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  • Ultrastructure  (805)
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  • Springer  (895)
  • Institute of Physics
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  • 1975-1979  (467)
  • 1970-1974  (428)
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  • Springer  (895)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Calcified tissue international 10 (1972), S. 38-48 
    ISSN: 1432-0827
    Keywords: Bivalve ; Molluse ; Shell ; Carbonates ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé La technique du bombardement à l'aide d'ion d'argon est utilisée pour réduire l'épaisseur de la coquille de carbonate de calcium des bivalvesMytilus etMercenaria pour examen au microscope électronique par transmission et en diffraction électronique; une comparaison est réalisée à l'aide de répliques simples, servant de témoins. Les résultats obtenus confirment les études antérieures de répliques et de microscopie par balayage. De plus, une structure “aérée” est mise en évidence dans la coquille des aragonites, et surtout dans le nacre deMytilus. Cette structure est interprêtée comme un artefact induit par la chaleur, formé par l'inclusion d'eau et de matériel organique, interprétation qui concorde avec les études chimiques et de microscopie électronique.
    Abstract: Zusammenfassung Die Beschießung mit Argonionen wurde angewendet, um die Dicke von Calciumcarbonat-Schalen der zweischaligen MuschelnMytilus undMercenaria zu reduzieren. Diese Technik erlaubte die Ausführung von Transmissions-Elektronenmikroskopie und Elektronendiffraktion, wobei gleiche Proben nach einer bereits bestehenden Methode vorbereitet und als Kontrollen herangezogen wurden. Es wurden zusätzliche Resultate zu den Muschelstruktur-studien erhalten, welche früher publizierte Arbeiten unterstützen, die mit der Abklatschmethode und der Raster-Elektronenmikroskopie ausgeführt worden waren. Zusätzlich wurde eine „schaumartige” Struktur der Muschelaragoniten, besonders im Perlmutter vonMytilus, beobachtet. Da es sich um ein durch Hitze verursachtes Artefakt handelt, wird diese Struktur als Einschlüsse von Wasser und organischem Material interpretiert, was den Befunden von verschiedenen veröffentlichten chemischen und elektronenmikroskopischen Arbeiten entspricht.
    Notes: Abstract Use is made of the argon ion-bombardment technique to reduce the thickness of calcium carbonate shells of the bivalvesMytilus andMercenaria for transmission electron microscopy and electron diffraction, with comparison of single-stage replicas of similar specimens serving as controls. As an additional approach to shell structure studies, it gives results which support earlier published work with both replicas and scanning microscopy. In addition, a “frothy” structure is detected in the shell aragonites, especially inMytilus nacre. As a heat-induced artifact, it is interpreted as representing trapped water and organic material inclusions, an interpretation consistent with several published chemical and electron microscope studies.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Calcified tissue international 10 (1972), S. 216-222 
    ISSN: 1432-0827
    Keywords: Ultrastructure ; Callus ; Osteoclast ; Endocytosis ; Lysosomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé La bordure en brosse des ostéoclastes de cals de fractures de rats présente des plissements complexes de la membrane cytoplasmique formant des canaux étroits. L'absorption d'un produit exogène opaque aux électrons (des macromolécules de dioxyde de thorium) s'effectue par l'intermédiaire de ces canaux, par un «courant» membranaire. Les contenus des canaux sont transférés à des lysosomes («granules spécifiques»), situés sous la bordure en brosse. Dans des «régions de transition», adjacentes à cette dernière, l'absorption de dioxyde de thorium se fait par «vésiculation membranaire» (endocytose classique).
    Abstract: Zusammenfassung Der gekrauste Rand der Osteoklasten im Frakturcallus von Ratten besteht aus komplexen Einstülpungen der Plasmamembran, die enge Kanälchen bildet. Die Absorption einer exogenen, elektronisch dichten Verbindung, Thoriumdioxyd, erfolgt durch diese Kanäle, offenbar durch einen „Membranfluß”. Der Inhalt der Kanäle wird zu den Lysosomen („spezifische Granula”) geführt, welche unter dem gekrausten Rand liegen. In „Übergangsgebieten”, welche sich neben dem gekrausten Rand befinden, scheint die Aufnahme der Thoriumdioxydpartikel durch „Bläschenbildung in der Membran” (konventionelle Endocytose) stattzufinden.
    Notes: Abstract The ruffled border of osteoclasts in the fracture callus of rat consists of complex infoldings of the plasma membrane forming narrow channels. Absorption of an exogenous, electron-dense compound, thorium dioxide, has been shown to take place via these channels, apparently through “membrane flow”. The contents of the channels are transferred to lysosomes (“specific granules”) located subjacent to the ruffled border. In “transitional regions” adjacent to the ruffled border, uptake of thorium dioxide particles appeared to occur through “membrane vesiculation” (conventional endocytosis).
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  • 3
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    Springer
    Calcified tissue international 25 (1978), S. 145-159 
    ISSN: 1432-0827
    Keywords: Bird egg shell ; Ultrastructure ; Calcification ; Electron diffraction ; Microanalysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The egg-shell of Japanese quail was studied by several techniques. Semithin sections (1μm thick) of non-decalcified shell were observed by normal and polarized light microscopy. Thin sections of non-decalcified shell, examined by transmission electron microscopy, permitted us to observe the forms and dimensions of crystals of calcite within different layers of the shell: mammilary layer, layer of cones, palissade layer and surface crystal layer. There appears to be two distinct zones in the layer of cones as well as in the superficial crystal layer. Electron microdiffraction revealed the orientation of calcite crystals in the columns. Some crystal defects (twins?) were described and the possibility of their artefactual formation during ultramicrotomy is discussed. Localization of Ca, Mg, P and S were made by X-ray microanalysis of semithin sections. This technique shows that shell membranes, and chiefly the true cuticle, are also mineralized but, in these layers, minerals are not crystallized. Otherwise the distribution of Mg is not uniform throughout the shell thickness; it is less concentrated in the external zone of the layer of cones. These results together with observation of developing shells by scanning electron microscopy allowed us to propose a scheme for shell organization of the quail egg. This organization was related with decalcification which occurs during hatching.
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  • 4
    Electronic Resource
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    Springer
    Calcified tissue international 24 (1977), S. 215-222 
    ISSN: 1432-0827
    Keywords: Mineralization ; Osteodentin ; Intracellular ; Ultrastructure ; Microanalysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Newly formed osteodentin obtained from the anterior extremities of fetal or young rat incisors was observed by means of electron microscopy and electron probe X-ray microanalysis. Cells related to osteodentin formation frequently showed membrane bound intracellular bodies containing varying amounts of fine, needle-shaped crystals, which were identified as apatite. The intracellular clusters of apatite crystals were extruded from the cells through membrane fusion or cellular degeneration. These extracellular clusters seemed to be gradually incorporated into the mineralizing collagenous matrix, which developed around them. Frequent occurrence of dense, dotshaped or filamentous profiles suggested that the dense bodies seen in the perinuclear regions or in the Golgi area were the sites of crystal formation. Energy dispersive X-ray point analysis showed that the intracellular or extracellular apatite clusters contained sulfur in a concentration higher than was present in the mineralizing collagenous matrix. Furthermore, wave dispersive X-ray line analysis showed that the concentration of sulfur was higher in the osteodentin matrix than in the dentin matrix. The sulfur detected is presumed to be contained in acid mucopolysaccharides, which were distributed more heavily in the osteodentin matrix than in the dentin matrix. On the basis of these data, it was concluded that the unique chemical and structural characteristics of the osteodentin result primarily from the incorporation of apatite clusters of intracellular origin and associated acid mucopolysaccharides.
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  • 5
    ISSN: 1432-0827
    Keywords: Bone resorption ; Osteogenesis ; Fish bone ; Osteocytes ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The comparative ultrastructure of fish bone osteogenesis and resorption induced by scale removal was described in the osteocytic (cellular-boned)Carassius auratus and the anosteocytic (acellular-boned)Tilapia macrocephala. Osteocytes, present in osteocytic bone, were lacking in anosteocytic bone. In osteocytic bone the osteoblast secreted a collagenous preosseous matrix in which it became enmeshed and then was termed a preosteocyte. When the preosseous matrix mineralized, the preosteocyte was termed an osteocyte and was completely surrounded by bone. In anosteocytic bone the osteoblasts receded from the mineralizing front and never became trapped as osteocytes. During resorption, types A and B resorptive cells, present in both bone types, invaded the matrix and demineralized the osseous zone. These cells were characterized by large amounts of granular endoplasmic reticulum and intracellular inclusions containing crystal-like material. Although functionally similar to mammalian osteoclasts, these cells lacked a characteristic ruffled border and were not multinucleated. The osteocytes of cellular bone did not appear to be involved during demineralization.
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  • 6
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    Calcified tissue international 9 (1972), S. 296-309 
    ISSN: 1432-0827
    Keywords: Osteoclasts ; Enzyme ; Parathyroid ; Microdissection ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Une nouvelle méthode d'isolement d'ostéoclastes est mise au point pour des analyses biochimiques et de microscopie électronique. Pour isoler les cellules par microdissection, des empreintes d'os métaphysaire sont utilisées. Cette méthode, supérieure aux coupes d'os, permet une meilleure préservation cytologique et enzymatique et permet d'obtenir des cellules totales plus faciles à manipuler, avec des résultats plus reproductibles. Par analyse planimètrique de cellules isolées, colorées histochimiquement, il apparait que les ostéoclastes constituent plus de 90% de la masse de l'échantillon. Les concentrations de la phosphatase acide et de certaines enzymes, liées au nucléotide pyridinique, entrant dans le métabolisme de l'acide citrique, sont déterminées dans des échantillons d'ostéoclastes, pesant de 0,2 à 2,0 μg, isolés à partir de rats normaux et parathyroidectomisés. L'activité en aconitase, mesurée en direction de la transformation de citrate en isocitrate, est de 0,5–0,8 M/Kd/H, la plus faible des activités étudiées. Les activités en GDH et NADP-ICDH sont 5 à 10 fois supérieures que celle de l'aconitase, mais seulement un dixième à un tiers de celle de la phosphatase acide, de la déshydrogénase lactique ou malique.
    Abstract: Zusammenfassung Es wird eine neue Technik beschrieben, welche die Isolierung von Osteoklasten für biochemische und elektronenmikroskopische Untersuchungen ermöglicht. Als Ausgangsmaterial zur Zellisolierung wurden Abstriche von Metaphysenknochen benützt. Die Verwendung von Abstrichen bietet gegenüber Knochenschnitten wichtige Vorteile, wie z.B. eine bessere Erhaltung der cytologischen und enzymatischen Eigenschaften sowie die Gewinnung von unverletzten Zellen, welche leichter verarbeitet werden können und besser reproduzierbare Daten ergeben. Durch planimetrische Analyse der histochemisch gefärbten Ausstriche von isolierten Zellen konnte nachgewiesen werden, daß die Osteoklasten über 90% des gesamten Probenmaterials ausmachen. Die Mengen verschiedener Enzyme, welche an Pyridinnukleotid gebunden und am Citronensäuremetabolismus beteiligt sind, sowie der sauren Phosphatase wurden in Osteoklastenproben bestimmt, welche ein Gewicht von 0,2–2,0 μg hatten und aus Knochen von normalen und mit Parathyroidextrakten behandelten Ratten isoliert worden waren. Die Aktivität der Aconitase, welche in der Richtung von Citrat zu Isocitrat gemessen wurde, war mit 0,5–0,8 M/Kd/H die niedrigste aller untersuchten Aktivitäten. Die Aktivitäten der GDH und der NADP-ICDH waren 5–10mal höher als jene der Aconitase, entsprachen jedoch nur einem Zehntel bis einem Drittel derjenigen der sauren Phosphatase, der Laktat- oder der Malatdehydrogenase.
    Notes: Abstract A new method is described by which osteoclasts can be isolated for biochemical and electron microscopic analyses. As a source of cells for isolation by microdissection, imprints of metaphyseal bone were used. The use of imprints provides important advantages over bone sections, including a higher degree of cytologic and enzymatic preservation, and the delivery of whole cells which are more readily manipulated and which yield data that are more readily reproduced. By planimetric analysis of the histochemically-stained isolated cell samples, it was shown that osteoclasts represent over 90% of the sample mass. The levels of several of the pyridine nucleotide-linked enzymes involved in citric acid metabolism, as well as acid phosphatase, were determined in osteoclast samples weighing 0.2 to 2.0 μg isolated from normal and parathyroid-treated rats. Aconitase activity measured in the direction of citrate to isocitrate was 0.5–0.8 M/Kd/H, the lowest of the activities studied. The activities of GDH and NADP-ICDH were 5 to 10 times higher than that of aconitase but only a tenth to a third that of acid phosphatase, lactic or malic dehydrogenase.
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  • 7
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    Calcified tissue international 7 (1971), S. 191-200 
    ISSN: 1432-0827
    Keywords: Serpulid ; Polychaete ; Hydroxyapatite ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Un petit groupe de cellules épithéliales de la surface antérieure du col du serpulidePomatoceros caeruleus contient des vacuoles, remplies de matériel cristallin. Les cristaux présenttent des aspects rhomboédriques ou rectangulaires. La diffraction électronique montre qu'ils sont constitués par de l'hydroxyleapatite et du phosphate de calcium et de magnésium. Les apex des cellules sont bordés de microvillosités. Certaines cellules ont des cils apicaux. Un appareil de Golgi est visible dans le cytoplasme apical. De nombreuses mitochondries sont dissé minées dans le cytoplasme. Le role éventuel de ces cellules, a contenu minéral, dans la mise en réserve de calcium et/ou de phosphore est envisagé.
    Abstract: Zusammenfassung Ein kleiner Zellverband im Epithel der vorderen Oberfläche am Hals des SerpulidsPomatoceros caeruleus enthält membrangebundene Vakuolen, welche mit kristallinem Material gefüllt sind. Die Kristalle haben rhomboide oder rechteckige Formen; mittels Elektronendiffraktion konnte nachgewiesen werden, daß sie aus Hydroxyapatit und Calciummagnesiumphosphat bestehen. Die oberen Enden der Zellen sind von Microvilli eingefaßt. Einige der Zellen haben zudem apikale Zilien. Die Zellen enthalten Golgi-Apparate im apikalen Cytoplasma. Eine große Anzahl von Mitochondrien sind über das, ganze Cytoplasma verteilt. Die mögliche Funktion dieser mineralhaltigen Zellen als Aufbewahrungsorte für Calcium und/oder Phosphor wird besprochen.
    Notes: Abstract A small patch of cells in the epithelium of the anterior surface of the collar of the serpulidPomatoceros caeruleus contains membrane-bound vacuoles filled with crystalline material. The crystals have rhomboidal or rectangular profiles and have been shown by electron diffraction analysis to be composed of hydroxyapatite and calcium magnesium phosphate. The apices of the cells are bordered by microvilli. Some cells also have apical cilia. The cells contain Golgi complexes in the apical cytoplasm. Large numbers of mitochondria are distributed thoughout the cytoplasm. The possible function of these mineral-containing cells as sites for storage of calcium and/or phosphorus is discussed.
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  • 8
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    Mycopathologia 59 (1976), S. 117-123 
    ISSN: 1573-0832
    Keywords: Ultrastructure ; Zygospore ; Mycorrhizal fungus ; Flaming crown
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The ultrastructural organization of the spores of the sporocarp of Endogone flammicorona was studied. Two types of organization are described. Initially the spore possessed a vacuolate protoplasm and was bound by two cell wall layers. The spore was surrounded by a hyphal mantle formed of a sheet of vacuolized hyphae with uniformly thin walls. Secondly, although the ultrastructural features of the spore appeared the same, it was now surrounded by a hyphal mantle with unevenly thickened walls (i. e., the so-called flaming crown) due to the gradual and irregular deposition of granules and lamellae. This crown gives the spore its most commonly observed morphological feature and is the preminent character employed taxonomically to speciate Endogone flammicorona Trappe & Gerdemann.
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  • 9
    ISSN: 1432-041X
    Keywords: Ultrastructure ; Scanning cytophotometry ; Chromatin ; Chondrocytes ; Regeneration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Les cellules cartilagineuses des membres postérieurs deTriturus cristatus en régénération après amputation, ont été étudiées en microscopie électronique et par cytophotométrie à balayage. Nous nous sommes intéressés à la structure et à la distribution de la chromatine mais aussi à différents organites cytoplasmiques. Dans l'étude de cytophotométrie à balayage, la chromatine a été considérée à travers son constituant majeur, l'ADN, coloré par la réaction de Feulgen. Au cours de la régénération du membre, l'hétérochromatine initialement condensée, essentiellement accolée à la membrane nucléaire se décondense. Les vacuoles du cytoplasme, caractéristiques des animaux âgés par rapport aux animaux jeunes, disparaissent, les mitochondries et le reticulum endoplasmique rugueux deviennent plus abondants. Les caractéristiques nucléaires de l'activation cellulaire apparaissent précocement, précédent les modifications cytoplasmiques et conduisent à des cellules en tous points identiques aux cellules d'animaux jeunes en dehors de tout processus régénératif. Cette phase d'euchromatisation et de restructuration cytoplasmique est peut-être nécessaire à l'accroissement d'activité métabolique et à la division cellulaire qui suivent. Son déroulement peut expliquer tout au moins le ralentissement de la régénération observé chez les animaux âgés par rapport aux animaux jeunes.
    Notes: Summary Cartilaginous cells of aged newts (Triturus cristatus) were studied during hind limb regeneration. The electron microscope was used to study the structure and distribution of chromatin in the cell nuclei, while the DNA content of the chromatin was measured by means of a scanning cytophotometer. Changes in the ultrastructure of the cytoplasm during regeneration were also studied. It was observed that the structure and distribution of chromatin in the activated cell is greatly modified. In the non-activated cell of the aged newt, the chromatin is found highly condensed and distributed peripherally close to the nuclear membrane. In contrast, in the activated cells, the chromatin is much less condensed and is distributed throughout the nucleus. Moreover, cytoplasmic vacuoles, found only in the non-activated aged cells, disappear and an increase in the mitochondria and rough endoplasmic reticulum is also observed. Changes in the nuclear structure are observed prior to the cytoplasmic modifications. It is interesting to note that the process of activation induces structural changes in the aged cells which make these cells appear to be structurally identical to the young cells. This process of rejuvenation takes 3–5 days in the newt. We suggest that these structural changes of the chromatin and cytoplasm in the aged cells are necessary to increase the metabolic activity which precedes cell division. It may also explain why regeneration takes a longer time in the aged animals than in the young ones.
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  • 10
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    Development genes and evolution 183 (1977), S. 233-248 
    ISSN: 1432-041X
    Keywords: Cytoplasmic architecture ; Ultrastructure ; Insect egg ; Pattern formation ; Yolk ; Cytoplasma-Architektur ; Ultrastruktur ; Insekten-Ei ; Musterbildung ; Dotter
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung 1. Das Ei der ZuckmückeSmittia spec. wurde licht- und elektronenmikroskopisch untersucht. Die vorliegende Arbeit beschreibt den Bau des Periplasmas und des Dotter-Endoplasma-Systems vor Bildung der Polzellen. 2. Das Periplasma, nach außen vom Oolemm und einer mehrschichtigen Eihülle begrenzt, besteht aus einer ribosomenreichen cytoplasmatischen Matrix, in die vor allem Mitochondrien und ER-Zisternen, wenig annulate lamellae und gelegentlich Golgi-Apparate eingelagert sind. Mikrotubuli wurden nur selten nachgewiesen. Öfters sind Anhäufungen einer dichten granulierten Substanz zu beobachten, die in ihrer Struktur dem Oosom-Material ähnelt. 3. Das Dotter-Endoplasma-System stellt ein Netzwerk aus Cytoplasma dar, in das Proteid-Dotterkugeln, Lipidtröpfchen sowie Glycogen-Anhäufungen eingelagert sind. Das Endoplasma, das sich zu 3–7 Plasma-Inseln erweitern kann und unmittelbar in das Periplasma übergeht, besteht wie dieses aus einer cytoplasmatischen Matrix und enthält die gleichen Zellelemente wie das Periplasma. Rosettenförmige Membran-Strukturen werden als “nuclear envelope organizing center” gedeutet. 4. Drei der sorgfältig analysierten Eier enthielten je 2 Kerne; sie lagen in Plasma-Inseln in der hinteren Eihälfte. 5. Sowohl im Periplasma wie im Dotter-Endoplasma-System sind alle Zellelemente unregelmäßig verteilt. Eine besondere Anordnung oder Zonierung ist nicht zu erkennen. 6. Die räumliche Verteilung der erfaßten Eikomponenten liefert keine Hinweise auf eine Funktion dieser Komponenten als Determinanten für die embryonale Musterbildung.
    Notes: Summary 1. Eggs of the midgeSmittia were investigated by light microscopy and transmission electron microscopy. This paper describes elements and architecture of periplasm and yolk endoplasm before the formation of pole cells. 2. The periplasm is coated externally by the oolemma and a multilayered egg shell. The periplasm consists of a cytoplasmic matrix rich in ribosomes; it contains mitochondria and ER cisternae, some annulate lamellae and an occasional Golgi complex. Microtubuli were demonstrated only rarely. Accumulations of a dense granulated substance resembling in its structure the oosome material were frequently observed. 3. The yolk endoplasm is a cytoplasmic network embodying proteid yolk particles, lipid droplets and accumulations of glycogen. The endoplasm is continuous with the periplasm and shows the same cell constituents. It may form between 3 and 7 cytoplasmic islands free of yolk particles. Rosette-shaped membranous structures in the yolk endoplasm are interpreted as nuclear envelope organizing centres. 4. Three carefully analysed eggs contained 2 nuclei each. both nuclei were situated in the posterior egg half. 5. Periplasm and yolk endoplasm are characterized by random distribution of cell elements. No zonation or special accumulations could be recognized. 6. The spatial distribution of the egg components studied did not indicate that any of these components could function as a determinant in embryonic pattern formation.
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  • 11
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    Development genes and evolution 181 (1977), S. 333-355 
    ISSN: 1432-041X
    Keywords: Barnacle eggs ; Constriction rings ; Microfilaments ; Ultrastructure ; Peristalsis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary 1. The egg ofPollicipes polymerus, the common intertidal gooseneck barnacle, has been studied by electron microscopy. Constriction rings, similar to the contractile rings of cleaving cells and polar lobes, move unidirectionally from the animal to the vegetal pole of newly fertilized eggs. This is referred to as peristaltic constriction. The present paper describes the fine structure of the egg during first polar body formation and peristalsis. 2. During formation of the polar body, dense bodies are produced by the Golgi and extracellular plaques are observed. Thin microfilaments (40–60 Å) are in the egg adjacent to the polar body. 3. In eggs undergoing peristalsis, the appearance of extracellular spheres, flocculent material and filaments is observed. Intracellularly large numbers of multivesiculate bodies, glycogen granules, mitochondria and protein-carbohydrate and lipid yolk bodies are seen at the level of constriction. 4. Thin microfilaments are found in the cortical area of newly-fertilized eggs exclusively in peristaltic constriction rings. Filaments are oriented primarily in a meshwork, although circumferentially-oriented filaments are also found in rings near the vegetal pole. Microvilli extend into the space created between a constriction and the elevated egg membrane. 5. A model is proposed to explain the peristalsis in this species. It is suggested that information from a pacemaker region activates peristalsis by affecting filament polymerization and orientation. One function of peristalsis may be elongation of the egg from a sphere to an ovoid, although other possibilities such as elevation of the egg membrane, segregation of the lipid yolk to the vegetal pole and predetermination of the first cleavage plane are also discussed.
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  • 12
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    Development genes and evolution 186 (1979), S. 65-70 
    ISSN: 1432-041X
    Keywords: Sea urchin ; Embryo ; Collagen ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Collagen fibrils with a main period banding of 610 Å and 220 Å in width were observed in the blastocoel of 72-h embryos of the sea urchin,Strongylocentrotus purpuratus. Non-striated fibrils of 50 Å diameter were also observed. The collagen is seen in highest concentration in the vicinity of mesenchyme cells which are richly endowed with endoplasmic reticulum and secretory vesicles. A role for collagen in cell attachment, orientation and spicule formation is discussed.
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  • 13
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    Development genes and evolution 185 (1978), S. 235-248 
    ISSN: 1432-041X
    Keywords: Liver ; Primary culture ; Ultrastructure ; Albumin synthesis ; Xenopus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Electron microscopic analysis of primary cultures derived from larvalXenopus liver has shown that these cells, although they form only two-dimensional aggregates, retain and presumably also develop structural characteristics typical of liver parenchyma cells, such as bile canaliculi with microvilli and epithelial junctional complexes. As judged from structural criteria, primary cultures contain 80–90% hepatocytes. In contrast to the intact tissue, primary cultures showed excessive development of microfilaments, however. Incorporation of labeled amino acids has revealed further that the capacity for protein synthesis is maintained in culture and that synthesis of liverspecific protein albumin is maintained in vitro, even in liver cultures derived from thyrostatic tadpoles. This latter result suggests that initiation of albumin synthesis in the larval liver is probably not dependent upon thyroid hormones but rather reflects the protodifferentiated state of this tissue.
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  • 14
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    Development genes and evolution 185 (1979), S. 333-346 
    ISSN: 1432-041X
    Keywords: Chick embryo ; Limb bud ; Ultrastructure ; Cell death
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The ultrastructural changes in the wing bud afterapical ectodermal ridge (A.E.R.) removal was studied to re-examine the issue of distal mesenchymal cell death. The A.E.R. of the right wing bud was removed microsurgically from chick embryos of stages 18 to 22 (HH 1951). The wing buds were examined at three hour intervals up to twelve hours after the operation with light, transmission and scanning electron microscopy. The main findings were: (1) Immediate and temporary shrinkage of the mesenchymal extracellular space 100 to 150 μm and chromatin condensation in the cells 50 to 75 μm from the wound. (2) Death of ectodermal and mesenchymal cells in the immediate vicinity of the wound. (3) Formation of a single squamous-like layer of mesenchymal cells to cover the wound. (4) Occasional evidence of cell death in the distal mesenchyme at later times after the operation. The pattern of cell death observed suggests only a traumatic etiology, and gives little evidence for the postulated developmental significance of cell death following A.E.R. removal.
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  • 15
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    Calcified tissue international 13 (1973), S. 83-92 
    ISSN: 1432-0827
    Keywords: Proteoglycan ; Collagen ; Cartilage ; Electron Microscopy ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé L'élimination de protéoglycans solubles de coupes de cartilage costal de boeuf, par extraction dans une solution de 4M d'hydrochlorure de guanidinium, permet de mettre en évidence des quantités abondantes de collagène dispersé et désagrégé dans la matrice. Les protéoglycanes, résistants à l'extraction, sont visibles sous forme de granules concentrés dans les régions périlacunaires. Les granulations plus importants des protéoglycanes semblent venir du chondrocyte. Dans la matrice, éloignée des chondrocytes, ces granules deviennent plus étroites. Un composant non granulaire “amorphe” masque les fibres de collagène, de telle sorte qu'elles sont difficilement visibles dans le cartilage intact.
    Abstract: Zusammenfassung Die löslichen Proteoglycane wurden mittels Extraktion in 4 M Guanidinhydrochlorid aus Rippenknorpelschnitten des Rindes entfernt. Dies erlaubte die Sichtbarmachung von großen Mengen von verstreuten und auseinandergerissenen Collagen in der Matrix. Die Protoglycane, welche sich nicht extrahieren lassen, erscheinen als kleine, in den perilacunären Regionen konzentrierte Körnchen. Die großen Proteoglycan-Körner scheinen in den Chondrocyten zu entstehen. Sobald sie sich in die Matrix, außerhalb der Chondrocyten, verlagern, werden die Körner kleiner. Ein nicht-granulärer, „amorpher” Bestandteil verhüllt die Collagenfasern, so daß diese im intakten Knorpel nicht deutlich gesehen werden können.
    Notes: Abstract Removal of the soluble proteoglycans from slices of bovine costal cartilage by extraction in 4 M guanidinium hydrochloride permitted the visualization of abundant amounts of dispersed and disaggregated collagen in the matrix. Proteoglycans which are resistant to extraction are seen as small granules which are concentrated in the perilacunar regions. Large proteoglycan granules appear to originate in the chondrocyte. As they come to occupy positions in the matrix distant from the chondrocyte, the granules become smaller. A non-granular, “amorphous” component masks the collagen fibers so that they cannot be readily seen in the intact cartilage.
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  • 16
    ISSN: 1432-0827
    Keywords: Shell formation ; Free nerve endings ; Ultrastructure ; Lymnaea stagnalis ; Biomphalaria pfeifferi
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The mantle edge of the freshwater pulmonate snailsLymnaea stagnalis andBiomphalaria pfeifferi was investigated with histochemical and ultrastructural methods. The mantle edge gland, which is involved in shell formation, consists of the periostracal groove and the belt. This belt appears to be composed of various regions. In the area of the periostracal groove a number of subepithelial gland cell types occur; these release their products into the groove. Between the groove cells ciliated free nerve endings terminate; the corresponding perikarya occur in the subepidermal connective tissue. Also in the posterior belt region free nerve endings were observed between the epithelial cells; in addition, a particular type of subepithelial gland cell was found in this area. The epithelial cells of this part of the belt have the ultrastructural characteristics of ion and water transporting cells; they are probably involved in calcium deposition and resorption. The possible role of the free nerve endings and of the subepithelial gland cells is discussed.
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  • 17
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    Calcified tissue international 7 (1971), S. 139-149 
    ISSN: 1432-0827
    Keywords: Bone ; Cartilage ; Estrogen ; Ultrastructure ; Growth
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Dix rats Holtzman mâles et sevrés sont sacrifiés injection intrapéritonéale d'oestradiol (Progynon, Schering) aqueux, à des doses quotiediennes de 1 μ g. par g de poids. Des témoins, ayant reçu une dose équivalente de liquide de dilution, sont sacrifiés à des intervalles de 1 heure à 6 jours, identiques aux temps de sacrifice des animaux injectés. Les cartilages épiphysaires supérieurs des tibias tibias (ECP) étudiés en microscopie électronique, montrent, dès trois heures après l'ionjection, une augmentation nette de 'activié sécrétoire, caractérisée, au niveau de la zone de sécrétion matricielle, par l'abondance dans les citernes golgiennes d'un matériel piqueté, constitué par des complexes protéino-polysaccharidiques. La désintégration de la membrane limitante de vésicules golgiennes individuelles est plus avancée après vingt quatre heures: après trois jours de traitement, seules quelques vésicules restent intactes et des plages d'un matériel initialement intravacuolaire sont visibles dans le cytoplasme. De longs filaments, rappelant les précurseurs ou les fibrilles primaires du collagène, sont visibles dans cette sécrétion. Après six jours, de grandes plages de cettre subestance remplissent les cellules de la couche pré-hypertrophieque, avec déplacement de l'ergastoplasme en périphérie. Des vacuoles cytoplasques, contenant un matériel semblable à celui qu'on retrouve dans la lacune, et présentant des filament finement moniliformes et disposés en rayons le long de la membrane limitante, sont visibles. Ces observations suggèrent une accélération initiale de l'activité sécrétoire chondrocytaire, suivie par un retard de transfert. La rétention consécutive et la polymérisation intracellulaire de produits précollagéniques accélèrent l'hypertrophie et favorisent ainsi la dégénérescence précoce des chondrocytes. Ces altérations ultrastructurales paraissent être spécifiques aux oestrog`enes.
    Abstract: Zusammenfassung Zehn männliche Hotlzmann-Ratten, die im Entwöhnungsstadium waren, erhielten täglich wässerige Oestradioldosen (Progynon, Schering) von 1 μ/g Körpergewicht i.p. Dann wurden sie gleichzeitig mit Kontrolltieren, welche die gleiche Menge Verdünnungsmittel erhalten hatten, in Intervallen von 1 Std bis zu 6 Tagen getötet. Platten des oberen tibialen Epiphysenknorples (ECP), welche für die Elektronenmikroskopie präpariert wurden, zeigtem, daß schon 3 Std nach der Injektion ein bemerkenswerte Erhöhung der sekretorischen Tätigkeit entsteht. Dies wurde in der Zone der Matrixausscheidung sichtbar, wo sich in den Golgi-Zisternen eine Anhäufung von punktiertem, aus Proteinpolysaccharid-Komplexen bestehendem Material zeigte. Der Zerfall der Membran, welche die einzelnen Golgi-Bläschen umgibt, nahm nach 24 Std zu; nach 3 Tagen Behandlung blieben nur wenige Gefäße intakt, und Ansammlungen von ursprünglich intravacuolörem Material konnten im Grundplasma beobachtet werden. Lange Fasern, welche auf primäre oder Prae-Kollagefibrillen hindeuteten, konnten in diesem Sekret gesehen werden. Nach 6 Tagen wurden die Zellen in der prähypertrophen Zone mit dieser Substanz richtiggehend überschwemmt, und das rauhe endoplasmatische Reticulum wurde anschließend gegen die Zellperipherie verlagert. Die oft beobachteten cytoplasmatischen Vacuolen enthielten ein Material, das dem in den Lacunen vorkommenden ähnlich ist und zeigten auf der ungebrenden Membran feinperlige, radial angeordnete Fasern. Unsere Beobachtungen deuten auf eine anfängliche Beschleuning der chondrocytischen sekretorischen Tätigkeit, mit nachfolgender Transportverlangsamung, hin. Die dadurch entstehende Retention und intrazelluläre Polymerisation von präkollagenen Produkten beschleunigt die Hypertrophie und begünstigt dadurch die frühe Degeneration von Chondrocyten. Diese ultrastrukturellen Veränderungen scheinen oestrogen-spezifisch zu sein.
    Notes: Abstract Ten male weanling Holtzman rats, injected intraperitoneally with aqueous estradiol (Progynon, Schering), in daily doses of 1 μg. per g body weight, were sacrificed, simultaneously with controls receiving an equivalent amount of diluent, at intervals ranging from one hour to six days. Upper tibial epiphyseal cartilage plates (ECP), procesed for electron microscopy, revealed, as early as three hours after injection, appreciable enhancement of secretory activity, evidenced, in the zone of matrix secretion, by the abundance in Golgi cisternae of stippled material representing proteinpolysaccharide complexes. Disintegration of the lining membrane of individual Golgi vesicles was advanced after twenty-four hours; following three days of treatment, few vesicles remained intact, and pools of initially intravacuolar material were observable in the gound plasm. Long filaments, suggestive of primary or precursor collagen fibrils were apparent in this secretion. After six days, virtual lakes of this substance filled cells in the zone of prehypertophy, with consequent displacement of the rough endoplasmic reticulum against the cell periphery. Cytoplasmic vacuoles, containing mateerial similar to that found in the lacunar moat, and displaying finely beaded, radially arrayed filaments on the lining membrane were frequently encountered. Our observations suggest an initial acclleration of chondrocytic secretory activity, with subsequent retardation of transport. The resultant retention and intracellular polymerization of precollagenous products accelerates hypertrophy, thereby promoting early degeneration of chondrocytes. These ultrastructural alterations are apparently estrogen-specific.
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  • 18
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    Calcified tissue international 5 (1970), S. 1-12 
    ISSN: 1432-0827
    Keywords: Periostracum ; Gastropod ; Shell ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Des glandes dorsales et ventrales, composées de larges cellules piriformes, situées à la périphérie de la paroi deLittorina, donnent respectivement naissance aux couches interne et externe du periostracum. Le matériel composant ce dernier provient de granules de sécrétion, élaborées au niveau de l'appareil de Golgi. Lorsque les granules golgiennes de la glande ventrale, contenant une substance, présentant une périodicité, déversent leur sécrétion en surface, en contact avec l'eau de mer, ce produit se disperse en particules, incluses dans un substrat. La formation du periostracum externe s'accompagne d'une réagrégation des particules sécrétoires golgiennes en une couche mince, présentant une structure périodique de 300 Å. En coupe transversale, le périostracum présente une structure régulièrement agencée, suggérant une nature cristalline. La couche externe atteint une épaisseur de 4–5 microns. La couche interne provient de granules de sécrétion de la glande dorsale. La formation de cette couche est identique à celle de la couche externe; cependant aucune périodicité n'y est visible. A l'état adulte, elle atteint une épaisseur de 0.4–0.5 micron. Outre son rôle de protection, le périostracum constitue une barrière entre l'eau de mer et l'espace pallial. Il est responsable, en outre, du dépôt et de l'orientation de cristaux inorganiques au niveau de la zone de développement de la carapace.
    Abstract: Zusammenfassung Eine dorsale und eine ventrale Drüse, die aus großen, kolbenförmigen Zellen bestehen und am Rande des Mantels vonLittorina gelagert sind, bewirken die Bildung der inneren und äußeren Schicht des Periostracums. Das entstandene Material, Periostracum inbegriffen, stammt von sekretorischen Granula, die vom Golgi-Apparat gebildet werden. Die Golgi-Granula bestehen aus einer Substanz, welche eine bestimmte Periodizität aufweist. Wenn nun die Golgi-Granula der ventralen Drüse an der Drüsenoberfläche erscheinen und mit Meerwasser in Kontakt kommen, sind sie weit verteilt und setzen sich aus Partikeln, die in ein Substrat eingebettet sind, zusammen. Die Bildung des äußeren Periostracums hat eine erneute Aggregation der sekretorischen Golgi-Partikeln zu einem dichten Blatt zur Folge, welches eine Periodizität von 300 Å zeigt. Betrachtet man das Periostracum in einem transversalen Schnitt, so findet man eine Gitterstruktur, die an eine kristalline Substanz denken läßt. Die äußere Schicht erreicht schließlich eine Dicke von 4–5 μ. Die innere Schicht entsteht durch die sekretorischen Granula der dorsalen Drüse. Die Bildung der inneren Schicht findet in ähnlicher Weise wie jene der äußeren statt, zeigt jedoch keine Periodizität. Im reifen Zustand erreicht sie eine Dicke von 0,4–0,5 μ. Zusätzlich zur Schutzfunktion bildet das Periostracum eine Schranke zwischen dem Meerwasser und dem Pallialraum; es reguliert zudem die Lage und die Anordnung der anorganischen Kristallbildung am Wachstumsrand der Muschel.
    Notes: Abstract A dorsal and ventral gland composed of large, flask-shaped cells located in the margin of the mantle ofLittorina give rise to the inner and outer layers of the periostracum respectively. The material comprising the periostracum is derived from secretory granules elaborated by the Golgi apparatus. When the Golgi granules of the ventral gland which consist of a substance exhibiting a definite periodicity, are discharged at the surface in contact with sea water, they are widely dispersed and consist of particles embedded in a substrate. Formation of the outer periostracum involves the re-aggregation of the Golgi secretory particles into a dense sheet which exhibits a periodicity of 300 Å. Viewed in transverse section the periostracum exhibits a lattice pattern suggestive of a crystalline substance. The outer layer eventually reaches a thickness of 4–5 μ. The inner layer is derived from the secretory granules of the dorsal gland. The formation of the inner layer occurs in a manner similar to that of the outer layer. It does not, however, exhibit a periodicity. In the mature state it attains a thickness of 0.4–0.5 μ. In addition to a protective function the periostracum provides a barrier between the sea water and the pallial space and also regulates the site and arrangement of mineral crystal formation at the growing margin of the shell.
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  • 19
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    Calcified tissue international 5 (1970), S. 270-276 
    ISSN: 1432-0827
    Keywords: Ultrastructure ; Cartilage ; Calcification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Une solution de sulfate de chrome est utilisée à la fois comme fixateur, colorant et agent de déminéralisation pour l'étude ultrastructurale de cartilage, en voie de minéralisation. Cette technique permet de mettre en évidence un “fantôme cristallin” organique, en rapport avec chaque cristal. L'intérêt du sulfate de chrome comme agent de déminéralisation est souligné.
    Abstract: Zusammenfassung Bei Ultrastrukturuntersuchungen von mineralisierendem Knorpel wurde eine Chromsulfatlösung als Agens zur kombinierten Fixation, Färbung und Demineralisierung verwendet. Diese Technik zeigte das Vorhandensein eines organischen “Kristallschattens”, der jedem Kriställchen zugehört. Die Tauglichkeit von Chromsulfat als demineralisierendes Agens wird besprochen.
    Notes: Abstract A solution of chromium sulphate was used as a combined fixative, stain and demineralizing agent for the ultrastructural study of mineralizing cartilage. This technique revealed the presence of an organic ‘crystal ghost’ associated with each crystallite. The effectiveness of chromium sulphate as a demineralizing agent is discussed.
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  • 20
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    Calcified tissue international 7 (1971), S. 12-22 
    ISSN: 1432-0827
    Keywords: Bone ; Cartilage ; Testosterone ; Ultrastructure ; Growth
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Bien que la clinique et l'expérimentation semblent démontrer que des doses élevées de testostérone provoquent un arrêt prématuré de la croissance, le mécanisme exact et le lieu précis de son action sur l'appareil de croissance des os longs restent indéterminés. Au cours de cette étude, des rats máles de 200 g sont injectés à l'aide de doses supra-physiologiques de testostérone pour observer les effects sub-microscopiques sur les diverses zones du cartilage épiphysaire. Au niveau de la zone de division cellulaire, on note une augmentation des cellules en division. Les cellules, en voie de maturation, présentent plus de produits de sécrétion, à un stade plus précoce de leur cycle d'évolution, et semblent subir une hypertrophie plus rapide. Dans la zone pré-hypertrophique, la matrice intercellulaire présente des foyers de calcification précoce, ainsi que des fibres collagènes plus longues et plus épaisses que chez les témoins. Il apparait que, chez l'animal entier, des doses même élevées de testostérone provoquent initialement une stimulation de la prolifération chondrocytaire, avant de favoriser les processus de maturation.
    Abstract: Zusammenfassung Obwohl experimentelle und klinische Erfahrung darauf hinweisen, daß hohe Dosen von Testosteron zu einem frühzeitigen Wachstumsabschluß führen, sind der genaue Mechanismus und der eigentliche Wirkungsort dieses Hormons im Wachstumsapparat der Röhrenknochen unbekannt geblieben. In diesem Experiment wurden 200 g schweren männlichen Ratten supraphysiologische Testosterondosen injiziert, um die submikroskopischen Auswirkungen auf die verschiedenen Zonen des Epiphysenknorpels zu beobachten. In der Zone der Zellmitosen fand sich eine erhöhte Anzahl von sich teilenden Zellen. Die reifenden Zellen häuften im Frühstadium ihres Lebenscyclus größere Mengen von Sekretionsprodukten an und schienen eine abruptere Hypertrophie durchzumachen. In der prähypertrophen Zone enthielt die interterritoriale Matrix Herde von früher und verfrühter Verkalkung, sowie dickere und längere Kollagenfasern als vergleichsweise in Kontrolltieren. Daraus wird geschlossen, daß bei unbehandelten Tieren sogar große Testosterondosen anfänglich eine Stimulation der Chondrocytenproliferation verursachen, bevor sie die Reifungsprozesse veranlassen.
    Notes: Abstract Although experimental and clinical experience indicates that large doses of testosterone lead to premature cessation of growth, the exact mechanism and precise site of action of this hormone on the growth apparatus of long bones remain unknown. In this study, plateaued male rats were injected with supraphysiologic doses of testosterone to observe the submicroscopic effects on the various zones of the epiphyseal cartilage. In the zone of cell division there were increased numbers of dividing cells. The maturing cells accumulated larger amounts of secretory products at earlier stages of their life cycle, and appeared to undergo a more abrupt hypertrophy. In the zone of prehypertrophy, the interterritorial matrix contained foci of early and premature calcification and thicker and longer collagen fibers than at comparable levels in controls. It is concluded that in intact animals, even large doses of testosterone initially cause a stimulation of chondrocyte proliferation, prior to promoting maturation processes.
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  • 21
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    Calcified tissue international 7 (1971), S. 31-45 
    ISSN: 1432-0827
    Keywords: Prism ; Crystals ; Growth ; Shell ; Formation ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Le début des prismes est visible au niveau de la région proximale de la surface externe du repli périphérique externe dans l'espace palléal, limité extérieurement par la périostracum. Le premier stade de formation d'un prisme est identique à celui observé dans la formation du nacre, à savoir l'élaboration d'une lamelle dense aux électrons qui sert de limite interne au futur prisme. Les fragments de lamelles se détachent et migrent vers un espace bordé extérieurement par le periostracum. Ces fragments lamellaires forment des enveloppes, au niveau desquelles on observe le dépôt initial et la croissance des cristaux. En même temps, on voit apparaitre des parois interprismatiques nettes, qui dérivent aussi des lamelles. La croissance de nouveaux cristaux et d'éléments organiques donne finalement un prisme adulte allongé. La croissance de la coquille se fait en périphérie, surtout par formation de nouveaux prismes. En outre, un environnement modifié, qui consiste en un dédoublement du periostracum au niveau de la surface distale, donne naissance à des ilôts étroits, contenant des prismes, qui se forment sur les bords de l'espace produit par la courbe du periostracum.
    Abstract: Zusammenfassung Die Prismenbildung beginnt in der proximalen Region der äußeren Oberfläche der äußeren Mantelfalte in Pallialraum, der gegen außen durch das Periostracum begrenzt wird. Der erste Schritt bei einer Prismenbildung verläuft gleich, wie dies bei der Perlmutterbildung beobachtet werden kann, nämlich in Form der Ausarbeitung einer elektronenoptisch dichten Lamelle, welche als innere Begrenzung des zukünftigen Prismas dient. Fragmente der Lamelle werden abgetrennt und wandern zu einem Zwischenraum, der gegen außen durch das Periostracum abgeschlossen wird. Diese Lamellenfragmente bilden Hüllen, innerhalb welcher der Kristall entsteht und sein Wachstum stattfindet. Gleichzeitig bilden sich dicke, zwischen den Prismen liegende Wände, die ebenfalls von den Lamellen abstammen. Das aus der Bildung zusätzlicher Kristalle bestehende Wachstum, zusammen mit den organischen Komponenten, läßt schließlich das reife längliche Prisma entstehen. Das Wachstum der Muschel spielt sich am Rande hauptsächlich durch Bildung neuer Prismen ab. Durch eine Veränderung der Umgebung, bestehend aus einer Verdoppelung des Periostracums an der distalen Oberfläche, entstehen zusätzlich dünne, prismenhaltige Sporne, welche innerhalb des begrenzten Raumes vorkommen, der sich durch das Überschlagen des Periostracums bildet.
    Notes: Abstract The initiation of prisms occurs in the proximal region of the outer surface of the outer mantle fold in the pallial space bounded externally by the periostracum. The first step in the formation of a prism is similar to that observed in the formation of nacre, namely, the elaboration of an electron-dense lamella that serves as the internal boundary of the future prism. Fragments of the lamella become detached and migrate to a chamber bounded externally by the periostracum. These lamellar fragments form envelopes within which crystal initiation and growth oocur. At the same time stout interprismatic walls appear. They are also derived from the lamellae. Growth consisting of the formation of additional crystals and the organic components finally give rise to the mature elongated prism. Growth of the shell occurs at the margin chiefly by formation of new prisms in this area. In addition a modified environment consisting of duplicature of the periostracum on the distal surface results in the formation of thin spurs containing prisms that occur within the confines of the space created by the periostracal loop.
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  • 22
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    Calcified tissue international 15 (1974), S. 201-212 
    ISSN: 1432-0827
    Keywords: Ultrastructure ; Alkaline Phosphatase ; Calcification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Des cals expérimentaux de neuf jours, formés au niveau de radius de jeunes rats, sont traités par la méthode calcium-cobalt de Gomori (1939) pour la mise en évidence ultrastructurale de la phosphatase alcaline afin d'étudier son rôle éventuel dans le dépôt du calcium. L'activité enzymatique apparait initialement sous forme de précipités globulaires en dehors de la membrane cellulaire de jeunes chondroblastes hypertrophiques. Ce précipité donne ensuite naissance à des corps sphériques de phosphatase alcaline qui se forme près de la cellule. Ces corps sphériques s'observent dans une zone intermédiaire plus éloignée. Une formation de cristaux en aiguilles (apparemment une calcification) se développe dans des corps isolés ou agrégés, laissant voir nettement leurs limites, même lorsque la calcification est plus avancée au point qu'on ne peut plus distinguer des cristaux individuels. Au niveau des coupes témoins, traitées de façon identique mais sans substrat ou avec de l'E.D.T.A., on n'observe ni précipité enzymatique ou corps sphériques. L'aspect des dépôts cristallins dans des corps qui contiennent de la phosphatase alcaline ne peut s'expliquer que par l'existence d'une association étroite entre enzymes et calcification.
    Abstract: Zusammenfassung Neun Tage alter experimenteller Kallus an Radii von jungen Ratten wurde mit Gomori's (1939) Calcium-Kobalt Methode untersucht, um die Verteilung der alkalischen Phosphatase und ihre Beziehung zur Calciumablagerung ultrastrukturell zu demonstrieren. Enzymaktivität zeigte sich zuerst als globulares Präzipitat außerhalb der Zellmembran von Knorpelzellen im Beginn der Hypertrophie. Aus dieser Präzipitatschicht entstanden dann gerundete Körperchen, die sich von der Zelle abtrennten. Solche Körperchen wurden auch in größerer Entfernung von der Zelle beobachtet, d.h. in einer Zwischenzone zwischen benachbarten Zellen. Nadelförmige Kristalle, wahrscheinlich von Calcium-Salzen, wurden in einzelnen oder aggregierten Körperchen beobachtet. Die äußere Zone der Körperchen blieb jedoch deutlich sichtbar, selbst dann, wenn der Calciumgehalt derart zugenommen hatte, daß einzelne Kristalle nicht länger erkennbar waren. In Kontrollen, die in gleicher Weise behandelt waren, aber ohne Substrat oder mit Zufügung von EDTA, wurden weder Präzipitate noch Körperchen beobachtet. Das Auftreten von Calciumablagerungen in alkalischer Phosphatase enthaltenden Körperchen scheint kaum anders erklärbar als durch eine enge funktionelle Verbindung zwischen Enzym und Calciumablagerung.
    Notes: Abstract Nine day old experimental calluses in radii of young rats were treated with Gomori's (1939) calcium-cobalt method to demonstrate ultrastructurally the presence of alkaline phosphatase in a search for its possible role in the desposition of calcium. Enzyme activity first appeared as globule-like precipitates outside the cell membrane of early hypertrophic cartilage cells. This precipitate layer then seemed to give rise to spherical bodies of alkaline phosphatase which occur at a slight distance from the cell. The spherical bodies were also observed further away from the cell in an intermediate zone between neighboring cells. Needle-like crystal formation, apparently calcification, occurred inside single or aggregated bodies, leaving their peripheral rim clearly visible, even when calcification had increased to such an extent that individual crystals could no longer be recognised. In controls, treated in the same way but without substrate, or with EDTA, no enzyme precipitate or spherical bodies were seen. The appearance of crystalline deposits in bodies which contain alkaline phosphatase seems difficult to explain on any other basis than that there is a close functional association between the enzyme and calcification.
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  • 23
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    Calcified tissue international 9 (1972), S. 238-242 
    ISSN: 1432-0827
    Keywords: Dentine ; Ultrastructure ; Tubule ; Tooth
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé L'étude ultrastructurale de la dentine humaine périphérique, de couronnes dentaires de sujets âgés de 11 à 75 ans, a montré trois aspects principaux du contenu des canalicules en coupe transversale. Il s'agit de canalicules apparemment vides, de canalicules contenant un matériel organique annulaire et, enfin, de canalicules totalement remplis d'un matériel organique d'aspect granulaire ou hyalin. Aucune terminaison nerveuse n'est visible à ce niveau.
    Abstract: Zusammenfassung Die ultrastrukturelle Untersuchung von peripherem menschlichem Zahnkronendentin bei Patienten im Alter von 11–75 Jahren hat drei Hauptaspekte des Inhaltes der Dentintubuli gezeigt. Sie bestehen bei transversalen Schnitten aus toten Gängen sowie beim Lumen der Tubuli entweder aus ringförmigen oder ganzausfüllenden Ablagerungen. Im äußeren Dentin wurden keine Nervenendigungen beobachtet.
    Notes: Abstract An ultrastructural study of peripheral human coronal dentin in patients aged 11 to 75 years, has shown main aspects of the dentinal tubular content. In transverse sections, they consist of dead tracts and annular or solid content to the tubular lumen. No nerve endings were observed in the outer dentin.
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    Calcified tissue international 7 (1971), S. 307-317 
    ISSN: 1432-0827
    Keywords: Ultrastructure ; Cartilage ; Calcification ; Inorganic ; Organic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé La phase organique (ou fantôme des cristaux) associéc à chaque cristal, ainsi que la substance de base associée à chaque cristal, ainsi que la substance de base associée à chaque amas cristallin, sont mises en évidence au niveau du cartilage calcifié en utilisant le sulfate de chrome basique comme agent de fixation, de coloration et de déminéralisation. Le traitement ultérieur du tissu, à l'aide de papaïne ou d'hyaluronidase, indique que les fantômes cristallins constitutent un complexe protéino-polysaccharidique et que la substance de base est formée par une protéine associée à un polysaccharide acide. Les rapports entre phases inorganique et organique sont discutés.
    Abstract: Zusammenfassung Die organische Phase (oder Kristallit-Schatten), die zu jedem Kristallit gehört, sowie das Hintergrundmaterial, das zu jeder Kristallitgruppe gehört, wurden in calcifiziertem Knorpel sichtbar gemacht. Zu diesem Zweck wurde basisches Chromsulfat als ein kombiniertes Fixierungs-, Färbe- und Demineralisierungsmittel verwendet. Nachfolgende Behandlung des Gewebes mit Papain oder Hyaluronidase läßt vermuten, daß die Kristallitschatten einen Proteinpolysaccharidkomplex darstellen und daß das Hintergrundmaterial hauptsächlich aus Protein mit einigen sauren Polysacchariden besteht. Die Beziehung zwischen anorganischen und organischen Phasen wird diskutiert.
    Notes: Abstract The organic phase (or crystallite ghost) associated with each crystallite, together with the background material associated with each crystallite cluster, was demonstrated in calcified cartilage using basic chromium sulphate as a combined fixative, stain, and demineralizing agent. Subsequent treatment of the tissue with papain, or with hyaluronidase, suggests that the crystallite ghosts represented a protein-polysaccharide complex and that the background material was principally protein together with some acid polysaccharide. The relationship between inorganic and organic phases is discussed.
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  • 25
    ISSN: 1432-2048
    Keywords: Festuca ; Frost damage ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Tillers of Festuca arundinacea Schreb. were subjected to-8°C in a bath of methylated spirits for three-quarters of an hour. They were thawed at room temperature and some material taken from the shoot apical meristem and leaf blade for electron microscopy. Similar material was taken from control plants for electron microscopy. Nine tillers subjected to-8°C and thawed subsequently failed to regrow. Nine control tillers regrew. All the treated meristem cells and about half the treated leaf mesophyll cells were extensively altered. Their nuclei were contracted, organelles were swollen or partly disrupted, plasmalemma and nuclear membranes were broken or absent and vacuoles were sometimes disrupted. Strongly osmiophilic material accumulated in the vicinity of membranes. About half the leaf mesophyll cells differed from the control mesophyll cells only in having more spherosomes and narrower thylakoids. Parallels with other ultrastructural studies of stress damage and the indications the results give of possible primary damaging events are discussed.
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  • 26
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    Planta 133 (1976), S. 15-19 
    ISSN: 1432-2048
    Keywords: Tropaeolum, Embryogenesis ; Differentiation ; Plastids ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Embryogeny in the nasturtium is characterized by the development of a large, tripartite suspensor and storing cotyledons. A light and electron microscopic study revealed an early diversification of the plastids in the various regions of the suspensor and the embryo proper. Amyloplasts are found in the developing cotyledons of the heart-like embryo, while chloroplasts occur within the meristematic part of the embryo and the adjacent portion of the suspensor. The cells between the meristem and the storing cotyledons display undifferentiated leukoplasts, whereas leukoplasts with an electron-dense matrix occur in the basal cell mass of the embryo-suspensor. Etioplasts develop in several cells of the placental haustorium of the suspensor. The carpel haustorium shows rather undifferentiated leukoplasts, which are transformed into electron-dense plastids during autolysis of the suspensor. This early plastidal differentiation in discussed with respect to its control and functional significance.
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  • 27
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    European journal of clinical pharmacology 5 (1972), S. 1-10 
    ISSN: 1432-1041
    Keywords: Tricyclic antidepressants ; desmethylimipramine ; nortriptyline ; single- and multiple-dose kinetics ; plasma concentration ; plasma clearance ; pharmacogenetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight healthy volunteers received single oral doses (1 mg/kg) and 6 received multiple doses (0.4 mg/kg t.i.d. for 2 weeks) of desmethylimipramine (DMI) and nortriptyline (NT) on different occasions. Kinetic analysis of plasma levels of the drugs showed that the ratios between single-dose peak-levels, plasma half-lives and apparent mean “steady-state” plasma levels of the two drugs were constant in all the subjects, and averaged 0.6. Despite their closely related chemical structures the apparent plasma clearance rate of DMI was about twice that of NT, and this might be associated with their different degrees of binding to plasma proteins. — The “steady-state” plasma level of NT in man is known to be genetically determined, and the conformity within each individual of the plasma clearance rates of DMI and NT indicates that the plasma kinetics of both these drugs are controlled by common genetic factors. — The study also shows that the “steady-state” plasma level of DMI, like that of NT, can be predicted accurately from single-dose plasma-level data. Thus, if the kinetic characteristics of one of these drugs in a subject are known, it is possible to predict the plasma kinetics of the other compound.
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    European journal of clinical pharmacology 5 (1972), S. 44-52 
    ISSN: 1432-1041
    Keywords: alprenolol ; serum drug level ; exercise ; man ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of alprenolol on heart rate and systolic blood pressure were studied in healthy subjects during standardized exercise on a bicycle ergometer. In one series of experiments, in which serum concentrations of alprenolol were also measured, the effects of single oral doses of 50, 100 and 200 mg of alprenolol and a placebo were compared by a double blind cross-over technique. In a second series of experiments 100 mg alprenolol was given four times in one day and the effect was followed for up to eighteen hours after the last dose. — Alprenolol diminished the expected increase in heart rate and systolic blood pressure during exercise. The reduction of exercise tachycardia in a given individual was linearly related to the logarithm of the dose or the serum concentration of alprenolol. The serum concentrations required for a given reduction of exercise tachycardia varied almost one hundred-fold amongst the subjects studied. The biological availability of alprenolol was dose-dependent, probably due to a limited capacity biotransformation of the drug before it entered the general circulation. After a single dose the serum level of alprenolol and its chronotropic effect diminished at a rate corresponding to an elimination half life of about two hours. This rate of elimination was consistent with that calculated from the results of the four dose study.
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  • 29
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    European journal of clinical pharmacology 5 (1973), S. 174-180 
    ISSN: 1432-1041
    Keywords: Tricyclic antidepressant ; nortriptyline ; metabolism ; urine ; pharmacokinetics ; twins ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The urinary excretion of nortriptyline (NT) and five of its metabolites was studied by quantitative gas chromatography in 22 twins and 7 unrelated healthy subjects after single (1 mg/kg) and multiple oral doses (0.4 mg/kg t.i.d.) of NT hydrochloride. A mean recovery of 62% of the dose was found after both single and multiple doses. The metabolite pattern in the urine was qualitatively and quantitatively identical in the two regimes, but there were marked variations in the pattern of metabolites between individuals. The disappearance rate of NT from the plasma was mainly determined by the metabolism of NT to 10-hydroxynortriptyline, which varied considerably between individuals. The data suggest that in certain rapid NT metabolizers, the upper limit for the overall clearance of NT from the plasma (if extrahepatic metabolism is assumed to be negligible) might be set by the blood flow through the liver.
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  • 30
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    European journal of clinical pharmacology 5 (1973), S. 181-185 
    ISSN: 1432-1041
    Keywords: Tricyclic antidepressant ; nortriptyline ; single-dose kinetics ; plasma/blood concentrations ; metabolites ; absorption ; availability ; apparent volume of distribution ; plasma/blood clearances ; gas chromatography-mass spectrometry ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The availability of an orally administered drug may be defined as the fraction of the total dose that enters the blood. Three healthy subjects were given identical doses of nortriptyline hydrochloride (NT-HCl) by the oral and intramuscular routes. The availability was assessed by comparing the total areas under the NT plasma concentration-time curves produced by the two methods of administration. The concentrations of NT in plasma and blood were determined by gas chromatography — mass spectrometry and were found to be almost identical. The observed availability of NT in these subjects ranged between 56 and 70% (mean 64%). The availability predicted from the parenteral plasma levels (assuming an average hepatic blood flow of 1.7 l/min) differed from the observed availability in one subject, perhaps because of the known variation in liver blood flow between individuals. The gastrointestinal absorption of NT-HCl was complete, since the recovery of the main metabolite, 10-hydroxynortriptyline, was the same after the two routes of administration. Pharmacokinetic analysis of the data showed that there might exist interindividual differences in the apparent volume of distribution of NT, (Vd)β. There was no apparent relationship between the variations in availability of NT and “steady-state” plasma levels or the disposition plasma half-lives of the drug. The calculated (Vd)β and (t 1/2)β of NT for each subject were in good agreement with those obtained from a previous study of single oral does of NT.
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    European journal of clinical pharmacology 6 (1973), S. 256-260 
    ISSN: 1432-1041
    Keywords: K 4277 ; anti-inflammatory agents ; metabolism ; man ; oral administration
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The fate of the new analgesic and anti-inflammatory agent α-[4-(1-oxo-2-iso-indolinyl)-phenyl]-propionic acid (compound K 4277) in healthy volunteers has been investigated by a radio-isotope method and gas-liquid chromatography. After oral administration, the drug was absorbed rapidly and completely and occurred in plasma mainly as unchanged compound bound extensively to plasma proteins. Its disappearance from plasma followed at least a bi-exponential function and was almost complete in 24 to 48 h. Most of the drug is excreted in urine as a glucuronide and a lesser amount as the unchanged compound. There were only negligible amounts of other metabolites.
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  • 32
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    European journal of clinical pharmacology 6 (1973), S. 57-60 
    ISSN: 1432-1041
    Keywords: Critical flicker fusion ; phenytoin ; phenobarbitone ; serum drug concentration ; man ; epilepsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The central effects of single oral doses of phenobarbitone and phenytoin have been determined in six normal volunteers by measuring the critical flicker fusion threshold (CFF) under double-blind, placebo controlled conditions at intervals of up to 7 h after ingestion of the drug. Blood samples were taken at the same time for estimation of the serum concentration of the drugs by gas chromatography. Phenobarbitone in a dose of 180 mg produced a significant fall in CFF, and the time-course of this change mirrored the time-course of the serum concentration of the drug, which reached a peak of 21.8 µM (5.2 µg/ml) at 1.5 h. Phenytoin in doses of 200 mg, 300 mg and 400 mg produced no significant change in CFF even though an adequate serum concentration of the drug had been achieved (28.8 µM, 7.2 µg/ml, with the 400 mg dose). It was concluded that the two drugs differ in their action on the neural mechanisms tested by this procedure.
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    European journal of clinical pharmacology 6 (1973), S. 177-180 
    ISSN: 1432-1041
    Keywords: Amphetamine ; drug dependence ; metabolism ; urine ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolism of (+)-[14C] amphetamine has been studied in two women who had been taking 90–100 mg of Dexedrine ((+)amphetamine sulphate; Smith, Kline & French) daily for several years but who showed no evidence of overt amphetamine toxicity. The urinary metabolites were identified, estimated and compared with the results previously obtained from two drug naive male subjects who had received 20 mg of (±)amphetamine (Caldwellet al., (1972b). The same metabolites were found, but the dependent subjects excreted in 24 h more unchanged amphetamine (about 30% of dose) than the naive subjects (20%). This may be a reflection of the dose, which in dependent subjects was five times that of naive subjects. The dependent subjects excreted in 24 h slightly more norephedrine (2.9, 4.1% of dose) and 4′-hydroxynorephedrine (1.1, 1.6%) than the naive subjects (norephedrine, 2.2, 2.6%; 4′-hydroxynorephedrine, 0.3, 0.4%), but the difference in percentage of dose may not be significant. However, in absolute terms the dependent subjects are producing at least five times as much norephedrines as the naive subjects because of the larger dose.
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  • 34
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    European journal of clinical pharmacology 7 (1974), S. 449-454 
    ISSN: 1432-1041
    Keywords: Methaqualone ; single and multiple dose kinetics ; dose-effect relationship ; sedation ; plasma concentration ; protein binding ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Three healthy subjects took methaqualone (1.0 mg/kg) once daily for 16 days. Equilibrium concentrations in plasma were established after multiple oral doses and there was a linear post-steady state decline in the log plasma concentration of methaqualone. The drug was also given as single oral doses and plasma concentrations were followed for 5 days (t1/2=36 to 38 h.). Sedative effects were studied by psychophysiological tests and subjective ratings both in the single and multiple dose experiments. A significant impairment of flicker fusion discrimination ability occurred during the increase in the plasma concentration of the drug; maximum effects preceded peak plasma concentrations and the impairment disappeared whilst plasma concentrations were still high. The same effects were found in the subjective ratings. The drug was shown to have a possible tremorogenic effect after a hypnotic dose. One subject experienced sedation during the multiple dose experiment, despite the use of a low dose, an observation that should be taken into account, e.g. in car driving.
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  • 35
    ISSN: 1432-1041
    Keywords: Oral antidiabetic drug ; butylbiguanide ; pharmacokinetics ; two-compartment open model ; plasma concentration ; liver concentration ; intestine concentration ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 50 mg14C-Butylbiguanide was administered intravenously to 4 diabetic patients and 100 mg14C-butylbiguanide orally to 5 further diabetics. The concentrations of the drug in plasma, intestinal fluid, intestinal epithelium and liver tissue were determined and the renal excretion of the biguanide measured. Irregularities in the plasma concentration curve were observed which appeared as systematic deviations from the ideal curve of a biexponential function. Because these deviations occurred only in the middle phase of the plasma concentration curve, it was nevertheless possible to calculate the pharmacokinetic parameters of butylbiguanide by use of a two-compartment open model. The principal pharmacokinetic parameters were determined according to this model after intravenous dosing and the following mean values were obtained:t 1/2 (β)=4.6 h (β=0.15 h−1),C P 0 =0.85µg/ml,V D =218 l,V T =157 l,V P =62 l,k 12=0.69 h−1,k 21=0.44 h−1,k el =0.54 h−1. Within 48 h after administration, an average of 72.4% of the intravenous and 74.4% of the oral dose had been excreted in the urine. Total clearance (Cl tot) averaged 536 ml/min and renal clearance (Cl ren) 393 ml/min. High concentrations of butylbiguanide were observed in the intestinal fluid (100–700 mg/ml) 20–40 min after oral administration. It was found that the drug accumulates in intestinal fluid, intestinal epithelium and liver tissue, and that it is secreted into the intestinal lumen. The concentrations of butylbiguanide in intestinal and liver tissue were 10–46 times higher than in plasma. The secretion of biguanide into the intestinal lumen may occur via the bile or the intestinal mucosa, but there is no evidence of significant biliary excretion of butylbiguanide.
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  • 36
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    European journal of clinical pharmacology 8 (1975), S. 97-105 
    ISSN: 1432-1041
    Keywords: Di-n-propylacetate ; 2-propyl-valeric acid sodium salt ; pharmacokinetics ; anti-epileptic ; drug monitoring ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the anti-epileptic drug di-n-propylacetate (DepakineR) have been studied in 7 patients, in whom plasma concentrations were determined during and following subchronic treatment. Elimination of the drug appeared to follow a monophasic exponential course; biological half lives were 8 to 15 hours. The data supported the assumption that an open one-compartment model can be used to describe the kinetics of dipropylacetate in man. The drug appeared to have a relatively restricted distribution: calculated relative distribution volumes ranged from 0.15 to 0.40 1/kg. There were large interindividual differences in clearance rate. The therapeutic range was considered to be between 50 and 100 mg/1 plasma. Plasma levels of phenobarbital were markedly raised during treatment with dipropylacetate for an unknown reason. Determination of the plasma concentrations of drugs at accurately fixed times appears to be a reliable method for pharmacotherapeutic monitoring of epileptic patients.
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  • 37
    ISSN: 1432-1041
    Keywords: Sympathetic activity ; plasma catecholamine concentration ; dopamine-β-hydroxylase activity ; graded physical exercise ; heart rate ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 11 healthy untrained volunteers the increase in plasma dopamine-β-hydroxylase (DBH) activity during graded physical exercise has been examined as a true measure of increased activity of the sympathetic nervous system. The correlation between DBH activity, catecholamine concentration (CA) in plasma and heart rate was studied. When work on an electrically braked bicycle ergometer was gradually increased from 12.5 to 100, 200 and 300 watts there was a linear increase in DBH activity and heart rate; the increase in CA concentrations followed an exponential function. The peak values for DBH activity and CA concentration in plasma after the 300 watt work load (as percentages of the resting levels) were 130±3% and 820±71%, respectively; the adrenaline concentration in plasma increased only to 150±19% (p〉0.05). There were significant correlations between heart rate and work load, DBH and work load and log CA and work load. The data imply direct correlations between heart rate and DBH, heart rate and log CA and DBH and log CA. The exponential increase in noradrenaline concentration in plasma might be due either to a greater net “overflow” from sympathetic nerve endings, and/or to increased secretion by the adrenal medulla. In the latter case, the release of noradrenaline would not be accompanied by secretion either of adrenaline or DBH. After work ceased there were sharp falls in heart rate and CA concentration, which indicate an immediate drop in sympathetic activity. DBH activity in plasma returned to normal very slowly; it reached half maximum values after 20 – 22 min. It is concluded that increased sympathetic activity in man can be estimated in vivo as changes in DBH and/or CA concentration in plasma. In contrast, a rapid decrease in sympathetic activity is directly reflected only by a rapid fall in the plasma concentrations of CA.
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    European journal of clinical pharmacology 8 (1975), S. 33-39 
    ISSN: 1432-1041
    Keywords: m-octopamine ; metabolism ; first-pass effect ; man ; enteric absorption ; monohydroxylated phenylalkylamines
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The diminished sympathomimetic pressor activity of monohydroxylated phenylalkylamines after oral administration has been attributed to incomplete enteric absorption. Therefore, urinary excretion of the unchanged drug and its metabolites has been compared after intravenous and oral administration of3H-m-octopamine to eight patients. Identical amounts of3H-activity (80% of the dose) were excreted after the two routes of dosing, so enteric absorption has been assumed to be complete. Significant differences were found in the fraction of free urinarym-octopamine, which amounted to 10.5% of the dose after infusion and 0.58% after oral administration. The only metabolic pathways form-octopamine are deamination and conjugation. Following oral administration the percentage of conjugates was considerably higher than after intravenous infusion. This metabolic pattern appears typical of all phenylalkylamines with a hydroxyl group in themeta position. Ring hydroxylation to catecholamines was not observed. The enzymes mainly responsible for conjugation after oral administration are located in the gut wall. The resulting “first pass effect”, i.e. metabolism prior to the access to the central compartment, can account for the diminished pharmacodynamic effect after dosing by this route.
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  • 39
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    European journal of clinical pharmacology 8 (1975), S. 161-166 
    ISSN: 1432-1041
    Keywords: Oxyfedrine ; norephedrine ; man ; urinary excretion ; sympathomimetic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After oral administration of oxyfedrine to healthy volunteers, norephedrine was identified in the urine by thin layer chromatography and gas liquid chromatography and mass spectrography. 30 hours after single oral doses of 8, 16 or 24 mg of oxyfedrine, about 4, 8 and 9 mg, respectively, of norephedrine were found in the urine, i.e. on a molar base 75–100% of the dose was excreted as norephedrine. The peak of excretion occurred within 2–4 hours after administration of the drug. No accumulation of oxyfedrine and/or its metabolite was observed after administration of 16 mg of oxyfedrine t.i.d. for three days. It could not be decided whether oxyfedrine was metabolized to norephedrine by liver enzymes, as in rats, or was spontaneously degraded to norephedrine, e.g. in duodenal fluid before absorption. 30–150 min after oral oxyfedrine (24 mg) norephedrine was demonstrable in duodenal fluid. Thus, in addition to the directβ-sympathomimetic effects of oxyfedrine, it may also have indirect sympathomimetic effects because of the noradrenaline-releasing properties of its metabolite norephedrine.
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    European journal of clinical pharmacology 8 (1975), S. 249-254 
    ISSN: 1432-1041
    Keywords: Clonazepam ; 7-amino-clonazepam ; pharmacokinetics ; side-effects ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonazepam (CNP) and its principal metabolite in plasma, 7-amino-CNP (ACNP), have been investigated in a prospective study of 27 newly diagnosed epileptics and correlated with specified side-effects. At a daily dose of 6 mg, the average plasma levels of both substances were about 50ng/ml, and individual values ranged from 30 to about 80ng/ml. There was a linear correlation between changes in dose and the resulting plasma levels, which indicates first order elimination kinetics. Side-effects were frequent, but neither their severity nor their occurrence could be related to plasma levels or to the rate of increase in plasma concentration of the drug. Three out of five patients who developed serious dysphoria had significantly high CNP levels. The concentration of ACNP was considerably increased in four patients who subsequently suffered from withdrawal symptoms. Drug interaction with diphenylhydantoin, i.e. decreased CNP level, was observed in all five patients who received both compounds. In general it is not yet possible to define an upper limit for the plasma levels of CNP and ACNP at which toxicity occurs. In patients treated with conventional doses of CNP, measurement of plasma concentration is not required, except in special circumstances, because of the lack of correlation between plasma level and side-effects.
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    European journal of clinical pharmacology 8 (1975), S. 343-347 
    ISSN: 1432-1041
    Keywords: Nortriptyline ; pharmacokinetics ; man ; two compartment model
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of nortriptyline have been assayed in four subjects after intravenous infusion of 57 mg nortriptyline hydrochloride. The data were evaluated according to a two compartment open model. The calculated best-fitting curves were in good agreement with the experimental data, better than could be expected from a simpler model. This justifies the assumption that the kinetics of nortriptyline in man may be described by this model with an appropriate input function. The data permitted estimation of all the parameters of the model. The meaning of the parameters is discussed, particularly in relation to individual variation.
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  • 42
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    European journal of clinical pharmacology 8 (1975), S. 285-285 
    ISSN: 1432-1041
    Keywords: Lithium ; intoxication ; man ; delayed absorption ; gastric contents
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A 55-year old man with lithium intoxication showed increasing serum concentrations in spite of forced diuresis and dialysis. A high lithium content was found in gastric juice three days after the compound had been taken. The serum lithium level began to fall after gastric lavage.
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  • 43
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    European journal of clinical pharmacology 6 (1973), S. 187-190 
    ISSN: 1432-1041
    Keywords: Methaqualone ; single dose kinetics ; plasma concentration ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of methaqualone were followed for several days after single oral doses in 5 healthy subjects. The analysis of methaqualone was performed by gas chromatography-mass spectrometry (mass fragmentography). The plasma levels of methaqualone were interpreted according to a two compartment model. The elimination rate of methaqualone was found to be much slower than has been reported previously, half lives in the β-phase ranging from 19.6 to 41.5 h.
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    European journal of clinical pharmacology 6 (1973), S. 228-233 
    ISSN: 1432-1041
    Keywords: Dopamine-β-hydroxylase ; man ; plasma ; sympathetic activity ; halothane
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary As an index of sympathetic nervous system activity, the level of dopamine-β-hydroxylase (DBH) in plasma was measured in 82 children, mean age 6±0.3 years, before and during halothane anaesthesia. Plasma DBH fell markedly in 50% of cases irrespective of the anaesthetic technique, i.e. halothane with or without nitrous oxide, and with or without premedication by pethidine and/or atropine; enzyme activity was unchanged in 25% of the children; and in the remaining 25%, DBH activity increased. The heart rate fell significantly in cases in whom DBH activity was lowered, and it remained almost unchanged, when DBH rose during anaesthesia. A fall in plasma DBH activity during anaesthesia was found particularly in children who appeared excited and anxious before anaesthesia; enhanced preanaesthetic sympathetic tone in this group was indicated by plasma DBH activities and heart rates higher than in the other groups. It is concluded that halothane may not only reduce elevated sympathetic activity, but also in most cases may oppose sympathetic counter-regulation which should occur in reponse to its direct cardiovascular depressant effect.
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  • 45
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    European journal of clinical pharmacology 8 (1975), S. 277-282 
    ISSN: 1432-1041
    Keywords: QX-572 ; quaternary ammonium compound ; plasma level ; urinary excretion ; man ; anti-arrhythmic drug
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A quantitative thin layer chromatographic (TLC) method has been developed for determination of the antiarrhythmic quaternary ammonium compound N, N-bis (phenylcarbamoylmethyl) dimethylammonium chloride (QX-572) in biological materials. Prior to chromatography QX-572 was transferred into chloroform as perchlorate by ion pair extraction. Tritium-labelled QX-572 was used as the internal standard and a TLC scanning spectrophotometer equipped with a linear detector system afforded the required accuracy, specificity and simplicity. The method was used to determine QX-572 in plasma from 11 patients with various cardiac diseases who received QX-572 8 mg/kg body wt. as an intravenous infusion over 30 min. There was a rapid initial decay of the plasma levels from 11.0±1.1 µg/ml (mean ± SE) at the end of infusion to 3.5±0.5 µg/ml after 30 min. 240 min after commencement of the infusion the plasma level was 0.7±0.1 µg/ml. In these patients 22±2% (mean±SE) of the total administered dose of QX-572 was excreted unchanged in urine during the 24 hours following infusion of the drug. A second group of 28 patients with acute myocardial infarction also received QX-572 8 mg/kg body wt. Their plasma levels did not differ significantly from those found in the first group of patients. There was a poor correlation between the amount of QX-572 administered and plasma level at the end of the infusion. The study has provided some preliminary data about the pharmacokinetics of QX-572, but before a detailed analysis can be done data from longer periods of observation is required. The present results suggest that in future QX-572 can be administered in a standardized dosage, what would be advantageous in practice.
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  • 46
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    European journal of clinical pharmacology 9 (1975), S. 135-145 
    ISSN: 1432-1041
    Keywords: Anturan® ; 14C-label ; man ; pharmacokinetics ; biotransformation ; C-glucuronidation
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption, biotransformation and elimination of sulfinpyrazone, 1,2-diphenyl-3,5-dioxo-4-(2′-phenylsufinylethyl)-pyrazolidine, have been studied by administration of single 200 mg oral doses of a14C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and complete and the plasma concentration of unchanged drug reached maximum values of 22.67 and 13.04 µg/ml, respectively, after 1 – 2 hours. The elimination half-life in the two subjects, calculated from the decline between 3 and 8 hours, was 2.7 and 2.2 hours. The integrated concentration of unchanged sulfinpyrazone in plasma, estimated from the area under the concentration curves (AUC), was almost as high as that of total14C-substances, so the proportion of metabolized drug in plasma was low. In no case did the AUC of the three specifically determined metabolites, i.e. the sulphone G 31 442, the “para-hydroxy”-compound G 32 642 and the “4-hydroxy”-compound GP 52 097, exceed 4% of the sulfinpyrazone value. More than 95% of whole blood radioactivity was confined to plasma. The oral dose was rapidly and completely excreted, since within 4 days more than 95% was recovered, 85% from urine and 10% from faeces. A large proportion of the dose was excreted as unchanged drug in the two volunteers: 51 and 54% of total urinary radioactivity was present as sulfinpyrazone; 8.2 and 8.8% was present as “para-hydroxy”-metabolite, 2.7 and 3.0% as sulphone-metabolite, and 0.6 and 0.8% as “4-hydroxy”-metabolite. About 30% of urinary radioactivity consisted of highly polar metabolites. Spectroscopy of them showed that they were the C-β-glucuronides of sulfinpyrazone (28%) and the corresponding sulfone (2%). In these metabolites the C(4) of the pyrazolidine ring was directly attached to glucuronic acid, and thus they represent a new type of biosynthetic conjugate.
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  • 47
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    European journal of clinical pharmacology 9 (1975), S. 155-159 
    ISSN: 1432-1041
    Keywords: Anticonvulsants ; benzazepines ; clonazepam ; pharmacokinetics ; gas chromatography ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight healthy volunteers were given single i.v. and oral doses of clonazepam (2 mg). The disposition curves after i.v. administration showed a biexponential decline and the data were applied to a two-compartment open model. The volume of distribution ((Vd)β) ranged between 1.5 and 4.4 l/kg and the plasma half-life (t1/2) between 19 and 60 hours. Absorption after oral administration was fast, with peak plasma concentrations within 4 hours in all subjects. Five of the subjects received repeated oral doses of clonazepam 0.5 mg bid for 15 days. The plasma level during steady state (estimated as Cmin within the dose interval) could be predicted from the constants A, B, α and β obtained in the single dose study with a coefficient of variation of 6%. The plasma half-lives after cessation of the subchronic dosing were of the same magnitude as after single doses.
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  • 48
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    European journal of clinical pharmacology 9 (1975), S. 193-198 
    ISSN: 1432-1041
    Keywords: (−)-[14C]-ephedrine ; metabolism ; urinary excretion ; tolerance ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolic fate of orally administered (−)-[14C]-ephedrine has been studied in 3 human subjects and the urinary excretion of metabolites determined quantitatively by solvent extraction, paper chromatography and reverse isotope dilution procedures. Following an oral dose of the drug (0.35 mg/kg, 1.6 µCi), 97% of the dose was excreted in the urine within 48 h, 88% in the first 24 h. Unchanged drug was the major urinary excretory product (53–74%), with N-demethylation occurring to a variable extent (8–20%) although there was little interindividual variation in urine pH. Oxidative deamination was also variable (4–13%); the main identified products of this were benzoic acid (free and conjugated) and 1,2-dihydroxy-1-phenylpropane (free and conjugated). No phenolic metabolites could be detected, and thus it would appear that these compounds cannot be implicated in the acquisition of tolerance to ephedrine which can occur on repeated dosage.
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  • 49
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    European journal of clinical pharmacology 9 (1975), S. 219-227 
    ISSN: 1432-1041
    Keywords: Rifampicin ; induction of drug metabolism ; hexobarbital kinetics ; tolbutamide kinetics ; plasma concentrations ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy volunteers took 1.2 g rifampicin daily for 8 days, and before and afterwards each received hexobarbital (7.32 mg/kg) and tolbutamide (20 mg/kg) by i.v. infusion on two consecutive days. The plasma concentrations of the two drugs were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 325 to 122 min and of tolbutamide from 418 to 183 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased about three-fold and that of tolbutamide more than two-fold. Significant changes in the distribution kinetics of the two drugs were not observed. The results suggest that rifampicin is capable of inducing drug metabolism in man, which leads to an increased rate of elimination of drugs that undergo biotransformation in the liver.
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  • 50
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    European journal of clinical pharmacology 9 (1975), S. 229-234 
    ISSN: 1432-1041
    Keywords: Quercetin ; flavonoids ; pharmacokinetics ; absorption ; disposition ; metabolism ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of quercetin, a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8±1.2 min for the α phase and 2.4±0.2 h for the β phase (predominant half life), respectively. Protein binding was 〉98%. The apparent volume of distribution was small at 0.34±0.03 l/kg. Of the intravenous dose 7.4±1.2% was excreted in urine as a conjugated metabolite, and 0.65±0.1% was excreted unchanged. After oral administration no measurable plasma concentrations could be detected, nor was any quercetin found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in faeces after the oral dose was 53±5%, which suggests extensive degradation by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.
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  • 51
    ISSN: 1432-1041
    Keywords: Aldosterone ; renin ; aldosterone antagonist ; canrenone ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Canrenone was administered in doses of 2×82 mg and 2×164 mg per day over a period of 10 days to diabetic patients without cardiovascular, liver or kidney involvement. Aldosterone excretion and plasma aldosterone increased only slightly during both regimes. There was a clear-cut increase in aldosterone excretion only after discontinuation of carenone. Excretion of sodium potassium and fluid was not significantly changed either during or after treatment. The lack of effect of canrenone on the kidney was in contrast to the significant decrease in serum sodium and increase in serum potassium, and the significant, dose-dependent rise in plasma renin activity following canrenone administration. The increased plasma renin activity persisted for some days after discontinuation of canrenone. It is suggested that canrenone primarily exerted its effect in the distal part of the large intestine where ionic movements are most affected by aldosterone. The disproportionately slight increase in plasma aldosterone concentration and aldosterone excretion, in spite of the greatly elevated plasma renin activity and serum potassium level, is considered to be due to a direct inhibitory effect of canrenone on aldosterone production in the adrenals.
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  • 52
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    European journal of clinical pharmacology 9 (1976), S. 291-298 
    ISSN: 1432-1041
    Keywords: Tricyclic antidepresent ; lofepramine ; single- and multiple-dose kinetics ; noradrenaline and 5-hydroxytryptamine uptake ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of lofepramine, an imipramine analogue, have been studied by administering single oral doses to volunteers, determination of plasma levels of lofepramine and desmethylimipramine after ten days of oral administration to patients, and by relating plasma levels to the effect on uptake of noradrenaline by isolated rat irides and brain slices of plasma samples collected during treatment. The results indicate that lofepramine undergoes pronounced first pass elimination and that desmethylimipramine is a major metabolite of it. During steady-state conditions the plasma level of lofepramine fluctuates considerably between doses. A linear relation was found between inhibition of neuronal uptake of noradrenaline and the plasma concentration of desmethylimpramine. No effect was seen on the uptake of 5-hydroxytryptamine in brain slices incubated in patients' plasma which suggests that neither lofepramine nor its metabolites formedin vivo in man affect neuronal uptake of this amine. Lofepramine belongs to the group of tricyclic anti-depressants which preferentially inhibit noradrenaline uptake.
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  • 53
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    European journal of clinical pharmacology 9 (1976), S. 307-314 
    ISSN: 1432-1041
    Keywords: Absorption ; man ; β-methyl-digoxin ; serum concentration ; urinary excretion ; radio-immunoassay
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Single doses of β-methyl-digoxin 0.4 mg were given to groups of 17 – 18 healthy volunteers as an intravenous infusion lasting 2 hours, or orally as Lanitop Liquidum® or Lanitop® tablets. The serum glycoside concentration and urinary glycoside excretion were measured over 8 and 32 h. The absolute bioavailability from the oral preparations in comparison with the infusion was lower for the first 8 h than for the entire 32 h of the investigation; the relative bioavailability from tablets was the same as from the solution for both periods. For both periods the area under the serum concentration/time curve and the urinary glycoside excretion were significantly lower after administration of the tablets than after intravenous infusion. Taking the average of both parameters, the absolute bioavailability of β-methyl-digoxin was about 80% from the solution and about 70% from the tablets. In 18 patients undergoing intravenous or oral therapy with β-methyl-digoxin steady state glycoside concentrations were compared in a cross-over study of intravenous maintenance therapy with Lanitop® ampoules or oral treatment with Lanitop® tablets. For a standard daily dose of 0.2 mg β-methyl-digoxin the serum concentrations were 1.35±0.10 ng/ml during both intravenous and oral administration. The intra-individual variation in glycoside concentration after changing from intravenous to oral maintenance therapy, or vice versa, was about the same as during continued intravenous or oral administration. It is concluded that the rate of rise of serum concentration after a single dose may be a useful indicator of the rate of absorption, but that the area under the serum concentration/time curve and the urinary glycoside excretion up to 32 h are unsuitable for determining equivalent doses of different formulations or routes of administration of digitalis glycosides.
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  • 54
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    European journal of clinical pharmacology 9 (1976), S. 345-354 
    ISSN: 1432-1041
    Keywords: 3H-digitoxin ; metabolism ; spironolactone ; enzyme induction ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of spironolactone on the metabolism of intravenously administered3H-digitoxin (80 µCi) was investigated in eight patients. In three of them the labelled glycoside was given on a second occasion after spironolactone treatment had been discontinued for at least 65 days. Of total urinary radioactivity 79 % was unaltered drug and 12 % consisted of water soluble compounds. No digitoxigenin or digoxigenin and only trace amounts (〈2 %) of digoxin and the bis- and monoglycosides of digoxigenin were found. After spironolactone total urinary radioactivity was unchanged but the fraction eliminated as unchanged digitoxin fell from 79 to 66 % and the water soluble compounds increased from 12 to 26 % (p〈0.05). In addition spironolactone caused a 20 % reduction in the half-life of serum radioactivity (p〈0.01) and a 16 % reduction in the volume of distribution (p〈0.05). Induction of hepatic enzymes by spironolactone is proposed to explain the alteration in the metabolism of digitoxin in man. Both the altered metabolic pattern and the reduction in the volume of distribution appear to contribute to the reduction in half-life.
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  • 55
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    European journal of clinical pharmacology 9 (1976), S. 423-428 
    ISSN: 1432-1041
    Keywords: Serum zinc concentration ; intestinal absorption ; portal vein ; transumbilical catheterization ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum zinc concentrations in peripheral venous blood were determined in 8 healthy volunteers at various times after oral administration of 50 mg Zn++. The same dose was given to 6 patients surgically treated for obesity by jejuno-ileostomy. In the healthy volunteers the mean serum zinc concentration before dosing was 0.89 µg/ml and a mean peak concentration of 2.39 µg/ml was found after 3 h. In the patients the starting level was lower, 0.67 µg/ml, and a mean peak concentration of 1.31 µg/ml was found 90 min after treatment. In the patients the areas under the serum concentration-time curve was approximately 1/3 of that in the healthy subjects. Zn++ 50 mg was also given to 3 patients undergoing transumbilical catheterization of the portal vein for diagnostic purposes and serum zinc concentrations were measured in portal and peripheral venous blood sampled simultaneously. No significant differences were found between the concentration of zinc in portal and peripheral venous blood during absorption, which suggests slow passage of zinc across the intestinal wall.
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  • 56
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    European journal of clinical pharmacology 5 (1973), S. 236-238 
    ISSN: 1432-1041
    Keywords: Activated charcoal ; tricyclic antidepressant ; nortriptyline ; intoxication ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers were given nortriptyline (NT) in doses of 0.86–1.00 mg/kg. There was a significant (P〈0.05) decrease in absorption of the drug if 5 g of activated charcoal was administered half an hour afterwards.
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  • 57
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    European journal of clinical pharmacology 7 (1974), S. 357-360 
    ISSN: 1432-1041
    Keywords: Tetracycline absorption ; iron salts ; drug absorption ; man
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    Notes: Summary The inhibitory effect of various iron salts, all containing 40 mg elemental iron, on the absorption of tetracycline (500 mg) administered simultaneously has been compared in a double-blind cross-over study in 6 healthy human volunteers. On the basis of changes in peak serum tetracycline concentration, area under individual serum tetracycline concentration-time curves and urinary excretion of tetracycline, the following order of inhibition of tetracycline absorption was found: ferrous sulphate 〉 ferrous fumarate, ferrous succinate, ferrous gluconate 〉 ferrous tartrate 〉 ferric sodium edetate. Thus, in addition to different pharmaceutical properties of iron tablets or capsules, the type of iron salt used may significantly influence the absorption of simultaneously ingested tetracycline.
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  • 58
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    European journal of clinical pharmacology 7 (1974), S. 375-380 
    ISSN: 1432-1041
    Keywords: Tranexamic acid ; pharmacokinetics ; man ; antifibrinolytic agents ; renal clearance ; two-compartment model
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tranexamic acid has been investigated in two healthy volunteers. The behaviour of the drug can be described in terms of a two compartment open model; the disposition (biological) half-life was 2.7 h and 1.9 h, respectively. In five normal volunteers the mean total recovery in urine 48 h after dosing was 94.8%. The renal clearance in the two subjects, adjusted to 1.73 m2 body surface area, was 135 and 132 ml/min/1.73 m2, respectively, indicating that tranexamic acid is eliminated by glomerular filtration and that neither tubular excretion nor absorption takes place.
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  • 59
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    European journal of clinical pharmacology 7 (1974), S. 81-86 
    ISSN: 1432-1041
    Keywords: Phenytoin ; single- and multiple dose pharmacokinetics ; dose-dependent kinetics ; bioavailability ; plasma concentration ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentration of phenytoin (diphenylhydantoin, DPH) have been studied in 5 volunteers after single oral and iv doses (5.0 mg sodium DPH/kg), and after multiple oral doses (2.0 mg sodium DPH/kg b.i.d. for 12 days). The data were analysed according to a one compartment model. The plasma half-life was 14.5 h±1.2 S.D. after i.v. administration, its apparent volume of distribution varied little (0.52 l/kg±0.04) and its bioavailability ranged between 0.70 and 1.0 (mean 0.87). After oral administration peak plasma concentrations were reached in 4 to 12 h. Elimination curves were slightly convex, probably due to an effect of slow absorption. Steady-state plasma levels varied twofold between individuals after multiple oral doses and exceeded those predicted from the single i.v. dose by 29 to 77%. The discrepancy was considered to be due to transition to dose-dependent kinetics.
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  • 60
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    European journal of clinical pharmacology 7 (1974), S. 213-216 
    ISSN: 1432-1041
    Keywords: Ergot alkaloids ; ergotamine ; caffeine ; tritium label ; intestinal absorption ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and urinary radioactivity were measured in 6 normal volunteers after oral intake of3H-labelled ergotamine tartrate, either alone or combined 1:100 with caffeine. Plasma level and cumulative urinary excretion were higher after the combination than after ergotamine alone and the difference was significant at certain times. A detectable plasma level was reached 30 min after taking the combination but only 1 h after ergotamine alone. These results indicate faster and more complete intestinal absorption of ergotamine administered in combination with caffeine.
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  • 61
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    European journal of clinical pharmacology 7 (1974), S. 253-257 
    ISSN: 1432-1041
    Keywords: Ajmaline ; haemodynamics ; man ; digitalis ; bundle branch block ; ECG
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effects of ajmaline have been studied in eleven patients during diagnostic cardiac catheterisation. Single doses of 50 mg were injected intravenously during two minute periods and brachial and pulmonary artery pressures, cardiac output, stroke volume, heart rate, peripheral vascular resistance and the E. C. G. were recorded continuously. Serum concentrations of ajmaline were also determined. No significant haemodynamic effects were observed, except a reduction in systolic arterial pressure during the first five minutes and a slight increase in heart rate. QRS-complexes became wider in all subjects and bundle branch block occurred in three of them who had been digitalized. It was concluded that ajmaline had no marked unfavourable haemodynamic effects in the dose used. However, until further experience has been gained, ajmaline should be used with caution in digitalized patients and in those with impaired intra-cardiac conduction.
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  • 62
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    European journal of clinical pharmacology 8 (1975), S. 227-231 
    ISSN: 1432-1041
    Keywords: Dixyrazine ; methaqualone ; etodroxizine ; Isonox® ; sleep stages ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Whole night EEG and polygraphic recordings were made in ten young, healthy, male volunteers after dixyrazine (12.5 mg, 25 mg, 50 mg), methaqualone (250 mg) and Isonox® (methaqualone 250 mg + etodroxizine 50 mg). A total of 156 recording nights (36 adaptation nights were not included in the analyses) were scored for different sleep stages according to accepted criteria. The smallest dose of dixyrazine (12.5 mg) had no significant effect upon sleep pattern: the larger doses (25 mg and 50 mg) caused significant decreases in REM-sleep during the first nights of administration. The decrease disappeared during the following two nights of treatment. No withdrawal effects were seen. Methaqualone also caused moderate depression of REM-sleep during the first night of treatment, and this effect, too, disappeared during prolonged administration. Isonox® (methaqualone + etodroxizine) had a somewhat stronger surpressive effect upon REM-sleep than methaqualone alone.
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  • 63
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    European journal of clinical pharmacology 7 (1974), S. 263-268 
    ISSN: 1432-1041
    Keywords: β-adrenoceptors ; subcutaneous administration ; isoprenaline ; salbutamol ; terbutaline ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The selectivity of salbutamol 250 and 500 µg and terbutaline 250 and 500 µg compared with isoprenaline when administered subcutaneously has been investigated in 6 human volunteers who showed consistant bronchospasm when challenged with histamine by nebulizer. Changes in heart rate, forearm blood flow, tremor and F.E. V.1 were recorded and subjected to analysis of variance. Measurements were made at a fixed time interval after administration of active drugs or placebo and compared with pre-drug baseline recordings. The study was performed double-blind. A statistically significant difference was observed when all active drugs were compared with placebo, in the parameters of heart rate, F.E.V.1 and tremor. However, when the active drugs were compared with each other, no statistically significant difference was observed.
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  • 64
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    European journal of clinical pharmacology 7 (1974), S. 415-419 
    ISSN: 1432-1041
    Keywords: Impulsin ; non-specific resistance ; acute respiratory tract infections ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two large scale, double-blind field trials were conducted to test the efficacy of Impulsin (N-2-hydroxyethyl palmitamide) in reducing the incidence and severity of respiratory tract infections. The results suggested that repeated daily intake of Impulsin 30 mg per kg helped to prevent virus infections of the respiratory tract, since it produced a statistically significant reduction in the incidence of illness. Prophylactic treatment with Impulsin markedly diminished the number of episodes of fever, headache and sore throat, whilst catarrhal symptoms were much less affected. The administration of Impulsin had no effect on the mean duration of disability and fever, which suggests that the severity of the diseases was not affected.
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  • 65
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    European journal of clinical pharmacology 8 (1975), S. 91-96 
    ISSN: 1432-1041
    Keywords: Carbamazepine ; pharmacokinetics ; man ; diphenylhydantoin ; phenobarbital ; plasma binding
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Carbamazepine (2.7–3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1 – 7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 l/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2 – 3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.
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    European journal of clinical pharmacology 8 (1975), S. 167-173 
    ISSN: 1432-1041
    Keywords: Disopyramide ; haemodynamic effect ; negative inotropic effect ; anticholinergic effect ; hear failure ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effects of disopyramide have been studied in 11 patients with manifest or imminent heart failure. Disopyramide, 2 mg per kg body weight, was given intravenously during right and left heart catheterisation. The cardiac index decreased by an average of 28% (p〈0.01); mean maximal left and right ventricular end-diastolic pressures were increased by 5.0±0.9 mm Hg (〈0.01) and 5.0±0.6 mm Hg (p〈0.05), respectively; and left ventricular systolic pressure fell slightly but significantly (p〈0.05). No significant change in right ventricular systolic pressure was seen. Pulmonary wedge pressure rose on average by 2.7 mm Hg (p〈0.05). No significant change in heart rate was observed in 5 patients with sinus rhythm. In 6 patients with atrial fibrillation, there was a significant (p〈0.01) increase in heart rate; the average increase in heart rate for the entire group was 19,6 heats per minute. The maximum effect on all the parameters occurred 7–11 minutes after the injection, and it gradually subsided during the following 10 minutes. It was concluded that disopyramide had a potentially serious myocardial depressant effect.
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    European journal of clinical pharmacology 8 (1975), S. 353-357 
    ISSN: 1432-1041
    Keywords: Chlormethiazole ; pharmacokinetics ; man ; plasma levels ; gas-liquid chromatography
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of chlormethiazole have been studied in six healthy volunteers following an intravenous infusion of the drug. The log. plasma concentration-time curve of chlormethiazole after cessation of the infusion was found to be curvilinear and was fitted therefore, by a bi-exponential equation computed by non-linear least squares regression analysis. Half-lives for the inital α-phase (0.54±0.05 h) and the terminal β-phase (4.05 ±0.60 h) were calculated together with other pharmacokinetic parameters of the two compartment open model. An explanation for the discrepancy between the presently reported plasma half-lives and those appearing in the literature has been presented. The pharmacokinetic treatment of the plasma concentration-time data obtained following intravenous infusion also enabled the prediction that the maximal systemic availability of an orally administered dose of chlormethiazole would be of the order of 15%.
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  • 68
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    European journal of clinical pharmacology 8 (1975), S. 371-376 
    ISSN: 1432-1041
    Keywords: Digoxin ; bioavailability ; plasma levels ; cumulative urinary excretion ; particle size ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Various brands of digoxin tablets, and even different batches of one brand, may differ greatly in bioavailability. Digoxin-Sandoz® tablets have been compared with Lanoxin® manufactured between 1969 and 1972 and after May 1972. Comparisons were also made between and within batches of Digoxin-Sandoz tablets. Three separate cross-over studies were conducted involving a total of 20 volunteers. Digoxin-Sandoz tablets were shown to have a constant bioavailability and to produce plasma concentrations very similar to “new” Lanoxin. Storage for 2 years of one batch of Digoxin-Sandoz did not alter the bioavailability. Particle size was shown to influence bioavailability. Care should be exercised when plasma data alone are interpreted as an index of bioavailability. Measures of bioavailability based on plasma data obtained up to 6 h after administration differed from those based on cumulative urinary excretion data (in this study by a factor of about 2), which can lead to the belief that a difference in bioavailability is much greater than is actually the case. Data from cumulative urinary excretion, collected over a sufficiently long period of time, are likely to be the most reliable method for determining the bioavailability of a substance such as digoxin.
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  • 69
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    European journal of clinical pharmacology 8 (1975), S. 421-425 
    ISSN: 1432-1041
    Keywords: Proscillaridin ; enteric-coated tablets ; plasma levels ; urine excretion ; 86Rb-erythrocyte assay ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of proscillaridin was measured by a modified86Rd method during treatment with multiple doses of a commercial preparation of proscillaridin. Despite high doses, very low plasma levels were found, and there were only minute amounts of glycoside activity in urine and faeces. Administration of an enteric-coated proscillaridin preparation gave higher plasma levels, which raises the possibility of inactivation of the glycoside by acid gastric juice. The results suggest that proscillaridin has low biological availability when given orally, and that it is extensively metabolised in the body.
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  • 70
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    European journal of clinical pharmacology 3 (1971), S. 106-112 
    ISSN: 1432-1041
    Keywords: Probenecid ; probenecid acyl glucuronide ; sulfinpyrazone ; renal ; man ; metabolism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolism of probenecid has been investigated in both normal and gouty subjects. To carry out these studies, specific spectrophotometric methods were developed for the measurement of a major metabolite of probenecid, the acyl glucuronide. This conjugate was isolated in semi-pure state and its identity as a mono acyl glucuronide established. Our experiments indicate that about 25% of probenecid is converted to its acyl glucuronide and that only a small amount of the drug is excreted unchanged. About 80% of orally administered14C probenecid could be accounted for in urine, and about half of this was found to consist of metabolites more polar than the parent drug. The renal clearance of probenecid acyl glucuronide was shown to be about 1/3 that of creatinine clearance, whereas the clearance of probenecid was lower. The present findings in man and those of other workers in animals, raise the important question of the possible contribution of these metabolites to the overall pharmacological effects resulting from the administration of probenecid.
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  • 71
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    European journal of clinical pharmacology 4 (1972), S. 201-205 
    ISSN: 1432-1041
    Keywords: Tricyclic antidepressant ; nortriptyline ; metabolism ; stereospecific hydroxylation ; plasma kinetics ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thecis andtrans isomers of 10-hydroxynortriptyline (10-OH-NT), the major metabolite of nortriptyline (NT) in man, have been separated and quantitated in urine from 6 healthy volunteers who received NT orally, 0.4 mg/kg body weight, three times daily. The isomers were separated by preparative thin layer chromatography and quantitatively determined by gas chromatography as the 10,11-dehydronortriptyline heptafluorobutyryl derivative. The structure of these derivatives producedin vitro was confirmed by gas chromatography — mass spectrometry. Less than 1% of totally excreted 10-OH-NT was accounted for as 10,11-dehydronortriptyline. — Despite interindividual differences in the mean steady-state plasma concentration of NT, the ratio between the two isomers was constant in all subjects (1:4–5). The isomers were both optically active and circular dichroism spectra showed that the asymmetric carbon atoms in the two compounds have different configurations. — It is concluded that NT undergoes stereospecific hydroxylation in man and that there is no correlation between the mean steady-state plasma concentration of NT and the proportion of thecis andtrans isomers formed.
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  • 72
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    European journal of clinical pharmacology 10 (1976), S. 251-256 
    ISSN: 1432-1041
    Keywords: Sisomicin ; pharmacokinetics ; bioavailability ; two-compartment analysis ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sisomicin, a new single component aminoglycoside antibiotic related to gentamicin c1a, were determined in four healthy volunteers after intravenous and intramuscular administration of a 1 mg/kg dose. The elimination profile of this antibiotic follows two-compartment model kinetics after I.V. administration. The fast (α) and slow (β) disposition rate constants averaged 0.072 and 0.004 min−1, respectively. The volume of distribution at the steady-state averaged 0.185 liters/kg which approximately corresponds to the volume of extracellular space. The physiological availability of an intramuscular dose appeared to be complete. A method of administration adapted to the kinetic properties of the drug is proposed.
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  • 73
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    European journal of clinical pharmacology 11 (1977), S. 141-147 
    ISSN: 1432-1041
    Keywords: Phenothiazine ; thioridazine ; plasma level ; metabolic pattern ; half life ; man ; schizophrenia
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma-levels of thioridazine, mesoridazine, sulphoridazine and two other metabolites were determined in ten older chronic psychotic patients on thioridazine therapy. The plasma-level before the morning dose of thioridazine was the most reliable parameter for clinical studies. An intra-individual relationship between lower doses of thioridazine and plasma-levels was found. The percentage contribution of psychoactive compounds to the total sum of “thioridazine plus metabolites” ranged from 43–74%. The mean “early disappearance half-life” of thioridazine was 5 hours, and its mean “late disapperance half-life” was 26 hours.
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  • 74
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    Keywords: cyproheptadine ; metergoline ; glucose tolerance ; insulin secretion ; chemical diabetes ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of short-term treatment with either placebo or two serotonin antagonists, cyproheptadine and metergoline, on oral glucose tolerance and insulin secretion have been evaluated in normal subjects and in patients with chemical diabetes. Placebo treatment was not associated with any significant change in the parameters examined. Glucose tolerance in chemical diabetics was significantly improved both after cyproheptadine and metergoline; fasting plasma glucose was also reduced by metergoline. Treatment with the latter drug was also associated with a significant decrease in incremental glucose area in healthy subjects, which was not affected by cyproheptadine. Basal and glucose-stimulated insulin secretion were not affected by either drug in any subjects. Cyproheptadine and metergoline improve glucose metabolism in chemical diabetes probably by reducing insulin resistance. This may depend either on decreased secretion of counter-regulatory hormones or on a direct pharmacological action of the drugs on glucose utilization, possibly mediated by their common antiserotoninergic properties.
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  • 75
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    Keywords: Acetylsalicylic acid ; surgery ; man ; bleeding ; pain ; wound-healing
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetylsalicylic acid (ASA) was tested against placebo in a double-blind crossover study, in which essentially the same operation was performed twice on 23 healthy patients who required surgical removal of bilateral “identically” impacted wisdom teeth. On the evening before one operation they received ASA 1.0 g (Globentyl®) followed by ASA 2.0 g daily for the next 3 days, and at the other operation placebo tablets. A number of objective and subjective parameters were recorded for paired comparison of the pre-, per-, and post-operative courses, including bleeding, pain, wound-healing, and preference. Tests of platelet aggregation before each operation indicated whether or not ASA had been taken. Pre-operative bleeding time was significantly increased (from 4.4 to 6.9 min) by ASA, as well as the per-operative blood loss (about 30%), and the post-operative bleeding tendency. Episodes of profuse post-operative haemorrhage were reported by 5 patients, always after the operation for which ASA had been given. ASA also significantly promoted the occurrence of ecchymosis and haematoma. The pre-operative bleeding time was not a reliable predictor for these complications. The drug was very well tolerated with respect to side effects such as abdominal discomfort. The post-operative pain scores were neither reduced nor increased significantly by ASA, and the preference scores were not in favour of the drug. The present patients were all young and denied any previous bleeding disorders; nevertheless, ASA resulted in post-operative haemorrhage, ecchymosis and haematoma formation in several cases.
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  • 76
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    European journal of clinical pharmacology 10 (1976), S. 257-262 
    ISSN: 1432-1041
    Keywords: Anti-inflammatory and analgesic drug ; indoprofen ; pharmacokinetics ; bioavailability ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a pharmacokinetic study of the new analgesic and anti-inflammatory drug indoprofen, plasma levels and urinary excretion were determined in four healthy volunteers after 100 mg and 200 mg iv, and after 100 mg (capsules) and 200 mg (tablets) oral doses. After iv administration, the mean biological half-life (t1/2 β) was about 2 h (range 1.4 to 3.2 h). The apparent volume of distribution Vdβ ranged between 11 to 17 % of body weight, indicating its limited extravascular distribution. Most of the drug was excreted in urine as glucuronide and a smaller proportion as unchanged indoprofen: the 24 h urinary excretion of these compounds accounted for 67 to 95 % of an iv dose. Peak plasma levels occurred between 30 and 120 minutes after oral administration of 100 mg as capsules or 200 mg as tablets. The mean biological half-life was about 2 h, as after iv administration. The bioavailability of oral doses was assessed using both plasma levels and urinary excretion data. The absorption of capsules and tablets was practically complete, that of the former being faster.
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  • 77
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    European journal of clinical pharmacology 10 (1976), S. 59-62 
    ISSN: 1432-1041
    Keywords: Tetracycline absorption ; zinc sulphate ; zinc citrate ; complex formation ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The inhibitory effect of zinc on the gastrointestinal absorption of tetracycline has been investigated in 7 healthy volunteers. Zinc (45 mg Zn++) was given as a solution of zinc sulphate and as a zinc citrate complex; tetracycline (500 mg) was administered as a commercially available preparation. Serum tetracycline concentrations and the area under the serum tetracycline concentration-time curve (up to 6 h) were significantly reduced when tetracycline was taken with either zinc sulphate or the zinc citrate complex. Although the reduction of absorption seemed more pronounced after zinc sulphate, the difference between the inhibitory effects of the two forms of zinc was not significant. It is concluded that simultaneous administration of zinc and tetracycline may reduce absorption of tetracycline.
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  • 78
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    European journal of clinical pharmacology 10 (1976), S. 127-131 
    ISSN: 1432-1041
    Keywords: Gallbladder emptying ; analgesics ; indoprofen ; pentazocine ; morphine ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A controlled study of the clinical pharmacology of the biliary tract has been made. The rate of gallbladder emptying induced by a fatty meal was taken as a parameter for assessment of the inhibitory effect of indoprofen, a new analgesic-anti-inflammatory drug, pentazocine and morphine. The compounds were administered as single doses by iv (indoprofen and pentazocine) or im (morphine) injection. Indoprofen up to 400 mg had no effect, whereas morphine and pentazocine exerted a significant inhibitory effect on emptying of the gallbladder. Adverse reactions of clinical significance were associated with morphine and pentazocine, but were negligible with indoprofen.
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  • 79
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    European journal of clinical pharmacology 10 (1976), S. 197-200 
    ISSN: 1432-1041
    Keywords: Dopamine-β-hydroxylase ; dopamine infusion ; blood pressure ; plasma ; man ; inter-individual variation
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to study the function of dopamine-β-hydroxylase (DBH) in human plasma, dopamine, its natural substrate, was infused intravenously in 22 healthy volunteers. Their plasma DBH activities showed great interindividual variations (31–301 units/ml). The infusion rates of dopamine required to increase systolic blood pressure (BP) by 30 mm Hg differed considerably between the subjects, and ranged from 3,0 to 11,6 µg/kg/min. No correlation could be shown between the various dopamine doses and individual plasma levels of DBH. It was concluded, therefore, that plasma DBH in the blood stream was enzymatically inactive. Experiments with human plasma DBH in vitro also support this interpretation. Consequently, interindividual differences in the effects on BP during dopamine infusion cannot be due to pressor effects of noradrenaline synthesized by plasma DBH.
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  • 80
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    European journal of clinical pharmacology 11 (1977), S. 337-344 
    ISSN: 1432-1041
    Keywords: Twin study ; ethanol metabolism ; intra-individual variation ; pharmacogenetics ; plasma level ; man ; heritability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of genetic and environmental factors on the metabolism of a single oral dose of ethanol 1.2 ml per kg body weight was analysed in 19 identical and 21 fraternal healthy, adult, un-selected male twin pairs. The heritability values of the rates of absorption, degradation and elimination of ethanol were 0.57, 0.41 and 0.46 respectively. Environmental factors, such as daily alcohol intake and smoking, increased the rate of elimination of blood alcohol. Intrasubject variation in ethanol metabolism was studied by repeated tests in 11 male volunteers at intervals of at least 2 months, under the same conditions as in the twins; the coefficients of variation for parameters of metabolism was about 8%. The results demonstrate both genetic control of ethanol absorption, degradation and elimination and the appreciable influence of environmental factors. The almost total genetic control of ethanol metabolism postulated by Vesell et al. (1971) could not be confirmed.
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  • 81
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    European journal of clinical pharmacology 11 (1977), S. 359-366 
    ISSN: 1432-1041
    Keywords: Phenylbutazone ; 14C-label ; oxyphenbutazone ; gas chromatography ; disposition ; oxidative metabolism ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption and elimination of orally administered14C-phenylbutazone and the role of oxidation in its metabolism have been studied. The main routes of excretion of14C-phenylbutazone and its metabolites were investigated in 3 patients with rheumatoid arthritis, and in 1 patient with a T-tube in the common bile duct. Up to 9 days after an oral dose of14C-phenylbutazone 600 mg (30 µCi) 63% of the radioactivity was found in the urine and 14% had appeared in the faeces. The cumulative excretion of radioactivity in bile amounted to 9.5% of the dose in 4 days. Only 1% of the radioactivity in the urine and bile was due to unchanged phenylbutazone. The role of oxidative metabolism of phenylbutazone in healthy human subjects was studied by gas chromatography. In 3 subjects given a single dose of phenylbutazone 600 mg, only 8.3% of the dose was excreted in urine as oxidized metabolites after 5 days. However, in 5 patients who had taken phenylbutazone for more than 5 weeks, these metabolites accounted for 23.4% of the dose. These results suggest that oxidative metabolism becomes more important after continued administration of the drug. After a single dose of phenylbutazone, the side-chain oxidized metabolite (II) was the major free derivative excreted in urine, but the ring oxidized metabolite, oxyphenbutazone (I), was much more important than the former in plasma. However, after prolonged treatment there was little difference between the concentration of the two metabolites in plasma. This finding suggests that side-chain oxidation is increased relative to ring oxidation on prolonged treatment with phenylbutazone. A third derivative containing hydroxyl groups both in the phenyl ring and in the side-chain (metabolite III) was found in urine in experiments with phenylbutazone, but in only one out of 3 volunteers given repeated doses of oxyphenbutazone.
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  • 82
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    European journal of clinical pharmacology 12 (1977), S. 153-158 
    ISSN: 1432-1041
    Keywords: Fentanyl ; radioimmunoassay ; cross-reaction ; plasma level ; dog ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Antiserum to fentanyl was obtained in rabbits repeatedly injected with carboxyfentanyl conjugated to bovine serum albumin. Using the antiserum, a highly sensitive radioimmunoassay has been developed, based on the dextran-coated charcoal method. It proved possible to assay the drug directly in plasma, in amounts as small as 30 picogram in 0.5 ml. The antibody was highly specific for fentanyl and no cross-reaction was observed with its major metabolites. This sensitive and specific radioimmunoassay method was employed to determine fentanyl in plasma from six volunteers after an intravenous bolus of 0.2 mg, and in plasma from dogs treated both intravenously and subcutaneously with 0.02 mg/kg. The plasma level of fentanyl could be followed for up to 6 h after a therapeutic dose in dogs and man.
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  • 83
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    European journal of clinical pharmacology 13 (1978), S. 213-218 
    ISSN: 1432-1041
    Keywords: Activated charcoal ; acute intoxication ; digoxin ; phenytoin ; aspirin ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The inhibitory effect of activated charcoal 50 g suspended in water on the absorption of digoxin, phenytoin and aspirin was studied in six healthy volunteers in a cross-over manner. The absorption of digoxin and phenytoin were almost completely prevented (about 98%) when activated charcoal was ingested immediately after the drug. The total absorption of aspirin was inhibited by 70%, with clear postponement of absorption and partial release of aspirin from the charcoal in the gut: The peak serum concentration of aspirin was reduced by 95% by charcoal. When activated charcoal was ingested 1 hour after the drugs the inhibition of absorption was considerably less. However, since the absorption of larger doses of the drugs is often slow, the administration of an adequate dose of activated charcoal will be of definite value in the treatment of acute intoxication, even if delayed for several hours.
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  • 84
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    European journal of clinical pharmacology 14 (1978), S. 129-131 
    ISSN: 1432-1041
    Keywords: Tetracycline absorption ; EDTA ; milk ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of tetracycline in man under the influence of concomitantly administered EDTA, milk and a combination of EDTA and milk has been investigated. Urinary excretion of the drug was measured for 30 h. The inhibitory effect of milk could be counteracted by simultaneous ingestion of EDTA, which resulted in almost equivalent urinary excretion of tetracycline compared to experiments done in the fasting state. Administration of EDTA alone, in a neutral dosage form, did not significantly change absorption of the drug, which contradicted previous findings. The possible use of EDTA during tetracycline therapy is discussed.
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  • 85
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    European journal of clinical pharmacology 14 (1978), S. 277-280 
    ISSN: 1432-1041
    Keywords: Doxycycline ; iron ; charcoal ; enteral cycling ; man ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to study the intestinal interactions of doxycycline (DC) with Fe++ and charcoal, two groups of healthy volunteers were given either 200 mg or 100 mg DC in capsules at 2 p. m. and 9 p. m., and blood samples for fluorimetric assay of DC were collected for 24 h starting at 8.30 a. m. on the following morning. A 24-h-urine was also collected. The test was subsequently repeated at one-week intervals, when the volunteers also ingested either ferrous sulphate (80 mg Fe++) or charcoal (4.0 g) immediately after the zero-time sample of DC and at 3, 8 and 12 h. Charcoal completely adsorbed DC in vitro in an artificial small intestinal fluid. Ferrous sulphate or charcoal did not modify the serum level or urinary excretion of DC after the 200 mg+200 mg dose, but ferrous sulphate did reduce the 24-h urinary excretion of DC after the 100 mg+100 mg dose. The serum half-life and AUC of DC were reduced by ferrous sulphate given after the 100 mg+100 mg dose of DC. Charcoal did not modify any parameter, even after the 100 mg+100 mg dose of DC. The results do not support existence of important enteral cycling of DC. Although oral ferrous sulphate can lower the serum level and shorten the serum half-life of DC, the acute experiment suggested that a therapeutic serum level of DC can be maintained despite treatment with iron in the doses used in iron-deficiency, and charcoal in the doses used in diarrhoeic states, if the drugs are administered several hours apart.
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  • 86
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    European journal of clinical pharmacology 15 (1979), S. 187-192 
    ISSN: 1432-1041
    Keywords: quinidine ; plasma protein binding ; pharmacokinetics ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant (β) varied from 0.071 to 0.146 h−1 (mean 0.113), and apparent volume of distribution (Vβ) varied from 1.39–3.20 l · kg−1β (mean 2.27). Total body clearance was 2.32–6.49 ml min−1 · kg−1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both Vβ (r=0.885, p〈0.01) and total body clearance (r=0.668, p〈0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.
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    European journal of clinical pharmacology 14 (1978), S. 69-73 
    ISSN: 1432-1041
    Keywords: Citalopram ; pharmacokinetics ; man ; steady state levels ; metabolism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of citalopram, a potent serotonin reuptake inhibitor, and its demethylated metabolite have been determined by a specific fluorescence coupling technique during single dose experiments in volunteers and in clinical tests. Citalopram was found to have linear kinetics within the dose range investigated, which were characterized by fairly rapid absorption and slow elimination (biological half-life 1–21/2 days). Steady state levels in the range 120–340 nM (i.e. slightly above those associated with pharmacodynamic activity in animals) were attained within a week. A drug/metabolite ratio of 2–3 was recorded.
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    European journal of clinical pharmacology 14 (1978), S. 425-430 
    ISSN: 1432-1041
    Keywords: Penta-acetyl-gitoxin ; 16-acetyl-gitoxin ; gitoxin ; mass spectrometry ; species-specific deacylation ; man ; rabbit ; guinea-pig ; rat ; blood ; intestinal mucosa ; liver homogenate
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Penta-acetyl-gitoxin (PAG) shows species-specific deacylation to 16-acetyl-gitoxin (16-AG; I and III) or gitoxin (II and IV) by homogenates of liver and intestinal mucosa of man (I), rabbit (II), guinea-pig (III) and rat (IV), whereas it is degraded into tri- and tetra-acetates by homogenates of guinea-pig myocardium as well as by human blood and serum. The identity of the principal and chloroform-extractable metabolites in human urine after PAG administration with 16-AG has been demonstrated by mass spectrometry.
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  • 89
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    European journal of clinical pharmacology 15 (1979), S. 73-81 
    ISSN: 1432-1041
    Keywords: simulation model ; diazoxide hypotension ; haemodynamics ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute haemodynamic effects of injected diazoxide (Hyperstat® Schering) have been studied in 8 hypertensive subjects. Aortic blood pressure was measured and cardiac output and peripheral conductance were assessed continuously using a simulation model. In six of the patients pulmonary artery end-diastolic pressure was also measured. Blood pressure fell in all subjects 5–10 min after injection of the drug cardiac output increased in all patients studied. However, the initial change in cardiac output differed, as it decreased in two subjects and did not change in one. The largest initial increases in cardiac output were seen in the subjects with the highest pulmonary artery end-diastolic pressure. Patients with an initial decrease in cardiac output were those with the least compliant (stiffest) aortas. We consider that the responsiveness of the baroreceptors determines the size of the increase in cardiac output immediately after reduction of blood pressure by diazoxide. Thus in a patient with a stiff aorta, particularly at low cardiac filling pressure, diazoxide might cause a fall in blood pressure to an unacceptable level.
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  • 90
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    Archives of microbiology 96 (1974), S. 145-153 
    ISSN: 1432-072X
    Keywords: Ultrastructure ; Scenedesmus Bristles ; Openings ; Props ; Ridges ; Tubules ; Brisble Origin
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    Topics: Biology
    Notes: Abstract Bristles radiating from openings were detected on colonies and unicells ofScenedesmus culture N 46, when examined with transmission and scanning electron microscopes. Although narrower, they correspond in gross appearance and ultrastructure to previously describedScenedesmus bristles. Openings, bordered by a series of props, are unlike those ofScenedesmus culture 614. Additional props are observed scattered independently on the cell wall; ridges are composed of a linear row of props. Sections of cells, or cell walls, reveal an additional prop, situated inside the openings; these props are composed of several tubules. Possible extrusion of bristles through these tubules, as well as the origin of the bristle from the cavity and vesicles immediately under the opening are discussed.
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    Archives of microbiology 96 (1974), S. 305-317 
    ISSN: 1432-072X
    Keywords: Marine Fungi ; Ultrastructure ; Multilamellate Sporangial Wall ; Sagenogenetosome ; Zoospore Cleavage
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    Topics: Biology
    Notes: Abstract The morphology and ultrastructure of aJaponochytrium sp. has been studied by light, scanning and transmission electron microscopy. The wall has been shown to be multilamellate and persistent. Stages in zoospore cleavage are described and sagenogenetosomes reported in mature sporangia.
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    Archives of microbiology 98 (1974), S. 147-158 
    ISSN: 1432-072X
    Keywords: Allomyces ; Zoospores ; Cell Wall ; Wall Formation ; Lomasome ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Ultrastructural observations on encysting haploid zoospores of Allomyces arbuscula are presented with special reference to cell wall deposition. Multivesicular bodies are observed in the cytoplasm of zoospores 15 min after inoculation, lomasomes after 30 min and fine membrane profiles between the plasmalemma and the cyst wall are observed after 4 h indicating a possible system for secretion of cell wall components.
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  • 93
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    Archives of microbiology 99 (1974), S. 331-344 
    ISSN: 1432-072X
    Keywords: Myxomycetes ; Ultrastructure ; Development ; Systematics ; Food Vacuoles ; Stalk Development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Observations of sporophore development in fresh and glutaraldehydeosmium sequentially-fixed material ofProtophysarum phloiogenum show the following sequence. Small plasmodia cease streaming and round up. Food vacuoles collect in the lower center of the cytoplasmic mass. As the cytoplasm rises the food vacuolar contents are excluded from the plasmalemma and become the stalk core. A continuous, fibrous peridium and stalk tube enclose cytoplasm and stalk core respectively. Capillitial formation just precedes spore cleavage. Sporophore development is marked by autophagic activity and calcium deposition. Stalks of dried herbarium specimens of seven additional species have been examined. A mature stalk morphology very similar toProtophysarum with recognizable remnants of microorganismal food material is seen in all of them. It is thought that this marker is indicative of non-stemonitaceous stalk development.
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  • 94
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    Archives of microbiology 96 (1974), S. 175-182 
    ISSN: 1432-072X
    Keywords: Ultrastructure ; Septa ; Schizophyllum ; Dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A strain ofSchizophyllum commune carrying a mutation in theB-mating factor (B-mut) shows septal dissolution when grown at 30° C for 2 to 3 days. The septa are intact if the organism is grown at 25° C for the same time, but begin to break down within 1 h after transfer to 30° C. At the ultrastructural level the dolipore swelling is the first part of the septal apparatus to be degraded, closely followed by the disorganization of the parenthesomes. A progressive thinning of the septal cross-wall produces an enlargement of the septal aperture sufficient to allow the passage of nuclei. It appears that degradative enzymes are probably carried to the site of septal dissolution in vesicles derived from endoplasmic reticulum in the area of the septal apparatus.
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  • 95
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    Archives of microbiology 96 (1974), S. 271-279 
    ISSN: 1432-072X
    Keywords: Anabaena cylindrica ; Nitrogen Starvation ; Pigmentation ; Ultrastructure ; Heterocyst Differentiation ; Nitrogenase Activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Nitrogen starvation, effected by incubating a culture ofAnabaena cylindrica in a medium free from combined nitrogen and under an atmosphere of 1% CO2 in argon, leads to rapid and characteristic changes in the appearance, structure and function of the alga. Change of colour, due apparently to a decrease in the amounts of nitrogenous pigments, is accompanied by a structural transformation of vegetative cells: cyanophycin granules and polyhedral bodies disintegrate, lipid and glycogen accumulate, and large membrane-bound spaces form by means of thylakoid swelling and vesiculation. The rate of heterocyst differentiation and nitrogenase activity is increased. These changes are fully reversed on addition of ammonia to the culture. It appears that thylakoids reform by coalescence of small vesicles assembled in the intrathylakoidal space. Rapid ammonia assimilation is indicated by ample formation of cyanophycin granules in vegetative cells and of “plugs” in the heterocysts.
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  • 96
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    Archives of microbiology 98 (1974), S. 199-206 
    ISSN: 1432-072X
    Keywords: Ultrastructure ; Chlamydomonas ; Senescent ; Microtubules ; Complexes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Complexes of twisted ribbons composed of ordered arrays of microtubules are identified in close association with the plasmalemma and the surfaces of some organelles in senescent cells of photoheterotrophically cultured Chlamydomonas dysosmos. The ribbon complexes occur throughout the cytoplasm, and do not appear related to the flagellar insertions. The component microtubules are approximately 26 nm in width, exhibiting a center-to-center spacing of about 44 nm. Additional cytoplasmic microtubules are often closely related to the tubular complexes. A detailed description of their fine structure is presented here which tends to support the ascribed function of microtubules in maintaining the structural integrity of the protoplasm.
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  • 97
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    Archives of microbiology 99 (1974), S. 221-230 
    ISSN: 1432-072X
    Keywords: Anabaena cylindrica ; Molybdenum ; Vanadium ; Nitrogenase ; Ultrastructure ; Storage Products ; Heterocyst Frequency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The structural and functional symptoms of molybdenum deficiency inAnabaena cylindrica grown in a medium without combined nitrogen and thus dependent on fixation of elemental nitrogen, resemble those brought about by nitrogen starvation. However, the substantially increased rate of heterocyst differentiation in this culture is not accompanied by a corresponding increase in nitrogenase activity; on the contrary, enzyme activity is severely impaired in the absence of molybdenum. When the supply of molybdenum, or of ammonia, is restored, the alga recovers rapidly. Vanadium exerts an inhibitory effect upon nitrogen-fixing ability of the alga, and its presence in the molybdenum-deficient culture results in the amplification of the symptoms of mlybdenum deficiency.
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  • 98
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    Archives of microbiology 99 (1974), S. 265-269 
    ISSN: 1432-072X
    Keywords: Ultrastructure ; Microbodies ; Vacuolaria ; Gonyostomum ; Chloromonadophyceae ; Chromophyta
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Microbody-like organelles occur in the cytoplasm of two chloromonadophycean algae,Vacuolaria virescens Cienkowsky andGonyostomum semen Diesing. Microbodies ofVacuolaria andGonyostomum have a granular matrix which lacks a crystalloid core; they are often present in close association with elements of the endoplasmic reticulum. The occurrence of microbodies in other algae is briefly reviewed.
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  • 99
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    European journal of clinical pharmacology 5 (1972), S. 62-64 
    ISSN: 1432-1041
    Keywords: GLC ; fenfluramine ; norfenfluramine ; blood levels ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new analytical procedure is described for the determination of fenfluramine and norfenfluramine in biological specimens. Fenfluramine and norfenfluramine are converted to the trichloroacetyl derivatives, separated on a 3% OV 17 — Chromosorb Q glass column and measured by ECD. The rapidity, sensitivity and specificity of the technique fulfil all the requirements for routine clinical use.
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  • 100
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    European journal of clinical pharmacology 6 (1973), S. 181-186 
    ISSN: 1432-1041
    Keywords: Phenothiazines ; thioridazine ; serum levels ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The rate of absorption of thioridazine varied greatly in ten healthy volunteers who took 100 mg in the morning after an overnight fast. The peak level in blood was also variable and it was reached 1 1/4 to 4 h after dosing. Maximal concentrations in the blood varied widely from 0.13 µg/ml to 0.52 µg/ml. No relation was found between the weight or sex of the subjects and the pharmacokinetics of the drug. The serum half life of thioridazine in three healthy volunteers was 9, 10 and 10 h respectively. In a group of 22 patients receiving less than 5 mg/kg body weight a day, there was a strong correlation between the dose and the morning or evening concentration of thioridazine in the blood. A positive correlation was also observed between the age of the patient and the serum level in those who received doses of less than 5 mg/kg body weight.
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