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  • Ultrastructure  (758)
  • pharmacokinetics  (599)
  • Electron microscopy  (538)
  • kinetics
  • man
  • Springer  (2,046)
  • American Chemical Society
  • 1980-1984  (1,007)
  • 1975-1979  (1,039)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of nutrition 22 (1983), S. 14-26 
    ISSN: 1436-6215
    Keywords: branched chain α-keto acids ; 4-methyl-2-oxopentanoate, 3-methyl-2-oxopentanoate ; 3-methyl-2-oxobutyrate ; dehydrogenation ; transamination ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Michaelis-Konstanten und Aktivitäten von Dehydrogenasen und Transaminasen der drei verzweigten α-Ketosäuren Keto-Valin, Keto-Leucin und Keto-Isoleucin in Leber, Niere, Skeletmuskel und Gehirn von Ratten werden mitgeteilt. Nach oraler Zufuhr passieren nur 11–22% der Ketosäuren unverändert die Leber. Aus pharmakokinetischen und Resorptions-Untersuchungen erhaltene Blutspiegel an Ketosäuren werden zu den Michaelis-Konstanten in Beziehung gesetzt. Bei den geringen Konzentrationen an Ketosäuren nach oraler Zufuhr kann angenommen werden, daß die oxidativen Prozesse in den nichthepatischen Geweben über die Transaminierung überwiegen. Daten über die Wachstumseffizienz von verzweigtkettigen α-Ketosäuren im Vergleich zu den entsprechenden Aminosäuren stimmen mit dieser Vorstellung überein. Bei intravenöser Verabreichung müßten die Voraussetzungen für Transaminierung besser sein als nach oraler Zufuhr. Auf der Basis von Daten aus der Literatur werden die Übertragbarkeit unserer Befunde auf den Menschen und die verschiedenen Faktoren, welche die Effizienz der verzweigten α-Ketosäuren durch Einwirkung auf ihren Stoffwechsel beeinflussen können, diskutiert.
    Notes: Summary Miehaelis-constants and enzyme activities for dehydrogenation and transamination of the three branched chainα-keto acids in liver, kidney, skeletal muscle, and brain of rats are reported. After oral load only 11–22 % of the keto acids pass the liver unchanged. Blood levels in pharmacokinetic and absorption studies are related to the Michaelis-constants. At the low keto-acid concentrations after oral application, dehydrogenation in the non-hepatic tissues is supposed to prevail over transamination. Data on feed efficiency of branched chain α-keto acids reported in the literature support this view. The chance for transamination is better after intravenous administration. The transferability of our data to humans, and various factors influencing the efficiency of branched chain α-keto acids are discussed in connection with data reported in the literature.
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  • 2
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    Colloid & polymer science 261 (1983), S. 188-189 
    ISSN: 1435-1536
    Keywords: Polymerization ; kinetics ; redox polymerization ; acrylamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
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  • 3
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    Colloid & polymer science 261 (1983), S. 373-374 
    ISSN: 1435-1536
    Keywords: Electron microscopy ; short-time staining ; nodular structure ; crystallization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
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  • 4
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    Colloid & polymer science 262 (1984), S. 366-373 
    ISSN: 1435-1536
    Keywords: kinetics ; isothermal crystallization ; polymer ; spherulite ; differential scanning calorimetry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract In the DSC technique, isothermal crystallization experiments are usually performed on thin flat specimens, but their interpretation generally uses theories developed for an unbounded volume. In this paper, isothermal crystallization of spherical entities in the volume limited by two parallel infinite planes is considered. Our model, derived from Avrami's theory, gives an analytical expression for the transformed volume fraction as a function of time. It is shown that the influence of thickness becomes important when thickness becomes of the order of or smaller than the average spherulite radius. The main effects of a decreasing thickness are a slower crystallization kinetics and a decrease in the Avrami exponent. These results can be used to interpret experimental data obtained in isothermal polymer crystallization.
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  • 5
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    Colloid & polymer science 260 (1982), S. 564-569 
    ISSN: 1435-1536
    Keywords: lin. Polyethylene ; Single crystals ; Heat of Fusion ; DSC ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract Recently published results for solution crystallized PE single crystals have shown, that the experimental heat of fusionΔH * is higher, if the solvent is exchanged to silicon oil (oil suspension samples) as compared with dried mats. This has been interpreted by the collapse of the original hollow pyramids during drying, inducing lateral defects within the lamellae. The present investigation does not confirm this unexpected result.ΔH * of dried mats (T c 66 to 91 °C) and of the corresponding oil suspension samples agree within the rather small limits of experimental error. The crystallinities as derived fromΔH *, density or WAXS are in excellent agreement. SEM micrographs of cold fractured dried mats show their spongy macromorphology, but TEM micrographs of stained ultra-thin sections reveal the lamellar morphology of the walls, consisting of curved lamellae and stacked hollow pyramides. If a dried mat is sintered at room temperature, a dense transparent film is obtained with a rather regular stacked morphology of large flat lamellae.ΔH * of these films agrees with that of the original mat.
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  • 6
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    Colloid & polymer science 261 (1983), S. 621-625 
    ISSN: 1435-1536
    Keywords: Polyamide 6 ; crystallisation ; kinetics ; titania
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract The kinetics of isothermal and nonisothermal crystallization of polyamide-6 (PA6) containing titania was studied by means of DSC. It was found thatTiO 2 causes an acceleration in the crystallization of polyamide-6 and lowers the value of the Avrami exponent,n. The presence of TiO2 does not affect equilibrium melting pointT m 0 , glass temperatureT g, or surface free energiesσ e andσ of the basal and lateral surfaces.
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  • 7
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    Fire technology 20 (1984), S. 47-63 
    ISSN: 1572-8099
    Keywords: Extinguishment ; fire modeling ; mass loss ; heat release ; char ; reflash ; sprinklers ; radiant flux ; kinetics ; reaction rate ; heat loss ; ash ; latent heat ; spray density ; extinguishing agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Architecture, Civil Engineering, Surveying
    Notes: Abstract The Ad Hoc Mathematical Fire Modeling Working Group was organized about seven years ago to facilitate voluntary cooperation and coordination in developing mathematical fire modeling capability. The group has a steering committee of representatives of agencies that support fire modeling and related research. These include the National Bureau of Standards' Center for Fire Research, Factory Mutual Research Corp., the Naval Research Laboratory, NASA, and the Federal Aviation Agency. The Group holds plenary meetings when it seems desirable to do so (about once each 1 1/2 years), and workshops on topical subjects. Three workshops were held in 1983. Normally, Group meetings are held before or after other meetings at which a number of interested personnel would likely be present. Minutes are mailed to those who attended and to others (including European and Japanese personnel) who have indicated interest. This workshop was arranged by Ron Alpert of Factory Mutual Research Corp. and held at their facilities at Norwood, MA, in November 1983.
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  • 8
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    Journal of solution chemistry 11 (1982), S. 339-346 
    ISSN: 1572-8927
    Keywords: Carbon dioxide ; hydrolysis ; aqueous solution ; kinetics ; activation volume
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pressure dependence of the dehydration reaction of H2CO3 was measured in acidic aqueous solution for pressures up to 1 kbar using a high-pressure stopped-flow instrument. The corresponding volume of activation was found to be 6.4±0.4 cm3-mol−1 at 25°C and 0.5 ionic strength. Volume equation calculations result in a value of −9.9±1.9cm3-mol−1 for the volume of activation for the hydrolysis of CO2 under the same conditions. For the first time, the reaction mechanism can be interpreted in terms of dissociative and associative modes, respectively. These data are used to construct an overall reaction volume profile.
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  • 9
    ISSN: 1572-8927
    Keywords: Temperature jump ; kinetics ; thermodynamics ; TRIS ; iminodiacetic acid ; magnesium ion ; phenol red
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Equations describing the temperature jump amplitudes associated with a system of two coupled reactions (TRIS-phenol red) as well as the ternary system (Mg2+-iminodiacetic acid-phenol red) are presented. The termodynamic parameters calculated from experimentally measured temperature perturbation amplitudes using a multiparametric curve fitting procedure are found to be in good agreement with those determined from pH- and costant rate thermometric titrations. For phenol red, pK I =7.55, ΔH I =3.45 kcal, and for Mg2+ iminodiacetic acid, log K M =2.84, ΔH M =3.25 kcal, were obtained. It is shown that this method can be used to determine accurate thermodynamic enthalpy changes over a narrow temperature interval of less than 1.0°C from a single experiment requiring about 50 μl of sample solution.
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  • 10
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    Journal of solution chemistry 12 (1983), S. 771-781 
    ISSN: 1572-8927
    Keywords: Ultrasonics ; kinetics ; aqueous solution ; iso-butyl cellosolve
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Ultrasonic absorption and velocity measurements in aqueous solution of iso-butyl cellosolve (ethylene glycol iso-butyl ether) as a function of the concentration are reported. The two relaxational absorptions have been attributed to the perturbation of the equilibria expressed by AB⇌A+B and Aα(1/n)An where A is the solute, B is the solvent, AB is the complex and A n is the solute aggregate. The rate constants for each step have been determined. From the concentration dependence of the maximum excess absorption per wave length, the enthalpy change and the volume change for the reaction between the solute and the solvent have been determined for aqueous solutions of butyl cellosolve (ethylene glycol n-butyl ether), iso-butyl cellosolve and propyl cellosolve (ethylene glycol n-propyl ether). The results are consistent with a hydrogen bonding reaction. The effect of the ethers on water structure are considered and it is clear that the fraction of water molecules which can hydrogen bond to the solute decreases with the increasing hydrophobicity of the solute.
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  • 11
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    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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  • 12
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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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  • 13
    ISSN: 1572-8927
    Keywords: Enthalpies of reaction ; heats of reaction ; kinetics ; ester hydrolysis ; microcalorimetry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The conditions under which the Picker flow microcalorimeter can be used to measure enthalpies and rates of reactions were investigated. For this purpose, systematic studies were made of the enthalpies of neutralization of HCl, HBr, HNO 3 , acetic, proprionic, and butyric acids with NaOH, enthalpies of hydrolysis of methyl and ethyl acetate with NaOH, and the reaction rates of the ester hydrolysis with NaOH. The general procedure and various sources of error are discussed and it is concluded that enthalpies of slow reactions can be measured to about 1% when the calorimeter is operated in the quasi-isothermal mode and the reaction rates to about 3% when operated in the quasi-adiabatic mode.
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  • 14
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    Calcified tissue international 33 (1981), S. 603-618 
    ISSN: 1432-0827
    Keywords: Preameloblasts ; Tooth germs ; Monkey ; Enamel ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Cytodifferentiation of inner enamel epithelium and the adjacent connective tissue from the tip of the cervical loop to the initiation of enamel elaboration in twoMacaca species was examined. Ten- to twelve-month-old specimens were fixed by perfusion and the permanent tooth buds were prepared for transmission electron microscopy. At the cervical loop proper, inner enamel epithelium cells have lobed nuclei, a paucity of cytoplasm, and wide extracellular spaces; the basal lamina facing the dental papilla is straight. With increasing distance from the tip of the cervical loop, the following changes occur gradually: (a) preameloblasts elongate from 15 to 45 µm, and their organelles, particularly mitochondria and profiles of rough endoplasmic reticulum, become more numerous; (b) extracellular spaces decrease between preameloblasts starting at the basal (infranuclear) end; (c) the basement membrane becomes convoluted and associated with aperiodic fibers; (d) preodontoblast projections penetrate the aperiodic fibers; (e) collagen fibers subjacent to the basement membrane increase in density, with particularly thick fibers paralleling the aperiodic fibers. These modifications occur within three-fourths of the distance from the tip of the cervical loop to the mineralization front. The condensation of preodontoblasts is followed immediately by predentin synthesis. Concomitantly, the basement membrane breaks down and the aperiodic fibers are engulfed by preameloblasts. Preameloblast projections penetrate junctional predentin, contact mineralized dentin, and enamel synthesis ensues. At this stage the ameloblast is 45 µm long, the nucleus is central or basal, the Golgi apparatus has migrated apically, but the Tomes' process has not yet formed. The results indicate that odontogenesis inMacaca monkeys more closely resembles human odontogenesis than does that in the murine rodents.
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  • 15
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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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  • 16
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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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  • 17
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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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  • 18
    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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  • 19
    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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  • 20
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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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  • 21
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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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  • 22
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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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  • 23
    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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  • 24
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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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  • 25
    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 192 (1983), S. 42-44 
    ISSN: 1432-041X
    Keywords: Chick embryo ; Gastrulation ; Adenylate cyclase ; cAMP phosphodiesterase ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The ultrastructural localization of adenylate cyclase (E.C. 4.6.1.1.) and cAMP phosphodiesterase (PDE) (E.C. 3.1.4.17.) in the ectoderm of the developmental stage 4 chick embryo was studied. Adenylate cyclase was localized in the lateral surfaces of the ectodermal cells. In the primitive streak cells the enzymatic activity was observed on all the lateral surfaces, whereas in the periphery of the blastoderm the reaction product was localized in the apical parts of the lateral plasma membranes only. cAMP PDE localized in the apical cytoplasm of the ectodermal cells, with highest activity in the globular projections.
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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 191 (1982), S. 205-207 
    ISSN: 1432-041X
    Keywords: Chitin inhibition ; Nikkomycin ; Cuticle ; Electron microscopy ; Epilachna varivestis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The nucleoside antibiotic nikkomycin has proved to be an effective inhibitor of chitin synthesis in the Mexican bean beetleEpilachna varivestis. Ultrastructural investigations show defects in the procuticular area after nikkomycin application which suggest the complete absence of chitin. A cuticle like this is inflexible and too brittle to satisfy its normal function as an exoskeleton. The individuals are not able to free themselves from the exuvia and finally die. Therefore nikkomycin seems to be a potential insecticide with high specifity.
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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 192 (1983), S. 171-178 
    ISSN: 1432-041X
    Keywords: Differentiation ; Digestive tract ; Endoderm ; Organ culture ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The self-differentiation potency of the endoderm of the chick embryo was investigated mainly by transmission electron microscopy. Endodermal fragments isolated from 4- to 6-day stomach or small intestine were cultured in the absence of mesenchyme and were able to differentiate in vitro into organ-specific epithelia. Endodermal fragments isolated from the stomach region differentiated into a pseudo-stratified epithelium with periodic acid Schiff-positive mucous granules in the apical cytoplasm, while those from the small intestinal region differentiated into a simple columnar epithelium with a striated border which was positive in alkaline phosphatase activity. These features are comparable with those of the mucous secretory epithelium of the normal embryonic stomach and the absorptive epithelium of normal embryonic small intestine, respectively. Next, the self-differentiation potencies were investigated of the upper and lower layers of the blastoderms, at stages 1–5 of Hamburger and Hamilton (H. and H.). Both stomach-type and small-intestine-type epithelia developed only when fragments of the lower layer isolated from the blastoderms older than stage 3 of H. and H. were cultured, suggesting that cells possessing the potency to differentiate into the stomach- and small-intestine-type epithelia exist in the definitive endoderm at the beginning of its formation.
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    Development genes and evolution 188 (1980), S. 65-73 
    ISSN: 1432-041X
    Keywords: Nuclear migration ; Cleavage ; Microtubules ; Ultrastructure ; Gall midge
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    Topics: Biology
    Notes: Summary In the eggs ofWachtliella persicariae the cleavage nuclei move relative to the surrounding ooplasm. This ‘active’ migration is caused by an organelle whose ultrastructure was studied throughout the mitotic cycle. It consists of a greatly enlarged polar cytaster derived from the mitotic apparatus, linked to the nucleus by 100 Å filaments. The microtubules of the cytaster were found only during periods of active nuclear migration, i.e., from the onset of anaphase to the early prophase of the next mitotic cycle. They are always solitary and follow the course of the astral rays, which are known to temporarily adhere to peripheral structures of the egg cell and to exert tractive forces. In contrast to the cytaster microtubules, the microtubules in the spindle are bundled and persist from early metaphase through late telophase. During ontogenesis the first migration cytaster is built up between 3 and 12 min after oviposition near the anterior egg pole, in the vicinity of the sperm nucleus. In non-inseminated eggs time lapse films show a migration cytaster to develop autonomously in a region free from nuclei, but it does not follow the normal path of the male pronucleus. In several cases the female pronucleus, which remains without a cytaster of its own, was observed to move to the cytaster generated in the absence of the male pronucleus. Whether or not it is adhering to a nucleus, the cytaster divides into two at the correct time, i.e, corresponding to the first cleavage division in fertilized eggs. In some non-inseminated eggs this type of ‘pseudocleavage’ has been observed to occur repeatedly, giving rise to an increasing number of anucleate cytasters.
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    Development genes and evolution 188 (1980), S. 163-177 
    ISSN: 1432-041X
    Keywords: Yolk sac ; Ultrastructure ; Embryogenesis ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Changes at the ultrastructural level during germ band extension in the embryo ofDrosophila melanogaster are described. Cytoplasmic connections between cells and the yolk sac are present during initial cellular movements. At this time, a continuous system of microfilaments is present adjacent to the membranes in the connections and at the periphery of the yolk sac. As germ band extension progresses, this system becomes discontinuous, and microfilaments are apparent only in the immediate vicinity of the connections. Cytoplasmic connections are disassembled at approximately the midpoint of extension; at the same time, extensive membrane associations develop between germ band cells and between these cells and adjacent yolk sac membranes. Positioning and orientation of cytoplasmic connections suggest that the yolk sac, via these connections, is actively involved in the cellular movements of early germ band extension.
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    Development genes and evolution 185 (1978), S. 235-248 
    ISSN: 1432-041X
    Keywords: Liver ; Primary culture ; Ultrastructure ; Albumin synthesis ; Xenopus
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    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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  • 35
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    Keywords: Synaptogenesis ; Electron microscopy ; Visual acuity ; Fish development
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    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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    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 33 (1981), S. 143-151 
    ISSN: 1432-0827
    Keywords: Calcium transport ; Cytochalasin B ; Dihydrocytochalasin B ; Colchicine ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary In vivo calcium absorption was studied in normal and rachitic chicks. Cytochalasin B (CB) at a concentration of 25 µg/ml added to the medium inside the duodenal lumen inhibited calcium absorption (20 min) from 82.5±1.9% of calcium absorbed in the controls to 59.2±3% in normal and from 70.0±2.3% to 47.0±2.1% in rachitic chicks. In vitro studies by everted ileal sacs of young rabbits also showed an inhibition of active transport of calcium due to CB. Whereas in the controls the ratio of45Ca concentrations in serosal and mucosal media (60 min) was 7.2±0.32, the ratios were 5.24±0.52; 4.40±0.36; 3.40±0.42; 5.77±0.52; 1.38±0.08; and 1.06±0.02 in the presence of CB at concentrations of 5, 10 and 25 µg/ml; colchicine 10−4M, Na citrate 0.02M, and heat-devitalized conditions, respectively.45Ca concentration in the mucosal scrapings was also affected. It showed an increase from controls (15,101±404 cpm/mg) and correlated with CB concentration: 17,378±489, 19,015±1000, and 20,201±362 at 5, 10, and 25 µg/ml, respectively. Dihydrocytochalasin B also inhibited active calcium transport and caused an increase in45Ca concentration in the mucosal scrapings. Correlated electron microscopic studies showed certain changes in the brush border, especially in some actin microfilaments in the terminal web region. It seems that these morphological alterations may be related to transcytoplasmic movement of calcium.
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  • 38
    ISSN: 1432-0827
    Keywords: Alcohol ; Electron microscopy ; Growth plate
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    Notes: Summary We have previously demonstrated that ethanol has a direct toxic effect on the rat skeleton characterized by decreased trabecular bone volume. In the present study, we examined the ultrastructure of the distal radial epiphyseal growth plates in these same animals. Eight weeks of ethanol administration to 12 male rats results in serum alcohol levels of 140 mg/dl but did not alter the width or light microscopic appearance of the radial growth plate. Quantitative electron microscopy failed to demonstrate morphologic evidence of toxicity in the skeletal cells. We conclude that although ethanol appears to have a direct effect on rat bone characterized by enhanced resorption, toxicity is not attended by ultrastructural changes in the skeletal cells.
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    Calcified tissue international 33 (1981), S. 529-540 
    ISSN: 1432-0827
    Keywords: Bone cells ; Electron microscopy ; PTH ; PGE1
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    Topics: Biology , Medicine , Physics
    Notes: Summary Four different cell populations—designated PF, OB, OC, and PC—were isolated from calvaria of 18-day-old chick embryos for analysis of the effects of hormones on bone tissue. The cell populations were studied with histological and biochemical methods. Apart from the well-known cell types present in calvaria, a new cell type was found in the noncalcified organic matrix between the osteoblastic layer and the calcified matrix. These cells were provisionally called osteocytic osteoblasts. They represent the “transition state” between osteoblasts and osteocytes. On the basis of histological studies with light microscopy (LM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM), the PF population was considered to originate primarily from the periosteal fibroblasts, the OB population from the osteoblasts and osteocytic osteoblasts. The population of cells still present in calvaria after removal of periosteal fibroblasts and osteoblasts was called the OC population. This cell population was very much enriched with osteocytes. The fourth isolated population (PC) was a mixed population of fibroblasts, osteoblasts, and preosteoblasts. On exposure to parathyroid hormone (PTH), all four cell populations showed increased lactate production, but only the OB and OC populations displayed increased cAMP production. Prostaglandin E1 (PGE1) stimulated cAMP production in both OB and PF cells. From the results of this study it was concluded that PTH receptors are present on all of the cell types studied, but that occupancy of the receptor induces adenylate cyclase stimulation only in osteocytes and fully differentiated osteoblasts.
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    Calcified tissue international 26 (1978), S. 181-190 
    ISSN: 1432-0827
    Keywords: Cellular calcium ; Electron microscopy ; Osteoblasts ; Chondrocytes ; Mineralization
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    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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  • 41
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    Keywords: Shell formation ; Free nerve endings ; Ultrastructure ; Lymnaea stagnalis ; Biomphalaria pfeifferi
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    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
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    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 30 (1980), S. 43-50 
    ISSN: 1432-0827
    Keywords: Osteogenesis ; In vitro ; Electron microscopy ; Mineralization
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    Topics: Biology , Medicine , Physics
    Notes: Summary Chick limb mesenchymal cells differentiate into muscle, cartilage, fibrous, and bone tissue. Previous reports show that when stage 24 limb mesenchymal cells are cultured in vitro, chondrocytes, myocytes, fibrocytes, and osteoblasts can be identified on the basis of morphological and biochemical parameters. The study reported here demonstrates that phenotypic expression in culture seems to be dependent on the initial plating density, Scanning electron microscopic observations indicate that when stage 24 limb mesenchymal cells are initially seeded at high densities (5 × 106 cells per 35 mm culture dish), mounds of cells appear in culture. These mounds represent cartilage nodules composed of a fine fibrous matrix and chondrocytes, surrounded by a loose fibrous connective tissue matrix. Cultures initially plated at intermediate densities (2.0–2.5 × 106 cells/35 mm culture dish) produce a flattened layer of fibrocytes overlying a matrix of collagen fibers and calcium phosphate deposits as determined by electron-microprobe analysis; these observations are indicative of osteoblast expression. Cells seeded at this intermediate density appear larger and possess greater surface area than cells seeded at high density. It is suggested that conditions that permit such increased cell surface area coupled with a relative compaction due to cell crowding may provide conditions permissive for osteogenesis. Based on morphological criteria, it appears that chick limb mesenchymal cell osteogenesis in vitro is not associated with chondrogenesis but represents a separate route of phenotypic expression.
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  • 44
    ISSN: 1432-0827
    Keywords: Rat ; Calvarium ; Electron microscopy ; Preosteoclasts ; Osteoclasts
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    Notes: Summary This is a study of the fine structure of cells of the 20-day fetal rat calvarium. Special attention is given to identifying and characterizing preosteoclasts. These cells are relatively common and located largely, but not exclusively, at the endocranial bone surface. The preosteoclasts are characterized by abundant mitochondria, an incomplete perinuclear Golgi apparatus, and variable-shaped dense granules. The dense granules are unique in appearance in that they contain an internal dense matrix surrounded by a clear halo. Most granules are circular in shape but some are elongate or tubular in form. Granules with identical appearance are observed in osteoclasts. The preosteoclasts are mononucleate, or occasionally binucleate. It is suggested that because preosteoclasts are morphologically distinctive and relatively abundant, it should be feasible to separate these cells from a heterogeneous cell isolate.
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  • 45
    ISSN: 1432-0827
    Keywords: Decalcification ; Electron microscopy ; Bone matrix ; Bone glycoproteins
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    Notes: Summary A solution of triethylammonium EDTA in 80% ethanol was evaluated as a demineralizing reagent for bone in comparison with aqueous solutions of EDTA. Biochemical analysis and acrylamide gel electrophoresis of extracts of finely powdered bovine bone showed that most of the macromolecular components of the organic matrix extractable in aqueous EDTA were retained when the triethylammonium EDTA reagent was used. Ultrastructural examination of chick tibias decalcified with the reagents showed a better preservation of cellular morphology, especially the membranous components, and more uniformly distributed ground substance, though slightly less in quantity, when the aqueous reagent was used. Use of the two reagents appears to be complementary, the alkylammonium reagent being more appropriate for use in studies of the organic matrix of bone, including immunohistochemical studies of bone glycoproteins. The aqueous reagent is more appropriate for use in studies of cellular ultrastructure.
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    Calcified tissue international 34 (1982), S. 273-279 
    ISSN: 1432-0827
    Keywords: Odontogenesis ; Ultrastructure ; Alkaline phosphatase
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    Topics: Biology , Medicine , Physics
    Notes: Summary The ultrastructural localization and gradient of activity of alkaline phosphatase were studied with respect to cell differentiation, matrix synthesis, and matrix mineralization in the incisor and molar teeth of 4-day-old Sprague-Dawley rats. The animals were perfused intracardially at room temperature with 2.5% glutaraldehyde in 0.1M sodium cacodylate (pH 7.4) with 3–4% sucrose. The jaws were dissected, immersion-fixed for 24 h, and the incisor and molar tooth germs removed. These were demineralized in 10% EDTA in NaOH (pH 7.4) with 7% sucrose. After reactivation of the enzyme with 0.1M MgCl in Tris-maleate buffer (pH 7.4) at 4°C, the teeth were incubated for alkaline phosphatase in a medium consisting of 6 ml 3% sodiumβ-glycerophosphate, 4 ml 0.2M Tris-HCl buffer (pH 9.2), 3 ml 1.6% MgSO4, 12 ml 0.5% lead citrate (pH⋍12), and 2.1 g sucrose. The pH was adjusted to 9.2 with 0.2M HCl, the volume made up to 30 ml, and the solution centrifuged for 10 min at 5000 rpm. Control teeth were incubated in medium minus the substrate. Finally, the specimens were routinely post-fixed and embedded for sectioning and examination with a Philips 300 electron microscope. A gradient of alkaline phosphatase activity was mapped along the developing teeth in the cells of the stratum intermedium, the proximal borders of the ameloblasts, the early dentine matrix, the predentine-dentine border, matrix vesicles, and the plasma membranes of odontoblasts and subodontoblast cells. The gradient of alkaline phosphatase activity was evident in the forming tooth from the cervical loop to the crown apex and was related to the cellular events, matrix synthesis, and matrix mineralization occurring during odontogenesis.
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  • 47
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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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    Topics: Biology , Medicine , Physics
    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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  • 48
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    Calcified tissue international 24 (1977), S. 191-197 
    ISSN: 1432-0827
    Keywords: Amelogenesis imperfecta ; Hypocalcification ; Hypoplasia ; Electron microscopy
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    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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    Topics: Biology , Medicine , Physics
    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
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    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
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    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 31 (1980), S. 93-108 
    ISSN: 1432-0827
    Keywords: Calculus ; Ultrastructure ; Apatite ; Transmission ; Scanning
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    Topics: Biology , Medicine , Physics
    Notes: Summary Using transmission and scanning electron microscopy, we have studied the ultrastructure of a number of urinary calculi, mainly composed of calcium phosphate. Three fundamental kinds of calcium phosphates were detected: nonstoichiometric carbonate apatite, nonhexagonal octacalcium phosphate, and calcium-magnesium whitlockite. The influence that the organic matter, substitutions in the phosphate lattice of CO3 and Mg, and apatitic stoichiometry have on the ultrastructure of the calcium phosphate calculi has been detailed. An originating apatitic unity named U2 is assumed to be the responsible for all the different structures of calcium apatites appearing in renal calculi. On the basis of our observations, a mechanism whereby apatites grow is postulated; magnesium functions as an inhibitor for the growing mechanism.
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    Calcified tissue international 33 (1981), S. 119-124 
    ISSN: 1432-0827
    Keywords: Avian eggshell ; Microstructure ; Electron microscopy ; Electron diffraction ; Calcite growth
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    Topics: Biology , Medicine , Physics
    Notes: Summary The eggshell of the domestic fowl has been studied by transmission electron microscopy and diffraction. Thin sections of shell were prepared by chemical and ion-beam thinning techniques. Each calcite column of the palisade layer consisted of crystallites of diameter 20 to 30 µm with some tendency for crystallite alignment within a single column. Evidence indicates that there was no significant preferred orientation in the palisade layer as a whole. Only in the surface layer was any preferred orientation detected, and here {1014} planes tended to lie parallel to the surface. The results are compared with previously published data, and calcite nucleation and growth are discussed.
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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 30 (1980), S. 27-34 
    ISSN: 1432-0827
    Keywords: Ultrastructure ; Calcium ; Cartilage ; Vesicles
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    Notes: Summary The potassium pyroantimonate technique was utilized for the selective subcellular localization of calcium in the mandibular condylar cartilage of 1-day-old rats. Electron dense calcium pyroantimonate precipitates were localized principally in mitochondria and at the cell membrane of the chondrocytes. In addition, small intracellular vesicles 0.1–0.2µm in diameter were observed in proximity to the cell membrane of chondrocytes of the mid-hypertrophic zone. The results suggest that these vesicles were being extruded from the cell into the extracellular matrix. Energy-dispersive analysis by X-rays confirmed that calcium is the principal cation of the electron-dense precipitates.
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    Calcified tissue international 36 (1984), S. 550-555 
    ISSN: 1432-0827
    Keywords: Enamel crystals ; Length ; Shape ; Apatite ; Ultrastructure
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    Topics: Biology , Medicine , Physics
    Notes: Summary An original method for fractionating and preparing isolated crystals of homogeneous size was developed. It was demonstrated that enamel apatite crystals are at least 100 µm long. The flexibility of the very long crystallites was demonstrated. Crystal curvatures, accounting for the irregular course of the prisms through the enamel thickness, were visualized and measured. It was shown that in the deep forming enamel layer, lateral branches may grow out of the crystals and crystal fusing often occurs, inducing the crystallites to assume pyramidal shapes with their wide bases pointing toward the dentino-enamel junction and one or two tops toward Tomes' processes. During the maturation process, the two tops of the still immature crystals also fuse so that the mature crystals acquire a rodlike aspect, with parallel faces and steplike graduations along thec axis, allowing a close contact between the crystals. These results support the hypothesis that the crystallites would be continuous from the dentino-enamel junction to the surface.
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    Calcified tissue international 34 (1982), S. 382-390 
    ISSN: 1432-0827
    Keywords: Avian osteopetrosis ; Avian oncornavirus ; Ultrastructure ; Calcification ; Bone cells
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    Topics: Biology , Medicine , Physics
    Notes: Summary Diaphyseal tibial bone of 12.5 – 13-day and 19-day-old embryos and 20-day-old hatched chicks infected with retrovirus MAV.2-O were examined by transmission electron microscopy. The viruses were associated with lining osteoblasts and osteocytes. Whereas the infection of the osteoblast layer seemed to be a transient stage, virus association with osteocytes was a constant and main ultrastructural feature. The viruses were found either in the osteoid or in the periosteocytic space of the bone lacunae. They arose from dense cytoplasmic areas located near the cell plasmalemma via a budding process. The newly budded virus particles often had a large tail or a fine stalk-like process lost in the extracellular space. The viruses underwent calcification by deposition of inorganic material and were incorporated in the bone trabeculae. No production of virus was observed in typical osteoclasts with well-differentiated ruffled borders. The viral-induced avian osteopetrosis seemed to result from increased bone deposition through stimulation of osteoblast and osteocyte activities, whereas osteoclastic bone resorption seemed to be undisturbed.
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  • 58
    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 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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  • 62
    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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    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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    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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    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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    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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    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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    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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  • 69
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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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  • 70
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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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  • 71
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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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  • 72
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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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  • 73
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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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  • 74
    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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  • 75
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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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  • 76
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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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  • 77
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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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  • 78
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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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  • 79
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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
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    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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  • 80
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    European journal of clinical pharmacology 9 (1975), S. 219-227 
    ISSN: 1432-1041
    Keywords: Rifampicin ; induction of drug metabolism ; hexobarbital kinetics ; tolbutamide kinetics ; plasma concentrations ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy volunteers took 1.2 g rifampicin daily for 8 days, and before and afterwards each received hexobarbital (7.32 mg/kg) and tolbutamide (20 mg/kg) by i.v. infusion on two consecutive days. The plasma concentrations of the two drugs were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 325 to 122 min and of tolbutamide from 418 to 183 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased about three-fold and that of tolbutamide more than two-fold. Significant changes in the distribution kinetics of the two drugs were not observed. The results suggest that rifampicin is capable of inducing drug metabolism in man, which leads to an increased rate of elimination of drugs that undergo biotransformation in the liver.
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  • 81
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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
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    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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  • 82
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    European journal of clinical pharmacology 9 (1975), S. 229-234 
    ISSN: 1432-1041
    Keywords: Quercetin ; flavonoids ; pharmacokinetics ; absorption ; disposition ; metabolism ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of quercetin, a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8±1.2 min for the α phase and 2.4±0.2 h for the β phase (predominant half life), respectively. Protein binding was 〉98%. The apparent volume of distribution was small at 0.34±0.03 l/kg. Of the intravenous dose 7.4±1.2% was excreted in urine as a conjugated metabolite, and 0.65±0.1% was excreted unchanged. After oral administration no measurable plasma concentrations could be detected, nor was any quercetin found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in faeces after the oral dose was 53±5%, which suggests extensive degradation by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.
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  • 83
    ISSN: 1432-1041
    Keywords: Aldosterone ; renin ; aldosterone antagonist ; canrenone ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Canrenone was administered in doses of 2×82 mg and 2×164 mg per day over a period of 10 days to diabetic patients without cardiovascular, liver or kidney involvement. Aldosterone excretion and plasma aldosterone increased only slightly during both regimes. There was a clear-cut increase in aldosterone excretion only after discontinuation of carenone. Excretion of sodium potassium and fluid was not significantly changed either during or after treatment. The lack of effect of canrenone on the kidney was in contrast to the significant decrease in serum sodium and increase in serum potassium, and the significant, dose-dependent rise in plasma renin activity following canrenone administration. The increased plasma renin activity persisted for some days after discontinuation of canrenone. It is suggested that canrenone primarily exerted its effect in the distal part of the large intestine where ionic movements are most affected by aldosterone. The disproportionately slight increase in plasma aldosterone concentration and aldosterone excretion, in spite of the greatly elevated plasma renin activity and serum potassium level, is considered to be due to a direct inhibitory effect of canrenone on aldosterone production in the adrenals.
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  • 84
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    European journal of clinical pharmacology 9 (1976), S. 291-298 
    ISSN: 1432-1041
    Keywords: Tricyclic antidepresent ; lofepramine ; single- and multiple-dose kinetics ; noradrenaline and 5-hydroxytryptamine uptake ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of lofepramine, an imipramine analogue, have been studied by administering single oral doses to volunteers, determination of plasma levels of lofepramine and desmethylimipramine after ten days of oral administration to patients, and by relating plasma levels to the effect on uptake of noradrenaline by isolated rat irides and brain slices of plasma samples collected during treatment. The results indicate that lofepramine undergoes pronounced first pass elimination and that desmethylimipramine is a major metabolite of it. During steady-state conditions the plasma level of lofepramine fluctuates considerably between doses. A linear relation was found between inhibition of neuronal uptake of noradrenaline and the plasma concentration of desmethylimpramine. No effect was seen on the uptake of 5-hydroxytryptamine in brain slices incubated in patients' plasma which suggests that neither lofepramine nor its metabolites formedin vivo in man affect neuronal uptake of this amine. Lofepramine belongs to the group of tricyclic anti-depressants which preferentially inhibit noradrenaline uptake.
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  • 85
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    European journal of clinical pharmacology 9 (1976), S. 307-314 
    ISSN: 1432-1041
    Keywords: Absorption ; man ; β-methyl-digoxin ; serum concentration ; urinary excretion ; radio-immunoassay
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Single doses of β-methyl-digoxin 0.4 mg were given to groups of 17 – 18 healthy volunteers as an intravenous infusion lasting 2 hours, or orally as Lanitop Liquidum® or Lanitop® tablets. The serum glycoside concentration and urinary glycoside excretion were measured over 8 and 32 h. The absolute bioavailability from the oral preparations in comparison with the infusion was lower for the first 8 h than for the entire 32 h of the investigation; the relative bioavailability from tablets was the same as from the solution for both periods. For both periods the area under the serum concentration/time curve and the urinary glycoside excretion were significantly lower after administration of the tablets than after intravenous infusion. Taking the average of both parameters, the absolute bioavailability of β-methyl-digoxin was about 80% from the solution and about 70% from the tablets. In 18 patients undergoing intravenous or oral therapy with β-methyl-digoxin steady state glycoside concentrations were compared in a cross-over study of intravenous maintenance therapy with Lanitop® ampoules or oral treatment with Lanitop® tablets. For a standard daily dose of 0.2 mg β-methyl-digoxin the serum concentrations were 1.35±0.10 ng/ml during both intravenous and oral administration. The intra-individual variation in glycoside concentration after changing from intravenous to oral maintenance therapy, or vice versa, was about the same as during continued intravenous or oral administration. It is concluded that the rate of rise of serum concentration after a single dose may be a useful indicator of the rate of absorption, but that the area under the serum concentration/time curve and the urinary glycoside excretion up to 32 h are unsuitable for determining equivalent doses of different formulations or routes of administration of digitalis glycosides.
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    European journal of clinical pharmacology 9 (1976), S. 327-332 
    ISSN: 1432-1041
    Keywords: Antipyrine ; pharmacokinetics ; half-life ; blood ; plasma ; saliva ; individual variation
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    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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  • 87
    ISSN: 1432-1041
    Keywords: Chlorthalidone ; diuretics ; drug plasma concentration ; protein binding ; red blood-cell concentration ; pharmacokinetics
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    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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  • 88
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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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    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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  • 90
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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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  • 91
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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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  • 92
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    European journal of clinical pharmacology 8 (1975), S. 227-231 
    ISSN: 1432-1041
    Keywords: Dixyrazine ; methaqualone ; etodroxizine ; Isonox® ; sleep stages ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Whole night EEG and polygraphic recordings were made in ten young, healthy, male volunteers after dixyrazine (12.5 mg, 25 mg, 50 mg), methaqualone (250 mg) and Isonox® (methaqualone 250 mg + etodroxizine 50 mg). A total of 156 recording nights (36 adaptation nights were not included in the analyses) were scored for different sleep stages according to accepted criteria. The smallest dose of dixyrazine (12.5 mg) had no significant effect upon sleep pattern: the larger doses (25 mg and 50 mg) caused significant decreases in REM-sleep during the first nights of administration. The decrease disappeared during the following two nights of treatment. No withdrawal effects were seen. Methaqualone also caused moderate depression of REM-sleep during the first night of treatment, and this effect, too, disappeared during prolonged administration. Isonox® (methaqualone + etodroxizine) had a somewhat stronger surpressive effect upon REM-sleep than methaqualone alone.
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  • 93
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    European journal of clinical pharmacology 8 (1975), S. 63-69 
    ISSN: 1432-1041
    Keywords: Diabetes mellitus ; sulfonylurea ; glipizide ; glibenclamide ; pharmacokinetics ; excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Four subjects received 5 mg14C-glipizide orally, 3 subjects 1 mg intravenously and 2 subjects 5 mg14C-glibenclamide orally. Plasma levels of radioactivity, and urinary and faecal excretion were measured. For both drugs the disappearance of radioactivity from plasma followed complex kinetics and the apparent half-lives increased steadily with time. The two sulfonylureas were extensively metabolized and were excreted in the urine as hydroxylated or conjugated metabolites. The effects of both drugs on blood glucose and immunoreactive insulin were comparable. The findings are compared with other published results.
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  • 94
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    European journal of clinical pharmacology 8 (1975), S. 91-96 
    ISSN: 1432-1041
    Keywords: Carbamazepine ; pharmacokinetics ; man ; diphenylhydantoin ; phenobarbital ; plasma binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Carbamazepine (2.7–3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1 – 7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 l/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2 – 3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.
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  • 95
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    European journal of clinical pharmacology 8 (1975), S. 167-173 
    ISSN: 1432-1041
    Keywords: Disopyramide ; haemodynamic effect ; negative inotropic effect ; anticholinergic effect ; hear failure ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effects of disopyramide have been studied in 11 patients with manifest or imminent heart failure. Disopyramide, 2 mg per kg body weight, was given intravenously during right and left heart catheterisation. The cardiac index decreased by an average of 28% (p〈0.01); mean maximal left and right ventricular end-diastolic pressures were increased by 5.0±0.9 mm Hg (〈0.01) and 5.0±0.6 mm Hg (p〈0.05), respectively; and left ventricular systolic pressure fell slightly but significantly (p〈0.05). No significant change in right ventricular systolic pressure was seen. Pulmonary wedge pressure rose on average by 2.7 mm Hg (p〈0.05). No significant change in heart rate was observed in 5 patients with sinus rhythm. In 6 patients with atrial fibrillation, there was a significant (p〈0.01) increase in heart rate; the average increase in heart rate for the entire group was 19,6 heats per minute. The maximum effect on all the parameters occurred 7–11 minutes after the injection, and it gradually subsided during the following 10 minutes. It was concluded that disopyramide had a potentially serious myocardial depressant effect.
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  • 96
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    European journal of clinical pharmacology 8 (1975), S. 217-222 
    ISSN: 1432-1041
    Keywords: Co-trimoxazole ; sulphamethoxazole ; trimethoprim ; pharmacokinetics ; paediatric-prescribing ; dosage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Co-trimoxazole, a mixture of one part trimethoprim (TMP) and five parts of sulphamethoxazole (SMX) in fixed ratio was given to 48 children aged between one and 48 months twice daily for up to seven days. Twenty were relatively healthy and 28 were very ill. Dosage was based on age. Plasma concentrations of both drugs were measured just before a dose was due and some three hours later. They were in the effective but not toxic range and serve to justify the simple regimen which generated them.
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  • 97
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    European journal of clinical pharmacology 8 (1975), S. 255-260 
    ISSN: 1432-1041
    Keywords: Vitamin D ; renal osteodystrophy ; 5,6-trans-25-hydroxycholecalciferol ; rickets ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Vitamin D analogues of high biological activity are probably useful in the treatment of renal osteodystrophy. The pharmacokinetics of the synthetic compound 5,6-trans-25-hydroxycholecalciferol have been studied in healthy subjects who were of normal vitamin D status. In comparison to natural 25-hydroxy-cholecalciferol, serum levels of the analogue were lower and its half-life in blood after oral or intravenous administration was considerably shorter. In normal subjects no increase of dihydroxylated metabolites in serum was observed within seven days of an intravenous dose.
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  • 98
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    European journal of clinical pharmacology 8 (1975), S. 353-357 
    ISSN: 1432-1041
    Keywords: Chlormethiazole ; pharmacokinetics ; man ; plasma levels ; gas-liquid chromatography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of chlormethiazole have been studied in six healthy volunteers following an intravenous infusion of the drug. The log. plasma concentration-time curve of chlormethiazole after cessation of the infusion was found to be curvilinear and was fitted therefore, by a bi-exponential equation computed by non-linear least squares regression analysis. Half-lives for the inital α-phase (0.54±0.05 h) and the terminal β-phase (4.05 ±0.60 h) were calculated together with other pharmacokinetic parameters of the two compartment open model. An explanation for the discrepancy between the presently reported plasma half-lives and those appearing in the literature has been presented. The pharmacokinetic treatment of the plasma concentration-time data obtained following intravenous infusion also enabled the prediction that the maximal systemic availability of an orally administered dose of chlormethiazole would be of the order of 15%.
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  • 99
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    European journal of clinical pharmacology 8 (1975), S. 371-376 
    ISSN: 1432-1041
    Keywords: Digoxin ; bioavailability ; plasma levels ; cumulative urinary excretion ; particle size ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Various brands of digoxin tablets, and even different batches of one brand, may differ greatly in bioavailability. Digoxin-Sandoz® tablets have been compared with Lanoxin® manufactured between 1969 and 1972 and after May 1972. Comparisons were also made between and within batches of Digoxin-Sandoz tablets. Three separate cross-over studies were conducted involving a total of 20 volunteers. Digoxin-Sandoz tablets were shown to have a constant bioavailability and to produce plasma concentrations very similar to “new” Lanoxin. Storage for 2 years of one batch of Digoxin-Sandoz did not alter the bioavailability. Particle size was shown to influence bioavailability. Care should be exercised when plasma data alone are interpreted as an index of bioavailability. Measures of bioavailability based on plasma data obtained up to 6 h after administration differed from those based on cumulative urinary excretion data (in this study by a factor of about 2), which can lead to the belief that a difference in bioavailability is much greater than is actually the case. Data from cumulative urinary excretion, collected over a sufficiently long period of time, are likely to be the most reliable method for determining the bioavailability of a substance such as digoxin.
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  • 100
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    European journal of clinical pharmacology 8 (1975), S. 421-425 
    ISSN: 1432-1041
    Keywords: Proscillaridin ; enteric-coated tablets ; plasma levels ; urine excretion ; 86Rb-erythrocyte assay ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of proscillaridin was measured by a modified86Rd method during treatment with multiple doses of a commercial preparation of proscillaridin. Despite high doses, very low plasma levels were found, and there were only minute amounts of glycoside activity in urine and faeces. Administration of an enteric-coated proscillaridin preparation gave higher plasma levels, which raises the possibility of inactivation of the glycoside by acid gastric juice. The results suggest that proscillaridin has low biological availability when given orally, and that it is extensively metabolised in the body.
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