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  • 1990-1994  (1,636)
  • 1985-1989
  • 1990  (1,636)
  • Cell & Developmental Biology  (1,448)
  • pharmacokinetics  (125)
  • Ultrastructure
Material
Years
  • 1990-1994  (1,636)
  • 1985-1989
Year
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Biology and fertility of soils 9 (1990), S. 101-109 
    ISSN: 1432-0789
    Keywords: Phryganella acropodia ; Testate amoeba ; Growth rate ; Rhizopoda ; Feeding ; Fungal species ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Summary Clones of Phryganella acropodia were cultivated under different trophic conditions with bacteria as the food source. The doubling time was estimated to be 3 days. The edibility of four species of fungi, Aspergillus niger, Cunninghamella echinulata, Penicillium echinulatum and Stilbella bulbicola, was tested, but only Penicillium enchinulatum and Stilbella bulbicola were eaten and digested by the amoeba. An ultrastructure examination showed that there are two contractile vacuoles, many dictyosomes, a single nucleus with several nucleoli, and peroxisomes. The pseudopodia are filiform when attached to the substrate but change to lobose when the animal is floating. A thin organic membrane covers the aperture of resting forms.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-2307
    Keywords: Gastric carcinoma ; Capillaries ; von Willebrand factor ; Ultrastructure ; Immuno-electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The microvasculature of the stroma of human gastric carcinoma was studied by immuno-electron microscopy for factor VIII/von Willebrand factor (vWF) and conventional electron microscopy. In differentiated type (intestinal) gastric carcinoma (9 cases), capillaries were distributed more densely around carcinoma cell nests. vWF was localized in endothelial cells and neighbouring stroma. Ultrastructurally, capillary endothelial cells showed considerable hypertrophic changes with well-developed rough endoplasmic reticulum (rER). vWF was localized in well-developed rER, granules, Weibel-Palade bodies (WPB), in the vascular lumen as clusters, and diffusely deposited in the subendothelium. This indicates that endothelial cells in this group are transformed into a state of active protein production. In undifferentiated type (diffuse) gastric carcinoma (12 cases), capillaries were uniformly distributed and endothelial hypertrophic changes were less remarkable. vWF was localized in WPB, scanty rER and subendothelial matrix. Solid capillary buds were observed in both types; they were composed of a solid strand of endothelial cells without a visible lumen. Our results reveal that the microvasculature in tumour stroma differs significantly according to its histological type.
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  • 3
    ISSN: 1432-2307
    Keywords: Mucus-granule-containing ciliated cell ; Ciliated metaplasia ; Transitional form ; Gastric mucosa ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ciliated cells were found in the gastric mucosa in close association with intestinal metaplasia, mainly in the pyloric mucosa, of Japanese patients. The occurrence of ciliated cells is believed to be an acquired phenomenon and is considered to be a type of metaplasia; the term “ciliated metaplasia” is used to describe this phenomenon. Ciliated cells are found in the basal part of the glands among normal-looking mucous cells, mucous neck cells and neuroendocrine cells, but never on the surface or in foveolar epithelium. In ciliated cellcontaining glands, mitoses were noted in the neck region and the ultrastructural features of these cells were identical to those of undifferentiated neck cells. However, cell metaplasia from undifferentiated cells to metaplastic ciliated cells has never been demonstrated previously. The small mucus-granule-containing ciliated cells found in our present study may arise subsequent to division of undifferentiated neck cells into mucous cells with some daughter cells then exhibiting differentiation characteristics specific to ciliated cells. Thus they contain a mixture of both small mucus granules and numerous basal bodies and cilia, at the same time as a transitional form.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-2307
    Keywords: Cardiomyopathies ; Ultrastructure ; Morphometry ; Mitochondria ; Myofibrils
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We performed an ultrastructural, morphometric comparison of mitochondria and myofibrils of cardiomyocytes using endomyocardial biopsy specimens in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Biopsies came from the right ventricular side of the interventricular septum in nine patients with HCM, nine with DCM, and nine controls with arrhythmia and/or ST depression. Morphometric analysis was carried out using electron microscopic photographs and an image analyser. Mitochondria were significantly greater in number and smaller in size in HCM than in the control group. In DCM, the size of mitochondria was also significantly smaller than in the control group, although their number was similar to that of the control group. No statistically significant difference was found regarding the size of mitochondria between HCM and DCM. The percentages of both mitochondrial and myofibrillar areas in cytoplasm were smaller in the DCM than the HCM and control groups, though no difference was seen between the latter two. The ratio of mitochondrial area to myofibrillar area was almost the same in each group. These results suggest increased mitochondrial function to match hypertrophic cardiomyocytes in HCM, and decreased mitochondrial function and cardiomyocytic contractility in DCM.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 417 (1990), S. 113-118 
    ISSN: 1432-2307
    Keywords: Minute chemodectoma ; Lung ; Ultrastructure ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary So-called minute pulmonary chemodectoma is a curious, small lung tumour found mainly in women. The nature and origin of the proliferating cells are still obscure. In the first report on the tumour, the component cells were described as resembling chemoreceptor cells and the tumour was named chemodectoma. However, electron microscopic studies of the tumour have revealed no evidence of neuronal characteristics and have shown a close resemblance to meningothelial cells. In this study, the electron microscopic findings were similar to those previously reported but in one of the two cases, tumour cells were filled with abundant cytofilaments, giving them an occasional dense, patch-like appearance. Immunostaining for myosin and vimentin was positive in all tumour cells, but epithelial membrane antigen staining was not seen. These findings indicate that the tumour might have its origin from muscle cells.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 417 (1990), S. 395-404 
    ISSN: 1432-2307
    Keywords: Ultrastructure ; Non-Hodgkin's lymphoma ; Signet-ring cell ; Endoplasmic reticulum ; Multivesicular body
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary New ultrastructural findings are reported from two lymphomas of vacuolar signet-ring cell morphology (SR+), one of B cell and one of T cell lineage. When these lymphomas were compared ultrastructurally a difference in the relationship of the endoplasmic reticulum (ER) to the vacuole was noted, although the fine structure of the vacuoles themselves was similar and they were interpreted as giant multivesicular bodies (mvbs). Smooth ER was found near the vacuoles in both cases. Dark mvbs with a complex, reticulate form are emphasised as readily identified but hitherto unreported cell components in these tumours. A further B cell lymphoma of centroblastic/centrocytic type which was SR− was found to be rich in mvbs and may be a transitional form between SR− and SR+ lymphomas. In addition, the occurrence of mvbs has been studied quantitatively in a number of other lymphomas and in B and T lymphocytes in reactive nodes. Although increased numbers of mvbs were found in neoplastic compared with reactive lymphocytes, and in T compared with B cell lymphomas, these differences were not statistically significant. The possible roles of endoplasmic reticulum and mvbs in the generation of SR+ change are discussed.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-2307
    Keywords: Purkinje fibres ; Transitional cells ; Working myocardium ; Global ischaemia ; Ultrastructure ; Contraction state
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Contraction bands usually occur in the intramural working myocardium following post-ischaemic reperfusion. In the subendocardium, however, they are found during ischaemia. Thus, we ascertained the contraction states of Purkinje fibres, transitional cells, subendocardial and intramural parts of the working myocardium during 30 min global ischaemia at 25° C. The effects with and without myocardial protection were compared. At the onset of pure ischaemia contraction bands are completely lacking in all cell types. During pure ischaemia contraction bands are found in all subendocardial cell types but not in the intramural working myocardium. A peak of pathological contraction states is found in the intramural working myocardium at the onset (0 min), in the subendocardial working myocardium at 10 min, in the transitional cells and Purkinje fibres at 30 min of pure ischaemia. Histidine-, tryptophan-, ketoglutarate-enriched (HTK) cardioplegia prevents contraction bands completely at the onset of ischaemia and prevents both contraction bands and pathological contraction states during ischaemia almost completely. Striking differences in the physiological contraction states are seen only in the working myocardium: HTK cardioplegia brings about dominance of relaxation during ischaemia. These findings may be due mainly to the effects of global ischaemia on the one hand and to catecholamines, calcium and oxygen on the other.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 417 (1990), S. 443-447 
    ISSN: 1432-2307
    Keywords: Mesothelioma ; Pathology ; Ultrastructure ; Peritoneum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Well-differentiated papillary mesothelioma (WDPM) is considered to be a distinct subtype of peritoneal mesothelioma. Although the WDPM is usually qualified as benign, the natural history of this lesion has not been clearly established. This report relates to two WDPMs which were found incidentally. In a 51-year-old man the WDPM developed over a period of 5 years into a typically malignant diffuse mesothelioma. Thus, although the WDPM morphologically lacks signs of malignancy, it should be regarded as a borderline mesothelioma.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0533
    Keywords: Olivopontocerbellar atrophy ; Argyrophilic inclusion ; Pontine nucleus ; Ubiquitin ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Patients with olivopontocerebellar atrophy (OPCA) were studied, and cytoplasmic inclusions were observed in some of the remaining neurons of the pontine nuclei, nuclei reticularis tegmenti pontis and arcuate nuclei. The cytoplasmic argyrophilic inclusions were demonstrated by silver impregnation techniques such as Bielschowsky and Bodian staining. With hematoxylin and eosin stain, the inclusions were sharply demarcated and appeared pale. The inclusions were not stained by the following routine histological methods: Klüver-Barrera, phosphotungstic acid hematoxylin, Holzer, periodic acid-Schiff, Mallory azan, alcian blue, nile blue, Masson trichrome, Congo red, thioflavine S, oil red O and Sudan black B stains. Immunohistochemistry with anti-ubiquitin antiserum showed that these inclusions were ubiquitinated. However, the inclusions did not react with any of the following antibodies (Abs) or antisera: anti-phosphorylated neurofilament (NF) Ab, anti-nonphosphorylated NF Abs (160 and 200 kDa), anti-paired helical filament antiserum, anti-tau antiserum, anti-tubulin Abs (alpha and beta), anti-microtubule-associated proteins antiserum, anti-glial fibrillary acidic protein antiserum, anti-vimentin Ab, anti-desmin Ab, anti-cytokeratin Abs (low and high molecular weights), anti-actin antiserum, anti-skeletal myosin antiserum and anti-myelin basic protein Ab. Ultrastructurally, the inclusion bodies noted in OPCA were composed primarily of fibrils having a width ranging from about 24 to 40 nm, which were entirely coated with osmiophilic granular material along their whole length. They were occasionally intermingled with a few filaments about 10 nm in width. Electron microscopical examination on silver-impregnated specimens revealed that each granule-coated fibril had a great affinity for silver particles. In elucidating the pathogenesis of OPCA, it was considered to be an important neuropathological finding that some of the remaining pontine neurons affected by OPCA developed characteristic cytoplasmic argyrophilic inclusions.
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  • 10
    ISSN: 1432-0568
    Keywords: Chloride cell ; Teleost ; Gills ; Ultrastructure ; Adaptation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The general gill morphology of Oreochromis alcalicus grahami, a teleost adapted to high salinity and hyperosmosis, is basically similar to that of other teleostean fish. The species has four pairs of gill arches, all of which have well developed filaments. Each of the arches (holobranchs) has two rows of filaments (hemibranchs). Bilaterally situated secondary lamellae branch from the central axis of the filaments. The lamellae reach their maximum size at the middle of the filament, gradually decrease in size and eventually disappear towards the tip of the filament, which is bare. The leading edge of the gill filament and the immediate interlamellar space is covered by a stratified epithelium consisting of pavement cells, mucous cells, chloride cells and undifferentiated cells. The surface of these cells is made up of concentric microridges. The chloride cells were found only on the primary epithelium (filamental epithelium) and very rarely on the secondary epithelium (lamellar epithelium). Two types of chloride cells were observed in the gills of Oreochromis. The superficial chloride cells have fewer mitochondria concentrated towards the basal aspect of the cell, and a network of tubules towards the apical surface and are less electron dense. These cells intercommunicate with the water through an apical pore. The deep chloride cells have numerous diffuse mitochondria intercalated between a fine profuse tubular network and are more electron dense. These cells are covered by one or more layers of pavement cells and thus do not have access to the external surface. After gradual dilution of the lake water in which the fish were kept, both types of chloride cells remained topographically and ultrastructurally distinct. However, in both kinds of cell the mitochondria decreased in number and size. Initially there was an increase in the diameter and the degree of interdigitation of the tubules followed by a gradual decrease. An increase in the quantity of rough endoplasmic reticulum, particularly at the perinuclear region of the cell, was noted. The morphometric analysis of the branchial system indicated that the gills of Oreochromis are well adapted for gas exchange by having numerous and relatively long gill filaments with a high lamellar density. These features provide a large surface for gas exchange which, when coupled with the notably thin water-blood barrier of an average thickness of only 0.83 μm, would facilitate efficient absorption of oxygen by the gills. Oreochromis alcalicus was observed to be incapable of adapting to freshwater. This may have been due to the progressive degeneration of the chloride cells. Also the arrangement of the chloride cells as a continuum from the central venous compartments to the free epithelial surface is a structural feature which may not be amenable to radical functional changes.
    Type of Medium: Electronic Resource
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 181 (1990), S. 195-213 
    ISSN: 1432-0568
    Keywords: Cell death ; Degeneration ; Embryo ; Development ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Physiological cell death is a widespread phenomenon in the development of both vertebrates and invertebrates. This review concentrates on an aspect of developmental cell death that has tended to be neglected, the manner in which the cells are dismantled. It is emphasized that the dying cells may adopt one of at least three different morphological types: “apoptotic”, “autophagic”, and “non-lysosomal vesiculate”. These probably reflect a corresponding multiplicity of intracellular events. In particular, the destruction of the cytoplasm in these three types appears to be achieved primarily by heterophagy, by autophagy and by non-lysosomal degradation, respectively. The various mechanisms underlying both nuclear and cytoplasmic destruction are reviewed in detail. The multiplicity of destructive mechanisms needs to be born in mind in studies of other aspects of cell death such as the signals which trigger it, since different signals probably trigger different types of cell death.
    Type of Medium: Electronic Resource
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 80 (1990), S. 118-122 
    ISSN: 1432-0533
    Keywords: Mitochondrial encephalomyopathy ; Extraocular muscle ; Ultrastructure ; Mitochondrial myopathy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We carried out a histological examination of the extraocular muscles (EOMs) in a case of myoclonus epilepsy associated with ragged-red fibers (MERRF) and two cases of mitochondrial myopathy, encephalopathy, laetic acidosis, and stroke-like episodes (MELAS), which did not manifest external ophthalmoplegia clinically. By light microscopy, many granular and vesicular fibers were seen associated with endomysial fibrosis. Electron microscopy revealed that the fibers showed prominent accumulation of abnormal mitochondria, extensive loss of myofibrils, proliferation of free sarcoplasmic reticulum and an increased amount of lipid vacuoles. These changes were more pronounced in MELAS than in MERRF. Hirano bodies were often seen in the subsarcolemmal area of muscle fibers and also in the intramuscular myelinated nerve fibers and axon terminals. These findings suggest the presence of mitochondrial myopathy of the EOMs in cases of MELAS and MERRF.
    Type of Medium: Electronic Resource
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  • 13
    ISSN: 1432-0533
    Keywords: Cerebral ischemia ; Delayed neuronal death ; Gerbil ; Hippocampus ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultrastructural damage leading to delayed neuronal death was investigated in the mid-CA1 region of the hippocampus from the stratum (str.) moleculare to oriens after transient bilateral forebrain ischemia in Mongolian gerbils. After ischemia for 5 min without recirculation, mild swelling of the peripheral part of the apical and basal dendrites was already apparent in the str. moleculare and str. oriens. Mitochondria in the dendrites were also swollen in the same area. During recirculation for 12 h to 3 days, swelling of the dendritic cytoplasm persisted with formation of microvacuoles, but swelling of mitochondria receded. Microvacuolation and loss of microtubules were also observed in the proximal part of the dendrites during this period, and swelling and disruption of internal cristae were observed in mitochondria after recirculation for 3 days. The dendrites became severely degenerated after recirculation for 4 days. In the pyramidal cell bodies, no abnormality was observed at the end of ischemia for 5 min, but disaggregation of polyribosomes and swelling of the endoplasmic reticulum were observed 12 h after recirculation. Proliferation of the endoplasmic reticulum in parallel arrays occurred after recirculation for 1 day and persisted. Severe degeneration of the pyramidal cell bodies was obvious after recirculation for 4 days. The findings observed in the present investigation suggested that the neuronal structure most vulnerable to ischemia was the peripheral part of the dendrites and postischemic neuronal damage occurred early in this part of the dendrites.
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  • 14
    ISSN: 1432-0533
    Keywords: Feline ; Olfactory neuroblastoma ; Type C retrovirus ; Immunocytochemistry ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Three cases of spontaneous olfactory neuroblastoma (ONB) in domestic cats were morphologically and immunocytochemically characterized. Diagnostic light microscopic features included Flexner and Homer-Wright rosettes, while ultrastructurally the cells had neuritic processes, intracellular intermediate filaments, and intercellular junctions. Immunocytochemically, the tumors stained positively for neuron-specific enolase, cytokeratins, and S-100 protein antigens. In each case, a key finding was the identification of numerous mature type C retroviral particles within the tumors. In one case, budding of viral particles from the plasmalemma of tumor cells suggested the source of mature particles. This cat and one other were tested, and both were serologically positive for feline leukemia virus (FeLV). The virus in the tumors was identified as FeLV by polymerase chain reaction and immunocytochemistry. No other neoplasms were found in any of the cats, nor was there similar evidence of active viral infection in other non-tumor tissues, including the brain. Although the relationship between FeLV infection and ONB is uncertain, our findings indicate that FeLV should be investigated as an etiologic agent of ONB.
    Type of Medium: Electronic Resource
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 80 (1990), S. 611-617 
    ISSN: 1432-0533
    Keywords: Intranuclear inclusions ; Endoplasmic reticulum ; Hyaline inclusions ; Striated muscle ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Large intracytoplasmic inclusions arising from the endoplasmic reticulum and nuclear envelope were found in the muscle fibers of a 32-year-old individual with a life-long, chronic and progressive sensory-motor neuropathy. The morphological features of the inclusions were similar to that occasionally reported in the striated muscles in several unrelated conditions as well as to “hyaline” or “colloid” inclusions commonly seen in motor neurons of the brain stem and spinal cord. The chemical nature of the inclusions is not known. Their occurrence in the muscle fibers is probably secondary to chronic denervation.
    Type of Medium: Electronic Resource
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 80 (1990), S. 597-603 
    ISSN: 1432-0533
    Keywords: Choroid plexus ; Amyloid ; Intracellular inclusions ; Ultrastructure ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Intracellular inclusions with staining properties of amyloid are very common in the aging choroid plexus epithelial cells. In many ways these inclusions show similarities with the neurofibrillary tangles, found in cerebral cortical neurons in patients with Alzheimer's dementia. We have now designed a purification method for choroid plexus amyloid and performed a transmission and scanning electron miscroscopic study. This shows that one form of choroid plexus inclusions, the Biondi ring, is a homogeneous globule covered with a thin layer of amyloid fibrils. Partial immunochemical characterization of the choroid plexus amyloid reveals that it is different from the neurofibrillary tangles although there are similarities.
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  • 17
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 182 (1990), S. 103-112 
    ISSN: 1432-0568
    Keywords: Fibroblast ; Myofibroblast ; Interstitial cell ; Vitamin A storing cell ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Scanning electron microscopic observations of connective tissue cells show a new aspect of the nature of fibroblasts, and the subsequent broad survey of references makes clear that fibroblasts of many tissues have various features which are regarded as atypical of fibroblasts, and at the same time that various connective tissue cells in different organs have features typical of fibroblasts. Both morphological and functional features of fibroblasts are more or less common to those of fibroblast-like cells, and differences among these cells are quantitative rather than qualitative. Therefore, it is almost impossible to set clear-cut criteria for distinguishing genuine fibroblasts from a large population of fibroblast-like cells. The majority of cells sharing features of fibroblasts, if not all, seem to belong to the same population of cells. They are probably adapted to special functional needs in their own micro-environment that are peculiar to local or pathological or experimental conditions. It is proposed to categorize these cells into subtypes depending on their main functions: 1, fibrogenesis; 2, tissue skeleton or barrier; 3, intercellular communication system; 4, gentle contractile machinery; 5, endocrine activity; and 6, vitamin A-storing. Re-evaluation of fibroblasts and fibroblast-like cells is required to facilitate their better understanding.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 181 (1990), S. 325-331 
    ISSN: 1432-0568
    Keywords: Oocyte maturation ; Ultrastructure ; Fox ; Ovulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Blood samples were taken weekly from seventeen mature blue fox vixens (average age five years), from late anoestrus until pro-oestrus, and then taken daily. The vixens were sacrificed at various stages of oestrus, and oocytes were collected from ovarian follicles by aspiration, and/or from oviducts by flushing. The structural features of oocyte maturation were related to the time of the luteinizing hormone (LH) peak. On days 1–2 after the LH peak the oocyte nucleus migrated from a central to a peripheral position in the ooplasm and assumed a flattened appearance. The cumulus investment expanded simultaneously and ovulation took place around day 2. On days 2–3 the oocyte nuclear envelope broke down, the nucleoli disappeared, the metaphase of the first meiotic division was reached, the Golgi complexes decreased in size, the perivitelline space enlarged, and all junctional contact between cumulus cell projections and oocyte was disrupted. On days 3–5 the first polar body was extruded, the metaphase of the second meiotic division was reached, and the cumulus cells degenerated. On day 5 the release of cortical granule content was occasionally seen, and from day 6 the oocytes showed signs of degeneration. In a few animals deviant oocyte maturation was noticed.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 181 (1990), S. 37-48 
    ISSN: 1432-0568
    Keywords: Axons ; Astrocytes ; Oligodendrocytes ; Ultrastructure ; Paedomorphosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In five species of lungless salamanders, family Plethodontidae, which all show highly developed visual abilities, the ultrastructure of the optic nerve was investigated and the total number of retinal ganglion cell axons, the percentage of myelinated axons, and the volume densities of glia and axons were determined. More than 80% of all axons were smaller than 0.4 μm and only 2–3% were larger than 0.8 μm. In individual nerves the degree of myelination varied between 1 and 9% which is in the range reported for other amphibian species. The miniaturized and highly paedomorphic species Batrachoseps attenuatus was an exception because only very few or even no myelinated axons were present in the nerve, which is unique among gnathostome vertebrates. The five investigated species had total numbers of axons ranging from 26000 in Batrachoseps attenuatus to about 50000 in Plethodon jordani. These numbers are the lowest found among vertebrates with an elaborated visual system. The amount of glial material in the optic nerve varied between 25 and 50%, with larger nerves possessing more glia than smaller ones. Ultrastructural analysis revealed that the optic nerve of each species contained both astrocytes and oligodendrocytes, although often in immature form. In Batrachoseps attenuatus the glia showed features of both astrocytes and oligodendrocytes which reflect an undifferentiated state.
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  • 20
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 181 (1990), S. 59-66 
    ISSN: 1432-0568
    Keywords: Ultrastructure ; Marmoset ; Chorionic villi
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructural morphology of developing chorionic villi in the marmoset monkey (Callithrix jacchus) placenta was studied in pregnant monkeys at known time intervals after ovulation. In samples obtained at 45 days after ovulation the mesoderm, which consists of primitive foetal blood vessels, is seen to extend down into cytotrophoblast columns. Syncytiotrophoblast completely surrounds maternal blood vessels and both basal laminae and endothelial cells of maternal origin show signs of disorganisation and degradation. Syncytiotrophoblast is first observed to breach the maternal circulation in samples collected from animals at 60 days after ovulation; this results in discrete haemochorial villi randomly distributed throughout the placental bed. Samples obtained at 80 days after ovulation and term placental samples (145 days after ovulation) exhibit tertiary haemochorial villi throughout the placenta, similar to those seen randomly distributed at 60 days after ovulation.
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  • 21
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 181 (1990), S. 75-82 
    ISSN: 1432-0568
    Keywords: Anuran lymph hearts ; Development ; Ultrastructure ; Myogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The early development of anuran posterior lymph hearts studied by light- and electron-microscopy in frog larval stages 25–29 (Gosner 1960) can be subdivided into three phases. In phase I, mesenchymal myogenic cells are found, each possessing a single 9 + 0 cilium and numerous filopode-like processes aggregated near the vena caudalis lateralis, forming up to three metameric organ anlagen arranged like a cuff around the preexisting lymphatics (stages 26/27). In phase II, cell proliferation starts at stage 28 within the lymph heart wall as does the formation of primarily polynuclear myofibres by fusion of several myoblasts. At this stage immature myofibres show a vast sarcoplasm, a poorly developed SR and only few myofibrils with not yet distinguishable A- and I-bands. In phase III, the afferent and efferent valves are formed at the onset of pulsation in stage 29. Contractile myofibres contain large glycogen fields and a considerable amount of myofibrils which frequently branch and show distinct Z-lines, A-, I-, H- and M-bands; 1–3 cilia were found lying within a channel-like cell invagination. The peculiarities of organogenesis and myofibre development are discussed.
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  • 22
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 79 (1990), S. 456-460 
    ISSN: 1432-0533
    Keywords: Rosenthal fibers ; Immunohistochemistry ; Ultrastructure ; Neoplastic and reactive astrocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The nature of Rosenthal fibres (RF) was investigated in eight cases each of low-grade astrocytoma and reactive gliosis using immunohistochemical (IH) staining for glial fibrillary acidic protein (GFAP), electron microscopy (EM) and immunoelectron microscopy (IEM) by immunogold labelling technique. By IH under light microscopy (LM), three types of RF were seen, uniformly positive (type I), rim positive (type II) and completely negative (type III). EM showed variation in structural pattern of RF. Some RF contained large amount of glial filaments (GF) intermingled with RF while others with a large amount of electron dense material and less GF. Thus, the presence and amount of GF in RF appear to be responsible for the different types of IH staining under LM. IEM showed that all RF including the ones consisting of entirelh amorphous material possess immunoreactivity for GFAP. It is suggested that RF formation is a two-stage process, staring with excessive accumulation of GF within astrocytic processes followed by their gradual alteration into electron-dense amorphous material under the influence of some unknown metablic or other factors. The quantitative analysis of different types of RF suggests a difference in the rate of formation of RF in neoplastic and reactive conditions.
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  • 23
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    Acta neuropathologica 79 (1990), S. 551-557 
    ISSN: 1432-0533
    Keywords: Cutaneous nerves ; Neuropathy ; Ultrastructure ; Herpesvirus ; Rabbits
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A light and electron microscopic study was undertaken to determine pathological changes in cutaneous spinal nerves of rabbits following intradermal inoculation with alphaherpesvirus saimiri (αHVS) isolate KM 322. Infected rabbits were killed at 3, 10, 17, 45 days and 2 years after infection. No abnormalities were seen at 3 days postinoculation. In the nerves of the rabbits killed at 10, 17 and 45 days after infection, axonal (Wallerian-type) degeneration was the main pathological feature. Regeneration, manifested by axonal sprouting, was observed in the nerves of the rabbits killed at 45 days post-inoculation. Neural fibrosis and paucity of unmyelinated axons was the final outcome. The severity of the neural damage not only varied according to the progression of the disease but between nerves taken from the same rabbit. This was probably associated with variation in the numbers of virus particles that had reached the dorsal root ganglion of the dermatome served by a particular nerve. Since αHVS (isolate KM 322) provides a model system for the study of virus latency in dorsal root ganglia, and consequently for the study of varicellazoster infection in man, these findings give further insight into the pathology of herpetic neuropathy.
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  • 24
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    Acta neuropathologica 80 (1990), S. 255-259 
    ISSN: 1432-0533
    Keywords: Meningioma ; Phospholipid ; Psammoma ; Ultrastructure ; Chromatography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Phospholipids in meningiomas were studied by light and electron microscopy, and by high-performance liquid chromatography. They were microscopically demonstrated in six of the ten cases by Sudan III staining after the fixation with potassium dichromate. However, the conventional ultrastructural fixation with glutaraldehyde and osmium tetroxide failed to confirm phospholipids, as most of them were dissolved during dehydration. In contrast, the specimens pretreated with tannic acid before osmication ultrastructurally retained phospholipids which were represented by multilamellar bodies or ribbon-like rings. Both were found in 23 of the 30 cases within the cytoplasm, among the plasma membranes and in the extracellular matrices. The outermost lamella or ribbon showed a direct continuity from the neighbouring plasma membranes of the cytoplasm or the mitochondria. The multilamellar bodies showed an overall distribution, while the ribbon-like rings were predominantly distributed around the psammoma bodies. Precipitation of hydroxyapatite crystals within the ribbon-like rings resulted in matrix minerals of psammoma bodies. Chromatographical analyses of meningiomas disclosed phospholipids including phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine, sphingomyelin and phosphatidyl inositol in that order. Psammomatous meningiomas contained a higher percentage of phosphatidyl serine than non-psammomatous tumors. Ultrastructural study of synthetic phospholipids adequately treated with tannic acid showed that the multilamellar bodies were similar to phosphatidyl choline, while the ribbon-like rings were similar to phosphatidyl serine. The role of phospholipids in meningiomas is discussed.
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  • 25
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    Anatomy and embryology 182 (1990), S. 1-10 
    ISSN: 1432-0568
    Keywords: Fish ; Muscle growth ; Hyperplasia ; Hypertrophy ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In this EM study of lateral muscle in Dicentrarchus labrax, we observed that during the larval period, growth of the presumptive red and white muscle layers occurs both by hypertrophy (as fibres already present at hatching complete their maturation) and by production of new fibres in germinal zones specific to the two muscle layers. In the first half of larval life the presumptive white muscle increases in thickness by the addition, superficially, of new fibres derived from a germinal zone of presumptive myoblasts lying beneath the red muscle layer. In the second half of larval life new fibres produced in this same zone form the intermediate (or pink) muscle layer. Dorsoventrally the myotome grows throughout larval life, largely by addition of new fibres from germinal zones at the hypo- and epi-axial extremities. Towards the end of larval life all these germinal zones are becoming exhausted, but another source of fibres arises as satellite cells, associated with large-diameter presumptive white muscle fibres, are activated to produce new fibres. The addition of small, new fibres gives the white muscle its mosaic appearance. Morphometric analysis of fibre diameters in the white muscle confirms that whereas these hyperplastic processes are important during the larval and juvenile periods, when growth is very rapid, they have ceased by the time the adult stage is attained. By contrast, fibre hypertrophy continues through into adult life. The presumptive red muscle consists initially of a monolayer of fibres present only near the lateral line, and during larval life it grows hypo- and epi-axially by addition of fibres derived from myoblasts already present in these areas at hatching. Lying superficially to the presumptive red muscle monolayer there is a near-continuous layer of external cells with a “flattened” profile. During the second half of larval life, differentiation of these external cells into myoblasts provides the source of new fibres which are added to the red muscle layer. This process, which occurs initially in the region around the lateral line and later spreads outwards, is responsible for the increase in thickness of the red muscle.
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  • 26
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    Anatomy and embryology 182 (1990), S. 41-52 
    ISSN: 1432-0568
    Keywords: Lamprey ; Pronephros ; Ultrastructure ; Regression ; Apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The regression of the pronephric kidney of the lamprey, Petromyzon marinus, is described using histochemical and ultrastructural techniques. Regression begins in the third year of larval life, and by the time the animal enters metamorphosis the tubules have all disappeared. The nephrostomes and the renal corpuscle, however, persist for the remainder of the life cycle and undergo little change in the larva. Iron is present within the tubular epithelium prior to the beginning of degeneration, but as degeneration proceeds iron is observed within the tubule lumina. Acid phosphatase is noted within the tubule epithelia prior to degeneration, but as degeneration proceeds acid phosphatase is also observed within the intertubular area. Features of tubular regression include a prominent and highly folded basal lamina, numerous cytoplasmic inclusions, and dense bodies in the epithelia and lumina. The intertubular region is invaded by lymphocytes, granulocytes, plasma cells, and macrophages. The process of pronephric regression possesses many features of the process of apoptosis, which has been noted in the regression of larval organs in other vertebrates.
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  • 27
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    Anatomy and embryology 181 (1990), S. 491-498 
    ISSN: 1432-0568
    Keywords: Serotonin ; Ultrastructure ; Caudal Neurosecretory Complex ; Neuroendocrine ; Monoamines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The caudal neurosecretory complex (CNc) of poecilids has previously been shown to receive serotonergic inputs. In the present study, immunohistochemical techniques were applied at the light and electron microscopic levels to characterize serotonergic terminals in the neuroendocrine nucleus. A dense plexus of varicose fibers observed in the rostral CNc neuropil was absent in the spinal cords of deafferented fish, indicating that the origin of this input was extranuclear. Ultrastructural study revealed no direct contacts between labeled structures and neuroendocrine cells. Non-synaptic terminals (varicosities) were the predominantly labeled structures in the neuropil. Synaptic terminals were observed on cellular and axonal targets in the CNc. Small cells containing 70 nm dense-core vesicles received serotonergic input on their perikarya. Labeled synapses were also found on unlabeled axon terminals which made axoaxonal synapses on neuroendocrine processes. Non-synaptic terminals may be responsible for a variety of serotonin-mediated effects in the CNc. Synaptic interactions with local catecholaminergic and afferent cholinergic inputs to the CNc are likely.
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  • 28
    ISSN: 1432-0568
    Keywords: Mandibular condyle ; Articular tissue layer ; Ultrastructure ; Maturation ; Load-dependence ; Macaca fascicularis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In an attempt to establish maturational alterations in the morphology of the articular tissue layer, mandibular condyles of four immature and four mature male monkeys (Macaca fascicularis) were studied using light microscopy as well as scanning and transmission electron microscopy. Specimens were fixed in situ by perfusion in the presence of ruthenium red to stabilize proteoglycans. Preparations intended for observation in the scanning electron microscope were first dehydrated and sputtered for the examination of articular surfaces, and afterwards treated with trypsin to expose the spatial arrangement of collagen fibrils. Gross anatomical relations between joint components indicated that the anterior and central, but not the posterior region of the condylar articular surface can be subject to compressional load. Load-bearing and non-load-bearing regions differed with respect to the morphology of the articular layer. Load-bearing surfaces were covered by a prominent articular surface lamina similar to that observed on articular cartilage. This lamina seemed to constitute an integral part of the articular layer, distinct from the lining of synovial fluid, and to be composed largely of proteoglycans. It was unaffected by maturation. The subjecent, load-bearing articular layer differed markedly in structure, both from articular cartilage, and between immature and mature animals. Articular cells of immature animals were classified as fibroblastlike, but unlike typical fibroblasts, were surrounded by a thin, often incomplete halo of fibril-free pericellular matrix, presumably consisting of proteoglycans. In mature animals, articular cells closely resembled chondrocytes, but exhibited prominent nuclear fibrous laminae, which usually are found only in fibroblasts. Thus, the load-bearing part of the articular layer seems to undergo a maturation-dependent metaplastic conversion, from a dense connective tissue with some features of fibrocartilage, to a fibrocartilage-like tissue containing chrondrocytelike cells with some features of fibroblasts. This conversion might reflect an adaptation to a maturation-associated increase in articular stress.
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  • 29
    ISSN: 1432-069X
    Keywords: Dysplastic naevi ; Superficial spreading melanoma ; Naevocellular naevi ; Ultrastructure ; Melanosomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Eleven dysplastic melanocytic naevi with various degrees of dysplasia, as judged by light microscopy, were studied by transmission electron microscopy, and their intra-epidermal melanocytes compared with those of five superficial spreading melanomas and seven common benign naevocellular naevi. Intra-epidermal melanocytes in dysplastic naevi exhibited signs of cellular atypia, which were most pronounced in the dysplastic naevi with histological high-grade dysplasia. A correlation between the degree of dysplasia at the light microscopic level and the degree of cytological atypia at the ultrastructural level was noted, and melanocytes in dysplastic naevi with a high degree of dysplasia had ultrastructural features similar to the melanocytes in superficial spreading melanomas. Our observations support the concept that dysplastic naevi fill the biological gap between benign naevocellular naevi and malignant melanomas and suggest that at least some of the dysplastic naevi must be regarded as potential precursor lesions of malignant melanoma, particularly those exhibiting a high degree of histological dysplasia.
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  • 30
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    Archives of dermatological research 282 (1990), S. 108-114 
    ISSN: 1432-069X
    Keywords: Porphyria ; Dermal vessels ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The skin of 20 patients with variegate porphyria (VP) was studied using light, fluorescent, and electron microscopy. Twelve patients had skin symptoms and markedly increased fecal protoporphyrin excretion. Their sun-exposed skin was characterized by homogeneous PAS-positive thickening and IgG deposition in the vessel walls. The basic ultrastructural change was thickening of the vascular walls caused by reduplication of the basal lamina and perivascular deposition of amorphous material. Qualitatively similar but less prominent histopathological changes occurred in sun-protected skin in some of the patients. Six patients had no skin symptoms but an increased porphyrin excretion. The light microscopical changes were comparable to those in the patients with skin symptoms, but the ultrastructural changes were less severe. No abnormal histopathological changes occurred in two symptomless patients who had low lymphocyte protoporphyrinogen oxidase activity but normal fecal porphyrin excretion. These results show that the primary site of skin damage in VP is the vessel wall, and that histopathological changes of the skin also occur in porphyric patients who have never had skin symptoms. Factors determining the occurrence of skin symptoms in VP are discussed.
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  • 31
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    Archives of dermatological research 282 (1990), S. 434-441 
    ISSN: 1432-069X
    Keywords: Hair cycle ; Human hair follicle ; Connective tissue sheath ; Hyaline membrane ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultrastructural changes of the connective tissue sheath (CTS), including the hyaline membrane, of human hair follicles during the hair cycle, were studied in normal scalp skin specimens. In early anagen, the CTS was composed of a thin basal lamina and surrounding collagen tissue. The collagen tissue gradually thickened during the development of the hair and hair follicle. In mature anagen hair follicles, the collagen tissue was separated into three layers. The inner collagen layer, just outside the basal lamina, was thin and composed of collagen fibres running longitudinally parallel to the hair axis. The middle collagen layer was very thick with its collagen fibres running transversely against the hair axis and surrounding the inner hair tissue. Many fibroblasts were present among the collagen fibres in the middle layer, whereas the inner layer contained almost none. In the outer collagen layer, collagen fibres ran in various directions parallel to the outer surface of the outer root sheath cells. In late anagen, the basal lamina became very thick. In catagen, the basal lamine and the inner collagen layer became corrugated and showed oedematous change and degeneration. Surrounding fibroblasts showed active production of new collagen fibres, which seemed to fill the spaces left by the retraction of the hair follicle and hyaline membrane. These ultrastructural changes of the CTS show that there may be dynamic metabolic changes of the connective tissue around human hair follicles during the hair cycle.
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  • 32
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    European journal of clinical pharmacology 39 (1990), S. 395-397 
    ISSN: 1432-1041
    Keywords: atropine ; exercise ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the mean volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t1/2, 4.2 vs 3.5 h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 ml·min−1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml−1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml−1). In T5, Ex significantly decreased the t1/2 (3.4 h), Vz (182 l) and CL (575 ml·min−1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min−1), elimination rate constant (ke, 0.0012 vs 0.0015 min−1), Cp (14 ng·ml−1) and AUC (53.3 ng·h·ml−1). These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.
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  • 33
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    European journal of clinical pharmacology 38 (1990), S. 343-346 
    ISSN: 1432-1041
    Keywords: indomethacin ; cerebrospinal fluid ; pharmacokinetics ; protein binding ; analgesic activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling. According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7±0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF. The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.
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  • 34
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    European journal of clinical pharmacology 38 (1990), S. 523-524 
    ISSN: 1432-1041
    Keywords: tolbutamide ; hydroxytolbutamide ; carboxytolbutamide ; urinary excretion ; age ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.
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  • 35
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    European journal of clinical pharmacology 38 (1990), S. 499-503 
    ISSN: 1432-1041
    Keywords: 2-mercaptopropionylglycine ; body clearance ; half-life ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 2-mercaptopropionylglycine (2-MPG) was studied in ten healthy volunteers after a single i. v. injection of 250 mg (1532 μmol). The total and non-protein-bound concentrations versus time curves were best described by a three-exponential function with terminal half-lives of 55 and 59 h respectively. Body clearance based upon the total concentration was estimated to be 105 and 231 ml/min based on the non-protein-bound 2-MPG. The corresponding values for Vss were 99 l and Vss,n 173 l, and for Vγ485 l and Vγ,n 1121 l respectively. 75% of the dose was excreted in the urine, mainly during the first 6 h after injection. The proportion of non-protein-bound 2-MPG diminished exponentially during the first 15 h and then levelled off at about 30%. There was a nonlinear increase in the non-protein-bound fraction of 2-MPG as the total plasma concentration of the drug increased.
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  • 36
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    European journal of clinical pharmacology 38 (1990), S. 526-527 
    ISSN: 1432-1041
    Keywords: phenytoin ; posture ; pharmacokinetics ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 37
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    European journal of clinical pharmacology 39 (1990), S. 487-490 
    ISSN: 1432-1041
    Keywords: sulphadimethoxine ; plasma concentration ; skin blister fluid concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-dependent concentration curves of sulphadimethoxine in plasma and cantharidin-induced skin blister fluid have been evatuated following a single oral dose of 1 g. In contrast to other drugs, sulphadimethoxine exhibited two-stage penetration into the blister fluid, the second peak concentration being higher than the first. The maximum plasma concentration of 94.1 mg·l−1 was observed after 4 h, and in skin blister fluid the first peak of 25.6 mg·l−1 was found after 7 h, and the second of 58.0 mg·l−1 occurred after 30 h. The penetration of sulphadimethoxine into skin blister fluid, defined as the ratio of the AUC there to that in plasma was 0.748. The results suggest that sulphadimethoxine penetrates into skin blister fluid to a great extent from plasma and achieves concentrations exceeding the MIC for susceptible pathogens, but it requires a relatively long time to do so.
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  • 38
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    European journal of clinical pharmacology 38 (1990), S. 209-211 
    ISSN: 1432-1041
    Keywords: Isradipine ; hypertension ; pharmacokinetics ; pharmacodynamics ; clinical trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In conjunction with a multicentre clinical trial of the calcium antagonist isradipine in hypertension, pharmacokinetic and pharmacodynamic studies were conducted in 9 subjects. An initial dose of 5 mg (capsule formulation) of isradipine was given orally. The mean Cmax, tmax and AUC(0–8) were 6.0 ng · ml−1, 1.5 h and 15.1 h · ng · ml−1 respectively. Seven subjects repeated the study at steady state after 10 week's dose titration with isradipine. Cmax, tmax and AUC(0–8) were 3.7 ng · ml−1, 1.2 h and 12.2 h · ng · ml−1 respectively indicating that the drug does not accumulate over time. Control of blood pressure paralleled plasma isradipine concentrations which suggested that the drug should be given at least twice daily. Pharmacokinetic studies performed in conjunction with clinical trials can provide valuable information about the patterns of drug response.
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  • 39
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    European journal of clinical pharmacology 39 (1990), S. 583-586 
    ISSN: 1432-1041
    Keywords: ranitidine ; piroxicam ; interaction ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng·ml−1 for ranitidine alone and 466 ng·ml−1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml−1 and 2551 h·ng ml−1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 μ·ml−1 in the presence of placebo and 2.0 μg·ml−1 in the presence of ranitidine respectively; mean AUC was 133 h·μg ml−1 and 137 h·μg ml−1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.
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  • 40
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    European journal of clinical pharmacology 39 (1990), S. 613-614 
    ISSN: 1432-1041
    Keywords: Thioridazine ; debrisoquine polymorphism ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 41
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    European journal of clinical pharmacology 38 (1990), S. 255-258 
    ISSN: 1432-1041
    Keywords: theophylline ; mequitazine ; drug interaction ; pharmacokinetics ; asthma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of an oral anti-allergic drug, mequitazine, on the pharmacokinetics of theophylline has been investigated in seven asthmatic patients. They received chronic theophylline therapy (a sustained-release theophylline tablet 200–400 mg b.d. at 12 h intervals) and coadministered mequitazine 6 mg for 3 weeks. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of mequitazine were compared. No significant change in the pharmacokinetic parameters of theophylline or in the urinary recovery of unchanged drug and its metabolites was observed. Thus, mequitazine did not influence the pharmacokinetics of theophylline and it should be safe for coadministration to asthmatic patients on chronic theophylline therapy.
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  • 42
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    European journal of clinical pharmacology 38 (1990), S. 259-263 
    ISSN: 1432-1041
    Keywords: tacrine ; amyotrophic lateral sclerosis ; postoperative sedation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 9-amino-1,2,3,4-tetrahydroacridine; tacrine, THA, was studied after intravenous administration and following the first and last oral doses of a seven week clinical trial involving 8 patients with amyotrophic lateral sclerosis, ALS. Two surgical patients given intravenous THA for reversal of postoperative sedation were also included. Plasma concentration of THA and in some cases the metabolite, 1-hydroxy-THA, were assayed using a selective and sensitive method with high performance liquid chromatography. After an intravenous dose of 30 mg THA, the plasma concentrations were fitted to a two-compartment model. Plasma clearance showed a threefold interindividual variation with a mean of 2.42 l·h−1. Volume of distribution, Vα varied 100–680 l with a mean of 349 l. The plasma half-lives of distribution and elimination were 1.8 and 98.2 min, respectively. Oral bioavailability showed large interindividual differences and ranged 6–36% in the four subjects studied. After seven weeks treatment with oral THA, plasma concentrations immediately prior to medication were below 10 ng/ml in three patients and above 100 ng/ml in two patients. At the same occasion the plasma metabolite concentrations considerably exceeded those of THA. THA medication was associated with side effects in the majority of the patients.
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  • 43
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    European journal of clinical pharmacology 38 (1990), S. 269-273 
    ISSN: 1432-1041
    Keywords: flecainide ; quinine ; pharmacokinetics ; metabolism inhibition ; drug interaction ; renal transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of flecainide and its two sequential metabolites, both free and conjugated, its pharmacodynamics, and the influence of simultaneously administered quinine, have been studied in 10 healthy subjects. The study comprised two, 48-h open phases at an interval of 1 week. Flecainide acetate 150 mg was given as a 30-min i.v. infusion and quinine sulphate orally 500 mg×3 over 24 h. Quinine administration did not change the apparent volume of distribution or the renal clearance of flecainide, but it significantly reduced its systemic clearance (9.2 vs 7.6 ml · kg−1 · min−1), thus increasing the elimination half-life (9.6 vs 11.5 h). The amount of flecainide transformed to its first, meta-O-dealkylated metabolite (MODF) fell with no change in the renal excretion of the latter, either in its free or conjugated forms. This finding, in association with a fall in amount of the second, meta-O-dealkylated lactam metabolite (MODLF) recovered in its conjugated forms in the urine, suggests that quinine inhibits both the first and the second steps of the sequential metabolism of flecainide. When the subjects received quinine in addition to flecainide, the PR interval in the ECG was slightly more prolonged than with flecainide alone. Due to the study design, an effect of quinine per se and the consequence of increased serum flecainide levels could not be distinguished.
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  • 44
    ISSN: 1432-1041
    Keywords: celiprolol ; renal failure ; pharmacokinetics ; enantioselective kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the ß1-selective adrenergic antagonist (R,S)-celiprolol has been studied after oral administration of 200 mg celiprolol-HCl to 8 healthy volunteers and 8 patients with various degrees of impaired renal function. No significant difference was found between the two enantiomers in the control group or in the patients. In healthy volunteers an average of 9.8% of the dose of R-(+)-celiprolol and 9.5% of S-(-)-celiprolol was recovered unchanged in the urine. Renal impairment reduced the urinary excretion of both enantiomers to the same extent according to the severity of the uraemia, producing higher AUCs. Nevertheless, the terminal half-lives of the R- and S-enantiomers were not significantly different between the groups. Dosage reduction in patients with renal impairment does not seem to be necessary.
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  • 45
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    European journal of clinical pharmacology 38 (1990), S. S53 
    ISSN: 1432-1041
    Keywords: nitrates ; pharmacokinetics ; pharmacodynamics ; nitrate tolerance ; isosorbide-5-mononitrate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Healthy male volunteers received three different dose regimens of a controlled-release form of isosorbide-5-mononitrate (IS-5-MN; 60 mg per tablet). Dose regimen I consisted of a single daily dose of 60 mg given for 5 days. Dose regimen 11 was started with a dose of 60 mg, followed by 30 mg 12 h later and thereafter every 8 h. The last dose, on the 5th day was again 60 mg. In dose regimen III60 mg followed by 30 mg 6 h later were administered every day for 5 days. The peripheral arterial and venous effects of IS-5-MN during the first and last dosing interval were followed by changes in the finger pulse curve, standing systolic blood pressure, heart rate, and venous distensibility. Plasma concentrations of IS-5-MN were measured frequently following the first and the last dose. Following dose regimen I all hemodynamic effects produced by the first dose were maintained during the study. The maximal plasma concentrations were about 400 ng/ml and the trough value, lower than 100 ng/ml. Following dose regimen II the hemodynamic effects of IS-5-MN and sublingual glyceroltrinitrate were completely abolished on the 5th day. Trough plasma concentrations were approximately 300 ng/ml during the entire study period. Following dose regimen III pronounced hemodynamic effects were seen on the 1st day. However, a significant attenuation of the hemodynamic effects was measured on the 5th day, when trough plasma concentrations were between 100 and 230 ng/ml. There was a significant negative correlation between the magnitude of hemodynamic effect remaining on the 5th day (measured by the area under the finger pulse curve) and the trough plasma concentration. Thus, the maintenance of minimum plasma concentrations of IS-5MN of 300 ng/ml or higher produces a rapid development of hemodynamic nitrate tolerance, whereas no tolerance was found when the plasma concentrations were allowed to decline below 100 ng/ml before the next dose was given. A significant attenuation of hemodynamic effects was found when minimum plasma concentrations were between 100 and 230 ng/ml. The degree of attenuation in this concentration range increased with increasing trough plasma concentrations.
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  • 46
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    European journal of clinical pharmacology 39 (1990), S. 189-190 
    ISSN: 1432-1041
    Keywords: Diltiazem ; bioinequivalence ; plasma concentration ; dissolution ; pharmacokinetics ; commercial brands
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A bioequivalence study of three brands of regular diltiazem — Angizem (A), Dilzem (B) and Herbesser (C) has been carried out in 5 healthy, male volunteers. After a single oral dose of 60 mg of each preparation, the mean AUC(0–8 h) and Cmax of preparation B was significantly higher than of brands A and C. The tmax of A and B was significantly lower than of C. B had a higher dissolution rate in vitro (98.8% dissolved in 45 min) than A and C. Thus, there was bioinequivalence of the three brands of diltiazem, due partly to differences in dissolution and perhaps in part to a first pass effect.
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  • 47
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    European journal of clinical pharmacology 39 (1990), S. 199-201 
    ISSN: 1432-1041
    Keywords: netilmicin ; pharmacokinetics ; diurnal variation ; circadian rhythm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Netilmicin 1.5 mg/kg body weight was administered intravenously every 8 h for 2 days to 8 patients with normal renal function. Significant elevation of mean and trough plasma concentrations was found at 05.00 h and 09.00 h. This was considered to be due to circadian variation, with possible accumulation during the night. The clinical importance of this phenomenon in relation to the development of aminoglycoside toxicity awaits further investigation.
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  • 48
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    European journal of clinical pharmacology 39 (1990), S. 507-513 
    ISSN: 1432-1041
    Keywords: Anthracyclines ; cancer patients ; iodo-doxorubicin ; doxorubicin ; pharmacokinetics ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of doxorubicin (DOX), iodo-doxorubicin (I-DOX) and their metabolites in plasma has been examined in five patients each receiving 50 mg/m2 of both anthracyclines as a bolus injection. Terminal half-life, mean residence time (MRT), peak plasma concentration Cmax, and area under the curve (AUC) appeared smaller for I-DOX, whereas its plasma clearance (CLp) and volume of distribution at steady state (Vss) were larger than for DOX. The major metabolite of I-DOX was iodo-doxorubicinol (I-AOL) followed by doxorubicinol aglycone (AOLON). The AUC of I-AOL was 6-times larger than that of its counterpart AOL, which is the major metabolite of DOX. AOLON generated after I-DOX administration is a further important metabolite, as its AUC was 10-times larger than that of AOLON generated from DOX. The other aglycones, such as doxorubicin aglycone (AON) and the 7-deoxy-aglycones were only minor metabolites after either I-DOX or DOX injection. The ratio AUCI-AOL/AOL/AUCI-DOX/DOX was 27 in the case of I-DOX and 0.4 after DOX. The terminal half-lives of the cytostatic metabolites I-AOL and AOL were similar, although a longer MRT for AOL was calculated. Both metabolites had much longer MRTs than their parent drugs. The MRTs of the aglycones AOLON and AON were greater than those of the 7-deoxy-aglycones after both I-DOX and DOX. Approximately 6% DOX and less than 1% I-DOX were excreted by the kidneys during the initial 48 h. About 5% of I-DOX was excreted via the kidneys as I-AOL. Aglycones were not detected in significant amounts. The plasma concentrations of all compounds measured were highest during the first few minutes after administration of I-DOX and DOX. The I-AOL concentration was comparable to that of I-DOX immediately after the injection, due to very rapid metabolism within the central compartment (vascular space) by the aldoketo reductase system in the erythrocytes. The plasma concentration-time curves of (7d)-aglycones showed a second peak between 2 and 9 h after injection, suggesting enterohepatic circulation of metabolites lacking the daunosamine sugar moiety.
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  • 49
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    European journal of clinical pharmacology 39 (1990), S. 577-581 
    ISSN: 1432-1041
    Keywords: Benzbromarone ; elimination phenotypes ; pharmacokinetics ; metabolism ; genetic variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Following oral administration of the uricosuric drug benzbromarone two major metabolites appear in the circulation, 1'-hydroxy-benzbromarone (M1), and a second product (M2) of unknown structure. The plasma concentrations of the parent drug and of M1 and M2 have now been compared in two different elimination phenotypes, 10 subjects who eliminated the drug rapidly (S1–10) and one individual (S11) whose elimination capacity was impaired, presumably due to genetic variation (S11). The AUC (0–96) of the parent drug in S11 was 145 gmg · ml−1 h, and in the other individuals it averaged 18.3 (11.4–24.5) μg · ml−1 h. The plasma elimination half life of benzbromarone was 3.34 (1.77–5.24) h in the rapid eliminators, and 13.08 h in the subject with the elimination defect. The mean plasma elimination half life of the metabolites in S1–10 amounted to 20.1 (11.9–41.2) h for M1, and 17.2 (12.9–30.7) h for M2. In S11 the plasma elimination half life of M1 was prolonged to 76.6 h, and of M2 to 75.4 h. Thus, the elimination defect in S11 was not restricted to the parent drug, but it also involved the two major metabolites M1 and M2. This might be a consequence of a hepatic enzyme deficiency, or be due to impairment of drug excretion.
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  • 50
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    European journal of clinical pharmacology 39 (1990), S. 603-605 
    ISSN: 1432-1041
    Keywords: Galanthamine ; Alzheimer's disease ; stereoselectivity ; cholinesterase inhibition ; side effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of galanthamine (GAL) and its 2 major metabolites on human cholinesterases has been explored. Epigalanthamine, a diastereomer of GAL, was 130-times less potent in vitro in its effect on acetylcholinesterase (AChE) in erythrocytes than the parent compound, and it did not differ significantly from the ketone galanthaminone. In vivo, the maximal 36–55% inhibition of AChE was approached 30 min after oral administration of 10 mg GAL. The duration of the catalytic inhibition corresponded to an elimination half-life of approximately 5–7 h. GAL was well tolerated in 8/8 healthy volunteers, and 3/4 Alzheimer patients tolerated the drug up to a daily dose of 40 mg.
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  • 51
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    European journal of clinical pharmacology 39 (1990), S. 165-167 
    ISSN: 1432-1041
    Keywords: Cyclosporin A ; ponsinomycin ; pharmacokinetics ; drug interaction ; macrolide antibiotic ; renal transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of treatment with ponsinomycin, a new macrolide antibiotic, on the pharmacokinetics of cyclosporin A has been studied in 10 renal transplant patients. The pharmacokinetics of cyclosporin A was investigated at steady state, before and during treatment with ponsinomycin. On average, the blood levels of cyclosporin A were doubled by the macrolide, possibly due to a decrease in elimination or/and to an increase in absorption. Ponsinomycin should be use very carefully in patients treated with cyclosporin A.
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  • 52
    ISSN: 1432-1041
    Keywords: Flurbiprofen ; sustained-release formulation ; tolerance ; pharmacokinetics ; adverse reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic profile of 200 mg sustained-release flurbiprofen capsules was compared in nine elderly (mean age 84.2 years) and 10 young (mean age 38.1 years) patients with arthritis. After a single capsule, a 48 h plasma concentration profile was performed. The patients then took 1 capsule daily for a further 13 days with plasma levels of the drug being measured pre-dose on alternate days. Following ingestion of the last capsule, a further 48 hour plasma concentration profile was performed. These results were compared with each other and with computer predicted data obtained from dosing with 200 mg conventional flurbiprofen (as 100 mg b.d.). In both young and elderly patients, the two 48 h plasma concentration profiles confirmed the sustained-release characteristics of the capsule. There was no evidence of dose-dumping, although, in one elderly patient with a partial gastrectomy, higher plasma concentrations were observed. Inter- and intra-patient variability was acceptable. A steady-state was achieved within the predicted four days in both groups and there was no evidence of accumulation with the daily dosing interval. A mean steady-state level of approximately 6 μg/ml was achieved for both populations. Computer predicted data for 200 mg conventional flurbiprofen (as 100 mg b.d.) showed a pre-dose/peak range of 1–12 μg/ml. The pre-dose/peak ranges for the young and old patients were 4–10 μg/ml and 4–8 μg/ml respectively. One young patient developed a hypersensitivity reaction of moderate severity; one young and four elderly patients developed a low haemoglobin concentration during the study. No other changes in haematological or biochemical parameters were seen.
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  • 53
    ISSN: 1432-1041
    Keywords: metoprolol ; oral osmotic drug delivery system (OROS) ; food intake ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the bioavailability of metoprolol from an OROS system has been investigated. No significant difference was found between OROS administration to fasting subjects or after breakfast in any of the kinetic parameters (AUC, Cmax, tmax, C24 and lag time). Therefore, metoprolol OROS can be administered with breakfast.
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  • 54
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    European journal of clinical pharmacology 39 (1990), S. 385-389 
    ISSN: 1432-1041
    Keywords: Levodopa ; Parkinson's disease ; pharmacokinetics ; pharmacodynamics ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant ke0 using model-independent analysis. The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was 〉4–5 μg·ml−1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min. The patients remained clinically stable during the period of the intraduodenal infusion.
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  • 55
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    European journal of clinical pharmacology 39 (1990), S. 569-572 
    ISSN: 1432-1041
    Keywords: Bopindolol ; cirrhosis ; antipyrine ; pharmacokinetics ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration-time curve of the hydrolysis product of bopindolol has been investigated in 14 patients with cirrhosis and in 15 healthy volunteers given a single oral dose of 2 mg bopindolol. Cirrhosis was confirmed by history and clinical examination or liver biopsy. The time to maximum concentration, maximum concentration and AUC of hydrolyzed bopindolol were similar in the patients and controls. However, the elimination half-life was 6.0 h in controls and 9.5 h in cirrhotics. Antipyrine clearance was markedly decreased in patients with cirrhosis, but no correlation was found with the pharmacokinetic parameters of hydrolysed bopindolol. Although the AUC was not significantly altered in patients with cirrhosis, the longer half-life of hydrolysed bopindolol suggests impairment of its disposition in liver disease, which could lead to significant accumulation of drug during chronic dosing.
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  • 56
    ISSN: 1432-1041
    Keywords: digoxin ; atrial fibrillation ; infusion ; pharmacokinetics ; simulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using available data on time-concentration and time-effect relationships in normal persons the results of infusion of digoxin in various time periods were simulated and compared with administration of digoxin by bolus injections, using a three-compartment pharmacokinetic model to which a separate small side-effect compartment was subsequently added. The validity of the simulations was tested in 11 patients with rapid atrial fibrillation. Serum digoxin concentrations, ventricular rate and side effects were monitored in a double-blind study comparing an infusion of 1.5 mg digoxin over 6 h with administration of three bolus injections of 0.5 mg digoxin 8 h apart. In agreement with the predictions of the model, the maximal fall in ventricular rate was reached after 8–9 h in the infusion group and after 19–20 h in the bolus injection group, without any detectable difference in side effects. There were certain discrepancies between the results of the clinical study and the predictions of the model, e.g. in serum digoxin concentrations, perhaps due to impaired clearance in the patients. However, it is concluded that the tested model is valid in elderly patients with rapid atrial fibrillation.
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  • 57
    ISSN: 1432-1041
    Keywords: benazepril ; benazeprilat ; ACE inhibitor ; pharmacokinetics ; pharmacodynamics ; elderly ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of a single oral dose benazepril·HCl 10 mg have been studied in 15 healthy volunteers aged 65 to 80 y. The kinetics of unchanged benazepril and its active metabolite benazeprilat did not differ significantly in males and females, so the combined kinetic data from all 15 elderly subjects were compared with a historical control group of 19–32 year-old healthy men treated in the same way. The disposition of benazepril was not affected by age. The time to maximum plasma concentration, tmax (0.5 h) and elimination half-life (0.6 h) in the elderly were the same as in young subjects. The kinetics of benazeprilat was slightly changed in the elderly; although its tmax (1.5 h) was not affected, Cmax and the AUC were 20–40% greater. The elimination half-life of benazeprilat during the first 24 h after doing in the elderly was increased by about 20% to 3.2 h. The renal plasma clearance of benazeprilat (18.1 ml·min−1) was about 20% smaller than in the young subjects. An average of 18.5% of the dose was recovered as benazeprilat in the 24 h urine from the elderly subjects, which was similar to the recovery in the young subjects. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 95%, respectively). Mean systolic and diastolic blood pressures in the elderly were reduced by a maximum of 37/16 mm Hg at 6 h, in association with a small rise in pulse rate. Treatment was generally well tolerated. Three of the 15 subjects reported clinical adverse experiences judged to be possibly drug related, namely headache, abdominal pain and cold extremities.
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  • 58
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    European journal of clinical pharmacology 38 (1990), S. 489-491 
    ISSN: 1432-1041
    Keywords: irtemazole ; dose-response relationship ; pharmacokinetics ; uricosuric drugs ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Irtemazole 12.5 to 50 mg in 6 healthy, normouricaemic subjects caused a maximal decrease in plasma uric acid (after 8 to 12 h) of 46.5%. The uricosuric effect began during the first 60 min after drug administration and it lasted for 7 to 24 h. Renal uric acid excretion returned to its base line value after 8 to 16 h and uric acid clearance after 10.0 to 12.0 h. Doses of irtemazole between 12.5 and 37.5 mg produced a dose-related rise in the uricosuric effect. There was no essential difference between the uricosuric effect of 37.5 mg and 50 mg irtemazole. The D50 dose (that producing a half-maximal effect) was between 16.3 mg and 34.2 mg, (average 24.7 mg). The value of irtemazole in the management of hyperuricaemia and gout remains to be determined.
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  • 59
    ISSN: 1432-1041
    Keywords: ibuprofen ; rheumatoid arthritis ; enantiomer ; stereoselectivity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S(+)-, R(−)- or racemic ibuprofen was administered orally to volunteers in doses of 150 mg, 300 mg and 500 mg pure S(+)-, 300 mg pure R(−)- and 600 mg racemic ibuprofen. The pharmacokinetic parameters in humans showed that S(+)-ibuprofen was not inverted to R(−)-ibuprofen, whereas R(−)-ibuprofen was inverted to S(+)-ibuprofen to a variable degree. S(+)-ibuprofen and R(−)-ibuprofen given alone more rapidly reached significantly higher maximal plasma concentrations than after the same doses of the racemic compound. The elimination half-lives and clearance values for all three forms of ibuprofen were comparable. The mean residence time of S(+)-ibuprofen after R(−)- and racemic ibuprofen was significantly longer than after administration of the pure S(+)-enantiomer. Judged by the AUC, the bioavailability of S(+)-ibuprofen was independent of the dose within the range tested. Administration of S(+)-ibuprofen to 6 rheumatic patients showed that the pharmacokinetic behaviour of S(+)-ibuprofen in patients was similar to that found in volunteers. S(+)-ibuprofen proved to be an effective analgesic antirheumatic drug in the dose range 1 to 1.5 g/day.
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  • 60
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    European journal of clinical pharmacology 38 (1990), S. 547-549 
    ISSN: 1432-1041
    Keywords: piroxicam ; tenoxicam ; cholestyramine ; pharmacokinetics ; enterohepatic circulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To assess the extent of enterohepatic recycling of piroxicam and tenoxicam, their pharmacokinetics have been compared in the absence and presence of concomitant treatment with cholestyramine. In a randomized crossover study 6 healthy volunteers received piroxicam and tenoxicam 20 mg p.o., alone or with cholestyramine 24 g/day for 4 days. Cholestyramine increased piroxicam & tenoxicam elimination approximately 2-fold (t1/2 50.3 vs 28.1 h and 73.6 vs 35.8 h, respectively). It also increased the apparent clearance (Cl/f) of piroxicam and tenoxicam by 58% and 112%. When cholestyramine was administered, the t1/2 of piroxicam & tenoxicam were correlated (r=0.89), which suggests that their hepatic biotransformation is under a common control. It is concluded that: piroxicam and tenoxicam are eliminated to a large and comparable extent through the biliary route, and the administration of cholestyramine may help to accelerate their elimination in cases of overdosage.
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  • 61
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    European journal of clinical pharmacology 38 (1990), S. 579-582 
    ISSN: 1432-1041
    Keywords: d-sotalol ; d,l-sotalol ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg·kg−1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg·kg−1 i.v. of dlsotalol. There was no significant difference in the disposition of the d-enantiomer and the racemate. The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l·h−1·kg−1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).
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  • 62
    ISSN: 1432-1041
    Keywords: Atenolol ; metoprolol CR ; elderly subjects ; subjective symptoms ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind, randomised, cross-over study, the pharmacokinetic/dynamic effects and subjective symptoms of a new controlled-release (CR) formulation of metoprolol (50 and 100 mg) have been compared with atenolol (50 mg) and placebo in 20 elderly healthy subjects. The metoprolol CR formulation displayed an even plasma concentration-time profile over the dosage interval while atenolol produced a peak at 2–4 h. All three active treatments produced significant β1-blockade at 24 h compared to placebo. Four hours after dose intake, the degree of β1-blockade was significantly greater with conventional atenolol 50 mg than with either dose of metoprolol CR. Subjective well-being was examined with a self-administered questionnaire (MSE-profile), including three dimensions: Contentment, Vitality and Sleep. No significant differences were detected between placebo and either dose of metoprolol CR. At 2 h, following atenolol, a deterioration in Vitality was observed compared to placebo and metoprolol CR 100 mg. At the end of the dosage interval there was no longer any significant difference between the treatments. Perceived leg fatigue during exercise, evaluated 4 h after dosing, was more pronounced during treatment with atenolol than metoprolol CR 50 mg. The results suggest that the metoprolol CR formulation was not associated with significant effects on subjective well-being, whereas atenolol caused a deterioration at the time of the peak plasma concentration of the drug.
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  • 63
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    European journal of clinical pharmacology 38 (1990), S. 587-593 
    ISSN: 1432-1041
    Keywords: prenylamine ; racemic drug ; stereoselectivity ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of S-(+)- and R-(−)-prenylamine was studied in eight healthy volunteers given single and repeated oral doses of the racemic drug. Distinct differences in various pharmacokinetic parameters were found between the S- and R-enantiomer. The maximum plasma concentrations and AUCs of the R-enantiomer exceeded those of the S-enantiomer five-fold; the apparent oral clearance of the S-form was five-times and the renal clearance three-times higher than of the R-form. Acid catalyzed hydrolysis of urine samples released more S-prenylamine, indicating stereoselective glucuronidation of unchanged prenylamine. Plasma protein binding also differed between the two enantiomers, generally with a higher unbound fraction of the S-form, whereas analysis of the bound fractions showed that prenylamine was bound to different plasma proteins with inverse stereoselectivity.
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  • 64
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    European journal of clinical pharmacology 38 (1990), S. 599-603 
    ISSN: 1432-1041
    Keywords: Isradipine ; cirrhosis ; systemic ; calcium antagonist ; aminopyrine breath test ; serum bile acids ; galactose elimination ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the dihydropyridine calcium antagonist isradipine has been examined in 8 healthy volunteers, 7 patients with non-cirrhotic chronic liver disease (CLD), and 8 patients with biopsy-proven cirrhosis (CIR). Isradipine was simultaneously given orally (12C 5 mg) and i.v. (13C 1 mg). Systemic availability was significantly increased from 17% and 16% in controls and CLD, respectively, to 37% in CIR. The corresponding systemic clearances averaged 1.1, 0.9 and 0.61 · min−1, the reduction in cirrhotics being significant. Both aminopyrine demethylation capcity, a measure of hepatic microsomal function, and indocyanine green disappearance, a measure of hepatic perfusion, were correlated with the reduction in systemic clearance, and the reduction in oral clearance was correlated with the reciprocal of the serum bile acid concentration. The loss of first-pass extraction should be considered when this calcium antagonist is given perorally in patients with hepatic cirrhosis.
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  • 65
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    European journal of clinical pharmacology 38 (1990), S. 595-598 
    ISSN: 1432-1041
    Keywords: flecainide ; pharmacokinetics ; absorption ; non-parenteral administration ; healthy subjects ; rectal administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption kinetics of different pharmaceutical formulations of orally and rectally administered flecainide have been assessed in a cross-over study in 7 healthy volunteers. The subjects received single doses of flecainide after a washout period of at least one week. A tablet, an oral solution, a rectal solution and a 10 min i.v. infusion during 10 min each containing 100 mg flecainide were administered to the subjects in a randomized order. The mean absolute bioavailability was 98%, 78% and 81% for the rectal and oral solutions and the tablet. The lag time after administration of the oral solution was 0.33 h and it was 0.86 h after the tablet and 0.18 h after the rectal solution. The mean time to the peak serum concentration (tmax) after the rectal solution (0.67 h) was shorter than after either the tablet (4 h) or oral solution (1 h). The maximum serum concentration (Cmax) was 0.29 mg · 1−1 after the rectal solution, 0.14 mg · 1−1 after the tablet and 0.17 mg · 1−1 after the oral solution. All the volunteers showed significantly higher serum flecainide concentrations during the first 20 min of the absorption phase after rectal administration of 100 mg flecainide as a solution compared to its oral administration. In conclusion: based on the absolute bioavailability, Cmax, tmax, and lag times, rectal administration of flecainide solution gave a better absorption profile than after oral tablet or solution.
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    European journal of clinical pharmacology 38 (1990), S. 605-608 
    ISSN: 1432-1041
    Keywords: albendazole ; albendazole sulphoxide ; absorption ; elimination ; benzimidazole ; pharmacokinetics ; echinococcosis ; cholestasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of albendazole and its main metabolite, albendazole sulphoxide, have been examined after giving a single oral dose of 200 mg albendazole to 19 patients with either Echinococcus multilocularis or E. granulosus, 5 of whom had significant extrahepatic obstruction due to the underlying disease. The AUC of albendazole sulphoxide was increased in the latter patients (mean 122 μmol · h · l−1 compared to 17 μmol · h · l−1 in the non-obstructed group). Obstructed patients had delayed absorption, ka averaging 0.39 compared to 1.41 h−1 in non-obstructed patients. The corresponding elimination rate constant, ke was also prolonged, averaging 0.041 and 0.13 h−1 in the two groups, respectively. Four patients were restudied after complete or partial resolution of the cholestasis. The pharmacokinetic parameters in them had returned towards values comparable to those in the non-obstructed patients.
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  • 67
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    European journal of clinical pharmacology 38 (1990), S. 609-615 
    ISSN: 1432-1041
    Keywords: Terguride ; partial dopamine agonist ; pharmacokinetics ; endocrine effects ; pituitary hormones ; 6β-OH cortisol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels of the partial dopamine agonist, terguride, were measured by RIA in healthy volunteers after a single i. v. dose of 50 μg and on the first and seventh day of an oral treatment with 250 μg, 500 μg and 750 μg b. d. Basal and releasing hormone (TRH, GHRH, CRF, LHRH) — stimulated pituitary hormone secretion (PRL, TSH, GH, FSH, LH) and cortisol were also determined by RIA. Following the i. v. injection, plasma terguride levels declined biphasically, with half-lives of 0.2 and 1.5 h; total clearance was 17 ml·min−1·kg−1. the oral bioavailability of terguride over all doses was about 20%. Basal and TRH-stimulated prolactin levels were dose-dependently depressed, but the secretion of other hormones remained unaffected. Tolerance of terguride was excellent and there was no negative effect on performance or mood, nor on mixed-function oxygenase activity, assessed as urinary 6β-OH cortisol.
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  • 68
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    European journal of clinical pharmacology 39 (1990), S. 261-265 
    ISSN: 1432-1041
    Keywords: Frusemide ; probenecid ; phenprocoumon ; anticoagulant ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of phenprocoumon with and without co-administration of frusemide and probenecid in two groups of 17 healthy volunteers. Frusemide 40 mg b.i.d. for 7 days did not interact with phenprocoumon to a significant extent. Probenecid 500 mg q.i.d. for 7 days significantly accelerated the overall elimination of phenprocoumon, as indicated by a decrease in AUC from 295 to 157 μg · h · ml−1, and a reduction in the fraction of the dose excreted by the kidneys. The data are consistent with inhibition of the glucronidation of phenprocoumon by probenecid. Its accelerated elimination may be a consequence of the increased formation of hydroxylated metabolites.
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  • 69
    ISSN: 1432-1041
    Keywords: Hypertension ; perindopril ; hydrochlorothiazide ; ACE inhibition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamic effects and acceptability of perindopril (4 mg daily) and hydrochlorothiazide (25 mg daily) given alone or in combination for 1 month were investigated in a double-blind, placebo controlled, parallel group study. The pharmacokinetics of perindopril and its active metabolite perindoprilat and the time course of angiotensin converting enzyme inhibition were studied for 72 h following the last dose of treatment in the two appropriate groups. Similar decreases in blood pressure were seen 24 h after the last dose of perindopril or hydrochlorothiazide (11/7 mm Hg supine) given alone at these doses. The effect of these drugs given together was additive on diastolic blood pressure and synergistic on systolic blood pressure (24.5/12.6 mm Hg supine) taking into account the placebo response. The significant increase in plasma renin activity produced by perindopril alone was potentiated by concurrent administration of hydrochlorothiazide. The formation of perindoprilat was slightly reduced in the group also receiving hydrochlorothiazide and there was a very small reduction in ACE inhibition in this group. Perindopril, whether given alone or in combination with hydrochlorothiazide, was well tolerated and produced no clinically significant change in routine haematology or serum biochemistry. The additive or synergistic effects of perindopril and hydrochlorothiazide on blood pressure must be due to their complementary physiological actions and not to a pharmacokinetic interaction.
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  • 70
    ISSN: 1432-1041
    Keywords: Furosemide ; triamterene ; drug combination ; absorption ; urine sodium ; urine potassium ; fixed combination ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F+T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men. A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC480) F 2.58 μg · h · ml−1; F+T 2.46 μg · h · ml−1; FT 1.97 μg · h · ml−1. There was a significant reduction in the AUC480 of plasma triameterene (F+T 204.9 μg · h · l−1; FT 130.2 μg · h · l−1). Sodium excretion after F+T and FT was more pronounced than after F (F+T 302 mmol; FT 311 mmol; F 259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F+T as well as after FT (F 121 mmol; F+T 104 mmol; FT 107 mmol). It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.
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  • 71
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    European journal of clinical pharmacology 39 (1990), S. 607-608 
    ISSN: 1432-1041
    Keywords: ivermectin ; pharmacokinetics ; plasma protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Human pharmacokinetic data on the new antiparasitic agent, ivermectin, are scanty. For the evaluation of its disposition a specific HPLC assay with sensitive fluorescence detection was developed. Applying equilibrium dialysis, plasma protein binding of ivermectin was measured in five healthy individuals and it averaged 93.2±4.4% (SD). Such strong binding should be taken into consideration, especially in patients with malnutrition or with diseases in which a decrease in plasma proteins and consequently a higher free fraction of ivermectin could be expected.
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  • 72
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    European journal of clinical pharmacology 38 (1990), S. 165-169 
    ISSN: 1432-1041
    Keywords: nicotine ; cimetidine ; ranitidine ; pharmacokinetics ; H2-receptor antagonists ; hepatic oxidation ; renal secretion ; tobacco smoking ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomized, double-blind, cross-over experiment, 6 healthy consenting male subjects were administered cimetidine 600 mg or ranitidine 300 mg or placebo p.o. q12h×2 days. Nicotine bitartrate was administered i.v. on day 2 (1 ug/kg/min)×30 min. After cimetidine mean nicotine total and metabolic clearances were decreased by 30% and 27% while after ranitidine the clearances were decreased by 10% and 7% respectively. Since smokers regulate their smoke intake based in large part on their nicotine blood levels these results suggest that the diminished nicotine total clearance in the presence of cimetidine could be important in assisting smoking reduction or cessation.
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  • 73
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    European journal of clinical pharmacology 38 (1990), S. 175-179 
    ISSN: 1432-1041
    Keywords: diflunisal ; smoking ; pharmacokinetics ; sex-differences ; oral contraceptive steroids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10–20 cigarettes/day). The plasma clearance of diflunisal was significantly higher in men (0.169 ml·min−1·kg−1) and in women on OCS (0.165 ml·min−1·kg−1) as compared to control women (0.108 ml·min−1·kg−1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml·min−1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml·min−1 respectively). Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2–87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.
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  • 74
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    European journal of clinical pharmacology 38 (1990), S. 181-184 
    ISSN: 1432-1041
    Keywords: cyclosporin A ; diabetic children ; pharmacokinetics ; dose adjustment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cyclosporin A (CsA) pharmacokinetics was studied in 19 diabetic children (mean age: 10.6 y). They were divided into prepubertal (I) and pubertal (II) groups according to plasma oestradiol or testosterone concentrations. The kinetic study was performed after a 72 h wash out period and a single oral dose of 7.5 mg/kg CsA. CsA in blood was measured by HPLC. The kinetic parameters: Cmax, tmax, t1/2, AUC, CL/f, Vz/f and tss were calculated. No significant difference was found between the two groups. A significant negative correlation was found between Vz and both total cholesterol (r=0.46), VLDL+LDL−cholesterol (r=−0.49) and VLDL+LDL−phospholipids (r=−0.58). CsA kinetics at steady-state were simulated by superimposition of single dose kinetics derived from each single dose. Measured steady-state blood concentrations were correlated (r=0.80) with the values predicted by the simulation. The results suggest that CsA adjustment dosage of the CsA may be performed after a single oral dose using blood levels measured by HPLC. This procedure requires validation in further studies.
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  • 75
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    European journal of clinical pharmacology 38 (1990), S. 189-193 
    ISSN: 1432-1041
    Keywords: estramustine phosphate ; prostatic cancer ; gastrointestinal absorption ; food intake ; calcium ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of milk and food on the pharmacokinetics of estramustine phosphate was investigated in six patients with prostatic cancer. In a randomized three-way cross-over study, the patients were given single doses of the drug together with low calcium water, low calcium food and milk. The evaluation was based upon the plasma concentration of two metabolites, estromustine and estrone, as parent drug could not be detected in plasma. The tmax and lag time of estromustine were significantly increased by milk and food intake and Cmax and AUC were significantly decreased. In comparison with water, the AUC of estromustine was 41% when the drug was taken with milk and 67% after simultaneous intake of standardized food. Corresponding figures for the peak values were 32 and 57%, respectively. The effect of milk and food intake on the pharmacokinetics of estrone was similar. Studies in vitro demonstrated that the dissolution of estramustine phosphate disodium was markedly impaired in the presence of calcium. It was concluded that the rate and extent of absorption of estramustine phosphate were decreased when the drug was taken with milk or food due to the formation of a poorly absorbable calcium complex. To obtain high and reproducible absorption of Estracyt®, the drug should not be taken together with milk, milk products or other calcium-rich food or drugs.
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  • 76
    ISSN: 1432-1041
    Keywords: pirenzepine ; renal insufficiency ; haemodialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral dose were evaluated in three groups of subjects: group I, end stage renal disease requiring maintenance haemodialysis (CLCR 0 to 10 ml·min−1); group II, moderate renal insufficiency (CLCR 10 to 30 ml·min−1); and group III, mild renal dysfunction (CLCR 30 to 70 ml·min−1). Additionally, subjects in group I received a 50 mg dose on a non-dialysis day and at least one week later, a 50 mg dose during haemodialysis. There was a linear relationship (r = 0.97) between pirenzepine renal clearance and renal function as measured by creatinine clearance. The harmonic mean terminal half-life for pirenzepine was 17.3 h in subjects with end stage renal disease, 18.0 h in subjects with moderate renal insufficiency and 14.7 h in subjects with mild renal dysfunction. Haemodialysis reduced the level of circulating pirenzepine by approximately 25%. The mean arterial to venous plasma pirenzepine ratio during hemodialysis was 1.29 (range 1.02–1.56). Based on subjective reporting of adverse experiences and clinical observation, pirenzepine appeared to have had a wide margin of safety in these patients. Dry mouth was the most frequently reported adverse experience attributable to pirenzepine administration. A reduction in dose or dosing frequency may be warranted only in end state renal disease (CLCR 0 to 10 ml·min−1).
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  • 77
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    European journal of clinical pharmacology 38 (1990), S. 421-424 
    ISSN: 1432-1041
    Keywords: felodipine ; bile ; dihydropyridines ; biliary secretion ; healthy volunteers ; drug metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The biliary secretion of [14C]felodipine in 4 healthy human subjects was studied by use of the multiple marker dilution principle with double lumen tubes placed in the stomach and intestine. Insignificant amounts of14C activity were recovered from gastric aspirates. The individual recovery from intestinal aspirates varied from 2.9 to 8.5% of the dose of radioactivity over the period of 4.5 h after dosing. Less than 0.1% was identified as unchanged felodipine. The results show that biliary secretion is a minor route of elimination of felodipine or its metabolites. Bile collection for 4.5 h had no significant effect on the pharmacokinetics of felodipine, although the 72 h urinary recovery of radioactivity tended to be lower when bile was collected (59%) than in the control experiment (66%).
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  • 78
    ISSN: 1432-1041
    Keywords: rifampicin ; cerebrospinal fluid ; children shunt infections ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal fluid concentrations and safety of intravenous rifampin in pediatric patients undergoing shunt placement. Nine patients (mean age 5.6 y) received a single dose of rifampin, 20 mg · kg−1, administered intravenously 1 h prior to surgery. The peak serum concentrations ranged from 13.5–26.7 μg · ml−1; cerebrospinal fluid concentrations ranged from 0.12–3.0 (mean: 1.4) μg · ml−1. The mean total clearance, apparent distribution volume, and elimination half-life were 0.291 · kg−1 · h−1, 1.11 · kg−1, and 2.8 h. The concentrations of rifampin achieved in the cerebrospinal fluid exceeded the minimum inhibitory concentrations by 100-to 1000-fold against Staphylococcus epidermidis. However, 5 of 9 patients developed cutaneous reactions during intravenous rifampin prophylactic therapy. Because of the high frequency of adverse effects and more than adequate rifampin concentrations achieved in the cerebrospinal fluid, rifampin doses lower than that used in this study may be evaluated in future studies.
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  • 79
    ISSN: 1432-1041
    Keywords: Cisapride ; pharmacokinetics ; bioavailability ; suppository ; tablet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng · ml−1) was significantly lower than after the tablets (74.3 ng · ml−1). The AUCs following the two treatments did not differ significantly from each other. The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).
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  • 80
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    European journal of clinical pharmacology 39 (1990), S. 195-197 
    ISSN: 1432-1041
    Keywords: Omeprazole ; metabolites ; bioavailability ; pharmacokinetics ; dose-dependent kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of dose on the kinetics of omeprazole and two of its metabolites, hydroxyomeprazole and the sulphone, has been studied. Ten healthy subjects were given omeprazole 10 and 40 mg iv and 10, 40 and 90 mg orally. No significant dose-related difference in any parameter calculated from the iv experiments was detected. Following the oral solutions, however, there was a dose-dependent increase in systemic availability, probably due to saturable first-pass elimination. The AUC of the sulphone also seemed to increase non-linearly with increasing dose, and that of the hydroxyomeprazole increased in proportion to dose. The slight dose-dependency of the bioavailability of the solution is considered to be of no or limited clinical relevance. Furthermore, since omeprazole is given orally as slowly absorbed enteric coated granules in the dose of 20 mg o.d., the potential for dose-dependent kinetics in clinical practice would be much less than in the present study.
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  • 81
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    European journal of clinical pharmacology 39 (1990), S. 193-194 
    ISSN: 1432-1041
    Keywords: methocarbamol ; haemodialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We determined plasma methocarbamol concentrations over 24 h following a 1.5 g methocarbamol dose (off-dialysis day) to 8 chronic haemodialysis patients and compared these results to those from 17 healthy male volunteers. The harmonic mean elimination half-life was similar between the two groups, 1.24 and 1.14 h, respectively. tmax and the weight-adjusted Cmax were 1.1 h and 27.0 mg · m−1 for haemodialysis patients and 1.1 and 23.1 mg · l−1 for normals. Relative systemic availability was assessed by comparing weight-normalized AUC × k10 products. These results indicate no significant differences with respect to methocarbamol absorption, with the relative systemic availability in patients being 113%. These data suggest that absorption and elimination of methocarbamol is similar between normal subjects and patients undergoing maintenance haemodialysis.
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  • 82
    ISSN: 1432-1041
    Keywords: Methotrexate ; folinic acid ; 7-hydroxymethotrexate ; pharmacokinetics ; 5-methyltetrahydrofolic acid ; leucovorin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g·m−2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL). The median steady-state concentration of MTX was 66 μmol·l−1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg·m−2·min−1. The 7-OHMTX level increased during each infusion and a Cmax of 19 μmol·l−1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8. The MTX metabolite APA was detected in concentrations less than 0.06 μmol·l−1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 μmol·l−1 and 18 h following the last dose of LCV it was 0.44 μmol·l−1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 μmol·l−1 with a median ratio of 5-MTHF to MTX of 2. Twenty infusions with 48 h MTX levels of less than 0.5 μmol·l−1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 μmol·l−1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue.
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  • 83
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    European journal of clinical pharmacology 38 (1990), S. 237-242 
    ISSN: 1432-1041
    Keywords: cyclosporin A ; diltiazem ; pharmacokinetics ; kidney transplantation ; drug metabolism ; cytochrome P-450 ; drug interactions ; human liver microsomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng·ml−1 to 170 ng·ml−1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng·ml−1 before to 336 ng·ml−1. Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitve inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.
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  • 84
    ISSN: 1432-1041
    Keywords: metipranolol ; pharmacokinetics ; pharmacodynamics ; β-adrenoreceptor blockade ; radioreceptor assay ; controlled release form
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and β-adrenoceptor blocking effects of conventional and sustained-release metipranolol have been studied in 6 healthy male volunteers given a single oral dose of 40 mg. Plasma drug concentrations determined by TLC and a radioreceptor assay, and the inhibition of exercise-induced tachycardia, were monitored for 48 h. Relevant amounts of active metabolites other than deacetylmetipranolol were not found. Compared to conventionally formulated metipranolol, the controlled-release product had a prolonged mean residence time (10.7 vs 5.5 h), the peak drug concentration was halved and the time to peak drug concentrations was delayed. Relatively constant plasma concentrations (cideal = 6.5 ng/ml) and a clinically significant reduction of exercise-induced tachycardia were maintained throughout a 24 h dosing interval. An individual deacetylmetipranolol plasma concentration-effect relationship was evaluated using the Emax model. Mean parameters were Emax 26% and C50 2.9 ng/ml.
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  • 85
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    European journal of clinical pharmacology 39 (1990), S. 275-279 
    ISSN: 1432-1041
    Keywords: Noscapine ; pharmacokinetics ; bioavailability ; dose dependency ; oral administration ; inter- and intra-individual variability ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The relative bioavailability in 20 healthy volunteers of 100 mg, 200 mg and 300 mg tablets of noscapine and 200 mg as a solution has been assessed in a four-way cross-over study, with repeated administration of the 200 mg dose to assess intraindividual variability. There was a disproportionate increase in the AUC of noscapine tablets, as a 3-fold increase in dose produced a 9-fold rise in AUC. This dose-dependency could mainly be attributed to saturable first-pass metabolism of the drug. Administration of noscapine as a solution resulted in a significantly higher maximal concentration at an earlier time-point and a higher AUC than the corresponding dose as tablets. Repeated administration of noscapine tablets and solution yielded higher AUC on the second dosing occasion. No cause for this carry-over effect was found, and the contribution of remaining noscapine was negligible. The terminal half-life of noscapine, which was independent of formulation or dose size was 4.5 h. Both inter- and intraindividual variability in noscapine kinetics were very high, e.g. 73% and 51% CV of the AUC for the 200 mg tablet.
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  • 86
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    European journal of clinical pharmacology 39 (1990), S. 391-394 
    ISSN: 1432-1041
    Keywords: propranolol ; beta-blockers ; pharmacokinetics ; exercise
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of submaximal exercise on the pharmacokinetics of low dose intravenous propranolol was studied in 15 healthy human subjects. There was a wide individual variation in the results for each subject and a large difference in the degree of changes with exercise. The effect of exercise on the pharmacokinetics of propranolol, a flow limited drug, is marked but variable. This phenomenon may have profound effects on patients taking the drug regularly who exercise intermittently and drug doses may have to be adjusted.
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  • 87
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    European journal of clinical pharmacology 39 (1990), S. 409-411 
    ISSN: 1432-1041
    Keywords: yohimbine ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic profiles were determined in seven healthy young male subjects following single oral and intravenous doses of 10 mg of yohimbine hydrochloride. The drug was rapidly eliminated (t1/2β 0.58 h orally and t1/2β 0.68 h intravenously). Following intravenous administration the data fit a two-compartment pharmacokinetic model, with a very rapid distribution phase (t1/2a was approximately 6 min). Both the oral and the intravenous yohimbine clearance values were high but oral clearance values were much higher (mean 9.77 ml·min−1·kg−1 intravenous versus 55.9 ml·min−1·kg−1 oral). The oral bioavailability showed great variability, ranging from 7% to 87% (mean value was 33%). The imcomplete oral bioavailability of yohimbine may reflect either incomplete absorption from the gastrointestinal tract or an hepatic first pass effect. Although yohimbine is rapidly absorbed when given orally, the bioavailability is quite variable and considerable individualization of dosing may be necessary when the drug is used orally for clinical indications.
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  • 88
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    European journal of clinical pharmacology 38 (1990), S. 21-24 
    ISSN: 1432-1041
    Keywords: bisoprolol ; atenolol ; hypertension ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have compared the efficacy and pharmacokinetics of bisoprolol, a new cardioselective beta-adrenoceptor antagonist, with atenolol in a randomized double-blind crossover study in 12 patients (mean age 53.5 y) with mild to moderate essential hypertension. After a two week placebo wash-out period without any antihypertensive therapy, the patients were given bisoprolol 10 mg daily or atenolol 50 mg daily, increasing to 20 mg or 100 mg respectively if the sitting diastolic blood pressure did not fall below 90 mm Hg after two weeks of therapy. Crossover occurred after six weeks of active therapy followed by two weeks of placebo wash-out. After 6 weeks of therapy both drugs significantly reduced sitting and standing diastolic blood pressures (bisoprolol by 15% and 16% respectively, atenolo by 11% in both cases). However, while sitting and standing systolic pressures were significantly reduced by bisoprolol (13% and 16% respectively), only standing systolic pressures were significantly reduced by atenolol (11%), and this reduction was significantly less than with bisoprolol (p〈0.05). Both drugs similarly reduced mean sitting and standing heart rates. There were no significant differences between the single-dose and steady-state kinetics of either bisoprolol or atenolol. The mean plasma elimination half-life (t1/2) increased from 12.9 to 13.2 h during steady state on bisoprolol and from 7.2 to 11.5 h on atenolol. The apparent volume of distribution (Vz) was greater for bisoprolol than for atenolol after single dosing (235 1 vs 146 1) and at steady state (216 1 vs 137 1), but clearances were similar for both drugs. The maximum plasma concentration (Cmax) of bisoprolol increased from 45 μg·l−1 to 72 μg·l−1 during steady state and the Cmax of atenolol increased from 321 μg·l−1 to 410 μg·l−1 Adverse effects occurred in only one patient (lethargy while taking atenolol). These results suggest that bisoprolol has similar efficacy, safety, and pharmacokinetics to atenolol in patients with mild to moderate essential hypertension.
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  • 89
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    European journal of clinical pharmacology 38 (1990), S. 71-75 
    ISSN: 1432-1041
    Keywords: Rolipram ; enantiomers ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels of S-(+)-rolipram and R-(−)-rolipram in six healthy male volunteers were measured by radioimmunoassay after intravenous injection of 0.1 mg and oral administration of 1.0 mg of the pure enantionmers. Following i.v. treatment, plasma levels of both isomers declined in three phases, with half-lives of 0.2 h, 0.6–0.9 h and 6–8 h. Total clearance was 6 ml · min−1 · kg−1. Oral administration of 1.0 mg gave a peak concentration of 16 ng · ml−1 after 0.5 h. Bioavailability of (+)-rolipram was 77% and of the (−) enantiomer it was 74%. There was no significant difference in Cmax, half-life, total clearance or bioavailability between the two enantiomers.
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  • 90
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    European journal of clinical pharmacology 38 (1990), S. 67-69 
    ISSN: 1432-1041
    Keywords: Cetirizine ; haemodialysis ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of Cetirizine, a histamine H1-receptor antagonist, were investigated in five renal failure patients undergoing chronic haemodialysis therapy. The patients received one 10 mg cetirizine dihydrochloride capsule 3 h before haemodialysis. Concentrations of cetirizine in serum and dialysate were determined by HPLC. The maximum serum cetirizine concentration and the time to reach that maximum were 285 μg·1−1 and 2.0 h, respectively. The terminal disposition half-life of cetirizine in these patients was 19.3 h. The haemodialysis clearance of cetirizine was 14.0 ml · min−1. Although this is approximately 33% of the apparent total body clearance of cetirizine in subjects with normal renal function, the fraction of the dose removed by dialysis was only 9.4%. Thus, since haemodialysis does not produce a clinically significantly alteration in cetirizine elimination, no supplemental dose should be necessary after dialysis.
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  • 91
    ISSN: 1432-1041
    Keywords: Midazolam ; Mepivacaine ; local anaesthetic ; lumbar epidural anesthesia ; children ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty children undergoing surgery received a lumbar block using 0.4 ml/kg mepivacaine 2.0%. They were randomized into two groups, one of which received midazolam 0.4 mg/kg rectally as premedication. Midazolam administration did not significantly influence the plasma concentrations of mepivacaine.
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  • 92
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    European journal of clinical pharmacology 38 (1990), S. 97-98 
    ISSN: 1432-1041
    Keywords: Acetaminophen ; estrogen ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 93
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    European journal of clinical pharmacology 38 (1990), S. 99-99 
    ISSN: 1432-1041
    Keywords: enalapril ; milk ; enalaprilat ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 94
    ISSN: 1432-1041
    Keywords: morphine ; cancer ; morphine-6-glucuronide ; renal function ; drug metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary There is growing evidence that renally-impaired patients receiving morphine therapy are at greater risk of developing opiate toxicity, due to the accumulation of an active metabolite, morphine-6-glucuronide (M6G), which is usually excreted by the kidneys. This study examined the relationships between morphine dosage, renal function, and trough plasma concentrations of morphine and its glucuronide metabolites in 21 patients (aged mean: 68.5 years; 11 males) receiving either oral or subcutaneous morphine for terminal cancer pain. The median daily morphine dosages (mg · kg−1) were: orally 1.87 (range 0.37–6.82) and subcutaneously 1.64 (range 0.22–3.60). The median plasma concentrations of morphine, morphine-3-glucuronide (M3G), and M6G (ng · ml−1) were: 36.0, 1035.2, and 142.3, respectively. The plasma concentrations of morphine, M3G and M6G were each significantly related to the daily morphine dosage (n=21, Spearman r=0.79, 0.91, and 0.88 respectively). Accumulation of the morphine glucuronides was dependent on renal function. The plasma concentrations of M3G and M6G, when divided by the morphine concentration, were significantly related to the caluclated creatinine clearance of the patient. Patients receiving oral morphine had higher plasma concentration ratios of glucuronide/morphine than those receiving subcutaneous therapy, presumably due to first-pass glucuronidation. The results of this study confirm that accumulation of the pharmacologically active M6G is related to renal function, which probably explains the observation that morphine dosage requirements are generally reduced in patients with renal impairment.
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  • 95
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    European journal of clinical pharmacology 39 (1990), S. 149-153 
    ISSN: 1432-1041
    Keywords: Cicaprost ; PGI2-mimetic drug ; pharmacokinetics ; pharmacodynamics ; volunteers ; dose titration ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a Phase I study, the tolerability, pharmacodynamics and pharmacokinetics of cicaprost have been investigated in 6 male volunteers given 5, 10, 15 and 20 μg as tablets of the β-cyclodextrin clathrate. Individual inhibition of platelet aggregation and changes in facial colour (measured by chromametry) were dose-dependent and reached a maximum 30 to 60 min post-dose. The maximum inhibition of platelet aggregation was about 40%. After 3 to 4 h pre-treatment values had returned. Blood pressure remained within the normal range. The peak plasma level of cicaprost was reached within 15 to 90 min after drug intake. Both Cmax-and AUC were individually dose-dependent. The terminal half-life in plasma of cicaprost was approx. 1 h, and its total clearance amounted to 4–7 ml·min−1·kg−1. The time courses of the plasma levels and of the pharmacodynamic actions were in agreement. Interindividual differences were observed in the occurrence of unwanted effects (e.g. headache). Thus, cicaprost is an orally available PGI2-mimetic, for which effects on platelet aggregation and vascular perfusion have been demonstrated in healthy volunteers after doses of 5 to 15 μg.
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  • 96
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    European journal of clinical pharmacology 38 (1990), S. 229-232 
    ISSN: 1432-1041
    Keywords: benzodiazepines ; elderly subjects ; excessive drug effect ; psychomotor performance ; pharmacokinetics ; adverse reaction ; age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of triazolam 0.25 mg p.o. and psychomotor coordination were compared in nine healthy, elderly volunteers and nine middle aged controls. Motor coordination, as measured by pursuit rotor performance, was impaired in the elderly even before triazolam administration, and in contrast to the controls it deteriorated to a critical level after the drug. Factors associated with the major decrease in psychomotor performance in the elderly volunteers were poor baseline performance, an additional independent-age factor, and the plasma concentration of free triazolam. Although short acting benzodiazepines may have a less detrimental effect on performance on the morning following their intake, there may be serious motor incoordination and falls may occur if the patients have to rise during the night, particularly when the plasma concentration is high, i.e. about 2 h after dosing.
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  • 97
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    European journal of clinical pharmacology 38 (1990), S. 289-291 
    ISSN: 1432-1041
    Keywords: valnoctamide ; valpromide ; valproic acid ; pharmacokinetics ; healthy subjects ; tranquiliser
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 400 mg oral dose of valnoctamide (VCD) has been investigated in seven healthy, adult, male volunteers. VCD was not biotransformed rapidly to its corresponding acid valnoctic acid (VCA), unlike its isomer valpromide (VPD). It had a mean residence time of 13.2 h and a terminal half-life of 9.3 h. Throughout the study, only low plasma levels of VCA could be detected. Thus, unlike VPD, which is a prodrug of the corresponding acid, (valproic acid, VPA). VCD appears to act as a drug in its own right, and it does not undergo similar hydrolysis. The pharmacokinetic difference may account for the different pharmacological activities of the two isomers.
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  • 98
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    European journal of clinical pharmacology 38 (1990), S. 281-287 
    ISSN: 1432-1041
    Keywords: Cotinine ; non-smokers ; saliva levels ; plasma levels ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cotinine is a major metabolite of nicotine in man. Its disposition kinetics has been followed in plasma and saliva from nine nonsmokers, 23 to 56 years of age. Cotinine 5, 10 and 20 mg was given intravenously and orally to each subject, and plasma, saliva and urine samples were collected for 96 h. The kinetics of cotinine was best described by a multi-compartment model with three distinct phases both in plasma and saliva. Regardless of the mode of administration, there was no indication of dose-dependent kinetics. Mean total plasma clearance was 63.8 ml·h−1·kg−1 and mean renal clearance was 4.7 ml·h−1·kg−1, i.e. only 10% of the dose was excreted unchanged in the urine. The volume of distribution, as calculated from the plasma curves, was slightly greater than the body weight, 1.1 l·kg−1. The concentration of cotinine was 20 to 40% higher in unstimulated mixed saliva than in plasma during the absorption, distribution and elimination phases. As the clearance and distribution values in saliva were directly proportional to the corresponding values in plasma, similar terminal half-life values were obtained in the two body fluids, 15.5 and 16.8 h for plasma and saliva, respectively. Thus the kinetics of cotinine is linear after intravenous and after oral dosing, and salivary concentrations give the same information about cotinine disposition in the body as do plasma concentrations.
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  • 99
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    European journal of clinical pharmacology 38 (1990), S. 293-295 
    ISSN: 1432-1041
    Keywords: Diclofenac sodium ; children ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Diclofenac sodium 0.5 mg/kg i. v. was given preoperatively to small children (age 4–6 y). Vt and total plasma clearance were higher than in adults but the elimination half-life was similar.
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  • 100
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    European journal of clinical pharmacology 38 (1990), S. 309-312 
    ISSN: 1432-1041
    Keywords: Acetyl-L-carnitine ; renal impairment ; pharmacokinetics ; adverse reactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetyl-L-carnitine 1.5 g and 3.0 g was administered as three divided doses on each of two occasions to 24 people with varying renal failure (creatinine clearance 127 – 8 ml·min−1). Plasma and urinary concentrations of total-L-carnitine, free (non-esterified) carnitine, short-chain esters and acetyl-L-carnitine were measured. The baseline (pre-study) concentrations of all four substances were related to renal function. Patients whose creatinine clearance was below about 30–40 ml·min−1 were had the highest concentrations. Renal elimination of all four substances was related to dose and to renal function. There was evidence for dose-related elimination, with greater elimination of the larger dose.
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