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  • Ultrastructure  (805)
  • Electron microscopy  (760)
  • pharmacokinetics  (230)
  • man  (90)
  • kinetics
  • Springer  (1,895)
  • American Chemical Society
  • 1975-1979  (1,039)
  • 1970-1974  (856)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of solution chemistry 6 (1977), S. 203-216 
    ISSN: 1572-8927
    Keywords: Glucose ; kinetics ; mixed solvent ; kinetic isotope effect ; enthalpy of activation ; entropy of activation ; tetrahydrofuran ; tert-butanol ; mutarotation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The mutarotation rates of glucose in aqueous mixtures of tetrahydrofuran andtert-butanol in the mole fraction (xi) range 0〈xi〈0.2 have been measured at 5° intervals in the range 5–35°C. The kinetic deuterium isotope effects have been determined for the same solvent compositions at 25 and 35°C. A statistical analysis of the Arrhenius plots indicates that the experimental errors, although small, are too large for the establishment of any compensation behavior between ΔH
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  • 2
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    Journal of solution chemistry 2 (1973), S. 217-238 
    ISSN: 1572-8927
    Keywords: Cation ; energies ; H. S. Frank ; M. Eigen ; R. G. Wilkins ; kinetics ; ligand substitution ; mechanism ; mixed solvents ; nonaqueous ; solvation ; solvent ; solvent structure ; solvent exchange ; transition metal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The role of the solvent in reactions involving ions is considered in relation to the structure of liquids. The rate constants and activation parameters for ligand substitutions at divalent transition metal cations in various solvents are compared with those for solvent exchanges. The differences are related to structural properties of the solvents, represented by their heats of evaporation and fluidities, and interpreted with the aid of a model developed from that of Frank and Wen. Water is not a typical solvent.
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  • 3
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    Journal of solution chemistry 5 (1976), S. 163-169 
    ISSN: 1572-8927
    Keywords: Solvent effects ; tetramethylurea ; hydrolysis ; hydrogen bonding ; kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Tetramethylurea was hydrolyzed in aqueous hydrochloric acid at temperatures of 80, 90, and 100°C. All reactions were carried out in an excess of both tetramethylurea and water, with first-order dependence on acid concentration being observed. As the concentration of water was increased, the rate of hydrolysis decreased until equimolar amounts of water and tetramethylurea were present. Subsequent addition of water had no effect on the observed rate.
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  • 4
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    Journal of solution chemistry 3 (1974), S. 881-887 
    ISSN: 1572-8927
    Keywords: Binary aqueous mixtures ; solubilities ; kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A treatment which predicts the solubilities of gases in solvent mixtures is examined in the context of the analysis of kinetic data for reactions in aqueous mixtures. The treatment is qualitatively successful to some extent in resolving the effects of changes in the initial state of the reacting substrate in the activation parameters.
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  • 5
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    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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  • 6
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    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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  • 7
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    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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  • 8
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    Calcified tissue international 25 (1978), S. 217-222 
    ISSN: 1432-0827
    Keywords: Bone mineral ; Electron microscopy ; X-ray diffraction ; Dark field
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Electron microscopical observations of the size and shape of bone mineral crystallites have not been in complete agreement with X-ray diffraction findings. The two prevalent viewpoints consider bone mineral crystals to be either rod, or plate like in habit. There appears to be agreement that the smallest dimension of the crystals is about 5 nm, but there is discrepancy in the reported c-axial lengths. The method of dark field imaging is used to obtain a quantitative measurement of the c-axial length distribution in rabbit, ox and human bone: mean c-axial lengths 32.6 nm, 36.2 nm and 32.4 nm, respectively, show no significant difference at the 5% level to the mean c-axial length measured by X-ray line broadening. Both bright and dark field images strongly suggest that bone mineral has a plate like form. Reasons for past discrepancies are discussed.
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  • 9
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    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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  • 10
    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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  • 11
    ISSN: 1432-0827
    Keywords: Parathyroid hormone ; Osteoclasts ; Electron microscopy ; Morphometry ; Metaphysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The effects of parathyroid hormone (PTH) on the size of the osteoclasts, nuclei, ruffled borders, and clear zones in long bones of thyroparathyroidectomized (TPTX) rats were quantitated as a function of time. These data were compared with the number of osteoclasts in the bone and with plasma calcium levels. A significant increase in the average size of the ruffled borders was demonstrated 30 min after injection of 50 U of purified bovine PTH, and of the clear zones 30–90 min after PTH. This was followed at 90 min by an increase in the average size of the cells. The sizes of ruffled borders and clear zones dropped sharply to control levels after 6 h, whereas the size of the cells remained elevated up to 12 h and returned to control values at 24 h. Plasma calcium levels were increased, but not significantly, between 30 min and 6 h. An increase in the number of osteoclasts was significant after 12 h. Removal of the parathyroid glands did not diminish the normal activity of osteoclasts. In animals with intact glands injection of 50 U of PTH did not cause a significant change in cell size or resorbing apparatus. It is concluded that PTH acts to rapidly stimulate the bone resorptive activity of osteoclasts and to cause a delayed increase in their number.
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  • 12
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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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  • 13
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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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  • 14
    ISSN: 1573-0832
    Keywords: Microsporon audouinii ; Pyrrolnitrin ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Scanning and transmission electron microscopy showed that a ceiling quantity (1.56 mcg) of antifungal antibiotic Pyrrolnitrin caused heavy damage to dermathophyteMicrosporon audouinii Gruby CBS 313-54in vitro. Suitable preparation technique made it clear that the changes involved consisted of hyphal collapse on the edge of the culture, with loss of euplasmic organelles identity and cell autolysis. The cell wall, however, was apparently undamaged. These findings fit in with the suggestion that the mode of action of the antibiotic leads to generalised lipoproteic membranes damage. They must, however, be considered as representing the result of the terminal phase of cell distress.
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  • 15
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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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  • 16
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    Mycopathologia 60 (1977), S. 175-177 
    ISSN: 1573-0832
    Keywords: Aspergillus fumigatus ; Spore formation ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 17
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    Mycopathologia 61 (1977), S. 117-119 
    ISSN: 1573-0832
    Keywords: Prototheca ; Colorless alga ; Plastids ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract An ultrastructural investigation of six different species of Prototheca showed that all of them contained starch grains enclosed in double-membrane-bounded structures recognized as plastids. It is concluded that these unicellular species of Prototheca must be considered as non-photosynthetic algae.
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  • 18
    ISSN: 1573-0832
    Keywords: Trichophyton mentagrophytes ; Thiocyanatopyrazole derivatives ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Four thiocyanatopyrazole derivatives were synthesized and their fungistatic activity was demonstrated in vitro against a number of dermatophytic fungi. In Trichophyton mentagrophytes, the most active compound induced an unusual increase of the plasma membrane with production of intra and extracytoplasmic complexes, a deterioration of nuclear and mitochondrial membranes and a formation of autophagic-like vacuoles. Plasmolysis, accompanied by an almost complete disorganization of cytoplasmic structures, seemed to be the final event. A possible mechanism of action of the compounds was discussed.
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  • 19
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    Applied physics 8 (1975), S. 319-331 
    ISSN: 1432-0630
    Keywords: Self-interstitials in silicon ; Swirls ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Abstract Point defect agglomerates in dislocation-free silicon crystals, usually called “swirls”, have been investigated by means of high-voltage electron microscopy. It was found that a single swirl defect consists of a dislocation loop or a cluster of dislocation loops. By contrast experiments it could be shown that these loops are formed by agglomeration of self-interstitial atoms. Generally the loops have a/2〈110〉 Burgers vectors, but in specimens with high concentrations of carbon (∼1017 cm−3) and oxygen (∼1016 cm−3) also dislocation loops including a stacking fault were observed. In crystals grown at growth rates higher thanv=4 mm/min no swirls are observed; lower growth rates do not markedly affect the size and shape of the dislocation loops. With decreasing impurity content (particulary of oxygen and carbon) the swirl density decreases, whereas the dislocation loop clusters become larger and more complex. A model is presented which describes the formation of swirls in terms of agglomeration of silicon self-interstitials and impurity atoms.
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  • 20
    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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    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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    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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    Development genes and evolution 186 (1979), S. 65-70 
    ISSN: 1432-041X
    Keywords: Sea urchin ; Embryo ; Collagen ; Ultrastructure
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    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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    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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  • 25
    ISSN: 1432-041X
    Keywords: Synaptogenesis ; Electron microscopy ; Visual acuity ; Fish development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The morphogenetic differentiation of synapses of the optic tectum of the rainbow trout was investigated at different stages of development (from hatching to adult) and compared with the improvement in visual discrimination (minimum separable). (1) The main phase of synaptogenesis (increase in number of synapses, length of contact zone and number of vesicles) begins about one week after hatching and continues up to the age of one month, when the larvae start swimming freely. (2) Myelination begins 26 days after hatching and induces the end of the synaptogenesis period. (3) The visual discrimination (minimum separable) of trout larvae improves from 30 degrees of arc on the 10th day after hatching to 1 degree on day 30, then to about 14 to 18 min of arc in the adult. The results are discussed with special reference to previous biochemical investigations on changes in the ganglioside composition of the trout brain during comparable periods of development.
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    Development genes and evolution 185 (1979), S. 333-346 
    ISSN: 1432-041X
    Keywords: Chick embryo ; Limb bud ; Ultrastructure ; Cell death
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    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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    Calcified tissue international 16 (1974), S. 93-107 
    ISSN: 1432-0827
    Keywords: Dentinogenesis ; Globules ; Pyrophosphatase ; Calcification ; Electron microscopy
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    Topics: Biology , Medicine , Physics
    Notes: Abstract Three-day-old rats were fixed by perfusion with glutaraldehyde and thin slices were cut of the first molar germs. The slices were treated with EDTA and “activated” with buffered solutions containing Mg2+, Ca2+ or Zn2+. Incubation was carried out in buffered solutions (pH 8.5) containing inorganic pyrophosphate and Pb2+. In the Mg2+-activated specimens incubation products were localized to the plasma membranes in the stratum intermedium and the subodontoblastic area. Lead deposits were found on the periphery of the dentinal globules. Incubation products were more randomly distributed in Ca2+-activated specimens whereas those activated with Zn2+ displayed a deposition of lead precipitates mainly corresponding to that seen after activation with Mg2+. The findings are discussed in reference to the localization of alkaline phosphatase in the dentin-producing tissues and it is proposed that the results are indicative of the presence of an inorganic pyrophosphatase in these tissues.
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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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    Calcified tissue international 26 (1978), S. 181-190 
    ISSN: 1432-0827
    Keywords: Cellular calcium ; Electron microscopy ; Osteoblasts ; Chondrocytes ; Mineralization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The calcium distribution in cartilage and bone cells during beginning ossification of fetal mouse long bones was studied after fixation with 2% K-pyroantimonate in 1% osmium. In the developing periosteum, the future osteoblasts showed a sparse cation-antimonate precipitate over the cytoplasm. In young osteoblasts the precipitate was accumulated on the mitochondrial membranes and the plasmalemma. Both organelles were sharply outlined by precipitate in the mature osteoblasts at the onset of mineralization. X-Ray microprobe analysis of these organelles demonstrated the presence of both Sb and Ca. In the extracellular compartment, a collagen-associated precipitate with 50 to 60 nm periodicity appeared during osteoblastic differentiation. During the initial phase of matrix mineralization, a random gross precipitate appeared in the matrix and seemed to be accumulated by osmiophilic matrix vesicles while the collagen fibrils lost their precipitate. Subsequently, during the confluent phase of matrix mineralization, the precipitate rapidly disappeared from the cells, leaving them devoid of precipitate once they were surrounded by mineralized matrix. Similar changes were found in the chondrocytes of the growth plate, but cartilage collagen, unlike osteoid collagen, did not bind precipitate. The results indicate that both osteoblasts and calcifying cartilage cells bind calcium prior to matrix mineralization. Bone collagen has strong pyroantimonate binding capacity, but it is not directly involved with initial stages of matrix mineralization, which starts in close association with matrix vesicles.
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    ISSN: 1432-0827
    Keywords: Shell formation ; Free nerve endings ; Ultrastructure ; Lymnaea stagnalis ; Biomphalaria pfeifferi
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    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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    Calcified tissue international 23 (1977), S. 215-223 
    ISSN: 1432-0827
    Keywords: Amorphous mineral ; Bone ; Electron microscopy ; Ultracryotomy ; Ultramicro-incineration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The fine structure of the extracellular phase of avian medullary bone and embryonic chick femur was examined in thin sections prepared by ultracryotomy and ultramicroincineration. Since contact with solutions was completely avoided, little or no loss or dislocation of mineral constituents could occur. Amorphous bone mineral (ABM) was present in two forms: as 15–30 nm spheres and as a structure-free haze. Removal of all organic material by low temperature ashing left the ABM intact. Crystals were usually associated with the ABM. In newly ossifying regions clusters or nodules of randomly oriented crystals and ABM appeared to coalesce when they reached approximately 1 μm in diameter. In highly calcified regions crystals appeared to be oriented along collagen fibers. ABM did not appear to be associated with collagen. Unmineralized collagen was visible in osteoid after staining with dry OsO4 vapor and it appeared to be diverted around nodules. Structures which resembled matrix vesicles were present. Selected area electron diffraction patterns indicated the presence of hydroxyapatite.
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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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    Calcified tissue international 8 (1971), S. 165-171 
    ISSN: 1432-0827
    Keywords: Bone ; Ceramic ; Tetracycline ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Un implant céramique non poreux est testé au niveau du fémur de rat en ce qui concerne son adhésivité à l'os. Un certain nombre de techniques morphologiques sont utilisées pour examiner le rapport entre l'implant et l'os néoformé. La microscopie électronique par transmission et la microscopie par fluorescence après marquage à la tétracycline ont donné les meilleurs résultats. Un rapport étroit entre l'os minéralisé et la céramique a été noté en microscopie électronique. Par marquage à la tétracycline, il semble que l'implant puisse stimuler la formation osseuse.
    Abstract: Zusammenfassung Ein unporöses keramisches Implantat in Rattenfemora wurde auf seine Fähigkeit geprüft, sich mit Knochen zu binden. Eine Anzahl morphologischer Techniken wurde verwendet, um die Beziehung zwischen den Oberflächen von Implantat und neuem Knochen zu untersuchen. Transmissions-Elektronenmikroskopie und Fluoreszenzmikroskopie nach Tetracyclinmarkierung waren die erfolgreichsten Techniken. Eine enge Beziehung zwischen mineralisiertem Knochen und dem Keramikimplantat konnte mit der Transmissions-Elektronenmikroskopie nachgewiesen werden. Das Aussehen der Tetracyclinmarkierung im keramischen Implantat deutet darauf hin, daß dieses wahrscheinlich die Fähighkeit hat, Knochenbildung zu erhöhen.
    Notes: Abstract A nonporous ceramic implant in rat femora was evaluated as to its ability to bond to bone. A number of morphologic techniques were utilized to examine the interfacial relationship of the implant to new bone. Transmission electron microscopy and fluorescence microscopy after tetracycline labelling were the most successful techniques. An intimate relationship between mineralized bone and the ceramic was demonstrated by transmission electron microscopy. The appearance of tetracycline labelling at the ceramic interface indicates that the implant may have capacity to enhance bone formation.
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    Calcified tissue international 25 (1978), S. 179-190 
    ISSN: 1432-0827
    Keywords: Decalcification ; Electron microscopy ; Calcified matrices
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    Notes: Summary The ultrastructure of calcifying cartilage and bone has been examined under the electron microscope after using three different methods of decalcification. The first was carried out before embedding (by soaking specimens in EDTA or formic acid), the second after embedding (by floating ultrathin sections on formic acid), and the third after embedding (by soaking embedded specimens in EDTA or formic acid), and with later re-embedding. The first procedure invariably induces drastic changes in the fine structure of the cells and calcified matrix, probably as a results of the extraction of organic material along with extraction of mineral. The second and third procedures make it possible to preserve ultrastructural details perfectly in both cells and calcified matrix. Of the two, the third procedure is preferable because of its greater simplicity. In areas that are still calcifying, these post-embedding decalcification techniques reveal the presence of crystal-associated, filamentous organic structures which are not recognizable in specimens decalcified before embedding. These structures, which could have a key role in inducing and regulating crystal formation and growth, are less evident in fully calcified areas (but not at their borders). This may partly be due to the loss of glycan components in the matrix during calcification. The most important determinant, however, seems to be the fact that during calcification the components of the matrix, including collagen fibrils, are involved in an aggregation process which reduces the amounts of free chemical groups available for reaction with the stain solution. Because post-embedding decalcification does not disturb this state of aggregation, the stainability of the matrix and the electron microscopic evidence of its components remain very low.
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    Calcified tissue international 24 (1977), S. 191-197 
    ISSN: 1432-0827
    Keywords: Amelogenesis imperfecta ; Hypocalcification ; Hypoplasia ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary An ultrastructural study of teeth with amelogenesis imperfecta revelaed various aspects of microcavities in the enamel surface, which ranged from isolated imprints of ameloblasts corresponding to the mildest lesions at the end of amelogenesis, to pits caused by the death of 20 to 30 ameloblasts at the beginning of amelogenesis. Abnormalities in the shape of the prisms can be observed. Further, crystals are distributed randomly within a prism or at the junction of 2 contiguous prisms while intercrystalline spaces are widened, indicating in various places the lack of a preferred orientation of the crystals. In amelogenesis imperfecta, two different crystalline periods are found: 1 of about 250 Å, the other of about 500 Å and over. The fact that amorphous areas are found among the crystals of enamel may be related to different stages of crystallization. However, it was not possible to find any lattice defect.
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    Calcified tissue international 24 (1977), S. 239-242 
    ISSN: 1432-0827
    Keywords: Cementum ; Lysis ; Electron microscopy
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    Notes: Summary Examination of microradiographs from the deciduous teeth of pigs revealed large lacunae or radiolucent zones close to the cemento-dentinal junction. Electron microscopic studies of the ground sections showed areas or irregularly shaped zones devoid of mineral and filled with collagen fibers. In the wide unmineralized zones, spherical clusters of crystallites were noted. Several cementum lacunae bordered by a broad rim of unmineralized collagen fibers were noted and some lacunae also contained zones of a moderately electron dense material. This material did not yield a diffraction pattern, while the mineralized part of the cementum gave the diffraction pattern typical of hydroxyapatite.
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    Calcified tissue international 25 (1978), S. 45-51 
    ISSN: 1432-0827
    Keywords: CaCO3 ; Amino acids ; Sheaths ; Ligament ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The aragonite crystals in the molluscan bivalve hinge ligament are surrounded by an organic sheath which is distinct from the remainder of the ligament matrix. Methods have been developed to isolate these sheathed crystals from the ligaments ofSpisula solidissima andMercenaria mercenaria employing a papain digestion of the matrix protein. The sheathed crystals fromSpisula have a CaCO3/protein ratio of 11.1 and those fromMercenaria a ratio of 29.6. The sheathed crystals and the empty crystal sheaths have been examined by electron microscopy for structural integrity. The sheath proteins exhibit much smaller proportions of the amino acids glycine and methionine than the hinge ligaments. These are characteristic amino acids of high concentration in the hinge ligaments of both species. The concentrations of acidic and basic amino acids are increased about two fold in the sheaths over those of the ligaments. Otherwise there is little similarity in the amino acid composition of the sheaths in the two species. However, SDS electrophoresis shows the sheaths of both to contain a major protein component with a molecular weight of about 25,000. The sheath protein from theMercenaria ligament contains about 5% carbohydrate and that ofSpisula sheaths less than 1% carbohydrate.
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    Calcified tissue international 29 (1979), S. 101-105 
    ISSN: 1432-0827
    Keywords: Osteon ; X-ray diffraction ; Pole figures ; Electron microscopy ; Calcification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The X-ray diffraction method based on pole figures has been applied to single osteon samples in order to obtain information about the texture of the inorganic bone fraction and the way it changes during calcification. The osteon samples were cylindrically shaped, with axes corresponding to those of the haversian canals. Selection was carried out according to the degree of calcification and the orientation of collagen bundles and inorganic particles. Osteons at both the initial and final stages of calcification were chosen. Arrangements of fiber bundles and inorganic particles in successive lamellae characteristic of three types of osteons were selected: longitudinal, alternate, and transversal. The results indicate that in all three types of osteons, the long axis of the sample is apparently the only direction of orientation because the transversally oriented crystallites give an isotropic diffuse scattering as would be expected if all the inorganic particles were irregularly oriented around the osteon axis. The number of longitudinally oriented crystallites increases progressively from transversally oriented osteons to alternately and longitudinally oriented ones. The crystallite orientation in an axial direction increases in fully calcified osteons. This last result is in agreement with the electron microscopic finding that the long needle-shaped crystallites covering much more than a major collagen period and measuring 40–45 Å in width increase in number as calcification proceeds.
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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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    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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    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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    Calcified tissue international 7 (1971), S. 31-45 
    ISSN: 1432-0827
    Keywords: Prism ; Crystals ; Growth ; Shell ; Formation ; Ultrastructure
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    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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    Calcified tissue international 8 (1971), S. 287-303 
    ISSN: 1432-0827
    Keywords: Calcification ; Bone ; Matrix ; Apatite ; Nucleation ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Du collagène d'os compact de mouton est préparé par décalcification dans I'EDTA et à partir de tendons de queux de rats, par extraction dans l'acide acétique et reconstitution dans NaCl. Le dépôt d'apatite dans le collagène osseux de mouton dans une solution de calcification métastable est étudié chimiquement et par microscopie électronique. Le collagène osseux est un bon catalyseur de nucléation pour le dépôt minéral, alors que le collagène de tendons de rat ne l'est pas. Le dépôt minéral du collagène osseux se produit en deux phases cinétiques séparées, une phase rapide de nucléation et une croissance cristalline, donnant naissance à de petits ilots calcifiés et une seconde phase lente de croissance dans des régions ne comportant pas de zones catalytiques. La seconde phase de dépôt minéral paraît être le résultat d'une diffusion inhibée d'ions à travers les fibrilles collagènes alignées, laissant de larges régions de collagène sans minéral, bien que le tampon reste hautement sursaturé. La microscopie électronique permet de penser que les zones de catalyse pourraient avoir un rapport avec la périodicité de 640 Å de collagène, mais l'importance d'un matériel noncollagènique, lié au collagène, n'est pas à exclure. L'activité catalytique faible du collagène reconstitué n'est pas liée à la présence d'inhibiteurs faiblement liés, bien que des inhibiteurs puissent être intimement liés à ce type de collagène, qui pourrait être absent du collagène osseux. La différence d'activité catalytique pourrait intervenir dans la calcification physiologique. Une hypothèse plus générale pour la nucléation de la phase minérale dans les systémes biologiques est nécessaire.
    Abstract: Zusammenfassung Kollagen wurde aus kompaktem Schafsknochen mittels EDTA-Entkalkung und aus Rattenschwanzsehnen durch Essigsäureextraktion und Rekonstitution mit NaCl gewonnen. Die Apatitablagerung aus einer metastabilen Verkalkungslösung auf Schafsknochenkollagen wurde chemisch und im Elektronenmikroskop untersucht. Es zeigte sich, daß das Knochenkollagen ein guter Nukleationskatalysator für die Mineralablagerung ist, was beim Rattenschwanzkollagen nicht zutraf. Im Knochenkollagen erfolgte die Mineralablagerung in zwei getrennten kinetischen Phasen: einer raschen Phase der Nukleation und des Kristallwachstums, welche kleine verkalkte Inseln entstehen läßt, und einer zweiten langsamen Phase, welcher das Wachstum in Bezierken, die keine katalytischaktiven Stellen einschließen, zuzuschreiben ist. Diese zweite Phase der Mineralablagerung wird als Resultat einer verminderten Ionendiffusion durch die enganeinanderliegenden Kollagenfibrillen angesehen, wodurch weite Kollagenbereiche ohne Mineral bleiben, obwohl der Puffer stark übersättigt ist. Elektronenmikrographien ließen vermuten, daß die katalytischaktiven Stellen in einem gewissen Verhältnis zur 640 Å-Periodizität des Kollagens stehen; es konnte jedoch nicht ausgeschlossen werden, daß nicht-kollagenhaltiges Material, welches an Kollagen gebunden ist, ebenfalls eine Rolle spielt. Die schlechte katalytische Aktivität des rekonstituierten Kollagens konnte nicht auf die Anwesenheit von schwachgebundenen Hemmstoffen zurückgeführt werden, obwohl Inhibitoren stark an dieses Kollagen gebunden sein könnten, die jedoch im Knochenkollagen nicht vorhanden sind. Die Unterschiede in der katalytischen Aktivität können mit der physiologischen Verkalkung in Beziehung stehen. Eine allgemeinere Hypothese für die Nukleation einer Mineralphase in biologischen Systemen wäre erforderlich.
    Notes: Abstract Collagen was prepared from compact sheep bone by decalcification with EDTA and from rat tail tendons by acetic acid extraction and reconstitution with NaCl. The deposition of apatite in sheep bone collagen in a metastable calcification solution was studied chemically and by electron microscopy. The bone collagen was shown to be a good nucleation catalyst for mineral deposition, while rat tail collagen was a poor catalyst. Mineral deposition in bone collagen occured in two separate kinetic phases, a rapid phase of nucleation and crystal growth, giving rise to small calcified islands, and a second slow phase, ascribed to growth in regions not involving the catalytic sites. This second phase of mineral deposition is considered to be the result of impaired ion diffusion through the closely-aligned collagen fibrils, thus leaving large areas of the collagen free of mineral even though the buffer remains highly supersaturated. Electron micrographs suggested that the catalytic sites might be in some relationship to the 640 Å periodicity of collagen, but a role for non-collagenous material bound to the collagen has not been excluded. The poor catalytic activity of reconstituted collagen was not due to the presence of loosely-bound inhibitors, although inhibitors could be strongly bound to this type of collagen and be absent from bone collagen. The differences in catalytic activity may have a bearing on physiological calcification. A more general hypothesis for nucleation of a mineral phase in biological systems is required.
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    Calcified tissue international 15 (1974), S. 213-220 
    ISSN: 1432-0827
    Keywords: Acid phosphatase ; Electron microscopy ; Shell Regeneration
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    Notes: Abstract Acid phosphatase activity was mainly localized in the lysosomes in all the regions of the outer epithelium. The transitional portion of the outer epithelium showed more intense activity than the other regions. During shell regeneration the activity of this portion decreased to a minimum level at 12 hours and was restored to normal at 72 hours. The other regions showed no change of activity during shell regeneration. It is postulated that the acid phosphatase in the transitional protion is responsible for conferring calcifiability to the organic matrix of the shell.
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    Calcified tissue international 15 (1974), S. 201-212 
    ISSN: 1432-0827
    Keywords: Ultrastructure ; Alkaline Phosphatase ; Calcification
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    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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    Calcified tissue international 25 (1978), S. 133-143 
    ISSN: 1432-0827
    Keywords: Osteon ; X-Ray diffraction ; Electron microscopy ; Calcification
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    Topics: Biology , Medicine , Physics
    Notes: Summary To obtain information on the changes in the inorganic bone fraction during calcification, low- and wide-angle X-ray diffraction techniques and electron microscopy have been applied to single osteon samples. The samples were cylindrically shaped and their axes corresponded to the axes of the Haversian canals. The selection was made according to the degree of calcification and the orientation of collagen bundles and inorganic particles. Osteons at both the initial and final stages of calcification were chosen. Arrangements of fiber bundles and inorganic particles in successive lamellae characteristic of three types of osteon were selected, that is, longitudinally structured osteons, transversely structured osteons, and alternately structured osteons. The results indicate that in osteonic lamellar bone there are two types of inorganic particles: (1) granules arranged in linear or needle-shaped entities with maximum width 40–45 Å, which are regularly distributed at the level of the main band of the collagen fibrils where their maximum length reaches the length of the main band itself; that is, about 400 Å; and (2) very long crystallites, with a diameter of 40–45 Å, which grow with their crystallographicc-axis parallel to the collagen fibrils and cover much more than a major collagen period.
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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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  • 49
    ISSN: 1432-2048
    Keywords: Festuca ; Frost damage ; Ultrastructure
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    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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    Planta 133 (1976), S. 15-19 
    ISSN: 1432-2048
    Keywords: Tropaeolum, Embryogenesis ; Differentiation ; Plastids ; Ultrastructure
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    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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    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
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    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
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    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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    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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    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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    European journal of clinical pharmacology 6 (1973), S. 268-270 
    ISSN: 1432-1041
    Keywords: Diphenhydramine ; orphenadrine ; gas-liquid chromatography ; N-selective detector ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A method is described for the assay of nanogram quantities of diphenhydramine and orphenadrine in human plasma. The procedure employs gas-liquid chromatography and a high sensitivity nitrogen detector. It has been used to assay diphenhydramine in plasma after oral administration of therapeutic doses.
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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
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    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
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    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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    European journal of clinical pharmacology 6 (1973), S. 234-238 
    ISSN: 1432-1041
    Keywords: Phenobarbital ; neonate ; maternal-fetal exchange ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of phenobarbital were measured in 18 newborn infants for one to two weeks after birth. The drug had been administered prenatally to the mothers as part of treatment for maternal hypertension or toxaemia. The plasma half-life of the drug in the infants (77–404 h) was inversely correlated with the extent of prenatal exposure to it. In three infants a bi-phasic plasma curve was found as there was a sudden change from slow to fast disappearance on the 5th to 7th day of life.
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    European journal of clinical pharmacology 7 (1974), S. 407-414 
    ISSN: 1432-1041
    Keywords: Diuretic ; indapamide ; human pharmacology ; toxicology ; pharmacokinetics ; TLC assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacology, toxicology and kinetics of a new diuretic indapamide, have been studied in six normal volunteers following a single oral dose of 40 mg. Pronounced diuresis was found, commencing three hours after ingestion, with a peak urinary flow at four to six hours, and continuing for a total of thirty-six hours. A fall in systolic standing blood pressure occurred twenty four hours after ingestion, coincident with the period of maximum dehydration. Free water clearance rose, accompanied by increased urinary losses of Na+, K+ and Cl− and alkalinisation of the urine comparable to the actions of benzothiadiazines. Total urinary losses of Ca2+, Mg2+ and PO 4 3− rose in spite of a fall in urinary concentrations of these ions. The Ca2+ effect compares with the acute ionic effects of other diuretics. No renal, hepatic or haematological toxic effect was demonstrated. The blood sugar level was not disturbed. Serum uric acid rose to abnormal levels although the change did not reach statistical significance. — A thin layer chromatographic method, with a sensitivity limit of 0.1 µg/ml., has been developed for the assay of indapamide in urine. The urinary excretion rates of the volunteers measured over forty-eight hours indicate that the drug is rapidly absorbed with a peak excretion, 2.9±1.3 µg/min occurring three hours after ingestion. The drug is eliminated bi-phasically with an initial short rapid elimination followed by a slower exponential decline with a mean elimination half-life of 10.3 ± 3.9 h. The mean urinary excretion of unchanged indapamide over forty-eight hours was 4.4±1.4% of the administered dose. — It is concluded that indapamide is an effective long-acting diuretic with comparable action to the benzothiadiazine diuretics, but without an effect on blood sugar level in single doses in normal subjects. In contrast with other diuretics, indapamide appears to be extensively metabolised in man, and its longer duration of action to be related to a longer elimination half-life.
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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
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    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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  • 62
    ISSN: 1432-1041
    Keywords: Oral antidiabetic drug ; butylbiguanide ; pharmacokinetics ; two-compartment open model ; plasma concentration ; liver concentration ; intestine concentration ; man
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    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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    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
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    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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    European journal of clinical pharmacology 8 (1975), S. 157-160 
    ISSN: 1432-1041
    Keywords: Isosorbide dinitrate ; pharmacokinetics ; metabolism ; pharmacological action ; nitrates
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An oral dose of 5 mg of14C-isosorbide dinitrate was rapidly absorbed, biotransformed and excreted by human subjects. Peak whole blood concentrations of radioactivity were reached after 1.5 to 2 hours and declined relatively slowly. The radioactivity in whole blood mainly represented metabolites, isosorbide mononitrates. The peak concentrations found were 4.5, 11.7 and 34.3 ng/ml of isosorbide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate, respectively, in the blood of one subject and 5.9, 15 and 61.3 ng/ml, respectively, in the blood of another subject. However, concentrations of the metabolites declined relatively slowly during 6 h after the oral dose. Up to 99% of an oral dose of isosorbide dinitrate was excreted during 5 days, mainly in the urine of the first day (ca. 78%). The results showed that isosorbide mononitrates were available to contribute to the pharmacological action.
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  • 65
    ISSN: 1432-1041
    Keywords: Sympathetic activity ; plasma catecholamine concentration ; dopamine-β-hydroxylase activity ; graded physical exercise ; heart rate ; man
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    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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  • 66
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    European journal of clinical pharmacology 7 (1974), S. 295-305 
    ISSN: 1432-1041
    Keywords: Mestranol ; ethynyloestradiol ; contraceptive compounds ; demethylation ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oestrogenic activity of mestranol depends on its demethylation to ethynyloestradiol. The reaction has been studied in man. The compound disappeared exponentially from plasma during the first 4 h after i.v. injection of [4-14C-] mestranol. The “metabolic clearance” for this phase amounted to 31.8 1/day per kg body weight. Methoxy-3H-labelled mestranol was prepared for the further studies, because if it is demethylated, the tritium would be transferred to HTO, which would equilibrate immediately with body water. The appearance in body water of tritium from [methoxy-3H-] mestranol could be described by two exponential functions, which corresponded to bi-phasic disappearance of the original compound from plasma. The rate constant of the first stage was: γ1=0.835 h−1, and of the second: γ2=0.034 h−1. HTO radioactivity was eliminated from the body by exchange of water. From the data obtained, a three-compartment model was constructed of the transfer of tritium from [methoxy-3H-] mestranolinto body water, which permitted computer simulation of the partial processes. The compartmental analysis suggested that mestranol differed from ethynyloestradiol mainly in the delayed and protracted manner in which hormonally active oestrogen entered the circulation. The proportion of [methoxy-3H-] mestranol demethylated to ethynyloestradiol (demethylation ratio) varied little, 53.7±5.0% (x±SD; n=6), and was consistent with clinical observations that mestranol is half as potent an oestrogen as ethynyloestradiol. Thus, the dose of mestranol required to produce a given effect has to be twice as large as that of ethynyloestradiol.
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  • 67
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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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  • 68
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    European journal of clinical pharmacology 8 (1975), S. 161-166 
    ISSN: 1432-1041
    Keywords: Oxyfedrine ; norephedrine ; man ; urinary excretion ; sympathomimetic
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    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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  • 69
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    European journal of clinical pharmacology 8 (1975), S. 241-248 
    ISSN: 1432-1041
    Keywords: pharmacokinetics ; experimental design
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is apparent from studying recent articles on pharmacokinetics that a number of misunder-standings exist, both about the design of experiments and the analysis of results. The purpose of this paper is to outline many of the common pitfalls associated with the design of experiments and also the limitations upon the analysis of results. The paper describes mathematical, laboratory and clinical aspects which must be examined in designing a protocol for pharmacokinetic experiments. Simulated data is presented to demonstrate the dangers of using standard computer programs for parameter estimation. Even when convergence is obtained the answers may be dependent on the method employed. A mathematical model is of little use unless a reasonable amount of good, accurate data is obtained.
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  • 70
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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
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    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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  • 71
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    European journal of clinical pharmacology 8 (1975), S. 271-275 
    ISSN: 1432-1041
    Keywords: Fluorophenindione ; vitamin K antagonist ; pharmacokinetics ; loading dose ; anticoagulant
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After administration of a single loading dose (80 mg p.o.) of fluorophenindione, the prothrombin level decreased to 37 % in 24 h, and the effect lasted for 48 h. Accordingly, fluorophenindione can be classified as an anticoagulant with an “intermediate” effect. Its elimination half-life was 31 h, which is longer than that of phenindione, because of the greater stability of the fluorinated derivate.
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  • 72
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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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  • 73
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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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  • 74
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    European journal of clinical pharmacology 6 (1973), S. 44-53 
    ISSN: 1432-1041
    Keywords: Nortriptyline ; pharmacokinetics ; plasma clearance ; gas chromatography — mass spectrometry ; pharmacogenetics ; twins
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five identical (monozygotic) and 6 fraternal (dizygotic) sets of healthy twins between 47 and 53 years of age were given a single oral dose of nortriptyline (NT) hydrochloride 1 mg/kg. The plasma half-life, the apparent volume of distribution, and the plasma clearance of NT were estimated for each subject as well as the urinary excretion rate of conjugated and unconjugated 10-hydroxynortriptyline (10-OH-NT). “Steady-state” plasma levels predicted from the reciprocal single dose plasma clearance rate of NT agreed well with those observed in a previous study of the same twins 2 years previously. In the present study, there was a 5-fold range of the plasma half-lives and 2-fold variation in the apparent volume of distribution of NT (assuming complete availability on oral administration). No correlation was found between the plasma half-life and the apparent volume of distribution. Analysis of variance showed that most of the variability between persons in plasma half-life, apparent volume of distribution and conjugation of 10-OH-NT was genetically determined. The plasma half-life and apparent volume of distribution may contribute independently to the total interindividual variability of the “steady-state” plasma level of NT.
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  • 75
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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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  • 76
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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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  • 77
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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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  • 78
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    European journal of clinical pharmacology 8 (1975), S. 283-284 
    ISSN: 1432-1041
    Keywords: Newborn infants ; carbamazepine ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma elimination of carbamazepine (Tegretol®) was studied in five newborns who had got the drug transplacentally from their epileptic mothers. The half-lives ranged from 8.2 – 27.7 hours which is comparable or even shorter than those found in adults after a single oral dose, but in the same range as those found in adults after multiple oral doses. This suggests that the newborns' drug metabolizing capacity has been induced during fetal life.
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  • 79
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    European journal of clinical pharmacology 9 (1975), S. 1-8 
    ISSN: 1432-1041
    Keywords: Serum concentrations ; individual drug dosage ; pharmacokinetics ; individual variation
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The importance of individualizing the dosage of potent drugs in order to maximize their therapeutic effectiveness and safety is generally accepted. Whenever possible the dosage of a drug should be “titrated” directly in each patient against the intensity of its therapeutic or toxic actions. Unfortunately, for many drugs convenient clinical yardsticks of the intensity of their pharmacologic effects are lacking. Determination of the serum concentration of such compounds can help to guide adjustment of dosage during their therapeutic use. By measuring the serum level of drugs one bypasses the largest source of individual differences in doseeffect relationships — the pharmacokinetic variation between subjects. However, the relationship between the serum concentration of a drug and the intensity of its pharmacodynamic action is influenced by many other factors, which must always be considered in interpretation of serum levels. Therapeutic decisions should never be based solely on the serum concentration of a compound, nor can such measurements ever substitute for careful medical observation and judgement.
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  • 80
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    European journal of clinical pharmacology 9 (1975), S. 57-61 
    ISSN: 1432-1041
    Keywords: Furosemide ; gastrointestinal absorption ; diuretics ; glucuronides ; pharmacokinetics ; metabolism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 35S-furosemide was administered orally (n=7) or i.v. (n=2) to healthy subjects. The average gastrointestinal uptake estimated by comparison of the urinary recovery of label and the areas under the plasma curves after the two routes of administration was 65%. The half life of radioactivity in the plasma after oral35S-furosemide was 90 ± 17 min (estimated on the slope between 2 and 6 h); the corresponding figure after35S-furosemide i.v. was 47–53 min (slope 0.5–4 h). There was probably a slower phase after 4–6 h. Fractionation of labelled material in urine from two subjects demonstrated that approximately two thirds of the label recovered at 24 h had the same chromatographic properties as furosemide. A major part of the metabolite(s) was probably furosemide glucuronide. There was no evidence that 4-chloro-5-sulfamoylanthranilic acid was formed in man. The total urinary recovery of label (5–7 d) after oral and intravenous administration was 55.1±3.2 (mean±SD) and 82–84%, respectively. After35S-furosemide i.v., 6–9% of the label was recovered in faeces, and it could not be accounted for solely by biliary excretion of furosemide.
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  • 81
    ISSN: 1432-1041
    Keywords: Pivampicillin ; ampicillin ; probenecid ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty male volunteers received oral doses (2100, 1050, and 525 mg) of a pivampicillin-probenecid salt in a 1 to 1 molar ratio (MK-356) at 12 hour intervals. After each dose peak serum concentrations of probenecid were observed 2 hours later than peak concentrations of ampicillin. Following the first dose of MK-356 the apparent elimination rate of ampicillin was dose-dependent and did not follow first order kinetics, as it showed a longer apparent half life after a higher dose. An equal dose of MK-356 administered 12 hours later caused an increase in the peak serum ampicillin level greater than expected from the concentration of ampicillin after the preceding dose. In twelve male volunteers who received at random 525 mg of MK-356 or 350 mg of pivampicillin, each three times daily for 4 days, the areas under the ampicillin concentration curve were the same after the first or last dose of either drug. When 2100 or 1050 mg of MK-356 was taken as an initial dose, 30 to 40 per cent of the ampicillin was recovered from urine in the ensuing 12 hours. The results indicate that when at least 400 mg probenecid was coadministered twice daily with 700 mg pivampicillin (MK-356), the peak serum concentrations of ampicillin were increased and its elimination rate slowed following successive doses.
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  • 82
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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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  • 83
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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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  • 84
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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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  • 85
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    European journal of clinical pharmacology 9 (1975), S. 179-187 
    ISSN: 1432-1041
    Keywords: Etilefrine ; pharmacokinetics ; metabolism ; first-pass effect
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic and metabolic studies with3H-etilefrine were performed to assess the importance of a first-pass effect on the pharmacodynamic action of this sympathomimetic amine. Identical amounts of3H-activity, ca. 80% of the dose, were excreted in the urine after intravenous or oral administration, which indicates complete enteral absorption of the drug. Comparison of the areas under the plasma curves of unchanged etilefrine after both routes of administration resulted in a bioavailability factor of 0.55, which can be explained by an extensive first-pass effect. The time curve of plasma levels of etilefrine was compatible with an open 2-compartment model characterized by a rather large volume of distribution (Vd, β) of 160 1, and a predominant half life of 2 hours. The pharmacodynamic action corresponded to the amount of drug in the central compartment. The major pathway of metabolism of etilefrine was conjugation to form the phenolic sulphate, and a very minor proportion of the drug was excreted as the corresponding hydroxymandelic acid. This metabolic pattern seems to confirm our hypothesis that phenylalkylamines with the hydroxyl group in the m-position of the benzene ring are predominantly conjugated in contrast to p-hydroxylated compounds which are mainly deaminated.
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  • 86
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    European journal of clinical pharmacology 9 (1975), S. 169-178 
    ISSN: 1432-1041
    Keywords: Heptabarbital ; heptabarbital sodium ; pharmacokinetics ; plasma concentration ; single and multiple dose kinetics ; relative bioavailability ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A method has been developed for the quantitative determination of heptabarbital [5-(1-cyclohepten-1-yl)-5-ethylbarbituric acid] in human plasma after administration of single therapeutic doses of the drug. It involves a single extraction step followed by gas chromatography with alkali flame ionization detection, and the results were linear in the concentration range 0.125 – 5.0 µg/ml plasma. The pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium were studied in a crossover design in 7 healthy volunteers after oral administration of 20 tablets containing 200 mg heptabarbital and hard gelatine capsules containing an equivalent amount of its sodium salt. Heptabarbital concentrations in plasma were determined at regular intervals. The absorption of heptabarbital from the tablets was quite slow and peak level times varied from 1.5 to 4 h. The sodium salt was absorbed more rapidly and peak concentrations occurred between 1/3 and 2 h. In all cases the elimination of heptabarbital could be described by a single first-order process with an average half-life of 7.6 h (range 6.1 – 11.2 h). The half-life of the drug in each individual was about the same in the two trials. The relative bioavailability in each volunteer was estimated by comparing the areas under the plasma concentration curves. The sodium salt had an average bioavailability of 83% relative to the free acid. In some volunteers urinary excretion of unchanged heptabarbital was measured; cumulative excretion amounted to 0.16 – 0.30% of the administered dose. Four volunteers received one tablet each night for eight or ten days, but no accumulation was found. In three volunteers the half-life of the drug prior to and after these experiments did not change, whereas in the other volunteer the half-life decreased from 7.1 to 4.6 h. The possibility of enzyme induction should be considered when heptabarbital is taken regularly. It was concluded that heptabarbital was a suitable drug for the treatment of insomnia, since its half-life was rather short. Heptabarbital sodium may be used for induction of sleep, whereas Medomin® tablets, i.e. heptabarbital free acid, may be prescribed when the maintenance of sleep is the primary reason for treatment with a hypnotic drug.
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  • 87
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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
    Source: Springer Online Journal Archives 1860-2000
    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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  • 88
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    European journal of clinical pharmacology 9 (1975), S. 199-207 
    ISSN: 1432-1041
    Keywords: Indomethacin ; acetylsalicylic acid ; drug interaction ; oral and rectal dosing ; serum levels ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A clinical-pharmacological study was performed to determine the effect of acetylsalicylic acid upon the serum concentration of indomethacin. 14 rheumatic patients were given indomethacin orally (25 mg × 4 for 4 days) and concurrently acetylsalicylic acid 3.7 g orally (0.9 g × 3 and 1.0 g × 1 daily), and 21 rheumatic patients were given indomethacin rectally in the morning (100 mg × 1) and concurrently acetylsalicylic acid 3.7 g orally (0.9 g × 3 and 1.0 g × 1 daily). On comparison with treatment with oral or rectal indomethacin alone, it was found that peak serum concentrations of indomethacin were significantly reduced (1% level), the times of the peaks were not shifted, and the areas beneath the serum concentration curves of indomethacin were smaller, but significantly so only if compared with rectal administration. In 12 rheumatic patients given indomethacin by rectum in the evening (100 mg × 1) and concurrently acetylsalicylic acid 3.7 g (0.9 g × 3 and 1.0 g × 1 daily), the serum level of indomethacin on the following morning (after 11 h) did not differ from that found after rectal treatment. A statistically but not biologically significant difference was observed between the mean serum half-lives of indomethacin given orally and rectally. For unknown reasons, concurrent doses of acetylsalicylic acid and indomethacin made the mean serum half-life of indomethacin longer than after its oral administration, but shorter than when the same dose of indomethacin was given rectally. There was no difference between serum levels of salicylate after oral administration of acetylsalicylic acid alone or after a concurrent oral or rectal dose of indomethacin. The results have been related to those reported previously, with respect to the interaction between indomethacin and acetylsalicylic acid, the serum levels of indomethacin after oral and rectal dosing, and the serum half-life of indomethacin based upon a one- or two-compartment model. The clinical relevance of the study is discussed.
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  • 89
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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
    Source: Springer Online Journal Archives 1860-2000
    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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  • 90
    ISSN: 1432-1041
    Keywords: Aldosterone ; renin ; aldosterone antagonist ; canrenone ; man
    Source: Springer Online Journal Archives 1860-2000
    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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  • 91
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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
    Source: Springer Online Journal Archives 1860-2000
    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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  • 92
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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
    Source: Springer Online Journal Archives 1860-2000
    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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  • 93
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    European journal of clinical pharmacology 9 (1976), S. 327-332 
    ISSN: 1432-1041
    Keywords: Antipyrine ; pharmacokinetics ; half-life ; blood ; plasma ; saliva ; individual variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A previously described GLC method has been modified and applied to measurement of antipyrine levels in plasma, blood and saliva of man following administration of a single oral dose (10 mg/kg). The levels in blood and saliva were comparable to those in plasma at every time studied. The half life of antipyrine determined in blood, plasma or saliva in any given individual was similar. The intersubject variation in half-life was about two-fold (n=5). Antipyrine levels in saliva were not affected by the rate of saliva flow when collections were made continuously for 20 minutes. This study has demonstrated that kinetic data about antipyrine comparable to that from plasma may also be obtained from readily accessible tissue fluids, such as saliva and capillary blood.
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  • 94
    ISSN: 1432-1041
    Keywords: Chlorthalidone ; diuretics ; drug plasma concentration ; protein binding ; red blood-cell concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A gas chromatographic method has been employed to determine chlorthalidone in plasma and whole blood after therapeutic doses. Radioactively labelled chlorthalidone was used for in vitro studies of the uptake of chlorthalidone from plasma by red blood cells. Chlorthalidone was markedly concentrated in red cells and as a compartment they would account for at least 30% of total drug in the body after multiple doses. The ratio between the plasma and red cell concentration of chlorthalidone varied between individuals. After a single oral dose of 50 mg in 6 healthy volunteers chlorthalidone was eliminated with a half-life of 51 to 89 hours. The apparent volume of distribution varied between 3 and 13 1/kg and the clearance between 53 and 145 ml/min. The mean steady-state plasma concentrations during treatment with a standard dose of 50 mg daily (n=10) varied 5-fold between individuals. During the steady state approximately 50% of the daily dose was excreted unchanged in the urine during 24 hrs. The plasma levels observed in patients were higher than those predicted from the single oral dose studies in healthy volunteers.
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  • 95
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    European journal of clinical pharmacology 9 (1976), S. 367-372 
    ISSN: 1432-1041
    Keywords: Sotalol ; β-adrenoceptor blocking drugs ; exercise tachycardia ; efficacy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of sotalol after oral administration were measured on the tachycardia induced by strenuous exercise in normal subjects. Plasma sotalol levels were also determined. The oral administration of sotalol (50, 100, 200 and 400 mg) to 6 subjects produced a progressive reduction in the tachycardia induced by severe exercise. This was similar to the effects of 25, 50, 100, 200, 400 and 800 mg given to different subjects. Each increase in sotalol dose produced a successively greater reduction in exercise tachycardia. This did not appear to be maximum even with 800 mg. Oral sotalol was rapidly absorbed and produced peak blood levels in 2 – 3 hours. The plasma levels of sotalol measured 2 hours after the oral administration of 25 to 800 mg showed never more than a six-fold variation between different subjects. The half-life of sotalol in plasma was 12.7 ± SE 1.6 hours. There was a significant correlation between the logarithm of the plasma sotalol concentration and the percentage reduction of exercise heart rate. It is concluded that the oral administration of sotalol either once or twice daily (depending on dose level) will provide satisfactory 24-hour blockade of β-adrenoceptors.
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  • 96
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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
    Source: Springer Online Journal Archives 1860-2000
    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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  • 97
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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
    Source: Springer Online Journal Archives 1860-2000
    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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  • 98
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    European journal of clinical pharmacology 9 (1976), S. 443-450 
    ISSN: 1432-1041
    Keywords: Cyclobarbital calcium ; pharmacokinetics ; plasma concentration ; relative bioavailability ; oral administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and relative bioavailability of cyclobarbital calcium have been studied after oral administration of Phanodorm, of tablets according to the Formularium Nederlandse Apothekers (1968; FNA), and an aqueous solution. Six healthy volunteers participated in the investigation on three occasions and each received the three preparations. The dose administered was 300 mg cyclobarbital calcium. Plasma concentrations of cyclobarbital were determined at regular intervals. Absorption from the three preparations was rapid and was faster from the solution. Peak concentrations were usually attained within 1 h. The elimination of cyclobarbital could be described by a single first-order process with an average half-life of 11.6 h (range 8 – 17 h). There was little intra-subject variation of the half-life. Relative bioavailability for each volunteer was estimated by comparing the areas under the plasma concentration curves. The FNA-tablets and Phanodorm exhibited similar bioavailability, whereas the average bioavailability of the solution was 78% of that of FNA-tablets; the reason for this unexpected finding is unknown. It was concluded that cyclobarbital cannot be regarded as a uniformly suitable drug for the treatment of insomnia. The long half-life that was apparent in some of the volunteers (15 – 17 h) creates a substantial risk of residual effects on the following morning. In principle, however, the calcium salt of cyclobarbital may be used for induction of sleep, because of its rapid absorption.
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  • 99
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    European journal of clinical pharmacology 4 (1971), S. 54-58 
    ISSN: 1432-1041
    Keywords: pharmacokinetics ; infusion ; plasma expander ; blood level fluctuation ; sulfonamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Description / Table of Contents: Summary A hypothetical pharmacokinetic model is reported which describes the decreasing fluctuations in the blood levels of a sulfonamide during infusion of a plasma expander. Its concentration in the serum increases reciprocally with the amount of plasma expander infused. These procedures can be described by simple equations, and it is possible therefore, to calculate the dose required to maintain a constant blood level during the infusion.
    Notes: Zusammenfassung Es wird über ein hypothetisch-pharmakokinetisches Modell berichtet, welches sich mit der absinkenden Serumkonzentration eines Sulfonamids nach Infusion eines Plasmaexpanders beschäftigt. Die Serumkonzentration fällt reziprok zur infundierten Menge des Plasmaexpanders ab. Die Vorgänge lassen sich durch einfache Gleichungssysteme beschreiben. Es gelingt daher, eine Zusatzdosis zu berechnen, welche den bei Infusionsbeginn bestehenden Plasmaspiegel annähernd konstant erhält.
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  • 100
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    European journal of clinical pharmacology 5 (1972), S. 58-61 
    ISSN: 1432-1041
    Keywords: Pralidoxime chloride ; pharmacokinetics ; anti-cholinesterase poisoning
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A dose of 1.0 g (10.0–14.0 mg/kg body weight) of pralidoxime mixed with various cholinolytics was given by i.m. injection to 29 healthy male subjects. A concentration of pralidoxime in blood of 4 µg/ml was reached after 5 to 10 min with all the mixtures and was maintained for about 1 to 2 h. The calculated half lives of pralidoxime in three groups of subjects were 62.2, 60.0 and 61.8 min., respectively. — The urinary excretions of pralidoxime during the first 4 h after the injections averaged 75.0, 79.6 and 69.6 per cent, respectively, of the total amount given. — The results are compared with published information about similar oximes.
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