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  • 1985-1989  (207)
  • 1965-1969
  • 1985  (207)
  • Ultrastructure  (112)
  • pharmacokinetics  (95)
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 406 (1985), S. 271-277 
    ISSN: 1432-2307
    Keywords: Cimetidine ; Duodenal ulcer ; Gastrin producing cells ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultrastructural examination of the antral G cells has been carried out on 11 patients with chronic duodenal ulcer, before and after treatment with a histamine H-2 - receptor antagonist (cimetidine 1 g/ day) for 8 weeks. The study demonstrated an increased area of the Golgi complex, rough endoplasmic reticulum and electron-dense granules, indicating increased G cell activity during treatment. An increased number of lysosomes was a constant feature during treatment. As an hypothesis we suggest that these lysosomes may participate in the secretory mechanism of human G cells, by destroying superfluous (Gastrin) components produced during hyperactivity.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 406 (1985), S. 351-365 
    ISSN: 1432-2307
    Keywords: Neuroepithelioma ; Histology ; Immunohistochemistry ; Neuron-specific enolase ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Seventeen cases of malignant peripheral neuroectodermal tumour (MPNT) were studied by means of light microscopy, immunohistochemistry and electron microscopy. There were nine males and eight females. The mean age of the 17 patients was 10 years with a range of seven months to 20 years. The vast majority of tumours was located in the trunk. Histologically, they closely resembled Ewing's sarcoma, although minor differences were obvious. Special findings included ganglion cells and Flexner rosettes. In 10/11 cases positive staining for neuron-specific enolase (NSE) was obtained. Five of 10 tumours were positive for protein S-100. Three contained vimentin, two neurofilaments and one vimentin, neurofilaments and GFAP. Neurosecretory granules were noted in the three cases studied. Five patients died, three are alive with disease and five patients are alive without evidence of disease. It is concluded that these tumours form a homogeneous group, although the grade of differentiation varies. The prognosis in most cases is poor. Distinction from Ewing's sarcoma is possible by staining for NSE and by electron microscopy.
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  • 3
    ISSN: 1432-2307
    Keywords: Glycogen-rich adenoma ; Salivary gland ; Epithelial cell ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A glycogen-rich adenoma occurring in the minor salivary gland of the nasopharynx in a 41-year-old woman was studied ultrastrucrurally. The cytoplasm of the tumour cells was abundantly filled with glycogen particles. The tumour cells possessed many mitochondria, a great number of microvillous processes and microvilli and were joined to each other by desmosomes. These findings suggest that this adenoma is of salivary duct epithelial origin most probably from storing striated ductal cells, and is a variant of monomorphic oxyphilic adenoma.
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  • 4
    ISSN: 1432-2307
    Keywords: Herpes simplex lymphadenitis ; Viral particles ; Ultrastructure ; Immunolabelling ; Histopathology ; Intra cellular viral antigen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A patient treated for Hodgkin's disease and presenting 12 years later with a left inguinal lymphadenopathy mimicking a relapse is reported. Histopathological study disclosed large histiocytic granulomas in the sinuses. Some of these granulomas showed necrotic areas with numerous neutrophils. At the edge of the necrotic zones, cells of undetermined origin exhibited intra-nuclear inclusions typical of Herpes simplex virus. The diagnosis was confirmed by immunolabelling, revealing Herpes simplex viral antigens in frozen and paraffin sections, and by ultrastructural studies. The diagnostic value of the histological methodology and pathological changes and the significance of the disease, appearing in a patient treated for Hodgkin's disease are discussed.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    International orthopaedics 9 (1985), S. 41-47 
    ISSN: 1432-5195
    Keywords: De Quervain ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Les gaines tendineuses du court extenseur et du long abducteur du pouce ont été étudiées du point de vue histologique et ultrastructural chez quatre patients atteints de maladie de de Quervain. Dans les gaines tendineuses, beaucoup plus épaisses que normalement, ont été identifiées trois couches différentes. La couche externe et la couche intermédiaire sont formées d'épais faisceaux de fibres collagènes qui contiennent peu de fibroblastes. La couche interne est formée principalement d'un tissu myxoïde et chondroïde; les fibrilles collagènes sont plus épaisses que la normale, atteignant le diamètre de 2100 nanomètres. De nombreuses cellules semblables à des «myofibroblastes» sont présentes dans toutes les couches de la gaine. Nos résultats semblent indiquer que l'augmentation d'épaisseur et de consistance de la gaine tendineuse du court extenseur et du long abducteur du pouce dans la maladie de de Quervain, est causée par l'augmentation de la synthèse de la matrice extra-cellulaire, par l'augmentation d'épaisseur des fibrilles collagènes et par des aires de métaplasie myxoïde et chondroïde.
    Notes: Summary The tendon sheaths of extensor pollicis brevis (EPB) and abductor pollicis longus (APL), obtained from four patients with de Quervain's disease were studied by light and electron microscopy. Three different layers were identified in the sheath which was much thicker than normal. Both the outer and the middle layers had thick bundles of collagen fibres with scattered fibroblasts. The inner layer was mainly formed by chondroid and myxomatous tissue. Collagen fibrils were thicker than normal, reaching 2100 nm in diameter. Numerous cells which resembled «myofibroblasts» were scattered throughout the whole thickness of the sheath. The results seem to indicate that thickening and hardening of the EPB and APL tendon sheaths in de Quervain's disease is caused by increased synthesis of the extracellular matrix, increased thickness of the collagen fibrils and areas of myxomatous and chondroid metaplasia.
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  • 6
    ISSN: 1432-2307
    Keywords: Pigmented adenoma ; Cushing's syndrome ; Lipofuscin ; Ultrastructure ; Steroid analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultrastructural and morphometrical analysis of brown pigment in pigmented (black) and non-pigmented adrenocortical adenomas of Cushing's syndrome and non-functioning pigmented adrenocortical nodules was performed in reference to tissue concentrations and in vitro production of steroids by the adenoma tissue. Pigment in pigmented adenomas was of membrane-bound lysosomal nature, while that of pigmented nodules contained membrane-unbound droplets of lipoid character. The morphometrical study showed little difference among individual adenomas. There was no difference between pigmented and non-pigmented adenomas in the amount of production and tissue concentrations of steroids. The steroid concentrations in a pigmented nodule were lower than those in an adenoma of Cushing's syndrome, but not significantly. Discussion is focused on the difference of pigment of lysosomal nature and of lipoid peroxidation.
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  • 7
    ISSN: 1432-2307
    Keywords: Gastrin ; Gastrinomas ; Ultrastructure ; Immunogold technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Localisation of C-terminal gastrin immunoreactivity has been studied, using the immunogold staining procedure, on ultrathin sections of 6 human gastrinomas conventionally processed for electron microscopy. The specific labelling, whose density depended on the mean diameter of the gold marker, was restricted to endocrine secretory granules. However, in poorly differentiated cells from malignant tumours, a number of granules remained unreactive. The labelling pattern depended also on the functional state of each cell. The immunoreactive granules showed various morphological features. A moderate number of gold particles was demonstrated over the floccular content of the infrequent diagnostic G-type granules. Non-diagnostic round granules of varying size and electron density were prevalent in most cells; their usually strong immunostaining allowed immediate recognition of cell specificity. Dense granules which were large in size and angular in shape and present in one case, were also intensely labelled. In the same tumour, unequal labelling occurred over polymorphous, often elongated granules, of varying size. Granules of different types, including intermediate forms, could be found in the same cell, indicating a spectrum of granule maturation towards well-defined types of the fetal or adult normal tissues. The present methodology would help to identify gastrin-producing cells in prospective or retrospective electron microscopy studies of multihormonal endocrine tumours.
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  • 8
    ISSN: 1432-2307
    Keywords: Normal Human Breast ; Mitosis ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In this study the proliferative (stem?) cells within the parenchyma of the normal “resting” breast were characterised by the ultrastructural examination of 60 mitotic cells. The parenchyma consists of epithelial and myoepithelial cells plus a few intraepithelial lymphocytes and macrophages. The majority of mitotic cells were randomly distributed throughout the lobules with a few present in ducts. In all cases the cells were identified as luminally positioned polarised epithelial cells. The proliferating cells had similar cytoplasmic features and were indistinguishable from adjacent interphase epithelial cells. No evidence was found for the division of subluminal epithelial or myoepithelial cells. These observations would be consistant with a single cell type giving rise to both epithelial and myoepithelial cells.
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  • 9
    ISSN: 1432-2307
    Keywords: Multiple myeloma ; Crystalline deposits ; Ultrastructure ; Image analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A 58-year-old man showed bone marrow crystalline structures associated with a lambda light chain producing multiple myeloma. Analysis and processing of electron images clearly displayed the periodic structure of the crystals. Immunochemistry suggested that they contained the whole or a fragmented constant portion of immunoglobulin.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 408 (1985), S. 1-13 
    ISSN: 1432-2307
    Keywords: Hepatitis, viral, human ; Plasma cell ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Plasma cells and their precursors were studied by electron microscopy in liver biopsies from 41 patients with acute viral or drug-induced hepatitis. Mature plasma cells showed the ultrastructural features of the reticular or lymphatic type. Blast cells of different types were also observed. Type 1 predominated in classical acute hepatitis, and appears to transform directly into mature plasma cells. Type 2 corresponds to the centroblast of lymphoid tissue. It was found in fully developed hepatitis, especially when necrosis was severe. Type 3 resembled the centrocyte of lymphoid organs; it was seen particularly in viral hepatitis, and only in severe cases with extensive necrosis. The type 4 plasmablast had the ultrastructural characteristics of a plasmacytoid T cell.
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 405 (1985), S. 439-452 
    ISSN: 1432-2307
    Keywords: T-cell lymphoma ; Microvasculature ; Ultrastructure ; Immunohistochemistry ; Ulex europaeus lectin I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The microvasculature of lymph nodes of 55 cases of T-cell lymphoma was studied by light microscopy, immunohistochemistry and electron microscopy. A modified peroxidase-antiperoxidase (PAP) method was used for staining paraffin sections with lectin I of Ulex europaeus (UEA-I), which is a specific marker for vascular endothelial cells. The T-cell nature of each case was proven by immunohistochemistry, including immunoperoxidase staining of frozen sections with monoclonal T-cell antibodies. The cases were subclassified according to previously established criteria, but with the addition of a separate group showing a high content of clear cells. For the purpose of the present study, the small blood vessels were separated into two main variants, viz.: high endothelial venules (HEV) and all other types of vessels with flat endothelium (SVFE). The development of each of these variants and the extent of lymphocyte migration through the vascular wall were assessed semiquantitatively. The findings suggest that the blood microvasculature, as a whole, is similar in all types of T-cell lymphoma. There were distinct differences, however, in the development of the two main categories of small vessels between the various types. Chronic lymphocytic leukaemia of T-type (T-CLL) and Sézary's syndrome were poor in SVFE and rich in HEV, and there was considerable lymphocyte traffic through the latter. In contrast, T-immunoblastic and especially T-lymphoblastic lymphomas showed numerous SVFE, only a few or no HEV and minimal lymphocyte traffic. The appearance of the microvasculature varied markedly in the various subtypes of “pleomorphic T-cell lymphoma”. In the small cell subtype HEV predominated and SVFE represented only a small or moderate fraction of the microvasculature. As the size of the neoplastic lymphoid cells increased towards the medium-sized and large cell
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  • 12
    ISSN: 1432-2307
    Keywords: Human bladder tumour ; Inverted papilloma ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Three cases of inverted papilloma of the urinary bladder were studied by transmission electron microscopy. Scanning electron microscopic observation was made in one of these. The surfaces of the outermost tumour cells were covered with short stubby microvilli. Multiple bud like proliferations of the tumour cells were compatible with a trabecular type of inverted papilloma. The tumour cells of the trabeculum mimicked the intermediate and basal cells of the epithelium which covered the surface. Microcysts are believed to be formed by epithelial migration into pits, creating an epithelial inversion, and do not represent central necrosis. Ultrastructure suggests that inverted papilloma is a very well differentiated tumour.
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  • 13
    ISSN: 1432-2307
    Keywords: Oligomeganephronic renal hypoplasia ; Tapetoretinal degeneration ; Ultrastructure ; Focal glomerular sclerosis ; Nephronic reduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Bilateral renal hypoplasia with oligomeganephronia, associated with bilateral tapetoretinal degeneration was observed in a child; this association has been reported only once before. Light, ultrastructural and immunofluorescent microscopic studies of the renal tissue were performed. The glomeruli were few and hypertrophic, with numerous mesangial cells, mesangial deposits, focal glomerular sclerosis and prominent thickened basement membrane. Two types of tubular changes were observed: focal necrosis of proximal tubules and focal atrophy of tubules surrounded by a thickened basement membrane. Mild fibrosis with few lymphocytes could be observed in the interstitium. A congenital reduction in the number of nephrons, related to a yet unknown pathological process may explain these morphological changes in part.
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  • 14
    ISSN: 1432-2307
    Keywords: Leukemia ; Liver ; Ultrastructure ; Endothelium ; Guinea pig
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The possible routes of transvascular migration of leukemic cells in the liver were studied in guinea pigs with an L2C lymphoblastic cell-line inoculation leukemia. Invasion of the hepatic parenchyma theoretically can occur in three ways: 1. Through the intact sinusoidal endothelium, utilizing either pre-existent gaps (normal in the liver), or newly created pores, whether interendothelial or intraendothelial. We could not convincingly demonstrate this, but could not wholly exclude this either. 2. After destruction or retraction of the endothelium, either on account of the remarkable sinusoidal engorgement and distension by masses of leukemic cells, or by direct assault on the endothelium by the leukemic cells. We can clearly demonstrate the former, and hold it to be the major cause of hepatic infiltration. Evidence for a direct endotheliolytic effect was not uncovered in our studies. 3. Secondary infiltration from the portal triads. Heavy leukemic infiltration of the triads, whether from the portal or hepatic veins, or from the lymphatics, is indeed and early an consistent feature - but the infiltration of the hepatic lobule shows no peripheral, or any other zonal preference. In both portal and hepatic veins, leukemic cells transverse the endothelium through a cytoplasmic “pore”, adjacent to cell junctions, without obvious damage to the endothelium.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 407 (1985), S. 97-105 
    ISSN: 1432-2307
    Keywords: Cardiomyopathy ; Leigh's disease ; Mitochondriopathy ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Clinical and postmortem findings in a female infant, suffering from Leigh's disease and cardiomegaly are described. The cardiac enlargement was due to symmetrical thickening of both ventricular walls and the septum. On light microscopy a widespread fibre disarray with a slight predilection for the ventricular septum was observed. Ultrastructural changes included an extreme reduction in the number of myofibrils and an excess of mitochondria. Abnormalities of the mitochondrial structure with tubular and myelinic transformation of the cristae suggested that a mitochondriopathy is responsible for the cardiomegaly in Leigh's disease.
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 407 (1985), S. 369-378 
    ISSN: 1432-2307
    Keywords: Breast ; Lymphocytes ; Macrophages ; Ultrastructure ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In this study the presence of intraepithelial cells within the normal breast parenchyma was investigated by electron microscopy and immunocytochemistry. Cells were observed which could be differentiated from the epithelial and myoepithelial cells by their cytoplasmic and nuclear morphology and the absence of cell junctions. Two cell types (lymphocytes and macrophages) were identified ultrastructurally and the bone marrow origin of the cells was confirmed by immunocytochemistry. The intraepithelial lymphocytes and macrophages were present in all samples irrespective of the physiological state. In the “resting”, pregnant, and lactating breast the majority of cells were lymphocytes while in the involuting breast there was a marked increase in the proportion of macrophages. The rarity of lymphoma of the breast may be related to the relatively small amount of lymphoid tissue present and the passive nature of the environment.
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  • 17
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 408 (1985), S. 29-41 
    ISSN: 1432-2307
    Keywords: Kaposi's sarcoma ; AIDS ; Ultrastructure ; Immunohistology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Comparison of idiopathic Kaposi's sarcoma in Europe and Africa and Kaposi's sarcoma in connection with AIDS shows an identical morphological appearance in all three types. Ultrastructural and immunohistological investigations indicate that the tumour originates from the endothelial cells of proliferating capillaries and is therefore a vascular tumour. The clinical course and the sites of manifestation differ slightly in idiopathic cases and those occurring in connection with AIDS. This effect may be determined by the general condition of the patient, the state of immune deficiency and the influence of opportunistic infections.
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  • 18
    ISSN: 1432-2307
    Keywords: Small cell carcinoma ; Amylase ; ACTH ; Ultrastructure ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Tumour tissue from a lung cancer patient who showed elevated serum amylase and adrenocorticotropin (ACTH) was studied ultrastructurally, immunohistochemically and biochemically. Histologically the tumour was a small cell carcinoma. On electron microscopic examination the tumour cells contained large zymogen-like granules within the cytoplasm. Furthermore, cells which possessed many small dense core granules of the endocrine type were also observed. It was of interest that the large zymogen-like granule-containing tumour cells had microvilli at the apical border, connected by desmosomes and forming lumina showing adenocarcinomatous differentiation. Electrophoretic analysis of the serum revealed that the major elevated amylase was of the salivary type with minor components. Immunostaining clearly demonstrated that most of the tumour cells possessed immunoreactive ACTH, whereas salivary amylase was only found in occasional clusters of the tumour cells. The results seem to indicate that the tumour showed both endocrine and exocrine characteristics - an amphicrine carcinoma, expressing amylase and ACTH simultaneously.
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  • 19
    ISSN: 1432-2307
    Keywords: Immunohistochemistry ; Ultrastructure ; Oncofoetal ; Antigens ; Bowel ; Carcinoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Seven large bowel carcinomas were examined by light and electron microscopy for the presence of five oncofoetal antigens. Ultrastructural investigations involved a novel method whereby thick sections of gluteraldehyde-fixed material were cut on a vibratome and then labelled using slight modifications of a standard unlabelled antibody-enzyme (PAP) technique, before further processing. Ultrastructural preservation, staining properties and the retention of antigen activity was seemingly better than that achieved by other investigators. Specific, positive labelling for carcinoembryonic antigen (CEA), colon specific antigen (CSA) and pregnancy-specificβ-1-glycoprotein (SP1) was seen in every case. Clear positive labelling for placental alkaline phosphatase (PLAP) and human chorionic gonadotropin (HCG) was seen in two cases. Extracellular labelling was found in areas of cell debris, free lying or in phagocytic cells and on tumour cell brush borders. The pattern of intracellular labelling, however, was different for each antigen and reflected the probable sites of synthesis and release from the cells. Thus CEA, a complex glycoprotein, was localised within the golgi apparatus, small apical cytoplasmic vesicles and mucous droplets in relatively well differentiated tumour cells. CSA, a chemically related glycoprotein, had a similar, but less dense distribution. SP1, by contrast, was localised within basally-located vesicles associated with the ribosomal endoplasmic reticulum and appeared to be released and persist as debris or taken up by phagocytic cells below the basal lamina. PLAP and HCG, both proteins, were found within simple single membrane-bound vesicles within relatively undifferentiated cells.
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  • 20
    Electronic Resource
    Electronic Resource
    Springer
    Neuroradiology 27 (1985), S. 172-175 
    ISSN: 1432-1920
    Keywords: Iohexol ; contrast media ; CSF ; pharmacokinetics ; myelography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The absorption of iohexol from the subarachnoid space was studied in 9 patients. Serum concentrations of iohexol were measured for a minimum of 24 hours after injection. Peak serum concentrations were observed after 2.2 (1.7–2.7) hours. The half-life of the subsequent decrease in serum concentrations was 3.4 (2.2–7.9) hours. Concentrations of iohexol in cerebrospinal fluid were 0.29–4.3 mg I/ml 24 hours after injection (7 patients). Serum and cerebrospinal fluid concentrations of iohexol are comparable to those found after intrathecal injection of metrizamide.
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  • 21
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 172 (1985), S. 101-113 
    ISSN: 1432-0568
    Keywords: Yolk sac ; Marmoset ; Ultrastructure ; Hydrolase cytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Yolk sacs from Callithrix jacchus were investigated light and electron microscopically as well as by qualitative light microscopic enzyme histochemistry on days 35 to 126 of gestation. The thin yolk sac wall of the early stages (day 35–41) consists of the cuboid, endodermal epithelium, the mesothelium of the exocoelom and some interposed blood vessels. The inner endodermal surface is rather smooth. At later stages, the epithelium becomes highly prismatic and forms folds which are lined by a mesenchyme and blood vessels. Microvilli and a small number of endocytotic vesicles are observed at the apices of the epithelial cells, which are interconnected by gap junctions, desmosomes and interdigitations. The cytoplasm of the epithelial cells is characterized by a well-developed rough endoplasmie reticulum, a large Golgi apparatus and glycogen deposits. Four different membrane-bordered types of inclusions can be distinguished in the cytoplasm of the epithelial cells: The type I and II inclusions are considered as secretion granules. Their increase and their localization in the cavities of the endoplasmic reticulum at later stages are ascribed to an inhibition of the intracellular transport at the onset of involution. The type III and IV inclusions may represent lysosomes and related organelles. Bile capillary-like spaces exist between the epithelial cells. The basement membrane is incomplete below the epithelium and absent around the capillaries, the endothelium of which is porous in certain areas. Aminopeptidase M is highly active in the plasmalemma and the bile capillary-like structures of the epithelium, dipeptidylpeptidase IV in the mesothelium and alkaline phosphatase in the blood vessel endothelium. Other membrane hydrolases are absent. Acid proteases, glycosidases, non-specific phosphatases and non-specific esterases can be detected stage-dependently with moderate to high activities in the yolk sac epithelium. Compared with other organs, the yolk sac structure and hydrolase equipment are similar to those of the liver and may, therefore, have similar functions, e.g. synthesis and secretion of proteins. In addition, however, the yolk sac epithelium might also be involved in resorptive processes of material from the lumen followed by lysosomal digestion. The Callithrix jacchus yolk sac starts involution on day 80 of gestation by disintegration of the cells. On day 100, this process is completed. the stage of involution which is late in comparison with other primates, e.g. man and Rhesus monkey, is ascribed to the strongly delayed development of Callithrix jacchus.
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  • 22
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 172 (1985), S. 247-254 
    ISSN: 1432-0568
    Keywords: Mouse ; Spermiogenesis ; Cytoplasmic organelles ; Ultrastructure ; Cytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An electron microscopic Ag-staining method was used to study the argyrophilia of specific cytoplasmic organelles that appear during mouse spermiogenesis. The microtubuli of the centrioles are surrounded by a thin layer of argyrophilic material that also surrounds the microtubuli of their derivatives, e.g., the centriolar adjunct, the axoneme, and some structures of the connecting piece. As the mantle, i.e., the junctional complex between Sertoli cell and spermatid, develops, the involved regions of its plasma membranes are covered with silver precipitates. The apical portion of the nuclear ring as well as that of the perforatorium show clear argyrophilia. Besides these structures, a number of ring-shaped and spheroidal bodies at various sites in the cell also are decorated with silver precipitates. Most of these argyrophilic structures show a positive reaction with the EDTA method, too, suggesting that they contain ribonucleoprotein and might be of nucleolar orgin. Since, furthermore, most of these structures are known to contain distinct cytoskeletal proteins, it is assumed that the staining reaction might be caused by proteins that are associted with the genuine cytoskeletal proteins.
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  • 23
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 172 (1985), S. 265-275 
    ISSN: 1432-0568
    Keywords: Ultrastructure ; Human knee joint capsule ; Free nerve endings ; Ruffini corpuscles ; Pacini corpuscles
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructure of sensory nerve endings in the human knee joint capsule was studied. Three types of nerve endings were found: free nerve endings (FNE), Ruffini corpuscles and Pacini corpuscles. In the joint capsule, FNE are located below the synovial layer and within the fibrous layer near blood vessels. These nerve terminals derive from myelinated Aδ-fibres or from unmyelinated C-fibres. Their structure is almost identical to FNE in human hairy and non-hairy skin. Ruffini corpuscles are present within the fibrous layer and the ligaments of the capsule in three variations: small Ruffini corpuscles without a capsule, small with a connective tissue capsule, and large Ruffini corpuscles with an incomplete perineural capsule. Their afferent axons are myelinated and measure 3–5 μm in diameter. Inside the corpuscle, nerve terminals are anchored in the connective tissue belonging to the fibrous layer or to the ligaments respectively. The presence of an incomplete perineural capsule depends on the structure of the surrounding connective tissue. In ligaments with collagenous fibrils oriented in a parallel fashion, the perineural capsule is well-developed and the Ruffini corpuscle resembles a Golgi tendon organ; in areas where the fibrils show no predominant orientation, Ruffini corpuscles lack a capsule. Small Pacini corpuscles are situated within the fibrous layer near the capsular insertion at the meniscus articularis or at the periost. They consist of one or several inner cores and a perineural capsule of 1–2 layers. Larger Pacini corpuscles with one or several inner cores and a perineural capsule consisting of 20–30 layers are found on the outer surface of the fibrous layer. The ultrastructure of these nerve endings is compared with the ultrastructure of articular receptors of various animals and with the ultrastructure of sensory nerve endings in the skin of several mammalian species including man.
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  • 24
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 172 (1985), S. 281-293 
    ISSN: 1432-0568
    Keywords: Pig ; Blastocyst ; Endometrium ; Implantation ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To elucidate the morphology of the initial stages of epitheliochorial placentation in the pig, material from 10 sows of the Danish Landrace and from one Göttinger minipig gilt from day 13 to day 26 of gestation was processed for scanning and transmission electron microscopy. The observed foetomaternal interaction from day 19 1/2 minipig placenta corresponded well to the observations on the Danish Landrace placenta. From the results and the discussion it was concluded that the following structures were implicated in the initial phases of placentation in the pig: (1) Protruding epithelial proliferations of the uterine epithelium enclosed by chorionic caps serving to immobilize the blastocyst (days 13 and 14). (2) A thick glycocalyx on the maternal and a thin one on the foetal epithelium before contact. (3) Close apposition between the apical plasma membranes from trophoblastic and uterine epithelium (day 14). (4) Development of interdigitating microvilli (days 15–16). (5) Formation of apical domes on the uterine epithelium closely related to the trophoblast provided with long cytoplasmic extensions into a luminal space between the apical domes, apparently representing a transition from histiotropic to haemotrophic nutrition (days 15–20). (6) Placentation, development of interdigitating microvilli between foetal and maternal epithelium, was extended but not terminated in the peripheral zone at day 26.
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  • 25
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    Anatomy and embryology 171 (1985), S. 259-265 
    ISSN: 1432-0568
    Keywords: Man ; Myoepithelial cell ; Submandibular gland ; Ultrastructure ; Cytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In human submandibular glands, two types of myoepithelial cells can be distinguished in serial, ultrathin sections. The dark myoepithelial cell type was stellate in shape and exhibited a pronouneced electron density due to numerous myofilaments with focal densities. Dark cell types accounted for the greater part (76%) of the myoepithelial cells and furthermore showed adenosine triphosphatase activity. This type of myoepithelial cell is considered to be that previously observed in mammalian salivary glands. Occasionally, desmosomes could be found between the processes of adjacent dark myoepithelial cell types, which is appropriate with respect to the strong compression of acinar or intercalated duct cells. The light myoepithelial cell type was large and ellipsoid with a few short-thick processes, and was characterized by an electron lucent cytoplasm which included scant and unevenly distributed myofilaments. Light cell types showed positive adenosine triphosphatase activity and accounted for only a small part (17%) of the myoepithelial cell number. Transitional forms between these two types were also observed. The light myoepithelial cell type may mature into the dark myoepithelial cell type by means of the transitional form. In addition, clear cells were sometimes encountered between the myoepithelial cell and the acinar or intercalated duct cells.
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  • 26
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    Anatomy and embryology 171 (1985), S. 297-304 
    ISSN: 1432-0568
    Keywords: Placenta (guinea pig) ; Permeability ; Freeze-Tracturing ; Ultrastructure ; Cell junctions ; Tracers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Permeability of the fetal endothelium within the guinea pig placental labyrinth is studied by means of horse-radish peroxidase (HRP) and ionic lanthanum as diffusion tracers. The paracellular transport of HRP is restricted by the occluding junctions of the fetal endothelium. In contrast, ionic lanthanum readily permeates most of the intercellular junctions and rapidly infiltrates the basal lamina. Freeze-fracture replicas reveal zonulae occludentes connecting the fetal endothelial cells. The network of the zonulae occludentes is variable, exhibiting highly complex areas as well as single strand interconnections. A correlation between the permeability studies and freeze-fracture findings is discussed.
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  • 27
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    Anatomy and embryology 172 (1985), S. 331-337 
    ISSN: 1432-0568
    Keywords: Ovary ; Oocyte ; Ovulation ; Follicle ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Follicular ruptures with intra-ovarian oocyte release (IOR) were studied in 17, 21 and 24-day-old rats by morphological methods. Using a light microscope, it was seen that IOR occurred at all times and the IOR frequency did not change. IOR developed in preantral follicles. Their oocytes were mostly found within the follicular compartment (incomplete IOR). Using an electron microscope, a circumscribed dissolution of the basal lamina was observed. IOR granulosa cells appeared activated. They rarely underwent typical necrosis after herniation into the extrafollicular area. Herniated granulosa cells tended either to stay intact or to shed cytoplasmic components into the extracellular space. whilst nuclei of active cell function were maintained. Tissue adjacent to an IOR seemed inactive with the exception of endothelial cells. Some endothelial cells underwent necrosis. Additionally, the endothelium was discontinous. The morphological data support the hypothesis that the mechanism of follicular rupture represents an inside to outside process.
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  • 28
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    Anatomy and embryology 172 (1985), S. 183-194 
    ISSN: 1432-0568
    Keywords: Cholinesterase ; Limb bud ; Chick embryo ; Ultrastructure ; Chondrogenesis ; Myogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cholinesterase (ChE) is transiently expressed in undifferentiated embryonic cells. In the chick limb bud ChE-activity was found in the apical ectodermal ridge and in the subridge mesenchyme. The reaction was localized in the perinuclear cisterna, in an extensive network of narrow profiles of endoplasmic reticulum (ER), and in the Golgi complex The chondroblasts emerging from the subridge mesenenyme, also showed strong ChE-activity. During differentiation the enzyme first disappeared from the Golgi zone. Then, the narrow ChE-positive ER was successively replaced by ChE-negative extended rough ER characteristic for the differentiated chondrocyte. The myoblasts showed weak ChE-activity with the same ultrastructural localization as in other mesenchymal cells. After fusion the myotubes exhibited strong ChE-activity in the perinuclear cisterna and the developing sarcoplasmic reticulum. In later stages of myogenesis the myoblasts were closely attached to the myotubes and had lost their ChE-activity. During mitosis of ChE-positive cells, ChE-activity was retained in fragments of perinuclear cisterna and ER. In ChE-active mesenchymal cells and chondroblasts we observed specialized contact zones between ER and plasma membrane. ChE-active cisternae of ER run parallel to the plasma membrane with a gap of approximately 10–15 nm. We discuss a possible function of a cholinergic system during morphogenesis.
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  • 29
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    Anatomy and embryology 173 (1985), S. 247-252 
    ISSN: 1432-0568
    Keywords: Ultrastructure ; Spermatozoa ; Zona pellucida ; Cumulus cells ; Human egg investments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructure of human spermatozoa located in the cumulus cells and the zona pellucida of a pronuclear egg, and in the zona pellucida of a two-cell egg, both fertilized in-vivo, has been analysed in order to understand how the human spermatozoon penetrates the investing coats of the oocyte. Among the 36 spermatozoa found in the cumulus cells, 31 were phagocytosed by cumulus cells and 5 were wedged in the matrix between the cells. These spermatozoa were acrosome-reacted and their equatorial segment was intact. Six of the seven spermatozoa found in the zona pellucida (four spermatozoa in the pronuclear egg and three in the two-cell egg) had lost the equatorial segment, while the other one was partially reacted. The sperm heads were located in slits with sharp edges. From these findings it was concluded that in the human (1) only few and normal spermatozoa seem to reach the cumulus cells after natural insemination, (2) the acrosome reaction probably occurs sometime before the spermatozoa reach the vicinity of the corona cells, (3) the reaction of the equatorial segment seems to occur during or before the initial phase of zona penetration, since the spermatozoa located in the matrix of the zona pellucida had no equatorial segment. No evidence of the presence of spermatozoa with an intact acrosome in the matrix of cumulus cells or with an intact equatorial segment in the zona pellucida were found.
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  • 30
    ISSN: 1432-0568
    Keywords: Dopamine-β-hydroxylase ; Anterior column ; Ultrastructure ; Immunohistochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Dopamine-β-hydroxylase (DBH) immunohistochemistry was used to demonstrate the noradrenergic fibers and terminals in the anterior column of the rat lumbosacral spinal segments. PAP-positive varicose fibers were widely distributed in the gray matter with preferential accumulation in the nuclear regions containing motoneurons involved in the contraction of perineal striated muscles. Unmyelinated DBH fibers were composed of nodular enlargements (varicosities, 0.4–3.0 μm in diameter) and very fine, short intervals (intervaricose segments, 0.1–0.2 μm in diameter and 1.0–4.0 μm in length). DBH-positive dense products were electron microscopically often confined within small granular particles and less frequently within large granules. Additionally, in order to characterize the innervation pattern of noradrenergic fibers on dendritic bundles organized in the motoneuronal pools innervating the pelvic small muscles, semi-quantitative analysis was done in the area of the dorsolateral nucleus endowed with especially well-developed dendritic bundles. DBH terminals contacting with unreactive dendrites were more common (67.9%) than those with neuronal somata (15.1%), and the remainder (17%) had no contacts with surrounding neuronal elements. Furthermore, specialized synaptic formations were observed in only 20.1% of these nodules. The results suggest that bulbospinal descending noradrenergic neuron systems influence the functioning of pelvic muscles principally via the neuronal contacts with dendritic bundles in the spinal cord.
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  • 31
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    Anatomy and embryology 171 (1985), S. 305-310 
    ISSN: 1432-0568
    Keywords: Pancreas ; Development ; Ultrastructure ; Freeze-fracture ; Intercellular junction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The formation of gap junctions was studied in pancreatic exocrine cells of rats and mice during late embryonic and neonatal development by the freeze-fracture replica method. Small gap junctions were present in association with tight junctional strands near the cell apex during embryonic development. Independently of tight junctions, small gap junctions were sometimes seen more basally on day 13 to 15 of gestation. The gap junctions increased in number and were rapidly enlarged by day 18 to 20 of gestation. Large particles 12–13 nm in diameter were frequently associated with the gap junction, which consisted of 10 nm particles. The large particles were either irregularly distributed or arranged in hexagonal patterns. The number of large particles decreased with time, so that they sparsely rimmed the gap junction in postnatal animals. This suggests that large particles are precursors of typical gap junctional particles, and that they participate in rapid growth of the gap junction during late embryonic development. It may be also possible that large particles represent functionally different gap junctions.
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  • 32
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    Anatomy and embryology 172 (1985), S. 145-156 
    ISSN: 1432-0568
    Keywords: Afferent nerve fiber ; Nociceptor ; Sensory terminal ; Tendon innervation ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In sympathectomized cats the innervation of the Achilles tendon by fine afferent nerve fibers was studied with semithin and ultrathin sections. Several different types of sensory endings of group III and group IV nerve fibers were identified. Of the five different types of endings in the group III range (T III endings), two are located within vessel walls. One of them ends in the circumference of the venous vessels (T III/VV). Its lanceolate terminals have characteristic receptor areas at their edges. The second type ends in the adventitia of lymphatic vessels (T III/LV). Its receptive areas are scattered along their terminal course. Two further group III endings ramify within the connective tissue compartments of the vessel-nerve-fascicles of the peritenonium externum and internum. One type is tightly surrounded by collagen fibrils (T III/PTic); the other terminates between the collagen fiber bundles (T III/PTgc). The latter arrangement recalls the ultrastructural relation between nerve terminals and collagen tissue in Golgi tendon organs. The fifth type innervates the endoneural connective tissue of small nerve fiber bundles (T III/EN). At least some of them come into close contact with bundles of collagen fibers which penetrate the perineural sheath to terminate within the endoneurium. The endings of group IV afferents (T IV endings) show a striking topographic relationship to the blood and lymphatic vessels of all connective tissue compartments of the Achilles tendon. They form penicillate endings which may contain granulated vesicles. In any event, they can easily be discriminated from the T III endings in the vessel walls. In close neighborhood to Remak bundles, a cell has been regularly found which fulfilled all ultrastructural criteria for mast cells. But this cell is not a mast cell proper because it is surrounded by a basal lamina (pseudo mast cell).
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  • 33
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    Acta neuropathologica 67 (1985), S. 254-264 
    ISSN: 1432-0533
    Keywords: Capillary ; Cerebellum ; Endothelial cell ; Hemangioblastoma ; Morphometry ; Pericyte ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Electron microscopy and computerized morphometric techniques were employed to examine pericyte ultrastructure and to assess quantitatively their relationship to endothelial cells in five cases of cerebellar capillary hemangioblastoma. A total of 97 cross-sectioned capillary profiles were studied. Pericyte coverage of capillary ranged from 30.2% to 97.3% with a mean value of 68.7%, which is higher as compared with the available data from the cerebral cortex, skeletal and cardiac muscle, and pulmonary capillaries. The higher pericyte coverage of capillary suggests that pericyte is an active component of cerebellar capillary hemangioblastoma and may have a close functional relationship to endothelial cells. Pericytes contained bundles of parallel microfilaments along the adluminal side and in the terminal processes, and exhibited an intimate “peg-and-socket” relationship with endothelial cells, suggesting a contractile function of pericytes and their possible role in regulating capillary lumina and focal blood flow. The finding of abundant micropinocytic vesicles along the abluminal side of the cytoplasmic membrane indicates an active metabolic exchange between pericytes and the interstitium. It is possible that in cerebellar hemangioblastoma pericytes may act as a mechanical and metabolic monitor barrier for endothelial cells.
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  • 34
    ISSN: 1432-0533
    Keywords: Becker's muscular dystrophy ; Neuromuscular junction ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultrastructural studies on muscle biopsies from three patients with Becker's muscular dystrophy showed that the i.m. nerves presented loss or disarrangement of the neurofilaments and an increased number of glycogen granules and/or myelin figures not infrequently in the myelinated and unmyelinated nerve fibers. The neuromuscular junctions showed markedly widened sole-plate areas, and several terminal axons frequently abutted and formed neuromuscular junctions on the same fiber. The secondary synaptic clefts were markedly decreased in number and short in length in type I fibers but not in type II fibers. Most terminal axons showed no degenerative changes. Therefore, the participation of a neural factor might be suggested as the cause of Becker's muscular dystrophy, although it does not mean denervation in the conventional sense of an axonal degeneration.
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  • 35
    ISSN: 1432-072X
    Keywords: Cyanophyta ; Chroococcidiposis ; Lichenphycobiont ; Cell wall ; “Outer membrane” ; Ultrastructure ; Freeze fracturing/etching ; Patchwork-like leaflet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Freeze etching studies in a symbiotic and a freeliving strain of Chroococcidiopsis revealed a specific layer in the outer cell wall not described so far from Cyanophyta. The layer showed a complex organisation: The main unit are ribbons, 2–3 nm thick, striated at right angle to the longitudinal axis. They are interwoven to a patchwork-like leaflet. The ribbons are virtually composed of globular particles associated in parallel rows. The cytoplasmic membrane and the cell walls of the symbiotic and the free-living strain were compared.
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  • 36
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    European journal of clinical pharmacology 28 (1985), S. 213-219 
    ISSN: 1432-1041
    Keywords: thiamine ; plasma level ; pharmacokinetics ; nonlinear renal elimination ; assay for clinical use
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A sensitive assay for thiamine suitable for clinical use has been developed. It is based on precolumn oxidation of thiamine to thiochrome followed by HPLC-separation and fluorescence detection. The assay is applicable to various biological materials, including human plasma. The minimum amount detectable was 5 fmol, minimum plasma concentration 0.5 nmol/l and minimum sample volume 0.3 ml plasma. Each chromatographic run took 3 min. Inter- and intra-assay relative standard deviations (RSD) were 8.3% and 6.3%, respectively, at a stock plasma concentration of 10.8 nmol/l. At 38.8 nmol/l, interassay RSD was reduced to 3.4%. The recovery of 5 nmol/l added thiamine was 102 (SD±17)%, that of 30 nmol/l was 94±5%. Plasma levels in 91 volunteers ranged from 6.6 to 43 nmol/l, showing a log normal distribution with a median of 11.6 nmol/l. Thiamine kinetics were studied in plasma and urine from 8 men after intravenous and oral doses of 50, 100 and 200 mg thiamine hydrochloride. In all individuals, nonlinear renal elimination kinetics were demonstrated by plotting the fractional amount of thiamine excreted unchanged in urine against the corresponding area under the plasma concentration — time curve.
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  • 37
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    European journal of clinical pharmacology 28 (1985), S. 231-233 
    ISSN: 1432-1041
    Keywords: erythromycin ; pharmacokinetics ; steady-state ; food effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady state absorption of erythromycin from enteric-coated pellets of erythromycin base was compared with that from enteric-coated tablets in a randomized, two-way cross-over study in 24 healthy adult volunteers. A higher mean individual peak concentration (p〈0.01), and a greater mean area under the serum concentration-time (0–8 h) curve (AUC,p〈0.01) was produced by the enteric-coated pellets, when the preparations were administered 1 hour before breakfast. No significant differences in the kinetic parameters between the two preparations were observed when they were taken during a non-standardized breakfast, as concomitant food intake was found to reduce both the peak levels and the AUC-values (p〈0.01) produced by the pelleted preparation.
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  • 38
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    European journal of clinical pharmacology 28 (1985), S. 305-309 
    ISSN: 1432-1041
    Keywords: piroxicam ; pharmacokinetics ; geriatrics ; renal insufficiency ; drug safety ; non-steroidal anti-inflammatory drugs ; osteoarthritis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Age-dependent changes in pharmacokinetics are considered a possible factor contributing to a higher risk of side-effects from drug treatment in the elderly. However, very little is known about the kinetics and metabolism of most NSAI agents in geriatric subjects. In a prospective age-comparison study, the single dose and steady-state pharmacokinetics of piroxicam 20 mg once daily were determined in 44 subjects ranging in age from 30 to 80 years. Plasma concentrations, elimination half-life, AUC, and volume of distribution were not influenced by age or sex and were in agreement with previously reported results in young adults. Pharmacokinetic parameters in 18 patients with evidence of mild or moderate renal impairment at study entry were not different from those in patients without impairment. Based on this and other studies, elderly patients receiving the recommended dose of piroxicam are not exposed to undue risk related to pharmacokinetic considerations.
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  • 39
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    European journal of clinical pharmacology 28 (1985), S. 469-471 
    ISSN: 1432-1041
    Keywords: interferon ; cancer patients ; recombinant leukocyte A interferon ; rIFN-αA ; i.v.-/i.m. administration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Interferon is currently being evaluated for the treatment of disseminated cancer and viral diseases. Alpha interferons have shown to be effective in the treatment of a number of malignancies. Recombinant leukocyte A interferon (rIFN-αA) is an alpha interferon produced by recombinant DNA techniques. A kinetic evaluation of rIFN-αA following intravenous and intramuscular administration has not been adequately defined. The present study was designed to evaluate the kinetics of rIFN-αA following intravenous and intramuscular administration of 3, 9 or 18×106 units to patients with disseminated cancer. A preliminary report of this study was presented at the meeting of the American Society for Clinical Pharmacology and Therapeutics in San Diego, March 1983 (1).
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  • 40
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    European journal of clinical pharmacology 28 (1985), S. 601-605 
    ISSN: 1432-1041
    Keywords: smectite ; phenylbutazone ; diazepam ; pharmacokinetics ; drug interactions ; drug adsorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction of phenylbutazone and diazepam with smectite were studied in in-vivo and in-vitro. The kinetics of both drugs were investigated in healthy subjects after oral administration as monotherapy or in association with smectite. Smectite did not substantially alter the kinetics of phenylbutazone, whereas the peak plasma concentration of diazepam was reduced to 91%, and the time of peak concentration was prolonged by 153% of the control values. The in-vitro investigations were conducted at pH 5.5 and 8 and showed that there was no interaction between phenylbutazone and smectite, but that it adsorbed diazepam. The findings suggest that smectite delays the absorption of basic drugs and does not alter the absorption kinetics of acidic drugs.
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  • 41
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    European journal of clinical pharmacology 28 (1985), S. 589-595 
    ISSN: 1432-1041
    Keywords: antipyrine ; chronic renal failure ; drug metabolism ; metabolism ; cumulation ; renal excretion ; pharmacokinetics ; clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides the parent drug, 3-hydroxymethylantipyrine (HMA) was present in plasma in the free and conjugated forms, whereas 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) were found only in the conjugated form. The same was true for urine. The plasma concentrations of these metabolites are too low to be measured in subjects with normal renal function. Plasma antipyrine clearance in the patients was in the same range as in healthy subjects. Investigation of metabolite kinetics, however, revealed that the rate of formation of NORA was preferentially decreased, whereas that of OHA and HMA were unaltered. Renal clearance of the metabolites of antipyrine was severely impaired in patients with renal insufficiency, and the resulting accumulation made it possible for the first-time to measure the antipyrine metabolites in plasma. Mean residence times of metabolites were longer than that of the parent compound. Renal clearances of the conjugates were correlated with the creatinine clearance, but were somewhat higher. Renal clearance of free HMA was lower and was also correlated with creatinine clearance. The mean clearance for glucuronidation of HMA was 93.1 ml/min. The results suggest that in healthy subjects Phase I metabolism is the rate-limiting step in the elimination of antipyrine, which is essential for its application as a model drug in metabolism studies.
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  • 42
    ISSN: 1432-1041
    Keywords: glibenclamide ; glipizide ; pharmacokinetics ; metabolic effects ; Type 2 diabetes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fifteen Type 2 diabetics were treated for 4-week periods with once daily (10 mg) glibenclamide, glipizide and placebo according to a double-blind cross-over protocol. Post-dose glipizide concentrations were three times higher than those of glibenclamide, due to the incomplete bioavailability of the latter. On the other hand, pre-dose drug levels were similar, as an expression of the slower absorption and/or elimination of glibenclamide. Both active treatments reduced postprandial blood glucose concentrations and 24-hour urinary glucose excretion to a similar degree, but fasting blood glucose concentrations were slightly lower during glibenclamide treatment. Both active treatments enhanced fasting and postprandial insulin and C-peptide concentrations, the C-peptide response being greater after glipizide than after glibenclamide. Plasma glucagon and GIP concentrations were not significantly affected. Insulin sensitivity was increased by glibenclamide but not by glipizide. Neither therapy affected insulin binding to erythrocytes. It appears that both glibenclamide and glipizide improved glucose metabolism by sustained stimulation of insulin secretion, which was most pronounced with glipizide. Only glibenclamide improved insulin sensitivity and was slightly more active than glipizide on fasting blood glucose levels. The differences may be consequences of the pharmacokinetics, but differences in pharmacodynamics cannot be excluded.
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  • 43
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    European journal of clinical pharmacology 28 (1985), S. 61-66 
    ISSN: 1432-1041
    Keywords: amiloride ; kidney function ; Na+ ; K+ ; Ca++ ; Mg++ excretion ; renal amiloride clearance ; chronic renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of a single oral dose of 10 mg amiloride was studied on urinary excretion of Na+, K+, Ca++ and Mg++ in healthy subjects and in patients with varying degrees of renal impairment. Amiloride produced a moderate diuresis and sodium excretion, and a slight calciuresis. Urinary excretion of potassium was significantly reduced as compared to the controls. Despite its diuretic and natriuretic effects, amiloride did not change the excretion of Mg++ as compared to the pretreatment period. When the creatinine clearance was below 50 ml/min, the net excretion of Na+ and Ca++ was drastically reduced. However, K+ retention and neutrality of Mg++ excretion were maintained down to end-stage renal disease. In the healthy volunteers the mean elimination half-life of amiloride was 20 h, and it rose to about 100 h in end-stage renal disease. This was because about 3/4 of native amiloride was eliminated through the kidney. Nonrenal elimination of amiloride was calculated to amount to only 1/4 of the total elimination. Therefore, the antikaliuretic amiloride is a valuable comedication in subjects with normal kidney function to prevent K+ and Mg++ loss. However, its use is hazardous if plasma creatinine is raised.
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  • 44
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    European journal of clinical pharmacology 27 (1985), S. 637-644 
    ISSN: 1432-1041
    Keywords: isosorbide-dinitrate ; pharmacokinetics ; analytical method ; bioavailability ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailabilities of a conventional and two slow release 20 mg isosorbide dinitrate (ISDN) formulations were compared after oral administration in a three way cross-over study in 8 male volunteers. In a further group of 6 male volunteers the pharmacokinetics and metabolism of ISDN were investigated after intravenous infusion of a median dose of 14.1 mg for 2.5 h. A new analytical procedure was developed for the determination of isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-Glu) and of isosorbide (IS). Kinetic data analysis on a molar basis was performed by the program package KINPAK providing model independent parameters. The median elimination half-lives of ISDN, IS-5-MN, IS-2-MN and IS-5-MN-2-Glu were 0.7, 5.1, 3.2 and 2.5 h, respectively. The systemic clearance of ISDN was 3.7 l/min and the distribution volume 2521 (3.1 l/kg). Apart from IS-5-MN-2-Glu, with a renal clearance of 5.9 l/min which suggested substantial glucuronidation in the kidney, the renal clearances of ISDN, IS-5-MN, IS-2-MN and the corresponding amounts excreted were negligible. 27.8% of the administered ISDN was excreted as IS-5-MN-2-Glu (8.7%) and IS (19.1%). Calculations based on the two mononitrate metabolites formed from ISDN showed an incomplete recovery of 84.1%, leading to the assumption that a simultaneous denitration to IS must have occurred. The rate of denitration at each nitro group in ISDN was almost twice as high as for the same position in the corresponding mononitrate. The bioavailability of the conventional ISDN formulation was 19%, although complete absorption was indicated by comparison of the percentages of mononitrate metabolites formed after the different routes of administration. On the same basis the absorption of the two sustained release formulations was found to be poor.
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  • 45
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    European journal of clinical pharmacology 27 (1985), S. 649-656 
    ISSN: 1432-1041
    Keywords: bucindolol ; propranolol ; beta-adrenoceptor blockade ; intrinsic sympathomimetic activity ; vasodilator ; pharmacokinetics ; blood pressure ; plasma renin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The β-adrenoceptor blocking properties and pharmacokinetics of bucindolol 150 mg were compared to those of propranolol 80 mg and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures and peak expiratory flow rate (PEFR) at rest and during vigorous exercise, and plasma renin activity (PRA) at rest, were measured before and at intervals up to 24 h after oral administration of the drugs. Bucindolol reduced exercise tachycardia and decreased exercise PEFR, thus behaving as a non-selective β-adrenoceptor blocking drug. In contrast to propranolol, bucindolol did not reduce resting HR and PRA, probably because of its intrinsic sympathomimetic activity. It decreased resting DBP in relation to its peripheral vasodilator properties. The effects of bucindolol developed as early as 30 min after administration and lasted up to 24 h, whereas its Tmax and T1/2 were 1.6 and 3.6 h respectively. Comparison of the time courses of plasma bucindolol and the cardiac β-adrenoceptor blockade strongly suggests that in man bucindolol undergoes an extensive first-pass effect, leading to the formation of one or more active metabolites.
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  • 46
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    European journal of clinical pharmacology 27 (1985), S. 677-681 
    ISSN: 1432-1041
    Keywords: morphine ; analgesic ; pharmacokinetics ; intramuscular administration ; CSF/plasma-morphine levels ; CSF kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Morphine concentrations in plasma and cerebrospinal fluid (CSF) were measured in 58 elderly patients after intramuscular administration of 10 mg morphine. The assay employed gas chromatography with electron capture detection. From 49 of the patients undergoing urological procedures plasma and lumbar CSF samples were obtained simultaneously as spinal analgesia was given, and in addition, repeated venous samples were obtained over 4 hours from 35 of the patients. A plasma-morphine concentration vs time plot was drawn from the mean values and a CSF-morphine vs time plot was calculated by pooling individual CSF concentrations and using the sliding mean technique. The individual CSF/plasma-morphine concentration ratio vs time was also plotted. In addition, 2 or 3 CSF and plasma samples were collected simultaneously from 3 patients undergoing thoracotomy. Large interindividual variation in the CSF concentration was found. The peak CSF level was reached after 3 h and, following pseudoequilibrium, CSF-morphine levels appeared only slightly lower than those found in plasma. The availability to spinal CSF amounted to no more than 0.005% of the administered dose. CSF-morphine concentrations were not related to plasma protein or albumin concentrations.
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  • 47
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    European journal of clinical pharmacology 27 (1985), S. 713-719 
    ISSN: 1432-1041
    Keywords: flucloxacillin ; cardiac pacemaker ; pharmacokinetics ; protein binding ; tissue fluid ; elderly patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of flucloxacillin in plasma and tissue fluid after i.v. infusion of 1 g was analyzed according to an open two-compartment model in 19 patients with bradyarrhythmias (mean age 70.8 years) admitted for implantation or replacement of a permanent pacemaker system. After the first infusion of flucloxacillin (5 min), the distribution phase was rapid (t1/2α=0.13 h). The plasma half-life of elimination (t1/2β) was 1.51 h, which is almost twice as long as reported in healthy volunteers. Total plasma clearance (93.1 ml/min) was also lower than is usually found in healthy individuals, due to low renal clearance of flucloxacillin (60.2 ml/min). The total apparent volume of distribution during the β-phase (Vdarea) was 0.172 l/kg and distribution in the central compartment (Vc) 0.064 l/kg. In each patient plasma protein binding and drug distribution to plasma water, proteins and blood cells in whole blood were determined. Binding in plasma to proteins was 91.0% and distribution to blood cells in whole blood 13.8%. The mean distribution volume of free flucloxacillin during the β-phase (Vdβ free) was 2.18 l/kg, which exceeds total body water, suggesting possible intracellular distribution and substantial tissue binding. Plasma concentrations of flucloxacillin after the fourth dose (1 g t.i.d.) were very similar to those obtained after the first infusion and those predicted from the single dose kinetics. The concentration of flucloxacillin in fluid from the pacemaker pockets in 5 patients averaged 12.1 µg/ml and 9.5 µg/ml at 1 and 5 h, respectively, which was more than ten times the MIC-values for Staphylococcus aureus and S. epidermidis. The average concentration ratio (tissue fluid/plasma) was 0.57. Thus the pharmacokinetics of flucloxacillin in these elderly patients exhibited marked differences from what has been found in healthy volunteers. Despite the high degree of plasma protein binding, flucloxacillin appears to distribute rapidly and efficiently to extravascular compartments, such as a pacemaker pocket.
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  • 48
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    European journal of clinical pharmacology 29 (1985), S. 21-24 
    ISSN: 1432-1041
    Keywords: nisoldipine ; nifedipine ; pharmacokinetics ; pharmacodynamics ; calcium channel blocking drugs ; hypertension ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamic and pharmacokinetic profiles of nifedipine and nisoldipine were compared in a double blind, placebo-controlled study. Nisoldipine, 10 mg significantly reduced systolic blood pressure but nifedipine 20 mg retard did not, although both drugs had significant pharmacodynamic effects as evidenced by increased heart rates. The terminal elimination half-life in plasma was similar for both drugs with a mean of 2 h. The pharmacodynamics of nisoldipine were studied in 8 hypertensives following both acute and chronic administration. Antihypertensive efficacy was demonstrated after acute dosing and was maintained over 4 weeks of twice daily treatment as monotherapy.
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  • 49
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    European journal of clinical pharmacology 29 (1985), S. 49-53 
    ISSN: 1432-1041
    Keywords: digoxin ; digoxin serum concentration ; drug interaction ; digoxin clearance ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An open, randomized, single-blind cross over trial to investigate phenytoin-digoxin interactions at steady state was performed in 6 healthy male volunteers. Coadministration of phenytoin caused a significant reduction in the elimination half-life of digoxin from 33.9 to 23.7 h and a diminution in AUC0–48 from 31.6 to 24.4 ng · ml−1 · h. Renal digoxin clearance was not significantly altered from 135.7 to 120.3 ml · min−1. Assuming no change in β-acetyldigoxin absorption, the in decrease time-course the serum digoxin concentration was due to a significantly increased total digoxin clearance from 258.6 to 328.3 ml · min−1. An insignificant reduction in the digoxin distribution volume from 749.4 to 668.0 l was also observed. No relevant change in the pharmacokinetic parameters (elimination half-life, area under the serum concentration time-curve, protein binding) of phenytoin was observed when phenytoin and digoxin were co-administered. The data suggest that with this drug combination the serum digoxin concentration should be carefully monitored and, if necessary, the daily digoxin dose should be increased.
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  • 50
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    European journal of clinical pharmacology 29 (1985), S. 61-66 
    ISSN: 1432-1041
    Keywords: ergotamine ; pharmacokinetics ; blood/plasma concentration ratio ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ergotamine tartrate 0.5, 0.25 and 0.125 mg was administered i.v. to 6 volunteers in a cross-over study. Its pharmacokinetic characteristics were evaluated from plasma concentration-time data determined by HPLC. The clearance and volume of distribution were independent of the dose. The ratio between blood and plasma ergotamine concentrations in 4 subjects ranged from 0.41–0.67, indicating the lack of binding to blood cells. Ergotamine was found to be a high clearance drug, average 2.21/min/70kg body wt. suggesting extrahepatic clearance. A possible transient decrease in liver blood flow caused by ergotamine did not seem to affect the linearity of its kinetics.
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  • 51
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    European journal of clinical pharmacology 29 (1985), S. 73-77 
    ISSN: 1432-1041
    Keywords: pirprofen ; arthritic disease ; pharmacokinetics ; elderly patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of pirprofen were measured in 11 elderly arthritic patients and 6 healthy young volunteers at the beginning and end of 8 days treatment with 400 mg doses twice daily. The mean ages of the two groups were 74.5 and 21.8 years, respectively. There were no statistically significant differences in peak concentrations, times to peak, areas under the curve or terminal elimination half-lives between the groups after single dosing. Repeated dosing increased plasma drug concentrations in both groups but the extent was as predicted from the single dose data. Again there were no statistically significant differences between the groups, although pre-dosing plasma concentrations were higher in the elderly compared with the young individuals. The results of this relatively small study suggest that advancing age and arthritic disease appear to have little influence on the pharmacokinetics of pirprofen and no modification in the dosage recommendation in elderly patients without overt renal or hepatic impairment is indicated.
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  • 52
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    European journal of clinical pharmacology 29 (1985), S. 85-89 
    ISSN: 1432-1041
    Keywords: triamcinolone acetonide ; triamcinolone acetonide phosphate ; pharmacokinetics ; high dose ; glucocorticoids ; renal excretion ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Triamcinolone acetonide in the form of its phosphate ester was given intravenously in two different doses (10 mg/kg and 80 mg). Plasma levels of the ester and triamcinolone acetonide were measured and pharmacokinetic parameters were calculated. The pharmacokinetics both of the phosphate and the free alcohol were dose-dependent. No unchanged ester was found in the urine, indicating complete conversion of the pro-drug. Triamcinolone was not a major metabolite of triamcinolone acetonide in humans. Renal clearance was low and independent of the dose. Only about 1% of the dose was found in the urine as triamcinolone acetonide.
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  • 53
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    European journal of clinical pharmacology 29 (1985), S. 79-84 
    ISSN: 1432-1041
    Keywords: dextropropoxyphene ; norpropoxyphene ; pharmacokinetics ; single dose ; multiple dose ; prediction ; saturation ; auto-induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of dextropropoxyphene (DP) and its main metabolite norpropoxyphene (NP) were studied in 6 healthy male subjects after a single oral dose of 195 mg DP HCl, and during and after 12 daily single oral doses of 195 mg DP HCl. The kinetics varied up to five-fold between individuals after the single dose, the apparent mean elimination half-life (t1/2) was 16 h for DP and 29 h for NP. The mean apparent overall plasma clearance (CL) for DP was 2.61/min. There was no systematic difference in DP clearance between the single and multiple doses, but the accuracy of individual predictions from single to multiple doses was poor, probably because of imprecise determinations of the AUC and t1/2 in the single dose experiments. The individual correlation between single and multiple dose kinetics was good for NP, although the predicted plasma levels during steady state were significantly higher than the observed levels (mean AUCss/AUCsd: 0.81). There was no sign of saturation kinetics on repeated administration. In fact, autoinduction, resulting in significantly lower plasma concentrations after treatment for 1 week was found for NP and was indicated for DP. On discontinuing DP after 12 days of treatment, the apparent mean t1/2 of DP was 23 h and of NP 25 h.
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  • 54
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    European journal of clinical pharmacology 29 (1985), S. 91-95 
    ISSN: 1432-1041
    Keywords: midazolam ; 1-hydroxymethylmidazolam ; pharmacokinetics ; dose proportionality ; benzodiazepine ; healthy volunteers ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the Cmax and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This ist not expected to have any clinical significance under the conditions of therapeutic use.
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  • 55
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    European journal of clinical pharmacology 29 (1985), S. 97-103 
    ISSN: 1432-1041
    Keywords: bupropion ; metabolites ; pharmacokinetics ; single and multiple dose ; side-effects ; enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions.
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  • 56
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    European journal of clinical pharmacology 29 (1985), S. 109-113 
    ISSN: 1432-1041
    Keywords: griseofulvin ; skin blister fluid levels ; pharmacokinetics ; healthy subjects ; bioavailability ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Griseofulvin and 6-demethylgriseofulvin (6-DMG) in plasma, suction blister fluid (SBF) and cantharides blister fluid (CBF) and urinary excretion of 6-DMG, were evaluated following administration of single oral doses of an ultramicrosize and a microsize formulation of griseofulvin to 6 healthy volunteers. The bioavailability of griseofulvin was higher following the ultramicrosize formulation when 64% of the dose was recovered (via metabolites) versus 52% after the microsize preparation. Penetration into skin blister fluid was delayed as compared to plasma levels; the peak concentration in plasma was observed at 3–4 h, whereas griseofulvin in CBF increased up to 6 h. The terminal half-live was calculated from plasma levels to 9.3 h. The half-lives calculated from SBF and CBF concentrations were 9.2 and 9.8 h, respectively, (n=5). In plasma 84% of griseofulvin was bound to proteins, predominantly to albumin; binding in SBF and CBF was 72 and 82%, respectively. 3 h after drug administration the free concentration in plasma significantly exceeded the free concentrations in SBF and CBF. Distribution equilibrium between plasma and skin blister fluid was observed after 27 h. Thus, during chronic administration, the plasma griseofulvin level should reflect its concentration in the target organ.
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  • 57
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    European journal of clinical pharmacology 29 (1985), S. 115-117 
    ISSN: 1432-1041
    Keywords: enprofylline ; theophylline ; pharmacokinetics ; patients ; theophylline requirement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In patients requiring a high or low dose of theophylline the pharmacokinetics of theophylline and enprofylline were studied. The low-dose group took an average daily dose of 8.91 mg/kg body wt. and the high-dose group 24.75 mg/kg body wt. The average half-life of theophylline in the former was 7.11 h and in the latter 4.72 h. The average clearances (CL) of theophylline were 2.83 and 4.58 l/h, respectively. The daily oral intake of theophylline was negatively correlated with the theophylline t1/2 (r=−0.63). While the t1/2 of enprofylline was similar in the two groups, CL and volume of distribution (Vc) were slightly (about 30%) but significantly higher in patients requiring a high dose of theophylline. CL of enprofylline did not correlate with CL of theophylline, nor was the Vc of the two drugs correlated. Interindividual variability in t1/2 and CL was considerably lower for enprofylline than for theophylline.
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  • 58
    ISSN: 1432-1041
    Keywords: metaclazepam ; benzodiazepines ; (KC-2547) ; N-desmethyl-methaclazepam KC-3755) ; pharmacokinetics ; old and young volunteers ; side-effects ; age effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single-centre, open, Phase I-study comparison of the pharmacokinetics of a single dose of metaclazepam 10 mg, a new 1,4-benzodiazepine has been done in 10 older and 20 younger volunteers. No important age-related effect was found on the kinetics of metaclazepam or its N-desmethyl derivative, the principal metabolite in man.
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  • 59
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    European journal of clinical pharmacology 29 (1985), S. 235-239 
    ISSN: 1432-1041
    Keywords: amoxycillin ; clavulanic acid ; pharmacokinetics ; side-effects ; paediatric formulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A combination of amoxycillin and clavulanic acid 4:1 was administered to 35 children (aged 2 to 10 years) with infections. The combination was administered orally as a suspension, every 8 h for 5 to 7 days. Sixteen children (aged 2 to 5 years), received 125 mg amoxycillin and 31.25 mg clavulanic acid, and 19 (6 to 10 years) received 250 mg amoxycillin and 62.5 mg clavulanic acid per dose. Following the first dose serum concentrations of amoxycillin and clavulanic acid were determined by microbiological assay. In the younger group receiving the lower dosage (mean: amoxycillin 9.11 mg/kg and clavulanic acid 2.34 mg/kg), the mean peak concentration of amoxycillin was 3.5 mg/l and of clavulanic acid 1.2 mg/l, occurring 1.32 h and 1.39 h, respectively, after administration. In the older group receiving the higher dosage (mean: amoxycillin 12.35 mg/kg and clavulanic acid 3.14 mg/kg) the mean peak serum level of amoxycillin was 4.0 mg/l and of clavulanic acid 1.3 mg/l, occurring 1.43 h and 1.23 h, respectively, after administration. The higher dose per kilogram body weight resulted in a higher peak serum concentration both of amoxycillin and clavulanic acid. The formulation was well tolerated by all the children and no serious side-effects were recorded. Treatment was considered clinically effective in all cases.
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  • 60
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    European journal of clinical pharmacology 29 (1985), S. 255-256 
    ISSN: 1432-1041
    Keywords: gentamicin ; malnutrition ; protein-energy deficiency ; malnourished children ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of i.m. gentamicin was the same in malnourished (n=6) and normal (n=4) children.
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  • 61
    ISSN: 1432-1041
    Keywords: trimazosin ; cimetidine ; pharmacokinetics ; alpha-adrenoceptor antagonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of cimetidine treatment on the pharmacokinetics and pharmacodynamics of single doses of trimazosin was studied in 6 normotensive volunteers. Co-administration of cimetidine did not significantly affect the overall magnitude of the hypotensive effect of trimazosin. However, the time profile of the blood pressure response was significantly modified particularly with attenuation of the delayed component. Co-administration of cimetidine did not alter alpha1-adrenoceptor antagonism by trimazosin. There was no significant change in the clearnace and volume of distribution of trimazosin but there was a significant reduction in the area under the concentration-time curve for the metabolite, 1-hydroxytrimazosin. The reduction in the AUC of 1-hydroxy-trimazosin corresponds in time with the attenuation of the delayed hypotensive response. This is consistent with the suggestion that the delayed hypotensive response is related to an active metabolite, probably 1-hydroxytrimazosin.
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  • 62
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    European journal of clinical pharmacology 29 (1985), S. 351-354 
    ISSN: 1432-1041
    Keywords: griseofulvin ; skin blister fluid ; plasma concentration ; blister fluid concentration ; pharmacokinetics ; microsize formulation ; urinary excretion ; bioavailability ; different formulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Griseofulvin was administered orally to 6 healthy volunteers for 6 days. The subjects received 500 mg of a microsize formulation and 330 mg of an ultramicrosize formulation, according to a cross-over design. The drug was determined in plasma, suction blister fluid (SBF) and cantharides blister fluid (CBF) following the last dose. Urinary excretion of the main metabolites 6-demethylgriseofulvin (6-DMG) and its glucuronic acid conjugate was also measured. The pharmacokinetic parameters were compared with those obtained from a recent single dose experiment. On repeated administration, the bioavailability of griseofulvin was significantly lower from the microsize formulation; the urinary recovery of total 6-DMG was 33.8% versus 53.6% on administration of the ultramicrosize material. Bioavailability was reduced as compared to ingestion of a single dose. The reduction was more prominent following the microsize (36%) than the ultramicrosize (17%) formulation. Penetration into skin blister fluid was not altered as compared to the single dose experiment. Relative areas under the blister fluid-time curves amounted to 51% (SBF) and 80% (CBF) of the area under the plasma level-time curve. The concentration of unbound griseofulvin in these body fluids was identical throughout the entire dosage interval. Unbound griseofulvin levels were low in comparison with the minimum inhibitory concentrations for strains of trichophyton and microsporum.
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  • 63
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    European journal of clinical pharmacology 29 (1985), S. 395-399 
    ISSN: 1432-1041
    Keywords: Ro 31-1118 ; cardioselectivity ; hypertension ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with mild hypertension were given single oral doses of Ro 31-1118 (10, 20, 40, and 80 mg) and placebo in a randomized, double-blind, within-patient study. Plasma concentrations of Ro 31-1118 and supine, standing, exercise, and post-exercise heart rates and blood pressures were measured before and at regular intervals after drug administration. The pharmacokinetic data were consistent with a one-compartment model with first-order absorption and a variable time lag. Peak plasma concentrations and area under curve were linearly related to dose, whereas time to peak concentration, half-time, clearance and apparent volume of distribution were dose-independent. There was a reduction in exercise and post-exercise heart rate of approximately 10% after 10 mg and 20 mg Ro 31-1118, and of approximately 15% after 40 mg and 80 mg. At all doses standing systolic blood pressure was reduced by approximately 5%. A similar fall was seen in exercise and post-exercise systolic blood pressures. There was no substantial effect of Ro 31-1118 on supine or standing heart rates nor on diastolic blood pressure. No adverse effects were reported. It is concluded that Ro 31-1118 has linear pharmacokinetics over the dose range 10–80 mg, and has a weak antihypertensive effect when administered in single doses to patients with mild hypertension.
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  • 64
    ISSN: 1432-1041
    Keywords: amiodarone ; desethylamiodarone ; iodine ; pharmacokinetics ; thyroid function ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 23 patients treated with the iodine-containing antiarrhythmic drug amiodarone, the plasma concentrations of amiodarone, desethylamiodarone and iodine have been studied. Besides amiodarone and desethylamiodarone, a pool of iodine-containing substances, NANDAI (non-amiodarone-, non-desethylamiodarone-iodine), was present. At steady state the iodine content of NANDAI amounted to 64% and the iodine content of amiodarone plus desethylamiodarone to 36% of total serum iodine. At steady state 26% of the NANDAI fraction was made up of inorganic iodide, the average plasma concentration of which was at least 40 times above the upper limit of the normal range. The serum elimination half-life of NANDAI of 57–160 days exceeded that of amiodarone (35–68 days) and of desethylamiodarone (31–110 days). At steady state the serum concentration of desethylamiodarone appears to be related to the concentration of amiodarone by a Michaelis-Menten type function, yielding a Km of amiodarone of 2.45 µmol/l and a maximal desethylamiodarone concentration of 3.61 µmol/l.
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  • 65
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    European journal of clinical pharmacology 29 (1985), S. 405-411 
    ISSN: 1432-1041
    Keywords: bornaprolol ; propranolol ; beta-adrenoceptor blockade ; duration of action ; pharmacokinetics ; plasma renin activity ; bronchoconstriction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The β-adrenoceptor blocking effects and pharmacokinetics of bornaprolol (FM 24), a new β-adrenoceptor blocking agent, have been compared with those of propranolol and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate, systolic and diastolic blood pressures and peak expiratory flow rate were measured at rest and at the end of 3 min vigorous exercise on a bicycle ergometer, before and 2, 24 and 48 h after single oral doses of bornaprolol (120, 240 and 480 mg) and propranolol (40, 80 and 160 mg). Plasma renin activity at rest and the plasma concentrations of the two drugs were determined. Bornaprolol significantly reduced resting heart rate, dose-dependently lowered exercise-induced tachycardia and decreased peak expiratory flow rate and plasma renin activity. In addition, exercise-induced tachycardia was significantly reduced by bornaprolol up to 48 hours after drug intake (pharmacodynamic half-life approximately 63–86 h) and there was a correlation between this reduction and the log plasma bornaprolol concentration over the 48-h period. Thus, bornaprolol behaved in man as a non-cardioselective and long-lasting β-adrenoceptor blocking drug, probably devoid of intrinsic sympathomimetic activity.
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  • 66
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    European journal of clinical pharmacology 29 (1985), S. 443-446 
    ISSN: 1432-1041
    Keywords: dysmenorrhoea ; ibuprofen ; intra-uterine pressure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Intra-uterine pressure was recorded in a dysmenorrhoeic patient for 10 h before and after administration of a single dose of ibuprofen 400 mg. Bloodsamples were obtained at regular intervals during the recording for determination of the serum concentration of ibuprofen by reverse HPLC. The maximum serum concentration (37.4 µg Ml−1) was achieved after 1 h and the terminal half-life of ibuprofen was approximately 2 h. A marked reduction in intra-uterine pressure and the severity of pain was recorded 1.5 h following the administration of ibuprofen. Despite low or non-detectable serum concentrations of ibuprofen after 4 h, intra-uterine pressure never regained the level recorded before treatment.
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  • 67
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    European journal of clinical pharmacology 29 (1985), S. 467-469 
    ISSN: 1432-1041
    Keywords: baclofen ; stroke ; elderly patients ; pharmacokinetics ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A double blind crossover trial of baclofen against placebo in elderly stroke patients was discontinued because the drug produced an unacceptably high level of drowsiness. In a subsequent study baclofen 10 mg was given orally to 12 elderly stroke patients, and drug concentrations measured from a series of plasma samples. A group of healthy subjects given the same dose in a previous study were used as controls. Elderly patients took longer to achieve peak plasma baclofen concentrations, but healthy controls had higher peak values and eliminated the drug more rapidly; areas under the curve were similar in the two groups. Simulations based on mean data suggest that increased drowsiness in the elderly was probably not due to changes in the drug's pharmacokinetic behaviour.
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  • 68
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    European journal of clinical pharmacology 28 (1985), S. 113-117 
    ISSN: 1432-1041
    Keywords: nadolol ; nifedipine ; tachycardia ; cardiovascular response ; healthy volunteers ; pharmacokinetics ; exercise heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a placebo controlled exercise protocol using healthy volunteers the effects of nadolol 80 mg and 160 mg orally and of nadolol 80 mg during treatment with nifedipine 20 mg 8 hourly were compared. Resting systolic and diastolic blood pressures were reduced by both nifedipine (p〈0.05) and nadolol (p〈0.01) acting alone. An unexpected finding was that nifedipine alone significantly inhibited exercise tachycardia (p〈0.01) (8 to 12 h post dose). Predictably both doses of nadolol produced significant reduction in exercise tachycardia which was still apparent at 24 h. There was a linear relationship between log10 plasma nadolol concentration and reduction in exercise heart rate. The combined inhibitory effects of nifedipine and nadolol 80 mg on exercise heart rate showed partial additivity but did not summate. There was no pharmacokinetic interaction between the 2 drugs. The inhibition of exercise tachycardia by nifedipine, not previously documented, is consistent with an effect of the drug on the sinus node, as has been reported in in-vitro studies, and may contribute to the drugs efficacy in angina.
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  • 69
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    European journal of clinical pharmacology 28 (1985), S. 171-175 
    ISSN: 1432-1041
    Keywords: pethidine ; drug metabolism ; pethidine metabolites ; renal excretion ; pharmacokinetics ; geriatrics ; old age ; meperidine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a previous study old subjects were found to eliminate pethidine and its active metabolite norpethidine more slowly than young people. To investigate whether this was due to the decline in renal function with age, the urinary output of pethidine and its metabolites pethidinic acid, norpethidine and norpethidinic acid was compared in old and young patients. The cumulative urinary excretion of pethidine and pethidinic acid over 24 h was similar in old and young patients. The slower elimination rate of pethidine from plasma might therefore be due to slower biotransformation of pethidine to norpethidine and norpethidinic acid. The cumulative urinary excretion of norpethidine and norpethidinic acid during 24 h was significantly lower in old patients than in young: 2.7% versus 7.1% (p〈0.001), and 5.5% versus 10.5% (p〈0.001). The renal clearance of norpethidine was inversely correlated with age. Thus, the slower disappearance of norpethidine from plasma in old patients is due to slower renal excretion of this metabolite. The renal clearance of pethidine showed pH-dependence and was usually smaller than the creatinine clearance. In contrast, renal clearance of norpethidine was correlated with creatinine clearance and was of the same magnitude. The difference in renal handling may be explained by the more polar character of norpethidine compared to its parent compound. The present study shows that not only the excretion of unchanged drugs may decline with increasing age but also that of drug metabolites, which may therefore reach higher plasma levels in old patients. If they are pharmacologically active they will increase and prolong the response to medication and possibly increase the risk of side effects.
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  • 70
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    European journal of clinical pharmacology 29 (1985), S. 215-219 
    ISSN: 1432-1041
    Keywords: penbutolol ; renal impairment ; beta-adrenoceptor blocking agents ; metabolism ; hypertension ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of penbutolol, its 4-hydroxylated metabolite and of their conjugates was studied in hypertensive patients with various degrees of renal impairment. A single oral dose of penbutolol 40 mg, was rapidly absorbed after a lag-time of 0.34 h. Its plasma concentration reached a maximum after 0.84 h and then declined bi-exponentially, with an apparent elimination half-life of 21.8 h. The hydroxylation of penbutolol was negligible and conjugation was of major importance for its elimination. Consequently, the kinetics of unchanged penbutolol were not altered by renal impairment. The 48 h-urinary excretion of penbutolol and its metabolites reached 13–14% of the administered dose, which is consistent with extensive metabolism of the drug. After treatment for 30 days with penbutolol 40 mg/d there was no accumulation of the parent drug but the concentration of its conjugates was increased. It is concluded that the dose of penbutolol need not be changed in patients with mild renal insufficiency, 4-hydroxypenbutolol is unlikely to participate in the anti-hypertensive effect of the drug, due to its low concentrations, and biotransformation of penbutolol may be enhanced during chronic treatment.
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  • 71
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    European journal of clinical pharmacology 29 (1985), S. 221-224 
    ISSN: 1432-1041
    Keywords: fenfluramine ; norfenfluramine ; isomers ; pharmacokinetics ; healthy volunteers ; chronic treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of accumulation and elimination of d- and l-fenfluramine (F) and norfenfluramine (NF) have been studied in 8 young healthy volunteers given daily doses of 60 mg of sugar-coated tablets of 20 mg dl-F hydrochloride (dl-F) t.i.d. and capsules of 15 mg d-F hydrochloride (d-F) b.i.d. for 15 days. Repeated doses of d-F plus l-F gave the same values for the parameters measured as did d-F administered alone. Steady-state concentrations of all compounds were achieved within 4–8 days. The predicted mean steady-state concentrations of d-F and elimination half-lives calculated from the results of a previous single dose study were similar to those measured at steady state in this study, confirming the lack of effect of the drug on hepatic microsomal enzymes and on kinetics after repeated dosing. d-NF concentrations were approximately half those of the parent drug and the half-life was almost twice as long. Steady state concentrations both of L-f and l-NF were consistently about 40–50% higher than of the d-isomers and there was a comparable in the half-life.
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  • 72
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    European journal of clinical pharmacology 29 (1985), S. 323-329 
    ISSN: 1432-1041
    Keywords: lignocaine ; pharmacokinetics ; proteinbinding ; indocyanine green ; ageing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Single dose studies were performed in six young and six elderly nonsmokers using lignocaine as a model drug with high intrinsic clearance. Subjects received lignocaine 250 mg orally and 50 mg intravenously in random order and drug concentrations in blood and plasma were measured for up to 8 h after dose. Protein binding was estimated at 37 °C by equilibrium dialysis. Indocyanine green kinetics were also calculated in each individual following 0.15 mg/kg intravenously. Bioavailability of lignocaine was greater in the elderly but there was no apparent difference in the rate of absorption. Intrinsic clearance of lignocaine was lower in the aged. Elimination half-life was longer in the elderly but there was no significant difference in apparent volume of distribution or systemic clearance of lignocaine. Plasma clearance of indocyanine green showed no correlation with systemic lignocaine clearance and was lower in the aged subjects. Blood/plasma lignocaine ratio was less than unity in both groups. Binding of lignocaine to plasma proteins showed concentration-dependence and was higher in the geriatric group. Maximum binding capacity of lignocaine was greater in the elderly but the binding affinity did not significantly change with age. Greater oral bioavailability of drugs like lignocaine may produce higher plasma concentrations in the elderly. Unlike indocyanine green, the systemic clearance of lignocaine was unaltered by age in this group of non-smokers. The protein-binding of lignocaine, like many other basic drugs, is increased in elderly subjects.
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  • 73
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    European journal of clinical pharmacology 29 (1985), S. 345-349 
    ISSN: 1432-1041
    Keywords: pefloxacin ; renal insufficiency ; pharmacokinetics ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of pefloxacin has been studied after a single intravenous infusion of 8 mg·kg−1 in 15 male patients with various degrees of renal failure. No difference in distribution or elimination of the drug was observed between patients with mild or severe renal impairment. The mean volume of distribution (Vd area) and the mean plasma clearance were 2.03l·kg−1 and 121.3 ml·min−1, respectively. The mean apparent elimination half-life was 13.5 h. These values are close to those observed in healthy subjects. No accumulation of the active N-desmethylmetabolite was observed in cases of severe failure as compared to mild impairment; its apparent elimination half-life was about twice that of the parent drug. The efficacy of a 4 h haemodialysis in 6 additional anuric subjects done to remove pefloxacin from the body was poor.
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  • 74
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    European journal of clinical pharmacology 29 (1985), S. 337-343 
    ISSN: 1432-1041
    Keywords: piretanide ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Piretanide 60 mg was administered intravenously over 30 min to 15 men with different degrees of renal failure. The mean piretanide serum concentration at the end of the infusion period was 5.72±1.51 µg/ml. Serum piretanide concentration-time curves declined biexponentially and 24 hours after medication the serum level had fallen to less than twice the detection limit. The terminal half-life ranged from 1.63 to 3.44 h. A relationship to creatinine clearance was not demonstrable. The mean metabolic clearance of piretanide was 107.7±47.6 ml/min/1.73 m2 body surface area and was the same as that reported for healthy subjects. The renal clearance of piretanide ranged from 3.33 to 43.9 ml/min/1.73 m2 body surface area and very closely correlated with the creatinine clearance (p〈0.01). Its renal clearance dependend principally on active secretion of the drug into the tubule, and glomerular filtration appeared unimportant. There was a close relationship between the amount of piretanide excreted in the urine and the creatinine clearance. Because the diuretic effect of piretanide depends on the concentration of the drug in the tubule, the observed correlation might be of use in evaluating the appropriate dosage of piretanide in patients with renal failure. The present data suggest that single daily doses of piretanide will not result in accumulation, even when high doses are administered to patients with advanced renal failure.
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  • 75
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    European journal of clinical pharmacology 28 (1985), S. 205-212 
    ISSN: 1432-1041
    Keywords: adriamycin ; cancer patients ; infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma pharmacokinetics of adriamycin has been studied in 21 cancer patients (31–85 years old) without liver tumours after short (3.00 min) and prolonged (45 min-16h) i.v. infusions. The area under the plasma concentration-time curve and the maximum plasma concentration compensated for dose variation showed a more than 3-fold individual variation. The pharmacokinetics of adriamycin was linear. There was no pharmacokinetic rational for variation of the dose with the age of the patients. There was good agreement between the measured plasma concentration-time curves for prolonged infusions and curves predicted from pharmacokinetic data from short term infusions.
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  • 76
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    European journal of clinical pharmacology 28 (1985), S. 333-337 
    ISSN: 1432-1041
    Keywords: cefotoxin ; renal failure ; peritoneal dialysis ; pharmacokinetics ; CAPD (continuous ambulatory dialysis) ; dialysate concentration ; intra peritoneal administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin was examined in 9 patients undergoing peritoneal dialysis for chronic renal failure. Cefoxitin was administered intraperitoneally in the dialysate fluid every 6 h for 24 h, in two different concentrations, 50 µg/ml and 100 µg/ml. The plasma half-life of cefoxitin was 20.2 h. The major route of elimination was non-renal, with a clearance of 8.0 ml/min. Peritoneal clearance was 4.1 ml/min. As expected, renal clearance was negligible. The peak plasma concentrations of cefoxitin at the two dose levels used were 7 µg/ml and 15 µg/ml, respectively, when assayed by HPLC, and 12 µg/ml and 24 µg/ml when determined by a microbiological assay. The cefoxitin concentration in the dialysate decreased from 50 µg/ml to 14 µg/ml and from 100µg/ml to 37 µg/ml during the 6 h of its retention in the peritoneal cavity.
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  • 77
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    European journal of clinical pharmacology 28 (1985), S. 317-320 
    ISSN: 1432-1041
    Keywords: bufuralol ; debrisoquine ; sparteine ; genetic/oxidative polymorphism ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bufuralol is a beta-adrenoceptor blocking drug whose oxidative metabolism is under the same genetic control as debrisoquine and sparteine. The pharmacokinetics of bufuralol were studied in 10 healthy subjects (7 extensive and 3 poor metabolizers of debrisoquine) after oral and intravenous administration. In extensive metabolizers the systemic availability of bufuralol was 43%. Poor metabolizers were characterized by a considerable increase in systemic availability due to a corresponding decrease in hepatic first-pass metabolism. After oral administration of bufuralol non-linear kinetics may occur.
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  • 78
    ISSN: 1432-1041
    Keywords: prenalterol ; cardiac failure ; pharmacokinetics ; concentration-effect relationships
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Prenalterol was administered as an intravenous infusion at three incremental rates (60, 120 and 240 nmol/min) to five patients with severe cardiac failure. Haemodynamic, hormonal and metabolic variables were measured at the same time as plasma prenalterol concentrations, and the pharmacokinetics of the drug were studied by following plasma concentrations and urinary excretion during and after the infusion. Concentration-dependent increases in cardiac index, stroke index and stroke work index were observed without increases in arterial pressure, heart rate or myocardial oxygen demand. The reninangiotensin-aldosterone system was stimulated, although the extent of stimulation varied among patients. No strong correlations were found between the logarithm of the plasma prenalterol concentration and effect. Plasma clearance of the drug was lower in cardiac patients than in normal volunteers, but a large decrease in renal clearance was partially balanced by an increase in nonrenal clearance. Over the observed range of concentrations, no deviation from linearity was evident, and plasma concentrations of about 150 nmol/l were effective in improving cardiac function without significant side-effects.
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  • 79
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    European journal of clinical pharmacology 28 (1985), S. 405-410 
    ISSN: 1432-1041
    Keywords: verapamil ; renal failure ; norverapamil ; pharmacokinetics ; haemodialysis ; ECG ; blood pressure ; heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of verapamil was studied in patients with end-stage chronic renal failure and in normal subjects after i.v. injection of 3 mg and a single oral dose of 80 mg. Plasma levels of verapamil and its active metabolite norverapamil were measured by HPLC. After i.v. injection, the terminal phase half-life and total plasma clearance of verapamil in both groups were similar. Haemodialysis did not change the time course of plasma verapamil levels after i.v. administration. After a single oral dose, the plasma levels of verapamil and norverapamil in both groups of subjects were similar. Subsequently, normal volunteers and patients with renal failure were treated for 5 days with oral verapamil 80 mg t.d.s. There was no difference between the 2 groups of subjects in the trough and peak levels of verapamil or of norverapamil. Intravenous and oral administration of the calcium channel blocking agent had similar effects on blood pressure, heart rate and the PR-interval in the electrocardiogram in both groups. The study demonstrated that the disposition of verapamil was similar in normal subjects and in patients with renal failure.
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  • 80
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    European journal of clinical pharmacology 28 (1985), S. 411-417 
    ISSN: 1432-1041
    Keywords: ketanserin ; ketanserinol ; pharmacokinetics ; age ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of ketanserin has been examined in a cross-over experiment in 21 elderly subjects (aged 59–72 years) by administration of tablets (40 mg), solution (40 mg) and injectable solution (10 mg). After two weeks of treatment with 40 mg ketanserin tablets further 18 blood samples for analysis were collected under steady-state conditions. Plasma levels were measured by HPLC. The absolute bioavailability of ketanserin tablets was 52.7%; their relative bioavailability compared to a solution containing an equal quantity of active compound was 85.5%. Therefore, the low absolute bioavailability of ketanserin cannot be attributed to the formulation. The active compound was rapidly liberated from the tablet, reaching a peak of 103.8 ng/ml after 0.97 h. Individual plasma level-time curves were fitted to an open three compartment model and a half-life of 17.7±7.26 h was calculated for the terminal elimination phase. An average terminal elimination half-life of 15.4±4.2 ng/ml was found after administration of the ketanserin solution. Multiple dosing with 40 mg tablets b.d.s. resulted in an AUC over one dosing interval at steady-state of 666±201 ng × h/ml. The AUC extrapolated to infinity was 1200±405 ng × h/ml for the last tablet. This is 1.8-times the AUC in one dosing interval, and 2.3-times the AUC of a single dose. Under steady-state conditions, the mean peak plasma level was 155.1 ng/ml (1.08 h after dosing) and the terminal half-life was 19.1±5.1 h. For the metabolite ketanserinol terminal half-lives of 21.4 h after a single tablet and 31.0 h after discontinuation of multiple dosing were calculated. Compared to the parent compound there was much more marked accumulation of ketanserinol. Despite moderate accumulation and prolongation of the terminal half-life of ketanserin under steady-state conditions, dosage adjustment is not required in elderly people. First-pass metabolism and bioavailability remained in the range found in previous studies of ketanserin in young subjects.
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  • 81
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    European journal of clinical pharmacology 28 (1985), S. 543-552 
    ISSN: 1432-1041
    Keywords: thiopentone ; anaesthesia ; intravenous anaesthesia ; multi-stage infusion ; exponential infusions ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Several multi-stage infusion regimens and a computer controlled exponentially decreasing infusion regimen were evaluated in twelve patients undergoing head and neck surgery or neurosurgery. Thiopentone dosage was based on the mean of pharmacokinetic parameter values from the literature and adjusted for each patient's lean body mass in order to rapidly achieve a predetermined plasma thiopentone concentration of 15 or 20 µg/ml in the period following the initial bolus dose to induce anaesthesia. Anaesthesia was satisfactory in all cases. Plasma thiopentone concentrations were maintained between 10–20 µg/ml during infusion in the five patients who received either a four or five stage infusion and in the six patients who received the exponential infusion, but not in the single patient who received a two-stage infusion. The mean recovery time was 111 min. The plasma concentrations of total and unbound thiopentone at awakening showed little intersubject variability, despite considerable differences in total dose and duration of infusion, suggesting the absence of acute tolerance to the drug. Plasma clearance of total thiopentone correlated strongly with calculated lean body mass and to a lesser extent with total body weight suggesting that lean body mass, in particular, should be an accurate predictor of thiopentone maintenance dose requirements. This study shows that it is feasible to use thiopentone as a primary anaesthetic agent during surgery by administering the drug either as an exponentially decreasing infusion or as an infusion comprising 4 or 5 stepwise decreasing rates.
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  • 82
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    European journal of clinical pharmacology 28 (1985), S. 585-588 
    ISSN: 1432-1041
    Keywords: isoxicam ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The accumulation and disposition of the non-steroidal antiinflammatory drug isoxicam were investigated following its oral administration to 6 subjects with normal renal function and 13 patients with diminished renal function. Isoxicam was given daily as a single oral dose for 14–15 consecutive days. Steady-state plasma levels were achieved after 13 days. The effect of differences in renal function on the kinetics of isoxicam appeared to be minimal. Accumulation of isoxicam was similar in both groups of subjects and there was no significant difference between the groups in the plasma clearance or terminal half-life of isoxicam. There were substantial differences between individuals in the apparent plasma clearance and half-life of the drug, and this is reflected in the 7-fold range of steady-state plasma isoxicam concentrations encountered in the subjects.
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  • 83
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    European journal of clinical pharmacology 28 (1985), S. 611-613 
    ISSN: 1432-1041
    Keywords: molsidomine ; angina pectoris ; pharmacokinetics ; molsidomine retard
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester; Cassella-Riedel Pharma GmbH, Frankfurt/M. FRG) has an antianginal effect for up to 3–5 h after oral administration of 2 mg Corvaton [1]. Plasma levels of the parent drug can be measured during this interval. A new galenic formulation (Corvaton retard) has been developed to prolong the duration of the therapeutic action and to improve patient compliance. The present study was carried out to establish whether the in vitro dissolution profile of the tablet was reflected in vivo, thus permitting prediction of plasma molsidomine levels in patients with coronary heart disease.
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  • 84
    ISSN: 1432-1041
    Keywords: omeprazole ; renal failure ; gastric secretion ; pharmacokinetics ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The inhibitory effect of omeprazole on gastric acid secretion was tested in a group of patients on haemodialysis for chronic renal failure. Single 30 mg doses almost totally inhibited basal acid output on both dialysis and non-dialysis days. Plateau acid output was reduced by a mean of 77% and 90% on non-dialysis and dialysis days respectively. The absorption and pharmacokinetic profile of omeprazole were not affected by dialysis. Omeprazole was not recoverable from dialysis fluid. It is concluded that omeprazole is a potent inhibitor of gastric acid secretion in patients with chronic renal failure, and its effect is not influenced by haemodialysis.
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  • 85
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    European journal of clinical pharmacology 28 (1985), S. 659-664 
    ISSN: 1432-1041
    Keywords: BTS 49465 ; hypertension ; pharmacokinetics ; blood pressure effect ; heart rate effect ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60° head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.
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  • 86
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    European journal of clinical pharmacology 28 (1985), S. 665-670 
    ISSN: 1432-1041
    Keywords: tocainide ; renal failure ; pharmacokinetics ; oral dosing ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels of tocainide have been followed after oral administration of 600 mg p.o. to 20 patients with renal failure due to various causes, and to 8 healthy controls. The peak plasma concentrations in the patients with pyelonephritis (3.80 µg/ml) and interstitial nephritis (3.74 µg/ml) but not in those with glomerulonephritis (3.17 µg/ml) differed from that in healthy volunteers (3.24 µg/ml). The renal clearance of tocainide was well correlated with the endogenous creatinine clearance and was dependent on urine pH. No difference in renal clearance was observed between the patients groups. It is suggested that the changes in plasma levels are a consequence of decreased renal clearance. Creatinine clearance was shown to be a poor estimator of tocainide clearance, which suggests that extrarenal clearance plays an important role in the handling of the drug in the body. The findings are used to suggest a safe dosage regimen.
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  • 87
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    European journal of clinical pharmacology 28 (1985), S. 721-722 
    ISSN: 1432-1041
    Keywords: chloroquine ; rheumatoid disease ; desethylchloroquine ; capacity limitation ; pharmacokinetics ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of chloroquine and its major metabolite desethylchloroquine were studied in patients with rheumatoid disease after single oral doses of chloroquine phosphate corresponding to 150 and 300 mg chloroquine base. The findings strengthen the previous finding that the disposition of chloroquine involves rate limiting steps.
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  • 88
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    European journal of clinical pharmacology 28 (1985), S. 689-692 
    ISSN: 1432-1041
    Keywords: isoxicam ; piroxicam ; pharmacokinetics ; elderly ; anti-inflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of isoxicam and piroxicam were compared in 12 young adults (〈40 years) and 12 elderly subjects (〉65 years). After a single oral dose of 200 mg isoxicam or 20 mg piroxicam blood samples were taken for 168 h and the plasma drug concentrations determined by HPLC. The elimination half life of piroxicam for the adults was 57.1±16.4 h (mean ± SD; harmonic mean 52.9 h) and for the elderly subjects was 57.8±22.1 h (harmonic mean 52.1 h). The corresponding values after isoxicam were 34.3±13.6 h (harmonic mean 31.6) for the adults and 39.1±22.7 h (harmonic mean 33.5) for the elderly subjects. Similarly no differences were noted in either the AUC0-∞ after piroxicam (adults 154.1±52.2 µg·h/ml, elderly 163.6±99.1 µg·h/ml) and isoxicam (adults 642.7±241.9 µg·h/ml, elderly 787.9±613.1 µg·h/ml) or the apparent oral clearance of piroxicam (adults 2.39±0.80 ml/min, elderly 2.51±0.90 ml/min) and isoxicam (adults 5.84±2.04 ml/min, elderly 5.59±2.12 ml/min). One adult and two elderly subjects exhibited slower elimination of both medicines than the remainder of each group. However determination of the oxidation phenotype using sparteine metabolism showed that this was not a likely determinant of the reduced clearance.
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  • 89
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    European journal of clinical pharmacology 28 (1985), S. 77-84 
    ISSN: 1432-1041
    Keywords: β-Blockers ; debrisoquine metabolism ; extensive metabolizers ; genetic polymorphism ; poor metabolizers ; glucuronidation ; lipophilicity ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Although β-Blockers are structurally closely related, there are marked differences in the extent of metabolism, related mainly to relative lipophilicity. Lipophilic β-Blockers are metabolized by C-oxidative pathways and glucuronidation. Metabolism of lipophilic β-Blockers is important in determining pharmacokinetics, formation of active metabolites, stereoselectivity and isomer preference, and interphenotypic variation. The oxidative clearance of metoprolol, timolol and bufuralol is regulated/influenced by the debrisoquine hydroxylation gene locus. The metabolism of these lipophilic β-Blockers thus exhibits polymorphic characteristics, there being significant interphenotype differences in pharmacokinetics (bioavailability, peak plasma level, plasma terminal t1/2) between the poor and extensive metabolizers of debrisoquine. There are similar interphenotype differences in β-blocker pharmacodynamics in terms of β-blockade. A number of adverse effects of lipophilic β-Blockers have been hypothesized to predominate in the poor metabolizer phenotype including unacceptable bradycardia, loss of cardioselectivity, greater CNS side-effects, and interactions with drugs metabolized by the same polymorphic systems. However, objective evidence for this is lacking.
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  • 90
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    European journal of clinical pharmacology 29 (1985), S. 461-465 
    ISSN: 1432-1041
    Keywords: carteolol ; chronic renal failure ; pharmacokinetics ; dosage adjustment ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels and urinary excretion of carteolol and its main metabolites 8-hydroxycarteolol and carteolol glucuronide were investigated in 6 healthy subjects and 9 patients with varying degrees of renal impairment following a single oral dose of 30 mg carteolol hydrochloride. In healthy subjects the half-life of carteolol was 7.1 h. 63% of the administered dose was recovered unchanged in urine, and in all 84% was excreted by the kidneys. The renal clearance of carteolol was 255 ml/min. In chronic renal failure (CRF) the terminal half-life was increased to a maximum of 41 h. Both the elimination rate constant and renal clearance were closely related to the creatinine clearance. In CRF the recovery of carteolol and its metabolites from urine was considerably reduced, suggesting that another pathway of drug elimination becomes relevant in renal disease. To avoid an increase in side-effects due to drug accumulation, the dosage of carteolol should be adjusted in relation to the reduction in creatinine clearance. The maintenance dose should be reduced to a half in patients with a creatinine clearance below 40 ml/min and above 10 ml/min. In those with a creatinine clearance of 10 ml/min or less, the dose should be reduced to 1/4.
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  • 91
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    European journal of clinical pharmacology 29 (1985), S. 477-481 
    ISSN: 1432-1041
    Keywords: budesonide ; glucocorticoid ; nasal administration ; pharmacokinetics ; bioavailability ; systemic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Budesonide, a topically potent glucocorticoid, was administered to 4 healthy volunteers by i.v. infusion and by nasal instillation of 100 µg tritium-labelled drug. Plasma was analyzed by liquid chromatography plus scintillation counting of collected fractions. After i.v. administration the plasma clearance was 0.92 l/min and the apparent volume of distribution was 2.8 l/kg. After nasal administration, the time to reach the peak plasma level was approximately 30 min, and the systemic availability was 102%. Budesonide had marginal effects on plasma cortisol and white blood cell counts either after i.v. or nasal administration. Thus, nasally instilled budesonide in solution is rapidly and completely absorbed from the nasal mucosa. The systemic effects after this clinically recommended nasal dose were negligible.
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  • 92
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    European journal of clinical pharmacology 28 (1985), S. 197-204 
    ISSN: 1432-1041
    Keywords: triprolidine ; BW 825C ; pharmacokinetics ; pharmacodynamics ; sedation ; intradermal histamine ; human performance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The new H1-receptor antagonist BW 825C and triprolidine (2.5 and 5 mg) were administered to 12 healthy male volunteers in a double blind placebo controlled, balanced, crossover design. Histamine antagonism was measured by assessment of flare and weal areas after intradermal injection of histamine. The 2 compounds were approximately equipotent in blocking the flare and weal response to intradermal histamine and had a similar duration of action. Triprolidine impaired performance of vigilance and reaction time (p〈0.05) compared with placebo while BW 825C did not. Drowsiness measured using visual analogue scales followed both triprolidine treatments, but not BW 825C. BW825C had a plasma half-life (t1/2) of 1.7±0.2 h and triprolidine of 4.6±4.3 h. The peak plasma level of BW 825C was approximately 6 times that of triprolidine. It was concluded that BW 825C might be a clinically active H1-antagonist with reduced sedative side-effects.
    Type of Medium: Electronic Resource
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  • 93
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    European journal of clinical pharmacology 28 (1985), S. 225-227 
    ISSN: 1432-1041
    Keywords: theophylline ; absorption ; food intake ; aqueous solution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of food on the rate and extent of absorption of theophylline was studied in healthy adults given a single dose of theophylline (aqueous solution of choline theophyllinate containing 270 mg of theophylline) in the evening either on an empty stomach or together with supper. Food appeared to decrease the absorption rate of theophylline significantly, tmax being prolonged from 1.34 h (mean) to 4.40 h and cmax decreased from 7.82 mg·l−1 to 5.47 mg·l−1. The area under the plasma concentration-time curve (AUC) after drug intake with supper was slightly but not significantly smaller, indicating that theophylline (as a solution of choline theophyllinate) can be taken together with food without substantial loss of the quantity of drug absorbed. The elimination rate was not influenced by concomitant intake of supper.
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  • 94
    ISSN: 1432-1041
    Keywords: amiodarone ; warfarin ; drug interaction ; metabolism ; inhibition ; plasma concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Potentiation of the anticoagulant-effect of warfarin by amiodarone was studied in 30 patients. Thirteen received both drugs concurrently, and 17 received warfarin alone and the combination sequentially. Warfarin doses were adjusted to maintain the prothrombin time between 25–30% of control and its kinetics were compared to those in 20 control patients who received warfarin alone. Potentiation occurred in 28/30 patients, presenting as a 35%–65% reduction in the required dose of warfarin, and was correlated with the dose of amiodarone (r=0.77, p〈0.01). The free warfarin fraction was not affected by amiodarone (1.8% vs 1.6% in the controls). Warfarin clearance was lower in amiodarone-treated patients than in the controls (1.4 vs 3.1 ml/min, p〈0.01) with similar plasma concentrations (1.5 vs 1.2 µg/ml) despite administration of lower doses (23.3 vs 39 mg/week respectively). The amiodarone concentration was significantly correlated with the warfarin concentrations independent of the effect of amiodarone on the dose of warfarin. Amiodarone hat no effect on prothrombin other than through its actions on the dose and plasma concentration of warfarin. The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose — and concentration — dependent inhibition of warfarin elimination.
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  • 95
    ISSN: 1432-1041
    Keywords: famotidine ; renal failure ; H2-receptor antagonist ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new, potent H2-receptor antagonist, famotidine, 20 mg i.v. was studied in 7 subjects with normal renal function and in 24 patients with varying degrees of renal impairment. The volume of distribution at steady state was 1.14 l/kg in normal subjects and was not altered in renal failure. The half-life of elimination was 2.59 h in normal subjects and was unchanged in mild renal failure (creatinine clearance, CLCR 90–60 ml/min/1.48 m2) but was increased to 4.72 h in moderate renal failure (CLCR 60–30 ml/min/1.48 m2), and to 12.07 h in severe renal failure (CLCR below 30 ml/min/1.48 m2). The cumulative urinary excretion and renal clearance of famotidine were correspondingly reduced in patients with impaired kidney function. In normal subjects and in patients with mild to moderate renal failure, about 70% of famotidine was excreted through the kidney, mainly by tubular secretion. In patients with a CLCR above 60 ml/min/1.48 m2 the normal daily dose of famotidine can be employed, but in those with a CLCR between 60 and 30 ml/min/1.48 m2 the dose should be reduced by half, and in patients with a CLCR below 30 ml/min/1.48 m2 a reduction by three quarters of the normal dose is recommended.
    Type of Medium: Electronic Resource
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  • 96
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    European journal of clinical pharmacology 28 (1985), S. 425-428 
    ISSN: 1432-1041
    Keywords: caffeine ; oral contraceptives ; pharmacokinetics ; elimination half-life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of chronic (〉3 months) administration of low-dose oestrogen-containing (〈50 µg oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.750 l/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 µg/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.
    Type of Medium: Electronic Resource
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  • 97
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    European journal of clinical pharmacology 28 (1985), S. 433-437 
    ISSN: 1432-1041
    Keywords: isofezolac ; probenecid ; pharmacokinetics ; anti-inflammatory drug ; drug interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between isofezolac and probenecid has been studied with the aid of a specific HPLC assay for isofezolac in plasma and urine. 8 healthy adult volunteers received a single 40 mg oral dose of isofezolac before and after 3 days of loading with 0.5 g probenecid t.i.d. There was an increase in the maximum plasma isofezolac concentration from 2.44 to 3.38 µg · ml−1 when probenecid was given. The AUC of isofezolac in plasma increased from 6.73 to 11.28 µg · h · ml−1. After the last dose in a 7 day treatment with 40 mg isofezolac t.i.d., there was an increase in the maximum plasma isofezolac level from 2.84 to 4.96 µg · ml−1 when probenecid was given. The rate of absorption of isofezolac was not affected. An increase in the AUC of isofezolac in plasma was observed from 11.74 to 26.34 µg · h · ml−1. The major effect of probenecid on isofezolac metabolism was a 50% reduction in total isofezolac (free+conjugates) excreted inurine. Because of this interaction, patients given isofezolac combined with probenecid will have a higher steady-state plasma level of isofezolac than when probenecid is not administered.
    Type of Medium: Electronic Resource
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  • 98
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    European journal of clinical pharmacology 28 (1985), S. 453-456 
    ISSN: 1432-1041
    Keywords: zimeldine ; norzimelidine ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of zimeldine (Z) and its demethylated metabolite, norzimelidine (NZ), were determined after administration of a single 200 mg oral dose of Z to 6 healthy volunteers (Group I), and to patients with mild (Group II) and severe renal failure (Group III). Z and NZ concentrations were assayed by HPLC in serial plasma and urine samples over 6 days following the dose. In Group I Z was rapidly absorbed and metabolized into NZ, and then the plasma concentrations declined with apparent elimination half-lives of 8.4 h and 24.9 h for Z and NZ respectively, whilst the renal clearance of both compounds was low, Z 15.7 ml/min and NZ 33.0 ml/min. The plasma level of Z differed little between Groups I and III, but the area under the curve was significantly higher in Group III than in Group I subjects (AUC0–144=17.3 and 6.8 µmol·l−1·h, respectively). Severe renal failure did not affect the peak plasma concentration of NZ but it did significantly increase peak time, apparent elimination half-life, and the area under the plasma concentration curve. A significant inverse relationship was found between renal clearance of NZ and plasma creatinine. Since NZ is as pharmacologically potent as Z, the results suggest that the dose of Z should be reduced in patients with severe renal insufficiency.
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  • 99
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    European journal of clinical pharmacology 28 (1985), S. 429-431 
    ISSN: 1432-1041
    Keywords: theophylline ; asthma ; personality measures ; pharmacokinetics ; volunteers ; patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirteen volunteers received an iv dose of theophylline followed by blood sampling for 8 h to calculate pharmacokinetic parameters. Ten patients with asthma undergoing chronic dosing with slow release aminophylline underwent 12 h of blood sampling to calculate theophylline clearance. Both groups completed an Eysenck Personality Inventory (EPI) from which was derived scores for neuroticism (N) and extroversion (E). Using multiple regression analysis no independent effect of either N or E score on theophylline clearance or half-life could be demonstrated.
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  • 100
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    European journal of clinical pharmacology 28 (1985), S. 439-445 
    ISSN: 1432-1041
    Keywords: acetohydroxamic acid ; staghorn renal calculi ; pharmacokinetics ; 14C-labeled drug ; acetamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetohydroxamic acid (AHA), a bacterial urease inhibitor, has been recently approved by the United States Food and Drug Administration as a potential drug for the successful treatment of patients with infection induced staghorn renal calculi. The present study was designed to evaluate the disposition of 14C-AHA following oral administration to patients. The results of the study, while in a limited number of patients, indicate that upon oral administration, AHA is very rapidly absorbed from the gastrointestinal tract. Evaluation of urinary excretion data suggests that patients with compromised renal function have low recoveries of AHA in the urine. These data are supported by a strong linear correlation between creatinine clearance and AHA elimination. Acetamide and CO2 are identified as the two major metabolites of AHA in man. CO2 is eliminated in the breath and accounts for 20–45% of the administered dose, while acetamide is eliminated in the urine and accounts for only 9–14% of the administered dose. The remaining dose is eliminated as intact AHA in the urine (19–48%). Saliva concentrations of total radioactivity depict a strong positive correlation with their respective plasma concentrations. Parameter estimates from 14CO2 concentrations in breath as a function of time data closely correspond to the pharmacokinetic parameters of AHA in patients indicating that CO2 may be a primary metabolite derived directly from AHA rather than a secondary metabolite formed by the metabolism of an intermediate product. Upon multiple dose administration of AHA, there is the potential for significant accumulation of acetamide due to its relatively long half-life.
    Type of Medium: Electronic Resource
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