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  • 1985-1989  (193)
  • 1980-1984
  • 1975-1979  (167)
  • 1987  (193)
  • 1978  (167)
  • Electron microscopy  (192)
  • Nuclear reactions
  • pharmacokinetics
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  • 1985-1989  (193)
  • 1980-1984
  • 1975-1979  (167)
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  • 1
    ISSN: 1437-160X
    Keywords: Chondrocalcinosis ; Calcium pyrophosphate dihydrate crystals ; Polymorphonuclear leukocyte ; Articular cartilage ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Electron microscopy was used to investigate the characteristics of calcium pyrophosphate dihydrate (CPPD) crystals in chondrocalcinosis (pseudogout syndrome). Crystals in midzone cartilage were frequently seen adjacent to chondrocytes. Great variation in crystal size and shape was observed. Most of the pyrophosphate crystals that had been phagocytosed by polymorphonuclear leukocytes of synovial fluid from patients with acute pseudogout were small (≦1 μm), indicating that small crystals can cause intense inflammation. Large numbers of polymorphonuclear leukocytes became attached to the eroded articular surface and phagocytosed microcrystals. Interaction of polymorphonuclear leukocytes with CPPD crystals in the superficial region of articular cartilage may stimulate the release of inflammatory mediators.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 65 (1987), S. 144-146 
    ISSN: 1432-1440
    Keywords: Campylobacter pyloridis ; Duodenal ulcer ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructure of campylobacter-like organisms found within duodenal biopsy specimens from 7 of 24 patients (28%) with active duodenal ulcer is described. Their curved shape and variable size are similar to what has previously been reported in descriptions of light microscopies. The organisms were found at the edge of active duodenal ulcers exclusively near neutral-mucous producing antral cells, to which they can adhere. The presence of these bacteria within cells and in the intercellular fluid implies that they can penetrate through the cell membrane or through tight intercellular junctions. The occurrence of these bacteria as well as numerous polymorphonuclear leukocytes in the afflicted regions suggests that the bacteria originally described by Warren and Marshall are indeed pathogenic and that their influence on ulcer healing should be included in designing treatment protocols.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular evolution 26 (1987), S. 347-357 
    ISSN: 1432-1432
    Keywords: Ribosome structure ; Electron microscopy ; Image analysis ; Evolutionary lineages
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Multivariate statistical analysis and classification techniques are powerful tools in sorting noisy electron micrographs of single particles according to their principal features, enabling one to form average images with an enhanced signal-to-noise ratio and a better reproducible resolution. We apply this methodology here to determining the characteristic views of the large (50S) ribosomal subunits from the eubacteriumEscherichia coli and the archaebacteriaMethanococcus vannielii, Sulfolobus solfataricus, andHalobacterium marismortui. Average images were obtained of the subunit in the common crown and kidney projections, but views of the particle in orientations intermediate between these two extremes were also elucidated for all species. These averages show reproducible detail of up to 2.0 nm resolution, thus enabling the visualization and interspecies comparison of many structural features as a first step toward comparing the actual three-dimensional structures. Our results disprove evolutionary lineages recently postulated on the basis of electron microscopical images of ribosomal subunits.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 410 (1987), S. 83-92 
    ISSN: 1432-2307
    Keywords: Buschke-Loewenstein tumour ; Giant condyloma ; Anogenital region ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Results on the light- and electron microscopic studies of six cases of Buschke-Loewenstein tumour are presented. The role of chronic irritation is emphasized in the aetiology of the tumour. Fistulas and abscesses arising in the tumour are dangerous as they give rise to chronic sepsis. In two perianal tumours, in situ or invasive carcinoma developed. Electron microscopy revealed varying degrees of differentiation of keratinocytes. As a result of the defective desmosomes, the tumour cell underwent segregation, with widened intercellular spaces containing oedema, erythrocytes and leucocytes. This phenomenon is probably responsible for frequent bleeding and fistula formation. The investigations disclosed that the Buschke-Loewenstein tumour is a special form of squamous carcinoma and therefore, radical surgical excision must be attempted even in case of a benign histological picture.
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  • 5
    ISSN: 1432-2307
    Keywords: Thrombocytopenic purpura ; Idiopathic thrombocytopenic purpura ; Liver sinusoidal fibrosis ; Electron microscopy ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 10 patients with thrombocytopenic purpura (TP) underwent splenectomy. Eight of these patients had idiopathic TP (certain or probable). All had normal liver function tests. Liver histology of the surgical biopsy was normal with the exception of a non specific mild portal infiltration in 6 cases. On Sirius red staining the perisinusoidal network was normal in 3 cases, mildly or moderately increased in 5 cases and often associated with perivenular fibrosis. Collagen types I, III, IV, laminin and fibronectin were increased in the 8 biopsies tested. On semi-thin sections, numerous Kupffer cells were observed. Under the electron microscope, sinusoidal abnormalities were very similar in all 7 patients studied: numerous Kupffer cells containing abundant lysosomes, numerous collagen bundles in the Disse space, active endothelial cells, transformation of some perisinusoidal cells into cells with some of the characteristics of fibroblasts (increased RER) and myofibroblasts (peripheral condensations of the filamentous network), increased fragments of basement membrane-like material. In two cases there was an increase in the number of perisinusoidal cells loaded with lipids. The similarity of the lesions and the absence of other fibrogenic causes (except in 2 cases) suggest that TP may represent another group of diseases with perisinusoidal fibrosis. The aetiology of fibrosis remains unknown but platelet derived growth factor and activated macrophages may play a major role.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 176 (1987), S. 251-258 
    ISSN: 1432-0568
    Keywords: Decidua ; Involution ; Electron microscopy ; Mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Involution of the antimesometrial decidua was analysed by electron microscopy on days 9, 10 and 11 of pregnancy in the mouse. During this period, the width of the antimesometrial decidua decreases considerably. Involution begins in the decidual cells situated closest to the embryo (internal decidua) and proceeds towards the myometrium. The cells of the internal decidua showed signs of deterioration characterized by accumulation of clumps of chromatin in the nuclei and dilation of the perinuclear cisterna and endoplasmic reticulum cisternae. Autophagosomes and heterophagosomes accumulated in the cytoplasm of these cells. Cells particularly strongly affected became spherical and were devoid of their plasma membrane. Some cells near the trophoblast as well as the mature decidual cells situated farther from the embryo showed a normal morphology. The trophoblastic cells established close contact with healthy decidual cells and engulfed fragments of disorganized decidual cells. It is suggested that the death of decidual cells is a type of programmed cell death and that it is not due to a direct lytic action by the trophoblast.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 73 (1987), S. 370-378 
    ISSN: 1432-0533
    Keywords: Electron microscopy ; Factor VIII ; Glial fibrillary acidic protein ; Hemangioblastoma ; Tissue culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The histogenesis of stromal cells in capillary hemangioblastoma has been the subject of debate. The light and electron microscopic studies of hemangioblastomas presented here showed pericytic and leiomyoblastic features in stromal cells. Cells cultured by the monolayer method showed similar features to those of the original tumors. Immunohistochemical studies for glial fibrillary acidic protein and factor VIII/von Willebrand factor indicated that stromal cells were antigenically distinct from astrocytes and endothelial cells. These findings suggest that stromal cells are closely related to pericytes and smooth muscle cells, and support Rhodin's speculation that pericytes serve as a precursor to smooth muscle cells.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Acta neurochirurgica 88 (1987), S. 142-146 
    ISSN: 0942-0940
    Keywords: Electron microscopy ; immunohistochemistry ; pituitary ; rhabdomyosarcoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Intracranial extension of rhabdomyosarcoma from the face, nasopharynx or middle ear is rare. A 16-year-old boy presented with deterioration of vision and headache. CT scan revealed a soft tissue mass occupying the sphenoid and ethmoid sinuses, extending to the suprasellar fossa and impinging on the optic chiasm. The tumour, mimicking pituitary carcinoma, was removed by transsphenoidal craniotomy. Morphologic studies, including immunohistochemistry and electron microscopy, revealed that the tumour was a rhabdomyosarcoma. This case stresses the value of immunohistochemical and ultrastructural studies in the diagnosis of tumours occurring in the region of the sella turcica. The origin of this tumour was thought to be the sphenoid or ethmoid sinus. The pituitary gland appeared intact.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 75 (1987), S. 131-139 
    ISSN: 1432-0533
    Keywords: Cerebral ischemia ; Hyperglycemia ; Substantia nigra ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Preischemic hyperglycemia induced by feeding or glucose infusion worsens the brain damage and the clinical outcome following ischemia of a given duration and density, and characteristically causes postischemic seizure activity. Light microscopy has previously showed that, in the rat, transient hyperglycemic ischemia induced by bilateral carotid occlusion in combination with arterial hypotension causes a uni- or bilateral lesion in the pars reticulata of the substantia nigra. Since this region has a central role in preventing seizure discharges the present study was carried out to determine the ultrastructural characteristics of this lesion. In rats with 10 min of transient hyperglycemic ischemia followed by recirculation for 1 to 18 h, the pars reticulata of the substantia nigra showed signs of status spongiosus, as well as extensive nerve cell alterations. These changes were observed after all recovery periods studied. The spongiotic appearance was mainly caused by swelling of dendrites and, to a lesser degree, by astrocytic swelling. The dendrites were expanded at all recovery times but the severity increased during the later periods of recirculation. These swollen dendrites contained severely expanded mitochondrias and endoplasmic reticulum. The cytoskeletal elements showed disordered lining of microtubules. Two major types of nerve cell alterations were present: a “pale” and a “dark” variety. The pale type was the most frequent cell alteration. It occurred in all experimental groups and at all time points. Redistribution of the nuclear chromatin and of cytoplasmic organelles as well as swelling of the same type as in the dendrites were the essential changes. The dark neurons were much fewer in number and occupied a peripheral position in the pars reticulata. Astrocytic foot processes appeared to be dilated around the dark neurons. Swelling of astrocyte processes was most pronounced in the 1 h recovery animals. Both types of neurons showed severe mitochondrial alterations of the type observed in dendrites. Occasionally, mitochondrial alterations were found in astrocytic processes as well. Blood vessel alterations were lacking. Previous studies have shown that in this model of ischemia the substantia nigra has a relatively well-preserved blood perfusion. In view of this the extensive histopathological lesions are surprising. We speculate that the lesions primarily involve excitotoxic damage to dendrites, with pronounced lactic acidosis playing a contributory role in causing axonal and glial pathology as well.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 176 (1987), S. 145-154 
    ISSN: 1432-0568
    Keywords: Neurological mutant mice ; ‘Purkinje cell degeneration’ (pcd) ; Weaver ; Neural transplants ; Cerebellum ; Light microscopy ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Embryonic cerebellar grafts from genetically normal donors were implanted into the cerebellomedullary cistern of adult ‘Purkinje cell degeneration’ (pcd) and weaver mutant mice, which are respectively characterized by the selective loss of Purkinje and granule cells. Grafts placed into both mutant recipients exhibited a layered cellular organization reminiscent of the normal cerebellar cortex. Molecular, Purkinje, and granule cell layers were identifiable. Grafted Purkinje cells displayed characteristic cytological features, such as hypolemmal cisterns in association with mitochondria in the perikaryon, and lamellar structures in their axons. The cytological features of granule cell somata in the grafts appeared similar to those of mature granule cells. Electron microscopic examination of the molecular layer of the grafts revealed the presence of parallel fibers, which were not oriented in a parallel fashion; axon terminals of such fibers were often presynaptic to dendritic spines. The number of parallel fibers was markedly reduced in grafts implanted into both mutants compared to the normal cerebellar cortex; however, this phenomenon is commonly seen in cerebellum in tissue culture and in cerebellar transplants into normal hosts. It is concluded, therefore, that the environment of the mutant hosts does not affect the survival of Purkinje or granule cells and that transplantation of solid cerebellar grafts in the neurological mutants studied does not seem to pose any apparent limitations beyond those inherent to the process of cerebellar growth and differentiation outside its normal environment.
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 176 (1987), S. 525-530 
    ISSN: 1432-0568
    Keywords: Placenta ; Guinea pig ; Labyrinth ; Syncytiotrophoblast ; Tracers ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The permeability of the materno-fetal barrier in the chorioallantoic placenta was studied in guinea pigs with gestation at term applying a variety of electron-opaque tracers via maternal circulation. None of the tracers tested was seen permeating the syncytiotrophoblast in the materno-fetal direction up to a 20 min interval when the fine structure of the placenta was satisfactorily preserved. The lanthanum chloride, cationized ferritin and horseradish peroxidase bound to the trophoblast surface, apparently due to electrostatic forces more than to specific receptors, and no uptake of these probes was detected in the cytoplasm. Albumin-colloidal gold complex, also used as a tracer, yielded similar results. As reported in other species with more complex syncytiotrophoblastic organization, this layer investing maternal lacunae is a highly selective permability barrier.
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 279 (1987), S. S30 
    ISSN: 1432-069X
    Keywords: Cicatricial pemphigoid ; Vegetating lesions ; Immunopathology ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A case with widespread vegetating-pustular skin lesions, oral erosions, ulcerations and scarring, and conjunctival synechiae is reported. Clinically, histopathologically, and by immunofluorescence and electron microscopy this patient combined the features of pemphigoid vegetans, as described by Winkelmann and Su, and the mucocutaneous type of cicatricial pemphigoid. This observation suggests that a third subset of cicatricial pemphigoid can now be added to the two existing ones, the mucocutaneous and Brunsting-Perry types, and the designation vegetating cicatricial pemphigoid is proposed for this heretofore undescribed condition.
    Type of Medium: Electronic Resource
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  • 13
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 75 (1987), S. 116-122 
    ISSN: 1432-0533
    Keywords: Rat ; Lead ; Brain edema ; Electron microscopy ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Newborn rats were exposed to daily intraperitoneal injections of 10 mg lead nitrate per kg body weight for the first 15 postnatal days. The growth and mortality of the lead-exposed animals did not differ from their control litter-mates, injected with vehicle only. In our previous studies, focal hemorrhages and spongy areas as well as breakdown of blood-brain barrier to plasma proteins were shown by light microscopy in the cerebellar parenchyma of 15-day-old rats exposed to this dose. In spite of these signs of edema, measurements of brain tissue specific gravity did not show increased water content. In the present investigation we examined the ultrastructure of the brain lesions in these rats with low-dose lead encephalopathy, focusing on signs of edema, and evaluated astroglial reaction by immunocytochemical staining for glial fibrillary acidic protein (GFAP). The electron microscopic findings were compatible with extracellular edema in the cerebellum of 15-day-old lead exposed rats. The number of GFAP-positive cell bodies in the gray substance of the cerebellar cortex was increased in the 15-day-old lead-exposed rats as compared with the controls of the same age, a finding which is presumably related to the leakage of plasma proteins. Both these findings were lacking at 20 days of age, suggesting reversibility of the lead-induced changes.
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  • 14
    ISSN: 1432-0533
    Keywords: Pleomorphic xanthoastrocytoma ; Epithelial properties ; Circumscribed growth ; Electron microscopy ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Three cases of pleomorphic xanthoastrocytoma (PXA), one of which showed anaplastic evolution, are described. In all three the PXA tumors were well circumscribed and could be totally removed. Light-microscopically, pleomorphic tumor cells clustered gregariously and often formed alveolar structures. Electron microscopy revealed various epithelial properties, such as junctions and interdigitations between apposing tumor cells, and prominent basal laminae surrounding tumor nests. The circumscribed growth of PXA, as contrasted with an infiltrative growth of usual astrocytoma, can be attributed to the cellular cohesion based on the epithelial properties of the tumor cells. In the third patient, tumor recurred 6 months postoperatively. Although the recurrent tumor retained the alveolar structures, pleomorphism and various degenerative features of the tumor cells diminished with advance in the proliferative activities.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 74 (1987), S. 169-178 
    ISSN: 1432-0533
    Keywords: Cerebral gangliocytoma ; Parieto-frontal lobe ; Intracytoplasmic inclusion bodies ; No synapse ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We report a case of cerebral gangliocytoma (GC) with a variety of unusual structures in the tumor cells. Light microscopically, the tumor consisted of typical ganglion cells, atypical cells which has argyrophilic granules in the cytoplasm, and a few astrocytes. Electron microscopically, the tumor cells showed typical gangliocytic features, which had abundant rough endoplasmic reticula, ribosomes and cored vesicles of 90–150 nm diameter, a few 50-nm-diametered non-cored vesicles, and other common organelles in their cytoplasm. Furthermore, neoplastic ganglion cells contained a variety of abnormal structures, including membranous cytoplasmic bodies (MCB), Zebra bodies (ZB), tubular structures, branched tubular structures (BTS), concentrical laminated bodies and curvilinear bodies (CB). The MCB, ZB and CB resembled those in GM2 gangliosidosis (GMG), and the BTS that in infantile neuroaxonal dystrophy (INAD). Although the significance of these inclusions is still unknown, it is considered that some common mechanism might play a role in the metabolism of both neoplastic neuronal cells and degenerating neurons (GMG and INAD). Synapses could not be observed anywhere despite complete neuronal differentiation of many tumor cells.
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  • 16
    ISSN: 1432-0533
    Keywords: Hypoglycemia ; Rat striatum ; Glutamate ; Excitotoxic nerve cell injury ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In rat striatum severe hypoglycemia causes an irreversible nerve cell injury, which does not become manifest until during the post-insult recovery period. This injury can be ameliorated by lesions of the glutamatergic cortico-striatal pathway, which suggests that an “excitotoxic” effect mediated by the glutamatergic input is the likely cause of the posthypoglycemic nerve cell destruction. In this paper we further characterize the protective effect of abolishing the glutamatergic innervation to striatum at the ultrastructural level. Two weeks after a unilateral cortical ablation rats were subjected to 30 min of severe hypoglycemia with isoelectric EEG and killed either immediately after the insult or following 60 min of recovery induced by restoring the blood glucose levels. Immediately after the hypoglycemic insult the structure of striatum was similar on both sides (except for the changes attributable to the ablation); i.e., the neurons and their dendrites had pale cytoplasm with condensed mitochondria, sparse RER and pinpoint ribosomes. After 60 min restitution numerous striatal neurons on the non-protected, non-ablated side had turned variably dark and condensed, whereas under-neath the ablation they remained similar as immediately after hypoglycemia. This sequence indicates that the most likely cause of nerve cell destruction on the non-protected side is the “excitotoxic” effect mediated by the glutamatergic innervation, which is superimposed on the action of the hypoglycemic insultper se. Furthermore, the primary condensation of neurons and their dendrites indicate existence of another type of acute “excitotoxic” nerve cell injury which differs from the previously described injury characterized by neuronal swelling.
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  • 17
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 72 (1987), S. 341-348 
    ISSN: 1432-0533
    Keywords: Carbon disulphide neuropathy ; Pacinian corpuscles ; Denervation and reinnervation ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Adult Wistar rats were exposed to carbon disulphide vapours at a concentration of 2.4 mg/l of air for 5 days a week (6 h a day), and the ultrastructure of Pacinian corpuscles and their nerve supply was investigated after 6 months of exposure. Both degenerative and regenerative changes were observed in sensory axons and the corpuscles. In a sample of corpuscles examined, 30% were denervated and about 60% showed clear signs of reinnervation. Some of the reinnervated corpuscles were supplied by unmyelinated axons. In others, one to three myelinated axons were already found at the nerve entry. The axons branched and formed three to eight terminals in the inner core. Due to continuous intoxication, most regenerated terminals were again undergoing degeneration. In peripheral nerves, the evidence of axonal regeneration has been reported in various toxic distal axonopathies. However, the reinnervation of Pacinian corpuscles has not been described before. It can be expected that reinnervation of Pacinian corpuscles and other end-organs also occurs in other axonopathies, if not during continuous poisoning, then at least after its cessation.
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  • 18
    ISSN: 1432-0533
    Keywords: Herpes simplex virus type 2 ; Genital infection ; Avidin-Biotin Method ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mice were infected by the vaginal route with the MS strain of herpes simplex virus type 2 (HSV-2). Serial vaginal cultures were used to confirm infection and to select mice for this study. Two mice were killed by perfusion on days 2–6 post infection (p.i.) and lumbar and sacral cord with cauda were fixed and embedded for electron microscopy. Semithin Epon-sections were stained for viral antigen using a rabbit anti-HSV-2 antiserum and the Avidin-Biotin (ABC) method. Thin sections from antigen-positive blocks were examined by electron microscopy, and the number and types of infected cells detected by these two methods were compared. A good correlation was found between detection of infected cells by these methods. Infected cells included neurons of dorsal root ganglia and spinal cord, satellite cells of dorsal root ganglia, non-myelinating Schwann cells, astrocytes, oligodendrocytes and arachnoidal cells. Infected cells were first detected in the cauda on day 3 p.i. and in the spinal cord on day 5 p.i. The temporal and spatial distribution of infected cells was consistent with neural spread to and within the CNS. The pathological lesions showed a good correlation with the distribution and number of infected cells and are probably due to a direct virus effect. The similar sensitivity of the Epon-ABC method to electron microscopy in detecting infected cells indicates that this method may have useful applications in both experimental and diagnostic work.
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  • 19
    ISSN: 1432-0533
    Keywords: Cerebral calcification ; Fahr's disease ; Electron microscopy ; Histochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A case of idiopathic nonarteriosclerotic cerebral calcification was studied post mortem by histochemical and scanning and transmission electron microscopic methods. Calcification was found bilaterally in the basal ganglia, cerebral cortex, granular layer and white matter of the cerebellum. Histochemical examination revealed that deposits were composed of a mixture of glycoproteins, mucopolysaccharides, calcium salts and iron. Transmission electron microscopy revealed minute deposits mainly in the cytoplasm of adventitial cells of blood vessels and sometimes in the cytoplasmic processes of glial cells. Scanning electron microscopy showed that some of the spherical and hemispherical bodies, which were formed in the adventitial cells of blood vessels, were connected with filamentous cytoplasmic processes of surrounding cells. Small uncalcified deposits occurring in the cytoplasm of the adventitial cells had subsequently had minerals deposited in them. Some kind of impairment of the pericytes may play an important role at the onset of this disease.
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  • 20
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 279 (1987), S. 270-272 
    ISSN: 1432-069X
    Keywords: Atopic eczema ; Hyperlinear palms ; Autosomal dominant ichthyosis vulgaris ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 21
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 279 (1987), S. 167-172 
    ISSN: 1432-069X
    Keywords: Morphometry ; Electron microscopy ; Cytological atypia ; Nevus cells ; Melanoma cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cytological atypia, revealed in the course of routine light microscopy, is considered a valuable indicator of malignancy in melanocytic lesions. A clear definition of the term cytological atypia, however, is lacking. Therefore, by morphometric analysis of ultrathin sections of 11 malignant melanomas (7 invasive, 3 in situ, and 1 lentigo maligna melanoma) and 10 compound nevi, we evaluated the discriminating power of the various facets of cytological atypia, i. e., nuclear area, area of the nucleolus, area of the total cell, and nuclear irregularity. In each case, at least 50 intraepidermal melanocytic cells were examined. The two-sided U-test showed significant differences between intraepidermal nevus and melanoma cells, with regard to the mean values (x) and standard deviations (s) of the nuclear area (x and s, p=0.00011), area of the nucleolus (x, p=0.00043; s, p=0.00011), and area of the total cell (x, p=0.00011; s, p=0.00093). However, only the mean values and standard deviations of the nuclear area allowed a clear distinction in each individual case. The area of the nucleus can be estimated in the course of routine histology. We therefore think that the size and variation of the nuclear area should be considered in the histological differential diagnosis between malignant melanomas and benign nevi.
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  • 22
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 279 (1987), S. 308-314 
    ISSN: 1432-069X
    Keywords: Congenital cutis laxa ; Collagen synthesis ; Electron microscopy ; Morphometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A case of congenital cutis laxa (CCL) of unclear mode of inheritance associated with multiple pulmonary artery branch stenosis was extensively investigated to assess possible correlations between clinical, ultrastructural, and biochemical features. Light microscopy revealed that elastic fibers were absent in the papillary dermis, while hypoplastic elsewhere. Transmission electron microscopy showed a poor elastin matrix content in some elastic fibers, variable diameters of collagen fibrils, and abundant glycogen granules in most dermal cells. Measurement of collagen fibril diameters, using an image analyzer, was carried out in the patient and two age- and site-matched controls. A biomodal distribution was found in the upper reticular dermis of the patient. In vitro analysis of collagen in skin fibroblast cultures of the patient showed increased collagen synthesis with a balanced production of type I and type III procollagens. Our study confirms that CCL represents a disorder both of collagen and elastic connective tissue.
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  • 23
    Electronic Resource
    Electronic Resource
    Springer
    Acta neurochirurgica 85 (1987), S. 56-62 
    ISSN: 0942-0940
    Keywords: Electron microscopy ; erythropoietin ; haemangioblastoma ; immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Immunohistochemical studies for erythropoietin were carried out in six capillary haemangioblastomas, three of which were also studied by electron microscopy. The immunohistochemical studies showed that positively stained cells were scattered in the vicinity of capillaries, and that neither endothelial cells nor stromal cells were stained. In their morphology and distribution, the positively stained cells were identical to mast cells as observed by electron microscopy. In one case, erythropoietin was demonstrated in the cyst fluid of the tumour. These findings suggest that mast cells with abundant secreting granules in haemangioblastomas are capable of producing erythropoietin.
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  • 24
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 113 (1987), S. 392-399 
    ISSN: 1432-1335
    Keywords: Paget's disease of bone ; Osteosarcoma ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The authors report 12 cases (8 men and 4 women) of sarcomatous degeneration in Paget's bone disease, with an average age of 72.3 years. Sarcomatous degeneration occurred often in polyostotic Paget's disease, and osteitis deformans was seen in 4 cases. Femur and pelvis were the most affected bones. Pain was a constant feature, whereas tumefaction and fracture were less common. Osteolytic lesions were more frequent than condensed or mixed lesions and radiological signs of malignancy were usually found. Seven cases were histologically clasiified as osteogenic sarcoma and 3 cases as fibrosarcoma. Electron microscopy was performed on 2 osteogenic sarcomas and in 1 case revealed microcylindrical inclusion in Pagetic osteoclasts and in multinucleated giant tumor cells, but none in mononucleated tumor cells. The average survival time for the patients in this study was only 4.5 months.
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  • 25
    ISSN: 1432-1106
    Keywords: Ventral mesencephalic grafts ; Electron microscopy ; Afferent synapses ; Tyrosine hydroxylase immunocytochemistry ; Dopaminergic neurons ; Dopaminergic boutons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In adult rats with a unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway, grafts of embryonic ventral mesencephalon can establish extensive efferent connections with the previously denervated host neostriatum and can compensate for motor and sensorimotor asymmetries induced by the lesion. The object of this study was to examine the afferent synaptic inputs to grafted dopaminergic neurons, implanted into a cortical cavity overlying the previously denervated caudate-putamen, using electron microscopic immunocytochemistry. The dopaminergic neurons of the grafts in the same animals had previously been shown to re-innervate the host neostriatum, to form synaptic connections therein and to attenuate the lesion-induced motor asymmetry that occured in response to amphetamine (Freund et al. 1985). In the light microscope, the grafts were found to contain numerous tyrosine hydroxylase-immunoreactive perikarya, dendrites, axons and axonal swellings which had distinct distributions. In addition axons and axonal swellings that were immunoreactive for either substance P or glutamate decarboxylase were present. Electron microscopic analysis of the boutons contacting tyrosine hydroxylase-immunoreactive neurons in the grafts revealed the presence of at least five distinct types of afferent synaptic boutons based on their immunochemistry, morphology, or types of membrane specialization. One type was itself immunoreactive for tyrosine hydroxylase; such synapses are extremely rare in the intact substantia nigra, none were found in the contralateral substantia nigrae or the substantia nigra of a control rat. Three of the remaining types had ultrastructural features that were similar to synaptic terminals that were immunoreactive for substance P or glutamate decarboxylase. These synapses were similar to the types of synapses found contacting dopaminergic neurons in the substantia nigra contralateral to the graft or the substantia nigra of a control rat. The results demonstrate that, in the absence of the normal extrinsic afferent inputs, the intracortical mesencephalic grafts have a well-developed local synaptic circuitry. It is suggested that local circuit regulation of dopaminergic neurons within the graft may, at least in part, be responsible for the maintenance of a normal or close to normal functional activity.
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  • 26
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    Experimental brain research 66 (1987), S. 175-184 
    ISSN: 1432-1106
    Keywords: Dorsal column nuclei ; Gracile nucleus ; Inferior olive ; Dorsal accessory olive ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This study examined the termination pattern within the dorsal accessory subdivision of the cat inferior olive of axons arising from the gracile nucleus. The gracile terminals were labeled by anterograde transport of wheat germ agglutinin complexed to horseradish peroxidase and visualized with tetramethyl benzidine. Gracile terminals were found to contain round synaptic vesicles and form asymmetric synaptic contacts. Of particular interest was the finding that gracile axons, like axons from the spinal cord, terminate primarily outside of synaptic glomeruli. Yet most of the gracile terminals did not synapse on isolated dendritic elements. Rather, the majority contacted distal dendrites which directly contacted other dendritic elements, forming simple complexes termed dendritic thickets. Typically the dendritic thickets were composed of two or three dendrites that received input from more than one round vesicle-containing synaptic terminal. Only one terminal per thicket was labeled by injections in the gracile nucleus. This clustering of pre-and postsynaptic elements within the thickets provides opportunities for many of the same interactions allowed by synaptic glomeruli, in particular divergence and convergence of information.
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  • 27
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    Experimental brain research 67 (1987), S. 380-390 
    ISSN: 1432-1106
    Keywords: Adrenal medulla ; Periaqueductal gray ; Neural implants ; Analgesia ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Recent findings in our laboratory indicate that adrenal medullary grafts produce significant alterations in pain sensitivity. Electron microscopic studies were undertaken to correlate these behavioral changes with the neural interactions of the host and graft tissue in the periaqueductal gray. A striking change found 8 weeks after transplantation is that pronounced myelination has taken place both in the graft and in the host tissue. The new myelin formation in the graft has the typical appearance of PNS myelination and, in the host the appearance of CNS myelination. The endothelial cells of the capillaries in the grafted tissue are attenuated and fenestrated in contrast to those of the surrounding parenchymal tissue of the host. By 8 weeks, the graft becomes heavily encapsulated with collagen, while the host CNS tissue develops layers of glial processes outlining the graft. However, collagen and glial layers apparently do not form an absolute barrier to either cellular or humoral interaction between the host and graft tissue. Chromaffin cells can be found protruding into the host CNS tissue and sometimes forming synapses with presumably the host neuronal processes. Grafted chromaffin cells may participate as both postsynaptic and, less often, as presynaptic components of synaptic junctions. The behavioral relevance of these synaptic contacts is unclear, since similar implants of adrenal medullary tissue into the dorsal spinal cord subarachnoid space, which also induce potent analgesia, do not contain synapses. Thus, it is more likely that behavioral changes are brought about by diffusion of neuroactive substances from grafted chromaffin cells to host receptors.
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  • 28
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    European journal of clinical pharmacology 32 (1987), S. 631-634 
    ISSN: 1432-1041
    Keywords: salbutamol ; albuterol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design. Pharmacokinetic parameters from intravenous data were similar to previously reported values obtained with oral administration, with a mean terminal half-life of 3.8 h and a mean clearance of 439 ml·min−1·1.73 m−2. Peak plasma concentrations of 10–20 ng·ml−1 were obtained 1–3 h following oral administration. The absolute bioavailability of each of the oral preparations was 44%. While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.
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  • 29
    ISSN: 1432-0983
    Keywords: Electron microscopy ; Replicative intermediates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Some physicochemical properties of the mitochondrial DNAs (mtDNA) from plants of flax, broad bean and mung bean, and from tissue culture cells of jimson weed, soybean, petunia and tobacco were determined. Circular molecules were observed in electron microscope preparations of each mtDNA. In soybean, petunia, broad bean and mung bean mtDNAs, the circular molecules had a continuous distribution of lengths (ranges between 1 to 36 kb, and 1 to 126 kb), heavily skewed toward smaller molecules. Eighty-six percent of the flax circular molecules were from 27 to 54 kb in size, and 78% of the jimson weed circular molecules were from 4 to 15 kb. Replicative forms of 1.2–1.6 kb circular molecules were observed in electron microscope preparations of broad bean mtDNA.
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  • 30
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    European journal of clinical pharmacology 32 (1987), S. 411-418 
    ISSN: 1432-1041
    Keywords: 5-fluorouracil ; colorectal carcinoma ; pharmacokinetics ; product-inhibition ; blood clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37°C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination. The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. These findings suggest the possibility of pulmonary clearance of 5-FU.
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  • 31
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    European journal of clinical pharmacology 32 (1987), S. 431-432 
    ISSN: 1432-1041
    Keywords: theophylline ; fluoroquinolones ; drug interaction ; pharmacokinetics ; ofloxacin ; norfloxacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pretreatment for 3 days with oral ofloxacin or norfloxacin had no significant effect on the disposition of a single i.v. dose the theophylline in healthy volunteers.
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  • 32
    ISSN: 1432-1041
    Keywords: growth hormone releasing factor ; radio-immunoassay ; pharmacokinetics ; variance model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Three ranges of doses of growth hormone releasing factor (2.5–80 µg, 80–320 µg and 75–600 µg) were intravenously administered to healthy young volunteers in three double blind studies. Serum circulating GRF levels were determined by radioimmunoassay. Experimental concentration curves were fitted, using the extended least squares method, to a biexponential model for the structural model and power function for the variance model. The power variance model, compared to the constant variance model greatly reduced the coefficient of variation of the biexponential parameters. The power of the variance model was estimated to be 1.95. The distribution half-life was 6.6 min and the elimination half-life was 39.0 min (harmonic means). Total clearance was 0.12±0.01 µg/l/min. No difference between these parameters was found for the various doses. GRF kinetics was linear established in the range 10 to 600 µg which means that elimination was not altered by the increased doses.
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  • 33
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    European journal of clinical pharmacology 32 (1987), S. 563-568 
    ISSN: 1432-1041
    Keywords: nitrendipine ; pharmacokinetics ; hepatitis ; liver cirrhosis ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty one patients with liver disease (cirrhosis 11, chronic hepatitis 5 and acute hepatitis 5) and 6 healthy volunteers were given a single i.v. dose of nitrendipine 5 mg. Afterwords nitrendipine 20 mg once daily were administered orally for seven days. With the intravenous injection a significant increase in the AUC and elimination half-life of nitrendipine was found in patients with cirrhosis as compared to the normal volunteers. After chronic oral dosing, the area under the plasma concentration-time curve, AUC (0–24), was 94.5 ng ml−1 h and the plasma clearance CL was 1380.6 ml/min in the healthy controls; in patients with cirrhosis the AUC (0–24) h was significantly greater at 309.4 ng ml−1 h and CL had fallen to 686.6 ml/min. Considerable accumulation of nitrendipine was also found in the patients with chronic hepatitis. Nitrendipine could not be detected in urine from any of the subjects. Blood pressure and heart rate were not significantly influenced by the treatment in the various groups investigated. Antipyrine clearance in the patients with cirrhosis was correlated with the nitrendipine plasma clearance. Thus, accumulation of nitrendipine has been demonstrated in the patients with cirrhosis and chronic hepatitis.
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  • 34
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    European journal of clinical pharmacology 32 (1987), S. 597-605 
    ISSN: 1432-1041
    Keywords: iloprost ; prostacyclin analogue ; pharmacokinetics ; pharmacodynamics ; radiolabeled study ; volunteers ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels and excretion of tritium-labeled iloprost in healthy elderly male and female volunteers have been measured after i.v. infusion of 2 ng·kg−1·min−1 for 4 h and oral administration of 0.1 and 0.48 μg/kg. During infusion, a steady-state of labeled compounds in the plasma was not achieved. Total radioactivity declined from a mean of 408 pg equiv/ml in three phases, with half-lives of 24 min, 1.7 h and 5.0 h, respectively. A steady-state of unchanged iloprost was reached rapidly with a peak of 81 pg/ml. Plasma levels declined biphasically with half-lives of 6 min and 31 min. Total clearance was 24 ml· min−1·kg−1. Maximum concentrations of labeled substances after oral administration were 307 and 1,051 pg equiv/ml after 29 and 39 min respectively. The peak of unchanged iloprost (116 pg/ml) was observed 7.5 min after an oral dose of 0.48 μg/kg. Bioavailability was 16%. Iloprost was totally metabolized and the metabolities were mainly excreted in urine. The main biotransformation products in plasma and urine were tentatively identified by cochromatography as dinor-and tetranoriloprost and their glucuronides. ADP-induced platelet aggregation was reduce by 60% during the i.v. infusion and 15 min after oral administration of 0.48 μg/kg. Heart rate and blood pressure were virtually unaffected. Common side-effects were facial flush, headache and nausea.
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  • 35
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    European journal of clinical pharmacology 32 (1987), S. 625-629 
    ISSN: 1432-1041
    Keywords: disopyramide ; bioavailability ; saturable binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of disopyramide were determined in 10 healthy volunteers after a 300 mg oral dose and again after a 2mg/kg i.v. dose. The unbound clearance was 599 ml/min and the unbound renal clearance 310 ml/min. The terminal elimination rate constant of unbound drug was 0.180 h−1 after the i.v. dose and 0.203 h−1 after the oral dose. The absorption rate constant was 0.53−1 and the maximum peak concentration occurred after 3.2 h. The bioavailability was 0.809 using the area under the unbound plasma concentration time curve. Although a saturable plasma protein binding was found in all subjects the bioavailability using the total concentration, in contrast to theoretical expectations, showed the same value (0.813) as the unbound concentrations.
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  • 36
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    European journal of clinical pharmacology 33 (1987), S. 197-201 
    ISSN: 1432-1041
    Keywords: ceftazidime ; renal impairment ; plasmapheresis ; pharmacokinetics ; cephalosporins ; autoimmune disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of plasmapheresis (PA) on the elimination kinetics of ceftazidime (Cef) has been investigated. A single dose of Cef was administered intravenously to 11 patients with autoimmune diseases and varying degrees of renal impairment (Group I CLCR〈50 ml/min, Group II CLCR〉50 ml/min). In Groups I and II the mean total clearance of Cef (CL) was 30 and 116 ml/min−1, respectively. The elimination half-life (t1\2β) and the volume of distribution (V) were significantly higher in Group I than in Group II (11.9 vs 2.0 h, 27.1 vs 18.5 l). PA had no influence on the plasma level-time profile of Cef. The amount of Cef recovered from separated plasma accounted for only 2 to 9% of the administered dose, being particularly low in patients with normal renal function (4.6%). Thus, since elimination of Cef via PA is negligible, dosage calculations should be based solely on renal function.
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  • 37
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    European journal of clinical pharmacology 33 (1987), S. 227-230 
    ISSN: 1432-1041
    Keywords: enoxacin ; theophylline ; drug interaction ; healthy volunteers ; adverse effects ; pharmacokinetics ; renal tubular excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The mechanism of the theophylline-enoxacin interaction has been studied in six healthy subjects. Theophylline 250 mg was administered p.o., twice daily for 11 days in a sustained release dosage form. On the 4th day of treatment, blood samples were taken every 2 h and urine was collected over 1 dose interval. From Days 5 to 11 coated tablets of enoxacin 400 mg b.i.d. were coadministered. On Day 11 blood and urine were collected as on Day 4. The mean plasma theophylline concentration rose from 4.4 to 15.1 mg/l, corresponding to a 73.6% reduction in total clearance. The urinary excretion of unchanged theophylline increased from 12.7 to 35.3%, whereas the production of metabolites was reduced (1-demethylation 81.4%; 3-demethylation 83.1%, 8-hydroxylation 74.6%). The results indicate that the theophylline-enoxacin interaction may be due to inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism. Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered. This led to unchanged or even to elevated plasma levels of the metabolites. The mechanism of this interaction is still to be elucidated, but it may be due to competition for renal tubular secretion.
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  • 38
    ISSN: 1432-1041
    Keywords: iron deficiency anaemia ; sulphadimidine ; absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of iron deficiency anaemia and its treatment on the absorption of sulphadimidine has been investigated in adult patients. The absorption judged by total % of the dose excreted in urine and Cmax, tmax, AUC and Kabs in plasma, was not significantly different before and after iron therapy or correction of anaemia. However, sulphadimidine absorption by the anaemic patients was significantly greater than in normals.
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  • 39
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    European journal of clinical pharmacology 33 (1987), S. 315-318 
    ISSN: 1432-1041
    Keywords: propranolol ; pharmacodynamics ; pharmacokinetics ; beta-blockade ; sustained-release propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0–24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.
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  • 40
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    European journal of clinical pharmacology 33 (1987), S. 355-361 
    ISSN: 1432-1041
    Keywords: metoprolol ; smoking ; gender ; pharmacokinetics ; HPLC ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The purpose of this study was to examine the influence of cigarette smoking and gender on the pharmacokinetics of metoprolol. Eighteen volunteers with no evidence of clinical disease each randomly received the following doses of metoprolol tartrate: 100 mg orally, 200 mg orally and 20 mg as a constant-rate intravenous infusion over 20 min. The only significant difference between smokers (S) and nonsmokers (NS) was that S had a larger steady-state volume of distribution (3.3 vs 2.5 l/kg). There were no differences in half-life, systemic clearance or bioavailability (f). No differences were observed between males (M) and females (FM) for any of the kinetic parameters examined. Systemic bioavailability varied markedly between subjects (range: 15 to 92%). In fifteen of the eighteen subjects, f was higher after the 200-mg dose compared to the 100-mg dose. These results suggest that metoprolol may be subject to saturable presystemic elimination and extend the previous observations of Johnsson et al. [1] who showed that f increased from 31% to 46% when doses were increased from 20 to 100 mg. However, the difference in f as the dose is increased is unlikely to be clinically significant since the mean difference is smaller than the variation in f among subjects.
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  • 41
    ISSN: 1432-1041
    Keywords: amodiaquine ; Plasmodium falciparum malaria ; monodesethylamodiaquine ; HPLC ; pharmacokinetics ; prophylaxis ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of monodesethylamodiaquine was studied in four healthy subjects after a single oral dose of 10 mg/kg amodiaquine base. Amodiaquine was not found in any sample, but the major metabolite monodesethylamodiaquine was detected and was assumed to be the sole derivative that contributed significantly to antimalarial activity in the blood. The best fit for the decay of the metabolite was obtained with a three-compartment model. The half-lives of the first two phases were 3.2 to 11.4 h for t1/2α1 and 22.7 to 50.3 h for t1/2α2 in plasma. The half-life of the terminal phase ( t1/2β) was between 9 and 18.2 days. The concentration in whole blood was 4- to 6-times higher than in plasma. Three schedules (alternate days, weekly, daily) of the conventional prophylactic dose of 10 mg/kg per week were compared in six other healthy subjects. There were significant differences in the plasma monodesethylamodiaquine levels between the three schedules.
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  • 42
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    European journal of clinical pharmacology 33 (1987), S. 423-426 
    ISSN: 1432-1041
    Keywords: Ketanserin ; pharmacokinetics ; hypertension ; ketanserinol ; predicted plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of ketanserin in 6 hypertensive patients after a single oral 40 mg dose and at steady-state after 4 weeks treatment with 20 mg and then 40 mg 12-hourly. Pharmacokinetic variables after a single dose were similar to those reported in healthy volunteers, with median values for Cmax 112 ng·ml−1, tmax 1 h, and t1/2 19 h. The corresponding values for the metabolite ketanserinol were Cmax 155 ng·ml−1, tmax 2 h, and t1/2 25 h. The median AUC was 3.3 times greater for ketanserinol than for the parent drug. These results were used to predict the mean steady-state plasma concentrations of ketanserin and ketanserinol. Predicted values were on average similar to those observed after four weeks treatment with 40 mg 12-hourly, although there were marked differences between the observed and predicted values in some patients. There was no evidence of time- or dose-dependent kinetics for ketanserin, but the study had insufficient power to exclude the occurrence of these phenomena entirely.
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  • 43
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    European journal of clinical pharmacology 33 (1987), S. 531-534 
    ISSN: 1432-1041
    Keywords: ketoconazole ; pharmacokinetics ; antimycotic drug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of the anti-mycotic ketoconazole in seven patients who took it for 1–6 months at a dose of 200 mg daily. The mean elimination half-life of the drug was 3.3 h, and although the ketoconazole was given only once daily, a satisfactory clinical response was obtained in all seven individuals. Only a small fraction of the absorbed drug (mean 0.22%) was excreted unchanged in the urine, suggesting almost complete metabolism. Our results support the concept that anti-mycotic activity in the tissues continues after the plasma drug concentration has fallen below a critical level. Our results also support the concept of a change in pharmacokinetics with chronic dosing.
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  • 44
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    European journal of clinical pharmacology 33 (1987), S. 67-72 
    ISSN: 1432-1041
    Keywords: cisplatin ; pharmacokinetics ; modelling ; drug dispositions ; cancer patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have fitted a first-order multicompartment pharmacokinetic model to plasma platinum concentrations measured in nine ovarian cancer patients who received intravenous infusions of cisplatin for 6 h. The time-course of ultrafilterable plasma platinum was similar in all patients studied, and was fitted by a single compartment within the limits of experimental detection. However, the time-course of protein-bound platinum showed marked differences between patients, the differences being explained by distribution to two peripheral compartments. The wide inter-patient variation observed in protein-bound plasma platinum concentrations supports the view that pharmacokinetic modelling should be carried out separately for each patient, since averaging plasma concentrations would have obscured some individual pharmacokinetic characteristics.
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  • 45
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    European journal of clinical pharmacology 33 (1987), S. 59-65 
    ISSN: 1432-1041
    Keywords: indoramin ; 6-hydroxyindoramin ; debrisoquine ; hydroxylators ; genetic polymorphism ; blood pressure ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five poor metabolisers (PM) and seven extensive metabolisers (EM), of debrisoquine, all healthy volunteers, received 50 mg indoramin orally following an overnight fast. Plasma concentrations of indoramin and 6-hydroxyindoramin were determined by HPLC with fluorimetric detection. In PM subjects, mean values of Cmax (158 ng/ml) and AUC(0–24) (2556 ng·h·m−1) for indoramin were substantially elevated and t1/2β (18.5 h) prolonged by comparison with values in the EM subjects (21.6 ng/ml, 151 ng·h·ml−1 and 5.2 h respectively). For 6-hydroxyindoramin, on the other hand, Cmax (12.4 ng/ml) and AUC(0–8) (47.5 ng·h·ml−1) in PM subjects were significantly lower than in the EM subjects (28.2 ng/ml and 94.7 ng·h·ml−1). There was a tendency to a higher incidence of side-effects in the PM group. Although the difference did not achieve statistical significance (0.1〉p〉0.05), all the PM subjects experienced sedation compared to only two in the EM group. Differences in blood pressure and pulse rate between the two groups were small. It is concluded that the oxidative metabolism of indoramin is subject to genetic polymorphism, which is probably under the control of the same gene locus as that influencing debrisoquine oxidation. The clinical consequences are discussed.
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  • 46
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    European journal of clinical pharmacology 33 (1987), S. 179-183 
    ISSN: 1432-1041
    Keywords: aminoglycosides ; haemodialysis ; gentamicin ; tobramycin ; pharmacokinetics ; renal failure ; kanamycin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The study was undertaken to look for a correlation between the measured elimination rate constants (k) of aminoglycosides and creatinine during haemodialysis. The pharmacokinetics of aminoglycosides were studied during 44 courses of haemodialysis in 21 patients. The measured k of gentamicin and tobramycin from the start until 30 min after the end of haemodialysis (mean 0.18 h−1; t1/2=3 h 51 min) was significantly correlated with the measured k of creatinine (mean 0.13 h−1; t1/2=5 h, 20 min), and also with the gentamicin and tobramycin k during haemodialysis (mean 0.20 h−1, t1/2=3 h, 28 min), as predicted by a computer program. Thus, serum concentrations of aminoglycosides 30 min after haemodialysis can be estimated by simple regression equations. However, because the measured and predicted values may diverge considerably in the individual patient, monitoring of aminoglycoside concentrations in serum after haemodialysis remains necessary.
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  • 47
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    European journal of clinical pharmacology 33 (1987), S. 287-292 
    ISSN: 1432-1041
    Keywords: praziquantel ; cysticercosis ; pharmacokinetics ; cerebrospinal fluid ; parasite drug level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two patients with cysticercosis received praziquantel (PZQ) 75 mg/kg/day orally together with 30 mg prednisone daily for 3 weeks. The first patient presented with grand-mal seizures, a pyramidal tract syndrome and subcutaneous cysticerci, and the other had internal hydrocephalus necessitating drainage. Serial plasma samples were taken after the first dose of PZQ. Lumbar CSF was obtained from the first patient and ventricular CSF from the second. Subcutaneous cysticerci were removed from the first patient. PZQ in the specimens was assayed by GLC. For distribution between plasma and CSF a rate constant of 4.9 h−1 for free PZQ, corresponding to a t1/2 of 8 min or less for the non-protein bound fraction was calculated for Patient 1. In the second patient the distribution was so rapid that the rate constant could not be calculated. The difference in distribution rate might have been due to use of different sampling times or to a time lag in the entry of PZQ between the ventricles and the lumbar sac. The rate constant for distribution of the drug between plasma and parasites was 1.4 h−1, corresponding to a t1/2 of 30 min or less. Thus PZQ penetrates rapidly into the CSF. It enters the parasite more slowly, although still more rapidly than the plasma half-life of PZQ (1–1 1/2 h).
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  • 48
    ISSN: 1432-1041
    Keywords: metoprolol ; neonates ; amniotic fluid ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven women were treated with metoprolol 50–100 mg twice daily for hypertension in pregnancy. The disposition of metoprolol and one of its metabolites alfa-OH-metoprolol was studied in venous plasma and amniotic fluid during labour, in mixed cord plasma and in capillary blood of the newborn. Peak concentrations of metoprolol and alfa-OH-metoprolol were reached 60 to 120 min after dosing in maternal plasma while the amniotic fluid levels of these compounds continued to increase from 60 to 180 min to the end of the study and were substantially higher than in the plasma after 4 to 5 h. It is postulated that a major fraction of metoprolol and alfa-OH-metoprolol reaches the amniotic fluid via the fetal urine and that the elimination from the amniotic fluid mainly proceeds via diffusion across fetal membranes and transfer across the fetal capillary bed. No measurable concentrations of metoprolol were found in two of the newborns 2 h after delivery. In the remaining four neonates the 2-h concentrations exceeded the corresponding cord plasma levels. In all neonates the alfa-OH-metoprolol levels in the capillary blood were higher 2 h after birth than in cord blood. In two newborns the metabolite levels continued to increase for 5 h and in one the highest blood concentrations of this metabolite was found 20 h after birth. Redistribution of metoprolol from tissue stores followed by metabolism might be the cause of these temporary elevations of the blood levels of metoprolol and alfa-OH-metoprolol.
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  • 49
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    European journal of clinical pharmacology 33 (1987), S. 431-434 
    ISSN: 1432-1041
    Keywords: phenylethylmalonamide ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of phenylethylmalonamide (PEMA) were studied in 6 elderly men after oral administration of a single 400 mg dose. Peak PEMA serum levels were obtained within 4 h of intake, half-life values ranged from 30.7–57.9 h in these elderly men. The elimination half-life was twice as long when compared to a study previously performed in young volunteers.
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  • 50
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    European journal of clinical pharmacology 33 (1987), S. 493-498 
    ISSN: 1432-1041
    Keywords: amiloride ; pharmacokinetics ; renal failure ; liver disease ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the antikaliuretic amiloride has been studied in healthy controls and in patients with chronic renal failure or hepatitis. It was 40% bound to protein. In healthy volunteers 49% of an oral dose was recovered unchanged in the urine. The renal clearance of amiloride was about 3 times the creatinine clearance, which means that it was predominantly excreted via tubular secretion. Renal impairment reduced the clearance of amiloride, causing a prolongation of the t1/2 and drug accumulation in plasma. In hepatitis the t1/2 of amiloride was prolonged and the AUC increased. Urinary recovery (Ae) of amiloride was greater in hepatitis patients than in controls.
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  • 51
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    European journal of clinical pharmacology 33 (1987), S. 499-504 
    ISSN: 1432-1041
    Keywords: morphine ; epidural administration ; pharmacokinetics ; CSF/plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to determine the rate and degree of redistribution of morphine within the cerebrospinal fluid (CSF), and whether it was affected by the site of and volume of the injection, morphine was given to 23 elderly patients undergoing thoracotomy — in 10 ml saline in the lumbar epidural interspace (n=5), in 10 ml saline in the thoracic epidural interspace (n=5), in 2 ml saline in the thoracic interspace (n=8) and in 10 ml saline in the lumbar epidural interspace (n=5). The plasma concentration of morphine in all patients was comparable and was much lower than in the CSF. The CSF morphine concentration, measured as the area under the CSF concentration curve (AUC), the maximal CSF concentration (Cmax) and the time to reach maximal CSF concentration (tmax), varied between the four groups. The variation was related to the site of the injection; the AUC and Cmax were lower and tmax appeared later after thoracic than lumbar injection. Lumbar CSF morphine concentrations were further reduced by thoracic epidural injection of morphine in a small as compared to a large volume. The permeability of the dura to morphine was not influenced by the volume used. The results show that morphine is not homogenously distributed within the CSF. The availability of morphine to CSF from the epidural space is not altered by the injection volume, but the drug remains more localized in CSF after epidural injection of morphine in a small volume. The findings imply that epidural injection of morphine in a small volume at a site of nociceptive input should evoke spinal analgesia with least risk of supraspinally mediated side effects.
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  • 52
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    European journal of clinical pharmacology 32 (1987), S. 273-277 
    ISSN: 1432-1041
    Keywords: pentobarbital ; hexobarbital ; dipyrone ; intensive care ; D-glucaric acid ; pharmacokinetics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml·min−1·kg−1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml·min−1·kg−1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methylaminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.
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  • 53
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    European journal of clinical pharmacology 32 (1987), S. 367-372 
    ISSN: 1432-1041
    Keywords: endralazine ; severe hypertension ; food intake ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A sensitive HPLC assay has been used to determine the effect of food on plasma endralazine levels in 8 patients with essential hypertension. Subjects were investigated whilst on maintenance therapy with endralazine combined with a fixed antihypertensive baseline treatment for at least 4 weeks, samples being collected after the usual oral morning dose of endralazine (5 mg and 10 mg), on two occasions at least 7 days apart. Endralazine was administered with the concomitant therapy in randomised order once 90 min before and once immediately after a standard breakfast. Acetylator status did not affect its pharmacokinetics in the postprandial study after a 5 mg dose, the peak endralazine concentration averaged 57.5% lower and the AUC had fallen significantly by 49.9%, whereas after 10 mg the postprandial peak level and the AUC were 82.9% and 64.7%, lower. In the 5 mg study the mean arterial blood pressure was decreased by 30 mm Hg in the fasting subjects and by 21 mm Hg in the post-prandial group. For the 10 mg dose the corresponding values were 35 and 24 mm Hg. The blood pressure lowering effect was only weakly correlated with the food — related reduction in the plasma endralazine levels. The results suggest that endralazine has a similar kinetic interaction with food as that found for hydralazine.
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  • 54
    ISSN: 1432-1041
    Keywords: triazolam ; troleandomycin ; benzodiazepines ; antibiotics ; drug interaction ; pharmacokinetics ; first-pass effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy volunteers received a single oral dose of triazolam 0.25 mg after 7 days on troleandomycin 2 g/day p.o. or placebo in a double-blind cross-over study. Plasma triazolam and psychometric and memory tests (including Critical Flicker Fusion threshold, Choice Reaction Time, Digit Symbol Substitution and Self-Rating Scales) were assessed at regular intervals after the final treatment. Troleandomycin was found to prolong the psychomotor impairment and amnesia produced by triazolam. There was a significant enhancement of the AUC, the peak concentration and the delay to tmax of triazolam after 7 days treatment with troleandomycin compared to placebo. Thus, there is a pharmacokinetic interaction, and the combination of triazolam and troleandomycin should be avoided or the dose of triazolam should be adjusted. The most likely mechanism is a diminished hepatic first-pass effect, and a decrease in the apparent oral clearance of triazolam.
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  • 55
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    European journal of clinical pharmacology 32 (1987), S. 577-582 
    ISSN: 1432-1041
    Keywords: yohimbine ; pharmacokinetics ; plasma levels ; renal elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetic disposition of yohimbine was examined in eight young male subjects following a single oral dose of 10 mg yohimbine hydrochloride. The drug was rapidly absorbed (absorption half-time 0.17±0.11 h) and rapidly eliminated from the plasma (elimination half-life 0.60±0.26 h). This clearance of yohimbine from plasma was constant over approximately 10 elimination half-lives, suggesting that distribution into a second pharmacokinetically distinct compartment was not responsible for the rapid decline in plasma yohimbine levels. Urinary excretion and the partitioning of the drug into red blood cells (RBC) was investigated. In the 24 h following oral administration of the drug, virtually no yohimbine was eliminated in the urine (0.35±0.50% of the administered dose). Furthermore, only 20% of blood-borne yohimbine was located in RBC. These results suggest that yohimbine is eliminated primarily through metabolism since the rapid plasma clearance of yohimbine was not the result of renal elimination or sequestration by RBC.
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  • 56
    ISSN: 1432-1041
    Keywords: moracizine·HCl ; antiarrhythmic ; ethmozine ; radiolabelled ; pharmacokinetics ; material balance ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Moracizine (ethmozine) is a phenothiazine derivative with demonstrated antiarrhythmic activity. To characterize the pharmacokinetics and material balance relationships in humans, we have given14C-moracizine·HCl as a single oral dose of 500 mg (50 μCi) to six healthy men. Plasma, urine, and faecal samples were collected for 7 days after administration and the concentrations of total radioactivity and intact moracizine were determined by liquid scintillation counting and HPLC, respectively. Urine and faecal recovery accounted for 95% of the administered radioactivity. Most of this radioactivity was found in the faeces (59%). Only 0.05% of the dose was recovered from urine as intact moracizine. The Cmax and AUC for moracizine equivalents of total radioactivity were 4- and 18-fold higher, respectively, than the corresponding values for intact moracizine. Additionally, both the disappearance of total radioactivity from plasma and its excretion rate into urine were slower in comparison to intact drug. Terminal t1/2 values calculated from plasma concentration-time data were 85.2 and 3.5 h for total radioactivity and intact moracizine, respectively. However, based on urinary excretion rates, the t1/2 for total radioactivity was shorter (29.3 h) while the t1/2 for intact drug was comparable (2.7 h) to the results obtained from the plasma data. The oral plasma clearance of moracizine was relatively large (2.2l·min−1), suggesting first-pass metabolism. The estimated oral systemic availability of moracizine was 34%.
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  • 57
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    European journal of clinical pharmacology 31 (1987), S. 711-714 
    ISSN: 1432-1041
    Keywords: flecainide ; pharmacokinetics ; moderate renal failure ; variability of elimination half-time
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of flecainide after the oral administration of 100 mg to 8 patients without renal impairment and 8 patients with mild to moderate renal failure. Both groups gave comparable results with respect to the peak plasma concentrations and the time to peak. There was a significant correlation between renal flecainide clearance and endogenous creatinine clearance. The elimination half-time in the patients with impaired renal function was significantly longer (19.9, SD 9.9 h) than that in the patients with normal renal function (11.5, SD 4.2 h), but the variability in the elimination half-time in renal failure could not be explained on the basis of the available results.
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  • 58
    ISSN: 1432-1041
    Keywords: captopril ; uraemia ; captopril disulfide ; dialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 µg·ml−1 vs 0.181 µg·ml−1) and the concentrations of the disulfides 4 times higher (3.62 µg·ml−1 vs 0.924 µg·ml−1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46±19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37±7 mmHg and 24±9 mmHg respectively, occurring 6 h after the dose, compared with 8±7 and 8±1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.
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  • 59
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    European journal of clinical pharmacology 32 (1987), S. 309-311 
    ISSN: 1432-1041
    Keywords: digoxin ; verapamil ; cirrhosis ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of a single low dose of verapamil (80 mg) on the serum levels of digoxin (single dose of 0.5 mg) was studied in 6 patients with hepatic cirrhosis and in 6 healthy volunteer controls. In the cirrhotic patients verapamil increased the peak serum level and the total AUC of digoxin by 98% and 32%, respectively. There was an associated 23% decrease in the renal digoxin clearance. In normal subjects only marginal alterations in digoxin kinetics were observed following verapamil administration. The results indicate that cirrhosis magnifies the influence of verapamil on digoxin kinetics.
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  • 60
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    European journal of clinical pharmacology 32 (1987), S. 303-307 
    ISSN: 1432-1041
    Keywords: azapropazone ; arthritis ; pharmacokinetics ; synovial fluid level ; synovial tissue level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentration-time curves of azapropazone in synovial fluid and tissues have been studied in arthritic patients after an i.v. bolus (600 mg) and under steady-state conditions. Synovial fluid and tissue samples were taken intraoperatively 0.45–60 h after administration. The azapropazone concentrations in synovial fluid, synovial tissue and plasma were correlated. The levels in synovial fluid were usually lower than corresponding plasma levels. Under steady-state conditions azapropazone did not accumulate in synovial tissues.
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  • 61
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    European journal of clinical pharmacology 32 (1987), S. 317-320 
    ISSN: 1432-1041
    Keywords: ranitidine ; amitriptyline ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.
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  • 62
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    European journal of clinical pharmacology 32 (1987), S. 351-355 
    ISSN: 1432-1041
    Keywords: nifedipine ; cimetidine ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma pharmacokinetics of nifedipine and the formation of its metabolites have been studied in volunteers under conditions which would affect the activity of the cytochrome P-450 system. The pharmacokinetics of a 10-mg capsule of nifedipine were not significantly different between smokers and non-smokers of similar age. After pretreatment with cimetidine, which inhibits the activity of cytochrome P-450, the peak plasma concentration and area under the plasma-time concentration curve for nifedipine were increased by a mean 84%. In contrast, pre-treatment with ranitidine which has little effect on cytochrome P-450, did not significantly alter nifedipine pharmacokinetics. Smoking does not contribute significantly to the variability in nifedipine pharmacokinetics. However, the interaction between nifedipine and cimetidine, but not ranitidine, may be of clinical importance.
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  • 63
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    European journal of clinical pharmacology 32 (1987), S. 377-382 
    ISSN: 1432-1041
    Keywords: morphine ; renal failure ; pharmacokinetics ; morphine-3-glucuronide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of morphine and its glucuronidated metabolites were investigated in seven patients with advanced renal failure. The terminal elimination half life of morphine varied between 1.5 and 4.0 h (mean 2.4 h), the volume of distribution between 2.5 and 6.3 l·kg−1 (mean 4.4 l·kg−1) and the total plasma clearance between 13.3 and 31.3 l·min−1·kg−1 (mean 21.1 l·kg−1). There were no statistically significant differences between the pharmacokinetic data in the uraemic patients and in a control group of cancer patients with normal kidney function. The concentrations of the glucuronidated metabolites rapidly rose to levels above those of morphine. The elimination half-life of M3G varied between 14.5 and 118.8 h (mean 49.6 h) in the renal failure patients, which is distinctly different from the 2.4 to 6.7 h (mean 4.0 h) found in patients with normal kidney function. There was a significant correlation between the half-life of M3G and renal function estimated as serum urea. Thus, the metabolism of morphine in patients with kidney disease is not significantly impaired. The clinical importance of the high concentrations of glucuronides in uraemic patients is not known.
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  • 64
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    European journal of clinical pharmacology 32 (1987), S. 395-401 
    ISSN: 1432-1041
    Keywords: probenecid ; Michaelis-Menten kinetics ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers were given probenecid 0.5, 1 and 2 g p.o. and 0.5 g i.v. The protein binding of probenecid at different concentrations in human plasma was estimated by equilibrium dialysis. The free fraction was found to increase nonlinearly with increasing total probenecid concentration, up to a maximum free fraction of 26%. The plasma concentration-time data after the oral doses were described by a one-compartment open model with first-order absorption and Michaelis-Menten elimination. The mean absorption rate constant 0.0072 min−1 was dose-independent, and the maximal rate of elimination (mean 1429 µg/min) did not differ between doses whether calculated from the total or free concentrations. The Michaelis-Menten constant decreased significantly from 67.1 to 55.5 µg/ml as the dose increased from 1 g to 2 g, while the unbound Michaelis-Menten constant remained unchanged. The elimination of probenecid after the 0.5 g dose was in the linear region of the Michaelis-Menten elimination when calculated from the total and the free concentrations. The volume of distribution increased only slightly from 9.5 to 11.4 l as the dose increased from 0.5 to 2 g, but the unbound volume of distribution decreased significantly from 164 to 99 l. Absorption was complete and was independent of the dose administered.
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  • 65
    ISSN: 1432-1041
    Keywords: adrenergic beta-receptors ; propranolol ; beta-blockade ; pharmacokinetics ; leukocyte beta-receptors ; leukocytes ; exercise tachycardia ; 4—OH-propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of β-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (predrug) at 2 h (rs=0.72), 4 h (rs=0.84) and 6 h (rs=0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.
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  • 66
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    European journal of clinical pharmacology 31 (1987), S. 695-699 
    ISSN: 1432-1041
    Keywords: doxorubicin ; sarcoma ; pharmacokinetics ; polychemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of doxorubicin has been studied in 26 sarcoma patients receiving polychemotherapy. Mean elimination half-life was 34.7±16.6 h and the total plasma clearance was 29.5±9.31·h−1·m−2. No relationship was found between the pharmacokinetic parameters and the response to treatment, or its toxicity. Special attention was paid to the early-phase kinetics of the drug (3–20 min after injection). A correlation between the early clearance and the ages of the patients was observed. The early clearance was clearly correlated with the total plasma clearance measured over 48 h after injection, indicating the importance of the distribution phase in the overall kinetics of the drug.
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  • 67
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    European journal of clinical pharmacology 31 (1987), S. 701-704 
    ISSN: 1432-1041
    Keywords: theophylline ; miocamycin ; drug interaction ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between a new macrolide antibiotic, miocamycin, and theophylline was evaluated in a single cross-over study in 5 asthmatic children. Each patient received a single dose of theophylline (4.3 mg/kg) delivered in 15 min using a constant-rate infusion pump, immediately before and after a 10 day course of miocamycin 17.5 mg/kg b.d. The pharmacokinetics of theophylline were calculated for each phase of the study. The elimination rate constant (3.92 vs 3.74 h−1), the mean total body clearance (1.71 vs 1.8 ml·min·kg−1) and the mean apparent volume of distribution (0.57 vs 0.58 l·kg−1) did not differ. The result can be explained by the inability of the antibiotic to form inactive cytochrome P-450 metabolite complexes which can interfere with the metabolism of theophylline. Thus, miocamycin can safely be administered to asthmatic children requiring theophylline treatment, when they have an infection due to susceptible pathogens.
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  • 68
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    European journal of clinical pharmacology 31 (1987), S. 733-736 
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; elderly patients ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have determined the pharmacokinetics of meptazinol after its intravenous and intramuscular administration in a crossover study in 7 elderly hospital in-patients (〉70 years), and have compared with the results from 14 healthy, young volunteers (ages 20–40 years). The systemic availability after i.m. administration was comparable to that after i.v. administration, a result consistent with the physicochemical properties of the drug. There was a slight, but statistically significant (p〈0.01) prolongation in t1/2z in the elderly (mean 2.93 h) compared with the young (mean 2.06 h). This was associated with a 25% lower clearance in the elderly rather than with any alteration in volume of distribution. However, these changes would not appear to be substantial enough to require a revised dosage recommendation for meptazinol for this age group.
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  • 69
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    European journal of clinical pharmacology 31 (1987), S. 743-743 
    ISSN: 1432-1041
    Keywords: chloroquine ; dose dependence ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 70
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    European journal of clinical pharmacology 32 (1987), S. 17-22 
    ISSN: 1432-1041
    Keywords: felodipine ; calcium antagonist ; normal man ; renal function ; albumin excretion ; beta2-microglobulin excretion ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute renal effects of a single oral dose of felodipine 0.15 mg/kg were studied in 8 healthy males. Thirty minutes after administration the mean plasma concentration was 25.7 nmol/l. There was a significant reduction in diastolic blood pressure (24%) and a concomitant rise in heart rate (38%), leaving the systolic pressure unchanged. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique using the clearance of125I-iothalamate and131I-hippuran respectively. GFR was unchanged and the filtration fraction (FF) was reduced, whilst there was a decrease in renal vascular resistance (RVR). The glomerular filter characteristics were unchanged, as estimated by the unchanged excretion rate of albumin. There was a significant rise in the clearance of sodium (176%) but only a small and insignificant increase in urine volume. Clearance of potassium was decreased. An increase in the clearance of uric acid and a rise in the beta-2-microglobulin excretion rate were found, both suggesting a proximal tubular effect of felodipine. The excretion rate of calcium was increased.
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  • 71
    ISSN: 1432-1041
    Keywords: atenolol ; amiloride ; hydrochlorothiazide ; young ; elderly ; pharmacokinetics ; pharmacodynamics ; volunteers ; patients ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.
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  • 72
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    European journal of clinical pharmacology 32 (1987), S. 165-172 
    ISSN: 1432-1041
    Keywords: warfarin ; cimetidine ; ranitidine ; stereochemistry ; drug-drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.
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  • 73
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    European journal of clinical pharmacology 32 (1987), S. 357-360 
    ISSN: 1432-1041
    Keywords: nitrendipine ; food intake ; pharmacokinetics ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of nitrendipine were measured, after single (20 mg) oral doses, in young healthy volunteers. On three occasions the subjects ingested the dose having fasted overnight. Data from these three occasions were used to assess variability in nitrendipine pharmacokinetics and both inter- and intra-subject variability were high. On a fourth occasion, the subjects took the tablet after a standard meal. The effects of food on nitrendipine pharmacokinetics, based on the comparison of data from the first fasting visit and the food visit, were negligible.
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  • 74
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    European journal of clinical pharmacology 32 (1987), S. 583-586 
    ISSN: 1432-1041
    Keywords: tiapride ; Huntington's disease ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic properties of a single oral dose of 100 mg of tiapride were studied in six patients with Huntington's disease. The results for five patients were consistent with a two compartment open model. Peak plasma concentrations were observed within 2 h following durg administration with a mean value of 0.92 μg/ml being recorded. The drug was rapidly eliminated as unmetabolised tiapride in the urine, 51% of the dose was recovered in 24 h. The plasma elimination half-life was 5.3 h and the average apparent plasma clearance was 16.6 l/h.
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  • 75
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    European journal of clinical pharmacology 32 (1987), S. 593-596 
    ISSN: 1432-1041
    Keywords: dexamethasone ; dexamethasone phosphate, antiemetic ; pharmacokinetics ; cancer chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have given single high doses of dexamethasone phosphate by intravenous infusion as an antiemetic to 15 cancer patients receiving regimens containing cisplatin and/or doxorubicin. The patients received graded doses of dexamethasone phosphate, in the range 40–200 mg, dependent upon nausea and vomiting scores, during up to three consecutive cycles of cancer chemotherapy. Plasma and urine concentrations of dexamethasone (dexamethasone alcohol) were measured by HPLC. The plasma concentration-time data were described by an open two-compartment model. The pharmacokinetic variables were independent of the dose of dexamethasone over the range studied. The terminal half-time was 4.0±0.4 h and the total body clearance was 3.5±0.4 ml·min−1·kg−1. The volume of the central compartment and the total apparent volume of distribution were 0.23±0.03 and 1.0±0.1 l·kg−1 respectively. Approximately 8% of the dose was excreted into the urine as dexamethasone.
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  • 76
    ISSN: 1432-0738
    Keywords: Isopropyl alcohol ; Tracheal mucosa ; Ciliary activity ; Recovery process ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The toxicity of isopropyl alcohol (IPA) on the tracheal mucosa was studied experimentally with special reference to the recovery process of the organ. The results showed that 400 ppm IPA has an acute effect on the mucociliary system in the tracheal mucosa, and that recovery from such degeneration can occur in 2 weeks. When functional and morphological damage was induced by a higher level (5500 ppm) of IPA, recovery did not occur in 2 weeks. The conclusion is that the present allowable level of IPA is reasonable from the viewpoint of the effects of short-term exposure to IPA on the tracheal mucosa. In addition, a higher level of IPA exposure has longer-term effects on the tracheal mucosa, and workers exposed to such a higher level of IPA vapor should be given careful otolaryngological follow-up observations.
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  • 77
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    Archives of toxicology 59 (1987), S. 385-390 
    ISSN: 1432-0738
    Keywords: Lung ; Methyl isocyanate ; Gas poisoning ; Electron microscopy ; Rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The static exposure of rats to 0.25 mg/l methyl isocyanate for 1 h resulted in damage to the epithelium of the proximal bronchioles and upper airways. Bronchiolar cells exhibited both nuclear and cytoplasmic damage; many epithelial cells, particularly in the bronchi and trachea, were killed and/or dislodged from the basement membrane. A “raft” of cell debris and fibrin lined most of the airways during the 1st week after exposure but repair to the underlying epithelium was well advanced within 2–3 days. The majority of airways were lined by a normal epithelium within 3 weeks of exposure, but isolated foci of hyperplasia and occluded airways probably accounted for continued respiratory impairment.
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  • 78
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    European journal of clinical pharmacology 31 (1987), S. 617-619 
    ISSN: 1432-1041
    Keywords: chronopharmacology ; indomethacin ; suppository ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 100 mg indomethacin suppository were studied in 12 healthy volunteers on two occasions at least 7 days apart. Suppositories were administered in randomised order at 9.00 and 21.00 hours to see if there was evidence of a diurnal variation in kinetic parameters. The study failed to show a significant change in single dose kinetics with the time of suppository administration. This is in contrast to previous work [1] demonstrating a circadian rhythm in the kinetics of a single oral dose of indomethacin. This suggests that the chronopharmacokinetics of indomethacin is dependent on the function of the upper gastrointestinal tract.
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  • 79
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    European journal of clinical pharmacology 31 (1987), S. 625-627 
    ISSN: 1432-1041
    Keywords: verapamil ; breast milk ; norverapamil ; breast feeding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentrations of verapamil and norverapamil have been measured in milk and plasma samples from a 32year-old woman treated with verapamil 80 mg tds while breast-feeding her child. The average steady-state concentrations of verapamil and norverapamil in milk were, respectively, 60% and 16% of the concentrations in plasma. The breast-fed child received less than 0.01% of the dose of verapamil given to the mother. No verapamil or norverapamil (〈1 ng/ml) could be detected in the plasma from the child.
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  • 80
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    European journal of clinical pharmacology 31 (1987), S. 575-578 
    ISSN: 1432-1041
    Keywords: felodipine ; metoprolol ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This double-blind, cross-over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. During three, five-day study periods, felodipine 10 mg b.d., metoprolol 100 mg b.d. and a combination of the two, were given in random order. There was at least a 7-day washout period between each pharmacokinetic study day. Plasma levels of unchanged felodipine and metoprolol were measured for 24 h after the last dose, on the 5th day of each treatment period. Eight subjects, aged 19–22 years, completed the study. Both felodipine and metoprolol, given alone and in combination, were well tolerated. None of the felodipine pharmacokinetic variables (tmax, Cmax, Cmin, AUC (0–12) and t1/2) changed significantly when felodipine and metoprolol were given in combination. Cmax and AUC (0–12) for metoprolol increased significantly when metoprolol and felodipine were combined, although tmax, Cmin and t1/2 for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.
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  • 81
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    European journal of clinical pharmacology 31 (1987), S. 583-588 
    ISSN: 1432-1041
    Keywords: cotinine ; pharmacokinetics ; non-smokers ; absolute bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cotinine, the main metabolite of nicotine, was administered intravenously to healthy male non-smoking volunteers in doses of 5, 10 and 20 mg, and orally in doses of 10 and 20 mg. Intravenous administration was characterized by a dose-independent half-life of 12.2 h, mean residence time of 15.9 h, total clearance of 3.64 l h−1 and a volume of distribution of 56.5 l. Renal clearance was 0.46 l h−1 and approximately 12.0% of the dose was excreted unchanged in the urine. The mean absorption time after oral dosing ranged between 1 and 3 h, the peak concentration was reached within 45 min and the mean elimination half-lives were 12.9 and 11.7 h, respectively, after the 10 and 20 mg doses. Systemic bioavailability ranged between 0.84 and 1.11 following 10 mg and between 0.97 and 1.03 following the 20 mg dose. Mean urinary recovery and renal clearance were almost identical with the values after iv administration.
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  • 82
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    European journal of clinical pharmacology 31 (1987), S. 595-600 
    ISSN: 1432-1041
    Keywords: caffeine ; exercise ; obesity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of obesity, exercise, and the interaction of obesity and exercise were examined in 6 caffeine naive, untrained, nonsmoking, college males (3 lean (LV), 3 obese (OV)). Each subject received caffeine (oral, 5.83 mg·kg−1 lean body weight) or placebo (50 mg citrate) prior to 3 h of seated rest and prior to 90 min of treadmill walking (40% of their maximal aerobic power) followed by 90 min of seated recovery. Serum samples were collected at various times and analyzed for caffeine by HPLC. Pharmacokinetic analysis indicated that at rest, OV had a significantly higher absorption rate constant (Ka 0.0757 vs. 0.0397 min−1), lower elimination rate constant (Ke 0.0027 vs. 0.0045 min−1), and longer serum half-life (t1/2 4.37 vs. 2.59 h) in comparison to LV. In exercise, as well as at rest LV and OV had a large difference in the volume of distribution (43.2 vs. 101. 1) (rest, 54.1 vs. 103.1). Exercise consistently resulted in a decrease in the maximal serum concentration of caffeine and the area under the curve in OV while having no consistent effect on LV. The interactive effects of obesity and exercise could not be dissociated. However, these results demonstrate that both obesity and exercise have modified the pharmacokinetics of caffeine.
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  • 83
    ISSN: 1432-1041
    Keywords: dextran ; hydroxyethylstarch ; haemodilution ; ischaemic stroke ; plasma viscosity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 21 patients with ischaemic strokes we have monitored plasma viscosity, total plasma concentration, numeric average molecular weight (Mn), and weight average molecular weight (Mw) of Dextran 40 (dextran) and hydroxyethylstarch 200/0.5 (HES) during 10 days of treatment (days 1–4, 2×500 ml; days 5–10, 1×500 ml). Plasma concentrations of dextran increased during the first 4 days (8.3 mg·ml−1 on the first day to 18.0 mg·ml−1 on the fifth day), reached an apparent steady state of 17.2 mg·ml−1 during the next 6 days, and declined subsequently with a half-time (t1/2) of 4.03 days. After ten days treatment Mn and Mw were shifted towards higher values. Plasma viscosity increased from 1.26 mPas to 1.69 mPas on Day 10 (p〈0.01) and was linearly correlated with the total plasma concentration of dextran (p〈0.001; r=0.88). Total plasma concentrations of HES averaged 11.7 mg·ml−1 on Day 1 and 12.4 mg·ml−1 on Day 5. The molecular weight distribution did not change during the infusions but decreased in comparison with the administered solution. Plasma viscosity fell from 1.40 mPas to 1.30 mPas at Day 10 (p〈0.05) and was not related to the concentration of HES. The haemodiluting effect, as indicated by a decrease of the haematocrit, was 22% and 16.8% for dextran and HES respectively. These data suggest several advantages of HES compared with dextran in haemodilution therapy of ischaemic stroke.
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  • 84
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    European journal of clinical pharmacology 31 (1987), S. 569-573 
    ISSN: 1432-1041
    Keywords: tolazoline ; neonates ; persistent fetal circulation ; pharmacodynamic effects ; pharmacokinetics ; pulmonary circulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of two doses of tolazoline have been compared in 2 groups of newborns suffering from the persistent fetal circulation syndrome. The effects on PaO2 and AaDO2 were similar in the 2 groups who received either a bolus of 1 or 0.5 mg·kg−1 tolazoline, followed by a continuous infusion of 1 or 0.5 mg·kg−1·h−1. The observed changes did not differ significantly from those previously observed in babies treated with 2 mg·kg−1. A rise in PaO2 and a reduction in AaDO2 were usually observed shortly after the bolus injection and at plasma levels between 1.5 and 4 µg·ml·−1. A progressive rise in plasma level over time occurred after 1 mg·kg−1 (and in the previous study of 2 mg) but not with 0.5g/kg tolazoline. The elimination half-life of tolazoline in 6 patients was 5 to 13 h. The data suggest that continuous infusion of tolazoline is not necessarily required and that the dose of 0.5 mg/kg is more appropriate and safer than the higher doses usually proposed.
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  • 85
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    European journal of clinical pharmacology 32 (1987), S. 67-70 
    ISSN: 1432-1041
    Keywords: enprofylline ; pharmacokinetics ; elderly ; renal excretion ; half-life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of enprofylline, a new potent antiasthmatic, has been studied in 20 healthy, elderly subjects, aged 65 to 81 years, and in 7 young adult controls, aged 23 to 37 years. The dose of 1 mg/kg body weight was given as an i.v. infusion. Plasma levels of enprofylline were followed for about 7 h and urine levels for 24 h. Both groups eliminated the major portion of the dose (about 83%) by renal excretion. As expected the mean creatinine clearance (92.5 ml·min−1· 1.73 m−2) was moderately decreased in the elderly subjects. The total clearance of enprofylline was 0.16 1·h−1·kg−1 and the renal clearance was 0.13 l·h−1·kg−1, which was significantly lower than that in the young controls (0.28 and 0.22 l·h−1·kg−1) respectively. Thus, the enprofylline clearance had fallen relatively more (about 40%) than the decrease in creatinine clearance (about 20%) with age. The half-life of enprofylline in old age was 2.5 h, which was significantly longer than in the younger adults (1.8 h). It is concluded that the pharmacokinetics of enprofylline was significantly influenced by advanced age, mainly due to reduced renal excretion. This reduction was more pronounced than anticipated from the age-dependent decline in creatinine clearance.
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  • 86
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    European journal of clinical pharmacology 32 (1987), S. 103-106 
    ISSN: 1432-1041
    Keywords: fenoldopam ; peripheral dopamine agonist ; pharmacokinetics ; absorption ; food effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight healthy volunteers participated in an open crossover study to assess the effect of a standardised meal on the systemic availability of a single oral dose of fenoldopam mesylate 100 mg. Subjects were studied on four separate occasions, twice fasting and twice fed in randomised, balanced order. Plasma and urine samples were obtained before and at regular intervals up to 25 h post dose. Measurement of fenoldopam (SK&F 82526) and its 8-sulphate metabolite (SK&F 87782) were by means of HPLC-EC analysis. Area under the plasma concentration time curve (AUC) and maximum detected plasma concentration (Cmax) for fenoldopam and SK&F 87782 were significantly reduced whereas time to maximum concentration was significantly increased with food. Using AUC's for fenoldopam and SK&F 87782, mean relative bioavailabilities were 35% and 81% respectively under fed compared with fasting conditions. Twenty-four hour excretion of fenoldopam was significantly reduced with food, but excretion of SK&F 87782 was apparently unchanged. Mean relative bioavailabilities calculated from these data were 83% and 86% respectively. Relatively large inter-subject variability in AUC and Cmax were seen, but intra-subject variability was not marked. Mild symptoms associated with vasodilation were reported on all study days.
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  • 87
    ISSN: 1432-1041
    Keywords: mefloquine ; mefloquine/sulphadoxine/pyrimethamine ; Thai subjects ; pharmacokinetics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of mefloquine were studied in 12 healthy Thai male and 12 healthy Thai female volunteers. Mefloquine (MQ) was administered either alone (750 mg orally) or in combination (MSP) with sulphadoxine (1.5 g) and pyrimethamine (75 mg) to each of 6 male and 6 female subjects. Plasma concentrations of MQ were measured by HPLC at intervals for 42 days. There was considerable interindividual variability in the pharmacokinetic parameters; for example in the male subjects receiving MQ alone peak concentrations ranged between 638 and 2494 ng·ml−1 with a mean concentration of 1442 ng·ml−1. Compared to previously published data on MQ concentrations in Caucasian male subjects, the present study indicates that higher concentrations are achieved in Thai subjects. The only significant difference in kinetic parameters between male and female subjects receiving MQ alone was in the mean residence time (MRT) which was greater in females. However, an analysis of pharmacokinetic parameters following administration of the combination preparation showed that the time to peak (tmax) was significantly reduced in females receiving MSP compared to the corresponding females given MQ alone and males given MSP. When data obtained from all subjects (male and female) receiving either MQ alone or MSP were combined, both MRT and half-life were significantly greater in subjects given MSP. There is therefore some evidence that therapeutic concentrations of MQ are maintained for a longer period of time following MSP administration.
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  • 88
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    European journal of clinical pharmacology 32 (1987), S. 179-185 
    ISSN: 1432-1041
    Keywords: melphalan ; protein binding ; plasma ; humans ; rats ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The binding of melphalan to plasma proteins from four healthy humans and from rats was measured by centrifugal ultrafiltration. Melphalan concentrations were determined by HPLC and by measuring 14C-melphalan activity. In whole blood, melphalan was distributed preferentially in plasma. However, a constant fraction, 37%, which was independent of the total melphalan concentration in whole blood, was present within the red blood cells. The binding of melphalan to plasma proteins from humans was less than that from rats. In both, however, the fraction bound was constant throughout the concentration range (0.1 to 9.0 µM) that is achieved during standard-dose melphalan therapy. Albumin was the primary binding protein. At concentrations equal to or in excess of 33 µM, which have been achieved during high-dose melphalan therapy, free plasma melphalan concentrations were no longer linearly related to total drug concentrations, and the plasma protein binding of melphalan in the human became concentration dependent. This occurred at concentrations of 70 µM in the rat. Scatchard analysis of the data indicated the presence of 2 groups of binding sites. Class I sites had 0.03 and 0.4 binding sites per albumin molecule in humans and rats, with respective association constants of 4.43 × 104M−1 and 1.92 × 104M−1. Class II sites had 5.18 and 2.60 binding sites per molecule, with repective association constants of 3.82 × 102M−1 and 2.01 × 102M−1.
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  • 89
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    European journal of clinical pharmacology 32 (1987), S. 203-205 
    ISSN: 1432-1041
    Keywords: paracetamol ; primaquine ; drug interaction ; metabolite formation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of paracetamol and the formation of metabolites were evaluated in 6 healthy volunteers before and during concomitant administration of a single dose (45 mg) of primaquine. There was no effect of the antimalarial drug on either conjugation (to paracetamol glucuronide and paracetamol sulphate) or oxidation (as judged by the presence of paracetamol cysteine and paracetamol mercapturate) pathways. Although primaquine inhibits certain oxidative metabolism (e.g. of antipyrine) it has no effect, in therapeutic doses, on paracetamol metabolism.
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  • 90
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    European journal of clinical pharmacology 32 (1987), S. 211-215 
    ISSN: 1432-1041
    Keywords: diazepam ; pharmacokinetics ; Chinese ; white Caucasians ; body fat ; skin-fold thickness
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have compared diazepam pharmacokinetics in 16 Chinese and 18 white Caucasian healthy male volunteers, resident in Hong Kong and have correlated them with physical attributes. Serum concentrations of diazepam and desmethyldiazepam were measured in venous blood by an enzyme-linked immunoassay (0–3 h samples) and HPLC (3–72 h samples). Pharmacokinetic parameters were derived assuming a two compartment model, distribution phase 〈6 h, and 100% oral systemic availability. Compared with the Chinese the white Caucasians were older, heavier, taller, and fatter, as judged by skin fold thickness (SFT) and total body weight to ‘Ideal’ body weight (TBW/IBW) ratio; respective mean differences being 16%, 27%, 4%, 26%, and 15% (p〈0.05). Mean diazepam apparent volume of distribution (V) and V/IBW were larger in the white Caucasians (52% & 39% respectively, p=0.002). SFT and TBW/IBW ratio yielded the best correlations with V, V/TBW and V/IBW (0.50–0.75, p〈0.05). Obesity indices contributed most to the overall regressions (R2 up to 0.52), and for V there was a further small effect (2%, partial F test) due to ethnic group, possibly reflecting stature. Mean peak diazepam concentration (Cmax) was similar in both ethnic groups. Time to Cmax (tmax) was more often prolonged in the Chinese (X 2 test, p=0.01). Body fat and stature may thus account for these inter-ethnic differences in the apparent volume of distribution of diazepam, a highly lipid-soluble drug.
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  • 91
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    European journal of clinical pharmacology 32 (1987), S. 259-265 
    ISSN: 1432-1041
    Keywords: ketanserin ; ketanserin-ol ; pharmacokinetics ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ketanserin and its main metabolite ketanserin-ol, and the antihypertensive effects of intravenous, single oral and chronic oral (40 mg once daily) administration of ketanserin, have been investigated in a single blind study of 10 patients with uncomplicated mild hypertension. Ketanserin had a terminal half-life of 29.2 h, a plasma clearance of 518 ml/min and a volume of distribution of 18.0 l/kg. Chronic oral intake of 40 mg ketanserin (tablet formulation) gave a peak concentration of unchanged ketanserin of 88 ng/ml after 1.1 h. Its absolute bioavailability was 48%. During chronic therapy the maximal concentration of ketanserin-ol was 208 ng/ml and its half-life of elimination was 35.0 h. As this metabolite can be oxidized back to ketanserin, it contributes to the prolonged half-life of unchanged ketanserin seen during chronic therapy. The blood pressure was reduced by approximately 15% by oral ketanserin. The maximal reduction in blood pressure coincided with the peak concentration of unchanged ketanserin. During chronic therapy with 40 mg once daily blood pressure was reduced over 24 h. The heart rate was slightly reduced and the cardiovascular responses and the plasma noradrenaline concentrations during isometric exercise were only slightly influenced by ketanserin therapy. Thus, unchanged ketanserin has a relatively long half-life during chronic oral therapy and its pharmacokinetics in middle-aged hypertensive patients is similar to that in normal young volunteers.
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  • 92
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    European journal of clinical pharmacology 32 (1987), S. 533-535 
    ISSN: 1432-1041
    Keywords: enprofylline ; children ; intravenous dose ; pharmacokinetics ; asthma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous enprofylline has been studied in 8 children with asthma. The mean plasma half-life of enprofylline (1.0 h) was considerably shorter than that previously reported in adults. The half-life determined from log urine excretion rate data was identical to the plasma half-life, so urine excretion could be used as a noninvasive method to study the elimination rate. As in adults, urinary recovery of unchanged drug averaged 89%, and the volume of distribution, Vz, averaged 0.58 l/kg. Clearance was higher in children than in adults when calculated per kg body weight, but not when calculated per m2 body surface area. The dosage of enprofylline in children would be more accurate if calculated in proportion to surface area rather than to body weight. Data agree with published information on creatinine clearance, which, adjusted for body surface area, stays constant from the age of 3 years until early adult life.
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  • 93
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    European journal of clinical pharmacology 33 (1987), S. 89-91 
    ISSN: 1432-1041
    Keywords: antipyrine ; prednisolone ; pharmacokinetics ; obstructive lung disease ; hepatic drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of prednisolone on the elimination of antipyrine has been investigated. The one-sample antipyrine clearance was estimated in 23 outpatients with obstructive lung disease before and after treatment with prednisolone 30 or 50 mg/day for 7 days. During prednisolone administration antipyrine clearance decreased from 54.9±14.8 to 51.7±14.6 ml/min (mean±SD; p〈0.05). The results indicate that prednisolone decreases the rate of antipyrine elimination, but not to an extent suggesting a clinically important change in hepatic drug metabolism.
    Type of Medium: Electronic Resource
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  • 94
    ISSN: 1432-1041
    Keywords: flecainide ; propranolol ; pharmacodynamics ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 95
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    Electronic Resource
    Springer
    European journal of clinical pharmacology 33 (1987), S. 101-104 
    ISSN: 1432-1041
    Keywords: enoxacin ; quinolone ; pharmacokinetics ; anti-bacterial ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of enoxacin in two groups of subjects, 10 young (18–45 years) and 10 elderly adults (〉65 years) after a single oral dose of enoxacin (600 mg). Enoxacin was absorbed rapidly, peak plasma concentrations being reached within two hours in both groups. However, the peak plasma concentration of enoxacin was significantly higher in the elderly than in the young adults. The area under the concentration-time curve extrapolated to infinity was also significantly greater in the elderly compared with the young subjects, and the apparent renal clearance was significantly less in the elderly than in the young adults. Consequently, the urinary elimination of unchanged enoxacin was significantly reduced in the elderly. The apparent volume of distribution in the elderly was significantly less than in the young adults. The elimination half-time of enoxacin was similar in the two groups.
    Type of Medium: Electronic Resource
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  • 96
    ISSN: 1432-1041
    Keywords: buserelin ; LHRH superagonist ; histamine-induced rhinitis ; pharmacokinetics ; serum LH
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of experimental rhinitis on the absorption of buserelin, measured as the serum luteinizing hormone (LH) response, has been investigated. A single dose of 200 µg buserelin was given to 24 healthy male volunteers after induction of experimental rhinitis with histamine and after use of a saline spray (placebo control). Except on one occasion, when the pump-spray apparently was incorrectly operated, serum LH concentration rose after buserelin. There was no difference in the LH response between histamine-induced rhinitis and saline controls. It was concluded that intranasal application of buserelin represents a reliable mode of application and that modification of the administration route or a change in the dosage schedule during naturally-occurring nasal inflammations, such as the common cold and allergic rhinitis, is unnecessary in patients undergoing chronic treatment with intranasal buserelin, e.g. for prostatic cancer, endometriosis, precocious puberty, and contraception.
    Type of Medium: Electronic Resource
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  • 97
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 33 (1987), S. 185-189 
    ISSN: 1432-1041
    Keywords: vinpocetine ; apovincaminic acid ; healthy volunteers ; elderly subjects ; pharmacokinetics ; age effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of vinpocetine and its main metabolite, apovincaminic acid (AVA), were studied in the aged. Vinpocetine was eliminated with a mean half-life of 2.12±0.51 h. Total plasma clearance (CL) and distribution coefficient (Δ) of the parent drug were 2.2±0.9 l · kg−1 · h−1 and 6.7±3.7 l · kg−1, respectively. The CL and Δ of vinpocetine differed significantly from young subjects but the elimination half-life was not altered. Significant changes in the elimination half-life and plasma clearance of AVA were found, perhaps because of the physiological decrease in renal function.
    Type of Medium: Electronic Resource
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  • 98
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 33 (1987), S. 211-214 
    ISSN: 1432-1041
    Keywords: temazepam ; pharmacokinetics ; oral dose ; distribution half-life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic disposition of temazepam was compared after a day-time and night-time dose in an open randomised crossover study. Twelve healthy male volunteers received a single oral dose of 20 mg temazepam in a soft gelatine capsule at 0900 h or 2200 h. Blood samples were taken immediately before dosing and at selected times over the 36-h period after each dose. The absorption of temazepam was slower after evening administration; the absorption half-life and time to reach maximal plasma concentration being 0.53 h and 1.67 h respectively, compared to 0.38 h and 1.02 h following morning administration. Considering distribution characteristics, evening administration produced a lower peak plasma temazepam concentration (362 ng/ml) compared with a day-time level of 510 ng/ml. Distribution half-life after night-time administration was increased compared with day-time administration (1.76 h vs 1.03 h). A significantly higher percentage of the drug, relative to Cmax, remained in the plasma at 8 and 24 h after evening dosing (39.3 and 15.4% compared to 24.7 and 11.2% following day-time administration). In spite of the half-lives of absorption, distribution and elimination all being longer after the evening dose, the overall bioavailability, as measured by the area under the curve (AUC) was comparable after the two times of administration. Similarly the difference in the mean residence time (MRT) of the two doses was within accepted limits. It is concluded that a chronopharmacokinetic effect was seen for temazepam; however it is unlikely to be of any clinical significance.
    Type of Medium: Electronic Resource
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  • 99
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 33 (1987), S. 237-242 
    ISSN: 1432-1041
    Keywords: thiazinamium ; asthma ; pharmacokinetics ; pharmacodynamics ; optimal concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction. Disposition after i.v. administration was described by a clearance of 0.54 l·min−1, central compartment volume of 14.8 l, distribution rate constant 0.092 min−1, and an elimination rate constant of 0.0044 min−1. The corresponding estimates after i.m. administration were 0.324 l·min−1, 34.1 l, 0.035 min−1, and 0.0018 min−1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC50 of 12.8 ng·ml−1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml−1, and 9 min. Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min−1, with an EC50 of 176 ng·ml−1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min−1, 250 ng·ml−1, and 3 min. The optimal plasma concentration of thiazinamium was about 100 ng·ml−1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min−1.
    Type of Medium: Electronic Resource
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  • 100
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 33 (1987), S. 303-310 
    ISSN: 1432-1041
    Keywords: bendazac ; renal insufficiency ; pharmacokinetics ; bendazac-lysine ; 5-hydroxybendazac
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bendazac and its major metabolite, 5-hydroxybendazac, have been investigated in 15 patients with moderate to severe renal insufficiency and renal failure following a single oral dose of 500 mg bendazac-lysine. The pharmacokinetic parameters were compared to those obtained in 10 healthy adult volunteers. The rate and the extent of absorption of bendazac was not modified in the patients with moderate and severe renal insufficiency, nor was there any change in plasma tmax, Cmax, apparent elimination t1/2 and AUC. There was a significant increase in the unbound fraction of bendazac in renal failure patients undergoing haemodialysis, with a consequent increase in the apparent volume of distribution (V/F) and apparent plasma clearance (CL/F), and a decrease in plasma Cmax and AUC. Simultaneous changes of V/F and CL/F lead to an unchanged plasma t1/2 in these patients. Renal clearance (CLR) was decreased, but CL/F was not affected, since renal excretion is a minor route of elimination of bendazac. Bendazac is mostly eliminated by metabolism to 5-hydroxybendazac, in healthy subjects 〉60% of a dose being excreted in urine as 5-hydroxybendazac and its glucuronide. In patients with renal insufficiency urinary excretion of 5-hydroxybendazac was decreased and the systemic availability of the metabolite (AUC), was increased about three-fold, irrespective of the degree of renal failure. Plasma 5-hydroxybendazac glucuronide accumulated according to the degree of renal insufficiency. Overall it can be assumed that the pharmacological effect of the drug will not be enhanced in renal failure and that the dosage regimen of bendazac-lysine in such patients need not be modified.
    Type of Medium: Electronic Resource
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