scheme was calculated on the basis of data published on the pharmacokinetics and pharmacodynamics of digoxin following bolus intravenous injection. The magnitude of the response (change in electromechanical systole) at the end of the plateau phase was comparable to that observed with the concentration in the therapeutic range at steady state.
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    European journal of clinical pharmacology 25 (1983), S. 449-453 
    ISSN: 1432-1041
    Keywords: canrenone ; pharmacokinetics ; plasma level ; bioavailability ; urinary excretion ; spironolactone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy male volunteers received canrenoate-K 200 mg (Sincomen® pro injectione) by intravenous injection and one week later spironolactone 200 mg (Sincomen®-100) orally. Plasma levels and urinary excretion of unchanged canrenone were determined up to 24 h by a specific HPLC method. Following intravenous administration, the maximum plasma level of 2066±876 ng/ml was found after 29±15 min and thereafter the concentration declined with a half-life of 3.7±1.2 h. Total clearance was 4.2±1.7 ml/min·kg. After oral ingestion, the maximum concentration of 177±33 ng/ml was observed at 4.4±0.9 h. The absolute bioavailability of canrenone was 25±9%. Within 24 h, respectively 0.4 and 0.6 mg, canrenone were excreted by the kidney after intravenous and oral administration. The half-life of elimination was 4.9±1.8 h (i.v.) and 3.9±1.2 h (p.o.).
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  • 77
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    European journal of clinical pharmacology 25 (1983), S. 497-501 
    ISSN: 1432-1041
    Keywords: methadone ; pharmacokinetics ; steady state ; addiction rehabilitation ; therapeutic failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Deuterated methadone (M-d3) and GC-MS analysis were used to study the steady state pharmacokinetics of methadone (M) in eight patients reported as therapeutic failures in a methadone maintenance treatment programme. The patients were compared to an unselected group of 12 patients stabilized on M for 25 days. During one dosage interval a pulse dose of M-d3 was administered intravenously instead of the oral M-dose (M-d0). The pharmacokinetic parameters, half-life in the β-phase (t1/2β), volume of distribution during the postdistributive phase (Vdβ) and during steady state (Vdss) were determined as well as the body (ClS) and renal (ClR) clearances of M. Pronounced differences in Vdβ and Vdss were found between the two groups. The therapeutic failures had a smaller Vdβ and Vdss 3.09±0.96 l/kg and 2.74±0.96 l/kg vs 4.56±1.00 l/kg and 4.20±0.78 l/kg in the control group. The differences were due to changes between the groups in the volume of the central compartment. Differences between the groups were also found in t1/2β — 24.5±2.6 h in the therapeutic failures and 34.0±7.0 h (p〈0.001) in the comparison group. However, the change in t1/2β was probably a consequence of the change in Vdβ, as the body clearance of M was similar in the two groups — 104±36 ml/min vs 111±36 ml/min. The smaller volume of distribution could lead to unacceptably high fluctuation of M in the central compartment, and withdrawal symptoms during the latter part of the dosage interval. The appropriate treatment of this subgroup of patients on methadone treatment is not to increase the dose but to shorten the dosage interval. Alternatively, a longer-acting opiate, such as 1-α-acetylmethadol (LAAM), may be used.
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    European journal of clinical pharmacology 25 (1983), S. 529-534 
    ISSN: 1432-1041
    Keywords: penbutolol ; pharmacokinetics ; blood pressure effect ; heart rate effect ; dose response relationship ; tolerance
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The present study was done to establish the dose-response relationships for effects on heart rate and systolic and diastolic blood pressure, tolerance and plasma disappearance kinetics after large intravenous and oral doses of penbutolol. Twelve healthy volunteers were randomly allocated to receive penbutolol (n=8) or placebo (n=4) in this single blind, placebo-controlled investigation. The degree of beta-blockade was measured by standarized exercise tests at work loads selected to produce a heart rate of 150/min without treatment. Penbutolol was given as single i.v. doses of 3, 6 and 12 mg and as 40, 80 and 120 mg once daily for one week, measurements being made 2 and 24 h after the last dose. Penbutolol i.v. did not influence the resting heart rate but it did reduce resting systolic blood pressure in a non-dose dependent manner. Exercise heart rate and systolic pressure were lowered by all the intravenous doses. All oral doses of penbutolol lowered exercise heart rate and systolic blood pressure to the same extent. The reductions in exercise tachycardia was still present after 24 h. After i.v. administration t1/2 was approximately 1.2 h and the volume of distribution was 32–42 l. All doses were well tolerated.
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  • 79
    ISSN: 1432-1041
    Keywords: delta-9-tetrahydrocannabinol ; mood ratings ; pharmacodynamics ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This study explored the relationships in man between various pharmacological effect of Δ9-tetrahydrocannabinol (THC), plasma THC concentration, and pharmacokinetic parameters of THC. Three male and three female experienced marihuana users smoked two standard marihuana cigarettes. The relationships between heart rate, subjective “high” rating, Linear Mood Scale factors, and plasma THC concentration were assessed. Significant correlations were observed between various Linear Mood Scale factors and pharmacokinetic parameters reflecting the magnitude of drug intake and the degree of temporal dissociation between the time courses of plasma THC concentration and pharmacological effects (tachycardiac effect, “high”). In particular, the disturbed/weird and sensitive/aware mood factors correlated positively with pharmacokinetic measures of drug intake and time lag to effect. A more reliable index of intoxication with THC may be provided by the global subjective “high” rating, rather than other ratings more specific for particular moods.
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  • 80
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    European journal of clinical pharmacology 25 (1983), S. 117-121 
    ISSN: 1432-1041
    Keywords: serum digoxin ; pregnancy ; digoxin-renal-clearance ; creatinine-clearance ; digoxin-elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Digoxin-renal-clearance, creatinine-clearance, 24-h urine elimination of digoxin and serum digoxin were studied in 15 patients in the third trimester of pregnancy and 6 to 12 weeks post-partum. There was significant fall post-partum in the first three. There was also a significant fall post-partum in serum digoxin levels. This finding was unexpected, but may be due to heightened absorption exceeding increased elimination because of the physiological status in pregnancy.
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  • 81
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    European journal of clinical pharmacology 11 (1977), S. 149-154 
    ISSN: 1432-1041
    Keywords: Hydroflumethiazide ; spectrofluorometry ; pharmacokinetics ; plasma half life ; renal excretion ; renal disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A spectrofluorometric method for determination of hydroflumethiazide in human plasma and urine has been developed. The limit of detection was 10 ng/ml plasma and 100 ng/ml urine. The plasma concentration of hydroflumethiazide was determined for 9–11 hours and excretion in urine for 24–37 hrs after oral administration of about 1 mg/kg body weight to 7 subjects. Plasma half life in healthy subjects was 1.9–2.1 h, and 2.7–8.6 h in patients during the period 4–9 hrs after dosing. Cumulative excretion in urine was 67–79% of the dose during 31–37 hrs in 6 subjects; one patient with renal disease was found to excrete only 25.8% of dose during 24 hours. Renal clearance of hydroflumethiazide was higher in the healthy subjects (0.29–0.44 1 h−1 kg−1) than in the patients (0.040–0.15 l h−1 kg−1). Plasma half life of hydroflumethiazide was not closely correlated with renal clearance of the drug, which suggests that other factors may play a role in determining plasma half life.
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  • 82
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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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  • 83
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    European journal of clinical pharmacology 17 (1980), S. 45-50 
    ISSN: 1432-1041
    Keywords: ketobemidone ; narcotic analgesic ; N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The basic pharmacokinetics and oral bioavailability of ketobemidone have been studied in 6 patients after surgery. Plasma concentrations were first determined following intravenous administration of Ketogin® 2 ml, containing ketobemidone chloride 10 mg and the spasmolytic N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride 50 mg, and then, on the second postoperative day, following oral administration of 2 tablets of Ketogin®, each containing ketobemidone chloride 5 mg and the spasmolytic agent 25 mg. The average oral bioavailability of ketobemidone was 34%±16% (SD, n=6). The mean plasma half-life of elimination (t1/2β) was about the same following oral (2.45±0.73 h; SD, n=5) as after intravenous administration (2.25±0.35 h; SD, n=6). The low oral bioavailability and rapid elimination of ketobemidone demonstrated in this study suggest that the usual dosage recommendation for oral Ketogin® (ketobemidone 5–10 mg every 6–7 h) in patients with severe pain is too low.
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  • 84
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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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  • 85
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    European journal of clinical pharmacology 12 (1977), S. 355-357 
    ISSN: 1432-1041
    Keywords: Nitrazepam ; placental transfer ; pharmacokinetics ; plasma levels ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six women from 14 to 17 weeks pregnant, and 12 woman from 36 to 40 weeks pregnant, were given nitrazepam 5 mg orally about 12 h before legal abortion by hysterotomy in the former group and elective caesarean section in the latter group. The concentration of nitrazepam was determined by gas-liquid chromatography. Binding to plasma proteins was evaluated by separation of the protein-free fraction by ultracentrifugation. In the first group (early pregnancy) the level of nitrazepam was found to be lower in the fetal than in the maternal circulation. The concentration in amniotic fluid was still lower. In the latter group (late pregnancy) the concentration both of unbound and total nitrazepam in maternal and fetal plasma were in equilibrium, which indicated an increase in transplacental transfer in late pregnancy. The percentage of unbound nitrazepam in both cases was 12%.
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  • 86
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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
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    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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  • 87
    ISSN: 1432-1041
    Keywords: beta-blocker ; metoprolol ; slow-release formulation ; multiple dosing ; blood pressure ; heart rate ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic and pharmacodynamic profiles for metoprolol have been measured in six healthy volunteers after single and multiple dosing with 100 mg conventional formulation twice daily and 200 mg slow-release formulation once daily. Both multidose regimes produced measurable predosing plasma concentrations of metoprolol. The plasma concentrations on the eighth day were greater than predicted by the single-dose data as indicated by the comparison of the total areas under the curve for the single dose and the dosage interval areas during multiple dosing. This increase may be associated with a change in the bioavailability and/or clearance of the drug and is currently being investigated. The peak concentrations for the two regimens were comparable but the times to peak with the slow-release regimen were significantly delayed. Both regimes produced significant beta-blocking effects over 24 h during multiple dosing, the reductions in exercise heart rate at 0 and 24 h on the eighth day corresponding to more than 20% of the maximum effect. Resting pulse rates and blood pressures were affected to a similar extent by the two regimens but neither significantly altered respiratory peak flow rates. The effects during multiple dosing were generally greater than those after a single dose and appeared to follow a more consistent trend. This observation, together with those for the plasma level data on the eighth day, illustrate the importance of performing multiple-dose studies in assessing beta-blocking drugs.
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  • 88
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    European journal of clinical pharmacology 12 (1977), S. 387-392 
    ISSN: 1432-1041
    Keywords: Digoxin ; β-methyldigoxin ; prolonged administration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy volunteers received digoxin 0.4 mg or β-methyldigoxin 0.4 mg i. v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and β-methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54±0.31 days was significantly shorter than the half life of 2.29±0.34 days for β-methyldigoxin. The distribution volume of 807±187 liters for digoxin was not significantly larger than the 735±227 liters for β-methyldigoxin. Renal digoxin clearance of 191±25 ml/min was significantly higher than both the renal clearance of β-methyldigoxin of 111±23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of β-methyldigoxin injected once a day, which was significantly higher than the 1.8-fold accumulation of digoxin.
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  • 89
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    European journal of clinical pharmacology 12 (1977), S. 451-456 
    ISSN: 1432-1041
    Keywords: Bioavailability ; carbamazepine ; elimination ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters:k abs =0.176±0.209 h−1;k=0.0203±0.0055 h−1; T1/2=37.5±13.1 h; VD=0.825±0.1041 · kg−1; Clearance=0.0163±0.0061 l · kg−1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.
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  • 90
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    European journal of clinical pharmacology 17 (1980), S. 189-196 
    ISSN: 1432-1041
    Keywords: flunitrazepam ; prolonged administration ; pharmacokinetics ; clinical observations ; sleep parameters
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight patients were given flunitrazepam 2 mg orally, once daily for 28 consecutive days. The time-course of the plasma concentration of unchanged flunitrazepam and its principal metabolites were studied in detail after the first and last doses. Additional blood samples were collected immediately before administration of the tablet on days 4, 7, 11, 14, 18, 21 and 25. Clinically there were no changes during the trial period in the onset of sleep, duration of sleep, depth of sleep measured as number of spontaneous awakenings, or in the patients' condition on awakening. The time-course of the plasma concentration of flunitrazepam could be described by a three-compartment model, assuming that the rate constants remained unchanged during treatment. Maximal plasma concentrations of unchanged flunitrazepam, found two hours after intake, reached 10–15 ng/ml after the first and 15–20 ng/ml after the last dose. The β-half-life was found to be between 20 and 36 h.
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  • 91
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    European journal of clinical pharmacology 17 (1980), S. 275-284 
    ISSN: 1432-1041
    Keywords: chlormethiazole ; cirrhosis of the liver ; antipyrine ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of chlormethiazole after oral and intravenous administration was studied in six healthy volunteers and eight patients with alcoholic cirrhosis of the liver. Plasma concentration-time curve after the intravenous infusion could adequately be described by two- or three-compartment open models both in healthy volunteers and in the patients. Based on the areas under the plasma concentration-time curves, the systemic bioavailability of oral chlormethiazole was about ten times greater in the patients than in healthy controls. The elimination of chlormethiazole was relatively less retarded in the patients, as indicated by a decrease of about 30% in its plasma clearance. In the patients the plasma protein binding of chlormethiazole was decreased, but the volume of distribution and half-life of elimination were unchanged. The increase in bioavailability of chlormethiazole was associated with significant alteration in the serum levels of bilirubin, albumin, alkaline phosphatase, prothrombin-proconvertin activity (P + P) and elimination rate of antipyrine or14C-aminopyrine. The increased bioavailability of oral chlormethiazole was due to impaired first-pass metabolism in the cirrhotic liver. A considerable reduction in dose seems to be indicated if oral chlormethiazole is used in patients with advanced cirrhosis of the liver. A substantial fraction of dose, averaging 15%, was lost during the intravenous infusion, presumably due to adsorption to the infusion tubing.
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  • 92
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    European journal of clinical pharmacology 18 (1980), S. 263-268 
    ISSN: 1432-1041
    Keywords: naproxen ; renal insufficiency ; metabolism ; protein binding ; single dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of naproxen after a single oral dose of 250 mg has been studied in 8 subjects with normal renal function and 16 patients with varying degrees of chronic renal insufficiency. Unchanged naproxen and its main unconjugated metabolite, 6-0-desmethylnaproxen, were determined fluorometrically in serum. In healthy subjects the elimination half-life of naproxen was 17.7± 3.0 h (mean±SD) and it was not significantly prolonged in patients with renal failure (18.1±5.3) h. No accumulation of naproxen in serum occurred in uraemic patients. On the contrary, serum drug levels were slightly but significantly lower in patients with severe renal failure. The total body clearance and apparent volume of distribution of naproxen were significantly increased in this group of patients. Decreased binding of naproxen to serum proteins was observed in patients with renal failure. The apparent half-life of desmethylnaproxen was of the same order of magnitude as that of naproxen (18.6± 4.4 h), and was also independent of renal function. A good correlation was found between the area under the curve (AUC), the peak concentration of the metabolite and the serum creatinine concentration. These observations suggest increased metabolism and an increased apparent volume of distribution of naproxen in severe renal failure, probably caused by decreased serum protein binding of the drug. However, it is proposed that in naproxen therapy no adjustment of the dosage regimen is necessary in patients with impaired renal function.
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  • 93
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    European journal of clinical pharmacology 18 (1980), S. 355-360 
    ISSN: 1432-1041
    Keywords: cis (Z)-flupentixol ; cis (Z)-flupentixol decanoate ; serum concentration ; biological half-life ; pharmacokinetics ; first-pass metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum concentrations of cis (Z)-flupentixol have been estimated in three male human volunteers who received cis (Z)-flupentixol by intravenous infusion, flupentixol (cis (Z)/trans (E) mixture, 1:1) orally as single and repeated doses, and i. m. cis (Z)-flupentixol decanoate in Viscoleo®. The intravenous data show that cis (Z)-flupentixol followed a multicompartment model, but it was not possible to fit the data to a two or three compartment model. The concentration curves after oral administration indicated relatively slow absorption with a peak concentration at 3–6 h, except for one case with peak at 1 h. The variation in the dosage interval after one daily oral administration was relatively limited (1.7–3.0 times), which indicates that 24 h is a reasonable dosage interval. Biological half-lives were estimated in different ways and showed some intra-individual variation; the half-life was of medium length (19–39 h). The serum concentrations after intramuscular injection of cis (Z)-flupentixol decanoate clearly demonstrated a depot effect, with a maximal concentration at 3–5 days after injection. The descending part of the serum curves allowed an approximate estimation of half-life of 3–8 days. This was not the elimination half-life, but in all probability the half-life of release of drug from the oil depot which was the rate-limiting step. From the areas under the serum concentration curves the fraction of orally administered cis (Z)-flupentixol available to the organism was calculated to be 55% (range 48–60%). The loss of drug might have been due to imcomplete absorption, but it is more likely that cis (Z)-flupentixol underwent first-pass metabolism in the gut wall and the liver. As the tablets contained about 50% cis (Z)-flupentixol, while the depot preparation contained 74% cis (Z)-flupentixol, the pharmacokinetically equivalent doses are: 10 mg tablet daily corresponds to 25 mg depot weekly. Calculation of systemic clearance gave values of 0.44–0.49 l/min, and an apparent volume of distribution was 12.5–17.2 l/kg.
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  • 94
    ISSN: 1432-1041
    Keywords: atenolol ; hypertension ; plasma renin activity ; pharmacokinetics ; pharmacodynamic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To show whether repeated administration of atenolol for several days would influence its pharmacokinetic parameters and the extent and duration of the pharmacologic responses, the plasma level of atenolol and changes in heart rate, blood pressure and plasma renin activity were measured in 12 hypertensive patients at various times of day (9 a. m., 12 noon, 3 p. m. and 7 p. m.) after oral administration of the first dose of atenolol 100 mg, again during the 7th and 14th days of continued once-daily administration of the same dose, and finally during the three days following withdrawal of the drug. The peak plasma concentration of atenolol (about 600 ng/ml) was found 3 h after administration of the first dose, and measurable amounts (50–70 ng/ml) were found after 24 h. None of the pharmacokinetic characteristics were changed by administration of a single daily dose for two weeks. After withdrawal of the drug, detectable amounts of atenolol were found in plasma for at least 48 h. The first dose of atenolol caused prompt (3 h) and prolonged (up to 24 h) lowering of supine and standing systolic and diastolic blood pressures, slowing of supine and standing heart rate, reduction of the blood pressure and heart rate responses to dynamic exercise, and a decrease in plasma renin activity. The extent and time-course of all these responses were not influenced by repeated once-daily administration of the 100 mg dose for two weeks. Most of the effects continued during the withdrawal days, the lowering of blood pressure being somewhat more prolonged than the slowing of heart rate. It is concluded that a once-daily dose of atenolol 100 mg decreases blood pressure and heart rate throughout the following 24 h, without excessive daily fluctuation in its effects, and without signs of tolerance or accumulation.
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  • 95
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    European journal of clinical pharmacology 18 (1980), S. 415-418 
    ISSN: 1432-1041
    Keywords: diclofenac ; acetyl salicylic acid ; intravenous bolus administration ; oral administration ; interaction ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Previous studies have shown that aspirin interacts with orally administered diclofenac sodium, causing reduced peak concentrations, lower levels and decreased areas under curves. In this study, diclofenac sodium was administered orally and intravenously with and without aspirin, to 6 healthy female volunteers. After intravenous dosing both plasma levels and areas under curves were significantly reduced although none of the rate constants was affected. The volume of distribution of diclofenac was increased as was the plasma clearance. Oral administration with aspirin also resulted in lower plasma levels, particularly peak levels, and areas under curves. Comparison of AUC's for both modes of administration with and without aspirin suggested that lower levels after oral administration were not due to impaired absorption. These observations are best explained by decreased protein binding and increased biliary excretion of diclofenac in the presence of salicylate.
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  • 96
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    European journal of clinical pharmacology 17 (1980), S. 309-315 
    ISSN: 1432-1041
    Keywords: valproic acid ; sodium valproate ; suppositories ; micro-enemas ; steady-state concentration ; absorption ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Rectal and oral absorption of valproic acid and its sodium salt by man were compared to explore the possibility of rectal administration of the drug. The plasma concentration of valproic acid was measured by gas chromatography after a single oral dose of sodium valproate 600 mg, and after single rectal doses of sodium valproate 600 mg and valproic acid 520 mg, in a cross-over study in 7 volunteers. The rectal dosage forms included fatty suppositories and aqueous solutions. Compared with oral administration, rectal absorption of sodium valproate from an aqueous micro-enema was fast and complete. The free acid was absorbed more rapidly from fatty suppositories than was the sodium salt. The absorption rate from the rectum increased with the dose of valproic acid. Both findings are consistent with a diffusion — absorption mechanism based on the pH-partition hypothesis. Differences in the chemical composition of the fatty suppository base were not reflected in differences in absorption rate and relative bioavailability. No essential difference in absorption rate was observed if volunteers remained lying or sitting during the experiment. Rectal dosing with valproic acid 520 mg dissolved in 4 ml suppositories, twice a day resulted in steady-state plasma concentrations of 50 to 100 µg · ml−1, within the therapeutic range.
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  • 97
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    European journal of clinical pharmacology 17 (1980), S. 339-348 
    ISSN: 1432-1041
    Keywords: acebutolol ; renal failure ; dialysis ; pharmacokinetics ; N-acetylmetabolite
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of acebutolol was studied in 10 healthy subjects with normal renal function (RN), in 13 patients with various degrees of renal failure (RI) and in 8 patients undergoing repeated haemodialysis (RD). A highly specific method was used to measure acebutolol (A) and N-acetylmetabolite (NAM). In RN the decrease in plasma levels was biexponential with an apparent plasma half lives in the slow phase of A: 8.8±2.3 h and NAM: 11.4±2.2 h. The percentage of the dose excreted unchanged was 13.9% and as NAM 25.8%. Renal clearances were A: 167±20 ml/min and NAM: 150±18 ml/min. The apparent plasma half life of acebutolol does not change according to the degree of renal insufficiency (RI: 7.0±2.7 h, RD: 7.5±2.7 h), while that of NAM is increased (RI: 21.5±10.1 h, RD: 32.3±16.8 h). There is a linear relationship between the apparent elimination rate constant of NAM and creatinine clearance (r=0.832,p〈0.001). In RI 21.7% of the dose is excreted in urine (A 5.0%, NAM 16.7%). When renal function is impaired, the renal clearance of A and NAM decrease in parallel with the creatinine clearance (A: r=0.874,p〈0.001; NAM: r=0.954,p〈0.001). During dialysis the plasma half life fell (A=3.4±0.9 h, NAM=7.4±2.6 h). The dialytic clearance was A: 42.6±12.7 ml/min and NAM: 40.4±16.3 ml/min, for a blood flow of 238±35 ml/min through a dialyser with a cuprophane membrane (Ultraflo II Travenol). Acebutolol is taken up by erythrocytes (λbc=0.50±0.04). The results suggest that the dosage of acebutolol should be adjusted according to the degree of renal insufficiency.
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  • 98
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    European journal of clinical pharmacology 17 (1980), S. 379-384 
    ISSN: 1432-1041
    Keywords: theophylline ; aminophylline ; obstructive lung disease ; microcrystalline ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Variation in the systemic disposition of theophylline after ingestion of a new microcrystalline product (Theolair®) has been investigated in 7 hospitalized patients with generalized obstructive lung disease. Disposition (absolute bioavailability) was determined by comparing in the same patients the areas under the serum concentration-time curves after a single oral dose of microcrystalline theophylline and after an intravenous infusion of aminophylline. Oral absorption appeared to be fast. The half-life of absorption was 19±9 min (mean±SD). Maximal serum concentrations reached after 100±30 min were found to be in a rather narrow range: 9.8±2.5 mg · 1−1. The absolute bioavailability of the microcrystalline preparation was high and it showed only small variation: 102.7±10.2% of the dose. Relevant pharmacokinetic parameters (half-life of elimination, volume of distribution and total body clearance) were determined after both routes of administration. Individual dosage regimens required to obtain a therapeutic serum concentration were calculated for each individual patient on the basis of the observed pharmacokinetic parameters.
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  • 99
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    European journal of clinical pharmacology 18 (1980), S. 391-394 
    ISSN: 1432-1041
    Keywords: propranolol ; hypertension ; beta-adrenergic blockade ; exercise heart rate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of propranolol in 16 hypertensive patients was compared after the first oral dose of 80 mg and during chronic treatment with 80 mg bd. The degree of beta-adrenergic blockade was estimated by the reduction in maximal exercise heart rate. No significant change in plasma half-life occurred and there was no correlation between the mean steady-state propranolol concentration and beta-adrenergic blockade or antihypertensive effect. A linear relationship was observed between the decrease in blood pressure and the reduction in heart rate during maximal exercise. Therefore, the antihypertensive effect of propranolol can be explained by its peripheral beta-adrenergic blocking properties.
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  • 100
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    European journal of clinical pharmacology 18 (1980), S. 279-283 
    ISSN: 1432-1041
    Keywords: glipizide ; diabetes ; food intake ; blood glucose ; blood insulin ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of a standardized breakfast on the single dose (5 mg) kinetics and effects of glipizide was examined in 9 healthy volunteers and in 14 diabetics not previously exposed to a sulfonylurea. In the volunteers, glipizide caused an increase in plasma insulin and a reduction in blood glucose both during continued fasting and when the drug was taken with the breakfast. Food intake did not influence the peak concentration, the elimination half-life or the bioavailability of the drug. However, food intake significantly delayed the absorption of glipizide by about 0.5 h. In the patients, glipizide produced a significant increase in plasma insulin and a significant diminution of the rise in blood glucose in response to the meal. Starting at breakfast and for 45 min thereafter serum glipizide concentrations were significantly higher when the drug was taken 0.5 h before the meal, than when ingested concurrently with it. With the former treatment, the increase in plasma insulin occurred earlier and the blood glucose reduction was pronouncedly greater than with the latter treatment. As the absorption of glipizide may be delayed by concurrent breakfast, this may help to explain, why the administration of glipizide 0.5 h before breakfast led to a more appropriate relation between the serum concentration of the drug and the metabolic impact of the meal, thereby promoting more appropriate insulin release and better glucose disposition than after concurrent intake of the drug and breakfast.
    Type of Medium: Electronic Resource
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