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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Entomologia experimentalis et applicata 37 (1985), S. 241-245 
    ISSN: 1570-7458
    Keywords: Coleoptera ; Bruchidae ; Callosobruchus ; cowpea weevil ; egg recognition ; oviposition deterrents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Plusieurs expériences ont été réalisées pour déterminer pour quelles raisons les femelles de Callosobruchus maculatus évitent de pondre sur les graines portant des oeufs. La répulsion a été associée à l'oeuf lui-même et non à une autre activité de l'adulte sur la graine. Des stimuli tant chimiques que physiques (tactiles) ont semblé impliqués dans la découverte des oeufs; la substance répulsive était plus soluble dans le méthanol que dans l'éther ou l'eau. Contrairement à des études antérieures sur C. chinensis, nous avons observé que les femelles n'étaient pas dissuadées de pondre sur des graines exposées préalablement à de fortes densités de mâles.
    Notes: Abstract Several experiments were conducted to determine the mechanism by which ovipositing cowpea weevils, Callosobruchus maculatus (F.), avoid egg-laden seeds. Deterrence was associated with the egg itself and not with other adult activities on the host. Both chemical and physical (tactile) stimuli appear to be involved in egg recognition; the chemical deterrent was more soluble in methanol than in ether or water. Contrary to a previous study using C. chinensis (L.), we found that females were not deterred from ovipositing on seeds that had been exposed to high densities of males.
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  • 2
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    Entomologia experimentalis et applicata 39 (1985), S. 81-84 
    ISSN: 1570-7458
    Keywords: induced change ; induced resistance ; chemical change ; feeding ; herbivore ; feeding tests ; feeding preferences ; Coleoptera ; Chrysomelidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Les choix alimentaires d'un groupe de chrysoméles spécialistes ou généralistes a été étudié en utilisant 3 méthodes: plantes entières, feuilles coupées, rondelles de feuilles. Les méthodes utilisées out eu un effet très significatif sur les préférences relatives des chrysomèles du maïs, du haricot et de la courge. Dans quelques cas le seuil de signification statistique pour un choix particulier a été modifié par la méthode utilisée et dans d'autres cas l'ordre de préférence a été totalement inversé. Les choix alimentaires des spécialistes ont été moins affectés par la méthode utilisée que pour les espèces les plus généralistes. Il y a eu aussi un effet plus important des différences entre les méthodes rondelle de feuilles et feuille entière qu'entre feuille entière et plante entière. Les changements chimiques induits dans les plantes par les dégâts sont probablement très répandus et les chercheurs devraient en tenir compte quand ils programment et interprètent des expériences sur les préférences alimentaires.
    Notes: Abstract Feeding preferences of a group of specialist and generalist chrysomelid beetles were examined using three test methods: whole plants, excised leaves and leaf discs. Method of testing had a very significant effect on relative preferences of the beetles for corn, bean and squash. In some cases the level of statistical significance for a particular preference was affected by test methodology and in other cases the direction of preference was reversed altogether. The feeding preferences of the specialist beetle species were less affected by test method than were the more generalist species. There was also a much greater effect of the difference in test method between the disc test and whole leaf test than between the whole leaf test and whole plant test. Chemical changes in plants induced by damage are probably quite widespread in plants and investigators should take this into account when designing and interpreting tests of insect feeding preference.
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  • 3
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    Entomologia experimentalis et applicata 37 (1985), S. 113-121 
    ISSN: 1570-7458
    Keywords: Hypera postica ; alfalfa weevil ; allozyme analysis ; Coleoptera ; Curculionidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Les allozymes d'Hypera de l'est des USA (Beltsville, Maryland; Washington Co., Illinois), de l'ouest des USA (Logan et St Georges, Utah) et ‘égyptiens’ (Yuma, Arizona; Westmorland, Californie) ont été analysés par électrophorèse sur gel d'acrylamide. L'étude a porté sur 22 loci de 12 enzymes (ACPH, ADH, AMY, AO, EST, GOT, G-6PDH, MDH, ME, SOD, TYR, XDH). L'hétérozygotie moyenne de la population était 0.231, avec une moyenne de loci polymorphes de 0.536. La distance génétique moyenne de l'ensemble des populations était de 0.033 et l'indice de fixation de 0.024. Des loci caractéristiques ont été trouvés qui pourraient permettre de distinguer les Hypera occidentaux des orientaux et des ‘égyptiens’. La faible distance génétique entre les Hypera orientaux et ‘égyptiens’ suggère qu'ils appartiennent à la même souche et sont certainement différents des occidentaux. A partir de cela et d'autres éléments, nous concluons que tous les Hypera des USA sont H. postica Gyllenhal et que l'utilisation d'H. brunneipennis Boheman pour désigner les Hypera ‘égyptiens’ d'Amérique du Nord doit être abandonnée.
    Notes: Abstract Allozyme profiles of eastern weevils (Beltsville, Maryland; Washington Co., Illinois), western weevils (Logan and St. George, Utah), and Egyptian weevils (Yuma, Arizona; Westmorland, California) were compiled by acrylamide gel electrophoresis. Twenty-two gene loci from 12 enzymes (ACPH, ADH, AMY, AO, EST, GOT, G-6PDH, MDH, ME, SOD, TYR, XDH) were analyzed. Mean heterozygosity of these populations was 0.231, with an average proportion of polymorphic loci of 0.536. The mean genetic distance of all weevil populations was 0.033 and the fixation index was 0.024. Diagnostic loci were found which could distinguish western weevils from eastern and Egyptian weevils. The small genetic distance between the eastern and Egyptian weevils suggests that they may be the same strain and are certainly different from the western weevil strain. Based on this and other evidence, we conclude that all weevil strains in the United States are Hypera postica (Gyllenhal), and that the use of H. brunneipennis (Boheman) for the Egyptian alfalfa weevil of North America should be discontinued.
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  • 4
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    Entomologia experimentalis et applicata 37 (1985), S. 229-233 
    ISSN: 1570-7458
    Keywords: alfalfa weevil ; Coleoptera ; Curculionidae ; Hypera postica ; mutation ; vestigial-wing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Des H. postica aux ailes postérieures vestigiales ont été découverts dans une population de Wageningen (Pays Bas) et deux des USA—une lignée orientale de Beltsville (Maryland) et une lignée de H. brunneipennis d'Atascadero (Californie). Ce mutant était absent de 23 autres populations examinées aux USA: 3 de l'est, 7 de l'ouest et 13 de H. brunneipennis. Cette mutation est due à un gène dominant antosomal avec aile normale comme récessif. Le gêne mutant peut être transféré des lignées orientales aux lignées occidentales. Le caractère aile courte peut être pratique pour les manipulations génétiques destinées à maîtriser les populations d'H. postica.
    Notes: Abstract Alfalfa weevils (Hypera postica (Gyllenhal)) with vestigial hind wings were discovered in a population from Wageningen, the Netherlands, and two populations from the United States—an eastern weevil strain from Beltsville, Maryland and an Egyptian weevil strain from Atascadero, California. Such a mutant was absent from 23 other populations surveyed in the United States—three from eastern, seven from western, and 13 from Egyptian weevil strains. This mutation is due to a dominant autosomal gene with normal-wing individuals as recessive. The mutant gene can be transferred from eastern weevil to the western weevil strain. The short-wing trait may be useful for genetic manipulation to control the alfalfa weevil.
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  • 5
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    Entomologia experimentalis et applicata 39 (1985), S. 223-232 
    ISSN: 1570-7458
    Keywords: Onitis alexis ; Coleoptera ; Scarabaeinae ; dung beetle ; crepuscular flight ; superposition eyes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé L'examen a porté sur le rôle de l'intensité lumineuse et de la température sur l'incitation au vol chez Onitis alexis. Le vol en lumière naturelle est fortement synchronisé, avec les deux tiers des adultes qui s'envolent en 10–12 min. Sur six vols pour différents jours, le moment moyen d'envol variait de 13 min, mais l'envol moyen avait lieu à une intensité lumineuse déterminée. La valeur absolue de l'intensité lumineuse paraît ainsi un signal crucial dans la détermination et l'incitation au vol. Le moment d'envol se maintient à cette intensité quand le crépuscule est artificiellement avancé jusqu'à 8 min environ. Cependant, quand le crépuscule est rendu encore plus précoce, l'envol moyen se produit à des intensités plus basses et est étalé. Ceci peut être interprété comme un chevauchement de la période des intensités lumineuses favorables à l'envol avec le rythme circadien qui conduit les bousiers à la surface. Aucun adulte ne vole quand il y a maintien de lumière constante ou d'obscurité à l'heure du crépuscule. En présence de crépuscule constant, les réponses sont hétérogènes, et, bien que le moment médian d'envol ne soit retardé que de 3 min, par rapport aux témoins, l'incitation à l'envol est étalée sur une période plus longue. Avec des températures au sol de 20–22 °C, plus de 90% des adultes s'envolent. Le pourcentage diminue avec la température, et moins de 10% s'envolent à 16–17 °C.
    Notes: Abstract The role of light intensity and temperature in determining the onset of flight in the crepuscular dung beetle Onitis alexis Klug (Coleoptera: Scarabaeidae) was examined. Flight under natural light was highly synchronized, with two-thirds of the beetles that flew flying over a period of 10–12 min. In six flights on different days, the mean time of onset varied by up to 13 min, but mean onset occurred at fixed light intensity. Absolute light intensity therefore appears to be a vital cue in determining flight onset. Mean onset remained at this intensity when dusk was advanced artificially by up to about 8 min. However, when dusk was brought further forward, mean flight occurred at lower intensities and onset of flight took place over a longer period. This is interpreted as an overlapping of the period of light intensities suitable for flight with the circadian rhythm that brings the beetles to the surface. No beetles flew when kept under constant bright light or in the dark during the dusk period. Under conditions of constant dusk, the beetles appeared uncoordinated and, although the median time of onset of flight was only 3 min later than in the control flight, onset of flight was spread out over a much longer period. At soil temperatures of 20–22 °C, over 90% of the beetles flew. This percentage decreased with decreasing temperature, and less than 10% flew at temperatures of 16–17 °C.
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  • 6
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    Entomologia experimentalis et applicata 37 (1985), S. 123-127 
    ISSN: 1570-7458
    Keywords: Coleoptera ; Carabidae ; Poecilus cupreus ; larva ; starvation ; digestion ; enzyme-linked immunosorbent assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung Mit eine quantitativen enzymabhängigen Immunoabsorptionstest wurde immunoreaktives Material aus Beutetieren als Eiweissgehalt (IRM/P) in Larven eines polyphagen räuberischen Carabiden, Poecilus cupreus, bestimmt. Wir bestimmten den Beuteverzehr und die Geschwindigkeit des IRM/P Abbaus bei Larven, die während verschiedener Zeit gehungert hatten. Der Beuteverzehr nahm exponentiell zu über 7 Tage Hunger. Die Geschwindigkeit des Beute- IRM/P Abbaus schien logarithmisch. Die Beuteaufnahme nahm fast zwanzigfach zu über 7 Tage Hunger von 2.7 ng auf 50.2 ng IRM/P/10 Mikroliter Larvenextrakt. Der grösste Teil der Verdauung erfolgte am zweiten bis dritten Tag nach der Nahrungsaufnahme, unabhängig von der verdauten Menge. Das Niveau 4 Tage nach der Fütterung zeigte, dass Larven, die vorgängig 7 Tage gehungert hatten, 5.0 ng IRM/P/10 Microliter Extrakt zurückhielten; dies war mehr als die Aufnahmemenge nichthungernder Larven. Die Verdauungsgeschwindigleit nahm zu mit der Dauer des Hungerns, doch wurde auch mehr Beute im Nahrungskanal zurückgehalten.
    Notes: Abstract Prey antigen levels were determined by a quantitative enzyme-linked immunosorbent assay in larvae of a carabid predator, Poecilus cupreus L. under laboratory conditions. We determined prey consumption and rate of prey protein decay in larvae having starved for different periods. Prey consumption increased exponentially over 7 days of starvation. The rate of prey immunoreactive material decay seemed to be logarithmic, similar in larvae which had starved for different periods. Most of the digestion took place in the first 3 days period after feeding, irrespective of the amounts ingested. The rate of decay increased with increasing period of starvation. There were also signs of food retention in the alimentary canal in larvae which starved longer.
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  • 7
    ISSN: 1570-7458
    Keywords: Coleoptera ; Bruchidae ; diapause reproductrice ; inflorescence ; Vigna unguiculata ; activité sexuelle mâle ; ovogenèse ; ponte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Summary Bruchidius atrolineatus (Pic) is a widely distributed bruchid in the Sahelian zone which shows a reproductive diapause during the dry season and part of the rainy season. Diapausing females do not produce vitellogenin and their ovaries are reduced to the germarium. Spermatogenesis is very much reduced and male accessory glands are inactive. When these insects were placed in the presence of inflorescences of Vigna unguiculata which were renewed daily, the reproductive diapause of both males and females was interrupted after 15–20 days. Vitellogenesis occurred in the females and spermatogenesis increased in the males whilst their accessory glands became functional. When diapausing bruchids, found in stores of on V. unguiculata seeds during the dry season, were placed near the host plant's inflorescences, diapause was also terminated. In all cases, diapause was not interrupted when the insects were offered dry pods of V. unguiculata in a water-saturated atmosphere. The pollen, which is hardly eaten by this bruchid, did not seem to stimulate termination of diapause. Sensory stimulations derived from the flowers or/and nutritional factors may be the cause of the development of the reproductive organs. After termination of the diapause the males showed normal sexual activity whereas female fecundity was rather low, at least in our experimental conditions. This type of reproductive regulation allows this sahelian bruchid to resume its sexual activity when the host plant's flowers appear in the field at the end of the rainy season. Then the beetles lay their eggs on the pods as soon as the pods are developed.
    Notes: Abstract Bruchidius atrolineatus (Pic) présente en zone sahélienne une diapause reproductrice durant la saison sèche et une partie de la saison des pluies. Les femelles diapausantes ne produisent pas de vitellogénine et le germarium des ovarioles est seul développé. Chez les mâles la spermatogenèse est très ralentie et les glandes annexes sont inactives. Lorsque les insectes diapausants sont placés en présence d'inflorescences de Vigna unguiculata Walp, leurs organes reproducteurs deviennent fonctionnels après un temps de latence de 15 à 20 jours. Il n'y a par contre aucune levée de la diapause chez des bruches placées en présence de gousses sèches de V. unguiculata dans une atmosphère saturée. Des informations sensorielles issues des pièces florales ou (et) des facteurs nutritionnels sans doute liés a la consommation de nectar semblent être à l'origine de cette levée de la diapause. Le pollen fort peu consommé n'a par contre aucun rôle. Cette régulation du cycle reproducteur de B. atrolineatus par les inflorescences de V. unguiculata permet l'émission des oeufs dès que les gousses commencent à se former à la fin de la saison des pluies.
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  • 8
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    Entomologia experimentalis et applicata 39 (1985), S. 61-71 
    ISSN: 1570-7458
    Keywords: Dacus tryoni ; Tephritidae ; Diptera ; fruit flies ; oviposition ; egg laying ; behaviour ; taste receptors ; chemoreceptors ; stimulant ; deterrent ; fructose ; calcium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Des mouches fruitières gravides du Queensland (Dacus tryoni), confinées au laboratoire dans des chambres d'oviposition sont stimulées par la présence de β-D(-)fructose, à pondre significativement plus d'oeufs dans un substrat gélosé. Ce composé est un véritable stimulant d'oviposition, accroissant le nombre d'oeufs déposés par mouche, plutôt que simplement localisant l'oviposition dans les substrats le contenant. Le fructose est effectif seulement lorsqu'il est accessible aux récepteurs gustatifs tarsaux et labelliaux et, apparement, agit en stimulant de plus fréquentes insertions de l'ovipositeur dans le substrat; le contact du fructose avec uniquement l'ovipositeur inséré, n'accroît pas l'oviposition. Le seuil de concentration pour obtenir une stimulation par le fructose est de 4 mM; la résponse maximale se produit à 50 mM et au delà, auxquelles concentrations l'oviposition est augmentée d'un facteur 6 par rapport au témoin, qu'il y ait ou non possibilité de choix de substrat. Le sucrose (testé à 100 et 1 000 mM) et le D-glucose (testé à 100 et 500 mM) ne stimulent pas l'oviposition chez D. tryoni. Le fructose favorise fortement l'oviposition grâce aux trous existants dans une surface impénétrable, et dans les conditions naturelles, D. tryoni l'utilise probablement comme un marqueur pour localiser les ruptures dans la peau des fruits, où l'insertion est plus facile. La présence de chlorure de calcium molaire dans la gélose fructose inhibe fortement l'oviposition, même lorsqu'il est inaccessible aux récepteurs gustatifs tarsaux et labelliaux. Le chlorure de sodium molaire n'est pas inhibiteur. Les ions calciums déploient apparemment leur effet inhibiteur par l'intermédiaire de récepteurs gustatifs localisés sur l'ovipositeur.
    Notes: Abstract Gravid Queensland fruit flies (Dacus tryoni) are stimulated by the presence of β-D(-) fructose to lay significantly more eggs in an agar substrate. Fructose is only effective when accessible to the tarsal and/or labellar gustatory sensilla; it greatly increases oviposition through holes in an impenetrable membrane. Threshold for the fructose effect is 4 mM, maximal response being at 50 mM and above. Sucrose and glucose are not oviposition stimulants for D. tryoni. In the field situation D. tryoni probably uses fructose as a marker to locate breaks in the skin of ripe fruit, where insertion of the ovipositor is easier. The flies are deterred from ovipositing in fructose agar by the presence of molar calcium chloride, even when this is inaccessible to the tarsal and labellar gustatory sensilla. Molar sodium chloride is not inhibitory. Calcium ions apparently exert their inhibitory effect via gustatory sensilla located on the ovipositor.
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  • 9
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    Methods in cell science 9 (1985), S. 83-93 
    ISSN: 1573-0603
    Keywords: keratinocytes ; human ; epidermis ; serum-free ; calcium ; differentiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Methods are described for serum-free culture of human epidermal keratinocytes derived from neonatal foreskin tissue. Cultures are initiated, stored frozen, and returned to active growth, all with bovine pituitary extract as the only undefined supplement. Clonal growth assays are then performed in a biochemically defined medium. The degree of stratification and differentiation in the defined medium (and also with pituitary extract) is controlled by the extracellular calcium ion concentration.
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  • 10
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    Cellular and molecular life sciences 41 (1985), S. 997-1001 
    ISSN: 1420-9071
    Keywords: Myosin light chain kinase ; calcium ; c-AMP ; calmodulin ; smooth muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 11
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    Cellular and molecular life sciences 41 (1985), S. 1048-1051 
    ISSN: 1420-9071
    Keywords: Na, K-ATPase ; calcium ; calmodulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The effect of calcium on Na, K-ATPase activity of rat brain homogenates and its modification by the chelating agent EDTA has been investigated. In the absence of EDTA, free calcium (approximately 10−6mol/l) stimulates Na,K-ATPase activity; in the presence of EDTA the same concentration of free calcium is without effect on the enzyme. In the absence of EDTA the stimulation by calcium of Na,-K-ATPase activity is enhanced by the additional presence of calmodulin but in the presence of EDTA, even when calmodulin is added to excess, calcium still fails to stimulate the enzyme. The possibility that EDTA interferes with an interaction between a calcium-calmodulin complex and Na,K-ATPase is discussed.
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  • 12
    ISSN: 1420-9071
    Keywords: Smooth muscle ; calcium ; myosin light chain kinase ; regulation of contraction ; ATPase ; mechanics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The contraction induced by a Ca2+-independent myosin light chain kinase (MLCK-) was characterized in terms of isometric force (Fo), immediate elastic recoil (SE), unloaded shortening velocity (Vus), shortening under a constant load and ATPase activity of chemically skinned smooth muscle preparations. These parameters were compared to those measured in a Ca2+-induced contraction to assess the nature of cross bridge interaction in the MLCK-induced contraction. Fo developed in chicken gizzard fibers as well as SE were similar in contractions elicited by either agent. Vus in the contraction induced by MLCK-(0.36 mg/ml) was similar though averaged 39.3±8.9% less than Vus induced by Ca2+ (1.6x10−6M) in the control fibers. Addition of Ca2+ (1.6x10−6M) to a contraction induced by MLCK-resulted in small increases in both Fo and Vus. Shortening under a constant load was similar for both types of contractions. The contraction induced by MLCK-was accompanied by an increased rate of ATP hydrolysis. The MLCK-induced contraction is thus kinetically similar though not identical to a contraction induced by Ca2+. We conclude that with respect to actin-myosin interaction, MLCK- and Ca2+-induced contractions are similar.
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  • 13
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    Cellular and molecular life sciences 41 (1985), S. 1020-1025 
    ISSN: 1420-9071
    Keywords: Smooth muscle energetics ; light chain phosphorylation ; crossbridges ; calcium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Conclusion On the basis of measurements of the high energy phosphate usage associated with different mechanical states, as well as the degree of myosin light chain phosphorylation and mechanical properties, information has been gained concerning the existence and regulation of different crossbridge states in smooth muscle. Although incomplete, a general operational scheme is shown in figure 5. At very low intracellular calcium concentrations, actin and myosin are dissociated, as shown by a loss of resistance to stretch in resting muscles. At somewhat higher intracellular calcium concentrations in atonic, resting muscles, crossbridges can attach and be manifest mechanically as an increased resistance to stretch without ATP-driven crossbridge cycling and active force production. When the muscle is activated, intracellular calcium increases further, the light chains of myosin are phosphorylated through the calcium-calmodulin activation of myosin light chain kinase, actin-activated myosin ATPase activity increases and crossbridges cycle. Calcium also appears to modulate the ATPase activity and the rate of cycling of the phosphorylated crossbridge. The crossbridge cycling rate is highest during force development and slows with time as maximum isometric force is maintained reflecting a change in the rate at which phosphorylated crossbridges cycle. This may result from a decrease in the intracellular free calcium concentration with continued stimulation. During relaxation, the intracellular calcium concentration decreases, there is net dephosphorylation of the myosin light chains, the rate at which phosphorylated crossbridges cycle slows further with a gradual return to the attached, but non-cycling state or the detached state.
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  • 14
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    Cellular and molecular life sciences 41 (1985), S. 516-519 
    ISSN: 1420-9071
    Keywords: Coleoptera ; chemical defense ; steroids ; pregnanes ; isoprenoids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The defensive anal effluent discharged bySilpha americana in response to disturbance contains a mixture of steroids stemming from a glandular annex of the rectum. The compounds have been characterized as 15β-hydroxyprogesterone (1, principal component), 5β-pregnan-15β-ol-3, 20-dione (2), 5β-pregnan-3α, 15β-diol-20-one (3), 5β-pregnan-7β, 15β-diol-3,20-dione (4), 5β-pregnan-3α, 7β, 15β-triol-20-one (5), 5β-pregnan-16α-ol-3,20-dione (6), and 5β-pregnan-3α, 16α-diol-20-one (7), none previously found in insects. Bioassays with jumping spiders showed compounds1 and6 to be feeding deterrents at the 1 μg level.
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  • 15
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    European journal of clinical pharmacology 29 (1985), S. 193-197 
    ISSN: 1432-1041
    Keywords: Glibenclamide ; intestinal absorption ; small and large intestine ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a study of eight volunteers and six patients, glibenclamide was placed at different sites of the gastro-intestinal tract under visual control. The dose was instilled once into the stomach and once into the duodenum of the eight volunteers in a randomized crossover design. The six patients underwent diagnostic colonoscopy, and the dose was placed into the ascending colon if pathological findings were not present. The area under the concentration-time curve, completed by extrapolation, and the mean residence time of the drug in the body were calculated. These pharmacokinetic characteristics were examined using a Jonckheere test for ordered alternatives and a Wilcoxon signed rank pair test. The means of the areas under the curve were 477±131 ng·h ml−1 for the stomach, 475±142 ng·h ml−1 for the duodenum and 486±301 ng·h ml−1 for the colon. The mean residence time changed from 2.67±0.35 h for the stomach to 2.42±0.48 h for the duodenum and 3.55±0.68 h for the colon. These results indicate that although glibenclamide is absorbed from all three sites of the gastro-intestinal tract to the same extent, the rates of absorption are different. It is discussed whether these findings really confirm the pH-partition hypothesis in drug absorption. Since glibenclamide — a weak acid — has a pK-value of about 6.5, these data seem to confirm the pH-partition hypothesis of drug absorption.
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  • 16
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    European journal of clinical pharmacology 29 (1985), S. 221-224 
    ISSN: 1432-1041
    Keywords: fenfluramine ; norfenfluramine ; isomers ; pharmacokinetics ; healthy volunteers ; chronic treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of accumulation and elimination of d- and l-fenfluramine (F) and norfenfluramine (NF) have been studied in 8 young healthy volunteers given daily doses of 60 mg of sugar-coated tablets of 20 mg dl-F hydrochloride (dl-F) t.i.d. and capsules of 15 mg d-F hydrochloride (d-F) b.i.d. for 15 days. Repeated doses of d-F plus l-F gave the same values for the parameters measured as did d-F administered alone. Steady-state concentrations of all compounds were achieved within 4–8 days. The predicted mean steady-state concentrations of d-F and elimination half-lives calculated from the results of a previous single dose study were similar to those measured at steady state in this study, confirming the lack of effect of the drug on hepatic microsomal enzymes and on kinetics after repeated dosing. d-NF concentrations were approximately half those of the parent drug and the half-life was almost twice as long. Steady state concentrations both of L-f and l-NF were consistently about 40–50% higher than of the d-isomers and there was a comparable in the half-life.
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  • 17
    ISSN: 1432-1041
    Keywords: metaclazepam ; benzodiazepines ; (KC-2547) ; N-desmethyl-methaclazepam KC-3755) ; pharmacokinetics ; old and young volunteers ; side-effects ; age effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single-centre, open, Phase I-study comparison of the pharmacokinetics of a single dose of metaclazepam 10 mg, a new 1,4-benzodiazepine has been done in 10 older and 20 younger volunteers. No important age-related effect was found on the kinetics of metaclazepam or its N-desmethyl derivative, the principal metabolite in man.
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  • 18
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    European journal of clinical pharmacology 29 (1985), S. 235-239 
    ISSN: 1432-1041
    Keywords: amoxycillin ; clavulanic acid ; pharmacokinetics ; side-effects ; paediatric formulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A combination of amoxycillin and clavulanic acid 4:1 was administered to 35 children (aged 2 to 10 years) with infections. The combination was administered orally as a suspension, every 8 h for 5 to 7 days. Sixteen children (aged 2 to 5 years), received 125 mg amoxycillin and 31.25 mg clavulanic acid, and 19 (6 to 10 years) received 250 mg amoxycillin and 62.5 mg clavulanic acid per dose. Following the first dose serum concentrations of amoxycillin and clavulanic acid were determined by microbiological assay. In the younger group receiving the lower dosage (mean: amoxycillin 9.11 mg/kg and clavulanic acid 2.34 mg/kg), the mean peak concentration of amoxycillin was 3.5 mg/l and of clavulanic acid 1.2 mg/l, occurring 1.32 h and 1.39 h, respectively, after administration. In the older group receiving the higher dosage (mean: amoxycillin 12.35 mg/kg and clavulanic acid 3.14 mg/kg) the mean peak serum level of amoxycillin was 4.0 mg/l and of clavulanic acid 1.3 mg/l, occurring 1.43 h and 1.23 h, respectively, after administration. The higher dose per kilogram body weight resulted in a higher peak serum concentration both of amoxycillin and clavulanic acid. The formulation was well tolerated by all the children and no serious side-effects were recorded. Treatment was considered clinically effective in all cases.
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  • 19
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    European journal of clinical pharmacology 29 (1985), S. 251-253 
    ISSN: 1432-1041
    Keywords: paracetamol ; antacids ; acetaminophen ; bioavailability ; kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of two antacids on the bioavailability of paracetamol has been investigated in 12 young healthy volunteers. Following a random cross over design, each subject swallowed, on three separate occasions, one weak apart, 500 mg paracetamol alone, or together with two different aluminium hydroxide, magnesium hydroxide preparations (Dimalan and Maalox). Plasma paracetamol levels were measured by HPLC. The bioavailability of paracetamol was not altered by either antacid, but they both delayed the time to peak plasma concentration (0.85 h; 1.43 h; 1.25 h, without antacid, with Dimalan and with Maalox respectively). The peak plasma concentration was not affected by concurrent antacid administration.
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  • 20
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    European journal of clinical pharmacology 29 (1985), S. 313-318 
    ISSN: 1432-1041
    Keywords: Cis-platinum ; nephrotoxicity ; longitudinal study ; plasma and urinary beta2 microglobulin ; urinary sodium excretion ; N-acetyl-glucosamidase ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty patients with epithelian ovarian cancer treated with DDP (cis-diammine-dichloroplatinum II) 50 mg/m2 were followed for 24 weeks in order to assess the nephrotoxicity of the drug. Ten patients received the total dose in one day with heavy osmotic hydration (Group A), and for the other 10 the dose was subdivided over 3 consecutive days (Group B). The renal tubular toxicity of DDP treatment was evaluated over a total of 120 courses. After the first DDP administration, there was a prompt, reversable and dose-dependent increase in the urinary excretion of β 2 microglobulin with no difference between the two groups: Group A from 405 to 990 and Group B from 109 to 585 ng/mg creatinine. An increase always occurred during subsequent courses, but it was significantly lower in Group B after the sixth course, from 125 to 331 ng/mg creatinine. A similar pattern was found for the urinary excretion of N-acetyl-glucosaminidase (NAG), a lysosomal enzyme of tubular origin. The percentage fraction of urinary sodium excretion (FeNa%) increased after each dose of DDP; Group A from 0.82 to 2.30 and Group B from 0.68 to 2.53. This effect was reversible and it occurred to the same extent during the subsequent courses. There was no impairment of the glomerular filtration rate. Thus, enzymuria and β 2 microglobulin excretion are a sensitive tool to reveal minor tubular damage. Their use to predict serious renal dysfunction in longitudinal studies, however, seems questionable.
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  • 21
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    European journal of clinical pharmacology 29 (1985), S. 331-336 
    ISSN: 1432-1041
    Keywords: nitroglycerin ; transdermal preparation ; blood viscosity ; plasma viscosity ; healthy volunteers ; haematocrit ; haemodilution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Transdermal nitroglycerin (Nitroderm TTS 5) and a placebo were applied to 10 healthy male volunteers for 10 days. Before the first application and 6, 24, 48, 96, and 240 h thereafter, the viscosity of plasma and whole blood was measured and the packed-cell volume determined. During nitroglycerin application, the viscosity of plasma and whole blood was significantly diminished, and after 10 days it averaged 5% below the initial value. The greater the initial viscosity, the more marked was the druginduced reduction: in 5 subjects with plasma and whole-blood viscosities near the lower limit of the normal range, there was only a temporary decrease and the values reverted to their initial levels after 4 days; in the other 5 subjects, whose whole-blood viscosities were near the upper limit of the normal range, a 10% reduction was still demonstrable after 10 days. In those subjects all values measured throughout the 10-day observation period were significantly below the initial values. The haematocrit readings followed the same pattern as the alterations in viscosity. It can be assumed, therefore, that the decrease in viscosity induced by nitroglycerin results from “internal haemodilution”. The clinical relevance of the changes observed is discussed. The improvement in the rheological properties of the blood may contribute to the anti-anginal effect of Nitroderm TTS.
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  • 22
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    European journal of clinical pharmacology 29 (1985), S. 383-389 
    ISSN: 1432-1041
    Keywords: felodipine ; hypertension ; calcium antagonist ; vasodilator ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Felodipine, a selective arteriolar dilator, was given to 13 hypertensive patients to assess its hypotensive effects and duration of action. Nine patients were treated with 5 mg three times a day and 4 with 10 mg three times a day. Mean blood pressures fell with both treatment regimens: 5 mg placebo 170/103 mmHg; 5 mg felodipine 148/91 mmHg; 10 mg placebo 154/93 mmHg; 10 mg felodipine 137/82 mmHg. Heart rates increased as blood pressures fell with both treatments. However, in the patients given 5 mg three times a day this effect was less noticeable after successive doses. Plasma concentrations of noradrenaline, both resting and tilted, increased after felodipine. There was a negative correlation between the fall in blood pressure and the increase in noradrenaline, suggesting that those patients with good baroreceptor reflexes were better able to counteract the effects of vasodilatation. Four of the nine patients treated with 5 mg felodipine three times a day experienced mild and transient adverse effects. Of the four patients treated with 10 mg three times a day, three experienced moderate to severe headache, and for this reason recruitment into this group was stopped. Felodipine at a divided daily dose of 15 mg effectively lowered blood pressure.
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  • 23
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    European journal of clinical pharmacology 29 (1985), S. 467-469 
    ISSN: 1432-1041
    Keywords: baclofen ; stroke ; elderly patients ; pharmacokinetics ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A double blind crossover trial of baclofen against placebo in elderly stroke patients was discontinued because the drug produced an unacceptably high level of drowsiness. In a subsequent study baclofen 10 mg was given orally to 12 elderly stroke patients, and drug concentrations measured from a series of plasma samples. A group of healthy subjects given the same dose in a previous study were used as controls. Elderly patients took longer to achieve peak plasma baclofen concentrations, but healthy controls had higher peak values and eliminated the drug more rapidly; areas under the curve were similar in the two groups. Simulations based on mean data suggest that increased drowsiness in the elderly was probably not due to changes in the drug's pharmacokinetic behaviour.
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  • 24
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    European journal of clinical pharmacology 28 (1985), S. 113-117 
    ISSN: 1432-1041
    Keywords: nadolol ; nifedipine ; tachycardia ; cardiovascular response ; healthy volunteers ; pharmacokinetics ; exercise heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a placebo controlled exercise protocol using healthy volunteers the effects of nadolol 80 mg and 160 mg orally and of nadolol 80 mg during treatment with nifedipine 20 mg 8 hourly were compared. Resting systolic and diastolic blood pressures were reduced by both nifedipine (p〈0.05) and nadolol (p〈0.01) acting alone. An unexpected finding was that nifedipine alone significantly inhibited exercise tachycardia (p〈0.01) (8 to 12 h post dose). Predictably both doses of nadolol produced significant reduction in exercise tachycardia which was still apparent at 24 h. There was a linear relationship between log10 plasma nadolol concentration and reduction in exercise heart rate. The combined inhibitory effects of nifedipine and nadolol 80 mg on exercise heart rate showed partial additivity but did not summate. There was no pharmacokinetic interaction between the 2 drugs. The inhibition of exercise tachycardia by nifedipine, not previously documented, is consistent with an effect of the drug on the sinus node, as has been reported in in-vitro studies, and may contribute to the drugs efficacy in angina.
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  • 25
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    European journal of clinical pharmacology 28 (1985), S. 155-158 
    ISSN: 1432-1041
    Keywords: digoxin ; digitoxin ; cardiac glycosides ; ventilation ; respiration ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight healthy volunteers were studied to ascertain the effect of digoxin and the relatively more lipophylic cardiac glycoside, acetyl-digitoxin on ventilation. Baseline ventilation as well as the response to the inspiration of 2.2% and 4.8% carbon dioxide were assessed. Digoxin produced a depression of minute volume and oxygen consumption whereas acetyl-digitoxin produced the opposite effect. This could be the result of a relatively greater vagomimetic effect with digoxin and a greater symphatomimetic effect with acetyl-digitoxin. These findings might have clinical implications in cardiac patients who have pulmonary disease.
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  • 26
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    European journal of clinical pharmacology 28 (1985), S. 159-162 
    ISSN: 1432-1041
    Keywords: terbutaline ; asthma ; slow-release formulation ; early morning dyspnoea ; side-effects ; serum terbutaline level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight male patients with partly reversible airflow obstruction, who had a diurnal variation in peak expiratory flow rate (PEFR) of more than 20% were treated with placebo and slow-release terbutaline tablets (5 mg at 08.00 hours and 10 mg at 20.00 hours) for 8 days. On Day 8 of each period, PEFR and serum terbutaline were measured at 4 and 2-h intervals, respectively. PEFR on the terbutaline day showed a significant increase at 08.00, 12.00, 24.00, 04.00 and 08.00 hours as compared to the placebo day. Slow-release terbutaline prevented early morning dyspnoea. The serum concentration was 3.3 ng/ml during the day and 3.5 ng/ml during the night. During terbutaline therapy the patients reported fewer complaints than during the placebo period. It was concluded that slow-release terbutaline tablets are suitable for twice daily treatment.
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  • 27
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    European journal of clinical pharmacology 28 (1985), S. 143-148 
    ISSN: 1432-1041
    Keywords: metoprolol ; beta-adrenergic blockade ; maximal aerobic power ; acute and chronic administration ; exercise ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute and long-term effects of the beta1-adrenoceptor blocking agent metoprolol on blood pressure and maximal aerobic power (Wmax) were studied in 10 healthy subjects. Progressive maximal bicycle ergometer tests were performed after intravenous administration of placebo and metoprolol (0.15 mg×kg−1 and 0.30 mg×kg−1), and at the end of 4-week treatment periods with placebo, conventional metoprolol (C-M) and slow-release metoprolol (SR-M). The reduction in maximal exercise heart rate (HRmax) was correlated with the log plasma metoprolol concentration. Despite a reduction in HRmax of 23 beats/min after 0.15 mg×kg−1 metoprolol, Wmax was unaffected. After 0.30 mg×kg−1 HRmax was reduced by 40 beats/min and Wmax by 5.0%. During chronic treatment, the reductions in HRmax and Wmax were 48 beats/min and 7.5% (C-M) and 45 beats/min and 6.9% (SR-M), respectively. Resting systolic blood pressure was not changed after acute administration of metoprolol but it was reduced during chronic beta-blocker treatment. Resting diastolic blood pressure was not affected after acute or chronic treatment. Exercise systolic blood pressure remained unchanged after 0.15 mg×kg−1 metoprolol i.v. The fall in exercise systolic pressure after 0.30 mg×kg−1 metoprolol i.v. (18±5 mmHg) was significantly smaller than that during chronic treatment (30±6 mmHg C-M; 30±6 mmHg, SR-M). During chronic metoprolol treatment a certain % HRmax corresponded to a higher % Wmax than during placebo treatment, but the shift appeared to be of minor practical importance. The results show that the reduction in maximal aerobic power was comparable after acute i.v. administration and after 4 weeks oral treatment with metoprolol, if the degree of beta blockade (i.e. reduction in maximal exercise heart rate) was similar.
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  • 28
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    European journal of clinical pharmacology 28 (1985), S. 433-437 
    ISSN: 1432-1041
    Keywords: isofezolac ; probenecid ; pharmacokinetics ; anti-inflammatory drug ; drug interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between isofezolac and probenecid has been studied with the aid of a specific HPLC assay for isofezolac in plasma and urine. 8 healthy adult volunteers received a single 40 mg oral dose of isofezolac before and after 3 days of loading with 0.5 g probenecid t.i.d. There was an increase in the maximum plasma isofezolac concentration from 2.44 to 3.38 µg · ml−1 when probenecid was given. The AUC of isofezolac in plasma increased from 6.73 to 11.28 µg · h · ml−1. After the last dose in a 7 day treatment with 40 mg isofezolac t.i.d., there was an increase in the maximum plasma isofezolac level from 2.84 to 4.96 µg · ml−1 when probenecid was given. The rate of absorption of isofezolac was not affected. An increase in the AUC of isofezolac in plasma was observed from 11.74 to 26.34 µg · h · ml−1. The major effect of probenecid on isofezolac metabolism was a 50% reduction in total isofezolac (free+conjugates) excreted inurine. Because of this interaction, patients given isofezolac combined with probenecid will have a higher steady-state plasma level of isofezolac than when probenecid is not administered.
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  • 29
    ISSN: 1432-1041
    Keywords: hypertension ; labetalol ; prazosin ; hydrochlorothiazide ; side-effects ; therapeutic efficacy ; atenolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After screening two local populations in the northern part of The Netherlands for hypertension, patients with a diastolic pressure (DP) between 95 and 120 mmHg were treated daily either with 50 mg hydrochlorothiazide or 100 mg atenolol. Non-responders were given the combination and if necessary the dose of atenolol was increased to 200 mg. Non-responders to the latter combination were randomized and treated either with 50 mg hydrochlorothiazide and labetalol or with 50 mg hydrochlorothiazide, 200 mg atenolol and prazosin. If after 1 month a DP≤90 mmHg had been reached the patient was reassessed after a further 3 months. If a DP〉90 mmHg was found the dose of labetalol or prazosin was increased and the patient was re-examined after 1 month. This protocol was followed until the maximum dose was reached or adverse reactions prevented a further increase in dosage. During 6 months of treatment there was a further drop in systolic and diastolic blood pressures under both regimens of, respectively, 8.6 and 2.4 mmHg for labetalol, and 7.7 and 5.0 mmHg for the prazosin group. At the end of the period the average daily doses of labetalol and prazosin were 1256 mg and 4.3 mg, respectively. There was no significant difference in the average number of complaints between the labetalol and the prazosin group.
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  • 30
    ISSN: 1432-1041
    Keywords: hypertension ; indenolol ; submaximal workload ; haemodynamic effects ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of indenolol on heart rate and blood pressure at rest and after submaximal workload has been studied in 19 patients with established essential hypertension. A stepwise increase from moderate to submaximal exercise was chosen to mimic challenges normally occurring in daily life. After 4 weeks of once a day indenolol therapy a significant, gradual reduction in the following cardiovascular parameters was observed: heart rate at rest fell by 20%, 30% after exercise and 31% after recovery; systolic blood pressure showed a fall of 15% at rest, 19% after workload and 14% after recovery; the reduction in diastolic blood pressure was 15% at rest, 11% after exercise and 12% after recovery. The rate-pressure product was decreased by 32% at rest, 43% after exercise and 42% after recovery. It is concluded that the most important pharmacological effect of indenolol is the significant decrease in myocardial oxygen demand. In patients with essential hypertension indenolol not only produces a definite antihypertensive effect, but it also increases workload tolerance and decreases subjective symptoms during physical activity. Compliance was good and no severe side effects were observed.
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  • 31
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    European journal of clinical pharmacology 28 (1985), S. 659-664 
    ISSN: 1432-1041
    Keywords: BTS 49465 ; hypertension ; pharmacokinetics ; blood pressure effect ; heart rate effect ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60° head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.
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  • 32
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    European journal of clinical pharmacology 28 (1985), S. 671-675 
    ISSN: 1432-1041
    Keywords: famotidine ; histamine H2-receptor antagonist ; diazepam ; hepatic elimination ; tubular secretion ; drug interaction ; cytochrome P450 ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 8 healthy male volunteers the pharmacodynamic responses to a single dose of diazepam and a single dose of procainamide were assessed before and after pre-treatment with the H2-receptor antagonist famotidine in a randomized crossover study. The pharmacokinetics of diazepam and procainamide were also studied, and the binding of famotidine to human liver microsomes was also measured. Cimetidine induced binding changes with a spectral dissociation constant (Ks) of 0.87 mM, whereas famotidine produced no measurable spectral alteration in concentrations up to 4 mM. The elimination half-life (t1/2: 45.6 h) and total plasma clearance (CL: 0.28 ml/min/kg) of diazepam were not significantly altered by famotidine (t1/2=39.0±11.4 h; CL =0.31±0.08 ml/min/kg). Similarly, there was no enhancement of the sedative effect of diazepam by famotidine. The pharmacodynamics and pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), too, were not significantly changed by famotidine: procainamide t1/2 2.9 vs 3.0 h under famotidine and renal clearance (CLR) 436 vs 443 ml/min; and NAPA CLR 195 vs 212 ml/min under famotidine. The data suggest that famotidine, in contrast to cimetidine, does not affect the pharmacokinetics of diazepam (hepatic elimination) or procainamide (tubular secretion). This new H2-receptor antagonist appears to be devoid of an interaction potential for either type of drug elimination.
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  • 33
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    European journal of clinical pharmacology 28 (1985), S. 125-130 
    ISSN: 1432-1041
    Keywords: hypertension ; clonidine ; beta-blocker ; renal failure ; side-effects ; blood pressure decrease ; cardiovascular complications ; atenolol ; propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The risk of cardiovascular and fatal complications and the antihypertensive effect of a clonidine-β-blocker combination was studied in 98 patients and was compared with the results for a group of patients treated with other antihypertensive regimens. The profile of complications was similar in the two groups for a total follow-up period of more than 2000 treatment-months. Clonidine in combination either with propranolol or atenolol had a distinct antihypertensive effect. However, clonidine plus atenolol resulted in a more immediate and pronounced fall in blood pressure. It is concluded that the combination of clonidine and a β-blocker is an effective antihypertensive medication, and that patients treated with it are apparently at no greater risk of serious cardiovascular incidents than are those treated with other regimens.
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  • 34
    ISSN: 1432-1041
    Keywords: atenolol ; bopindolol ; metoprolol ; oxidation polymorphism ; debrisoquine ; bufuralol ; stereoselective metabolism ; pharmacological effect ; healthy volunteers ; beta-blocker
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten healthy subjects whose genetic oxidative phenotype had been determined (6 extensive and 4 poor metabolizers of the debrisoquine-sparteine type of polymorphism) received single oral doses of 3 beta-blockers: atenolol, bopindolol and metoprolol. The plasma concentrations and the extent of the decrease in exercise-induced tachycardia were determined. The oxidative polymorphism was only significant for substances that had a high hepatic first pass metabolism, such as metoprolol. The metabolic pathway under genetic control was highly stereoselective. This observation must be taken into account when assessing the relation between the plasma concentration and effect of these drugs, which are often administered as racemic mixtures.
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  • 35
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    European journal of clinical pharmacology 28 (1985), S. 241-244 
    ISSN: 1432-1041
    Keywords: muzolimine ; hydrochlorothiazide + amiloride ; antihypertensive treatment ; hypertensive patients ; side-effects ; serum potassium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thiazide therapy is a widely used first line treatment for arterial hypertension. Its useful value, particularly in mild or moderate hypertension, is sometimes reduced by metabolic side-effects, as hypokalaemia and hyperuricaemia. In the present study the antihypertensive efficacy of a new, non-sulphonamide diuretic Bay g 2821 (muzolimine) was evaluated in comparison with the combination of hydrochlorothiazide-amiloride over a period of 4 weeks. A highly significant decrease in systolic and diastolic blood pressures was produced by both treatments. No decrease in serum potassium nor an increase in cholesterol, triglycerides, uric acid or glucose was detected during the 4 week treatment period. Subjective side-effects, such as headache and dizziness, were very rarely observed during Bay g 2821 treatment. The new diuretic appears, therefore, to be effective in the treatment of arterial hypertension without untoward side-effects.
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  • 36
    ISSN: 1432-1041
    Keywords: converting enzyme inhibitor ; CGS 14824A ; pharmacodynamics ; plasma renin ; plasma angiotensin ; aldosterone ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The converting enzyme inhibitor CGS 14824A was evaluated in 15 healthy male volunteers. First, the efficacy of a single 5 or 10 mg oral dose in antagonizing the pressor response to exogenous angiotensin I was tested in 2 subjects. Blood pressure and heart rate were monitored continuously through an intra-arterial catheter. CGS 14824A 5 mg reduced the response to angiotensin I within 75 min to 50%, and 10 mg within 1 h to less than 25%, and for a period of more than 4 h. Subsequently, plasma renin and converting enzyme activity, plasma angiotensin I, angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of 2, 5, 10 or 20 mg CGS 14824A to groups of 5 volunteers. Plasma converting enzyme activity fell to well below 10% of baseline within 1 h after administration of 5 mg or more CGS 14824 A. Within 2 h following 2 mg p.o., a similarly low level was reached. Twenty four hours following the 20 mg dose, plasma converting enzyme activity was still below 10%. As expected, plasma renin activity and angiotensin I rose while angiotensin II and aldosterone fell following the 2 mg dose. This pattern of effects was enhanced by increasing the dose. Nonetheless, 24 h after the 20 mg dose, plasma angiotensin II and aldosterone had returned to their baseline levels. No side-effects occurred. Thus, in normal volunteers, CGS 14824A was an effective, potent and long acting converting enzyme inhibitor.
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  • 37
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    European journal of clinical pharmacology 28 (1985), S. 273-277 
    ISSN: 1432-1041
    Keywords: ketanserin ; catecholamines ; renin activity ; norepinephrine ; epinephrine ; dopamine ; healthy volunteers ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a placebo controlled, single blind, randomized cross over study catecholamines (CA) and renin activity (PRA) in plasma were measured in 2 female and 4 male healthy volunteers, at rest in the supine position, following a single intravenous injection of 0.15 mg/kg ketanserin (K) and placebo (P, 10 ml saline). K caused a significant increase in the area under the plasma norepinephrine (NE) time curve (AUCNE) from 13,200 to 18,100 ng × 1−1 × min for 1 hour after the injection. The area under the plasma epinephrine (E) time curve (AUCE) was also increased but to a lesser extent; it was significantly elevated from 54 to 68 ng × 1−1 × min for 1 minute after the injection. Dopamine (DA) and PRA did not show any significant response to ketanserin. Following the P injection, none of the four parameters showed any significant change.
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  • 38
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    European journal of clinical pharmacology 28 (1985), S. 229-230 
    ISSN: 1432-1041
    Keywords: diazepam ; dipotassiumchlorazepate ; benzodiazepines ; bioavailability ; administration ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dipotassium chlorazepate (DPC) and diazepam (DZM) were given i.m. and i.v. to 6 healthy volunteers in doses of 20 mg (48.9 µmol) DPC and 15 mg (52.0 µmol) DZM. The interval between the injections was at least 1 week. Plasma samples were analyzed for DPC and DZM by HPLC. The bioavailability of DPC and DZM after i.m. administration, determined from computer calculated AUCs, was 1.04 and 0.85, respectively.
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  • 39
    ISSN: 1432-1041
    Keywords: atenolol ; hypertension ; side-effects ; dose-response relationship ; initial treatments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After screening a local population in the northern part of The Netherlands for hypertension, 59 patients with a diastolic pressure (DP) between 95 and 130 mmHg were randomized and treated either with 50 mg atenolol (n=29) or 100 mg atenolol (n=30) for 1 month. There was no significant difference between the two treatments, neither in the fall in systolic and diastolic pressures nor in the number of complaints reported. It is concluded that in the initial treatment of uncomplicated mild to moderate hypertension, 100 mg atenolol has no advantage over a 50 mg dose.
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  • 40
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    European journal of clinical pharmacology 28 (1985), S. 375-380 
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; dialysis ; vasodilator ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open study, thirteen chronic dialysis patients with nonvolume dependent uncontrolled hypertension were treated with pinacidil for a mean period of 43 weeks. Seven patients were taking concomitant antihypertensive therapy. Twelve patients achieved long-term blood pressure control on a mean dose of 33 mg/day. The baseline supine blood pressure was 184/116 mmHg. After 1 week it had fallen to 161/95 mmHg and blood pressure control was maintained over the study period. Patient weight remained stable. The baseline reading was 61.6 kg and at the end of the study it was 59.7 kg. Pulse rate did not change significantly. For the eight patients not taking beta-blockers the mean change in pulse rate was 7.6 beats/min supine and 6.3 beats/min erect (NS). Pretrial urea and creatinine were 27.6 mmol/l and 1027 µmol/l and after 25 weeks they were 29.6 mmol/l and 1087 µmol/l, respectively (NS). Four patients had ECG evidence of left ventricular hypertrophy before the study and one on completion of the trial. Five patients showed correction of T-waves on their ECG's. Six patients experienced side effects, none of which warranted withdrawal of treatment. These findings suggest that pinacidil is a valuable alternative treatment for hypertensive dialysis patients.
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  • 41
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    European journal of clinical pharmacology 28 (1985), S. 381-386 
    ISSN: 1432-1041
    Keywords: pinacidil ; renal impairment ; hypertension ; vasodilator ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty patients with uncontrolled hypertension were treated with pinacidil for a mean period of 43 weeks (range 10–63 weeks). All patients achieved and maintained significant reductions in blood pressure. The supine blood pressure at base-line was 184/116 mmHg; after one week it was 161/95 mmHg and at 43 weeks it was 138/79 mmHg. The mean dose of pinacidil was 30 mg/day. There was no significant difference between the two groups with respect to the dose of pinacidil or the blood pressure response. Pulse rate and weight remained stable for the group as a whole. Five patients were not taking beta-blockers. The mean baseline pulse rate for this group was 78 beats/min and when maintained on pinacidil it was 82 beats/min (NS). Six patients were not taking diuretics. The mean baseline weight for this group was 78.5 kg and while maintained on pinacidil it was 79.2 kg (NS). There was no occurrence of oedema, hirsutism or first dose phenomenon. The mean glomerular filtration rate and renal plasma flow for the renal group was 35.4 ml/min and 192.3 ml/min before pinacidil and after six months they were 32.7 ml/min and 183.2 ml/min (NS) respectively. Six patients experienced minor side-effects. We conclude that pinacidil is a potent, well tolerated antihypertensive agent which merits further study.
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  • 42
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    European journal of clinical pharmacology 28 (1985), S. 463-467 
    ISSN: 1432-1041
    Keywords: ceftizoxime ; cephalosporins ; renal excretion ; tubular reabsorption ; tubular secretion ; healthy volunteers ; biliary excretion ; clearance studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of ceftizoxime, a newly developed cephalosporin, were evaluated in 6 healthy subjects, with respect to its excretory pathways especially by the biliary route. Total, renal and biliary clearance were determined at two different steady states. Steady state was achieved by constant intravenous infusion (604.1 mg/h) over 6 h after an initial loading dose (750 mg); 1.5 h after discontinuation of that infusion, a further infusion was commenced at a lower rate (284 mg/h) over 3 h, the second steady state being reached 0.5 to 1.0 h later. The drug was mainly excreted by the kidneys (56.7 to 92.9% of the dose). Biliary excretion, measured by the duodenal perfusion and marker dilution technique, was low (0.2 to 7.8% of the dose). Urinary and biliary excretion as well as total clearance were not dose-dependent. However, there was pronounced interindividual variation in total (35.2 to 236 ml/min) and renal clearance (10.6 to 208 ml/min), which could both be explained by varying interindividual urinary flow rates (mean flow rate: 0.99 ml/min to 3.14 ml/min). Intraindividual variation in renal clearance was less pronounced, but in the same subject changes in renal clearance were correlated with changes in urinary flow rate. From the varying renal clearance, which exceeded the glomerular filtration rate at high urinary flow rates and was below it at low urinary flow rates, it can be concluded that, in addition to glomerular filtration, tubular secretion and tubular reabsorption are involved in the renal excretion of ceftizoxime. The half-life calculated from two point estimates after discontinuation of the infusion at the higher rate tended to be longer in subjects with high total clearance (e. g. 1.4 h, clearance 223 ml/min) and shorter in subjects with low total clearance (e.g. 0.85 h, clearance 35.2 ml/min). From this it is concluded that the true half-life was not observed after discontinuation of the infusion.
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  • 43
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    European journal of clinical pharmacology 28 (1985), S. 607-609 
    ISSN: 1432-1041
    Keywords: growth hormone ; valproate ; GABA ; stress ; exercise ; healthy volunteers ; GABAergic transmission
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of the GABAergic drug sodium valproate (SV) on the exercise-induced release of growth hormone (GH) was investigated in 10 healthy males. The exercise test consisted of using a stationary bicycle ergometer at 450 kg/min for 20 min. SV 600 mg blunted the increase in GH induced by the exercise, suggesting GABAergic regulation of GH secretion in man, at least under certain physiological conditions.
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  • 44
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    European journal of clinical pharmacology 28 (1985), S. 495-499 
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; plasma catecholamines ; plasma renin activity ; diuretic drugs ; side-effects ; hydrochlorothiazide ; amiloride
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pinacidil, a new cyanoguanidine derivative, is an antihypertensive agent with arteriolar vasodilating properties, which acts on precapillary resistance vessels. A trial was carried out in 30 patients with essential hypertension WHO I-II. The treatment period was divided into three phases. Hydrochlorothiazide (HCTZ) and amiloride were administered for 4 weeks in Phase 1 and supine and standing blood pressure decreased significantly. During Phase 2 pinacidil was added to HCTZ/amiloride for the following 3 months. A further significant reduction in blood pressure was obtained. In the next period of treatment (Phase 3) patients were divided into two groups. For 1 month Group A (15 patients) received pinacidil alone and Group B (15 patients) received HCTZ/amiloride. Conventional laboratory blood tests in all patients remained unchanged during treatment. Reported side effects during Phase 2 were headache (2 patients), dizziness (3 patients), palpitations (2 patients) and ankle oedema (2 patients). Plasma renin activity was slightly increased at the end both of Phases 1 and 2. Plasma catecholamines were increased but not significantly at the end of Phase 2 as compared to Phase 1. The results indicate that pinacidil is effective in lowering blood pressure in mild to moderate essential hypertension.
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  • 45
    ISSN: 1432-1041
    Keywords: citalopram ; serotonin uptake inhibition ; depressed patients ; steady state levels ; clinical effect ; desmethylcitalopram ; platelets ; side-effects ; dose-response relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Three dose levels (5, 25, and 50 mg once daily) of the selective serotonin uptake inhibitor citalopram were compared in a four-week, double-blind trial in depressed patients. Serum levels of citalopram and desmethylcitalopram, and the inhibitory effect of serum on serotonin uptake by fresh platelets, were assessed once weekly during the trial. The serum concentrations of citalopram were highly correlated with inhibition of serotonin uptake. Less of the metabolite was found, it being detected only in the higher dose groups. Steady state levels of citalopram, attained after 1 week, were linearly related to dose. The relationship between improvement (percentage reduction in total score on the Montgomery-Åsberg Depression Rating Scale) and serum level of citalopram indicated a lower limit of effect in endogenous depression at about 100 nM, corresponding to an average dose of 15 mg. Marked improvement was seen in ten patients with steady state levels in the range 70 to 335 nM. The ten nonendogenously depressed patients had steady state levels from 15 to 620 nM; complete remission was seen in the three with the lowest levels (15–25 nM). No significant correlation was found between serum drug level and the few reported side effects.
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  • 46
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    European journal of clinical pharmacology 28 (1985), S. 11-15 
    ISSN: 1432-1041
    Keywords: prazosin ; hypertension ; concurrent medication ; side-effects ; dose frequency ; slow release formulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 20 patients with long-standing essential hypertension, a comparison was made in a randomized cross-over study of the effect of once and twice daily prazosin administration on blood pressure levels. Concurrent medication (beta-blocker and/or saluretic once daily) remained constant throughout the study. Blood pressure measurements were carried out by a nurse using a Hawksley random zero sphygmomanometer, both in the clinic and at home, and using a Roche Kontron Arteriosonde SR-2 at home. Observations made in the morning and in the evening showed no significant difference in blood pressure between the once and twice daily treatments. Eight patients complained of dizziness and faintness half an hour after taking the once daily dose. However, they felt quite well on the twice daily regimen. The mean daily dose in these 8 patients was prazosin 8.4 mg, range 6–12 mg. No indication was found that the subjective adverse side effects were correlated with the serum prazosin level. The complaints noted may possibly be overcome by taking the once daily dose late in the evening, just before retiring. Better still, the development of a slow-release formulation for daily dosages of 6 mg and over is suggested.
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  • 47
    ISSN: 1432-1041
    Keywords: moclobemide ; Ro 11-1163 ; pharmacokinetics ; bioavailability ; MAO activity in platelets ; monoamine metabolites in urine ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of the MAO-inhibitor moclobemide (Ro 11-1163) were determined in six healthy male subjects after oral (tablets) administration. Effects on MAO activity in platelets and excretion of monoamine metabolites in urine were investigated. The design of the study was a double-blind cross-over study with single oral doses of placebo, 50, 100 and 200 mg of moclobemide. The elimination profile of the drug showed that the half life of the unchanged drug ranged between 1 and 2 h except in one subject with a half-life of about 4 h. The mean bioavailability calculated using flow model concepts was F=0.43 after 50 mg, F=0.47 after 100 mg and F=0.59 after 200 mg. The outlier with a t1/2 of 4 h was found to have a bioavailability of more than 0.80 after all 3 doses. The slightly increasing bioavailability with higher doses was interpreted as evidence of saturable hepatic first-pass elimination of the drug. MAO activity in platelets was measured before and 2, 6 and 24 h after drug administration. No inhibition of platelet MAO was obtained at any point in time or dose level, as to be expected since moclobemide preferentially inhibits MAO A. Urine excretion of the monoamine metabolites homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxy-phenylglycol (MOPEG) and 5-hydroxyindoleacetic acid (5-HIAA) was followed during 48 h after placebo, 50 and 200 mg of moclobemide. Time but not dose contributed significantly to the variability in excretion of the monoamine metabolites. An apparent reduction of HVA and DOPAC levels was obtained in the early phase after the administration of 200 mg of moclobemide. In 1 subject with a mild drug reaction a pronounced decrease in the levels of all the metabolites was obtained. In the other 5 subjects, the compound was very well tolerated with a few reported side-effects like increased activity, somnolence or sweatings. There was a slight but significant increase in blood pressure following 50 and 100 mg but not 200 mg of moclobemide.
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  • 48
    ISSN: 1432-1041
    Keywords: sulphinpyrazone ; metabolism ; single dose ; chronic treatment ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulphinpyrazone and its major metabolites (sulfide, sulfone, p-hydroxysulfone and p-hydroxy-sulphinpyrazone) were investigated in 9 volunteers after a single oral dose as well as after chronic treatment for 23 days. Chronic administration of sulphinpyrazone, in comparison with a single oral dose, led to significant changes in plasma AUC (115.86 to 42.90 mg/l·h), in renal clearance (1.06 to 1.80l/h), in hepatic intrinsic clearance (319.0 to 598.0l/h), and in the unbound fraction in plasma 1.15 to 1.69%) and in tissue (2.73 to 1.31%). The volume of distribution changed from 20.24 to 52.041. The steady state concentrations predicted from the single dose were significantly higher than the values found after chronic treatment. The results suggest that sulphinpyrazone induces its own metabolism. The metabolism of the sulfone, p-hydroxysulfone and the p-hydroxy-sulphinpyrazone to further degradation products was also induced. Chronic treatment with sulphinpyrazone reduced the plasma AUC of the sulfide and caused a decrease in its elimination half-life (20.9 to 14.3 h). Since considerable amounts of the sulfide are formed in the G.I. tract, it is suggested that besides the induction of metabolism, bacteria which reduce sulphinpyrazone to the sulfide may also be responsible for the observed pharmacokinetic changes.
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  • 49
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    European journal of clinical pharmacology 28 (1985), S. 53-59 
    ISSN: 1432-1041
    Keywords: furosemide ; respiratory failure ; furosemide glucuronide ; first-pass metabolism ; diuretic effect ; bioavailability ; food effect ; chronic treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability and diuretic effect of furosemide 40 mg administered orally for at least 6 months have been compared in patients with chronic respiratory failure and in healthy controls. The mean urinary recovery of unchanged drug was 11.5 mg and 9.41 mg in 24 h after pre- and postprandial administration to 10 patients, whereas the recovery was 14.4 mg in 10 healthy subjects. The diuretic effect, in terms of urine flow and sodium ion excretion in the 6 h after administration, was also less in patients than in healthy subjects. This was ascribed to the lower bioavailability of furosemide in patients, based on the urinary recovery of unchanged drug, and not to a lower level of response to furosemide than in healthy subjects. The mean absolute bioavailability of furosemide in 6 patients was 41.3% and 63.4%, respectively, calculated from unchanged drug and total drug (unchanged plus glucuronide conjugate). Approximately 53.9% of the dose of furosemide was excreted as the glucuronide conjugate after oral administration, and 34.2% after i.v. injection in the 6 patients. In 3 of the 6 patients studied, a distinct first-pass effect for glucuronidation of furosemide was observed after oral administration. In another study, the mean glucuronide fraction recovered in 24-h urine was 20.7% and 7.3% (p〈0.01) in 38 patients and 12 healthy subjects, respectively. The fraction in urine was not affected by changing the dose of furosemide from 20 to 120 mg. The lower bioavailability in patients as compared to healthy subjects is ascribed to enhanced glucuronidation and incomplete drug absorption.
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  • 50
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    European journal of clinical pharmacology 28 (1985), S. 85-88 
    ISSN: 1432-1041
    Keywords: bioavailability ; distribution-free statistical method ; confidence limits
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The confidence interval approach to bioavailability assessment depends first on selection of the confidence level, usually 95%, and then determination of the confidence limits for the expected bioavailability ratio AUC(Test)/AUC(Reference). In practice, however, it is sometimes of greater interest to know the probability that the expected bioavailability will fall below a critical value, for example 0.75, or within a clinically set bioequivalence range, for example 0.80 to 1.25. Up to now, posterior probability distributions have been suggested, based on classical analysis of variance (ANOVA) with its rather restrictive assumptions, including that of a (logarithmic) normal distribution. In this report, a distribution-free confidence interval based on the Wilcox-on signed-rank statistic has been generalized so that confidence probabilities can be obtained for any given confidence limits. In the case of unimodal and almost symmetrical sampling distributions, the results obtained are very similar to those of the ANOVA-based posterior probability distribution. However, skewed or multimodal sampling distributions are better reflected by the proposed distribution-free method, and more valid information is obtained in these cases, as demonstrated by examples.
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  • 51
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    European journal of clinical pharmacology 27 (1985), S. 637-644 
    ISSN: 1432-1041
    Keywords: isosorbide-dinitrate ; pharmacokinetics ; analytical method ; bioavailability ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailabilities of a conventional and two slow release 20 mg isosorbide dinitrate (ISDN) formulations were compared after oral administration in a three way cross-over study in 8 male volunteers. In a further group of 6 male volunteers the pharmacokinetics and metabolism of ISDN were investigated after intravenous infusion of a median dose of 14.1 mg for 2.5 h. A new analytical procedure was developed for the determination of isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-Glu) and of isosorbide (IS). Kinetic data analysis on a molar basis was performed by the program package KINPAK providing model independent parameters. The median elimination half-lives of ISDN, IS-5-MN, IS-2-MN and IS-5-MN-2-Glu were 0.7, 5.1, 3.2 and 2.5 h, respectively. The systemic clearance of ISDN was 3.7 l/min and the distribution volume 2521 (3.1 l/kg). Apart from IS-5-MN-2-Glu, with a renal clearance of 5.9 l/min which suggested substantial glucuronidation in the kidney, the renal clearances of ISDN, IS-5-MN, IS-2-MN and the corresponding amounts excreted were negligible. 27.8% of the administered ISDN was excreted as IS-5-MN-2-Glu (8.7%) and IS (19.1%). Calculations based on the two mononitrate metabolites formed from ISDN showed an incomplete recovery of 84.1%, leading to the assumption that a simultaneous denitration to IS must have occurred. The rate of denitration at each nitro group in ISDN was almost twice as high as for the same position in the corresponding mononitrate. The bioavailability of the conventional ISDN formulation was 19%, although complete absorption was indicated by comparison of the percentages of mononitrate metabolites formed after the different routes of administration. On the same basis the absorption of the two sustained release formulations was found to be poor.
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  • 52
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    European journal of clinical pharmacology 27 (1985), S. 721-725 
    ISSN: 1432-1041
    Keywords: alizapride ; cancer ; chemotherapy ; substituted benzamide ; nausea ; vomiting ; side-effects ; antiemetic therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In early clinical trials alizapride showed a better antiemetic activity with fewer side effects than metoclopramide. Alizapride has now been evaluated in an open dose — ranging study in 24 patients receiving strongly emetic chemotherapy. Alizapride 4–8 mg/kg was given as a 15 min infusion 0.5 h before and 1.5, 3.5, 5.5 and 8.5 h after the chemotherapy. At the dose levels of 6 and 8 mg/kg × 5, respectively 6 out-of 9 and 4 of 4 patients experienced side effects (hypotension, dizziness, profuse sweating, general malaise and diarrhoea). At 4 mg/kg × 54 of 15 patients experienced side effects due to alizapride (dyspnoea 1, diarrhoea 2, extrapyramidal syndrome 1 patient). Overall, 9 of 24 patients were partially or completely protected from nausea and vomiting. Based on this experience alizapride has antiemetic activity and few side effects in the dose of 4 mg/kg × 5.
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  • 53
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    European journal of clinical pharmacology 27 (1985), S. 737-738 
    ISSN: 1432-1041
    Keywords: flecainide ; atrial fibrillation ; cardioversion ; sinus rhythm ; side-effects ; propranol ; quinidine
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  • 54
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    European journal of clinical pharmacology 29 (1985), S. 21-24 
    ISSN: 1432-1041
    Keywords: nisoldipine ; nifedipine ; pharmacokinetics ; pharmacodynamics ; calcium channel blocking drugs ; hypertension ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamic and pharmacokinetic profiles of nifedipine and nisoldipine were compared in a double blind, placebo-controlled study. Nisoldipine, 10 mg significantly reduced systolic blood pressure but nifedipine 20 mg retard did not, although both drugs had significant pharmacodynamic effects as evidenced by increased heart rates. The terminal elimination half-life in plasma was similar for both drugs with a mean of 2 h. The pharmacodynamics of nisoldipine were studied in 8 hypertensives following both acute and chronic administration. Antihypertensive efficacy was demonstrated after acute dosing and was maintained over 4 weeks of twice daily treatment as monotherapy.
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  • 55
    ISSN: 1432-1041
    Keywords: cianergoline ; hypertension ; dopaminergic agonist ; renin angiotensin aldosterone ; lipid metabolism ; benign essential hypertension ; side-effects ; prolactin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cianergoline is a new dopaminergic agonist with a predominant cardiovascular action. Its effects on blood pressure, the renin-angiotensin-aldosterone axis, the sympathetic nervous system and lipid metabolism were assessed in 20 patients with benign essential hypertension. Cianergoline given in increasing doses for 4 weeks (maximum daily dose 12±2 mg (SD)) and placebo both caused a slight decrease in arterial pressure, (from 159/104 to 152/98 mm Hg and from 154/104 to 149/103 mm, respectively; difference not significant). Supine and upright plasma renin activity, plasma aldosterone, norepinephrine, epinephrine and dopamine levels, urinary catecholamine excretion rates as well as serum prolactin, low and high density cholesterol and triglyceride concentrations were not changed after cianergoline or placebo. Total serum cholesterol and triglyceride levels decreased significantly after placebo, but were unchanged after cianergoline. 3 out of 10 patients in the cianergoline group complained of nausea. The findings indicate that the new dopaminergic agonist cianergoline exerts only a mild blood pressure lowering effect in patients with essential hypertension and does not modify the release of prolactin, lipid metabolism or the basal activity or postural responsiveness of the renin-angiotensin-aldosterone axis and of the sympathetic nervous system.
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  • 56
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    European journal of clinical pharmacology 29 (1985), S. 67-71 
    ISSN: 1432-1041
    Keywords: dipyrone ; dipyrone metabolites ; human protein binding ; analgesic antipyretic drugs ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Four metabolites of dipyrone, 4-methyl-aminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylamino-antipyrine (AAA) can be identified in human plasma after its oral administration. The plasma protein binding of the metabolites in samples from 20 healthy volunteers was determined by ultrafiltration. None of the metabolites were found to be extensively bound to plasma proteins. The binding of MAA and AA was relatively higher than of FAA and AAA, as expected from their chemical structure. The mean percentage plasma protein binding was 57.6% for MAA, 47.9 for AA, 17.8 for FAA and 14.2% for AAA. The correlation between the unbound concentration in plasma and the total concentrations of MAA, AA, FAA and AAA was linear. No association was evident between the total protein plasma concentration and the extent of binding. The possible therapeutic implications related to protein binding of several analgesic and non-steroidal anti-inflammatory drugs are discussed.
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  • 57
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    European journal of clinical pharmacology 29 (1985), S. 91-95 
    ISSN: 1432-1041
    Keywords: midazolam ; 1-hydroxymethylmidazolam ; pharmacokinetics ; dose proportionality ; benzodiazepine ; healthy volunteers ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the Cmax and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This ist not expected to have any clinical significance under the conditions of therapeutic use.
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  • 58
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    European journal of clinical pharmacology 29 (1985), S. 97-103 
    ISSN: 1432-1041
    Keywords: bupropion ; metabolites ; pharmacokinetics ; single and multiple dose ; side-effects ; enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions.
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  • 59
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    European journal of clinical pharmacology 29 (1985), S. 109-113 
    ISSN: 1432-1041
    Keywords: griseofulvin ; skin blister fluid levels ; pharmacokinetics ; healthy subjects ; bioavailability ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Griseofulvin and 6-demethylgriseofulvin (6-DMG) in plasma, suction blister fluid (SBF) and cantharides blister fluid (CBF) and urinary excretion of 6-DMG, were evaluated following administration of single oral doses of an ultramicrosize and a microsize formulation of griseofulvin to 6 healthy volunteers. The bioavailability of griseofulvin was higher following the ultramicrosize formulation when 64% of the dose was recovered (via metabolites) versus 52% after the microsize preparation. Penetration into skin blister fluid was delayed as compared to plasma levels; the peak concentration in plasma was observed at 3–4 h, whereas griseofulvin in CBF increased up to 6 h. The terminal half-live was calculated from plasma levels to 9.3 h. The half-lives calculated from SBF and CBF concentrations were 9.2 and 9.8 h, respectively, (n=5). In plasma 84% of griseofulvin was bound to proteins, predominantly to albumin; binding in SBF and CBF was 72 and 82%, respectively. 3 h after drug administration the free concentration in plasma significantly exceeded the free concentrations in SBF and CBF. Distribution equilibrium between plasma and skin blister fluid was observed after 27 h. Thus, during chronic administration, the plasma griseofulvin level should reflect its concentration in the target organ.
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  • 60
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    European journal of clinical pharmacology 29 (1985), S. 159-164 
    ISSN: 1432-1041
    Keywords: domperidone ; metoclopramide ; sympathetic activity ; endogenous dopamine ; DA2 receptors ; norepinephrine ; side-effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of placebo and DA2 antidopaminergic agents on basal and stimulated catecholamine (CA) plasma levels in humans have been evaluated by administration either of domperidone or metoclopramide to separate groups of subjects. The latter group was subjected domperidone to sympathetic stimulation by handgrip coldpressor tests, and standing. Pharmacological DA2 receptor blockade, either peripheral by or central and peripheral by metoclopramide, did not modify plasma CA whilst resting or during acute sympathetic stimulation. It is concluded that endogenous dopamine does not seem to play a significant role in modulating NE release in man, at least not under the physiological conditions examined.
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  • 61
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    European journal of clinical pharmacology 29 (1985), S. 281-285 
    ISSN: 1432-1041
    Keywords: bopindolol ; metoprolol ; blood pressure ; heart rate ; effect duration ; hypertension ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 14 male hypertensive patients, mean age 53 years first took part in a 3 month, double-blind crossover comparison of 1–2 mg bopindolol, a nonselective β-blocker with ISA, and 100–200 mg metoprolol. Effects on blood pressure and heart rate were followed. One patient dropped out after the initial phase and the remaining 13 patients were followed for 1 year on bopindolol. 8 patients measured blood pressure at home, and in them bopindolol 1 mg o.d. and 8 mg once weekly were compared in a double-blind fashion, for 3 weeks on each regimen. Finally, after 1 year on bopindolol, treatment was withdrawn and blood pressure and heart rate were followed in 10 of the initial patients. Bopindolol in a mean doese of 1.35 mg/day caused a significant reduction in blood in pressure (26/15 mmHg), as did metoprolol (24/13 mmHg) in a mean dose of 144 mg/day. No significant difference in antihypertensive response was observed. Supine and standing heart rate were reduced both during bopindolol and metoprolol treatment. During long-term therapy with bopindolol, satisfactory blood pressure control was maintained up to 1 year in all patients, the average supine blood pressure being reduced from 173/107 to 144/90 mmHg. During treatment with bopindolol 8 mg once weekly, the blood pressure control was satisfactorily maintained over the week and no significant difference was observed in comparison with daily administration (1 mg) of the drug. When active treatment was withdrawn, a gradual increase in blood pressure and heart rate was observed, the pretreatment values being reached 8 weeks after discontinuation of bopindolol therapy. Thus, effective blood pressure control was achieved with bopindolol in patients with mild hypertension. The effect was sustained over 12 months and tolerance was good. The relatively long half-life of the drug made it possible to use it in once weekly regimen.
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  • 62
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    European journal of clinical pharmacology 29 (1985), S. 351-354 
    ISSN: 1432-1041
    Keywords: griseofulvin ; skin blister fluid ; plasma concentration ; blister fluid concentration ; pharmacokinetics ; microsize formulation ; urinary excretion ; bioavailability ; different formulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Griseofulvin was administered orally to 6 healthy volunteers for 6 days. The subjects received 500 mg of a microsize formulation and 330 mg of an ultramicrosize formulation, according to a cross-over design. The drug was determined in plasma, suction blister fluid (SBF) and cantharides blister fluid (CBF) following the last dose. Urinary excretion of the main metabolites 6-demethylgriseofulvin (6-DMG) and its glucuronic acid conjugate was also measured. The pharmacokinetic parameters were compared with those obtained from a recent single dose experiment. On repeated administration, the bioavailability of griseofulvin was significantly lower from the microsize formulation; the urinary recovery of total 6-DMG was 33.8% versus 53.6% on administration of the ultramicrosize material. Bioavailability was reduced as compared to ingestion of a single dose. The reduction was more prominent following the microsize (36%) than the ultramicrosize (17%) formulation. Penetration into skin blister fluid was not altered as compared to the single dose experiment. Relative areas under the blister fluid-time curves amounted to 51% (SBF) and 80% (CBF) of the area under the plasma level-time curve. The concentration of unbound griseofulvin in these body fluids was identical throughout the entire dosage interval. Unbound griseofulvin levels were low in comparison with the minimum inhibitory concentrations for strains of trichophyton and microsporum.
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  • 63
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    European journal of clinical pharmacology 29 (1985), S. 379-381 
    ISSN: 1432-1041
    Keywords: confidence intervals ; bioavailability ; Bayesian analysis
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  • 64
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    European journal of clinical pharmacology 29 (1985), S. 413-416 
    ISSN: 1432-1041
    Keywords: nifedipine ; indomethacin ; whole blood aggregometry ; 6-keto-prostaglandin F1α ; blood pressure ; platelet aggregation ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pre-incubation of human platelets with nifedipine in vitro or treatment of normal volunteers with nifedipine, 30 mg daily for one week, did not alter ADP induced aggregation measured by whole blood aggregometry. 6-oxo-Prostaglandin F1α remained undetectable in plasma following oral administration of nifedipine to normal volunteers. The hypotensive response to intravenous nifedipine administration was similar in spontaneously hypertensive rats pretreated with indomethacin or placebo. These results conflict with previous reports that nifedipine alters platelet aggregation and prostaglandin metabolism.
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  • 65
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    European journal of clinical pharmacology 29 (1985), S. 391-393 
    ISSN: 1432-1041
    Keywords: diabetes mellitus ; hypertension ; guanfacine ; glucose tolerance ; insulin ; side-effects ; coronary risk
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In the present study the effect of 1 year of antihypertensive treatment with guanfacine (g) has been evaluated in 18 hypertensive patients with adult-onset, non-insulin-dependent diabetes mellitus (WHO Type II). The treatment produced a marked improvement in the oral glucose tolerance test; guanfacine significantly decreased serum glucose levels, and affected only slightly the insulin secretion. It is suggested that the effect of g may be mediated via a reduction in catecholamine and/or growth hormone and ACTH secretion. The present results also suggest that treatment with guanfacine may improve individual coronary risk in hypertensive diabetic patients.
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  • 66
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    European journal of clinical pharmacology 29 (1985), S. 477-481 
    ISSN: 1432-1041
    Keywords: budesonide ; glucocorticoid ; nasal administration ; pharmacokinetics ; bioavailability ; systemic effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Budesonide, a topically potent glucocorticoid, was administered to 4 healthy volunteers by i.v. infusion and by nasal instillation of 100 µg tritium-labelled drug. Plasma was analyzed by liquid chromatography plus scintillation counting of collected fractions. After i.v. administration the plasma clearance was 0.92 l/min and the apparent volume of distribution was 2.8 l/kg. After nasal administration, the time to reach the peak plasma level was approximately 30 min, and the systemic availability was 102%. Budesonide had marginal effects on plasma cortisol and white blood cell counts either after i.v. or nasal administration. Thus, nasally instilled budesonide in solution is rapidly and completely absorbed from the nasal mucosa. The systemic effects after this clinically recommended nasal dose were negligible.
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  • 67
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    European journal of clinical pharmacology 28 (1985), S. 135-138 
    ISSN: 1432-1041
    Keywords: hypertension ; cadralazine ; vasodilators ; chlorthalidone ; atenolol ; side-effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive efficacy of a new long-lasting vasodilator, cadralazine, and the diuretic chlorthalidone have been compared in hypertensive patients receiving concurrent treatment with atenolol. After a 4-week run-in period with atenolol alone 100 mg/day, two groups of 10 patients whose diastolic blood pressure exceeded 100 mm Hg were given for a period of 65 days either cadralazine 15 mg/day or chlorthalidone 25 mg/day, according to a randomized, double-blind, between-patients design. Compared to atenolol alone, both cadralazine and chlorthalidone induced a statistically and clinically significant decrease in blood pressure. The antihypertensive effect did not differ significantly between groups. Good compensation of the atenolol-induced decrease in heart rate was obtained with cadralazine, whereas during atenolol + chlorthalidone treatment at times the standing heart rate was significantly lower than during treatment with atenolol + cadralazine. Side-effects, many of which were already present during atenolol treatment, occurred with a similar frequency in both groups. It is concluded that atenolol + cadralazine and atenolol + chlorthalidone are equally well tolerated, acceptable and effective in the treatment of hypertension, but that further studies are warranted to explore the potential haemodynamic advantages of the cadralazine + atenolol combination.
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  • 68
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    European journal of clinical pharmacology 28 (1985), S. 221-222 
    ISSN: 1432-1041
    Keywords: calcium entry blockers ; bronchomotor tone ; ethanol ; nifedipine ; flunarizine ; diltiazem ; verapamil ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of various Calcium Entry Blockers (CEBs; nifedipine, flunarizine, diltiazem, verapamil) on ethanol-induced bronchoconstriction was studied in normal healthy volunteers. Nifedipine and diltiazem inhibited the bronchoconstriction and verapamil and flunarizine had no effect. The data favour the general hypothesis of differential tissue sensitivity to the various CEBs. The activity of CEBs on bronchomotor tone may be of therapeutic value in patients in whom bronchodilator activity is recommended in addition to the cardiovascular action.
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  • 69
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    European journal of clinical pharmacology 28 (1985), S. 347-349 
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; vasodilation ; side-effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty three patients with essential hypertension who were uncontrolled on diuretic and/or β-receptor antagonist therapy were treated additionally with the vasodilator, pinacidil, in an open study. Significant reduction in mean blood pressure was achieved. Supine and erect systolic and diastolic blood pressure fell by 44/25 mmHg and 37/24 mmHg respectively over the study period of 12 weeks. Side-effects such as dizziness, headache, facial flushing and mild oedema were experienced by 10 patients during the study, all of which were mild and transient and did not require withdrawal from pinacidil therapy. Pinacidil is an effective and well tolerated agent in the treatment of essential hypertension.
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  • 70
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    European journal of clinical pharmacology 28 (1985), S. 411-417 
    ISSN: 1432-1041
    Keywords: ketanserin ; ketanserinol ; pharmacokinetics ; age ; healthy volunteers ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of ketanserin has been examined in a cross-over experiment in 21 elderly subjects (aged 59–72 years) by administration of tablets (40 mg), solution (40 mg) and injectable solution (10 mg). After two weeks of treatment with 40 mg ketanserin tablets further 18 blood samples for analysis were collected under steady-state conditions. Plasma levels were measured by HPLC. The absolute bioavailability of ketanserin tablets was 52.7%; their relative bioavailability compared to a solution containing an equal quantity of active compound was 85.5%. Therefore, the low absolute bioavailability of ketanserin cannot be attributed to the formulation. The active compound was rapidly liberated from the tablet, reaching a peak of 103.8 ng/ml after 0.97 h. Individual plasma level-time curves were fitted to an open three compartment model and a half-life of 17.7±7.26 h was calculated for the terminal elimination phase. An average terminal elimination half-life of 15.4±4.2 ng/ml was found after administration of the ketanserin solution. Multiple dosing with 40 mg tablets b.d.s. resulted in an AUC over one dosing interval at steady-state of 666±201 ng × h/ml. The AUC extrapolated to infinity was 1200±405 ng × h/ml for the last tablet. This is 1.8-times the AUC in one dosing interval, and 2.3-times the AUC of a single dose. Under steady-state conditions, the mean peak plasma level was 155.1 ng/ml (1.08 h after dosing) and the terminal half-life was 19.1±5.1 h. For the metabolite ketanserinol terminal half-lives of 21.4 h after a single tablet and 31.0 h after discontinuation of multiple dosing were calculated. Compared to the parent compound there was much more marked accumulation of ketanserinol. Despite moderate accumulation and prolongation of the terminal half-life of ketanserin under steady-state conditions, dosage adjustment is not required in elderly people. First-pass metabolism and bioavailability remained in the range found in previous studies of ketanserin in young subjects.
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  • 71
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    European journal of clinical pharmacology 28 (1985), S. 567-571 
    ISSN: 1432-1041
    Keywords: vinpocetine ; cognitive function ; information processing ; memory ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve healthy female volunteers received pre-treatments with vinpocetine 10, 20, 40 mg and placebo (t.d.s.) for two days according to a randomised, double-blind crossover design. On the third day of treatment and 1 h following morning dosage, subjects completed a battery of psychological tests including Ciritcal Flicker Fusion (CFF), Choice Reaction Time (CRT), Subjective Ratings of Drug Effects (LARS) and a Sternberg Memory Scanning Test. No statistically significant changes from placebo were observed on CFF, CRT or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was found to be significantly improved following treatment with vinpocetine 40 mg when compared to placebo and results suggested a localised effect of the drug on the serial comparison stage of the reaction process.
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  • 72
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    European journal of clinical pharmacology 28 (1985), S. 581-583 
    ISSN: 1432-1041
    Keywords: piretanide ; liver cirrhosis ; ascites ; bioavailability ; pharmacokinetics ; diuretic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of piretanide, a new loop diuretic, were studied in seven patients with severe liver disease before and after resolution of ascites. The time to maximum concentration was significantly prolonged by the presence of ascites. Tmax after relief of ascites was similar to that seen for normal volunteers. Area under the curves, bioavailability, volumes of distribution and elimination half-lives did not change after resolution of the ascites: two patients in whom diuretic resistant ascites occurred showed similar pharmacokinetics to that of the diuretic responders. Reduced responsiveness to piretanide therapy in patients with gross ascites does not appear to be the result of decreased bioavailability.
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  • 73
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    European journal of clinical pharmacology 28 (1985), S. 631-636 
    ISSN: 1432-1041
    Keywords: salbutamol ; histamine plasma concentration ; bronchorelaxation ; healthy volunteers ; induced bronchoconstriction ; carbachol ; bronchoconstrictor mediators
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma histamine in 8 normal subjects was measured before and after inhalation of carbachol to induce a 50% fall in specific airway conductance (SGaw). The measurements were repeated 5 min after inhalation of salbutamol or placebo. No significant change in plasma histamine occurred after placebo or carbachol inhalation, despite the persistent induced bronchospasm after the latter treatment. In contrast, plasma histamine was significantly increased from 0.25 to 0.43 ng/ml after salbutamol inhalation. Simultaneously, induced bronchospasm was relieved, from 51% to 103% of baseline SGaw. Thus, the relief of carbachol-induced bronchospasm by salbutamol was associated with a rise in plasma histamine. Since salbutamol itself is a potent inhibitor of mast cell degranulation and histamine release, the present findings suggest that histamine may be released and sequestered within the lungs during carbachol-induced-bronchospasm, and also that desequestration of bronchoconstrictor mediators accumulated at the point of contact of bronchial smooth muscle may contribute to the relief of bronchospasm by salbutamol.
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  • 74
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    European journal of clinical pharmacology 28 (1985), S. 649-652 
    ISSN: 1432-1041
    Keywords: digitoxigenin ; monodigitoxoside ; bisdigitoxoside ; biovailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic behavior of digitoxigenin is affected by the number of glycosides present. This study was conducted to compare the bioavailabilities of the bis- and monodigitoxosides of digitoxigenin in man. Intravenous and oral doses of the two drugs were administered to six normal volunteers. Blood samples were collected up to 28 days after each dose, and assayed for the specific drug administered and for total radioassayable drug. Both drugs were virtually completely absorbed, based on serum concentrations of administered drug plus metabolites. However, the mean bioavailability of unchanged bisdigitoxoside was only 56.3% indicating that substantial metabolism occurred prior to entry into the systemic circulation. Monodigitoxoside was virtually completely metabolized prior to entry into the systemic circulation.
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  • 75
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    European journal of clinical pharmacology 28 (1985), S. 685-688 
    ISSN: 1432-1041
    Keywords: prostaglandin analogue ; renal function ; vasodilator ; L-644,122 ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary L-644,122 is a chemically stable vasodilator prostaglandin analogue. It is a selective renal vasodilator in dogs. The object of the present study was to determine whether it increases effective renal plasma flow (ERPF) in man. L-644,122 was administered intravenously to 4 healthy volunteers and by mouth to 4 mild hypertensives. It did not increase ERPF. Instead it acted as a non-specific vasodilator, lowering diastolic blood pressure and increasing heart rate. An unexpected increase in glomerular filtration rate (19% greater than placebo) after low dose intravenous L-644,122 merits further study.
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  • 76
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    European journal of clinical pharmacology 28 (1985), S. 35-39 
    ISSN: 1432-1041
    Keywords: urapidil ; clonidine ; hypertension ; side-effects ; hypotensive effect
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effects of urapidil and clonidine have been studied in a double-blind cross-over trial in 11 hypertensive outpatients with mild to moderate hypertension, at rest and during isometric exercise. Urapidil 30 mg b.i.d. significantly decreased the standing diastolic blood pressure (p〈0.05) and the systolic blood pressure at the end of isometric exercise (p〈0.05). Clonidine 0.075–0.15 mg b.i.d. was more effective in decreasing both systolic and diastolic blood pressure in the supine and standing positions as well as during isometric work (p〈0.05–0.001). Urapidil caused fewer side-effects than clonidine. Overall, in the doses used urapidil had a weaker antihypertensive effect and caused fewer side-effects than clonidine.
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  • 77
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    Molecular and cellular biochemistry 66 (1985), S. 111-116 
    ISSN: 1573-4919
    Keywords: Adenosine triphosphatase ; Na+ ; K+ ; catecholamines ; calcium
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    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction of noradrenaline, various cation chelators and calcium on Na+, K+-ATPase from rat cerebral cortex plasma membranes was studied. It was shown that chelation of inhibitory cations by EGTA, EDTA and dipyridyl activated Na+, K+-ATPase to the same extent as noradrenaline but at higher concentrations; increasing concentrations of EGTA depressed the activation by noradrenaline; calcium in the form of a calcium-EGTA buffer depressed Na+, K+-ATPase at physiological concentrations; the inhibition of Na+, K+-ATPase by calcium is dependent on the magnesium concentration in the assay and the inhibition by calcium was partially reversed by noradrenaline.
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    Molecular and cellular biochemistry 66 (1985), S. 145-149 
    ISSN: 1573-4919
    Keywords: calcium ; cyclic GMP ; gonadotropin releasing hormone ; guanylate cyclase ; manganese
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    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Summary Gonadotropin releasing hormone enhanced guanylate cyclase [E.C.4.6.1.2] two- to threefold in pituitary, testis, liver and kidney. Dose response relationships revealed that at a concentration of 1 nanomolar, gonadotropin releasing hormone caused a maximal augmentation of guanylate cyclase activity and that increasing its concentration to the millimolar range caused no further enhancement of this enzyme. There was an absolute cation requirement for gonadotropin releasing hormone's enhancement of guanylate cyclase activity as there was no increase without any cation present. Gonadotropin releasing hormone could increase guanylate cyclase activity with either calcium or manganese in the incubation medium but more augmentation was observed with manganese. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of gonadotropin releasing hormone.
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    Molecular and cellular biochemistry 67 (1985), S. 145-150 
    ISSN: 1573-4919
    Keywords: calcium ; harmaline ; smooth muscle ; sodium
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    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of changing the extracellular concentration of both Na+ and K+ on the longitudinal muscle of the guinea-pig ileum was studied in the presence and absence of harmaline. A decrease in extracellular Na+ concentration was found to produce a dose-dependent contractile response, which may suggest the existence of a Na...Ca exchange mechanism in this muscle. Harmaline (2 × 10−4 M) was found to reversibly inhibit this contraction and was also found to selectively block the tonic component of high-K induced contradictions. In view of the fact that harmaline is a non-competitive inhibitor of Ca-induced contractions (Hider et al., Europ. J. Pharmacol., 71, 87, 1981), the action of harmaline was interpreted as being a specific inhibitor of the Na... exchange mechanism, binding specifically to Na+ coordination sites.
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  • 80
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    Molecular and cellular biochemistry 68 (1985), S. 115-120 
    ISSN: 1573-4919
    Keywords: pyruvate kinase isoenzymes ; pancreatic islets ; kinetic and immunological studies ; calcium ; alanine ; phenylalanine ; fructose bisphosphate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract To determine which of the major isoenzymes of pyruvate kinase pancreatic islet pyruvate kinase most resembled, it was compared to pyruvate kinase from other tissues in kinetic and immunologic studies. The pattern of activation by fructose bisphosphate and the patterns of inhibition by alanine and phenylalanine were most similar to those of the M2 isoenzyme from kidney and were dissimilar to those of the isoenzymes from skeletal muscle (type M1) and liver (type L). The islet pyruvate kinase was inhibited by anti-M1 pyruvate kinase serum (which crossreacts with the M2 isoenzyme), but not by anti-L pyruvate kinase. These results are most consistent with islets possessing predominantly, if not exclusively, the M2 isoenzyme of pyruvate kinase. We previously showed that rat pancreatic islet cytosol contains protein kinases that can catalyze a calcium-activated phosphorylation of an endogenous peptide that has properties, such as subunit molecular weight and isoelectric pH, that are identical to those of the M2 and M, isoenzymes of pyruvate kinase, and that islet cytosol can catalyze phosphorylation of muscle pyruvate kinase. In the present study it was shown that incubating islet cytosol with ATP under conditions known to permit phosphorylation and inhibition of liver pyruvate kinase did not affect the islet pyruvate kinase activity. It is concluded that phosphorylation of the islet pyruvate kinase has no immediate effect on enzyme activity.
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  • 81
    ISSN: 1573-1561
    Keywords: Chiral semiochemicals ; pheromones ; enantiomeric composition ; Ips pini ; Coleoptera ; Scolytidae ; Apis mellifera ; Hymenoptera ; apidae ; Cryptolestes Ferrugineus ; Cucujidae ; acetyl lactate diastereoisomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract A method is described for determining the enantiomeric composition of chiral alcohols, lactones, and hydroxy acids in quantities ranging from 25 ng to 10 μg. Derivatization of the substance with chirally pure acetyl lactate, followed by splitless capillary gas chromatography, enables enantiomeric determinations to be made within 1–3% of the actual value. This technique was applied in the determination of semiochemical inIps pini (Say),Apis mellifera (L.), andCryptolestes ferrugineus (Stephens). The results indicate that considerable variability exists within populations of some insects in the composition of their chiral semiochemicals, whereas others produce substances of constant composition.
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  • 82
    ISSN: 1573-1561
    Keywords: Isoflavonoids ; structure-activity relationships ; insect feeding-deterrent activity ; Costelytra zealandica ; Coleoptera ; Scarabaeidae ; stereochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract A number of naturally occurring isoflavonoids of differing substitution patterns and oxidation states have been tested for feeding deterrent activity in a bioassay with larvae ofCostelytra zealandica White. The most active deterrents, which reduced feeding significantly at 0.2-1.0 μg/g, are those compounds containing a ring B-fused cycloprenoid moiety. The least active compounds were highly oxidized coumestans and isoflavones. The ring B-fused cyclic isoprenoid moiety and the presence of a 2'-oxy function appear to be structural features important for high activity. It is suggested that the feeding deterrent activity of isoflavonoids relates to their stereochemistry and that the most active compounds have or can adopt a similar nonplanar molecular shape with a similar arrangement of polar and lipophilic groups.
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    The journal of membrane biology 86 (1985), S. 113-125 
    ISSN: 1432-1424
    Keywords: epithelial monolayers ; MDCK cells ; tight junctions ; calcium ; biosynthesis of junctions ; junctional assembly ; apical/basolateral polarization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary Synthesis and assembly of tight junctions are studied in monolayers of MDCK cells plated at a density sufficient for confluence, allowed to attach for 1 hr, and transferred to fresh media without cells containing or not Ca2+, 20 hr later, while monolayers with Ca2+ have fully developed junctions that confer an electrical resistance across of 346±51 Ω cm2, those without Ca2+ have a negligible resistance. If at this time Ca2+ is added, junctions assemble and seal with a fast kinetics, that can be followed through the development of electrical resistance, penetration of ruthenium red, and electron microscopy. Drugs that impair synthesis, maturation and transport of proteins (cycloheximide, tunicamycin, monensin) indicate that protein components are synthesized early upon plating, do not seem to require N-glycosylation, and are stored in the Golgi compartment. Upon addition of Ca2+ they are transferred to the membrane with the participation of microfilaments but not of microtubules. These components seem to insert directly in the position they occupy in the strands, and the cell circles its perimeter with one strand as early as 15 min, even if in some segments it only consists of a row of particles. New strands develop in association with previous ones, and the pattern completes in 4 to 6 hr. Ca2+ is required for the maintenance of the assembly and also for the sealing with neighboring cells. These processes cannot occur below 25°C. Serum is not required. Polarized distribution of intramembrane particles (IMP) in apical and basolateral regions follows the same time course as junction formation, in spite of the fence constituted by those strands that are already assembled. This suggests that IMP do not redistribute by lateral displacements in the plane of the membrane, but by removal and insertion in the apical and basolateral domains.
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  • 84
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    The journal of membrane biology 85 (1985), S. 269-280 
    ISSN: 1432-1424
    Keywords: cell fusion ; electrofusion ; dielectrophoresis ; calcium ; magnesium ; membrane lipid ; lymphoma cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary Mouse leukemic lymphoblasts (L5178Y) brought into close contact by dielectrophoresis underwent cell fusion following the application of electrical pulses in the presence of electrolytes. The electrically fused cells became spherical after switching off the dielectrophoretic field. Fusion between a cell vitally stained with Janus Green and that with Neutral Red resulted in the homokaryon with a mixed color. Intracellular potentials simultaneously recorded from the two cells located on both sides of the homokaryon were identical. The fusion efficiency was remarkably dependent upon temperature, displaying a discontinuity at about 11°C in the Arrhenius plot. The extracellular application of phospholipase-A2 or-C suppressed the fusion yield. Thus, it appears that the phospholipid domains play a crucial role in the electric pulse-induced cell fusion. Treatment of the cells with proteolytic enzymes markedly enhanced the fusion yield, presumably due to removing the glycocalix and/or giving rise to fusion-potent, protein-free lipid domains. The presence of millimolar concentrations of divalent cations (irrespective of Mg2+ or Ca2+) as well as of micromolar concentrations of Ca2+ (but not Mg2+) was prerequisite to the resealing of membranes suffered from electrical breakdown upon exposure to electric pulses. In addition, extracellular Ca2+ (but not Mg2+) ions at more than micromolar concentrations were indispensable for the cell fusion.
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  • 85
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    The journal of membrane biology 86 (1985), S. 9-15 
    ISSN: 1432-1424
    Keywords: molluscan neurone ; patch voltage-clamp technique ; single Cl channel ; calcium ; potassium ; multiplicity of the condutance states
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary Properties of the single Cl− channels were studied in excised patches of surface membrane from molluscan neurones using single-channel recording technique. These channels are controlled by Ca2+ and K+ acting on cytoplasmic and outer membrane surfaces, respectively, and by the membrane potential. The channels display about 16 intermediate conductance sublevels, each of them being multiples of ∼12.5 pS. The upper level of the channel conductance is about 200 pS. The channel behavior is consistent with an aggregation of channel-forming subunits into a cluster.
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  • 86
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    The journal of membrane biology 83 (1985), S. 147-156 
    ISSN: 1432-1424
    Keywords: Exocytosis ; proton pump ; calcium ; secretion ; adrenal medulla
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary Calcium-dependent exocytosis in ‘leaky’ bovine adrenal medullary cells has a requirement for Mg-ATP. One possibility is that exocytosis depends in some way on the operation of the ATP-dependent proton pump that serves to maintain the core of the secretory vesicles both acid and at a positive potential with respect to the cytosol. This possibility has been tested in ‘leaky’ cells by monitoring exocytosis under conditions where the secretory vesicle pH and potential gradients are measuredin situ. The results show rather clearly that exocytosis can persist, with unchanged Ca-activation kinetics, in the virtual absence both of a difference in pH between the cytosol and secretory vesicle core and also of a difference in potential across the vesicle membrane. The results do not, however, exclude a small modulating effect of vesicle pH or potential on exocytosis and shed no light on whether or not the plasma membrane potential, which is maintained close to zero in these experiments, influences exocytosis.
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  • 87
    ISSN: 1432-1424
    Keywords: sodium/calcium exchange ; excitation-contraction coupling ; sarcolemma ; membrane potential ; sodium ; calcium ; heart
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary The effect of membrane potential on sodium-dependent calcium uptake by vesicles in an isolated cardiac sarcolemma preparation was examined. Initial time course studies showed that the reaction deviated from initial velocity conditions within minutes. This appeared to be due, in part, to loss of the sodium gradient. Assays carried out to 10 sec revealed a linear component of uptake (2 to 10 sec) and a faster component (complete by 2 sec). The latter was eliminated by loading the preparation with ethyleneglycol-bis-(β-aminoethyl ether)N,N′-tetraacetic acid (EGTA). This maneuver did not affect the slow component, and subsequent studies used preparations containing EGTA. Potassium Nernst potentials (E K), established by potassium gradients in the presence of valinomycin, were varied from −100 to +30 mV by changing [K+] o from 1.18 to 153.7mM ([K+] i =50mM). The initial velocity of sodium-dependent calcium uptake was stimulated twofold by changingE K from −100 to 0 mV and another twofold by raisingE K from 0 to +30 mV. For the total range ofE K and [K+] o , 32 to 36% of the increase appeared to reflect stimulation by extravesicular potassium. The remainder appeared to be due to membrane potential. The profile of sodium-dependent calcium uptake versusE K suggested that calcium influx through electrogenic sodium/calcium exchange may be much more affected by the positive region of the cardiac action potential than by the negative region.
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  • 88
    ISSN: 1432-1424
    Keywords: calcium ; rod photoreceptors ; surface potentials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary The nature of the Ca2+ buffer sites in intact rod outer segments isolated from bovine retinas (ROS) was investigated. The predominant Ca2+ buffer in intact ROS was found to be negatively charged groups confined to the surface of the disk membranes. Accordingly, Ca2+ buffering in ROS was strongly influenced by the electrostatic surface potential. The concentration of Ca2+ buffer sites was about 30mm, 80% of which were located at the membrane surface in the intradiskal space. A comparison with observations in model systems suggests that phosphatidylserine is the major Ca2+ buffer site in ROS. Protons and alkali cations could replace Ca2+ as mobile counterions for the fixed negatively charged groups. At physiological ionic strength, the total number of these diffusible, but osmotically inactive, counterions was as large as the number of osmotically active cations in ROS. The surface potential is dependent on the concentration of cations in ROS and can be measured with the optical dye neutral red. Addition of cations to the external solution led to the release of the internally bound dye as the cations crossed the outer membrane. The chemical and spectral properties of the dye enable its use as a real-time indicator of cation transport across the outer envelope of small particles in suspension. In this study, the dye method is illustrated by the use of well-defined ionophores in intact ROS and in liposomes. In the companion paper this method is used to describe the cation permeabilities native to ROS.
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  • 89
    ISSN: 1432-1424
    Keywords: surface charge ; potassium channel ; calcium ; phosphatidylserine ; planar bilayer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary A Ca-activated, K-selective channel from plasma membrane of rat skeletal muscle was studied in artificial lipid bilayers formed from either phosphatidylethanolamine (PE) or phosphatidylserine (PS). In PE, the single-channel conductance exhibited a complex dependence on symmetrical K+ concentration that could not be described by simple Michaelis-Menten saturation. At low K+ concentrations the channel conductance was higher in PS membranes, but approached the same conductance observed in PE above 0.4m KCl. At the same Ca2+ concentration and voltage, the probability of channel opening was significantly greater in PS than PE. The differences in the conduction and gating, observed in the two lipids, can be explained by the negative surface charge of PS compared to the neutral PE membrane. Model calculations of the expected concentrations of K+ and Ca2+ at various distances from a PS membrane surface, using Gouy-Chapman-Stern theory, suggest that the K+-conduction and Ca2+-activation sites sense a similar fraction of the surface potential, equivalent to the local electrostatic potential at a distance of 9 Å from the surface.
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  • 90
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Reversed-phase ; Codeine phosphate drug substance ; Opium alkaloids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary A rapid procedure for the evaluation of codeine phosphate drug substance derived from poppy straw or opium concentrate is described. The gradient HPLC procedure employs a pH 2.5 phosphate buffer, methanol and acetonitrile mobile phase at 40°C and a μBondapak C-18 column. Eight opium alkaloids, including the four major alkaloids, are separated from each other. The paper describes details of the assay procedure and presents data documenting the linearity, specificity, precision, and sensitivity of the method.
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  • 91
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; External variance determinations ; Column and system compatibility ; Microbore and fast LC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The demand for faster, more economic and convenient high-efficiency LC analyses has led to the development of microbore and fast columns. However, to utilize their benefits, the low column dispersions produced by these new technologies necessitate low external variances in the total system. This paper describes the determination of the external variance of microbore, fast and conventional LC systems by a column method. Compatibility with the relevant column technologies is evaluated by a method involving the comparison of the external and column dispersions. Direct comparison of chromatograms of an 8-component mixture, on a set of columns of various diameters and lengths, shows the relative speed, economy and sensitivity obtainable in practice. The problem of reduced sample loadability is considered and the practical solution of peak compression illustrated.
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  • 92
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Retention prediction system ; UV multichannel detector ; Polycyclic aromatic hydrocarbons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The retention prediction system assisted by a micro-computer coupled with an UV multichannel detector has been investigated in the separation of polycyclic aromatic hydrocarbons. The method offered very precise identification of components in NBS-SRM-1647 sample without any standard reference substances. It has been proven that the system makes very precise, non-pollutive and convenient environmental analysis possible.
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  • 93
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    Chromatographia 20 (1985), S. 313-322 
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Tetracyclines antibiotics ; Quantitation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The use of high-performance liquid chromatography (HPLC) for the identification and determination of tetracycline antibiotics is reviewed. HPLC chromatograms provide fast identification by retention time, tR, and precise quantitation by measurement of peak height or peak area. For separation of tetracycline compounds, most HPLC methods use reversed-phase C18 or C8 columns and UV detection. The HPLC solvent system should have a pH of about 6 to prevent steric changes in the tetracycline molecule. For accurate quantitation it is necessary to avoid tailing and this is accomplished by adding a zwitter ion to the solvent system. Methanol and acetonitrile are frequently used as organic modifiers in these solvent systems. In a single analysis, HPLC methods can be used to separate as many as nine or ten commercially used tetracycline compounds and to determine four to five tetracyclines in commercial tetracycline preparations or in biological fluids.
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  • 94
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Resolution of optical isomers ; Chiral column ; Pyrethroids ; Fenvalerate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The separation of the optical isomers of fenvalerate [cyano(3-phenoxyphenyl)methyl 2-(4-chlorophenyl)-3-methylbutyrate] has been carried out by high-performance liquid chromatography (HPLC) on a chiral column with (R)-N-3,5-dinitrobenzoyl-phenyl-glycine (DNBPG) covalently bonded on aminopropyl silica and eluted with mixtures of methanol, 2-propanol, and hexane. The system was applied to the analysis of Pydrin®, an emulsifiable concentrate formulation of fenvalerate, and to the residue analysis of fenvalerate in milk samples. For the analysis of Pydrin® the only requirement was the proper dilution of Pydrin® with hexane. For the analysis of residues in milk, fenvalerate was extracted with hexane after precipitating the milk proteins with acetonitrile and removing the precipitate by filtration; the hexane extract was concentrated to small volume and filtered before being analyzed by HPLC.
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  • 95
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    Chromatographia 20 (1985), S. 487-494 
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Size-exclusion chromatography ; Controlled-porosity glasses ; Boron-enriched glass surface ; Adsorptive properties
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Controlled-porosity glasses (CPG) are sieves for macromoleculars, very widely applied in chromatographic columns for the separation of polymers and biopolymers by means of size-exclusion chromatography (SEC) and affinity chromatography. This paper deals with the influence of the thermal treatment of CPG on the elution of polymers in SEC columns. The problem is examined for a few mobile phases and for glasses having different porosities. Additionally, the SEC results obtained are compared with the adsorption properties of the glases investigated.
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  • 96
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    Bulletin of experimental biology and medicine 99 (1985), S. 417-420 
    ISSN: 1573-8221
    Keywords: rat neuromuscular junction ; calcium ; tetanus toxin ; ouabain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 97
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    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 571-587 
    ISSN: 1573-8744
    Keywords: theophylline ; bioavailability ; variability in clearance ; siow-release preparations ; urinary metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Variability in an individual's clearance of theophylline is an important consideration when estimating bioavailability. A method is described for compensating for this problem, using the serum concentration of theophylline and urinary excretion data on its major metabolites to make an estimation of the clearance after oral administration using the intravenous dose as reference. The method is particularly useful for assessing the bioavailability of slow-release theophylline preparations.
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  • 98
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    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 73-92 
    ISSN: 1573-8744
    Keywords: pharmacokinetic theory ; venous equilibration (“well-stirred”) model ; compartment model ; linear pharmacokinetics ; nonlinear pharmacokinetics ; bioavailability ; intrinsic clearance ; liver blood flow ; clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The two-compartment model of Rowland et al.,(2) has been extended by replacing first order elimination with Michaelis-Menten elimination kinetics. All of the equations for steady-state concentrations and clearances for zero order (constant rate) input orally (into compartment #2) and intravenously (into compartment #1) are derived and reported. The steady-state concentration in compartment #1, following intravenous administration, is shown to be a nonlinear function of maximal velocity of metabolism, Vm,the Michaelis constant, Km,and liver blood flow, Q;and, following oral administration is dependent only upon Vm and Km and is independent of Q.However, oral bioavailability is a function of Vm, Km,and Q.The model allows physiologic pharmacokinetic interpretation of both linear and nonlinear data; and, together with simple modification of the model, can explain much observed pharmacokinetic data to date particularly for first-pass drugs. Future articles in the series will be concerned with single doses, evaluation of literature data in terms of the model, application of the theory in toxicology and in clinical pharmacokinetics and therapeutics.
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  • 99
    ISSN: 1573-5117
    Keywords: calcium ; bicarbonate ; sulphate ; acidity ; Rhine ; Rhone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Data on the chemical composition of the hard water rivers Rhine and Rhone, published elsewhere, are stored in a new data bank, RRQUE. In this paper the seasonal variation in pH and concentrations of calcium, bicarbonate and sulphate at 7 stations in the Rhine and 7 in the Rhone are described. The concentrations of calcium, bicarbonate and sulphate show important increases with increasing distance from the source. In both rivers acidification gradually occurs downstream and is thought to be caused by the decomposition of disposed organic matter. It is shown that the normal seasonal patterns of these 4 chemical variables are negated by anthropogenic effects.
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  • 100
    ISSN: 1573-5117
    Keywords: pH ; calcium ; bicarbonate ; sulphate ; Rhine ; Rhone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract In the hard water rivers Rhine and Rhone the quotient Ca/HCO3 is strongly related to the sulphate concentration and not to the pH. The relationship can be described (by least square analysis) for the Rhine: Ca/HCO3) = 0.70 + 0.5 (SO4), for the Rhone: (Ca/HCO3) = 0.85 + 0.43 (SO4). With a Teissier analysis (reduced major axis) a slope for both rivers of 0.58 has been found. These values equal the theoretically expected value of 0.5, when a solution of CaSO4 is added to a saturated solution of CaCO3. The source of the CaSO4 (gypsum) is thought to be natural in the Rhone and anthropogenic in the Rhine. Acidification of both rivers is probably the result of decomposition of disposed organic matter.
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