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  • 1980-1984  (966)
  • Ultrastructure  (541)
  • pharmacokinetics  (424)
  • Nuclear reactions
  • 1
    Electronic Resource
    Electronic Resource
    Study of porcine and human isophane (NPH) insulins in normal subjects (1984)
    Springer
    Diabetologia 26 (1984), S. 261-265 
    Details
    ISSN: 1432-0428
    Keywords: Porcine NPH insulin ; semi-synthetic and biosynthetic human NPH insulin ; pharmacokinetics ; pharmacodynamics ; normal subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The plasma glucose, C-peptide and insulin responses to subcutaneously administered highly purified porcine, ‘semi-synthetic’ and ‘biosynthetic’ human isophane (NPH) insulin and diluting medium as control in normal male subjects were evaluated. Porcine and semi-synthetic human NPH insulins were administered at two dose levels of 0.15 and 0.30 U/kg body weight and biosynthetic human NPH at 0.15 U/kg body weight only. At the low dose level the three insulin preparations resulted in a similar maximal hypoglycaemic effect within 3–5 h after administration. However, over the remainder of the 11 h post-injection period, the plasma glucose level was lower after semi-synthetic human insulin. In contrast, at the 0.30 U/kg dose level, there was no difference in the early or late hypoglycaemic response between porcine and semi-synthetic human NPH insulins of equivalent pharmaceutical formulation. The clinical relevance of these findings needs further evaluation. The data suggest that for the ‘intermediate-acting’ NPH insulin preparations, both the species of insulin, nature and quantity of the retarding protein and their subsequent interaction may determine their time-action characteristics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00283647
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  • 2
    Electronic Resource
    Electronic Resource
    Serotonin nerve fibers in the primary visual cortex of the monkey (1984)
    Springer
    Anatomy and embryology 169 (1984), S. 1-8 
    Details
    ISSN: 1432-0568
    Keywords: Serotonin ; Primary visual cortex ; Monkey ; Ultrastructure ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A quantitative and immunoelectronmicroscopical analysis of serotonin nerve fibers in the primary visual cortex of the monkey (Macaca fuscata) was made using a sensitive immunoperoxidase method for serotonin. The overall numerical density of serotonin-containing varicosities in the primate striate cortex was approximately 770,000/mm3 and the highest concentration of immunore-active varicosities (ca. 1,400,000/mm3) was observed in the upper portion of layer IVc, the next highest concentration being in layer IVb (ca. 1,180,000/mm3). At the ultrastructural level, the electron dense immunoreactive products were observed in the small granules (10–65 nm in diameter). The varicosities were usually small (0.5–1.0 μm in diameter) and made contact with both stellate and pyramidal cells. Serotonin fibers were often in close apposition to the poorly myelinated axons in layers IVb, V, and VI, and they rarely formed distinct synaptic structures with unlabelled neuronal elements.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00300581
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  • 3
    Electronic Resource
    Electronic Resource
    The response of the uterine surface to ovarian hormones in the aged rat (1984)
    Springer
    Anatomy and embryology 169 (1984), S. 205-208 
    Details
    ISSN: 1432-0568
    Keywords: Rat uterus ; Epithelium ; Aging ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary By scanning electron microscopy uterine luminal epithelium of the rat was studied to determine whether aging alters ovarian hormone stimulated ultrastructural changes in that portion of the endometrial surface into which implantation takes place in the younger animal. Results show that in the aged rat this surface differentiates in response to ovarian hormones in a manner qualitatively similar to that which occurs in the young animal. Epithelial cells of ovariectomized rats, both young and aged, were polygonal in outline, flattened, or even somewhat concave, and had short microvilli. Following estrogen treatment cells of both groups were round or oval and bulged into the lumen. Cells of young rats were covered with long microvilli. Most cells of aged rats had microvilli of equal or greater length; a small number of epithelial cells had fewer and shorter microvilli. Cells of progesterone-treated young and aged animals both were covered with short microvilli and bore membrane protrusions. The protrusions varied in size, shape and numbers both within and between age groups. These findings suggest that differences in the surface ultrastructure of the aged uterus reflect age-related changes in hormone levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00303150
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  • 4
    Electronic Resource
    Electronic Resource
    Ultrastructure of the cumulus cell mass surrounding a human egg in the pronuclear stage (1984)
    Springer
    Anatomy and embryology 170 (1984), S. 107-112 
    Details
    ISSN: 1432-0568
    Keywords: Ultrastructure ; Cumulus ; Oocyte complex ; Human egg
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The cumulus cell mass enclosing a penetrated human egg was studied. The egg, recovered from the Fallopian tube approximately 80 h after luteinizing hormone peak and 35 h after insemination, was surrounded by a large, expanded and dissociated cumulus. Dispersions of the outermost cumulus cell layers occurred during processing, the innermost cell layers remained attached enclosing the egg. The photomicrographs showed that the follicular cells were embedded in an intercellular matrix and contact via gap-junction-like structures between neighboring cells existed. Cumulus cell processes traversing the zona pellucida were not found. Two types of follicular cells coexisted within the cumulus, light and dark cells. These cellular types, were different in morphology and size. Light cells displayed cytoplasmic organelles normally associated with protein synthesis and steroidogenesis. Dark cells with long cytoplasmic processes were involved in sperm phagocytosis. It is suggested from the characteristics of the cytoplasmic organclles that dark cells seem to be modified light follicular cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00319465
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  • 5
    Electronic Resource
    Electronic Resource
    X-ray microanalysis of monoaminergic terminals in the nucleus tegmentalis dorsalis of the chicken (1984)
    Springer
    Anatomy and embryology 170 (1984), S. 87-91 
    Details
    ISSN: 1432-0568
    Keywords: Monoamine ; X-ray microanalysis ; Ultrastructure ; Brain stem ; Chicken
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary X-ray microanalysis after aldehyde-chromatedichromate treatment served to confirm the presence of monoaminergic terminals in the nucleus tegmentalis dorsalis (NTD) of the chicken. The monoaminergic terminals were represented as neuronal elements with electron-dense vesicles (EDVs) of several different shapes as seen in Eponembedded semi-thin sections. Conventional electron microscopic observations of the adjacent ultra-thin sections showed the EDVs to be comprised of spherical medium-sized (about 80 nm in diameter), large dense-cored (about 120 nm) and elongated granular vesicles (100–220 nm) in the same nerve varicosities. It is probable that the NTD, being a center of catecholaminergic efferent projections, may also receive direct monoaminergic inputs from an unknown area of the brain and/or from recurrent collaterals of the same catecholamine-containing neurons in the NTD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00319462
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  • 6
    Electronic Resource
    Electronic Resource
    Neurofibromatosis tumor and skin cells in culture (1984)
    Springer
    Acta neuropathologica 63 (1984), S. 269-275 
    Details
    ISSN: 1432-0533
    Keywords: Neurofibromatosis ; Cell culture ; Cell surface ; Cytoskeleton ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Structural proteins of cultured neurofibromatosis (NF) tumor and skin cells were studied with reference to control skin fibroblasts. In polyacrylamide gel electrophoresis (PAGE)/fluorography the banding patterns of the cell lysates were markedly similar. NF tumor cells, however, produced a 60 kD band with a stronger and a 48 kD band with a lighter protein staining and metabolic labeling intensity. Furthermore, skin cells were also characterized by a 26 kD protein and the tumor cells by a 22 kD protein with high metabolic labeling intensity. Neuraminidase/galactose oxidase/NaB3H4-labeled NF skin and control skin cells possessed a 220 kD protein that was less intensively labeled in the tumor cells. The banding pattern of the skin cells was also characterized by a protein with slightly lower molecular weight (86 kD) than that of the tumor cell lysates (90 kD). In all cell lines studied indirect immunofluorescence stainings revealed bright arrays of vimentin type intermediary filaments but no desmin, cytokeratin, glial fibrillary acidic protein (GFAP), or neurofilament proteins. NF skin and control skin cells possessed well developed actin-containing bundles of microfilaments, while those of the tumor cells lacked a typical stress-fiber organization. The general morphology of the tumor cell cultures was also irregular. Transmission electron microscopy revealed no basic differences in the structure of intermediary filaments or microfilaments. The present data provide basic knowledge of neurofibromatosis skin and tumor cells and demonstrate that cultured cells originating from neurofibromas are defective in both their intracellular and extracellular organization.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00687332
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  • 7
    Electronic Resource
    Electronic Resource
    Ultrastructural observation on a colloid cyst of the third ventricle (1984)
    Springer
    Acta neuropathologica 65 (1984), S. 41-45 
    Details
    ISSN: 1432-0533
    Keywords: Colloid cyst ; Third ventricle ; Ultrastructure ; Pathogenesis ; Rathke's cyst
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The case involves a colloid cyst of the third ventricle in a 20-year-old man. The lining epithelia of the cyst were composed of two different types of epithelial cells; stratified squamous cells and mucincontaining columnar cells. The presence of both squamous and glandular cells in the cyst wall supports the contention that the colloid cyst in the present case derived from an non-neuroepithelial source. The clinico-pathology of this cystic tumor is compared here with other epithelial cysts of the central nervous system (CNS), especially Rathke's cyst.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689826
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  • 8
    Electronic Resource
    Electronic Resource
    Cytoplasmic tubular inclusion in ganglioneuroma (1984)
    Springer
    Acta neuropathologica 64 (1984), S. 81-84 
    Details
    ISSN: 1432-0533
    Keywords: Ganglioneuroma ; Cytoplasmic tubular inclusion ; Smooth endoplasmic reticulum ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Unusual tubular inclusions were observed in the cytoplasm of ganglion cells of a mediastinal ganglioneuroma in a boy of 7 years. The inclusions consisted of an aggregation of about 100-nm-sized tubular structures resembling ‘honeycomb-like’ tubular structures in the axoplasm of rats and mice and suggested to be derived from dilated rough endoplasmic reticulum. These structures differ from profiles reported in normal and pathologic conditions and seem to be related to the neoplastic character of the ganglion cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00695612
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  • 9
    Electronic Resource
    Electronic Resource
    Ultrastructure of cerebellar capillary hemangioblastoma (1984)
    Springer
    Acta neuropathologica 64 (1984), S. 308-318 
    Details
    ISSN: 1432-0533
    Keywords: Angiogenesis ; Cerebellar hemangioblastoma ; Degranulation ; Heparin ; Mast cell ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The topographic distribution, population density, and ultrastructural features of mast cells were studied in six cases of cerebellar capillary hemangioblastoma. The vascular area of tumor tissue contained large numbers of mast cells (6.3 cells/high power field, ×400) in comparison with hyalinized area (0.3 cell) and adjacent cerebellar tissue (〈0.1 cell). Close association of mast cells with endothelial cells and stromal cells was found. The morphology of mast cell granules and their degranulation through dissolution of granule contents and exocytosis were illustrated. The findings suggest that an increased number of mast cells may represent one of the characteristic histological features of capillary hemangioblastoma, and continuous degranulation of mast cell granules with release of heparin may play an important pathophysiologic role in the vascular proliferation and expansion of the tumor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00690396
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  • 10
    Electronic Resource
    Electronic Resource
    Ultrastructural and histophysiological studies on the blood-nerve barrier and perineurial barrier in leprosy neuropathy (1984)
    Springer
    Acta neuropathologica 64 (1984), S. 282-296 
    Details
    ISSN: 1432-0533
    Keywords: Blood-nerve Barrier ; Perineurial barrier ; Leprosy neuropathy ; Ultrastructure ; Ferritin ; Ageing ; Drug treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Onset and nature of ultrastructural changes in endoneurial vasa nervorum during the pathogenesis of leprosy neuropathy and possibly associated alterations in the “blood-nerve barrier” were investigated, together with perineurial barrier functioning, in mice infected 20–28 months previously withMycobacterium leprae and in (ageing) non-infected mice. Barriers were tested by i.v. administration of markers (Trypan blue and ferritin) 1–4 days before killing the mice. Twenty-eight months after infection, histopathology of sciatic nerves was comparable to that seen in sensory nerves in clinically early human (borderline-) lepromatous leprosy. Schwann cells and endoneurial macrophages were bacillated, endothelia of endoneurial vessels not, and the perineurium rarely. Many infected mice and all (ageing) controls possessed ultrastructurally and functionally normal endoneurial vessels. Their continuous endothelium with close junctions had prevented marker passage, even when surrounding endoneurial tissue cells were quite heavily bacillated. The perineurium was also normal. By contrast, in infected mice showing hind limb paralysis serious histopathologic involvement and large globi of bacilli intrafascicularly in sciatic nerves, endoneurial blood vessels were abnormal. Open endothelial junctions, extreme attenuation, fenestrations, and luminal protrusions were all features comparable to neural microangiopathy encountered in leprosy patients (Boddingius 1977a, b). The “blood-nerve barrier” clearly had become defective allowing excessive exudation of Trypan blue and ferritin, via four pathways from the vessel lumen, deep into surrounding endoneurial tissues but halted by a normal perineurial barrier. Markers in such “blue” nerves were not found in bacillated or non-bacillated Schwann cells, thus denying significant phagocytotic and lysosomal activities of Schwann cells at this stage of neuropathy. Possible implications of barrier performances for anti-leprosy drug treatment of patients are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00690394
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  • 11
    Electronic Resource
    Electronic Resource
    Paired twisted filaments a new ultrastructural marker of human pinealomas? (1984)
    Springer
    Acta neuropathologica 65 (1984), S. 163-165 
    Details
    ISSN: 1432-0533
    Keywords: Human pinealomas ; Ultrastructure ; Paired twisted filaments ; Paired helical filaments ; Cytoskeleton
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Paired twisted filaments (PTF) forming helices are described in tumor cells of three human pine-alomas. Each filament was 8.11±1.55 nm wide. The maximal width of the helix was 16.62±2.62 nm. The periodicity of the constrictions was 26.63±4.49 nm. These characteristics appeared original, suggesting protein, filaments possibly specific of pinealocytes. The similarities and discrepancies between PTF and Alzheimer's paired helical filaments (PHF) are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00690471
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  • 12
    Electronic Resource
    Electronic Resource
    Ultrastructure of the wall of the Dandy-Walker cyst (1984)
    Springer
    Acta neuropathologica 62 (1984), S. 225-229 
    Details
    ISSN: 1432-0533
    Keywords: Dandy-Walker syndrome ; Dandy-Walker cyst ; Ependymal cell ; Ultrastructure ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructure of the wall of the Dandy-Walker cyst has been described rarely. A boy aged 2 years was confirmed clinically, neuroradiologically, and operatively as having a Dandy-Walker cyst in the posterior fossa. The cyst wall obtained during surgery consisted of an outer arachnoid cell layer, intermediate interwoven neuroglial strands, and an inner layer of cells which lacked the characteristic appearance of ependyma. An unusual finding was a small, buried island of ependymal cells in the intermediate layer of the neuroglial tissue. Ultrastructural study of the cyst wall provides a better understanding of the pathogenesis of the Dandy-Walker syndrome.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00691856
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  • 13
    Electronic Resource
    Electronic Resource
    Induction of the morphologic changes of both acute and chronic experimental myasthenia by monoclonal antibody directed against acetylcholine receptor (1984)
    Springer
    Acta neuropathologica 63 (1984), S. 131-143 
    Details
    ISSN: 1432-0533
    Keywords: Anti-acetylcholine receptor antibody ; Experimental autoimmune myasthenia gravis ; Monoclonal antibody ; Myasthenia gravis ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To investigate pathogenic mechanisms in experimental autoimmune myasthenia gravis (EAMG) and myasthenia gravis (MG), we studied the acute and chronic effects in rats of injection of rat monoclonal antibodies (MCABs) directed against the acetylcholine receptor (AChR). Animals were severely weak 12 h after a single injection, at which time macrophages were found invading endplate regions of muscle and cholinesterase-stained regions were separted from the underlying muscle fibers. Ultrastructural studies showed findings identical to the acute phase of EAMG: degenerating postsynaptic membranes and invasion and phagocytosis of endplate regions by macrophages. Animals receiving sublethal doses of MCAB recovered clinically by 4–5 days after injection. Recovery was accompanied by a progressive decrease in the number of macrophages associated with endplates and reapposition to the myofibers of the cholinesterasestained regions. Animals injected once, or repeatedly over several months, remained clinically and electromyographically normal after recovery from the initial episode of weakness, but their endplate ultrastructure was highly simplified with blunted or absent synaptic folds and shallow or absent secondary synaptic clefts. These studies demonstrate that anti-AChR MCABs can induce the changes of both acute and chronic EAMG. There is good correlation between the inflammatory changes and the acute clinical disease but poor correlation between morphological and clinical parameters in the chronic syndrome. The latter observation suggests that severe ultrastructural changes, similar to those seen in chronic EAMG and MG, cannot account, at least in rats, for the clinical and electrophysiologic abnormalities of MG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00697195
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  • 14
    Electronic Resource
    Electronic Resource
    Ultrastructural changes in rat Clara cells induced by a single dose of O,S,S-trimethyl phosphorodithioate (1984)
    Springer
    Archives of toxicology 56 (1984), S. 59-65 
    Details
    ISSN: 1432-0738
    Keywords: Trialkylphosphorothioates ; Rat ; Lung ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The oral administration of an LD50 dose (25 mg/kg) of O,S,S-trimethyl phosphorodithioate to rats induced immediate, cholinergic symptoms. A delayed respiratory crisis followed, 3–4 days later, involving a pronounced increase in lung weight and extensive injury to the alveolar epithelium. This compound also induced the immediate liberation of secretory granules from the Clara cells. Minor changes in the surface appearance of these cells were also observed but no signs of injury were found in any cells of the bronchiolar epithelium. The complement of secretory granules was monitored, by the morphometric analysis of ultrathin sections. Clara cells from control animals were found to contain 9.55±1.16 (SEM) granules per cell profile. The Clara cells from dosed animals were largely devoid of granules until the 3rd day after administration. Many of these agranular cells were arranged in clusters and often showed signs of mitotic division. In surviving animals the subsequent replacement of granules resulted in a large increase in the numbers present and many exhibited abnormal morphology. Over twice the normal complement of granules, 22.45±0.42 (SEM) per cell profile, was found 6 days after dosing. The complement of granules subsequently returned to normal levels and the clusters of Clara cells were resolved within 14 days of dosing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316355
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  • 15
    Electronic Resource
    Electronic Resource
    Epidermoid metaplasia in apocrine cystadenoma of the penis (1984)
    Springer
    Archives of dermatological research 276 (1984), S. 170-177 
    Details
    ISSN: 1432-069X
    Keywords: Penile apocrine cystadenoma ; Ultrastructure ; Filamentous fuzzy coat ; Epidermoid metaplasia ; Peridermlike cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Two cystadenomas occurring near the frenulum of the penis revealed a predominantly secretory pseudostratified columnar epithelium with PAS-reactive dome-shaped cytoplasmic protrusions at the luminal cellular parts. The content of secretory vacuoles was discharged into the cyst lumen by an exocytotic (eccrine) and ballooning type of extrusion. There were no indications of a real apocrine extrusion mechanism. No histogenetic derivation of these penile cystadenomas from apocrine sweat glands could be proved. An antennalike filamentous fuzzy coat on the luminal cytoplasmic membrane was most remarkable. Regionally, an epidermoid differentiation had developed. Morphologically, this process had begun just above the basal cell layer which had remained unchanged and led to the establishment of a stratified epithelium.Hyalin lamellarlike flattened cells at the luminal part displayed necrobiotic features and resembled periderm cells. There was no keratin pattern. Luminal cells of epidermoid differentiation still revealed a filamentous fuzzy coat which indicated that the undifferentiated cuboidal basal cells basically had a prospective secretory meaning and probably represented the target cells in the process of metaplasia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00414015
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  • 16
    Electronic Resource
    Electronic Resource
    Length and shape of enamel crystals (1984)
    Springer
    Calcified tissue international 36 (1984), S. 550-555 
    Details
    ISSN: 1432-0827
    Keywords: Enamel crystals ; Length ; Shape ; Apatite ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary An original method for fractionating and preparing isolated crystals of homogeneous size was developed. It was demonstrated that enamel apatite crystals are at least 100 µm long. The flexibility of the very long crystallites was demonstrated. Crystal curvatures, accounting for the irregular course of the prisms through the enamel thickness, were visualized and measured. It was shown that in the deep forming enamel layer, lateral branches may grow out of the crystals and crystal fusing often occurs, inducing the crystallites to assume pyramidal shapes with their wide bases pointing toward the dentino-enamel junction and one or two tops toward Tomes' processes. During the maturation process, the two tops of the still immature crystals also fuse so that the mature crystals acquire a rodlike aspect, with parallel faces and steplike graduations along thec axis, allowing a close contact between the crystals. These results support the hypothesis that the crystallites would be continuous from the dentino-enamel junction to the surface.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02405364
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  • 17
    Electronic Resource
    Electronic Resource
    Isolation and characterization of a new coccoid methanogen, Methanogenium tatii spec. nov. from a solfataric field on Mount Tatio (1984)
    Springer
    Archives of microbiology 137 (1984), S. 308-315 
    Details
    ISSN: 1432-072X
    Keywords: Methanogenium tatii ; Ultrastructure ; Physiology ; Glycoproteins ; DNA-DNA Homology ; Taxonomy ; Archaebacteria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A new coccoid methanogen, Methanogenium tatii, was isolated and characterized. The mesophilic isolate can grow on and produce methane from H2:CO2 and formate. For growth acetate is strictly required. The cell shape, the G+C content of 54 mol% and DNA-DNA homology data suggest it to be a Methanogenium species.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00410727
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  • 18
    Electronic Resource
    Electronic Resource
    Membrane-bound nitrite oxidoreductase of Nitrobacter: evidence for a nitrate reductase system (1984)
    Springer
    Archives of microbiology 140 (1984), S. 153-158 
    Details
    ISSN: 1432-072X
    Keywords: Nitrobacter hamburgensis ; Nitrite oxidoreductase ; Nitrate reductase ; Molybdenum iron-sulfur protein ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Nitrite oxidoreductase, the essential enzyme complex of nitrite oxidizing membranes, was isolated from cells of the nitrifying bacterium Nitrobacter hamburgensis. The enzyme system was solubilized and purified in the presence of 0.25% sodium deoxycholate. Nitrite oxidoreductase oxidized nitrite to nitrate in the presence of ferricyanide. The pH optimum was 8.0, and the apparent K m value for nitrite amounted to 3.6 mM. With reduced methyl-and benzylviologen nitrite oxidoreductase exhibited nitrate reductase activity with an apparent K m value of 0.9 mM for nitrate. NADH was also a suitable electron donor for nitrate reduction. The pH optimum was 7.0. Treatment with SDS resulted in the dissociation into 3 subunits of 116,000, 65,000 and 32,000. The enzyme complex contained iron, molydbenum, sulfur and copper. A c-type cytochrome was present. Isolated nitrite oxidoreductase is a particle of 95±30 Å in diameter.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00454918
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  • 19
    Electronic Resource
    Electronic Resource
    Fine structure of the knobby spore type of Streptomyces torulosus (1984)
    Springer
    Archives of microbiology 138 (1984), S. 229-232 
    Details
    ISSN: 1432-072X
    Keywords: Actinomycetes ; Streptomyces torulosus ; Morphology ; Ultrastructure ; Verrucate spores ; Knobby ornamentation ; Sheath
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The type strain of Streptomyces torulosus Lyons and Pridham (1971) was studied by scanning- and transmission electron microscope. Spore chains were formed in spirals by aerial mycelium. The spores were connected by nozzles in which small channels could be observed. The knobby ornamentations of the spores arised on a thin fibrous sheath, enveloping the spore chains. These irregular blunt projections, called knobs, had varying diameters of 100 to 250 nm. The base of the knob, consisting of globose to flattened electron dense material, was sitting directly on the sheath. It was covered by several small vesicles of the same material. Each hollow vesicle beared a thin bowlshaped shell of electron transparent material. In general, the cupular bowls and their supporting vesicles became easily depressed on their base, but not detached from the surface of the spores. This type of knobby spore ornamentation was suggested to be designated as a verrucate spore type.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00402126
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  • 20
    Electronic Resource
    Electronic Resource
    Synaptology of the hypoglossal nucleus in the rat (1984)
    Springer
    Experimental brain research 57 (1984), S. 22-32 
    Details
    ISSN: 1432-1106
    Keywords: Ultrastructure ; Synaptology ; Hypoglossal nucleus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of this study was to define the types and distribution of synaptic terminals in the hypoglossal nucleus (XII) of the rat. Based on differences in bouton and vesicle size and shape, synaptic specializations and association with postsynaptic organelles, five types of terminals were identified in XII. In order of decreasing frequency they were: 1) S-boutons (spherical vesicles with an asymmetrical synapse); 2) F-boutons (flattened vesicles with a symmetrical synapse); 3) P-boutons (pleomorphic admixture of flattened and spherical vesicles with a symmetrical synapse); 4) C-boutons (pleomorphic vesicles with a subsynaptic cistern); and 5) Tboutons (spherical vesicles with an asymmetrical synapse and subsynaptic dense bodies). S-boutons were the predominant type found on dendrites, while boutons containing flattened vesicles were more prevalent on motoneuron somata. C-boutons were restricted exclusively to cell bodies and large dendrites, and T-boutons were seen primarily on smaller dendritic profiles. These results are, in general, comparable to those previously described in the ventral horn and cranial nerve motor nuclei in several species. However, differences were noted. Specifically, large M-boutons and axo-axonic synapses were not observed in the present study. The functional significance of these findings are discussed in relation to oro-lingual behaviour.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00231128
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  • 21
    Electronic Resource
    Electronic Resource
    4-Ammopyridine-induced ultrastructural alterations of pinched-off nerve terminals from rat cerebral cortex (1984)
    Springer
    Experimental brain research 54 (1984), S. 385-389 
    Details
    ISSN: 1432-1106
    Keywords: Synaptosome ; 4-Aminopyridine ; Ultrastructure ; Exocytosis ; Recycling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pinched-off nerve terminals (synaptosomes) from rat cerebral cortex were depolarized with 60 mM KCl and treated with 20 mM 4-aminopyridine in order to evaluate ultrastructural alterations. The empty presynaptic terminals were counted and their number was given as a percentage of the normal terminals. The proportion of empty terminals increased from 10.47±1.56% to 32.45±1.88% (P 〈 0.001) following treatment with 20 mM 4-aminopyridine. This effect of 4-aminopyridine depended on the presence of Ca++ in the incubation medium. The results are discussed in terms of facilitation by 4-aminopyridine of exocytotic transmitter release. We think that the increase of the empty synaptosomes was due to the exhaustion or inhibition of the synaptic vesicle recycling mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00236242
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  • 22
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of cefoperazone in patients undergoing chronic ambulatory peritoneal dialysis: Clinical and pathophysiological implications (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 609-612 
    Details
    ISSN: 1432-1041
    Keywords: cefoperazone ; peritoneal dialysis ; pharmacokinetics ; terminal renal failure ; peritonitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoperazone after i.p. and/or i.v. administration were studied in 12 CAPD patients. After i.v. injection, the plasma half-life was 2.65±0.4 h, the total clearance amounting to 70.1±19.2 ml/min. Peritoneal clearance was calculated to be 6.9±1 ml/min. After peritoneal instillation, the bioavailability was 63.9±5%. After repeated i.p. administration, no accumulation of the drug in the body was observed. Thus, cefoperazone can be safely administered for the treatment of peritonitis in CAPD patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543494
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  • 23
    Electronic Resource
    Electronic Resource
    Intrapatient variation in tobramycin kinetics in low birth weight infants during first postnatal week (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 647-649 
    Details
    ISSN: 1432-1041
    Keywords: tobramycin ; newborn infants ; intrapatient variations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nineteen newborn infants receiving tobramycin, 2.5 mg/kg every 12 h were studied on two occasions at steady-state during the first week of postnatal age. The two studies were separated by two to four days. Total body clearance of tobramycin averaged 1.15 and 1.14 ml/min/kg (p〉0.05), apparent volume of distribution averaged 0.82 and 0.68 l/kg (p〉0.05), and elimination half-life averaged 8.6 and 7.1 h (p〉0.05), during the first and second study, respectively. When the data were further analyzed based on the birth weight, tobramycin kinetics changed during the second study compared to the first study in very low birth weight infants. In eight infants ⩽1.5 kg birth weight, although total clearance of tobramycin was similar, the average apparent volume of distribution decreased from 1.04 l/kg during the first study to 0.73 l/kg during the second study (p〈0.05) and elimination half-life from 11.1 h during the first study to 8.7 h during the second study (p〈0.05). These data indicate that these infants may require a change in dosing interval with continued tobramycin therapy during the first week of postnatal age. Intrapatient variation in tobramycin kinetics should be considered, in addition to the interpatient variation reported previously, when monitoring the serum concentration to individualize tobramycin therapy in newborn infants ⩽1.5 kg birth weight.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543504
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  • 24
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of S-adenosyl-L-methionine in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 119-121 
    Details
    ISSN: 1432-1041
    Keywords: S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S-Adenosyl-L-methionine (AdoMet) kinetics was studied in 6 male subjects given 100 and 500 mg i. v. Drug concentrations in plasma and urine were assayed using a radioenzymatic method. Pharmacokinetic parameters were estimated according to an open two-compartment model. The apparent volumes of distribution after the 100 and 500 mg doses were 407±27 and 443±36 ml/kg (mean±SEM), terminal half-lives 81±8 and 101±7 min and body clearances 3.7±0.5 and 3.1±0.2 ml/min per kg. Urinary excretion was 34±3 and 40±2% of the administered dose. The results demonstrate that drug disposition occurs more via metabolism than via renal excretion, and it is not dependent on the administered dose. Binding of AdoMet to serum proteins is negligible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553166
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  • 25
    Electronic Resource
    Electronic Resource
    Papaverine disposition in cardiac surgery patients and the effect of cardiopulmonary bypass (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 127-130 
    Details
    ISSN: 1432-1041
    Keywords: papaverine ; cardiopulmonary bypass ; pharmacokinetics ; cardiac surgery patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cardiac surgery involving cardiopulmonary bypass (CPB) causes substantial physiologic changes which may potentially alter the pharmacokinetic properties of drugs used during and after the procedure. Studies with fentanyl have implied a relationship between prolonged elimination half-lives following CPB and decreased liver perfusion during and after the procedure. To further test this hypothesis, the effects of CPB on the pharmacokinetics of papaverine, a coronary vasodilator currently being added to the cardioplegic solution to prevent vasospasm, were studied. The drug was given to two groups of patients, one (n=6) undergoing surgery with and one (n=5) without CPB, the latter serving as controls. Plasma papaverine concentrations declined biexponentially in the control patients with a mean elimination half-life of 1.30±0.25 h, total plasma clearance of 13.8±3.75 ml/min/kg, volume of distribution of 1.52±0.45 l/kg and volume of distribution, steady-state, of 0.992±0.530 l/kg. For the CPB group, only half-life was estimated, and averaged 2.77±0.28 h, significantly greater (p〈0.01) than that in the controls. These results further confirm the increased half-lives seen with other hepatically cleared drugs following CPB and have implications in the clinical management of patients given drugs eliminated in this manner.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544033
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  • 26
    Electronic Resource
    Electronic Resource
    Clinical pharmacological studies with the vasodilator endralazine in patients with renal impairment (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 159-163 
    Details
    ISSN: 1432-1041
    Keywords: endralazine ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of renal impairment on the pharmacokinetics of endralazine was studied in 12 patients; 4 patients on regular haemodialysis therapy (creatinine clearance less than 5 ml/min) and 8 patients with varying degrees of renal impairment (creatinine clearance 11–52 ml/min). Following an oral dose of 10 mg endralazine the mean terminal elimination half-life (βt1/2) in the dialysis sub-group was prolonged at 7.1 h (range 3.3 to 14 h), compared to 3.6 h in the other renal patients (and compared to 2.3 h in hypertensive patients with normal renal function). After one week's therapy with 10 mg B.D. endralazine in the 8 patients with moderate renal impairment there was a significant increase in βt1/2 to 8.6 h but there was no significant change in the area under the drug concentration-time curve and no evidence of drug accumulation. In this study those patients with the poorest renal function had the longest βt1/2 after acute dosing. There was a significant correlation between creatinine clearance and acute βt1/2 but there was considerable variability in individual patients and, even with severe degrees of renal impairment, major dose adjustments do not appear necessary.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544039
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  • 27
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of the ergot derivative, transdihydrolisuride, in man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 335-339 
    Details
    ISSN: 1432-1041
    Keywords: transdihydrolisuride ; dopamine agonist ; pharmacokinetics ; pharmacodynamics ; prolactin levels ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels and urinary excretion of the dopamine agonist, transdihydrolisuride (TDHL), were measured by radioimmunoassay in healthy male volunteers given TDHL 50 µg i.v. and oral doses of 200, 400 and 800 µg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of TDHL declined with a half-life of 37±19 min. The total clearance was 38±27 ml/min/kg and the apparent volume of distribution was 1.3±0.4 l/kg. The bioavailability of oral TDHL was proportional to the dose; after 200, 400 and 800 µg the bioavailability was 20±25%, 31±24% and 48±26%. TDHL was almost totally metabolized and less than 0.5% of the dose was excreted unchanged in urine in 24 h. Plasma prolactin levels were depressed by 66±15%, 75±11% and 80±7% after TDHL 200 µg, 400 µg and 800 µg. The effect lasted for more than 12 h after the lowest dose and for more than 24 h after 400 and 800 µg. Side effects, mainly nausea and headache, only occurred at the two highest dose levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542171
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  • 28
    Electronic Resource
    Electronic Resource
    Pharmacokinetic study of the new sulfamethopyrazine-trimethoprim combination (kelfiprim) in renal insufficiency (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 345-348 
    Details
    ISSN: 1432-1041
    Keywords: kelfiprim ; trimethoprim combination ; sulfamethopyrazine combination ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The combination of trimethoprim (TMP) and sulfamethopyrazine (SMP) has been successfully used to treat chronic urinary tract infections. Since parenchymal involvement associated with renal insufficiency of varying degree is not infrequent in these patients, it was considered important to study the pharmacokinetics of TMP and SMP in a fixed dose combination. Four groups of patients were studied: 1) 4 patients with endogenous creatinine clearance (CLcR) between 80 and 40 ml/min; 2) 3 patients with CLcR between 40 and 10 ml/min; 3) 3 patients on chronic peritoneal dialysis (CAPD); and 4) 3 patients on haemodialysis. A single oral dose of 250 mg TMP and 200 mg SMP was given to each patient. Multiple samples were collected over 9 days and the following pharmacokinetic parameters were calculated: total area under the plasma level curve, slow disposition rate constant β and the corresponding t1/2β, plasma clearance and the apparent volume of distribution. The results show that the two moieties of the TMP-SMP combination behaved differently in uraemic patients as fas as elimination rate was concerned. TMP was eliminated more slowly both in patients with diminished renal function and in those subjected to haemo- or peritoneal dialysis. The reduction in the rate of elimination of TMP was significantly correlated with the degree of renal impairment. The elimination of SMP, however, was not significantly affected by the reduced renal function; indeed a tendency to increase was noted, at least in dialyzed patients. However, as in patients with mild renal insufficiency (CLcR〉40 ml/min) no substantial change in plasma clearance rate need be expected, the TMP-SMP combination could be given to them in the same dose schedule as in people with normal renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542173
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  • 29
    Electronic Resource
    Electronic Resource
    Effect of a reversible and selective MAO-A inhibitor (cimoxatone) on diurnal variation in plasma prolactin level in man (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 71-77 
    Details
    ISSN: 1432-1041
    Keywords: cimotaxone ; MAO inhibitor ; plasma prolactin ; circadian rhythm ; healthy volunteers ; hypothalamic MAO ; prolactin secretion ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Prolactin (PRL) secretion is stimulated by serotonin (5-HT) and inhibited by dopamine (DA). 5-HT is generally recognized as a substrate for type A monoamine oxidase (MAO), whereas DA is considered as a substrate for either A or B, or both forms of MAO, depending on the species and tissues used. The effect of cimoxatone, a reversible, selective MAO-A inhibitor, on diurnal variation in plasma PRL level was investigated in healthy adults after a single 40 mg oral dose, as an indirect approach to investigating whether DA is preferentially a substrate for Type A or B MAO in man. The circadian rhythm in PRL, stress conditions and diet were taken into account in the present study, which was placebo-controlled. There was a slight but significant reduction in circulating PRL in the six subjects, which persisted for at least 9 h after cimoxatone. However, the duration of the decrease in plasma PRL was shorter than the inhibition of MAO-A. The results are not inconsistent with the presence of both forms of MAO in the human hypothalamus and with DA as a substrate for both forms in this region, if it is assumed that the hypothalamic concentrations of the drug during the period 0–9 hours was sufficiently high to inhibit DA deamination by both forms of MAO.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546712
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  • 30
    Electronic Resource
    Electronic Resource
    Pharmacokinetic evaluation of haemoperfusion in phenobarbital poisoning (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 109-112 
    Details
    ISSN: 1432-1041
    Keywords: phenobarbital poisoning ; charcoal haemoperfusion ; distribution volume ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Charcoal haemoperfusion was performed for 5–12 h in three patients with maximal plasma phenobarbital concentrations of 600, 946 and 1044 µmol/l (138, 217 and 240 µg/ml). During haemoperfusion with constant blood flow phenobarbital elimination followed first order kinetics with half-lives of 11.1, 10.0 and 7.2 h, respectively. After termination of the haemoperfusion there was no rebound effect in plasma phenobarbital concentration and the elimination was first order with half-lives of 51, 82 and 48 h, respectively. Thus, the plasma phenobarbital half-life was reduced by 78–88% during haemoperfusion. In the same period 76–86% of the total body clearance of phenobarbital was due to the haemoperfusion column at a calculated volume of distribution of phenobarbital of 1.1–1.2 l/kg. This is clear evidence for recommending haemoperfusion in cases of serious poisoning with phenobarbital.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546717
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  • 31
    Electronic Resource
    Electronic Resource
    Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 121-124 
    Details
    ISSN: 1432-1041
    Keywords: methotrexate ; psoriasis ; pharmacokinetics ; plasma levels ; urinary excretion ; renal clearance ; tubular absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500–800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52–102 ml/min (mean±SD, 83±19.4 ml/min).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546719
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  • 32
    Electronic Resource
    Electronic Resource
    Acetaminophen accumulation in pediatric patients after repeated therapeutic doses (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 57-59 
    Details
    ISSN: 1432-1041
    Keywords: acetaminophen ; pediatric patients ; fever therapy ; accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetaminophen serum concentrations were studied in 21 infants and children with fever. The maximum serum concentrations ranged from 9.96 to 19.6 µg/ml after a single dose of 12–14 mg/kg and 13.9 to 40.1 µg/ml after a single dose of 22–27 mg/kg. Ten patients were restudied at steadystate after repeat doses had been given every 4 or 8 h for 1 to 3 days. Total area under the acetaminophen serum concentration-time curve normalized for dose averaged 0.181 (ml/min/kg)−1 after the first dose and 0.202 (ml/min/kg)−1 at steady-state (p〈0.05). Five patients showed a 13 to 44% increase in the AUC; one had a 10% decrease in the AUC; and four had less than 6% change in the AUC. There was no evidence of hepatotoxicity. These data suggest that acetaminophen may accumulate after repeated therapeutic doses in children with fever.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395207
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  • 33
    Electronic Resource
    Electronic Resource
    Comparison of the short-term effects of the loop diuretic piretanide and furosemide in patients with renal insufficiency (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 413-418 
    Details
    ISSN: 1432-1041
    Keywords: piretanide ; furosemide ; renal insufficiency ; loop diuretic ; natriuresis ; pharmacokinetics ; diuretic effect ; kaliuresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The natriuretic effect of the new loop diuretic piretanide was investigated in patients with severe renal insufficiency and was compared with that of furosemide. In the first study 4 hospitalized patients (serum creatinine 407 to 1220 µmol/l) were examined after administration of piretanide (12, 24, 48 and 96 mg to two patients, and 24, 48, 96 and 192 mg to 2 other subjects, given every third day). In the second study 6 hospitalized patients (serum creatinine 194 to 698 µmol/l) were studied after receiving orally 2 different doses of piretanide and 2 different doses of furosemide orally, given every fourth day. The mean natriuretic effect of 48 mg and 96 mg piretanide was 250 and 340% of the control value for the entire group, and 311 to 480% in the subgroup of patients with serum creatinine below 530 µmol/l. For a given dose the natriuresis was inversely correlated with renal function, and at a given serum creatinine level the natriuretic response was dose-dependent. The drug had less effect on water and potassium diuresis than on natriuresis. No significant difference in natriuretic effect was found on comparison with furosemide given in the ratio furosemide: piretanide 3.33:1. The pharmacokinetic data showed a direct correlation between the dose and the mean plasma concentration and also between urinary recovery of the drug and the measured natriuretic response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542133
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  • 34
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 441-446 
    Details
    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; metabolites ; pharmacokinetics ; single/multiple oral doses ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of canrenone and ‘total metabolites’ after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and ‘total metabolites’ were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2α) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2β) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of ‘total metabolites’ after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of ‘total metabolites’ was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and ‘total metabolites’ were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549592
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  • 35
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of a new radiosensitiser, Ro 03-8799 in humans (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 483-489 
    Details
    ISSN: 1432-1041
    Keywords: radiosensitiser ; pharmacokinetics ; healthy volunteers ; tumour patients ; Ro 03-8799
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new hypoxic cell radiosensitiser, Ro 03-8799 has been administered intravenously to human volunteers and its kinetic parameters derived from plasma and urine data. Good penetration of drug into tumour tissue is found, consistent with its large volume of distribution. The plasma clearance of this compound is rapid due to high metabolic and renal clearances. These parameters combine to produce an elimination half-life of 5.6 h, approximately half that of misonidazole, a well studied radiosensitiser. It is hoped that this decrease in total body exposure will also reduce the cumulative toxicity seen when misonidazole is administered repeatedly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549599
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  • 36
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and pharmacodynamic interaction study of diazepam and metoprolol (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 223-226 
    Details
    ISSN: 1432-1041
    Keywords: diazepam ; metoprolol ; drug combination ; pharmacodynamics ; pharmacokinetics ; drug metabolism ; sedation ; interaction study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 normotensive, healthy male volunteers the pharmacodynamic responses (blood pressure, heart rate; sedation index, tracking test, reaction time) to metoprolol (100 mg bid orally), diazepam (0.1 mg/kg intravenously) and to their combination were studied. The pharmacokinetics of diazepam were also compared in a cross-over experiment, with and without pretreatment by the β-adrenoceptor antagonist to evaluate the possibility of a drug interaction. The pharmacodynamic and pharmacokinetic investigations indicated that metoprolol only slightly impaired the elimination of diazepam (18% decrease in total clearance, 25% increase in elimination half-life). The pharmacodynamics of metoprolol (17% decrease in heart rate, 17% decrease in diastolic RR) was not significantly altered by the bolus injection of diazepam. The extent of prolongation in choice reaction time (RT2) induced by diazepam was significantly (p=0.001) more pronounced following the co-administration of metoprolol. However, the results of RT1, the tracking test and the sedation index did not indicate any increased effect due to the β-blocking agent. It is concluded that concomitant treatment with metoprolol and diazepam causes only minor and clinically irrelevant changes in drug metabolism and drug response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630289
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  • 37
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and pharmacodynamic modelling with pancuronium (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 243-250 
    Details
    ISSN: 1432-1041
    Keywords: pancuronium ; neuromuscular relaxants ; simultaneous modelling ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of pancuronium were studied following intravenous infusion in eleven patients undergoing surgical anaesthesia. Measurement of the plasma concentrations (Cp) of the neuromuscular blocking agent (NMBA) and the concomitant intensities of paralysis allowed their simultaneous modelling. The pharmacokinetic parameters derived for pancuronium were in the range of previously reported values, except that the mean total systemic plasma clearance (0.79±0.28 ml·min−1·kg−1) was reduced and the mean terminal phase half-life (169 min) was longer in these patients. Plasma concentration and % paralysis data were successfully fitted to a previously proposed pharmacodynamic model. This model assumes a separate effect compartment which exchanges drug directly with the central kinetic compartment (integrated effect model). The ‘steady-state’ Cp necessary to produce 50% paralysis (ECpss(50)) was estimated to be 0.21±0.08 µg·ml−1 (mechanical response) and 0.18±0.05 µg·ml−1 (EMG response). An analysis using the Hill equation of the Cp-response relationship, during and after the constantrate infusion of pancuronium bromide, resulted in effective plasma concentrations for 50% paralysis (ECp50) of 0.35±0.06 µg·ml−1 and 0.20±0.09 µg·ml−1, respectively, for mechanical twitch response. The corresponding values for EMG response were 0.32±0.06 µg·ml−1 and 0.17±0.06 µg·ml−1. Using this latter approach, the ECp50 estimated during onset of paralysis was significantly higher than that estimated during offset of paralysis (p〈0.05); no such difference was apparent between this latter parameter and the ECpss(50) of the integrated effect model (p〉0.05). No significant differences were observed between any of the pharmacodynamic parameter estimates generated from the data obtained from the two methods of assessment of neuromuscular function (mechanical vs. EMG response) (p〉0.05).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630293
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  • 38
    Electronic Resource
    Electronic Resource
    Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 341-343 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; ranitidine ; carbamazepine ; sodium valproate ; pharmacokinetics ; drug metabolism ; inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single oral dose (400 mg) of carbamazepine and sodium valproate were compared in peptic ulcer patients before and after four weeks of a therapeutic course of either cimetidine (1 g/day, n=6 subjects) or ranitidine (300 mg/day, n=6 subjects). There was a small (up to 20%) but statistically significant decrease in oral clearance of carbamazepine after cimetidine treatment. A similar fall in sodium valproate clearance in five cimetidine-treated patients was accompanied by a significantly prolonged elimination half-life. No such trends were demonstrated during ranitidine treatment. Since both anticonvulsants are partly metabolized by hepatic mixed function oxidases, an inhibition by cimetidine at this level may be responsible for the observed impairment of clearance. Thus a potentially important clinical interaction may occur in patients taking anticonvulsants and cimetidine concurrently.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542172
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  • 39
    Electronic Resource
    Electronic Resource
    Lack of clinically important interaction between erythromycin and theophylline (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; erythromycin ; interaction ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 11 healthy volunteers the kinetics of theophylline and the plasma levels and the urinary excretion of its metabolites were studied before and after treatment with erythromycin for 10 days. Theophylline was administered as an intravenous bolus injection (280 mg) followed by a constant intravenous infusion (23.8±4.1 mg/h) for 6 hours. The total clearance of theophylline at steady-state (63.4±9.9 vs 63.8±14.4 ml/min, before vs after erythromycin treatment) and the elimination half-life after cessation of the infusion (6.7±2.6 vs 7.5±1.8 h, before vs after treatment) did not change during the treatment with erythromycin. No difference in the formation of metabolites before and after treatment with erythromycin was detected; the findings in urine were 40.4±5.0 vs 42.1±5.4% 1,3-dimethyluric acid, 29.6±4.6 vs 30.1±5.9% 1-methyluric acid and 13.4±3.5 vs 12.5±2.2% 3-methylxanthine before and after erythromycin treatment, respectively. It is concluded that a clinically relevant interaction between erythromycin and theophylline does not occur.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542146
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  • 40
    Electronic Resource
    Electronic Resource
    Individualizing theophylline dosage: Evaluation of a single-point maintenance dose prediction method (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 491-498 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; computer simulation ; pharmacokinetics ; single-point dose prediction ; nomogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A dosage prediction method to estimate theophylline clearance and dose requirement was evaluated in 22 outpatients with partly reversible obstructive airways disease. The steady state theophylline dose required to achieve a target concentration (Css) was predicted using a single serum theophylline determination 8 h after a single oral test dose. In 17 nonsmoking patients a mean absolute deviation of 8.2% (range 0.0–21.7%) between predicted and observed Css was found, and in 5 smoking patients the mean deviation was 34.0% (range 2.2–53.8%). In 17 healthy smokers the single-point method was found to predict theophylline clearance at a sampling time of 8 h with a prediction error of 11.3 (range 0.8–25.3%) compared to the clearance determination using the area under the curve. In addition, a numerical simulation program to assess the influence of absorption, elimination and sampling time on predictive accuracy showed that the method could be successfully applied to a patient population with elimination rate constants between 0.07 1/h and 0.25 1/h, allowing a mean prediction error of 15%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542147
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  • 41
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and hypotensive effect in healthy volunteers of pinacidil, a new potent vasodilator (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 603-608 
    Details
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; pinacidil pyridine-N-oxide ; urinary excretion ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7±6.0 mmHg. Maximum rise in heart rate was 23.8±6.6 beats/min. Pinacidil serum distribution half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\alpha }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\alpha }$}}}$$ ) was 13.4±8.5 min and elimination half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\beta }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\beta }$}}}$$ ) was 2.13±0.49 h. The apparent volume of distribution (Vdβ) was 90.3±13.21 and total body clearance was 31.1±9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40–400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 ± 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6±9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543493
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  • 42
    Electronic Resource
    Electronic Resource
    Comparison of radioreceptor assay and radioimmunoassay for atropine: Pharmacokinetic application (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 613-617 
    Details
    ISSN: 1432-1041
    Keywords: atropine ; radioreceptor assay ; radioimmunoassay ; serum levels ; pharmacokinetics ; assay comparison
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A membrane suspension prepared from rat brain was able to bind the potent muscarinic antagonist quinuclidinyl benzilate (QNB). The KD for binding was 0.48 nM and Bmax was 1.42 pmol/mg protein. Atropine competitively inhibited the binding of tritiated QNB to muscarinic receptors. This new radioreceptor assay (RRA) for atropine has been compared with a radioimmunoassay (RIA) for atropine. The RRA measures only the active component of atropine, 1-hyscyamine and in this respect it differs from the RIA. As little atropine as 1.25 ng/ml (4.33 nmol/l) in a 25 µl serum sample could be reliably assayed by the RRA. Using both assay techniques the pharmacokinetics of atropine was studied after a single 0.02 mg/kg i.v. dose given to 8 anaesthetized patients. The half-life calculated by the RRA was 3.7±2.3 h (m ± SD) and by the RIA 4.3±1.7 h. Both the volume of distribution and the total clearance were higher according to the RRA than the RIA: 3.9±1.5 vs 1.7±0.71/kg and 15.4±10.3 vs 5.9±3.6 ml/min/kg, respectively. The AUC measured by the RRA and RIA was 29.8±18.9 and 103.9±110.7 µg·h/l, respectively. The differences in the pharmacokinetics according to the 2 methods are presumably due to preferential tissue uptake of the l-form.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543495
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  • 43
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and bioavailability of digitoxin by a specific assay (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 85-89 
    Details
    ISSN: 1432-1041
    Keywords: digitoxin ; radioimmunoassay ; pharmacokinetics ; bioavailability ; digitoxin metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395212
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  • 44
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 115-117 
    Details
    ISSN: 1432-1041
    Keywords: benzodiazepine antagonist ; Ro 15-1788 ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40±8%, mean±SD). A negligible amount (〈0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9±0.2 h, and high total plasma and blood clearances of 691±216 ml/min and 716±199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395217
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  • 45
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of S-adenosyl-L-methionine in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 119-121 
    Details
    ISSN: 1432-1041
    Keywords: S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S-Adenosyl-L-methionine (AdoMet) kinetics was studied in 6 male subjects given 100 and 500 mg i. v. Drug concentrations in plasma and urine were assayed using a radioenzymatic method. Pharmacokinetic parameters were estimated according to an open two-compartment model. The apparent volumes of distribution after the 100 and 500 mg doses were 407±27 and 443±36 ml/kg (mean±SEM), terminal half-lives 81±8 and 101±7 min and body clearances 3.7±0.5 and 3.1±0.2 ml/min per kg. Urinary excretion was 34±3 and 40±2% of the administered dose. The results demonstrate that drug disposition occurs more via metabolism than via renal excretion, and it is not dependent on the administered dose. Binding of AdoMet to serum proteins is negligible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395218
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  • 46
    Electronic Resource
    Electronic Resource
    Inter- and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 47-53 
    Details
    ISSN: 1432-1041
    Keywords: verapamil ; first-pass metabolism ; pharmacokinetics ; interindividual variation ; intraindividual variation ; chronic administration ; deuterated verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of verapamil in five healthy volunteers were investigated on 4 occasions during chronic administration of deuterated verapamil. There was no statistically significant difference in oral clearance, terminal half-life, bioavailability, morning trough level and peak concentration or in the time of their occurrence on the four occasions. The plasma clearance, however, exhibited considerable inter- and intra-individual variation, ranging between 26.3% and 85.4% and 12.0% and 48.0%, respectively. Comparison of these pharmacokinetic parameters with data from previous single dose studies in the same subjects revealed a significant (p〈0.05) decrease in the clearance and an increase in the apparent bioavailability of verapamil during chronic administration, although no difference in the half-life was found. Due to the considerable variation in the oral clearance of verapamil during chronic dosing, steady-state conditions in a strict pharmacokinetic sense may never be attained, and pharmacokinetic data obtained in single dose studies will be of limited value in predicting steady-state plasma concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546708
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  • 47
    Electronic Resource
    Electronic Resource
    Naproxen disposition in patients with alcoholic cirrhosis (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 291-296 
    Details
    ISSN: 1432-1041
    Keywords: naproxen ; cirrhosis ; pharmacokinetics ; protein binding ; nonsteroidal antiinflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chronic liver disease is known to alter the absorption and disposition of many drugs. To assess the influence of chronic alcoholic liver disease on the disposition of naproxen, we administered the drug both as a single dose and to steady state to 10 individuals with alcoholic cirrhosis and to 10 healthy controls. Plasma and serum samples collected after naproxen dosing were assayed for both total and (following equilibrium dialysis) unbound drug concentration. Clearance calculated based on both total and unbound naproxen concentration revealed no change in total plasma clearance of the drug at steady state but a marked reduction of approximately 60% in clearance based on unbound drug. Naproxen volume of distribution changed only minimally. Because clearance based on unbound drug concentration at a given dosing rate determines the plasma or blood free drug concentration, this concentration may increase significantly in patients with alcoholic liver disease given usual doses of naproxen. Unbound drug concentration is thought to determine the pharmacologic effect of a drug. We therefore recommend that naproxen dosing be reduced by at least half in patients with chronic alcoholic liver disease. In the absence of data to the contrary, this recommendation can be extended to individuals with other forms of hepatic disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542162
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  • 48
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of propranolol during pregnancy (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 583-587 
    Details
    ISSN: 1432-1041
    Keywords: propranolol ; pregnancy ; beta-adrenoceptor antagonist ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Propranolol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32 and 36 weeks gestation and when at least 6 weeks postparum. On both occasions, subjects were given propranolol 120 mg orally or 10 mg intravenously in randomised order with a minimum washout period of 1 week. Propranolol was assayed in plasma by gas-liquid chromatography with electron-capture detection and the pharmacokinetic parameters were investigated. There were no significant alterations in elimination half-life, clearance or apparent volume of distribution per kilogram antenatally compared with postnatally: bioavailability was also unchanged. It is concluded that the disposition of propranolol is not altered during pregnancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556896
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  • 49
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 197-207 
    Details
    ISSN: 1432-1041
    Keywords: furosemide ; bioavailability ; pharmacokinetics ; oral administration ; i.v. administration ; drug absorption ; moment analysis ; food effect ; dissolution effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 40 mg was administered to 8 healthy subjects as an i.v. bolus dose, as 1 tablet in the fasting state, and as 1 tablet and a solution after food intake. The i.v. data gave a total body clearance of 162±10.8 ml/min and a renal clearance of 117±11.3 ml/min; the volume of distribution at steady state was 8.3±0.61. Oral administration gave a bioavailability of the tablet (fasting) of 51%. Food intake slightly reduced the bioavailability, but not to a significant extent. There was no significant difference in availability between the tablet and the solution. Moment analysis gave a mean residence time after the i.v. dose, MRTi.v., of 51±1.5 min. The mean absorption times (MAT) for all oral doses were significantly longer than the MRTi.v., indicating absorption rate-limited kinetics of furosemide. On average, food delayed the absorption by 60 min. The MAT for the tablet in the postprandial state was significantly longer than for the solution, indicating dissolution rate-limited absorption of the tablet.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630286
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  • 50
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of high doses of piretanide in moderate to severe renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 589-593 
    Details
    ISSN: 1432-1041
    Keywords: piretanide ; renal insufficiency ; furosemide ; pharmacokinetics ; loop diuretic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of piretanide was studied in 10 patients with chronic renal failure. After administration of a high oral dose (12 to 192 mg) of piretanide the kinetics behaved according to an open 2-compartment model. The elimination constant in the first phase (α) ranged from 0.385 to 0.756 h−1 and in the second phase (β) from 0.079 to 0.274 h−1. The corresponding elimination half-lives ranged from 55 to 108 min (t1/2 α) and from 152 to 524 min (t1/2 β). Only an average of 2.8% of the orally administered drug was recovered in 24 h urines. Nevertheless, a good correlation was found between urinary recovery or renal clearance of the drug and residual renal function. The elimination of piretanide by non-renal mechanisms appeared to be increased when renal function was greatly diminished.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556897
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  • 51
    Electronic Resource
    Electronic Resource
    Effect of liver failure on the pharmacokinetics of cyclophosphamide (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 591-593 
    Details
    ISSN: 1432-1041
    Keywords: cyclophosphamide ; liver failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cyclophosphamide was investigated in 7 patients in severe liver failure. The pharmacokinetic data were compared with those derived from a matched control group of patients with normal liver function. The half-life (t1/2) of cyclophosphamide following intravenous administration in patients with liver failure was 12.5±1.0 h (m±SD), which was significantly longer than in the normal controls in whom it was 7.6±1.4 h (p〈0.001). The mean total body clearance (Clt) was significantly smaller in liver failure at 44.8+8.6l·kg−1 than in the controls in whom it was 63.0±7.6l·kg−1 (p〈0.01). It is concluded that severe liver disease has a significant effect on the disposition of cyclophosphamide, and that it could lead to accumulation of the drug in the body.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543491
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  • 52
    Electronic Resource
    Electronic Resource
    Oral pharmacokinetics of omeprazole (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 641-643 
    Details
    ISSN: 1432-1041
    Keywords: omeprazole ; gastric acid secretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of omeprazole were studied in a group of healthy male subjects after single and repeated oral doses of 30 and 60 mg. Absorption of omeprazole from its enteric-coated formulation was unpredictable. There was a highly significant increase in the area under the plasma concentration time curve (AUC) after repeated dosing. Omeprazole increases its own relative availability following repeated dosing. This may be due to inhibition of gastric acid secretion by omeprazole which is an acid-labile compound.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543502
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  • 53
    Electronic Resource
    Electronic Resource
    Intra-individual consistency of prednisolone kinetics during long-term prednisone treatment (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 651-653 
    Details
    ISSN: 1432-1041
    Keywords: prednisolone ; prednisone treatment ; pharmacokinetics ; individual variation ; microsomal enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eleven patients on long-term prednisone treatment were studied on two occasions separated by 45 to 325 days. In 10 patients the total body clearance of prednisolone only changed about 10%. In one case a 78.5% decrease was observed after stopping treatment with rifampicin and isoniazide. No association was found between the prednisone dose rate (mg/kg per month), patient age or mean endogenous plasma hydrocortisone level and prednisolone clearance/kg. The results indicate considerable intra-individual consistency of prednisolone kinetics if other conditions are not changed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543505
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  • 54
    Electronic Resource
    Electronic Resource
    Acetaminophen accumulation in pediatric patients after repeated therapeutic doses (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 57-59 
    Details
    ISSN: 1432-1041
    Keywords: acetaminophen ; pediatric patients ; fever therapy ; accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetaminophen serum concentrations were studied in 21 infants and children with fever. The maximum serum concentrations ranged from 9.96 to 19.6 µg/ml after a single dose of 12–14 mg/kg and 13.9 to 40.1 µg/ml after a single dose of 22–27 mg/kg. Ten patients were restudied at steadystate after repeat doses had been given every 4 or 8 h for 1 to 3 days. Total area under the acetaminophen serum concentration-time curve normalized for dose averaged 0.181 (ml/min/kg)−1 after the first dose and 0.202 (ml/min/kg)−1 at steady-state (p〈0.05). Five patients showed a 13 to 44% increase in the AUC; one had a 10% decrease in the AUC; and four had less than 6% change in the AUC. There was no evidence of hepatotoxicity. These data suggest that acetaminophen may accumulate after repeated therapeutic doses in children with fever.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553155
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  • 55
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and bioavailability of digitoxin by a specific assay (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 85-89 
    Details
    ISSN: 1432-1041
    Keywords: digitoxin ; radioimmunoassay ; pharmacokinetics ; bioavailability ; digitoxin metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553160
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  • 56
    Electronic Resource
    Electronic Resource
    Effect of food on pharmacokinetics of chlorambucil and its main metabolite, phenylacetic acid mustard (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 111-114 
    Details
    ISSN: 1432-1041
    Keywords: chlorambucil ; chronic lymphocytic leukaemia ; phenylacetic acid mustard ; food intake ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the pharmacokinetics of chlorambucil (C) and its cytotoxic metabolite, phenylacetic acid mustard (PAM), has been studied in man after oral doses of chlorambucil. The administration of chlorambucil with food resulted in slower absorption than when fasting. However, the area under the plasma concentration-time curve (AUC) was unaffected. The mean ratio AUCPAM/AUCC was 2.8 (range 1.4–7.1) under fasting and 3.3 (range 1.3–7.4) under nonfasting conditions. The metabolite very probably plays an important role in the cytotoxic effects observed after administration of C, since calculations show that a major fraction of the metabolite is eliminated by alkylation reactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553164
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  • 57
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 115-117 
    Details
    ISSN: 1432-1041
    Keywords: benzodiazepine antagonist ; Ro 15-1788 ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40±8%, mean±SD). A negligible amount (〈0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9±0.2 h, and high total plasma and blood clearances of 691±216 ml/min and 716±199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553165
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  • 58
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    Electronic Resource
    Pharmacokinetics of cimetidine in critically ill patients (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 341-346 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; pharmacokinetics ; critically ill patients ; intravenous administration ; dose individualization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cimetidine disposition was studied after rapid (1 min) intravenous infusion in eight critically ill patients aged between 20 years and 77 years; one patient was studied on two occasions. Cimetidine dose was 300 mg in seven patients and 400 mg in the remaining patient. Arterial plasma cimetidine concentrations at the end of the infusion were very high and ranged from approximately 15–35 mg/l. Pharmacokinetic parameters displayed wide interpatient variability (coefficients of variation of 30–50%) and significant relationships emerged between some of these parameters and certain patient characteristics. Most notable, total systemic plasma clearance of cimetidine was directly related to estimated creatinine clearance (p〈0.01). This relationship might prove to be a useful method of individualizing cimetidine dosage in critically ill patients.
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    URL: http://dx.doi.org/10.1007/BF00548765
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    Electronic Resource
    Pharmacokinetics of cimetidine in advanced cirrhosis (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 347-355 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; cirrhosis ; pharmacokinetics ; bioavailability ; clearance reduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of impaired liver function on the pharmacokinetics of cimetidine was studied in 8 patients with advanced cirrhosis given single doses of 100 mg i.v. and 400 mg p.o. on separate days. Compared to a control group of 10 healthy volunteers, the total renal and nonrenal clearance was significantly reduced in the cirrhotic patients; (total plasma clearance mean ± SD) 356±181 vs 789±262 ml/min (p〈0.01); renal clearance (Clr) 296±100 vs 588±181 ml/min (p〈0.01) and nonrenal clearance (Clnr) 97±111 vs 205±89 ml/min (p〈0.05). Compared to published results for age-matched ulcer patients, both total and nonrenal clearance were lower whereas renal clearance was within the reported normal range. A significant reduction in volume of distribution (Vdβ) was found, from 2.1±0.1 l/kg in controls to 1.0±0.4l/kg, and in the patient group there was a significant correlation between Vdβ and total plasma clearance (r=0.72, p〈0.05). Volume of distribution in steady state (Vdss) did not differ from published results in age-matched controls. No significant change in half-life was found. Bioavailability, estimated by AUC-measurement, showed considerable patient variability (21–143%), with a mean of 70±39%. This was lower than in the controls. In contrast, measurement of urinary excretion showed higher bioavailability in the patients (66±23 vs 51±8%). No correlation was found between any of the kinetic parameters and the clinical and laboratory data. It is suggested that patients with advanced cirrhosis should be closely observed when given cimetidine, and a reduction in dose should be concidered if side effects are to be avoided.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548766
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  • 60
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    Electronic Resource
    Pharmacokinetics of cefoxitin administered by i.v. infusion to patients with a pleural effusion (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 389-392 
    Details
    ISSN: 1432-1041
    Keywords: cefoxitin ; beta-lactam antibiotics ; pharmacokinetics ; serum concentration ; pleural fluid concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin was studied in 6 healthy volunteers and in 5 patients with a pleural effusion after administration of a single dose of 30 mg/kg i.v. infusion. The serum and pleural fluid concentrations of cefoxitin were determined microbiologically. The elimination half-life of the antibiotic from pleural fluid in all cases was 2–3fold longer than from serum, which shows a difference between the kinetic elimination processes of the antibiotic from the two fluids. The slow elimination of cefoxitin from pleural fluid facilitates its accumulation in this compartment during a multiple dosage regimen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548772
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  • 61
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    Electronic Resource
    Pharmacokinetics of midazolam in the aged (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 381-388 
    Details
    ISSN: 1432-1041
    Keywords: midazolam ; hypnotic drug ; benzodiazepine ; pharmacokinetics ; aged patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of midazolam, an imidazo-benzodiazepine derivative, have been studied in 13 subjects over the age of 60 years who received the drug intravenously (0.07 mg kg−1) as an induction agent for endoscopy. Two to three days later, 6 of these subjects received 5 mg of midazolam intramuscularly, and another 6 of the subjects received 10 mg of the drug orally. The plasma concentration-time curves were again studied pharmacokinetically. After intravenous dosing, the mean (± SD) elimination half-life (2.14±1.24 h) showed a statistically significant trend to increase with age in the subjects older than 60 years. While the mean (± SD) clearance value (0.30±0.19 l kg−1h−1) tended to fall with age in the elderly subjects, this trend was not statistically significant. Apparent volume of distribution did not appear to be related to advancing age beyond 60 years, and this parameter (mean ± SD) did not differ to a statistically significant extent between the aged subjects (0.77±0.47 l kg−1) and the young subjects studied previously (1.09±0.58 l kg−1). Atropine premedication did not appear to alter the dispositional parameters of the intravenously administered drug. Intramuscularly administered midazolam was absorbed rapidly. Bioavailability appeared incomplete (F=0.59±0.15, mean ± SD), possibly due to saturable elimination of the drug at the higher plasma levels which were obtained after intravenous midazolam. Oral bioavailability, relative to intravenous, was 0.34±0.17, (mean ± SD), with an appreciable but variable lag time (0.74±0.40 h, mean ± SD). Orally, in the dose used, the drug was an inefficient hypnotic with four of the six subjects failing to attain the plasma drug level of 44–50 µg l−1, which appeared to be the approximate threshold for sleep. It is impossible to know whether this failure represents an age related effect on drug absorption, or is a consequence of the upper alimentary tract abnormalities for which the endoscopies were done.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548771
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  • 62
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    Steady state pharmacokinetics of trimethoprim 300 mg once daily in healthy volunteers assessed by two independent methods (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 393-397 
    Details
    ISSN: 1432-1041
    Keywords: trimethoprim ; concentration ; urinary excretion ; healthy volunteers ; steady state ; pharmacokinetics ; serum creatinine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady state pharmacokinetics of trimethoprim was determined after 300 mg orally once daily to 6 healty volunteers for 9 days. The microbiological assay of plasma level was unreliable at trimethoprim concentrations 〉4 µg/ml, so results from an HPLC-assay are given. Steady state was present after 3 days. The plasma concentration peaked 1 to 4 h (mean 2.0 h) after the dose at a mean of 6.0 µg/ml (range 3.1–9.5 µg/ml); the minimum value was 1.5 µg/ml (range 0.6–2.9 µg/ml). The mean AUCss was 77 µg/ml · h and the mean plasma clearancess was 67 and 74 ml/min on Days 8 and 9. Renal clearance was about 60% of the plasma clearance. The average plasma half life was 10.6 h (range 8.7–15.3 h). Thus, there was considerable interindividual variation in all pharmacokinetic parameters. 72 h after the last dose trimethoprim was detectable in plasma in only 1 of the 6 subjects. The minimum urinary concentration of trimethoprim during treatment was always well above (range 22 to 220 µg/ml) the MIC values for most urinary tract pathogens. Therefore, a daily dose of 300 mg trimethoprim results in a therapeutic concentration in urine at steady state that lasts throughout the dosing interval and in most subjects probably lasts also for a further 24 h. Trimethoprim administration raised mean serum creatinine from 67 to 97 µmol/l, probably due to competitive inhibition of the tubular secretion of creatinine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548773
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    Electronic Resource
    Bioavailability and pharmacokinetics of phenytoin during pregnancy (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 105-110 
    Details
    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395215
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  • 64
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    Effect of food on pharmacokinetics of chlorambucil and its main metabolite, phenylacetic acid mustard (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 111-114 
    Details
    ISSN: 1432-1041
    Keywords: chlorambucil ; chronic lymphocytic leukaemia ; phenylacetic acid mustard ; food intake ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the pharmacokinetics of chlorambucil (C) and its cytotoxic metabolite, phenylacetic acid mustard (PAM), has been studied in man after oral doses of chlorambucil. The administration of chlorambucil with food resulted in slower absorption than when fasting. However, the area under the plasma concentration-time curve (AUC) was unaffected. The mean ratio AUCPAM/AUCC was 2.8 (range 1.4–7.1) under fasting and 3.3 (range 1.3–7.4) under nonfasting conditions. The metabolite very probably plays an important role in the cytotoxic effects observed after administration of C, since calculations show that a major fraction of the metabolite is eliminated by alkylation reactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395216
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    Pharmacokinetics of tolfenamic acid: Disposition in bile, blood and urine after intravenous administration to man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 349-354 
    Details
    ISSN: 1432-1041
    Keywords: tolfenamic acid ; anti-inflammatory agents ; biliary excretion ; pharmacokinetics ; intravenous administration ; bile duct cannulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To study its pharmacokinetics and especially its biliary excretion, 14C-tolfenamic acid 9.84 µCi/100 mg was infused i.v. in 8 patients with a T-tube inserted in the common bile duct at choledocholithotomy 7–10 days prior to the study. Bile was collected in fractions by continuous suction over a 24 h period. Blood samples were taken and urine collected up to 48 h after the dose. Tolfenamic acid and its metabolites were separated by TLC and were quantitated by liquid scintillation counting. The pharmacokinetics of tolfenamic acid could be described by a two compartment open model with V1 of 3.67±0.68 l and Vss of 8.0±1.0 l. The total plasma clearance of tolfenamic acid averaged 106±8 ml/min and t1/2β was 1.38±0.32 h. A three compartment open model was required to describe the kinetics of total 14C. The plasma clearance of total 14C was 15.4±3.9 ml/min and its terminal half life averaged 19.0±4.1 h. The long half-life was caused by the slow elimination of tolfenamic acid metabolites. Four metabolites were measured in plasma and bile. The principal metabolites in bile were glucuronide/sulphate conjugates of hydroxylated derivatives of tolfenamic acid. The recovery of tolfenamic acid in bile was 1.1±0.3% of the dose, whereas the recovery of total 14C was 18.6±4.9%. The biliary clearances of tolfenamic acid and total 14C were 1.2±0.3 and 5.0±2.1 ml/min, respectively. Thus, biliary excretion plays a considerable part in the pharmacokinetics of tolfenamic acid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542174
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    A “once a day administration” sustained-release theophylline formulation: Disposition and pharmacokinetics (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 325-328 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; sustained release ; pharmacokinetics ; chronic administration ; healthy volunteers ; plasma levels ; GCMS assay ; stable isotope technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new sustained-release preparation of theophylline (Dilatrane à Action Prolongée capsules filled with homogenous microgranules) has been after its studied administration to 7 healthy volunteers at 8 p.m. in order to achieve therapeutic levels at night and in the morning. In separate trials the test dose of 500 or 600 mg was administered for 7 days, once daily at 8 p.m. Plasma theophylline levels were measured by capillary gas chromatography with a mass specific detector after pentylation, using internal standards labelled with stable isotopes (15N-1,3 and 13C-2 theophylline). The new sustained-release preparation showed a monophasic regular absorption phase with very low interindividual variability. After administration, the plasma level stayed within 80% of the peak levels for 8.5±1.5 h. There was a good correlation between the dose and the steady state plasma level (r=0.9587; p〈0.05). This preparation can be chronically administered once daily day at 8 p.m. in order to achieve a therapeutic level during the night and the morning, and to provide sufficient protection during the nycterohemeral period, with a once dose a day schedule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542169
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    Absorption of enprofylline from the gastrointestinal tract in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 329-333 
    Details
    ISSN: 1432-1041
    Keywords: enprofylline ; healthy subjects ; absorption ; pharmacokinetics ; oral- ; duodenal- ; colonic administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1–4 mg/l, i.e. in the assumed “therapeutic interval” according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean±SEM) were 32.5±8.7, 13.3±2.5, and 157±23 min.
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    URL: http://dx.doi.org/10.1007/BF00542170
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    Pharmacokinetics of the oral narcotic analgesic bezitramide and preliminary observations on its effect on experimentally induced pain (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 615-618 
    Details
    ISSN: 1432-1041
    Keywords: Bezitramide ; oral absorption profile ; pharmacokinetics ; male volunteers ; experimental pain ; biliary excretion in rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oral absorption of bezitramide 5 mg was studied in 7 human volunteers, using a specific radioimmuno-assay which measured both bezitramide and its active metabolite R-4618. A lag time of 0.5–1.0 h and a Cmax of 5.4 ng/ml plasma were found, the latter occurring 2.5–3.5 h after administration. The apparent elimination half-life varied from 11 to 24 h. Less than 0.3% of the dose was excreted unchanged in the urine. High concentrations in the faeces of some individuals indicate incomplete absorption and/or biliary secretion. The analgesic effect, using a standardized superficial electrical stimulation method, reached its maximum between 2.5 and 3.5 h after dosing, in accordance with the absorption phase. The duration of the effect was highly variable. Experiments in rats (n=6,3H-bezitramide 2.5 µg), demonstrated extensive biliary excretion (up to 70% of total radioactivity) and less than 3% of the label was removed by urinary excretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556902
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    Pharmacokinetics of meptazinol after single and multiple oral administration to elderly patients (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 223-226 
    Details
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; multiple dosing ; elderly patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Oral administration of meptazinol (200 mg Meptid®) to male and female geriatric patients (〉70 years) resulted in rapid absorption, with peak drug concentrations at 0.5 to 3 h after dosage. Subsequent elimination also proceeded rapidly with a half-life of 3.39 h (±0.26 SEM) after a single dose and 4.97 h (±0.80 SEM) after 13 consecutive 6-h doses. These values were not statistically different. There was no accumulation of meptazinol above that expected from the single-dose kinetics. Plasma protein binding of meptazinol was 33.8% (±0.74 SEM). No sex difference was apparent in any of the pharmacokinetic parameters determined. Comparison of these results with those obtained in an earlier study in young volunteers showed that although the half-life of meptazinol was somewhat longer than the value of 2 h seen in the young, peak plasma concentrations after single and multiple dosing were similar for both age groups, implying that clearance remained largely unaltered. It was concluded that there was no pharmacokinetic basis for recommending a reduction in dosage when treating elderly patients with oral meptazinol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544049
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  • 70
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    Lack of effect of haemodialysis on mebendazole kinetics: Studies in a patient with echinococcosis and renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 243-245 
    Details
    ISSN: 1432-1041
    Keywords: mebendazole ; haemodialysis ; echinococcosis ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of haemodialysis on mebendazole kinetics has been studied in a patient receiving both mebendazole therapy and haemodialysis. The procedure of haemodialysis did not influence the plasma concentration — time profiles or the mean daily plasma levels. The arterio-venous difference in the dialyser was negligible and no mebendazole could be detected in the dialysate. Protein binding of mebendazole was 90% before dialysis and 88% during dialysis and not significantly different from the binding in patients without renal disease (91.4±1.9%, n=22).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544053
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  • 71
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    Identification of a prazosin metabolite and some preliminary data on its kinetics in hypertensive patients (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 275-280 
    Details
    ISSN: 1432-1041
    Keywords: prazosin ; hypertensive patients ; prazosin metabolite ; HPLC assay ; pharmacokinetics ; hypotensive effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A metabolite of prazosin was detected in serum from hypertensive patients treated with prazosin. Its structure as 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline was established by UV, IR, and mass-spectrometry. An assay method for simultaneous determination of prazosin and its metabolite in serum, urine and saliva is described. Preliminary data about the kinetics of prazosin and the metabolite after a single oral dose of prazosin 1 mg, and after multiple doses of 1 to 5 mg t.i.d. for 6–82 days in 7 patients with hypertension, are presented. After the single dose the metabolite level was much lower than that of intact drug, even though the former was eliminated much more slowly than the latter. The slow elimination of the metabolite led to its eventual accumulation in serum during multiple administration. The mean accumulation ratio of the metabolite was estimated to be at least 5.5 (from 3.0 to 7.9). Prazosin itself had a low accumulation ratio, so the mean steady-state level of the intact drug on multiple administration was several times lower than that of metabolite. As this metabolite has some hypotensive effect in animals, it may account for part of the therapeutic activity of parzosin in patients. The mean steady-state concentration of intact prazosin during the course of treatment were found to be significantly lower than that predicted from a single dose study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542159
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  • 72
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    Single and multiple dose kinetics of clobazam, and clinical effects during multiple dosage (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 499-503 
    Details
    ISSN: 1432-1041
    Keywords: benzodiazepines ; clobazam ; desmethylclobazam ; pharmacokinetics ; sedation ; accumulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sixteen healthy volunteers, aged 19 to 62 years, took a single 20-mg oral dose of clobazam and the serum concentrations of clobazam and desmethylclobazam were measured for the following 7 days. The mean kinetic variables for clobazam were: volume of distribution 1.31/kg, elimination half-life 24 h, total clearance 0.47 ml/min/kg. 13 of the volunteers then took clobazam 5 mg twice daily for 22 consecutive days. Serum concentrations were measured during and after this period. Both clobazam and desmethylclobazam showed slow and extensive accumulation, their steady-state kinetics being entirely consistent with those observed after single doses. Elimination of both compounds after termination of treatment was equally slow. Clinical self-rating of morning sedation indicated a significant increase over baseline in subjective perception of sedation during the treatment period, and this effect persisted into the washout period. However, sedation did not increase in parallel with accumulating levels of clobazam and desmethylclobazam, probably due to functional adaptation or tolerance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542148
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  • 73
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    Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 505-511 
    Details
    ISSN: 1432-1041
    Keywords: prednisolone ; prednisone ; oral contraceptives ; 6β-hydroxylase ; transcortin ; protein-binding ; steroid metabolism ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n=10) had higher mean (±SD) area under the plasma concentration versus time curves of total (428±67 µg/ml/min vs 188±28 µg/ml/min, p〈0.001) and unbound prednisolone (64±10 µg/ml/min vs 41±10 µg/ml/min, p〈0.001) than women not taking oral contraceptive steroids (n=10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p〈0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.
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    URL: http://dx.doi.org/10.1007/BF00542149
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  • 74
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    D-propoxyphene kinetics in man: Significance of a deep third compartment (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 749-752 
    Details
    ISSN: 1432-1041
    Keywords: dextropropoxyphene ; pharmacokinetics ; half-life ; 3-compartment model ; steady state prediction ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Data from a previously published single dose study of d-propoxyphene 65 mg given i.v. to 8 healthy subjects have been subjected to non linear regression analysis by a curve-fitting program to test the applicability of a 2- and a 3-compartment open model. Analysis of residuals (difference between observed and computed concentrations) revealed similar systematic deviations in all 8 subjects when the 2-compartment model was used (5–10 h negative residuals, after 13 h positive residuals). In contrast, curve-fit by a 3-compartment model (with two parallel peripheral compartments) was good with no systematic deviations. The data show that a terminal monoexponential decline in d-propoxyphene concentrations cannot be expected until 15–30 h after single dose administration, and that the determination of the corresponding half-life is rather inaccurate. Accordingly, precise steady state level predictions may be difficult to obtain from conventional single dose studies with d-propoxyphene.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541937
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  • 75
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    Electronic Resource
    Bioavailability and pharmacokinetics of phenytoin during pregnancy (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 105-110 
    Details
    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553163
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  • 76
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    Pharmacokinetics of mepindolol in patients with chronic renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 429-433 
    Details
    ISSN: 1432-1041
    Keywords: mepindolol ; renal failure ; haemodialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with a creatinine clearance of 14 to 37 ml/min/1.73 m2 were each given an oral dose of 10 mg of the beta-blocker mepindolol sulphate (Corindolan). In addition, two dialysis patients received the same dose either during hemodialysis or on a dialysis-free day. Plasma levels of mepindolol were measured by a sensitive, specific HPLC method. Mepindolol was rapidly absorbed in all the patients. The maximum plasma level of 35±8 ng/ml was reached after 1.4±0.5 h. The half-life of disposition was 4.0±1.5 h. The area under the plasma concentration-time curve was 237±84 ng × h/ml. The data obtained were no different from those found in normal healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549590
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  • 77
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    Tolerance and pharmacokinetics of A515U, an acyclovir analogue, in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 471-475 
    Details
    ISSN: 1432-1041
    Keywords: acyclovir ; A515U ; 6-deoxyacyclovir ; pharmacokinetics ; prodrug ; antiviral chemotherapy ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A515U (6-deoxyacyclovir) is an analogue of acyclovir devoid of antiviral activity in vitro but which is well absorbed and undergoes conversion to acyclovir after oral administration to rats. The tolerance and pharmacokinetics of various doses of A515U have been studied in 8 healthy volunteers. Single oral doses of 25, 50, 100, 200 and 400 mg A515U and 400 mg acyclovir for comparison were administered to the volunteers at weekly intervals. Concentrations of the parent drug and acyclovir were determined in plasma and urine. The prodrug was well tolerated and did not cause adverse reactions or changes in haematological or biochemical variables. It was well absorbed and conversion to acyclovir was rapid and extensive at all doses. Plasma concentrations of acyclovir achieved with 50 mg A515U orally were comparable to and less variable than those produced by 400 mg acyclovir. A515U was rapidly cleared with a short plasma elimination half life of approximately 0.5 h. The attainment of high plasma concentrations of acyclovir by oral administration of a prodrug may represent an important advance in antiviral chemotherapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549597
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  • 78
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    Electronic Resource
    Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 577-581 
    Details
    ISSN: 1432-1041
    Keywords: HOE 498 ; ACE inhibitor ; pharmacokinetics ; pharmacodynamics ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme inhibitor HOE 498 were investigated in 10 healthy normotensive male subjects. Serum levels of the active metabolite M 1 (dicarboxylic acid) of HOE 498 were measured by HPLC up to 14 days after a single oral dose of 10 m g HOE 498. Peak serum concentration of M 1 between 5–50 ng/ml was observed 1.5–3.0 h after administration. The serum concentration-time curve of M 1 was polyphasic and exhibited a prolonged terminal phase with a half-life of approximately 110 h. Despite the long terminal half-life M 1 could not be detected in urine later than 72 h after administration. The activity of the angiotensin converting enzyme in plasma was completely suppressed for up to 12 h, and 72 h after dosing 50% inhibition of the enzyme was still observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556895
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  • 79
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    Electronic Resource
    Relationship between the cardiovascular effects and steady-state kinetics of clonidine in hypertension (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 309-313 
    Details
    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; therapeutic window ; steady state concentration ; pharmacokinetics ; cardiovascular effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonidine was given orally as monotherapy in increasing daily doses from 3.1 to 25.7 µg/kg to patients with essential hypertension (n=6). When a steady state concentration in plasma was reached at each dose level, the blood pressure (BP) and heart rate were measured during a dosage interval. Effect time — plasma concentration data were submitted to nonlinear regression analysis, which showed that the observed BP effects could be dissociated into depressor and pressor components. A window for the antihypertensive effect was established. At a plasma clonidine concentration of 0.65±0.07 ng/ml 50% of the maximal depressor effect was found, and it was only separated by a factor of 2 from the half maximal pure pressor concentration in plasma. No relationship between the change in heart rate and the plasma clonidine was observed. The findings strengthen the importance of close monitoring of clonidine therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548760
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  • 80
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    Electronic Resource
    Pharmacokinetics and pharmacodynamics of transdermally administered clonidine (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 79-85 
    Details
    ISSN: 1432-1041
    Keywords: clonidine ; transdermal application ; pharmacodynamic effect ; pharmacokinetics ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonidine was applied to the skin of healthy volunteers once weekly by means of a Transdermal Therapeutic System (TTS). The plasma concentration and renal excretion of clonidine, and its effects on mean arterial blood pressure (MAP) and heart rate (HR) were recorded for 7 days, followed by a three-day observation period when a second TTS was applied. Subjective side effects were semiquantitatively recorded. Four differents TTS formulations were tested; of which TTS-RP 600679 was the most effective. Following application of this formulation, the plasma level of the drug built-up up during the first 2 days and then remained stable for 120 h at therapeutic concentrations between 0.5 and 0.7 ng/ml; MAP was consistently reduced. During the steady state period the daily urinary clonidine excretion was in the same range as during chronic administration of Catapres tablets 0.15 mg every 12 h, or Catapres Perlongets 0.25 mg every 24 h. Transdermal clonidine applications renewed weekly provide the following therapeutic advantages: 1. patients are protected continuously throughout the entire steady state period; 2. daily fluctuations in plasma clonidine concentration are minimized, which may result in a marked reduction in side effects; and, 3. drug compliance should be improved.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546713
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  • 81
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    Electronic Resource
    Correlation between the pharmacokinetics and pharmacodynamics of dopamine in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 163-169 
    Details
    ISSN: 1432-1041
    Keywords: dopamine ; pharmacokinetics ; pharmacodynamics ; adrenaline plasma level ; noradrenaline plasma level ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and the pharmacodynamic action of dopamine were investigated in 5 healthy subjects. Dopamine was given in different doses (200, 400 and 800 µg/min) by constant intravenous infusion over 90 min. In order to control the influence of the procedure on the measured parameters the subjects also received a similar infusion of saline. Dopamine, noradrenaline and adrenaline levels in plasma were followed for up to 6 h after the infusion, and arterial pressure and heart rate were monitored. Dopamine reached a steady state level within 15 to 30 min after commencement of the infusion; the steady state levels averaged 36.5 µg/l at 200 µg/min, 73.8 µg/l at 400 µg/min and 207 µg/l at 800 µg/min. The corresponding total clearances were 5.8 l/ min, 5.51/min and 3.9 l/min suggesting non-linear kinetics. The kinetics could not be described by compartmental model. Noradrenaline and adrenaline levels were found to be elevated during infusion of dopamine. Noradrenaline had returned to its pretreatment level within 15 to 30 min after cessation of the infusion, whereas the adrenaline level did not return to the pretreatment value within the observation period. Heart rate was increased by the dose of 400 µg/min, and the systolic and mean arterial pressures were elevated, whereas distolic blood pressure remained unchanged. Elevated systolic blood pressure was better correlated with plasma dopamine than with noradrenaline concentration. This finding, in conjunction with the unchanged diastolic blood pressure, indicates that elevation of the systolic blood pressure is a direct rather than an indirect effect of dopamine. The increased heart rate was not correlated with the dopamine level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630281
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  • 82
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    Electronic Resource
    Pharmacokinetic and pharmacodynamic study of the combination of furosemide retard and triamterene (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 191-195 
    Details
    ISSN: 1432-1041
    Keywords: furosemide ; triamterene ; drug combination ; pharmacodynamics ; pharmacokinetics ; furosemide retard ; triamterene metabolite ; urine potassium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamics and pharmacokinetics of the combination of furosemide retard (30 mg)/triamterene (50 mg) were compared with furosemide (30 mg) in 18 healthy male volunteers aged 39.3±6.3 years. After the administration of furosemide the onset of its effect was very rapid, reaching a maximum between 1.5 to 3 h, and followed by rebound after 9 to 10.5 h. In contrast the combination furosemide retard/triamterene showed a protracted course with a duration of effect up to 12 h. The general effect over 12 h of the two preparations was equivalent with respect to the excretion of urine, sodium, chloride and calcium, but the combination caused significantly less excretion of potassium (p≤0.05) than furosemide. After a lag-phase of 33.9±5.4 min the maximum plasma concentration of furosemide was reached after 3.47±0.66 h, and the elimination half-life was approximately 2 h. After a lag-phase of 33.0±17.8 min the maximum plasma concentration of the main metabolite of triamterene, the OH-TA sulphuric acid ester, was reached after 1.7±0.59 h, and its elimination half-life amounted to 1.25±0.37 h. Because of the sustained release of furosemide from the retard-formulation, its principal pharmacokinetic parameters were better adapted to those of triamterene. The consequences were not only a protracted effect but also an improved electrolyte profile, especially with regard to reduced loss of potassium. In the case of renal insufficiency, however, the potassium level in serum might be increased to an undesirable extent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630285
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  • 83
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    Electronic Resource
    Intravenous and oral administration of molsidomine, a pharmacodynamic and pharmacokinetic study (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 203-208 
    Details
    ISSN: 1432-1041
    Keywords: molsidomine ; vasodilators ; pharmacokinetics ; pharmacodynamics ; dose-response relationship ; haemodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 12 healthy male volunteers, molsidomine 1, 2 and 4 mg i.v. increased resting heart rate and decreased systolic blood pressure, the latter still being affected after 8 hours. After single oral doses of 1 and 2 mg, systolic pressure tended to be reduced for 90 minutes and exercise heart rate tended to be increased. After oral treatment with 2 mg molsidomine three times daily for 1 week, the pharmacokinetic parameters and the effects on heart rate and blood pressure after the final dose were not different from those after the first dose. The terminal half-life was independent of dose and route of administration. Clearance and distribution volume were not dose-dependent. The bioavailability of a 2 mg oral dose of molsidomine was 44%. Inter-individual variation in heart rate, blood pressure and pharmacokinetics was observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544046
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  • 84
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    Electronic Resource
    Pharmacokinetics of metoprolol in healthy, elderly, non-smoking individuals after a single dose and two weeks of treatment (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 217-222 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; pharmacokinetics ; age effect ; repeated doses ; pre-systemic elimination ; total body clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of long-term treatment on the absorption and dispsoition of metoprolol has been evaluated in 8 healthy, non-smoking, elderly individuals (mean age 74.5 years) and in a control group of 8 healthy, young individuals. Two trace doses of [3H]metoprolol were given i.v., first concomitantly with a single oral 50 mg dose of cold metoprolol, and second, with the morning dose after 2 weeks of treatment with 50 mg b.d. In the elderly, the mean AUC increased by about 45% (p〈0.05) over the treatment period, while in the control group the mean AUC was 18% greater (p〈0.05) on Day 14 than on Day 1. In the elderly, changes both in pre-systemic elimination and in total body clearance accounted for the elevation of the AUC, whereas reduced first-pass effect appeared to be the major cause of the increased steady-state plasma level in the control group. With the exception of the volume term, V β , the pharmacokinetic parameters were not significantly different between the elderly and the young individuals. For this reason, almost identical steady-state plasma levels were attained in the two groups. The results suggest that age-related physiological changes may have some minor effects on the pharmacokinetics of metoprolol, and also that the changes do not lead to significantly altered plasma concentrations compared to those in young individuals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544048
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  • 85
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    Electronic Resource
    Pharmacokinetics of enprofylline in patients with impaired renal function after a single intravenous dose (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 87-93 
    Details
    ISSN: 1432-1041
    Keywords: enprofylline ; pharmacokinetics ; renal elimination ; renal insufficiency ; healthy subjects ; creatinine clearance ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Enprofylline, a new bronchodilating drug, was given i.v. at 1.0 mg/kg to 7 healthy subjects and to 14 patients with differing degrees of chronic renal insufficiency. Plasma and urine concentrations of unchanged drug were followed by HPLC. In the patients the plasma half-life was prolonged and the total and renal clearances were reduced in direct proportion to the degree of renal insufficiency as determined by creatinine clearance. The unbound fraction of enprofylline in plasma increased from 55% in the healthy subjects to 66% in the group of patients with the highest degree of renal impairment. The volume of distribution terms, Vβ and Vss, both tended to decrease with decreasing creatinine clearance. When the volume term calculations were based on the unbound drug level in plasma, this tendency was enhanced. Side-effects were noted in 4 subjects, and to some extent were related to the plasma level of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546714
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  • 86
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    Electronic Resource
    Assessment of drug metabolism in hepatic disease: Comparison of plasma kinetics of oral cyclobarbital and the intravenous aminopyrine breath test (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 95-101 
    Details
    ISSN: 1432-1041
    Keywords: cyclobarbital ; aminopyrine ; liver disease ; 14CO2 breath test ; barbiturate ; pharmacokinetics ; hepatic drug metabolism ; cirrhosis ; alcoholic liver disease ; viral hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The exhalation of 14CO2 derived from an i.v. tracer dose of [dimethylamine-14C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled 14CO2 occurred 0.5–2 h after 14C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of 14CO2 exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546715
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  • 87
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    Electronic Resource
    Pharmacokinetics of estramustine phosphate (Estracyt®) in prostatic cancer patients (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 113-119 
    Details
    ISSN: 1432-1041
    Keywords: estramustine phosphate ; prostatic cancer ; pharmacokinetics ; metabolism ; estramustine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of estramustine phosphate (EMP) was studied in five prostatic cancer patients given single i.v. and oral doses of EMP in a cross-over study. Plasma and urinary concentrations of parent drug, estramustine, estromustine (the estrone analogue), estradiol and estrone were followed for 32 h. The elimination of intravenous EMP from plasma was biphasic. The mean volumes of distribution were small, being 43 and 108 ml/kg for the central and peripheral compartments, respectively. The plasma clearance was 64 ml/kg/h, and the half-lives of the two phases were 0.16 and 1.27 h. Metabolism was the major route of elimination of EMP. It was readily dephosphorylated and oxidized to yield the cytotoxic metabolites estramustine and estromustine. Estromustine was the main metabolite in plasma. When given orally EMP underwent extensive presystemic dephosphorylation, which started in the gastrointestinal tract. The relative bioavailability of estromustine after administration of EMP-capsules was 44%, which reflects incomplete absorption of EMP rather than first-pass metabolism of estromustine. The terminal half-life of estromustine was 10–20 h, which suggests that EMP might be given once or twice a day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546718
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  • 88
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    Electronic Resource
    Pharmacokinetics of nadolol in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 125-127 
    Details
    ISSN: 1432-1041
    Keywords: nadolol ; pharmacokinetics ; plasma levels ; urinary excretion ; bioavailability ; circadian rhythm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 7 healthy subjects (3 males and 4 females), the kinetics of nadolol was investigated after oral doses of 60 and 120 mg. The t1/2 was 14.0±1.8 h. The peak plasma level was doubled on doubling the dose (from 69±15 to 132±27 ng/ml, respectively) and the urinary excretion (13.5%) rose similarly. The half-life of elimination was longer at night than in the day, probably because of the slower nocturnal flow of urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546720
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  • 89
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    Electronic Resource
    Dose-dependent pharmacokinetics of aprindine in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 129-131 
    Details
    ISSN: 1432-1041
    Keywords: aprindine ; antiarrhythmic agent ; healthy volunteers ; plasma level ; oral administration ; pharmacokinetics ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t1/2β) increased from 8.0±2.1 h (SD) after a 25 mg dose to 9.4±2.9 h after 50 mg and to 15.8±2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (Vdss/F) and during β-phase (Vdβ/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (Cmax) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t1/2β after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546721
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  • 90
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of a fixed combination of sotalol and hydrochlorothiazide in hypertensive patients with moderate renal insufficiency (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 361-362 
    Details
    ISSN: 1432-1041
    Keywords: sotalol ; hydrochlorothiazide ; pharmacokinetics ; moderate renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542176
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  • 91
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    Electronic Resource
    Pharmacokinetics of epidural morphine in man (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 233-237 
    Details
    ISSN: 1432-1041
    Keywords: morphine ; anesthesiology ; epidural application ; pharmacokinetics ; plasma level ; CSF level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cerebrospinal fluid (CSF) and plasma morphine concentrations were determined in 5 patients after epidural administration of 6 mg morphine; plasma samples were collected frequently during the initial 6 h and 6–7 CSF samples were obtained from each patient over a 24 h period. Morphine was analysed using gas chromatography and electron capture detection. Individual morphine concentration-time curves were plotted for plasma and CSF and various pharmacokinetic variables were calculated. Plasma morphine concentrations after epidural injection were similar to those found after intramuscular administration; Cmax (66±8 mg/ml: mean±SEM) appeared within 12±3 min, and the terminal elimination half-life in plasma was 213±24 min. In CSF, morphine reached a peak (1575±359 ng/ml) after 135±40 min. The terminal elimination half-life for morphine in CSF was 239±10 min. The CSF bioavailability of morphine after epidural administration was calculated to be 1.9±0.5%. The study showed that epidural administration of morphine resulted in CSF concentrations many times higher than those in plasma, but still only 2% of the dose administered was available to the CSF compartment. Morphine was eliminated with similar speed from CSF and plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630291
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  • 92
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    Electronic Resource
    Bioequivalence studies in humans of indomethacin capsules marketed in India (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 261-264 
    Details
    ISSN: 1432-1041
    Keywords: indomethacin capsules ; bioequivalence ; volunteers ; pharmacokinetics ; statistical significance ; bioavailability ; comparative bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two, separate 6×6 Latin square cross-over bioequivalence studies were performed in adult male volunteers using 10 different indomethacin capsule preparations marketed in India together with the pure drug powder as the standard. The products were evaluated with respect to plasma level at various times up to 8 h following administration of a 50 mg (2 × 25 mg) dose. Plasma samples were analysed by a fluorimetric method. Various pharmacokinetic parameters were calculated according to a two compartment model. Statistical evaluation of the data employed analysis of variance for a cross-over design (ANOVA) and Duncan's multiple range test to ascertain the significance of differences between the products. Of the 10 products studied, two were found to be bioinequivalent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630296
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  • 93
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    Electronic Resource
    Bioavailability of cyclophosphamide from oral formulations (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 269-270 
    Details
    ISSN: 1432-1041
    Keywords: cyclophosphamide ; cytostatic drug ; cancer therapy ; female breast cancer ; bioavailability ; rapid release formulations ; gastric juice resistant formulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Cyclophosphamide (CP) is an alkylating cytostatic compound, which is activated to its cytotoxic form in the liver [1]. Since the therapeutic range of CP in the treatment of human tumours, is small like other cytostatics, a constant high bioavailability is essential for its oral administration. Although CP has become one of the most widely used cytostatics [2], there do not appear to have been any bioavailability investigations providing the necessary information. The development of a very sensitive gas chromatographic analytical method has now permited investigation of the pharmacokinetics of oral CP in conventional clinical doses [3, 4, 5, 6].
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630298
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  • 94
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    Electronic Resource
    Effect of aluminium phosphate on the bioavailability of cimetidine and prednisolone (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 271-273 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; prednisolone ; aluminium phosphate ; antacids ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten fasting subjects received 200 mg cimetidine orally either with water or 11 g aluminium phosphate mixture in a randomized, single dose, two-way cross-over study. Blood samples were taken for 12 h and urine was collected for 24 h. Cimetidine in plasma and urine was analysed by HPLC. There were no significant differences between the treatments with respect to peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, and urinary excretion. In 12 healthy subjects the absorption of prednisolone was investigated when given alone and together with 11 g aluminium phosphate. Blood samples were taken over 16 h and prednisolone in plasma was analysed by HPLC. There were no significant differences in the values of area under curve (AUC), Cmax and tmax. The results indicate that aluminium phosphate does not reduce the bioavailability of cimetidine and prednisolone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630299
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  • 95
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    Electronic Resource
    Comparative pharmacokinetics of sulphasalazine and sulphapyridine after rectal and oral administration to patients with ulcerative colitis (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 275-277 
    Details
    ISSN: 1432-1041
    Keywords: sulphapyridine ; sulphasalazine ; pharmacokinetics ; rectal administration ; oral administration ; plasma levels ; ulcerative colitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Rectal administration of sulphasalazine to patients with ulcerative colitis has recently been shown to have similar therapeutic activity but fewer side effects than oral treatment. The present study is a comparison of the pharmacokinetics of sulphasalazine (SASP) and its metabolite sulphapyridine (SP) after rectal and oral administration of SASP to 6 patients with ulcerative colitis. The areas under the concentration-time curves (AUC) and the maximum concentrations (Cmax) of SASP and SP were significantly lower after rectal than oral administration of SASP (p〈0.05). These findings support the view that the lower frequency of side effects after rectal administration of SASP may result from the lower plasma levels of SASP and SP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630300
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  • 96
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 501-503 
    Details
    ISSN: 1432-1041
    Keywords: valpromide ; valproic acid ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79±0.24 and 0.77±0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, non-hygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549603
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  • 97
    Electronic Resource
    Electronic Resource
    Biperiden effects and plasma levels in volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 619-621 
    Details
    ISSN: 1432-1041
    Keywords: biperiden ; pharmacokinetics ; pharmacodynamics ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of biperiden was studied and compared with pharmacodynamics (pupil size, accomodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 h, biperiden was rapidly absorbed with a half-life of 0.3 h, plasma peak levels of 5 ng/ml being reached after 1.5 h. Biperiden showed good tissue penetration (distribution half-life 0.6 h; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 h, and the oral clearance was 146 l/h. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 h (accommodation).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556903
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  • 98
    Electronic Resource
    Electronic Resource
    Mammosomatotroph hyperplasia associated with acromegaly and hyperprolactinemia in a patient with the McCune-Albright syndrome (1984)
    Springer
    Virchows Archiv 403 (1984), S. 77-86 
    Details
    ISSN: 1432-2307
    Keywords: Acromegaly ; hyperprolactinemia ; McCune-Albright syndrome ; pathology ; Pituitary ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An 11-year-old girl, with the McCune-Albright syndrome, exhibited fibrous dysplasia of several bones, skin pigmentation, precocious puberty, growth hormone hypersecretion, acromegaly and hyperprolactinemia. Histologic, immunocytologic and ultrastructural investigation of the surgically-removed pituitary showed massive mammosomatotroph hyperplasia. Since no adenoma was found, the abundance of these bihormonal cells, capable of producing both growth hormone and prolactin, was implicated in the causation of growth hormone and prolactin excess. Somatoliberin overproduction and/or somatostatin and dopamine deficiency could not account for the hypophysial abnormality, since changes in secretory rates of these hypothalamic hormones would lead to proliferation of mature somatotrophs and lactotrophs, rather than mammosomatotrophs. In our patient, a congenital hypothalamic malfunction might have been accompanied by hypersecretion of an unidentified releasing factor, resulting in pathologic differentiation of the pituitary and mammosomatotroph hyperplasia. Alternatively, mammosomatotroph hyperplasia may have been due to an inherent genetic or embryonic defect affecting primarily the pituitary. According to this interpretation, the pituitary lesion represented yet another developmental error in the setting of the McCune-Albright syndrome.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689340
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  • 99
    Electronic Resource
    Electronic Resource
    Herpes oesophagitis (1984)
    Springer
    Virchows Archiv 404 (1984), S. 177-185 
    Details
    ISSN: 1432-2307
    Keywords: Oesophagitis ; Herpetic cell change ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultra-thin sections obtained from routine biopsy specimens and cytological smears of 3 cases, together with one autopsy case suggestive of herpes oesophagitis, clearly demonstrate herpes viruses. The infected epithelial cells reveal different stages of virus replication and propagation. Cowdry A type inclusion bodies, however, representing early alterations in the course of infection are less frequent. Ground-glass looking nuclei of light microscopical balloon cells and infected multinuclear giant cells of epithelial origin are characteristic changes of the late ulcerative stage of herpes oesophagitis usually seen at the time of detection. These typical virus induced cell changes are mostly to be found at the ulcers edge.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00704062
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  • 100
    Electronic Resource
    Electronic Resource
    Ameloblastic fibrosarcoma in the maxilla, malignant transformation of ameloblastic fibroma (1984)
    Springer
    Virchows Archiv 404 (1984), S. 253-263 
    Details
    ISSN: 1432-2307
    Keywords: Ameloblastic fibrosarcoma ; Histogenesis ; Histopathology ; Ultrastructure ; Fatal case
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This report presents a fatal case of ameloblastic fibrosarcoma arising from an ameloblastic fibroma, originating in the maxilla of 19-year-old Japanese male. An analysis of previously reported fatal cases of ameloblastic fibrosarcoma is included. In the course of the disease, the mesenchymal component of ameloblastic fibroma showed a dramatic histopathological transformation into sarcoma following multiple recurrence and the patient died of uncontrollable local infiltration of the cranial base. Although many cases have seemed to show disappearance of the epithelial component as malignant transformation progressed, many benign appearing ameloblastoid epithelial masses were scattered throughout the sarcomatous area even in the fatal stage in the present case. No distant metastases were found at autopsy. During multiple recurrences of the lesion, a little dysplastic dentin which was closely associated with both epithelial and mesenchymal components was found, though it could not be observed in autopsy material. Ultrastructural findings in autopsy material showed that the mesenchymal component consisted of undifferentiated mesenchymal cells, fibroblastic and fibrocytic cells with marked cellular and nuclear pleomorphism and that the epithelial component closely resembled the enamel organ.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00694891
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