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  • 1990-1994
  • 1985-1989  (1,560)
  • 1975-1979
  • 1987  (1,560)
  • Cell & Developmental Biology  (1,362)
  • pharmacokinetics  (127)
  • Ultrastructure
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Years
  • 1990-1994
  • 1985-1989  (1,560)
  • 1975-1979
Year
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Archives of gynecology and obstetrics 240 (1987), S. 33-43 
    ISSN: 1432-0711
    Keywords: Ovary ; Surface epithelium ; Perfusion ; Rabbit ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Using transmission electron microscopy we examined the morphology of the surface epithelium of the isolated and perfused rabbit ovary after an ovulatory dose of HCG. Rupture of follicles occurred in vitro approximately 13 h after HCG-injection and 6 h after the start of perfusion. The ultrastructural changes during the perfusion were similar to those occurring in vivo. The perfused ovarian epithelium had villous processes of varied architectural complexity with squamoid and cuboid epithelial cells. The superficial cells contained pinocytotic vesicles, coated and noncoated endocytotic caveolae, and occasional vacuoles. Dense bodies were more commonly found in vitro than in vivo. Occasionally structures similar to “Call-Exner-bodies” were found on the surface epithelium near to preovulatory follicles. Intercellular spaces of various sizes were also numerous. Disappearance of surface epithelium in the apex of follicles was often observed and the matrix of the tunica albuginea consisted of dissociated fibers and degenerating cells. This study showed that the isolated perfused rabbit ovary can serve as a model for studying the biology and pathology of ovarian surface epithelium.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Archives of gynecology and obstetrics 240 (1987), S. 137-146 
    ISSN: 1432-0711
    Keywords: Preovulatory granulosa cells ; Call-Exner body ; Fibrin ; Human ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructure of preovulatory granulosa cells may be distinct in follicles containing competent as opposed to non-competent oocytes. To test this assumption, granulosa cells were looked for in 36 follicular fluid aspirates from 8 patients taking part in an in vitro fertilization and embryo transfer program. Granulosa cells were absent from 16 aspirates and present in 20. Both aspirate types contained oocytes able to develop in culture. Granulosa cells were subdivided into three developmental stages. Stage 1 (5% of aspirates) showed proliferating cells, while stage 2 (60% of aspirates) and 3 (35% of aspirates) cells were in the preluteinization stage. These cells were recognizable by their number of lipid droplets and differentiated according to possession of a rough (stage 2) or smooth (stage 3) endoplasmic reticulum. Luteinization did not occur in these cells. All stages displayed desmosomes, gap junctions, and annular junctions. The structure of Call-Exner bodies and of fibrin deposits were unexpected findings. Our study indicates that there is no correlation between the previously used morphological parameters of granulosa cells and oocyte maturity.
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  • 3
    ISSN: 1432-2285
    Keywords: Cambial activity ; Frost hardiness ; Phenology ; Salix ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Summary The ultrastructure of cells in the cambial region of Salix dasyclados Wim. (clone 78056) was studied during the development of winter hardiness and the onset of cambial activity in spring. Plants were grown at relative growth rates (RG) of 8% and 12% respectively, resulting in different nitrogen content in the stems. Frost hardiness of the plants was estimated by standardized freezing tests. Plants with a higher nitrogen status ceased growth later and started re-growth earlier in spring than plants with lower nitrogen content. Differences in ability to withstand low temperatures during autumn and spring were found between plants grown in the two nutrient treatments. During the development of frost hardiness in the autumn, the number of meristematic cells in the cambial region decreased. The cessation of meristematic activity was accompanied by cell wall thickening and ultrastructural changes in the cells. Frost hardiness increased from the ability to survive -6° C in October to survival of -80° C at the beginning of December. From November to February the cambial region comprised a layer of 2–3 thick-walled cells with conspicuous ultrastructural features. Starch accumulated in plastids in September, decreased during November to March and then increased again in accordance with changes of frost hardiness. Onset of cambial activity began between the end of March and the beginning of April, as shown by increased vacuolization of meristematic cells and mitotic activity. By April, the starch content had increased and lipolysis was observed. Frost hardiness had decreased, and plants with low and high nitrogen content were able to survive -15° C and -10° C, respectively. After budburst, all axillary shoot parts were damaged at temperatures below-3° C.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-2307
    Keywords: Soft tissue neoplasm ; Sarcoma ; Rhabdoid cell ; Rhabdoid tumor ; Ultrastructure ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We report the occurrence of rhabdoid cells in several specified soft tissue sarcomas of round cell variety. The rhabdoid cells had an acidophilic cytoplasm containing a globular perinuclear inclusion and were characterised ultrastructurally by the presence of aggregates of 10 nm intermediate filaments. These filaments contained both cytokeratin and vimentin, as demonstrated immunohistochemically. Extensive sampling of soft tissue sarcomas revealed the presence of such cells in different types of soft tissue round cell sarcomas as follows: 12 of 13 cases of epithelioid sarcomas, 8 of 13 synovial sarcomas (composed predominantly of round cells), 6 of 20 extraskeletal myxoid chondrosarcomas and 4 of 4 round celled malignant mesotheliomas. We wish to stress that the appearance of rhabdoid cells is not a monopoly of one particular type of tumour.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 412 (1987), S. 175-182 
    ISSN: 1432-2307
    Keywords: Appendix ; Colorectal neoplasm ; Carcinoid ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The clinicopathological features of six appendix and five bowel tumours with features of the so-called ‘goblet cell carcinoid’ are described. By light microscopy, these tumours were composed predominantly of mucous cells, together with variable proportions of endocrine and Paneth cells. Immunohistochemical and ultrastructural study confirmed this impression and no amphicrine cells were seen. The clinical course of all cases arising in the bowel, and three out of six appendix tumours was characterised by an aggressive behaviour with the development of widespread lymphatic and often intraperitoneal metastasis, but liver metastasis occurred in only one instance. We conclude, both from this study and from a review of the literature, that the ‘mixed crypt cell carcinoma’ forms a distinct clinicopathological entity justifying separate classification from adenocarcinoma and carcinoid tumour.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 411 (1987), S. 93-98 
    ISSN: 1432-2307
    Keywords: Gliomatosis cerebri ; Brain tumour ; Ultrastructure ; Glial cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructural features of five biopsies of gliomatosis cerebri (GC) are described. Four main types of tumour cells are seen: anaplastic astrocytes poor in organelles with a variable amount of glial microfilaments; atypical oligodendrocytes with scanty cytoplasm in which microtubules are present; intermediate forms with aboundant cytoplasm rich in organelles, with microtubules and microfilaments; and small cells with round nuclei and a very scanty rim of cytoplasm. In two cases several concentrically folded cytoplasmic lamellae of glial processes were arranged either around themselves or around the perikaryon of other cells. This ultrasructural study indicates that GC is a neoplastic process of small undifferentiated elements, transitional forms of astroglia (to oligodendroglia) and anaplastic cells of astrocytic origin in all stages of development.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 411 (1987), S. 293-298 
    ISSN: 1432-2307
    Keywords: Ectocervix ; Serotonin cells ; Calcitonin cells ; Ultrastructure ; Transitional epithelium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A systematic study of endocrine cells in the ectocervix was carried out using histochemical, immunohistochemical and ultrastructural techniques. Serotonin and calcitonin immunoreactive cells were demonstrated in this site. Serotonin and calcitonin immunoreactivities were coexpressed in the same endocrine cell. These distinctive cells were encountered in two main morphological varieties of ectocervical epithelium. Normal-appearing stratified squamous epithelium contained only very rare serotonin and calcitonin cells. In contrast, endocrine cells were fairly abundant in a specific epithelium termed “transitional-like”. This type of epithelium was not only confined to the transformation zone but could also extend onto the portio as far as the vaginal cut margin. In some cases, transitional-like epithelium bore morphological resemblance to urothelium. In other cases, it could be regarded as basal cell hyperplasia or immature squamous metaplasia. Of interest, serotonin and calcitonin cells have been well-documented as normal inhabitants of some other non-squamous epithelia, such as urothelium or pseudostratified columnar epithelium. Therefore, it is suggested that certain ectocervical epithelia show some similarities to urothelium, in respect of their morphological appearance and endocrine profile. Further investigations using more objective and specific markers of urothelial cells are needed to assess the exact degree of homology connecting all these types of epithelium.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 412 (1987), S. 119-125 
    ISSN: 1432-2307
    Keywords: 16,16-dimethyl prostaglandin E2 ; Aspirin ; Tight junctions ; Stomach ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The canine gastric epithelium was exposed to solutions containing 20 mM aspirin and 20 mM aspirin + 30 µg/kg 16,16-dimethyl prostaglandin E2 (dmPGE2) for periods of three and forty minutes. No macroscopic hemorrhagic lesions were seen. Light microscopically, surface lesions were reduced from 10 percent (aspirin alone) to 2.5% (aspirin+dmPGE2). However, dmPGE2 does not appear to attenuate aspirin induced tight junction alterations. Discontinuities in the apical occluding complexes, hyperplastic tight junctions and stand number variability were documented in freeze frature replicas of aspirin as well as aspirin+ dmPGE2 treated dog stomachs. The results of these experiments would seem to suggest that 30 µg/kg dmPGE2 does not prevent aspirin induced damage to the tight junctions of the canine gastric epithelium or enhance their repair.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 411 (1987), S. 561-568 
    ISSN: 1432-2307
    Keywords: Psammous desmo-osteoblastoma ; Ultrastructure ; Osteonectin ; Bone tumours ; Fibro-osseous lesion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Fibro-osteo-cemental lesions of the jaw bones are a heterogeneous group of diseases which present problems in classification. Psammous desmo-osteoblastoma is one of four newly proposed entities (Makek 1983) and has until now been characterized by its light microscopic, clinical and radiological features. On electron microscopy this tumour exhibits fibroblastic (preosteoblastic), osteoblastic and osteocytic cells and a globular mineralization unlike the mineralization of the psammoma bodies. Immunohistological investigations with anti-osteonectin, a bone specific protein linking mineral to collagen, showed positive intracellular staining in all tumour cells and extracellular staining in the osteoid. The psammoma bodies were, however, not stained. These results confirm the view of the osteogenic histogenesis of psammous desmo-osteoblastoma, with an osteogenic differentiation of the tumour cells, bone formation and association of psammoma bodies which are not of bone origin. This combination of findings supports the view that psammous desmo-osteoblastoma represents a new and distinct entity occuring in desmal preformed cranio-facial bones which should be incorporated in a revised WHO-classification.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 410 (1987), S. 93-96 
    ISSN: 1432-2307
    Keywords: Heterogeneity ; Ultrastructure ; Colonic carcinoid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This report describes a colonic carcinoid tumor in which three, and possibly four, distinct cell types are distinguishable on the basis of their ultrastructure and granule morphology. These cell types closely resemble the normal endocrine cells of the large bowel, both in appearances and in relative frequency. The mixed composition of this tumor may have arisen either by parallel differentiation of distinct cell types, or by sequential maturation of one cell type.
    Type of Medium: Electronic Resource
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 410 (1987), S. 317-326 
    ISSN: 1432-2307
    Keywords: “Primary” endothelial cilia ; Endothelial centrioles ; Human atherosclerosis ; Ciliary transitional fibers ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary “Primary” cilia were present in the endothelial cells of human aortic fatty dots and streaks but not in those of normal intima. They had the features of cilia of the “9+0” axonemal configuration observed in many other cells. A lateral foot process and transitional fibers “anchored” the ciliary basal body in the cytoplasm, but rootlets were not identified in material examined. Ladder-like configurations interconnected the two centrioles (=diplosome) of control endothelium. The “primary” cilia of endothelium differed from those of the rudimentary type observed in smooth muscle cells in similar lesions of man, but shared many features with cilia of those present in experimental atherosclerosis in rabbit. Cilia were rarely described in vascular endothelium. It is believed that, to date, they were not reported to occur in normal or pathological arteries in man. It is being stressed that whereas the significance of these unusual organelles remains uncertain, their widespread occurrence may indicate that their role is more important than was believed previously, and they should cease being a curiosity only.
    Type of Medium: Electronic Resource
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 176 (1987), S. 281-294 
    ISSN: 1432-0568
    Keywords: Myotendinous junction ; Human growth ; Skeletal muscle ; Tendon ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The myotendon junction of human paravertebral skeletal muscle was studied by light and electron microscopy. Transverse and longitudinal sections of myotendinous regions of normal multifidus muscles were examined at three chronological stages from birth to maturity. Variations in the appearance of surface extensions at the terminal ends of muscle fibers consisted of brush-like evaginations at birth and villous-like projections in the adult. Regardless of age, they were invariably covered by a prominent external lamina, and mutually interdigitated with connectivetissue elements in the adjacent tendon. Various stages of myofibrillar assembly and sarcomere alignment were evident in the muscle fiber terminus at birth. With advancing age, splitting of terminal sarcomeres at Z bands commonly gave rise to diverging myofilament bundles that attached to electron-dense patches under the sarcolemma. In these regions, leptomeric organelles were also encountered in neonatal and adolescent myotendons. At all stages, the ends of muscle fibers possessed cytological features consistent with active synthesis and secretion. Densely-packed sarcoplasmic organelles including multiple Golgi complexes, clusters of ribosomes, mitochondria, cytoplasmic vesicles, and elements of rough- and smooth-surfaced endoplasmic reticulum were prevalent. Peripheral and centrally-placed heterochromatic nuclei with prominent nucleoli were arranged singly or in groups at the ends of muscle fibers. Satellite cell profiles and unmyelinated axons in the subjacent tendon were also identified at these sites in the adult. Fibroblasts in growing tendon were plentiful, and at all stages, possessed morphological features indicative of high metabolic and secretory activities.
    Type of Medium: Electronic Resource
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  • 13
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 177 (1987), S. 131-138 
    ISSN: 1432-0568
    Keywords: Capillaries ; Tooth pulp ; Tight junctions ; Odontoblasts ; Ultrastructure ; Mineralisation ; Cat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The relative roles of capillaries and odontoblasts in the process of dentinogenesis and in pulp reactions to trauma and pathology are not clear. Contributing to the problem is the paucity of information on odontoblast —capillary relationships and tight junctions between odontoblasts. Using light microscopy the capillaries have now been examined in semithin transverse sections of perfusion fixed teeth at different positions in the long axis from the apical foramina to the pulp horns. Odontoblastic capillaries were prominent in the coronal and middle regions of canines and present at the same levels of incisors. In the pulp horns and just coronal to the pulp horns capillaries were all subodontoblastic but near the apex there were also a few odontoblastic capillary profiles. Transmission electron microscopy on ultrathin sections revealed that a high proportion of middle and coronal odontoblastic capillary profiles were fenestrated but subodontoblastic profiles coronal to the pulp horns were the most fenestrated. In a search for tight junctions in ultrathin sections some typical strands were observed between odontoblasts. The difficult of obtaining the latter evidence was explained by the cellular arrangement of the odontoblasts which differed markedly from an ideal parallel, apically coplanar arrangement. The results question the possibility that there is a direct exchange of materials between pulp capillaries and dentine in teeth of limited growth and provide a baseline for future experiments to test the permeability of the odontoblast layer.
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  • 14
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 73 (1987), S. 281-286 
    ISSN: 1432-0533
    Keywords: Teratoma ; Nervous tissue ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructure of the nervous tissue in a benign ovarian teratoma is described. This tissue was organized into areas having both “meningel” and “ependymal” surfaces, between which were found astrocytes, ependymal cells, neurones with synapses and microglia. These cells all had ultrastructural similarities to their normal counterparts in the nervous system. In addition, some signs of degenerative change — due possibly to the abnormal location of the nervous tissue — were observed. Oligodendrocytes and myelin were absent, possibly because of vascular insufficiency.
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  • 15
    ISSN: 1432-0533
    Keywords: Cerebellum ; Histogenesis ; Cisdichlorodiammineplatinum ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of this electron microscopy study was to further investigate the effects of cis-dichlorodiammineplatinum (cis-DDP) on the cerebellum of the immature rat. Ten-day-old animals were treated with cis-DDP subcutaneously and killed after 1, 7, 15 or 21 days. On postinjection day 1, cis-DDP effects were evident mainly in the external granular layer, with nuclear damage in many dividing cells, while their cytoplasm appeared to be less affected. Some binucleate cells were also present. On the contrary, in postmitotic or more differentiated cells, only cytoplasmic alterations were found. At later stages (postinjection day 7), the frequency of damaged cells in the external granular layer decreased, but there was a cellular deficit in the internal granular layer. Many postmitotic neurons underwent coagulative necrosis. Finally (postinjection days 15 and 21), the cellular deficit was partly compensated for by “reactive” structures, e.g., glial cell fibers, which underwent hypertrophy after initial edema. Moreover, packing densities of Bergmann astrocytes and oligodendrocytes were higher.
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 73 (1987), S. 92-98 
    ISSN: 1432-0533
    Keywords: Spinal gliomas ; Vascular proliferation ; Ethylnitrosourea ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The histology and ultrastructure of ten spinal cord gliomas, mainly oligodendrogliomas, induced transplacentally in rat with ethylnitrosourea were studied. The characteristic feature of seven spinal tumours was distinct delineation of neoplastic tissue from the edematous surrounding zone by a ring of irregular, proliferating capillaries, among which immature capillary buds prevailed. The alterations were proliferation of endothelium with endothelial overlapping, elongation of interendothelial junctions and enhancement of pinocytotic vesicles on luminal and abluminal surfaces. The basal membranes, besides other changes, were often replaced by some floccular condensations. In the edematous zone the capillary walls were deprived of contact with glial processes. The lack of contact between astrocytic processes and vascular wall may contribute to the persistent immature state of peripheral capillaries.
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  • 17
    ISSN: 1432-0568
    Keywords: Serotonin ; Substantia nigra ; Mammals (rat, cat, Macaca fuscata) ; Immunohistochemistry ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The distribution of serotonin-containing nerve fibers in the substantia nigra of the rat, cat and monkey was studied with a highly sensitive peroxidase-antiperoxidase immunohistochemical method. Serotonin fibers in the substantia nigra of all species consisted of fine varicose fibers and formed a fine network. In the zona compacta of all species, serotonin fibers were sparsely distributed. In the zone reticularis of the rat and cat, these fibers were densely distributed and their distributional pattern was almost uniform, while in the monkey such fibers were unevenly distributed and high and low dense areas were intermingled. In the pars lateralis of all species, serotonin fibers were diffusely distributed, and the distributional density was much higher in the cat and monkey than in the rat. Immunoelectron-microscopic studies further revealed that a majority of the labeled varicosities in the rat substantia nigra were in close apposition to peridendritic axon terminals and were also free in the neuropil; occasionally they exhibited symmetrical synapses of “en passant” type with non-immunoreactive dendrites or somata. Our results support a functional significance of serotonergic regulation of the substantia nigra in mammals.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 175 (1987), S. 467-475 
    ISSN: 1432-0568
    Keywords: Mouse spermiogenesis ; Constitutive heterochromatin ; Nucleolus organizing regions ; Fluorochrome ; Staining ; EM silver staining ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In this study, the selective fluorochrome staining of constitutive heterochromatin and a specific ultrastructural silver-staining of nucleolar material (i.e., the nucleolus organizing regions) were undertaken to be used as indicators for the chromosomal arrangement during mouse spermiogenesis. Since in mice all somatic chromosomes are telocentric and the constitutive heterochromatin and nucleolar organizing regions are closely associated to the centromeres, this combination of techniques provided for the first time ultrastructural evidence 1) for the dispersion of the constitutive heterochromatic chromocentre and a centrifugal migration to the postacrosomal portion of the nuclear envelope where constitutive heterochromatin seems to mediate the assembling of microtubules in the so-called manchette. As elongation continues, the constitutive heterochromatin migrates back into central position and forms the “focous of earlier condensing chromatin”, which initiates further chromatin condensation. 2) The fate of the nucleolus during spermiogenesis could also be further clarified: The nucleolus is first associated with the chromocentre, but starts to disintegrate during elongation phase. However, argyrophilic remnants are still visible in the centre of the nucleus, pointing to an ongoing transcriptional activity. When they final disappear, they leave behind “nuclear vacuoles” in the dense chromatin mass of the mature sperm nucleus.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 176 (1987), S. 35-40 
    ISSN: 1432-0568
    Keywords: Bovine ; Oocyte maturation ; Meiosis ; Nucleus ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cumulus-oocyte complexes were obtained from cow ovaries by aspiration from small (1–6 mm in diameter) antral follicles after slaughter. Complexes with a compact multilayered cumulus investment were cultured and subsequently processed for electron microscopy after various periods of culture. By morphological criteria the oocytes could be divided into the following sequence of meiotic stages. The oocyte nucleus I stage was characterized by a spherical nucleus located peripherally in the ooplasm while undulation of the nuclear envelope and initial chromatin condensation was seen at the oocyte nucleus II stage. The oocyte nucleus breakdown stage was characterized by formation of long slender projections from the nuclear envelope in which the envelope doubled back on itself, appearance of dense areas and haphazardly oriented microtubules in the nucleus, marked condensation of the chromatin, and dissolution of the nuclear envelope into irregular vesicles and tubules. The condensed chromatin I stage was characterized by the location of condensed chromatin configuration and uniformly oriented microtubules in a dense area peripherally in the ooplasm while the final condensed chromatin II stage was characterized by a gradual invasion of condensed chromatin configurations into a dense area combined with the presence of the first polar body in the perivitelline space.
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  • 20
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 177 (1987), S. 91-96 
    ISSN: 1432-0568
    Keywords: Ultrastructure ; Human egg ; Human embryo ; Cleavage embryo
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A two-cell human embryo recovered from the Fallopian tube 82 h following the LH peak in plasma and 37 h after a single episode of intercourse was examined by transmission electron microscopy. At the time of recovery the embryo was denuded of cumulus cells, and both the zona pellucida and the two adjoining blastomeres were intact. The finding of two polar bodies in the perivitelline space, two nucleated blastomeres and remnants of the fertilizing sperm tail within the cytoplasm of one of them, were considered as evidences that the embryo was normally fertilized. Among the most compicuous features found were the presence of very distinct desmosome-like structure between blastomeres, and the cytoplasmic cell organelles distribution in three areas referred as: a sub-cortical, a middle and a perinuclear bands. An outstanding feature was the extensive blebbing of the nuclear envelope. In general, the features seem to correspond to a normally developing two-cell embryo undergoing cleavage at a normal rate.
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  • 21
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 177 (1987), S. 147-152 
    ISSN: 1432-0568
    Keywords: Atrial myocardium ; Vagotomy ; Monkey ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructure of the atrial myocardium in the monkey (Macaca fascicularis) was studied after bilateral cervical vagotomy and survival times of 1, 3, 5, 7, 10, 21 and 28 days. During the first week after vagotomy, a few atrial cells showed a reduction in the sarcoplasm, crowding of the myofibrils, peripheral dispersion and reduced intercristal density of the mitochondria and increased sarcoplasmic reticulum and glycogen particles. In some profiles, there was increased electron density and granularity at the I bands and the intercalated discs. The number of such affected cells increased in the subsequent days such that by 21 to 28 days about 50% of the cells were estimated to be affected. During the latter stages further changes included, the degradation of the myofilaments and increased electron density, disorganisation and disintegration of the digital extensions at the intercalated discs. Throughout the experiments there was a leucocytic infiltration, more evident in the longer survival times.
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  • 22
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 175 (1987), S. 399-410 
    ISSN: 1432-0568
    Keywords: Implantation ; Marmoset ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructural morphology of the initial stages of implantation in the marmoset monkey (Callithrix jacchus) was studied in pregnant monkeys at known time intervals after ovulation. The earliest samples, obtained 13 days after ovulation, displayed both cytotrophoblast and syncytiotrophoblast. The cytotrophoblast was restricted to the blastocoel, whilst syncytiotrophoblast intruded to the endometrial basal lamina. At later stages, days 16 and 19 after ovulation, both cytotrophoblast and syncytiotrophoblast had extended laterally around the uterus, and the syncytiotrophoblast also extended deeper into the maternal tissnes. The mesoderm layer was first discernible at 19 days after ovulation. At 23 days after ovulation the syncytiotrophoblast surrounded the maternal blood vessels entirely. In this study syncytiotrophoblast was not observed to breach the maternal blood vessels, even at 31 days after ovulation. Early cytotrophoblast columns could be seen at 31 days after ovulation. The endothelial cells lining the maternal blood vessels displayed hypertrophy from the earliest stages (day 13) onwards, although a true decidual response was only observed in samples of 23 and 31 days after ovulation.
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  • 23
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 176 (1987), S. 41-44 
    ISSN: 1432-0568
    Keywords: Bovine ; Oocyte maturation ; Meiosis ; Gap junction ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cumulus-oocyte complexes were obtained from cows by aspiration of small (1–6 mm in diameter) antral follicles after slaughter. Complexes with a compact multilayered cumulus investment were cultured and processed for transmission electron microscopy after different periods of culture including a 0 h control group. In 0 h control oocytes the cumulus cells had numerous projections which penetrated the zona pellucida and established gap junctions with the oolemma. A partial loss of these junctions was noticed as an early event of oocyte maturation occurring within the first 3 h of culture. A low frequency of gap junctions was maintained until 12–18 h of culture where the junctional contact was completely disrupted. This decrease in intercellular communication was parallelled by resumption of oocyte meiosis.
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  • 24
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    Anatomy and embryology 176 (1987), S. 231-237 
    ISSN: 1432-0568
    Keywords: Embryonic chick heart ; Interventricular septum ; Mesenchymal tissue ; Endocardial activation ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Light and electron microscopic studies of frontal and sagittal sections of embryonic chick hearts (Stages 25, 28–29), reveal mesenchymal tissue in the cephalic portion of the interventricular septum. The endocardium of this cephalic portion contains reoriented and invaginated cells with pseudopodia; in addition there are cells immediately subjacent to the endocardium. Similar cellular events take place during the formation of mesenchymal tissue in the atrioventricular and conotruncal regions. In these regions the mesenchymal tissue originates by means of an endocardial activation process. The structural characteristics of the formation of the cephalic portion of the interventricular septum suggest that local mesenchymal tissue is contributed by the endocardium. However, based upon the close anatomic relationship observed by us between the mesenchymal tissues of the atrioventricular canal, conotruncal region and the cephalic portion of the interventricular septum; we do not discard a contribution by migration of cells from atrioventricular and conotruncal regions to the interventricular septum.
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  • 25
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    Archives of dermatological research 279 (1987), S. 459-464 
    ISSN: 1432-069X
    Keywords: All-trans retinoic acid ; Epidermal cells ; Ultrastructure ; Differentiation ; Stratification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of all-trans retinoic acid on human epidermal cell cultures were studied using ultrastructural techniques. Differentiation and stratification were reduced in retinoic acid treated epidermal cells. Treated cells developed a rounded appearance and seemed to contain more granules and vacuoles than usual. Desmosomes were not found in treated cells.
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  • 26
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    Acta neuropathologica 75 (1987), S. 147-155 
    ISSN: 1432-0533
    Keywords: Esthesioneuroepithelioma ; Ultrastructure ; Immunohistochemistry ; Neurofilament protein (NFP) ; Keratin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A case of esthesioneuroepithelioma was investigated ultrastructurally and immunohistochemically, using antibodies against neurofilament protein (NFP), glial fibrillary acidic protein (GFAP), keratin, neuron-specific enolase (NSE), S-100 protein (S-100), and tyrosine hydroxylase (TH). The tumor initially manifested as an epidural mass in the anterior cranial fossa in a 64-year-old man, and about 31/2 years later, autopsy further revealed extensive metastases to the lymph nodes of the neck and thoracic cavity. In the cranial and nasal cavities, the tumor was composed of fairly uniform, ill-defined cells arranged in nests which were surrounded by a fibrovascular stroma. These histological features were reproduced in the metastatic tumor nodules with frequent occurrence of tubular arrangements of the tumor cells. Ultrastructurally, two different cell types were well recognized by their characteristic morphological features, which were reminiscent of sensory neurons and sustentacular cells of the olfactory epithelium. No dense-cored secretory granules were observed in the tumor cells. Immunohistochemically, the tumor showed a variable number of cells positive for NFP, keratin, NSE and S-100. NFP was present in a relatively small number of cells, which were found diffusely in the nests. Keratin was observed in the cells mainly located at the periphery. NSE-positive cells tended to form irregular clusters in the center. A few S-100-positive cells were found, without any particular arrangement. These findings indicated that the present tumor, which actually arose in the superior nasal cavity, consisted of cells differentiating in at least two distinct directions, neuronal and epithelial, and strongly suggested that the tumor was of true olfactory epithelium origin, or more precisely, derived from the bipotential, undifferentiated basal cells of this epithelium.
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  • 27
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    Acta neuropathologica 74 (1987), S. 307-312 
    ISSN: 1432-0533
    Keywords: Ganglioglioma ; Neuronal degeneration ; Ultrastructure ; Brain stem ; Brain tumor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A brain stem ganglioglioma in a 9-year-old female was examined ultrastructurally. The constituent neuronal (ganglion) cells displayed various ultrastructural features of neuronal degeneration including Hirano, Lafora and zebra bodies, inclusion-like aggregates of neurofilaments and large dilatations of rough endoplasmic reticulum. Although similar observations have been reported in peripheral neuronal tumors, this is the first reported occurrence in ganglioglioma, an uncommon tumor in the central nervous system. The coincidence of these alterations in the present tumor appeared to be of great interest, however, their exact etiology remained uncertain.
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  • 28
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    Acta neuropathologica 73 (1987), S. 400-402 
    ISSN: 1432-0533
    Keywords: Ultrastructure ; Ependyma ; Experimental hydrocephalus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary New ultrastructural alterations of the ependymal cells in the altered container model of experimental feline hydrocephalus are described. These include half desmosomes and a basal lamina on the apical surface of the ependymal cells, punctate adhesion-like structures between intraventricular mononuclear cell and the apical surface of the ependymal cells and unusual distortion of the ependymal cells. The significance of these previously unreported morphological alterations is unknown.
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  • 29
    ISSN: 1432-0533
    Keywords: Brain ; Global ischemia ; Ultrastructure ; Ionic changes ; Ca
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A time course of tissue ionic changes, and their relation to ultrastructural findings during reperfusion following a 15-min global ischemic brain insult was studied in a dog model. Parietal cortex was analyzed for Ca, Na, K, Mg and Fe in controls and after 10 min, 2, 4, and 8 h of reperfusion. After 8 h of reperfusion, the mean values (μmol/g tissue wet wt.) for Ca (control=1.43, 8 h=2.76) and Na (control 60.4, 8 h=107.4) doubled and K (control=90.4, 8 h=48.5) decreased to half that of the control. Ultrastructural studies and subcellular localization of calcium in parietal cortex of in situ-fixed brains after 8 h showed cortical neurons with clumping of nuclear chromatin, dilatation of endoplasmic reticulum and disruption of plasma membranes. Large amounts of electron-dense precipitates of calcium were present within dilated astrocytic processes, synaptic vesicles, cytoplasm of edematous dendrites and mitochondria. Cortical neurons from postischemic dogs without reperfusion showed only slight chromatin clumping and edema of astrocytic processes, but no calcium accumulation. The large ionic shifts noted between 4 and 8 h of reperfusion, indicate a progressive inability of the cells to maintain normal transmembrane gradients of these ions and may reflect a membrane destructive process, as demonstrated ultrastructurally at 8 h. Enhanced calcium entry into the neuron during reperfusion appears to be a part of the cytotoxic mechanism leading to neuronal necrosis.
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  • 30
    ISSN: 1432-0533
    Keywords: Intermediate filaments ; Glial fibrillary acidic protein (GFAP) ; Vimentin ; Ultrastructure ; Glioma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glial filaments contain vimentin and glial fibrillary acidic protein (GFAP). The question of how glial filaments change morphologically according to the expression of vimentin and/or GFAP has remained unclear. In this study, immunohistochemical and ultrastructural examinations were performed on the subcutaneously transplanted tumors of two clones (F6B3 and G10A10) derived from a mouse glioma. F6B3 tumor expressed GFAP and vimentin in large quantities. G10A10 tumor expressed plenty of vimentin but only a little of GFAP. Ultrastructurally, F6B3 tumor contained abundant cytoprocesses in most of which numerous intermediate filaments (IFs) were arranged in a parallel array. On the other hand, only a small number of the processes were seen in G10A10 tumor, which showed a few IFs arranged either randomly or sparsely in the processes. Both tumors commonly had the IFs accompanied by visible sidearms, but there was a difference in that the smooth and firm IFs were confined to part of F6B3 tumor. Thus, the comparison made between the two models presented differences in the content, arrangement and morphology of IFs, as well as in the manner of GFAP expression, suggesting correlation between these differences.
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  • 31
    ISSN: 1432-0533
    Keywords: Neuronal ceroid-lipofuscinosis ; Membranous cytoplasmic body ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An autopsy case of adult neuronal ceroid-lipofuscinosis was examined. The clinical picture was charaterized by gait disturbance, bulbar palsy and dementia. Histopathologically, diffuse neuronal loss was found throughout the central nervous system. The remaining neurons, predominantly in the motor nuclei of the spinal cord and brain stem, were swollen with storage material. Observed under the electron microscope the storage material showed various ultrastructures, such as lipofuscin-like bodies, pleomorphic lipid bodies, curvilinear profiles and finger-print profiles, in different regions of the central nervous system. In the ballooned neurons of the spinal anterior horn, many membranous cytoplasmic bodies and curvilinear profiles were intermingled within the same cell and were continuous with each other. Biochemically,N-acetyl neuraminic acid content was significantly increased in the spinal anterior horn. These findings suggest the localized increase of ganglioside in that region.
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  • 32
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    Archives of dermatological research 279 (1987), S. 173-179 
    ISSN: 1432-069X
    Keywords: UV-A pigmentation ; Ultrastructure ; Morphometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary UV-A-induced skin pigmentation was investigated morphologically in semithin and thin sections from 11 volunteers, using different irradiation modalities (single doses of 10,50 and 100 J/cm2). Visible skin pigmentation was observed in all but two probands, and erythema in two; pronounced pigmentation was present after repeated irradiation only. Contralateral non-irradiated, UV-B-irradiated and suntanned skin specimens were used as controls. There was an increase in the number of clear cells in the basal layer (x 1.6) and particularly of large clear cells (x 1.7) after repeated irradiation. Also, the number of melanosomes in melanocytic dendrites (x 2.8) increased after repeated irradiation. The number, size and shape of the melanosome complexes in both basal and suprabasal keratinocytes remained unchanged, even when a distinction was made between central and peripheral location. In contrast, suntanned skin showed an increase in melanosome complexes in basal (x 5.8) and suprabasal (x 3.7) keratinocytes. It is concluded that UV-A-induced skin pigmentation differs in some ways from UV-B or sun-induced melanogenesis, and that the clinical grade of tanning cannot accurately be determined by ultrastructural methods.
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  • 33
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    Development genes and evolution 196 (1987), S. 367-371 
    ISSN: 1432-041X
    Keywords: Vitellogenesis ; Bufo marinus oocyte ; Yolk-platelet membrane ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Oocytes of the toad Bufo marinus have been studied by means of thin section and particularly freeze-fracture electron microscopy to characterize the cytoplasmic membranes around the yolk organelle, and the storage of yolk material in precursors and platelets. This appears to be a previously unknown type of yolk-platelet formation. During yolk-organelle development from the primordial precursor to the bi-partite fully grown yolk platelet, numerous lipoid droplets are attached to the periphery of the platelet, indicating an intense uptake of lipids. As is typical for amphibians, the fully grown yolk platelet has a crystalline internum covered by a dense osmiophilic externum, and the whole organelle is enveloped by a plasma membrane that shows no direct connection or fusion with endocytotic vesicles. The yolk membrane exhibits few intramembraneous particles (IMPs) at the core areas and some more where it borders fields of lipoid droplets. Here the IMPs show a net-like arrangement in the furrows between adjacent droplets.
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  • 34
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    Experimental brain research 67 (1987), S. 41-51 
    ISSN: 1432-1106
    Keywords: Trauma ; Neuron ; Culture ; Calcium ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cultured mouse spinal neurons were fixed at three different intervals after dendrite amputation: within the first 15 min, at 2 h and at 24 h. Dendrites were amputated at lesion distance of either 50 μm (31% probability of cell survival) or 100 μm (53% probability of cell survival) from the edge of their perikarya. When fixed within 15 min, operated neurons showed a two-phase gradient of ultrastructural damage which spread from the transection site towards the perikaryon. At 2 h after dendrite amputation all neurons operated close to their perikarya were categorized as either viable, moribund or dead, based on their appearance with phase contrast microscopy. These categories of response to physical trauma corresponded to distinctly different ultrastructural changes. Moribund neurons were filled with membrane-bound vesicles which were derived from swollen mitochondria and grossly dilated cisternae of the smooth endoplasmic reticulum. The cytoplasm of dead neurons contained large clear areas and many condensed, dark mitochondria. Both moribund and dead neurons lacked cytoskeletal elements. All of these ultrastructural changes are hypothesized to be the result of an increase in the intracellular concentrations of free calcium. Although evidence of residual mitochondrial swelling was present in some surviving neurons at 24 h, the ultrastructure of others was comparable to that of control cells. Some surviving neurons had terminal swellings at the ends of the severed neurites which were very similar to retraction balls of transected axons after CNS trauma.
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  • 35
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    European journal of clinical pharmacology 32 (1987), S. 631-634 
    ISSN: 1432-1041
    Keywords: salbutamol ; albuterol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design. Pharmacokinetic parameters from intravenous data were similar to previously reported values obtained with oral administration, with a mean terminal half-life of 3.8 h and a mean clearance of 439 ml·min−1·1.73 m−2. Peak plasma concentrations of 10–20 ng·ml−1 were obtained 1–3 h following oral administration. The absolute bioavailability of each of the oral preparations was 44%. While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.
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  • 36
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    European journal of clinical pharmacology 32 (1987), S. 411-418 
    ISSN: 1432-1041
    Keywords: 5-fluorouracil ; colorectal carcinoma ; pharmacokinetics ; product-inhibition ; blood clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37°C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination. The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. These findings suggest the possibility of pulmonary clearance of 5-FU.
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  • 37
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    European journal of clinical pharmacology 32 (1987), S. 431-432 
    ISSN: 1432-1041
    Keywords: theophylline ; fluoroquinolones ; drug interaction ; pharmacokinetics ; ofloxacin ; norfloxacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pretreatment for 3 days with oral ofloxacin or norfloxacin had no significant effect on the disposition of a single i.v. dose the theophylline in healthy volunteers.
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  • 38
    ISSN: 1432-1041
    Keywords: growth hormone releasing factor ; radio-immunoassay ; pharmacokinetics ; variance model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Three ranges of doses of growth hormone releasing factor (2.5–80 µg, 80–320 µg and 75–600 µg) were intravenously administered to healthy young volunteers in three double blind studies. Serum circulating GRF levels were determined by radioimmunoassay. Experimental concentration curves were fitted, using the extended least squares method, to a biexponential model for the structural model and power function for the variance model. The power variance model, compared to the constant variance model greatly reduced the coefficient of variation of the biexponential parameters. The power of the variance model was estimated to be 1.95. The distribution half-life was 6.6 min and the elimination half-life was 39.0 min (harmonic means). Total clearance was 0.12±0.01 µg/l/min. No difference between these parameters was found for the various doses. GRF kinetics was linear established in the range 10 to 600 µg which means that elimination was not altered by the increased doses.
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  • 39
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    European journal of clinical pharmacology 32 (1987), S. 563-568 
    ISSN: 1432-1041
    Keywords: nitrendipine ; pharmacokinetics ; hepatitis ; liver cirrhosis ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty one patients with liver disease (cirrhosis 11, chronic hepatitis 5 and acute hepatitis 5) and 6 healthy volunteers were given a single i.v. dose of nitrendipine 5 mg. Afterwords nitrendipine 20 mg once daily were administered orally for seven days. With the intravenous injection a significant increase in the AUC and elimination half-life of nitrendipine was found in patients with cirrhosis as compared to the normal volunteers. After chronic oral dosing, the area under the plasma concentration-time curve, AUC (0–24), was 94.5 ng ml−1 h and the plasma clearance CL was 1380.6 ml/min in the healthy controls; in patients with cirrhosis the AUC (0–24) h was significantly greater at 309.4 ng ml−1 h and CL had fallen to 686.6 ml/min. Considerable accumulation of nitrendipine was also found in the patients with chronic hepatitis. Nitrendipine could not be detected in urine from any of the subjects. Blood pressure and heart rate were not significantly influenced by the treatment in the various groups investigated. Antipyrine clearance in the patients with cirrhosis was correlated with the nitrendipine plasma clearance. Thus, accumulation of nitrendipine has been demonstrated in the patients with cirrhosis and chronic hepatitis.
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  • 40
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    European journal of clinical pharmacology 32 (1987), S. 597-605 
    ISSN: 1432-1041
    Keywords: iloprost ; prostacyclin analogue ; pharmacokinetics ; pharmacodynamics ; radiolabeled study ; volunteers ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels and excretion of tritium-labeled iloprost in healthy elderly male and female volunteers have been measured after i.v. infusion of 2 ng·kg−1·min−1 for 4 h and oral administration of 0.1 and 0.48 μg/kg. During infusion, a steady-state of labeled compounds in the plasma was not achieved. Total radioactivity declined from a mean of 408 pg equiv/ml in three phases, with half-lives of 24 min, 1.7 h and 5.0 h, respectively. A steady-state of unchanged iloprost was reached rapidly with a peak of 81 pg/ml. Plasma levels declined biphasically with half-lives of 6 min and 31 min. Total clearance was 24 ml· min−1·kg−1. Maximum concentrations of labeled substances after oral administration were 307 and 1,051 pg equiv/ml after 29 and 39 min respectively. The peak of unchanged iloprost (116 pg/ml) was observed 7.5 min after an oral dose of 0.48 μg/kg. Bioavailability was 16%. Iloprost was totally metabolized and the metabolities were mainly excreted in urine. The main biotransformation products in plasma and urine were tentatively identified by cochromatography as dinor-and tetranoriloprost and their glucuronides. ADP-induced platelet aggregation was reduce by 60% during the i.v. infusion and 15 min after oral administration of 0.48 μg/kg. Heart rate and blood pressure were virtually unaffected. Common side-effects were facial flush, headache and nausea.
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  • 41
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    European journal of clinical pharmacology 32 (1987), S. 625-629 
    ISSN: 1432-1041
    Keywords: disopyramide ; bioavailability ; saturable binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of disopyramide were determined in 10 healthy volunteers after a 300 mg oral dose and again after a 2mg/kg i.v. dose. The unbound clearance was 599 ml/min and the unbound renal clearance 310 ml/min. The terminal elimination rate constant of unbound drug was 0.180 h−1 after the i.v. dose and 0.203 h−1 after the oral dose. The absorption rate constant was 0.53−1 and the maximum peak concentration occurred after 3.2 h. The bioavailability was 0.809 using the area under the unbound plasma concentration time curve. Although a saturable plasma protein binding was found in all subjects the bioavailability using the total concentration, in contrast to theoretical expectations, showed the same value (0.813) as the unbound concentrations.
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  • 42
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    European journal of clinical pharmacology 33 (1987), S. 197-201 
    ISSN: 1432-1041
    Keywords: ceftazidime ; renal impairment ; plasmapheresis ; pharmacokinetics ; cephalosporins ; autoimmune disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of plasmapheresis (PA) on the elimination kinetics of ceftazidime (Cef) has been investigated. A single dose of Cef was administered intravenously to 11 patients with autoimmune diseases and varying degrees of renal impairment (Group I CLCR〈50 ml/min, Group II CLCR〉50 ml/min). In Groups I and II the mean total clearance of Cef (CL) was 30 and 116 ml/min−1, respectively. The elimination half-life (t1\2β) and the volume of distribution (V) were significantly higher in Group I than in Group II (11.9 vs 2.0 h, 27.1 vs 18.5 l). PA had no influence on the plasma level-time profile of Cef. The amount of Cef recovered from separated plasma accounted for only 2 to 9% of the administered dose, being particularly low in patients with normal renal function (4.6%). Thus, since elimination of Cef via PA is negligible, dosage calculations should be based solely on renal function.
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  • 43
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    European journal of clinical pharmacology 33 (1987), S. 227-230 
    ISSN: 1432-1041
    Keywords: enoxacin ; theophylline ; drug interaction ; healthy volunteers ; adverse effects ; pharmacokinetics ; renal tubular excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The mechanism of the theophylline-enoxacin interaction has been studied in six healthy subjects. Theophylline 250 mg was administered p.o., twice daily for 11 days in a sustained release dosage form. On the 4th day of treatment, blood samples were taken every 2 h and urine was collected over 1 dose interval. From Days 5 to 11 coated tablets of enoxacin 400 mg b.i.d. were coadministered. On Day 11 blood and urine were collected as on Day 4. The mean plasma theophylline concentration rose from 4.4 to 15.1 mg/l, corresponding to a 73.6% reduction in total clearance. The urinary excretion of unchanged theophylline increased from 12.7 to 35.3%, whereas the production of metabolites was reduced (1-demethylation 81.4%; 3-demethylation 83.1%, 8-hydroxylation 74.6%). The results indicate that the theophylline-enoxacin interaction may be due to inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism. Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered. This led to unchanged or even to elevated plasma levels of the metabolites. The mechanism of this interaction is still to be elucidated, but it may be due to competition for renal tubular secretion.
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  • 44
    ISSN: 1432-1041
    Keywords: iron deficiency anaemia ; sulphadimidine ; absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of iron deficiency anaemia and its treatment on the absorption of sulphadimidine has been investigated in adult patients. The absorption judged by total % of the dose excreted in urine and Cmax, tmax, AUC and Kabs in plasma, was not significantly different before and after iron therapy or correction of anaemia. However, sulphadimidine absorption by the anaemic patients was significantly greater than in normals.
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  • 45
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    European journal of clinical pharmacology 33 (1987), S. 315-318 
    ISSN: 1432-1041
    Keywords: propranolol ; pharmacodynamics ; pharmacokinetics ; beta-blockade ; sustained-release propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0–24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.
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  • 46
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    European journal of clinical pharmacology 33 (1987), S. 355-361 
    ISSN: 1432-1041
    Keywords: metoprolol ; smoking ; gender ; pharmacokinetics ; HPLC ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The purpose of this study was to examine the influence of cigarette smoking and gender on the pharmacokinetics of metoprolol. Eighteen volunteers with no evidence of clinical disease each randomly received the following doses of metoprolol tartrate: 100 mg orally, 200 mg orally and 20 mg as a constant-rate intravenous infusion over 20 min. The only significant difference between smokers (S) and nonsmokers (NS) was that S had a larger steady-state volume of distribution (3.3 vs 2.5 l/kg). There were no differences in half-life, systemic clearance or bioavailability (f). No differences were observed between males (M) and females (FM) for any of the kinetic parameters examined. Systemic bioavailability varied markedly between subjects (range: 15 to 92%). In fifteen of the eighteen subjects, f was higher after the 200-mg dose compared to the 100-mg dose. These results suggest that metoprolol may be subject to saturable presystemic elimination and extend the previous observations of Johnsson et al. [1] who showed that f increased from 31% to 46% when doses were increased from 20 to 100 mg. However, the difference in f as the dose is increased is unlikely to be clinically significant since the mean difference is smaller than the variation in f among subjects.
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  • 47
    ISSN: 1432-1041
    Keywords: amodiaquine ; Plasmodium falciparum malaria ; monodesethylamodiaquine ; HPLC ; pharmacokinetics ; prophylaxis ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of monodesethylamodiaquine was studied in four healthy subjects after a single oral dose of 10 mg/kg amodiaquine base. Amodiaquine was not found in any sample, but the major metabolite monodesethylamodiaquine was detected and was assumed to be the sole derivative that contributed significantly to antimalarial activity in the blood. The best fit for the decay of the metabolite was obtained with a three-compartment model. The half-lives of the first two phases were 3.2 to 11.4 h for t1/2α1 and 22.7 to 50.3 h for t1/2α2 in plasma. The half-life of the terminal phase ( t1/2β) was between 9 and 18.2 days. The concentration in whole blood was 4- to 6-times higher than in plasma. Three schedules (alternate days, weekly, daily) of the conventional prophylactic dose of 10 mg/kg per week were compared in six other healthy subjects. There were significant differences in the plasma monodesethylamodiaquine levels between the three schedules.
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  • 48
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    European journal of clinical pharmacology 33 (1987), S. 423-426 
    ISSN: 1432-1041
    Keywords: Ketanserin ; pharmacokinetics ; hypertension ; ketanserinol ; predicted plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of ketanserin in 6 hypertensive patients after a single oral 40 mg dose and at steady-state after 4 weeks treatment with 20 mg and then 40 mg 12-hourly. Pharmacokinetic variables after a single dose were similar to those reported in healthy volunteers, with median values for Cmax 112 ng·ml−1, tmax 1 h, and t1/2 19 h. The corresponding values for the metabolite ketanserinol were Cmax 155 ng·ml−1, tmax 2 h, and t1/2 25 h. The median AUC was 3.3 times greater for ketanserinol than for the parent drug. These results were used to predict the mean steady-state plasma concentrations of ketanserin and ketanserinol. Predicted values were on average similar to those observed after four weeks treatment with 40 mg 12-hourly, although there were marked differences between the observed and predicted values in some patients. There was no evidence of time- or dose-dependent kinetics for ketanserin, but the study had insufficient power to exclude the occurrence of these phenomena entirely.
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  • 49
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    European journal of clinical pharmacology 33 (1987), S. 531-534 
    ISSN: 1432-1041
    Keywords: ketoconazole ; pharmacokinetics ; antimycotic drug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of the anti-mycotic ketoconazole in seven patients who took it for 1–6 months at a dose of 200 mg daily. The mean elimination half-life of the drug was 3.3 h, and although the ketoconazole was given only once daily, a satisfactory clinical response was obtained in all seven individuals. Only a small fraction of the absorbed drug (mean 0.22%) was excreted unchanged in the urine, suggesting almost complete metabolism. Our results support the concept that anti-mycotic activity in the tissues continues after the plasma drug concentration has fallen below a critical level. Our results also support the concept of a change in pharmacokinetics with chronic dosing.
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  • 50
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    European journal of clinical pharmacology 33 (1987), S. 67-72 
    ISSN: 1432-1041
    Keywords: cisplatin ; pharmacokinetics ; modelling ; drug dispositions ; cancer patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have fitted a first-order multicompartment pharmacokinetic model to plasma platinum concentrations measured in nine ovarian cancer patients who received intravenous infusions of cisplatin for 6 h. The time-course of ultrafilterable plasma platinum was similar in all patients studied, and was fitted by a single compartment within the limits of experimental detection. However, the time-course of protein-bound platinum showed marked differences between patients, the differences being explained by distribution to two peripheral compartments. The wide inter-patient variation observed in protein-bound plasma platinum concentrations supports the view that pharmacokinetic modelling should be carried out separately for each patient, since averaging plasma concentrations would have obscured some individual pharmacokinetic characteristics.
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  • 51
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    European journal of clinical pharmacology 33 (1987), S. 59-65 
    ISSN: 1432-1041
    Keywords: indoramin ; 6-hydroxyindoramin ; debrisoquine ; hydroxylators ; genetic polymorphism ; blood pressure ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five poor metabolisers (PM) and seven extensive metabolisers (EM), of debrisoquine, all healthy volunteers, received 50 mg indoramin orally following an overnight fast. Plasma concentrations of indoramin and 6-hydroxyindoramin were determined by HPLC with fluorimetric detection. In PM subjects, mean values of Cmax (158 ng/ml) and AUC(0–24) (2556 ng·h·m−1) for indoramin were substantially elevated and t1/2β (18.5 h) prolonged by comparison with values in the EM subjects (21.6 ng/ml, 151 ng·h·ml−1 and 5.2 h respectively). For 6-hydroxyindoramin, on the other hand, Cmax (12.4 ng/ml) and AUC(0–8) (47.5 ng·h·ml−1) in PM subjects were significantly lower than in the EM subjects (28.2 ng/ml and 94.7 ng·h·ml−1). There was a tendency to a higher incidence of side-effects in the PM group. Although the difference did not achieve statistical significance (0.1〉p〉0.05), all the PM subjects experienced sedation compared to only two in the EM group. Differences in blood pressure and pulse rate between the two groups were small. It is concluded that the oxidative metabolism of indoramin is subject to genetic polymorphism, which is probably under the control of the same gene locus as that influencing debrisoquine oxidation. The clinical consequences are discussed.
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  • 52
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    European journal of clinical pharmacology 33 (1987), S. 179-183 
    ISSN: 1432-1041
    Keywords: aminoglycosides ; haemodialysis ; gentamicin ; tobramycin ; pharmacokinetics ; renal failure ; kanamycin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The study was undertaken to look for a correlation between the measured elimination rate constants (k) of aminoglycosides and creatinine during haemodialysis. The pharmacokinetics of aminoglycosides were studied during 44 courses of haemodialysis in 21 patients. The measured k of gentamicin and tobramycin from the start until 30 min after the end of haemodialysis (mean 0.18 h−1; t1/2=3 h 51 min) was significantly correlated with the measured k of creatinine (mean 0.13 h−1; t1/2=5 h, 20 min), and also with the gentamicin and tobramycin k during haemodialysis (mean 0.20 h−1, t1/2=3 h, 28 min), as predicted by a computer program. Thus, serum concentrations of aminoglycosides 30 min after haemodialysis can be estimated by simple regression equations. However, because the measured and predicted values may diverge considerably in the individual patient, monitoring of aminoglycoside concentrations in serum after haemodialysis remains necessary.
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  • 53
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    European journal of clinical pharmacology 33 (1987), S. 287-292 
    ISSN: 1432-1041
    Keywords: praziquantel ; cysticercosis ; pharmacokinetics ; cerebrospinal fluid ; parasite drug level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two patients with cysticercosis received praziquantel (PZQ) 75 mg/kg/day orally together with 30 mg prednisone daily for 3 weeks. The first patient presented with grand-mal seizures, a pyramidal tract syndrome and subcutaneous cysticerci, and the other had internal hydrocephalus necessitating drainage. Serial plasma samples were taken after the first dose of PZQ. Lumbar CSF was obtained from the first patient and ventricular CSF from the second. Subcutaneous cysticerci were removed from the first patient. PZQ in the specimens was assayed by GLC. For distribution between plasma and CSF a rate constant of 4.9 h−1 for free PZQ, corresponding to a t1/2 of 8 min or less for the non-protein bound fraction was calculated for Patient 1. In the second patient the distribution was so rapid that the rate constant could not be calculated. The difference in distribution rate might have been due to use of different sampling times or to a time lag in the entry of PZQ between the ventricles and the lumbar sac. The rate constant for distribution of the drug between plasma and parasites was 1.4 h−1, corresponding to a t1/2 of 30 min or less. Thus PZQ penetrates rapidly into the CSF. It enters the parasite more slowly, although still more rapidly than the plasma half-life of PZQ (1–1 1/2 h).
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  • 54
    ISSN: 1432-1041
    Keywords: metoprolol ; neonates ; amniotic fluid ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven women were treated with metoprolol 50–100 mg twice daily for hypertension in pregnancy. The disposition of metoprolol and one of its metabolites alfa-OH-metoprolol was studied in venous plasma and amniotic fluid during labour, in mixed cord plasma and in capillary blood of the newborn. Peak concentrations of metoprolol and alfa-OH-metoprolol were reached 60 to 120 min after dosing in maternal plasma while the amniotic fluid levels of these compounds continued to increase from 60 to 180 min to the end of the study and were substantially higher than in the plasma after 4 to 5 h. It is postulated that a major fraction of metoprolol and alfa-OH-metoprolol reaches the amniotic fluid via the fetal urine and that the elimination from the amniotic fluid mainly proceeds via diffusion across fetal membranes and transfer across the fetal capillary bed. No measurable concentrations of metoprolol were found in two of the newborns 2 h after delivery. In the remaining four neonates the 2-h concentrations exceeded the corresponding cord plasma levels. In all neonates the alfa-OH-metoprolol levels in the capillary blood were higher 2 h after birth than in cord blood. In two newborns the metabolite levels continued to increase for 5 h and in one the highest blood concentrations of this metabolite was found 20 h after birth. Redistribution of metoprolol from tissue stores followed by metabolism might be the cause of these temporary elevations of the blood levels of metoprolol and alfa-OH-metoprolol.
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  • 55
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    European journal of clinical pharmacology 33 (1987), S. 431-434 
    ISSN: 1432-1041
    Keywords: phenylethylmalonamide ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of phenylethylmalonamide (PEMA) were studied in 6 elderly men after oral administration of a single 400 mg dose. Peak PEMA serum levels were obtained within 4 h of intake, half-life values ranged from 30.7–57.9 h in these elderly men. The elimination half-life was twice as long when compared to a study previously performed in young volunteers.
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  • 56
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    European journal of clinical pharmacology 33 (1987), S. 493-498 
    ISSN: 1432-1041
    Keywords: amiloride ; pharmacokinetics ; renal failure ; liver disease ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the antikaliuretic amiloride has been studied in healthy controls and in patients with chronic renal failure or hepatitis. It was 40% bound to protein. In healthy volunteers 49% of an oral dose was recovered unchanged in the urine. The renal clearance of amiloride was about 3 times the creatinine clearance, which means that it was predominantly excreted via tubular secretion. Renal impairment reduced the clearance of amiloride, causing a prolongation of the t1/2 and drug accumulation in plasma. In hepatitis the t1/2 of amiloride was prolonged and the AUC increased. Urinary recovery (Ae) of amiloride was greater in hepatitis patients than in controls.
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  • 57
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    European journal of clinical pharmacology 33 (1987), S. 499-504 
    ISSN: 1432-1041
    Keywords: morphine ; epidural administration ; pharmacokinetics ; CSF/plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to determine the rate and degree of redistribution of morphine within the cerebrospinal fluid (CSF), and whether it was affected by the site of and volume of the injection, morphine was given to 23 elderly patients undergoing thoracotomy — in 10 ml saline in the lumbar epidural interspace (n=5), in 10 ml saline in the thoracic epidural interspace (n=5), in 2 ml saline in the thoracic interspace (n=8) and in 10 ml saline in the lumbar epidural interspace (n=5). The plasma concentration of morphine in all patients was comparable and was much lower than in the CSF. The CSF morphine concentration, measured as the area under the CSF concentration curve (AUC), the maximal CSF concentration (Cmax) and the time to reach maximal CSF concentration (tmax), varied between the four groups. The variation was related to the site of the injection; the AUC and Cmax were lower and tmax appeared later after thoracic than lumbar injection. Lumbar CSF morphine concentrations were further reduced by thoracic epidural injection of morphine in a small as compared to a large volume. The permeability of the dura to morphine was not influenced by the volume used. The results show that morphine is not homogenously distributed within the CSF. The availability of morphine to CSF from the epidural space is not altered by the injection volume, but the drug remains more localized in CSF after epidural injection of morphine in a small volume. The findings imply that epidural injection of morphine in a small volume at a site of nociceptive input should evoke spinal analgesia with least risk of supraspinally mediated side effects.
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  • 58
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    European journal of clinical pharmacology 32 (1987), S. 273-277 
    ISSN: 1432-1041
    Keywords: pentobarbital ; hexobarbital ; dipyrone ; intensive care ; D-glucaric acid ; pharmacokinetics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml·min−1·kg−1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml·min−1·kg−1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methylaminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.
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  • 59
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    European journal of clinical pharmacology 32 (1987), S. 367-372 
    ISSN: 1432-1041
    Keywords: endralazine ; severe hypertension ; food intake ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A sensitive HPLC assay has been used to determine the effect of food on plasma endralazine levels in 8 patients with essential hypertension. Subjects were investigated whilst on maintenance therapy with endralazine combined with a fixed antihypertensive baseline treatment for at least 4 weeks, samples being collected after the usual oral morning dose of endralazine (5 mg and 10 mg), on two occasions at least 7 days apart. Endralazine was administered with the concomitant therapy in randomised order once 90 min before and once immediately after a standard breakfast. Acetylator status did not affect its pharmacokinetics in the postprandial study after a 5 mg dose, the peak endralazine concentration averaged 57.5% lower and the AUC had fallen significantly by 49.9%, whereas after 10 mg the postprandial peak level and the AUC were 82.9% and 64.7%, lower. In the 5 mg study the mean arterial blood pressure was decreased by 30 mm Hg in the fasting subjects and by 21 mm Hg in the post-prandial group. For the 10 mg dose the corresponding values were 35 and 24 mm Hg. The blood pressure lowering effect was only weakly correlated with the food — related reduction in the plasma endralazine levels. The results suggest that endralazine has a similar kinetic interaction with food as that found for hydralazine.
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  • 60
    ISSN: 1432-1041
    Keywords: triazolam ; troleandomycin ; benzodiazepines ; antibiotics ; drug interaction ; pharmacokinetics ; first-pass effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy volunteers received a single oral dose of triazolam 0.25 mg after 7 days on troleandomycin 2 g/day p.o. or placebo in a double-blind cross-over study. Plasma triazolam and psychometric and memory tests (including Critical Flicker Fusion threshold, Choice Reaction Time, Digit Symbol Substitution and Self-Rating Scales) were assessed at regular intervals after the final treatment. Troleandomycin was found to prolong the psychomotor impairment and amnesia produced by triazolam. There was a significant enhancement of the AUC, the peak concentration and the delay to tmax of triazolam after 7 days treatment with troleandomycin compared to placebo. Thus, there is a pharmacokinetic interaction, and the combination of triazolam and troleandomycin should be avoided or the dose of triazolam should be adjusted. The most likely mechanism is a diminished hepatic first-pass effect, and a decrease in the apparent oral clearance of triazolam.
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  • 61
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    European journal of clinical pharmacology 32 (1987), S. 577-582 
    ISSN: 1432-1041
    Keywords: yohimbine ; pharmacokinetics ; plasma levels ; renal elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetic disposition of yohimbine was examined in eight young male subjects following a single oral dose of 10 mg yohimbine hydrochloride. The drug was rapidly absorbed (absorption half-time 0.17±0.11 h) and rapidly eliminated from the plasma (elimination half-life 0.60±0.26 h). This clearance of yohimbine from plasma was constant over approximately 10 elimination half-lives, suggesting that distribution into a second pharmacokinetically distinct compartment was not responsible for the rapid decline in plasma yohimbine levels. Urinary excretion and the partitioning of the drug into red blood cells (RBC) was investigated. In the 24 h following oral administration of the drug, virtually no yohimbine was eliminated in the urine (0.35±0.50% of the administered dose). Furthermore, only 20% of blood-borne yohimbine was located in RBC. These results suggest that yohimbine is eliminated primarily through metabolism since the rapid plasma clearance of yohimbine was not the result of renal elimination or sequestration by RBC.
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  • 62
    ISSN: 1432-1041
    Keywords: moracizine·HCl ; antiarrhythmic ; ethmozine ; radiolabelled ; pharmacokinetics ; material balance ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Moracizine (ethmozine) is a phenothiazine derivative with demonstrated antiarrhythmic activity. To characterize the pharmacokinetics and material balance relationships in humans, we have given14C-moracizine·HCl as a single oral dose of 500 mg (50 μCi) to six healthy men. Plasma, urine, and faecal samples were collected for 7 days after administration and the concentrations of total radioactivity and intact moracizine were determined by liquid scintillation counting and HPLC, respectively. Urine and faecal recovery accounted for 95% of the administered radioactivity. Most of this radioactivity was found in the faeces (59%). Only 0.05% of the dose was recovered from urine as intact moracizine. The Cmax and AUC for moracizine equivalents of total radioactivity were 4- and 18-fold higher, respectively, than the corresponding values for intact moracizine. Additionally, both the disappearance of total radioactivity from plasma and its excretion rate into urine were slower in comparison to intact drug. Terminal t1/2 values calculated from plasma concentration-time data were 85.2 and 3.5 h for total radioactivity and intact moracizine, respectively. However, based on urinary excretion rates, the t1/2 for total radioactivity was shorter (29.3 h) while the t1/2 for intact drug was comparable (2.7 h) to the results obtained from the plasma data. The oral plasma clearance of moracizine was relatively large (2.2l·min−1), suggesting first-pass metabolism. The estimated oral systemic availability of moracizine was 34%.
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  • 63
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    European journal of clinical pharmacology 31 (1987), S. 711-714 
    ISSN: 1432-1041
    Keywords: flecainide ; pharmacokinetics ; moderate renal failure ; variability of elimination half-time
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of flecainide after the oral administration of 100 mg to 8 patients without renal impairment and 8 patients with mild to moderate renal failure. Both groups gave comparable results with respect to the peak plasma concentrations and the time to peak. There was a significant correlation between renal flecainide clearance and endogenous creatinine clearance. The elimination half-time in the patients with impaired renal function was significantly longer (19.9, SD 9.9 h) than that in the patients with normal renal function (11.5, SD 4.2 h), but the variability in the elimination half-time in renal failure could not be explained on the basis of the available results.
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  • 64
    ISSN: 1432-1041
    Keywords: captopril ; uraemia ; captopril disulfide ; dialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 µg·ml−1 vs 0.181 µg·ml−1) and the concentrations of the disulfides 4 times higher (3.62 µg·ml−1 vs 0.924 µg·ml−1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46±19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37±7 mmHg and 24±9 mmHg respectively, occurring 6 h after the dose, compared with 8±7 and 8±1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.
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  • 65
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    European journal of clinical pharmacology 32 (1987), S. 309-311 
    ISSN: 1432-1041
    Keywords: digoxin ; verapamil ; cirrhosis ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of a single low dose of verapamil (80 mg) on the serum levels of digoxin (single dose of 0.5 mg) was studied in 6 patients with hepatic cirrhosis and in 6 healthy volunteer controls. In the cirrhotic patients verapamil increased the peak serum level and the total AUC of digoxin by 98% and 32%, respectively. There was an associated 23% decrease in the renal digoxin clearance. In normal subjects only marginal alterations in digoxin kinetics were observed following verapamil administration. The results indicate that cirrhosis magnifies the influence of verapamil on digoxin kinetics.
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  • 66
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    European journal of clinical pharmacology 32 (1987), S. 303-307 
    ISSN: 1432-1041
    Keywords: azapropazone ; arthritis ; pharmacokinetics ; synovial fluid level ; synovial tissue level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentration-time curves of azapropazone in synovial fluid and tissues have been studied in arthritic patients after an i.v. bolus (600 mg) and under steady-state conditions. Synovial fluid and tissue samples were taken intraoperatively 0.45–60 h after administration. The azapropazone concentrations in synovial fluid, synovial tissue and plasma were correlated. The levels in synovial fluid were usually lower than corresponding plasma levels. Under steady-state conditions azapropazone did not accumulate in synovial tissues.
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  • 67
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    European journal of clinical pharmacology 32 (1987), S. 317-320 
    ISSN: 1432-1041
    Keywords: ranitidine ; amitriptyline ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.
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  • 68
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    European journal of clinical pharmacology 32 (1987), S. 351-355 
    ISSN: 1432-1041
    Keywords: nifedipine ; cimetidine ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma pharmacokinetics of nifedipine and the formation of its metabolites have been studied in volunteers under conditions which would affect the activity of the cytochrome P-450 system. The pharmacokinetics of a 10-mg capsule of nifedipine were not significantly different between smokers and non-smokers of similar age. After pretreatment with cimetidine, which inhibits the activity of cytochrome P-450, the peak plasma concentration and area under the plasma-time concentration curve for nifedipine were increased by a mean 84%. In contrast, pre-treatment with ranitidine which has little effect on cytochrome P-450, did not significantly alter nifedipine pharmacokinetics. Smoking does not contribute significantly to the variability in nifedipine pharmacokinetics. However, the interaction between nifedipine and cimetidine, but not ranitidine, may be of clinical importance.
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  • 69
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    European journal of clinical pharmacology 32 (1987), S. 377-382 
    ISSN: 1432-1041
    Keywords: morphine ; renal failure ; pharmacokinetics ; morphine-3-glucuronide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of morphine and its glucuronidated metabolites were investigated in seven patients with advanced renal failure. The terminal elimination half life of morphine varied between 1.5 and 4.0 h (mean 2.4 h), the volume of distribution between 2.5 and 6.3 l·kg−1 (mean 4.4 l·kg−1) and the total plasma clearance between 13.3 and 31.3 l·min−1·kg−1 (mean 21.1 l·kg−1). There were no statistically significant differences between the pharmacokinetic data in the uraemic patients and in a control group of cancer patients with normal kidney function. The concentrations of the glucuronidated metabolites rapidly rose to levels above those of morphine. The elimination half-life of M3G varied between 14.5 and 118.8 h (mean 49.6 h) in the renal failure patients, which is distinctly different from the 2.4 to 6.7 h (mean 4.0 h) found in patients with normal kidney function. There was a significant correlation between the half-life of M3G and renal function estimated as serum urea. Thus, the metabolism of morphine in patients with kidney disease is not significantly impaired. The clinical importance of the high concentrations of glucuronides in uraemic patients is not known.
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  • 70
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    European journal of clinical pharmacology 32 (1987), S. 395-401 
    ISSN: 1432-1041
    Keywords: probenecid ; Michaelis-Menten kinetics ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers were given probenecid 0.5, 1 and 2 g p.o. and 0.5 g i.v. The protein binding of probenecid at different concentrations in human plasma was estimated by equilibrium dialysis. The free fraction was found to increase nonlinearly with increasing total probenecid concentration, up to a maximum free fraction of 26%. The plasma concentration-time data after the oral doses were described by a one-compartment open model with first-order absorption and Michaelis-Menten elimination. The mean absorption rate constant 0.0072 min−1 was dose-independent, and the maximal rate of elimination (mean 1429 µg/min) did not differ between doses whether calculated from the total or free concentrations. The Michaelis-Menten constant decreased significantly from 67.1 to 55.5 µg/ml as the dose increased from 1 g to 2 g, while the unbound Michaelis-Menten constant remained unchanged. The elimination of probenecid after the 0.5 g dose was in the linear region of the Michaelis-Menten elimination when calculated from the total and the free concentrations. The volume of distribution increased only slightly from 9.5 to 11.4 l as the dose increased from 0.5 to 2 g, but the unbound volume of distribution decreased significantly from 164 to 99 l. Absorption was complete and was independent of the dose administered.
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  • 71
    ISSN: 1432-1041
    Keywords: adrenergic beta-receptors ; propranolol ; beta-blockade ; pharmacokinetics ; leukocyte beta-receptors ; leukocytes ; exercise tachycardia ; 4—OH-propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of β-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (predrug) at 2 h (rs=0.72), 4 h (rs=0.84) and 6 h (rs=0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.
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  • 72
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    European journal of clinical pharmacology 31 (1987), S. 695-699 
    ISSN: 1432-1041
    Keywords: doxorubicin ; sarcoma ; pharmacokinetics ; polychemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of doxorubicin has been studied in 26 sarcoma patients receiving polychemotherapy. Mean elimination half-life was 34.7±16.6 h and the total plasma clearance was 29.5±9.31·h−1·m−2. No relationship was found between the pharmacokinetic parameters and the response to treatment, or its toxicity. Special attention was paid to the early-phase kinetics of the drug (3–20 min after injection). A correlation between the early clearance and the ages of the patients was observed. The early clearance was clearly correlated with the total plasma clearance measured over 48 h after injection, indicating the importance of the distribution phase in the overall kinetics of the drug.
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  • 73
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    European journal of clinical pharmacology 31 (1987), S. 701-704 
    ISSN: 1432-1041
    Keywords: theophylline ; miocamycin ; drug interaction ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between a new macrolide antibiotic, miocamycin, and theophylline was evaluated in a single cross-over study in 5 asthmatic children. Each patient received a single dose of theophylline (4.3 mg/kg) delivered in 15 min using a constant-rate infusion pump, immediately before and after a 10 day course of miocamycin 17.5 mg/kg b.d. The pharmacokinetics of theophylline were calculated for each phase of the study. The elimination rate constant (3.92 vs 3.74 h−1), the mean total body clearance (1.71 vs 1.8 ml·min·kg−1) and the mean apparent volume of distribution (0.57 vs 0.58 l·kg−1) did not differ. The result can be explained by the inability of the antibiotic to form inactive cytochrome P-450 metabolite complexes which can interfere with the metabolism of theophylline. Thus, miocamycin can safely be administered to asthmatic children requiring theophylline treatment, when they have an infection due to susceptible pathogens.
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  • 74
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    European journal of clinical pharmacology 31 (1987), S. 733-736 
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; elderly patients ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have determined the pharmacokinetics of meptazinol after its intravenous and intramuscular administration in a crossover study in 7 elderly hospital in-patients (〉70 years), and have compared with the results from 14 healthy, young volunteers (ages 20–40 years). The systemic availability after i.m. administration was comparable to that after i.v. administration, a result consistent with the physicochemical properties of the drug. There was a slight, but statistically significant (p〈0.01) prolongation in t1/2z in the elderly (mean 2.93 h) compared with the young (mean 2.06 h). This was associated with a 25% lower clearance in the elderly rather than with any alteration in volume of distribution. However, these changes would not appear to be substantial enough to require a revised dosage recommendation for meptazinol for this age group.
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  • 75
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    European journal of clinical pharmacology 31 (1987), S. 743-743 
    ISSN: 1432-1041
    Keywords: chloroquine ; dose dependence ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 76
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    European journal of clinical pharmacology 32 (1987), S. 17-22 
    ISSN: 1432-1041
    Keywords: felodipine ; calcium antagonist ; normal man ; renal function ; albumin excretion ; beta2-microglobulin excretion ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute renal effects of a single oral dose of felodipine 0.15 mg/kg were studied in 8 healthy males. Thirty minutes after administration the mean plasma concentration was 25.7 nmol/l. There was a significant reduction in diastolic blood pressure (24%) and a concomitant rise in heart rate (38%), leaving the systolic pressure unchanged. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique using the clearance of125I-iothalamate and131I-hippuran respectively. GFR was unchanged and the filtration fraction (FF) was reduced, whilst there was a decrease in renal vascular resistance (RVR). The glomerular filter characteristics were unchanged, as estimated by the unchanged excretion rate of albumin. There was a significant rise in the clearance of sodium (176%) but only a small and insignificant increase in urine volume. Clearance of potassium was decreased. An increase in the clearance of uric acid and a rise in the beta-2-microglobulin excretion rate were found, both suggesting a proximal tubular effect of felodipine. The excretion rate of calcium was increased.
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  • 77
    ISSN: 1432-1041
    Keywords: atenolol ; amiloride ; hydrochlorothiazide ; young ; elderly ; pharmacokinetics ; pharmacodynamics ; volunteers ; patients ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.
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  • 78
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    European journal of clinical pharmacology 32 (1987), S. 165-172 
    ISSN: 1432-1041
    Keywords: warfarin ; cimetidine ; ranitidine ; stereochemistry ; drug-drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.
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  • 79
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    European journal of clinical pharmacology 32 (1987), S. 357-360 
    ISSN: 1432-1041
    Keywords: nitrendipine ; food intake ; pharmacokinetics ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of nitrendipine were measured, after single (20 mg) oral doses, in young healthy volunteers. On three occasions the subjects ingested the dose having fasted overnight. Data from these three occasions were used to assess variability in nitrendipine pharmacokinetics and both inter- and intra-subject variability were high. On a fourth occasion, the subjects took the tablet after a standard meal. The effects of food on nitrendipine pharmacokinetics, based on the comparison of data from the first fasting visit and the food visit, were negligible.
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  • 80
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    European journal of clinical pharmacology 32 (1987), S. 583-586 
    ISSN: 1432-1041
    Keywords: tiapride ; Huntington's disease ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic properties of a single oral dose of 100 mg of tiapride were studied in six patients with Huntington's disease. The results for five patients were consistent with a two compartment open model. Peak plasma concentrations were observed within 2 h following durg administration with a mean value of 0.92 μg/ml being recorded. The drug was rapidly eliminated as unmetabolised tiapride in the urine, 51% of the dose was recovered in 24 h. The plasma elimination half-life was 5.3 h and the average apparent plasma clearance was 16.6 l/h.
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  • 81
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    European journal of clinical pharmacology 32 (1987), S. 593-596 
    ISSN: 1432-1041
    Keywords: dexamethasone ; dexamethasone phosphate, antiemetic ; pharmacokinetics ; cancer chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have given single high doses of dexamethasone phosphate by intravenous infusion as an antiemetic to 15 cancer patients receiving regimens containing cisplatin and/or doxorubicin. The patients received graded doses of dexamethasone phosphate, in the range 40–200 mg, dependent upon nausea and vomiting scores, during up to three consecutive cycles of cancer chemotherapy. Plasma and urine concentrations of dexamethasone (dexamethasone alcohol) were measured by HPLC. The plasma concentration-time data were described by an open two-compartment model. The pharmacokinetic variables were independent of the dose of dexamethasone over the range studied. The terminal half-time was 4.0±0.4 h and the total body clearance was 3.5±0.4 ml·min−1·kg−1. The volume of the central compartment and the total apparent volume of distribution were 0.23±0.03 and 1.0±0.1 l·kg−1 respectively. Approximately 8% of the dose was excreted into the urine as dexamethasone.
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  • 82
    ISSN: 1432-0738
    Keywords: Silver toxicity ; Cultured macrophages ; Cell death ; Ultrastructure ; Lipid peroxidation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of silver on cultured mouse peritoneal macrophages were examined by estimation of cell survival and by light and electron microscopy. Additon of silver lactate to the culture medium at final concentrations of 40 and 80 μM resulted in coagulation necrosis and rapid cell death. At lower concentrations cell structure appeared normal. However, the rate of cell death at 20 μM silver lactate was increased as compared to controls. Silver, visualized by physical development/autometallography, was invariably located in lysosomes. The production of malondialdehyde in mouse liver of silver-treated mice as compared to controls was also examined. This lipid peroxidation product had increased to the same amount in animals treated with silver for either 3 days or with only one silver injection 4 h before examination. This study has demonstrated that silver affects viability and structure of cultured macrophages, possibly due to induction of lipid peroxidation, as demonstrated to occur in the liver of silver-exposed mice.
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  • 83
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    European journal of clinical pharmacology 31 (1987), S. 617-619 
    ISSN: 1432-1041
    Keywords: chronopharmacology ; indomethacin ; suppository ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 100 mg indomethacin suppository were studied in 12 healthy volunteers on two occasions at least 7 days apart. Suppositories were administered in randomised order at 9.00 and 21.00 hours to see if there was evidence of a diurnal variation in kinetic parameters. The study failed to show a significant change in single dose kinetics with the time of suppository administration. This is in contrast to previous work [1] demonstrating a circadian rhythm in the kinetics of a single oral dose of indomethacin. This suggests that the chronopharmacokinetics of indomethacin is dependent on the function of the upper gastrointestinal tract.
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  • 84
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    European journal of clinical pharmacology 31 (1987), S. 625-627 
    ISSN: 1432-1041
    Keywords: verapamil ; breast milk ; norverapamil ; breast feeding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentrations of verapamil and norverapamil have been measured in milk and plasma samples from a 32year-old woman treated with verapamil 80 mg tds while breast-feeding her child. The average steady-state concentrations of verapamil and norverapamil in milk were, respectively, 60% and 16% of the concentrations in plasma. The breast-fed child received less than 0.01% of the dose of verapamil given to the mother. No verapamil or norverapamil (〈1 ng/ml) could be detected in the plasma from the child.
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  • 85
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    European journal of clinical pharmacology 31 (1987), S. 575-578 
    ISSN: 1432-1041
    Keywords: felodipine ; metoprolol ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This double-blind, cross-over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. During three, five-day study periods, felodipine 10 mg b.d., metoprolol 100 mg b.d. and a combination of the two, were given in random order. There was at least a 7-day washout period between each pharmacokinetic study day. Plasma levels of unchanged felodipine and metoprolol were measured for 24 h after the last dose, on the 5th day of each treatment period. Eight subjects, aged 19–22 years, completed the study. Both felodipine and metoprolol, given alone and in combination, were well tolerated. None of the felodipine pharmacokinetic variables (tmax, Cmax, Cmin, AUC (0–12) and t1/2) changed significantly when felodipine and metoprolol were given in combination. Cmax and AUC (0–12) for metoprolol increased significantly when metoprolol and felodipine were combined, although tmax, Cmin and t1/2 for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.
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  • 86
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    European journal of clinical pharmacology 31 (1987), S. 583-588 
    ISSN: 1432-1041
    Keywords: cotinine ; pharmacokinetics ; non-smokers ; absolute bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cotinine, the main metabolite of nicotine, was administered intravenously to healthy male non-smoking volunteers in doses of 5, 10 and 20 mg, and orally in doses of 10 and 20 mg. Intravenous administration was characterized by a dose-independent half-life of 12.2 h, mean residence time of 15.9 h, total clearance of 3.64 l h−1 and a volume of distribution of 56.5 l. Renal clearance was 0.46 l h−1 and approximately 12.0% of the dose was excreted unchanged in the urine. The mean absorption time after oral dosing ranged between 1 and 3 h, the peak concentration was reached within 45 min and the mean elimination half-lives were 12.9 and 11.7 h, respectively, after the 10 and 20 mg doses. Systemic bioavailability ranged between 0.84 and 1.11 following 10 mg and between 0.97 and 1.03 following the 20 mg dose. Mean urinary recovery and renal clearance were almost identical with the values after iv administration.
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  • 87
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    European journal of clinical pharmacology 31 (1987), S. 595-600 
    ISSN: 1432-1041
    Keywords: caffeine ; exercise ; obesity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of obesity, exercise, and the interaction of obesity and exercise were examined in 6 caffeine naive, untrained, nonsmoking, college males (3 lean (LV), 3 obese (OV)). Each subject received caffeine (oral, 5.83 mg·kg−1 lean body weight) or placebo (50 mg citrate) prior to 3 h of seated rest and prior to 90 min of treadmill walking (40% of their maximal aerobic power) followed by 90 min of seated recovery. Serum samples were collected at various times and analyzed for caffeine by HPLC. Pharmacokinetic analysis indicated that at rest, OV had a significantly higher absorption rate constant (Ka 0.0757 vs. 0.0397 min−1), lower elimination rate constant (Ke 0.0027 vs. 0.0045 min−1), and longer serum half-life (t1/2 4.37 vs. 2.59 h) in comparison to LV. In exercise, as well as at rest LV and OV had a large difference in the volume of distribution (43.2 vs. 101. 1) (rest, 54.1 vs. 103.1). Exercise consistently resulted in a decrease in the maximal serum concentration of caffeine and the area under the curve in OV while having no consistent effect on LV. The interactive effects of obesity and exercise could not be dissociated. However, these results demonstrate that both obesity and exercise have modified the pharmacokinetics of caffeine.
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  • 88
    ISSN: 1432-1041
    Keywords: dextran ; hydroxyethylstarch ; haemodilution ; ischaemic stroke ; plasma viscosity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 21 patients with ischaemic strokes we have monitored plasma viscosity, total plasma concentration, numeric average molecular weight (Mn), and weight average molecular weight (Mw) of Dextran 40 (dextran) and hydroxyethylstarch 200/0.5 (HES) during 10 days of treatment (days 1–4, 2×500 ml; days 5–10, 1×500 ml). Plasma concentrations of dextran increased during the first 4 days (8.3 mg·ml−1 on the first day to 18.0 mg·ml−1 on the fifth day), reached an apparent steady state of 17.2 mg·ml−1 during the next 6 days, and declined subsequently with a half-time (t1/2) of 4.03 days. After ten days treatment Mn and Mw were shifted towards higher values. Plasma viscosity increased from 1.26 mPas to 1.69 mPas on Day 10 (p〈0.01) and was linearly correlated with the total plasma concentration of dextran (p〈0.001; r=0.88). Total plasma concentrations of HES averaged 11.7 mg·ml−1 on Day 1 and 12.4 mg·ml−1 on Day 5. The molecular weight distribution did not change during the infusions but decreased in comparison with the administered solution. Plasma viscosity fell from 1.40 mPas to 1.30 mPas at Day 10 (p〈0.05) and was not related to the concentration of HES. The haemodiluting effect, as indicated by a decrease of the haematocrit, was 22% and 16.8% for dextran and HES respectively. These data suggest several advantages of HES compared with dextran in haemodilution therapy of ischaemic stroke.
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  • 89
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    European journal of clinical pharmacology 31 (1987), S. 569-573 
    ISSN: 1432-1041
    Keywords: tolazoline ; neonates ; persistent fetal circulation ; pharmacodynamic effects ; pharmacokinetics ; pulmonary circulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of two doses of tolazoline have been compared in 2 groups of newborns suffering from the persistent fetal circulation syndrome. The effects on PaO2 and AaDO2 were similar in the 2 groups who received either a bolus of 1 or 0.5 mg·kg−1 tolazoline, followed by a continuous infusion of 1 or 0.5 mg·kg−1·h−1. The observed changes did not differ significantly from those previously observed in babies treated with 2 mg·kg−1. A rise in PaO2 and a reduction in AaDO2 were usually observed shortly after the bolus injection and at plasma levels between 1.5 and 4 µg·ml·−1. A progressive rise in plasma level over time occurred after 1 mg·kg−1 (and in the previous study of 2 mg) but not with 0.5g/kg tolazoline. The elimination half-life of tolazoline in 6 patients was 5 to 13 h. The data suggest that continuous infusion of tolazoline is not necessarily required and that the dose of 0.5 mg/kg is more appropriate and safer than the higher doses usually proposed.
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  • 90
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    European journal of clinical pharmacology 32 (1987), S. 67-70 
    ISSN: 1432-1041
    Keywords: enprofylline ; pharmacokinetics ; elderly ; renal excretion ; half-life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of enprofylline, a new potent antiasthmatic, has been studied in 20 healthy, elderly subjects, aged 65 to 81 years, and in 7 young adult controls, aged 23 to 37 years. The dose of 1 mg/kg body weight was given as an i.v. infusion. Plasma levels of enprofylline were followed for about 7 h and urine levels for 24 h. Both groups eliminated the major portion of the dose (about 83%) by renal excretion. As expected the mean creatinine clearance (92.5 ml·min−1· 1.73 m−2) was moderately decreased in the elderly subjects. The total clearance of enprofylline was 0.16 1·h−1·kg−1 and the renal clearance was 0.13 l·h−1·kg−1, which was significantly lower than that in the young controls (0.28 and 0.22 l·h−1·kg−1) respectively. Thus, the enprofylline clearance had fallen relatively more (about 40%) than the decrease in creatinine clearance (about 20%) with age. The half-life of enprofylline in old age was 2.5 h, which was significantly longer than in the younger adults (1.8 h). It is concluded that the pharmacokinetics of enprofylline was significantly influenced by advanced age, mainly due to reduced renal excretion. This reduction was more pronounced than anticipated from the age-dependent decline in creatinine clearance.
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  • 91
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    European journal of clinical pharmacology 32 (1987), S. 103-106 
    ISSN: 1432-1041
    Keywords: fenoldopam ; peripheral dopamine agonist ; pharmacokinetics ; absorption ; food effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight healthy volunteers participated in an open crossover study to assess the effect of a standardised meal on the systemic availability of a single oral dose of fenoldopam mesylate 100 mg. Subjects were studied on four separate occasions, twice fasting and twice fed in randomised, balanced order. Plasma and urine samples were obtained before and at regular intervals up to 25 h post dose. Measurement of fenoldopam (SK&F 82526) and its 8-sulphate metabolite (SK&F 87782) were by means of HPLC-EC analysis. Area under the plasma concentration time curve (AUC) and maximum detected plasma concentration (Cmax) for fenoldopam and SK&F 87782 were significantly reduced whereas time to maximum concentration was significantly increased with food. Using AUC's for fenoldopam and SK&F 87782, mean relative bioavailabilities were 35% and 81% respectively under fed compared with fasting conditions. Twenty-four hour excretion of fenoldopam was significantly reduced with food, but excretion of SK&F 87782 was apparently unchanged. Mean relative bioavailabilities calculated from these data were 83% and 86% respectively. Relatively large inter-subject variability in AUC and Cmax were seen, but intra-subject variability was not marked. Mild symptoms associated with vasodilation were reported on all study days.
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  • 92
    ISSN: 1432-1041
    Keywords: mefloquine ; mefloquine/sulphadoxine/pyrimethamine ; Thai subjects ; pharmacokinetics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of mefloquine were studied in 12 healthy Thai male and 12 healthy Thai female volunteers. Mefloquine (MQ) was administered either alone (750 mg orally) or in combination (MSP) with sulphadoxine (1.5 g) and pyrimethamine (75 mg) to each of 6 male and 6 female subjects. Plasma concentrations of MQ were measured by HPLC at intervals for 42 days. There was considerable interindividual variability in the pharmacokinetic parameters; for example in the male subjects receiving MQ alone peak concentrations ranged between 638 and 2494 ng·ml−1 with a mean concentration of 1442 ng·ml−1. Compared to previously published data on MQ concentrations in Caucasian male subjects, the present study indicates that higher concentrations are achieved in Thai subjects. The only significant difference in kinetic parameters between male and female subjects receiving MQ alone was in the mean residence time (MRT) which was greater in females. However, an analysis of pharmacokinetic parameters following administration of the combination preparation showed that the time to peak (tmax) was significantly reduced in females receiving MSP compared to the corresponding females given MQ alone and males given MSP. When data obtained from all subjects (male and female) receiving either MQ alone or MSP were combined, both MRT and half-life were significantly greater in subjects given MSP. There is therefore some evidence that therapeutic concentrations of MQ are maintained for a longer period of time following MSP administration.
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  • 93
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    European journal of clinical pharmacology 32 (1987), S. 179-185 
    ISSN: 1432-1041
    Keywords: melphalan ; protein binding ; plasma ; humans ; rats ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The binding of melphalan to plasma proteins from four healthy humans and from rats was measured by centrifugal ultrafiltration. Melphalan concentrations were determined by HPLC and by measuring 14C-melphalan activity. In whole blood, melphalan was distributed preferentially in plasma. However, a constant fraction, 37%, which was independent of the total melphalan concentration in whole blood, was present within the red blood cells. The binding of melphalan to plasma proteins from humans was less than that from rats. In both, however, the fraction bound was constant throughout the concentration range (0.1 to 9.0 µM) that is achieved during standard-dose melphalan therapy. Albumin was the primary binding protein. At concentrations equal to or in excess of 33 µM, which have been achieved during high-dose melphalan therapy, free plasma melphalan concentrations were no longer linearly related to total drug concentrations, and the plasma protein binding of melphalan in the human became concentration dependent. This occurred at concentrations of 70 µM in the rat. Scatchard analysis of the data indicated the presence of 2 groups of binding sites. Class I sites had 0.03 and 0.4 binding sites per albumin molecule in humans and rats, with respective association constants of 4.43 × 104M−1 and 1.92 × 104M−1. Class II sites had 5.18 and 2.60 binding sites per molecule, with repective association constants of 3.82 × 102M−1 and 2.01 × 102M−1.
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  • 94
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    European journal of clinical pharmacology 32 (1987), S. 203-205 
    ISSN: 1432-1041
    Keywords: paracetamol ; primaquine ; drug interaction ; metabolite formation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of paracetamol and the formation of metabolites were evaluated in 6 healthy volunteers before and during concomitant administration of a single dose (45 mg) of primaquine. There was no effect of the antimalarial drug on either conjugation (to paracetamol glucuronide and paracetamol sulphate) or oxidation (as judged by the presence of paracetamol cysteine and paracetamol mercapturate) pathways. Although primaquine inhibits certain oxidative metabolism (e.g. of antipyrine) it has no effect, in therapeutic doses, on paracetamol metabolism.
    Type of Medium: Electronic Resource
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  • 95
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    European journal of clinical pharmacology 32 (1987), S. 211-215 
    ISSN: 1432-1041
    Keywords: diazepam ; pharmacokinetics ; Chinese ; white Caucasians ; body fat ; skin-fold thickness
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have compared diazepam pharmacokinetics in 16 Chinese and 18 white Caucasian healthy male volunteers, resident in Hong Kong and have correlated them with physical attributes. Serum concentrations of diazepam and desmethyldiazepam were measured in venous blood by an enzyme-linked immunoassay (0–3 h samples) and HPLC (3–72 h samples). Pharmacokinetic parameters were derived assuming a two compartment model, distribution phase 〈6 h, and 100% oral systemic availability. Compared with the Chinese the white Caucasians were older, heavier, taller, and fatter, as judged by skin fold thickness (SFT) and total body weight to ‘Ideal’ body weight (TBW/IBW) ratio; respective mean differences being 16%, 27%, 4%, 26%, and 15% (p〈0.05). Mean diazepam apparent volume of distribution (V) and V/IBW were larger in the white Caucasians (52% & 39% respectively, p=0.002). SFT and TBW/IBW ratio yielded the best correlations with V, V/TBW and V/IBW (0.50–0.75, p〈0.05). Obesity indices contributed most to the overall regressions (R2 up to 0.52), and for V there was a further small effect (2%, partial F test) due to ethnic group, possibly reflecting stature. Mean peak diazepam concentration (Cmax) was similar in both ethnic groups. Time to Cmax (tmax) was more often prolonged in the Chinese (X 2 test, p=0.01). Body fat and stature may thus account for these inter-ethnic differences in the apparent volume of distribution of diazepam, a highly lipid-soluble drug.
    Type of Medium: Electronic Resource
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  • 96
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    European journal of clinical pharmacology 32 (1987), S. 259-265 
    ISSN: 1432-1041
    Keywords: ketanserin ; ketanserin-ol ; pharmacokinetics ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ketanserin and its main metabolite ketanserin-ol, and the antihypertensive effects of intravenous, single oral and chronic oral (40 mg once daily) administration of ketanserin, have been investigated in a single blind study of 10 patients with uncomplicated mild hypertension. Ketanserin had a terminal half-life of 29.2 h, a plasma clearance of 518 ml/min and a volume of distribution of 18.0 l/kg. Chronic oral intake of 40 mg ketanserin (tablet formulation) gave a peak concentration of unchanged ketanserin of 88 ng/ml after 1.1 h. Its absolute bioavailability was 48%. During chronic therapy the maximal concentration of ketanserin-ol was 208 ng/ml and its half-life of elimination was 35.0 h. As this metabolite can be oxidized back to ketanserin, it contributes to the prolonged half-life of unchanged ketanserin seen during chronic therapy. The blood pressure was reduced by approximately 15% by oral ketanserin. The maximal reduction in blood pressure coincided with the peak concentration of unchanged ketanserin. During chronic therapy with 40 mg once daily blood pressure was reduced over 24 h. The heart rate was slightly reduced and the cardiovascular responses and the plasma noradrenaline concentrations during isometric exercise were only slightly influenced by ketanserin therapy. Thus, unchanged ketanserin has a relatively long half-life during chronic oral therapy and its pharmacokinetics in middle-aged hypertensive patients is similar to that in normal young volunteers.
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  • 97
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    European journal of clinical pharmacology 32 (1987), S. 533-535 
    ISSN: 1432-1041
    Keywords: enprofylline ; children ; intravenous dose ; pharmacokinetics ; asthma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous enprofylline has been studied in 8 children with asthma. The mean plasma half-life of enprofylline (1.0 h) was considerably shorter than that previously reported in adults. The half-life determined from log urine excretion rate data was identical to the plasma half-life, so urine excretion could be used as a noninvasive method to study the elimination rate. As in adults, urinary recovery of unchanged drug averaged 89%, and the volume of distribution, Vz, averaged 0.58 l/kg. Clearance was higher in children than in adults when calculated per kg body weight, but not when calculated per m2 body surface area. The dosage of enprofylline in children would be more accurate if calculated in proportion to surface area rather than to body weight. Data agree with published information on creatinine clearance, which, adjusted for body surface area, stays constant from the age of 3 years until early adult life.
    Type of Medium: Electronic Resource
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  • 98
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    European journal of clinical pharmacology 33 (1987), S. 89-91 
    ISSN: 1432-1041
    Keywords: antipyrine ; prednisolone ; pharmacokinetics ; obstructive lung disease ; hepatic drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of prednisolone on the elimination of antipyrine has been investigated. The one-sample antipyrine clearance was estimated in 23 outpatients with obstructive lung disease before and after treatment with prednisolone 30 or 50 mg/day for 7 days. During prednisolone administration antipyrine clearance decreased from 54.9±14.8 to 51.7±14.6 ml/min (mean±SD; p〈0.05). The results indicate that prednisolone decreases the rate of antipyrine elimination, but not to an extent suggesting a clinically important change in hepatic drug metabolism.
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  • 99
    ISSN: 1432-1041
    Keywords: flecainide ; propranolol ; pharmacodynamics ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 100
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    European journal of clinical pharmacology 33 (1987), S. 101-104 
    ISSN: 1432-1041
    Keywords: enoxacin ; quinolone ; pharmacokinetics ; anti-bacterial ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of enoxacin in two groups of subjects, 10 young (18–45 years) and 10 elderly adults (〉65 years) after a single oral dose of enoxacin (600 mg). Enoxacin was absorbed rapidly, peak plasma concentrations being reached within two hours in both groups. However, the peak plasma concentration of enoxacin was significantly higher in the elderly than in the young adults. The area under the concentration-time curve extrapolated to infinity was also significantly greater in the elderly compared with the young subjects, and the apparent renal clearance was significantly less in the elderly than in the young adults. Consequently, the urinary elimination of unchanged enoxacin was significantly reduced in the elderly. The apparent volume of distribution in the elderly was significantly less than in the young adults. The elimination half-time of enoxacin was similar in the two groups.
    Type of Medium: Electronic Resource
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