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  • 1985-1989  (987)
  • 1975-1979  (745)
  • 1960-1964
  • Ultrastructure  (951)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 414 (1989), S. 113-119 
    ISSN: 1432-2307
    Keywords: Gastric mucosa ; Intestinal metaplasia ; Ciliated cell ; Ciliated metaplasia ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Intestinal metaplasia of the gastric mucosa occurs commonly in aged Japanese patients and has been discussed in relation to the high incidence of gastric cancer in Japanese. Ciliated cells in the gastric mucosa have frequently been found in association with intestinal metaplasia in the pyloric gland and rarely in the cardiac gland in many Japanese patients, and exceptionally in one Chinese and in one Swedish patient. Electron microscopic examination of 12 Japanese patients has revealed that these structures are not metaplastic stereocilia, but true cilia. Ciliated cells have been found in the basal part of the gastric glands and never in the surface epithelium. The fine structure of the gastric cilia was almost the same as that of normal respiratory cilia. However, in the gastric cilia, most dynein arms were inconspicuous even after tannic acid fixation, indicating that ciliary beating of the gastric cilia is problematic. Abnormal cilia and basal bodies also were found. Ciliated cells have always occurred in association with intestinal metaplasia, therefore this phenomenon might be a type of metaplasia and is named “ciliated metaplasia” of the gastric mucosa.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 414 (1989), S. 459-464 
    ISSN: 1432-2307
    Keywords: Sebaceous carcinoma ; Parotid gland ; Salivary gland ; Ultrastructure ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Sebaceous carcinoma of salivary gland origin is extremely rare and, because of its rarity, the clinicopathological characteristics and the histogenesis are not fully understood. We present a case of sebaceous carcinoma of the parotid gland which brings the total number of reported cases to 22. The tumor showed epithelial cell nests which were mainly composed of sebaceous cells with marked cellular atypia. In most of the nests, glandular spaces lined by ductal epithelium were present. Scattered mucous cells and flattened eosinophilic cells at the periphery of the nests were also seen. Ultrastructural and immunohistochemical observations of the tumour revealed coexistence of sebaceous and glandular differentiations in some tumour cells. Tumour cells with lipid granules often participated in the formation of glandular structures or exhibited intracytoplasmic lumina, and immunohistochemical localization of lactoferrin and secretory component, the functional markers of ductal epithelium of salivary gland, was demonstrated not only in duct-forming tumour cells but also in many sebaceous tumour cells. It seems likely that sebaceous carcinoma originates from pluripotential duct cells which can differentiate into sebaceous, ductal and mucous cells.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 415 (1989), S. 145-149 
    ISSN: 1432-2307
    Keywords: Paracrystalline inclusion ; Microtubule ; Ciliogenesis ; Gastric ciliated cell ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Unusual electron-dense paracrystalline inclusions were found in metaplastic ciliated cells in the stomachs of three Japanese male patients with gastric carcinoma. These patients had not been given antitumour drugs before surgery and ethrane (enflurane) was used as the anaesthetic. Ciliated cells in the gastric mucosa are found not infrequently in the pyloric glands in association with intestinal metaplasia in elderly Japanese patients. Paracrystalline inclusions were found only in the ciliated cells and never in any other types of gastric mucosal cell. These inclusions were located in the apical portion of the ciliated cells in intimate association with the basal bodies. They consisted of twisted strings about 27 nm wide with a regularly repeated spacing of about 30 nm. On highly magnified electron micrographs, granules about 4 nm in diameter were detected. These paracrystalline inclusions have never been reported previously, although their location in ciliated cells and their morphological characteristics suggest an intimate relationship with the ciliogenesis of metaplastic ciliated cells in the human stomach.
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  • 4
    ISSN: 1432-2307
    Keywords: Malignant fibrous histiocytoma ; Ultrastructure ; Enzyme histochemistry ; Immunohistochemistry ; “Fibrohistiocytoid cell”
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultrastructural, enzyme histochemical and immunohistochemical studies were performed on tissue obtained from eight cases of malignant fibrous histiocytoma (MFH) and five cases of sacral decubitus ulcer. The MFH was composed of two major tumour cell types: fibroblast-like and histiocyte-like cells. Both cell types demonstrated abundant branching, fragmented rough endoplasmic reticulum (rER), many free ribosomes, occasional small mitochondria, an oval, elliptical or irregularly shaped nucleus with one or two prominent nucleoli and often a few dense bodies. However, pseudopodial projections, multivesicular bodies and phagosomes, common histiocyte organelles, were not seen. With little difference between cases or selection sites, the MFH cells reacted to acid phosphatase (AcP) and α-naphtyl butyrate esterase (ANBE) by enzyme histochemistry and with ferritin (Fer), α1-antitrypsin (AT), α1-antichymotrypsin (ACT), fibronectin (FN), HLA-DR, HLA-DP, Leu 10 and OKT 9 in immunohistochemical studies. MFH tumour cells did not immunostain with monocyte/macrophage markers (Leu M1, Leu M3, Mo 1, Mo 2 and Macrophage) although non-neoplastic histiocytes did react to these markers. In addition, granulation tissue, such as that found in sacral decubitus ulcers, was examined and the existence of a specific cell type called the “fibrohistiocytoid (FH) cell” was documented. The FH cell was short, spindle shaped and elliptical. Ultrastructurally, it had fragmented rER distributed in a branching pattern, dispersed free ribosomes, small mitochondria and a few dense bodies, but lacked diverse fused lysosomes and distinct pseudopodial cytoplasmic extensions. The FH cells reacted with AcP, alkaline phosphatase and ANBE but not with peroxidase using enzyme histochemistry and with Fer, AT, ACT, FN, HLA-DR, HLA-DP, Leu 10 and OKT 9 but not with monocyte/macrophage markers, C3d receptor, C3bi receptor in immunohistochemical studies. The FH cells had morphological, enzyme histochemical and immunohistochemical characteristics intermediate between fibroblasts and histiocytes. Similarities between MFH cells and the FH cells seen in chronic inflammation are discussed.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 415 (1989), S. 21-29 
    ISSN: 1432-2307
    Keywords: Alcoholic liver disease ; Ultrastructure ; Phagocytosis ; Cell shedding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Sinusoidal macrophages were studied by light and electron microscopy in 49 liver biopsies from alcohol-abusers with a variety of alcohol-related liver lesions or with near-normal livers. Changes were related to those in nearby hepatocytes. A reduction in the number of macrophages was noted in the more severely damaged livers. Hepatocytes formed blebs at their sinusoidal poles, and these protruded into the space of Disse and into the sinusoidal lumen. It is postulated that reduced phagocytic activity in the livers of patients with severe alcohol-related liver disease leads to increased shedding of hepatocellular material into the circulation. This may promote the development of autoimmune reactions directed against hepatocytes.
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  • 6
    ISSN: 1432-0533
    Keywords: Neuronal inclusions ; Leigh disease ; Tropomyosin ; Actin ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A novel type of non-viral cytoplasmic inclusion is described, which was seen in virtually every neuron in the brain and spinal cord of a child with a presumed metabolic disorder whose clinical picture and CNS pathology were compatible with Leigh Syndrome. The ovoid to round inclusions were sharply demarcated, measuring up to 11 μm in diameter. They showed no distinctive staining with a battery of routine histological techniques. The ultrastructural features are unique, comprising non-membrane-bounded aggregates of randomly oriented plate-like structures with parallel linear densities depicting a periodicity of 11–16 nm. Immunocytochemical studies revealed strong staining with antisera to tropomyosin and weaker staining with antisera to actin. There was no reactivity with antibodies against neurofilaments, microtubules and their associated proteins, paired helical filaments, ubiquitin, vinculin or alpha-actinin. It is postulated that the metabolic disorder resulted in a neurodegenerative condition which manifested pathologically with lesions compatible with those of Leigh Syndrome. Associated with the condition was the discrete accumulation of cytoplasmic proteinaceous components, including tropomyosin, in the form of neuronal cytoplasmic inclusions possibly resulting from an alteration of the neuronal cytoskeleton.
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  • 7
    ISSN: 1432-0533
    Keywords: Cerebral hypoxia ; Cerebral ischemia ; Ultrastructure ; Neocortex ; Brain isolation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The acute cortical response to surgical brain isolation and subsequent extracorporal normoxic or 30 min hypoxic (PaO2=20 mm Hg) perfusions (hypoxic hypoxia with relative ischemia) was evaluated. Cerebral blood flow, arterial pH and CO2 were maintained constant during both perfusions; only the arterial oxygen content was changed. The isolated brain model used in this and previous investigations produces no qualitative ultrastructural changes in the neocortex following brain isolation and normoxic perfusion. However, the acute cortical structural response to 30 min of hypoxic hypoxia with relative ischemia demonstrated a number of important observations. Hypoxic hypoxia produced ultrastructural responses common to cerebral ischemia such as nuclear chromatin clumping, nucleolar condensation and cytoskeletal breakdown. Although neuronal abnormalities seen after 30 min of hypoxic hypoxia were similar to those acute neuronal changes observed following complete cerebral ischemia without recirculation, they differed three ways: (a) mitochondrial swelling and microvacuolation were observed in many cortical pyramidal neurons. (b) Glycogen particles within astroglial processes were observed even after a 30-min period of hypoxic hypoxia. (c) Perivascular astroglial swelling was minimal despite considerable perineuronal swelling. In contrast, incomplete cerebral ischemia produces mitochondrial changes similar to those in hypoxic hypoxia but also causes the depletion of tissue glycogen and perivascular glial swelling. Thus, hypoxic hypoxia with relative ischemia produces a unique acute ultrastructural response compared to either complete or incomplete cerebral ischemia.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 79 (1989), S. 168-175 
    ISSN: 1432-0533
    Keywords: Muscular ; Dystrophy ; Ovine ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The initial ultrastructural changes in skeletal myofibers in ovine muscular dystrophy (MD) consisted of focal degeneration of myofibrils and the formation of Z-disc abnormalities, including nemaline rods, in adjacent sarcomeres. Peripheral and central sarcoplasmic masses, which occurred initially in large diameter fibers, contained a mixture of normal organelles and abnormal tubular and fibrillar formations. Vesiculate sarcolemmal nuclei with prominent nucleoli accumulated in central and subsarcolemmal locations in small clusters and short rows. Deformed individual nuclei were sometimes present within nuclear rows. Loss of the myofibrillar mass, increased density of small spherical nuclei, collections of fibrillar and tubular arrays, excessive folding of the sarcolemma and greatly reduced fiber diameter were seen in the end stage of the dystrophic process. Resting satellite cells were present at all stages of lesion development. The morphological progression of the lesions suggested an inherited inability to effectively replace lost myofibrils with ultimate exhaustion of the capacity for repair followed by pathological fiber atrophy.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 180 (1989), S. 175-178 
    ISSN: 1432-0568
    Keywords: Paratympanic organ ; Reciprocal synapses ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The innervation pattern of the paratympanic organ was studied by TEM. The paratympanic organ is a small tapering vesicle, typical of birds, situated in the medial wall of the tympanic cavity; it contains hair cells which are similar to type II receptors of the acoustic-lateral system; these cells are characterised by synapses which are not only afferent and efferent, as previously described, but also reciprocal with efferent fibers. Our observation revealed some efferent nerve fibers which form a relationship with hair cells containing synaptic bodies situated next to the plasma membrane and near the fibers themselves. Since synaptic bodies are commonly considered to be the site where the transmission of the impulse from the receptor to the nerve fiber takes place, our pictures suggest that the efferent fibers and hair cells may be either presynaptic or postsynaptic with respect to each other in the paratympanic organ. The hypothesis is formulated that reciprocal synapses allow interaction between hair cells, thus determining an increase in the contrast of information sent by the paratympanic organ to the CNS.
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  • 10
    ISSN: 1432-0568
    Keywords: Cecum ; Germ-free rat ; Microflora inoculation ; Morphometry ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The structural changes of the cecal wall in germfree rats were observed at regular intervals after the inoculation of fecal microflora from conventional rats. Quantitative light microscopy showed that most of the elements in the cecal wall increased at 12 or 24 h and reached peak values at 4 days after inoculation. On the 7th day, they decreased approximately to the values for conventional rats. The crypts were bent or widely open till 24 h but were not after the 4th day. Hyperplasia of the crypt epithelial cells including mucous-type cells was observed following microbial inoculation. Electron microscopy revealed that most of the epithelial cells lining the mucosa were typical columnar cells. Desquamation of the epithelial cells and contraction of the muscle fibers were often seen on 4th day. The mucous-type cells were divided into two types, goblet and non-goblet mucous-type cells. Reduction of cecal volume after microbial inoculation may be mainly caused by muscle contraction in the early period and hyperplasia and desquamation of the epithelial cells may suggest their role as the first and non-specific defense line prior to operation of the specific immune system.
    Type of Medium: Electronic Resource
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 179 (1989), S. 435-442 
    ISSN: 1432-0568
    Keywords: Ultrastructure ; In vitro fertilization ; Bovine ; Ova ; Cortical granules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Heifers were superovulated by PMSG or FSH, and oestrus was induced by prostaglandin. One group of animals was ovariectomized 19–26 h after the LH peak, the content of preovulatory follicles aspirated, and the oocytes processed for in vitro fertilization. Another group was inseminated and ova were collected from the oviducts for study of in vivo fertilization. All ova were examined ultrastructurally. The developmental rate following in vitro fertilization was delayed compared to fertilization in vivo. A high proportion of the in vitro fertilized ova showed polyspermic penetration of the zona pellucida, and supernumerary spermatozoa were found in the ooplasm of some ova. In vivo fertilization was associated with release and subsequent dispersal of the cortical granule content in the perivitelline space. In contrast to this the released granule content of the in vitro fertilized ova remained undispersed close to the oolemma. This feature may account for the high incidence of polyspermic penetration of the zona pellucida. In addition, the study provided an ultrastructural visualization of the initial contact between the equatorial segment of the spermatozoon and the microvilli of the oocyte, and the subsequent internalization of the sperm head.
    Type of Medium: Electronic Resource
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 179 (1989), S. 497-501 
    ISSN: 1432-0568
    Keywords: Parotid gland ; Ultrastructure ; Amylase ; Secretion ; Isoproterenol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of continuous light on ultrastructural organization and sympathetic secretory responses of the rat parotid gland are reported. After 50 days of continuous light exposure, the fine structure of the parotid gland exhibited features of enhanced secretory activity as judged by the striking development of rough endoplasmic reticulum and Golgi complexes, the depletion of secretory granules and the increased turnover of secretory cells. The secretory responses of parotid gland to isoproterenol revealed that continuous light induced a 30% increase in amylase release. This secretory hyperactivity appears to be related to a postsynaptic supersensitivity of sympathetic fibers of the autonomic nervous system.
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  • 13
    ISSN: 1432-0568
    Keywords: Sympathetic ganglion ; Binucleate cells ; Ultrastructure ; Feulgen staining ; Computerized image analysis ; DNA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The relative proportion, ultrastructure and DNA-content of the binucleate cells in the celiac superior mesenteric ganglion of the guinea pig was studied using light and electron microscopy as well as computerized image analysis of Feulgen stained cells. The number of mono — versus binucleate cells was found to vary with stage of development with about 40% of the cells being binucleate in adult animals and 50% in late prenatal stage. No difference in ultrastructure was observed between the nuclei of the two cell types. The binucleate cells contain twice the amount of DNA found in the mononucleate cells.
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  • 14
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 179 (1989), S. 591-604 
    ISSN: 1432-0568
    Keywords: Fetus ; Membranes ; Placenta ; Green monkey ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This study examined developmental changes in fetal membranes and placenta of Cercopithecus aethiops from a Carnegie developmental stage 12 embryo to nearterm fetuses. Ultrastructurally, yolk sac cells (endoderm and mesothelium) were similar to comparable stages in other primates. Endodermal cells had few apical microvilli, abundant rough-endoplasmic reticulum, electron dense mitochondria and dense bodies. In contrast, mesothelial cells were squamous with numerous microvilli, small mitochondria and a few short strands of rough endoplasmic reticulum. Amnion cells early in gestation were squamous with few microvilli, large glycogen deposits and poorly developed cytoplasmic components. Tight junctions and desmosomes held adjacent cells together. The basal surface was smooth and the basal lamina was distinct. As development proceeded the amniotic cells became cuboidal and possessed numerous microvilli. Cytoplasmic organelles were better developed and glycogen deposits increased by mid-gestation. A thick layer of microfibrils and collagen fibers was prominent below the basal lamina. Near-term, the glycogen had virtually disappeared and the amount of lipid droplets increased. Basal infoldings and podocytic processes and the extracellular matrix had increased. The smooth chorion consisted of pseudostratified columnar cells. Cells had short microvilli, numerous granules and vesicles of variable size and electron density in early gestation. With increasing age, amounts of granules and vesicles decreased, as the endoplasmic reticulum became prominent. The chorionic trophoblast was a continuous layer in mid-pregnancy and its cells had well-developed organelles and inclusions. Late in gestation, the trophoblastic layer became discontinuous and wide intercellular spaces and channels were present. In the placenta, the trophoblastic elements showed features characteristic of primate placenta.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 180 (1989), S. 103-108 
    ISSN: 1432-0568
    Keywords: Ultrastructure ; Gut ; Endocrine cells ; Testudo graeca ; Chelonia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The digestive tract of Testudo graeca (Chelonia) was investigated by means of electron microscopy using both conventional and immunocytochemical techniques. EC-, L-, D-, G-, B-, N- and EC-L-cells were detected. These cells share several common ultrastructural characteristics with the endocrine cells of mammals (i.e. clear cytoplasm, prominent Golgi apparatus, secretory granules etc.). EC and D1 cells have so far not been described in the esophagus of any animal species; in the present study these cells have been observed in the esophagus of T. graeca. Of special interest was the presence of B-cells in the intestine, suggesting that the migration of B-cells from the gut to the pancreas to constitute pancreatic islets is not concluded in T. graeca. The present study demonstrates that the gut endocrine system of T. graeca is a complex structure containing a large variety of endocrine cell types similar in morphology to those found in higher vertebrates.
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  • 16
    ISSN: 1432-0568
    Keywords: Monkey ; Ultrastructure ; Pinealocytes ; Axon terminals ; Synapses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The present study described the normal ultrastructure of the monkey pineal gland. The gland was composed of the principal pinealocytes, intramural neurons and glial cells. The nucleus of the pinealocytes was deeply infolded with evenly distributed chromatin materials. The abundant cytoplasm was rich in organelles including the well-developed Golgi apparatuses, multivesicular bodies, dense-cored vesicles and widely scattered free and polyribosomes. A variety of axon terminals was observed and the majority of them contained pleomorphic agranular vesicles with a few large dense-cored vesicles. A few terminals showed flattened vesicles or small dense cored vesicles. Some of the axon terminals formed synaptic contacts with the cell bodies of pinealocytes. These synapses were mainly concentrated in the posterior third of the gland. The occasional intramural neurons observed were postsynaptic to axon terminals containing round agranular vesicles. The sources of the nerve fibres and terminals forming synaptic junctions with pinealocytes and intramural neurons were discussed.
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  • 17
    ISSN: 1432-0533
    Keywords: 2,4-Dithiobiuret ; Thioimidodicarbonic diamide ; Motor endplate ; Neuromuscular junction ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 2,4-Dithiobiuret was given i.p. to rats for 4 days at a daily dosage of 1 mg/kg and the development of the lesion associated with neuromuscular dysfunction studied in hindlimb lumbrical muscles. The first morphological indication of neurointoxication was the appearance in some motor endplates of masses of branching tubular smooth endoplasmic reticulum (SER) on day 2 which correlated with the initial functional disturbances. By the 3rd day, most motor endplates were distended by accumulations of densecored, lucent and synaptic vesicles, abnormally swollen mitochondria, intermediate filaments and branching, tubular SER. Evidence of collateral axonal sprouting was seen first at this time. On days 4 and 5, many motor endplates were markedly enlarged and showed axoplasmic organelle congestion. A significant increase in synaptic vesicle size was noted at these times in some terminals. Interposition of Schwann cell processes between the pre- and postsynaptic membranes and terminal retraction was now evident. Some intramuscular nerves showed hydropic Schwann cell cytoplasm with separation of the outermost myelin lamellae, mitochondrial swelling and adaxonal vacuoles as early as the 1st day. Proliferation and segregation of SER around central cores of neurofilaments was seen in myelinated nerve fibres and preterminals on the 3rd day. At this and later times accumulations of SER and swollen mitochondria were found at sites of axonal varicosities and at the paranodal constrictions at nodes of Ranvier. These ultrastructural data are discussed with regard to reduced terminal Ca2+ content (demonstrated by oxalate-pyroantimonate cytochemistry) and compared with the sequelae of botulinum intoxication.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 79 (1989), S. 336-339 
    ISSN: 1432-0533
    Keywords: AIDS ; Cytomembranous inclusions ; Tubuloreticular inclusions ; Ultrastructure ; Peripheral nerve
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We report finding tubuloreticular inclusions (TRI) in the endothelial cells of endo- and epineurial vessels in the sural nerve of 11 patients with AIDS. Six patients had a painful peripheral neuropathy, one a non-painful sensory neuropathy, one an acute inflammatory demyelinating polyradiculoneuropathy and one a thalidomide-related neuropathy. Two patients had no clinical evidence of neuropathy. The TRI are not specific to one neuropathy and are unlikely to contribute to the pathogenesis of peripheral nerve syndromes in AIDS.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 77 (1989), S. 654-658 
    ISSN: 1432-0533
    Keywords: Melanotic neuroectodermal tumor ; Immunohistochemistry ; Ultrastructure ; Pineal origin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A case of a melanotic neuroectodermal tumor arising from pineal region of a 4-year-old girl is presented. The tumor had spread diffusely to the meninges, consistent with malignant behavior. Histologically, the tumor consisted primarily of epithelial elements arranged in tubules, cords and nests separated by fibrous vascular tissue in addition to a small neuroblastomatous focus. Melanin pigment was frequently observed in the epithelial tumor cells, and melanin-laden macrophages were also often observed. No teratoid elements were found. Immunohistochemically, tumor cells were positive for neuron-specific enolase but were nonreactive for S-100 protein, epithelial membrane antigen, glial fibrillary acidic protein, vimentin, α-fetoprotein and human chorionic gonadotrophin. Ultrastructurally, the epithelial nature of the tumor cells could be easily demonstrated. In addition, melanosomes in various stages in maturation were observed, indicating melanogenesis of the tumor. On the basis of the tumor location and the histological similarities previously observed for the fetal pineal body, it is very likely that this melanotic epithelial tumor could have originated from the fetal pineal gland.
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  • 20
    ISSN: 1432-0533
    Keywords: Gangliocytoma ; Ganglioglioma ; Ultrastructure ; Immunohistochemistry ; Neuroendocrine markers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We studied five cases of central nervous system neuronal tumor, one gangliocytoma and four gangliogliomas, both ultrastructurally and immuno-histochemically, using antibodies to neuroendocrine markers including tyrosine hydroxylase (TH), serotonin (5HT), somatostatin (SOM), met-enkephalin (MEK), leu-enkephalin (LEK), substance P (SP), gastrin, vasopressin, oxytocin, vasoactive intestinal polypeptide, adrenocorticotropic hormone and calcitonin. In all cases, the presence of dense-core vesicles (60–250 nm) in the neuronal elements was the characteristic ultrastructural finding. Synapses were observed in two cases. Immunohistochemically, variable numbers of neuronal cells showed positive staining for SOM in five cases, TH, MEK and LEK in three cases, and 5HT and SP in one case each. The others were negative. Positive immunoreactivity for multiple markers was shown in all cases. SOM, TH, 5HT and SP were present in the small- to medium-sized cells, while MEK and LEK were almost exclusively confined to the large cells. Our study clearly indicated that these tumors contained neuronal cells which were not homogeneous with regard to neuroendocrine markers.
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  • 21
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 77 (1989), S. 258-266 
    ISSN: 1432-0533
    Keywords: Neurofibrillary tangles ; Alzheimer's disease ; Pick bodies ; Immunohistochemistry ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have studied the immunohistochemical reactivity and ultrastructure of both neurofibrillary tangles (NFTs) occurring with severe neurofibrillary diseases, and Pick bodies (PBs) associated with Pick's disease. The NFTs and PBs did not react immunohistochemically with the anti-nonphosphorylated neurofilament monoclonal antibody irrespective of whether they were pretreated with alkaline phosphatase. In granular neurons of the dentate fascia of Ammon's horn in cases of dementia of the Alzheimer type (DAT), NFTs either resembled PB-like inclusion bodies (Horoupian's inclusion bodies) in form, or had a perinuclear structure. Immunohistochemically and ultrastructurally, the NFTs in the dentate fascia in cases of DAT, including Horoupian's inclusion bodies, were similar to the NFTs in the pyramidal neurons of Ammon's horn, which are found most frequently in association with severe neurofibrillary diseases. Under a light microscope, Horoupian's inclusion bodies and PBs could not be differentiated and appeared to be argyrophilic round cytoplasmic inclusions in granular neurons of the dentate fascia. There were, however, ultrastructural differences. Horoupian's inclusion bodies consisted of bundles made up of straight tubules (STs), each about 15 nm in diameter. These bundles were intermixed with a few paired helical filaments which occurred at intervals of about 80 nm. On the other hand, PBs were composed of randomly distributed 15-nm-wide STs, intermixed with a very few fibrillary structures. These fibrils had a periodicity of about 160 nm, and ranged in width from about 15 nm to 30 nm. Horoupian's inclusion bodies associated with DAT and PBs associated with Pick's disease are different in this neuropathological aspect. The NFTs, including Horoupian's inclusion bodies in the dentate fascia in cases of DAT, are considered to be a manifestation of neurofibrillary degeneration.
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  • 22
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 79 (1989), S. 86-93 
    ISSN: 1432-0533
    Keywords: Primary malignant CNS lymphoma ; Ultrastructure ; Intracytoplasmic tubuloreticular, membranous structures ; Intranuclear inclusions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultrastructural studies of 17 primary malignant CNS lymphomas revealed 6 tumors with abnormal intracytoplasmic and/or intranuclear membranous structures, most frequently, associated with the endoplasmic reticulum or perinuclear envelope. In most cases, tubuloreticular inclusions and paired cisternae were present. Less frequent were accumulation of mictotubules, concentric lamellar bodies, and rod-like or paracrystalline intranuclear inclusions. The specificity and significance of these membranous structures remain questionable because of their frequent occurrence in a variety of normal and pathological conditions. Some of these changes may be considered as cellular reactions to viral infections, others may indicate cellular activity or degeneration.
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  • 23
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 281 (1989), S. 35-39 
    ISSN: 1432-069X
    Keywords: Pseudo-Kaposi's sarcoma ; Bluefarb-Stewart syndrome ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An ultrastructural study of the skin lesion of a young patient affected by pseudo-Kaposi's sarcoma of the Bluefarb-Stewart type (BSS) is reported. The neoplasm consisted of a proliferation of vascular structures mostly consisting of a solid bud of endothelial cells surrounded by a thinned and polystratified basement membrane and several pericytes. Both endothelial cells and pericytes were of normal ultrastructural appearance. Intervascular “stromal” cells were few and morphologically identified as macrophages and/or phagocytic fibroblasts. Masses of hemosiderin were detected outside the cells and in the macrophages, endothelial cells, and pericytes. Intracytoplasmatic crystalloid inclusions similar to those found in fetal endothelium and hemangiomas were observed in a few endothelial cells. These findings are different from those of previously reported cases of pseudo-Kaposi's sarcoma and may be helpful in distinguishing Kaposi's sarcoma from BSS. The role of immunodeficiency in the onset of BSS is discussed.
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  • 24
    ISSN: 1432-0428
    Keywords: Islet amyloid polypeptide ; Pancreatic islets ; B cells ; Ultrastructure ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet amyloid polypeptide is a novel 37 amino-acid-residues polypeptide which has been isolated from amyloid deposits in an insulinoma, and in human and cat islets of Langerhans. The molecule has 46% homology with the calcitonin gene-related peptide. Light microscopy examination of the pancreas shows that islet amyloid polypeptide immunoreactivity is restricted to the islet B cells. The present study utilized a rabbit antiserum against a synthetic peptide corresponding to positions 20–29 of islet amyloid polypeptide, a sequence without any amino-acid identity with calcitonin gene-related peptide. By applying the immunogold technique at the ultrastructural level, it was shown that both insulin and islet amyloid polypeptide immunoreactivity occurs in the central granular core of the human B cell secretory granules, while the A cells remain unlabelled. The demonstration that islet amyloid polypeptide is a granular protein of the B cells may indicate that it is released together with insulin. Further studies are necessary to evaluate the functional role of islet amyloid polypeptide.
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  • 25
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    Development genes and evolution 198 (1989), S. 92-102 
    ISSN: 1432-041X
    Keywords: Vitellogenesis ; Xenopus oocyte ; Yolk-platelet membrane ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The yolk platelets ofXenopus laevis have been studied by thin-section and freeze-fracture electron microscopy to characterize the boundary membrane during yolk formation. Throughout vitellogenesis, large yolk platelets are in close contact with smaller nascent yolk organelles. Two types of primordial yolk platelets (I and II) have been discriminated. After membrane fusion these precursors can be completely incorporated into the main body of existing platelets, numerous yolk crystals then merge and form one uniformly stratified core. Lipid droplets are tightly attached to the membrane at all developmental stages of yolk platelets. A direct connection of endoplasmic reticulum to the membranes of yolk platelets was not observed. On freezeetching replicas, yolk-platelet membranes present fracture faces with intramembranous particles (IMP) of various sizes and a heterogeneous distribution of approximately 200–600 IMP/μm2 at the E face, and 1200–2100 IMP/μm2 at the P face. Again, this presentation of the membrane exhibits neither anastomoses to the endoplasmic reticulum, nor caveolae that exclude the uptake of yolk-containing vesicles into these yolk organelles. Proteinaceous yolk platelets tend to fracture along their periphery through the superficial layers.
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  • 26
    ISSN: 1432-1106
    Keywords: Calcitonin gene-related peptide (CGRP) ; Bed nucleus of the stria terminalis ; Central nucleus of the amygdala ; Ultrastructure ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Light and electron microscopic analysis of calcitonin gene-related peptide (CGRP)-like immunoreactive (LI) terminals in the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce) was carried out using the peroxidase-antiperoxidase method. CGRP-LI fibers were densely distributed in the dorsal subdivision of the lateral BST (BSTL) and the lateral and lateral capsular subdivisions of the Ce, where the CGRP-LI terminals formed symmetrical and asymmetrical axo-dendritic, and symmetrical axosomatic synapses. One of the most characteristic features of the CGRP-LI terminals was the presence of large, long boutons, each of which surrounded a cell soma and made many synaptic contacts. These findings suggest that CGRP exerts a significant influence on neurons in the BSTL and Ce.
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  • 27
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    Experimental brain research 76 (1989), S. 12-20 
    ISSN: 1432-1106
    Keywords: Distribution ; Ultrastructure ; Biopsy ; Catecholamines ; Interneurons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In freshly fixed biopsies of human cerebral cortex obtained at surgery, immunocytochemical staining with antibodies against tyrosine hydroxylase (the rate limiting biosynthetic enzyme for catecholamines) revealed, in addition to a dense axonal plexus, a population of immunoreactive cell bodies. The neuronal nature of these cells was ascertained by: i) the presence of a rich rough endoplasmic reticulum in the cell body and of synapses on the cell body and dendrites, and ii) the demonstration of the lack of reactivity with the astroglial marker, glial fibrillary acidic protein, in the tyrosine hydroxylase-immunoreactive cells. The tyrosine hydroxylase-immunoreactive neurons were found in all areas of cortex sampled, and were located almost exclusively in the infragranular layers. Most tyrosine hydroxylase-immunoreactive cells were bipolar and were vertically oriented, but a few had a multipolar or horizontal dendritic arbor. The dendrites of these cells were varicose and aspiny, and the axons were very thin. Tyrosine hydroxylase-immunoreactive neurons were reported to be present transiently in the developing mammalian cerebral cortex and only recently in cerebral cortex of mature mammalian brains. Internuncial neurons in the human cerebral cortex containing a catecholamine synthesizing enzyme would be significant, in particular considering that catecholamines are likely to be involved in some major mental disorders.
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  • 28
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    Sexual plant reproduction 2 (1989), S. 154-166 
    ISSN: 1432-2145
    Keywords: Helianthus annuus ; Unfertilized ovule culture ; Parthenogenesis ; Ultrastructure ; Proembryo
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Electron microscope studies have been conducted on the parthenogenesis induced by in vitro culture of unfertilized ovules of sunflower (Helianthus annuus). In comparison with the state of the egg prior to inoculation, some eggs 5 days after culture show striking ultrastructural changes, which include, among others, nuclear migration, an increase in the number and activity of the organelles, a loss of polarity and wall formation at the chalazal end of the cell. Most of these changes are similar to those that occur normally in the zygote, indicating that parthenogenic development has been triggered in these eggs. Such eggs have been termed activated and are presumed to be capable of undergoing parthenogenesis. The parthenogenic proembryos which result share some features in common with zygotic proembryos. In addition, some parthenogenic proembryos exhibit unique properties not found in zygotic proembryos. These include embryos that consist of two parts differing markedly in density, an inversion of polarity, the frequent occurrence of autophagic vacuoles, the thickening of cell walls, a centripetal growth mode of wall formation, the appearance of an incomplete cell wall, free nuclear division, amitosis and degeneration. We believe that these ultrastructural peculiarities are the effects of in vitro culture.
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  • 29
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    Sexual plant reproduction 2 (1989), S. 193-198 
    ISSN: 1432-2145
    Keywords: Polymorphism ; Ultrastructure ; Pollen grains ; Canna indica L ; Tannin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Our investigations on Canna indica L. indicate that the pollen of this species is polymorphic: there are two types of pollen — a larger type and a comparatively smaller type. Transmission electron microscopy (TEM) revealed the presence of small vacuoles containing tannic substances in the generative cell (GC) of the larger grains: the GC of the mature grain contained a higher quantity of tannins than the GC of the immature grain. Mitochondria, lipid bodies, rough endoplasmic reticulum (RER) and microtubular bundles were present in the cytoplasm of the GC. Numerous mitochondria, lipid bodies and plastids were also present in the vegetative cell (VC), with the mitochondria clustered around the vegetative nucleus. The plastids were observed to be associated with the RER cisterns. During the maturation process, the number of starch grains contained in the plastids decreased.
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  • 30
    ISSN: 1432-1041
    Keywords: diflunisal ; pharmacokinetics ; healthy volunteers ; kidney failure ; rheumatoid arthritis ; aged subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single-dose plasma kinetics of diflunisal was studied in healthy young and old subjects, in patients with rheumatoid arthritis, and in patients with renal failure. The plasma and urine kinetics of the glucuronidated metabolites of diflunisal were studied in the healthy elderly subjects and in the patients with renal failure. In addition, the multiple-dose plasma kinetics of diflunisal was assessed in healthy volunteers and in patients with rheumatoid arthritis. After a single dose of diflunisal the terminal plasma half-life, mean residence time and apparent volume of distribution were higher in elderly subjects than in young adults. No difference was observed in any pharmacokinetic parameter between age-matched healthy subjects and patients with rheumatoid arthritis. The elimination half-life of unchanged diflunisal was correlated with the creatinine clearance (r=+0.89) and its apparent total body clearance exhibited linear dependence on creatinine clearance (r=+0.78). In patients with renal failure, the terminal plasma half-life and mean residence time of diflunisal were prolonged. The renal and apparent total body clearances were lower, the mean apparent volume of distribution was higher and the mean area under the concentration-time curve extrapolated to infinity (AUC) was greater in the renal failure patients than in controls. The plasma concentration of the glucuronidated metabolites rapidly rose to levels above those of unchanged drug in renal patients, whereas they were lower than those of unchanged diflunisal in controls. The AUC (0–96 h) of diflunisal glucuronides in the patients was four-times that in controls, and the terminal elimination half-life of the glucuronides was prolonged in them. The renal excretion and clearance of diflunisal glucuronides were reduced when renal function was impaired. After multiple dosing, the pre-dose steady-state plasma-concentration increased with decreasing creatinine clearance (r=-0.79). When the plasma concentration exceeded 200 µmol·1−1, the elimination half-life was doubled, due to partial saturation of diflunisal conjugation. This finding suggests that lower doses could be used in long-term treatment. Thus, old age and arthritic disease appear to have little influence on the kinetics of diflunisal in the absence of renal functional impairment. Ordinary doses can be given for short term treatment of elderly patients with or without RA. In patients with renal failure, however, reduced doses of diflunisal are recommended.
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  • 31
    ISSN: 1432-1041
    Keywords: ipratropium bromide ; radioceptor assay ; pharmacokinetics ; inhalation ; systemic administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Single doses of ipratropium bromide were administered intravenously, orally and by slow inhalation to ten healthy male volunteers. The plasma level after oral administration followed a low but broad plateau persisting for several hours. After i.v. administration the kinetic parameters were: Vc=25.9 l, Vα=13.1 l, Vβ=338 l, $$t_{{1 \mathord{\left/ {\vphantom {1 {2_\alpha }}} \right. \kern-\nulldelimiterspace} {2_\alpha }}} = 3.85\min $$ , $$t_{{1 \mathord{\left/ {\vphantom {1 {2_\beta }}} \right. \kern-\nulldelimiterspace} {2_\beta }}} = 98.4\min $$ , AUC=15.0 h · ng/ml, kel=11.8 l/h and total clearance is 2325 ml/min. The bioavailability was 3.3% (range 0.9–6.1%) on comparing the plasma AUCs following i.v. and 20 mg oral administration. The cumulative renal excretion (0–24 h) after i.v. administration was compared with that after oral administration and inhalation. Following oral administration, the apparent systemic availability was around 2%, and after inhalation it was 6.9%. In comparison with oral placebo administration, only after i.v. administration was there a significant change in heart rate (from 63.7 to 90.2 beats/min). The systolic blood pressure rose from 115.1 to 119.6 mm Hg and the diastolic blood pressure from 68.3 to 78.3 mm Hg.
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  • 32
    ISSN: 1432-1041
    Keywords: nabumetone ; rheumatoid arthritis ; pharmacokinetics ; old patients ; NSAID
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have performed a detailed pharmacokinetic study of the plasma concentrations of the major active metabolite of nabumetone, 6-methoxy-2-naphthylacetic acid (6 MNA), attained after a single dose and during chronic administration comparing the results of a group of young healthy volunteers with those of a group of elderly arthritic patients. The latter had higher peak plasma concentrations of 6MNA and slower rates of elimination but there is no tendency for the drug to accumulate unpredictably in the old. Disease activity also influences plasma concentration, those with more active disease, and lower serum albumin concentrations had lower AUC values.
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  • 33
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    European journal of clinical pharmacology 36 (1989), S. 291-297 
    ISSN: 1432-1041
    Keywords: paracetamol ; renal failure ; drug disposition ; polar metabolites ; cumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of paracetamol following an oral dose of 1.0 g was compared in 10 healthy volunteers, 7 patients with moderate chronic renal failure and 6 patients with end stage renal failure on maintenance haemodialysis. Paracetamol absorption was normal in the patients with renal failure. The mean plasma half-life of paracetamol from 2 to 8 h was similar in the 3 groups (2.1 to 2.3 h) but from 8 to 24 h it disappeared much more slowly in the renal failure patients (half-life 11.7 compared with 4.9 h in the healthy volunteers). Plasma concentrations of paracetamol glucuronide and sulphate conjugates were greatly increased in the patients with moderate renal failure and the mean plasma half-lives were 30.5 and 21.8 h respectively compared with about 3 h in the healthy volunteers. Plasma concentrations of these metabolites were even higher in the dialysis patients and there was no significant fall over 24 h. The cysteine and mercapturic acid conjugates of paracetamol could only be measured in plasma in the patients with renal failure and concentrations were very low. The fractional urinary recovery of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates was similar in healthy volunteers and patients with moderate renal failure. The mean renal clearances of paracetamol and its glucuronide and sulphate conjugates in the healthy volunteers and patients with moderate renal failure were 15.7, 137 and 172, and 5.9, 14.5 and 14.8 ml/min respectively. In the latter patients the mean renal clearances of the cysteine and mercapturic acid conjugates were much greater at 35.4 and 80.2 ml/min. In the patients with moderate renal failure the AUC's of the glucuronide and sulphate conjugates were related to the plasma creatinine and there were significant negative correlations with the renal clearances of these metabolites and total urinary recovery. Marked cumulation of the polar glucuronide and sulphate conjugates of paracetamol would seem inevitable in patients with renal failure and the parent drug is apparently regenerated to a limited extent from retained metabolites.
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  • 34
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    European journal of clinical pharmacology 37 (1989), S. 257-260 
    ISSN: 1432-1041
    Keywords: nifedipine ; propranolol ; indocyanine green ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nine healthy adults were administered indocyanine green (ICG) 0.5 mg·kg−1 IV alone and after the administration of the following oral drugs: nifedipine 10 mg, propranolol 80 mg, propranolol 80 mg and nifedipine 10 mg, and propranolol 80 mg after nifedipine 10 mg every 8 h for 5 days. Heart rate and mean arterial blood pressure (MAP) were also determined. Nifedipine increased ICG clearance by 14% and decreased t1/2 by 26%. Propranolol decreased ICG clearance by 21% and increased t1/2 42%. Nifedipine and propranolol given together increased ICG clearance 63% and decreased t1/2 by 19%. All changes were statistically significant. Propranolol given after multiple doses of nifedipine did not change ICG kinetic parameters. Propranolol Cmax, tmax, oral clearance, and t1/2 did not change after nifedipine therapy. However, partial propranolol AUC values between 0–0.33, 0–0.5, 0–1.0 and 0–1.5 h were significantly larger after single and multiple doses of nifedipine indicating higher propranolol concentrations during the absorption phase. Heart rate and MAP did not change after nifedipine treatment. Similar declines in heart rate and MAP occurred after propranolol alone and propranolol after single and multiple doses of nifedipine.
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  • 35
    ISSN: 1432-1041
    Keywords: ramipril ; renal insufficiency ; hypertension ; pharmacokinetics ; ramiprilat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 25 hypertensive patients with various degrees of renal insufficiency given 5 mg ramipril p.o. for 14 days. Ramipril was rapidly absorbed and reached a peak concentration after 1–2 h. Cmax was greater in patients with severe renal insufficiency, which might indicate a reduced renal elimination rate, although, the rapid decline of the concentration-time curve for ramipril was almost independent of renal function. The mean initial apparent half-lives on Days 1 and 12, respectively, were 2.8 and 3.4 h (Group I: creatinine clearance 5–15 ml/min), 1.8 and 2.3 h (Group II: creatinine clearance 15–40 ml/min), and 1.9 and 1.9 h (Group III: creatinine clearance 40–80 ml/min). No accumulation was observed after multiple dosing. In contrast, the kinetics of its active acid metabolite ramiprilat was significantly influenced by renal function. The mean times to the peak plasma concentration were 5.7 h in Group I, 4.4 h in Group II and 3.8 h in Group III. The initial decline in plasma ramiprilat was dependent upon renal function; the mean initial apparent half-lives (Days 1 and 12, respectively) were 16.0 and 14.8 h (Group I), 10.1 and 9.5 h (Group II) and 10.6 and 8.0 h (Group III). Mean trough concentrations and absolute accumulation also increased with worsening renal function, and the renal clearance of ramiprilat was significantly correlated with the creatinine clearance. The subsequent long terminal phase at low plasma ramiprilat concentrations represented slow dissociation of the ACE-inhibitor complex. The study indicates that in patients with severe renal insufficiency (creatinine clearance below 30 ml/min) smaller doses of ramipril are required than in patients with normal or borderline renal function.
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  • 36
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    European journal of clinical pharmacology 37 (1989), S. 279-283 
    ISSN: 1432-1041
    Keywords: ketoconazole ; terbinafine ; microsomal metabolism ; caffeine ; male volunteers ; pharmacokinetics ; drug interaction ; cytochrome P-450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of single oral doses of ketoconazole 400 mg and terbinafine 500 mg on the hepatic microsomal system have been investigated in 8 healthy male volunteers. Microsomal activity caffeine was assessed by following the metabolism of 3 mg/kg bodyweight i.v. administered 1 h after the drug. The inhibitory effect of terbinafine was more pronounced than that of ketoconazole: clearance was decreased from 1.34 ml·kg−1·min−1 in controls to 1.06 and 1.21 ml·kg−1·min−1, respectively, and the corresponding half-life was increased from 5.8 h in controls to 7.6 and 6.7 h, respectively. The apparent volume of distribution remained unchanged. The serum levels of the antimycotics were within the therapeutic range in each subject. Although all three substances are metabolised by microsomes, the kinetic parameters (Cmax, half-life, elimination constant) of the antimycotics were poorly if at all correlated with the elimination of caffeine.
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  • 37
    ISSN: 1432-1041
    Keywords: repirinast ; theophylline ; asthma ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A possible pharmacokinetic interaction between theophylline and repirinast has been investigated in asthmatic patients. The kinetics of theophylline was studied in seven adult in-patients given theophylline 400–800 mg b.d. alone and after three weeks of co-administration of repirinast. There was no effect on the kinetics of the combined treatment.
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  • 38
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    European journal of clinical pharmacology 37 (1989), S. 309-311 
    ISSN: 1432-1041
    Keywords: pyrazinamide ; haemodialysis ; pharmacokinetics ; uraemic patients ; drug metabolites ; anti-tuberculous chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of PZA during haemodialysis were determined in 6 patients with chronic renal impairment after a single oral dose of 25.7 (1.9) mg·kg−1. The dialysis clearance of PZA and of its metabolites were: pyrazinamide 132 ml·min−1; pyrazinoic acid 121 ml·min−1; 5-hydroxy-pyrazinamide 107 ml·min−1; 5-hydroxy-pyrazinoic acid 118 ml·min−1. The average amount extracted during a dialysis session of 4.1 h was 926 mg after an oral dose of 1700 mg. The high dialysability shows that PZA can property be administered at the end of each dialysis session in the usual dose of 25 to 30 mg·kg−1.
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  • 39
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    European journal of clinical pharmacology 37 (1989), S. 375-379 
    ISSN: 1432-1041
    Keywords: dihydrocodeine ; pharmacokinetics ; young/elderly patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Although poor renal function reduces clearance of dihydrocodeine in man, and renal impairment occurs with ageing, no significant differences occurred in the handling of single doses of dihydrocodeine between elderly patients and young, normal subjects. After multiple dosing, the maximum concentration was significantly different between the groups, being higher in the elderly. The increase in the area under the curve in the elderly was 25% greater than in the young on chronic therapy. This difference was not statistically significant, but was likely to be of clinical significance. The elderly patients' mean creatinine clearance (61.8 ml per min) was significantly lower than that in the young (137 ml per min), and there was a significant correlation between the half-life at single dosing and the blood urea concentration. Variability in all measurements was marked in both groups, and hence no clear guidelines can be given on therapeutic dosing. The small initial dose with alterations thereafter depending on clinical effect is the best advice.
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  • 40
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    European journal of clinical pharmacology 37 (1989), S. 381-385 
    ISSN: 1432-1041
    Keywords: nicardipine ; first pass effect ; pharmacokinetics ; stable isotope assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic elimination of nicardipine has been studied by an initial oral administration of nicardipine followed 1.25 h later by intravenous injection of the deuterium-labelled molecule (D3 nicardipine). To check that intravenous kinetics was not modified by the oral administration, an i.v. injection of unlabelled nicardipine (D0 nicardipine) was also given. The study was carried out in six healthy male volunteers, aged between 24 and 27 years, according to a Latin square cross-over design. Similar values were found for each kinetic parameter after i.v. administration regardless of whether it was administered alone by that route or with an oral dose. The plasma level-time curves of nicardipine were described by a three open compartment model. The total plasma clearance was about 800 ml/min, the volume of distribution was of the order of 1 l/kg and the half-life of β-elimination ranged from 4 to 5 h. The elimination rate constant β was independent of the route of administration.
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  • 41
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    European journal of clinical pharmacology 37 (1989), S. 423-426 
    ISSN: 1432-1041
    Keywords: prednisolone ; food intake ; enteric-coated tablets ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Prednisolone absorption and bioavailability of 10 mg enteric-coated (EC) and plain (uncoated) tablets were investigated after fasting and heavy meals (EC only) consumed to satiety in normal healthy volunteers. The same volunteers had also received 16 mg of prednisolone intravenously. In fasted subjects, the absolute bioavailability fraction, as normalised for intravenous doses, of prednisolone from plain tablets was 1.055 and from EC tablets was 0.996. The peak concentrations after plain and EC tablets were 309 and 249 ng/ml attained at 0.98 and 5.14 h, respectively. The means plasma elimination half-lives following the plain, EC tablets and intravenous administration in fasting conditions were 3.73, 3.89 and 3.78 h, respectively. Food interfered with both the absorption and the pharmacokinetics of prednisolone after EC tablets resulting in variability in its plasma levels. In some cases absorption of prednisolone was delayed for 12 h and remained at a measurable level for 24 h. In other cases, a normal absorption pattern was observed. This inter- and intrasubject variability of the effect of food appears to be related to its quantity, constituents and also the subjects physiological characteristics. It is concluded that enteric-coated prednisolone tablets should be administered at least 2 h between meals. However, for more predictable corticosteroid absorption (perhaps thus avoiding the therapeutic failure), plain prednisolone tablets are preferable.
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  • 42
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    European journal of clinical pharmacology 36 (1989), S. 629-632 
    ISSN: 1432-1041
    Keywords: trimethadione ; antipyrine ; metabolite formation ; drug interaction ; cytochrome P-450 ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten healthy male volunteers were given trimethadione (TMO) 4 mg/kg and antipyrine (AP) 500 mg alone or concomitantly to determine whether the metabolism of the drugs was mediated by the same or closely related forms of cytochrome P-450. Whether administered alone or together the clearance (CL) and half-life (t1/2) of TMO and AP were the same, and there was a good correlation between the CL and t1/2 of TMO and AP (aloner=0.755 and 0.623, respectively; coadministeredr=0.771 and 0.503, respectively). Excretion of AP and its main metabolite and the clearance for production of AP metabolites after AP was administered alone were not significantly different when TMO and AP were taken together. When the two drugs were administered alone or coadministered, the correlation between the CL of TMO and the excretion of 3-hydroxymethyl-3-norantipyrine (NORA) was close (aloner=0.734, coadministeredr=0.749). The correlation between the CL of TMO and CLm of NORA when TMO and AP were given alone or concomitantly was 0.762 and 0.772, respectively. The findings suggest that TMO metabolism and the formation of NORA in healthy subjects are mediated by a closely related form(s) of the cytochrome P-450 system.
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  • 43
    ISSN: 1432-1041
    Keywords: FCE 22101 ; penem antibiotic ; pharmacokinetics ; single dose ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical tolerance and pharmacokinetics of FCE 22101 (sodium (5R, 6S)-6-[(1R)-hydroxyethyl]-2-carbamoyloxymethyl-2-penem-3-carboxylate), a new penem antibiotic, have been studied after giving a single i.v. dose of 4 mg·kg−1 to ten healthy male volunteers. The pharmacokinetics was estimated according to a two-compartment open model. The peak plasma concentration (Cmax) was 15.5 (1.08) µg·ml−1, mean (SEM). FCE 22101 was rapidly cleared from the systemic circulation [ $$t_{1/2\lambda _z } $$ =44.2 (4.2) min; CL=7.21 (0.47) ml·kg−1·min−1]. The mean apparent volume of distribution at steady-state was 246 (16.9) ml·kg−1. The mean residence time relative to the 10 min infusion was 39.4 (1.5)min. Urinary recovery of FCE 22101 showed wide inter-subject variation, ranging from 10.2 to 53.6% of the dose. No subject complained of adverse effects.
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  • 44
    ISSN: 1432-1041
    Keywords: zidovudine ; azidothymidine ; pharmacokinetics ; metabolism ; HIV seropositivity ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 45
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    European journal of clinical pharmacology 37 (1989), S. 487-491 
    ISSN: 1432-1041
    Keywords: almitrine ; drug absorption ; liver metabolism ; pharmacokinetics ; biliary excretion ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of almitrine from the upper gastrointestinal tract has been evaluated in 6 healthy volunteers by an intubation technique. Almitrine bismesylate dissolved in malic acid was introduced into the stomach after homogenization with a meal containing the marker14C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was infused into the second part of duodenum throughout the experiment. Samples of the luminal content were collected every 15 min for four hours from the stomach and at the ligament of Treitz. Blood was also collected. Almitrine was neither absorbed from nor metabolized in the stomach. About 37% of the quantity of drug emptied from the stomach was absorbed from the duodenum. Almitrine was detected in plasma 50 min after ingestion of the meal and its plasma concentration-time profile reflected the cumulative gastric emptying rate. The metabolite tetrahydroxy almitrine was found in intestinal samples as soon as unchanged drug was detected in plasma. The intraluminal rate of formation of the metabolite increased with time. The results suggest hepatic metabolism of almitrine followed by rapid excretion of the metabolite in the bile.
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  • 46
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    European journal of clinical pharmacology 37 (1989), S. 617-619 
    ISSN: 1432-1041
    Keywords: clotiazepam ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the single dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets in a cross-over study in 6 healthy volunteers (median age 28 years). The formulations had similar systemic availability. Compared with oral tablets the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly.
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  • 47
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    European journal of clinical pharmacology 37 (1989), S. 101-104 
    ISSN: 1432-1041
    Keywords: theophylline ; ponsinomycin ; pharmacokinetics ; drug interactions ; macrolide antibiotic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of ponsinomycin on the pharmacokinetics of theophylline has been studied in 12 young healthy volunteers. They received 10 doses of theophylline 200 mg every 8 h p.o., successively in the absence and then in the presence of ponsinomycin. This new macrolide, structurally related to midecamycin, was given in the therapeutic dose of 800 mg b.d. for 5 days, starting 2 days before the second phase of treatment with theophylline. The pharmacokinetic parameters of theophylline, calculated from its plasma concentration at steady-state, were not affected by the co-treatment. In particular, there was no significant difference between the peak and trough plasma levels, apparent clearance or apparent elimination half-life of theophylline in the absence and the presence of ponsinomycin. Only renal clearance was slightly (27%) but significantly increased by the co-treatment. The results suggest that ponsinomycin would be a good choice if a macrolide antibiotic were needed in patients being treated with theophylline.
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  • 48
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    European journal of clinical pharmacology 37 (1989), S. 167-171 
    ISSN: 1432-1041
    Keywords: amiloride ; hydrochlorothiazide ; pharmacokinetics ; steady-state ; elderly ; fixed combination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of amiloride and hydrochlorothiazide were studied in 12 healthy young volunteers following a single dose of a fixed combination of amiloride and hydrochlorothiazide and in 11 elderly hypertensive patients at steady-state. Following modelling of the single dose data, simulated steady-state plasma concentrations for the 2 drugs were generated to examine the effect of age and/or hypertension on pharmacokinetics. The apparent systemic plasma clearance for both amiloride and hydrochlorothiazide was significantly reduced in the elderly when compared to the young (from 753 to 325 ml·min−1, amiloride; and from 418 to 157 ml·min−1, hydrochlorothiazide). The plasma concentrations at steady state for both drugs were greatly increased in the elderly patients (Amiloride: from 7 to 25 ng·ml−1, Css,max; from 2 to 8 ng·ml−1, Css,min; and from 4 to 14 ng·ml−1, Cav; Hydrochlorothiazide: from 184 to 651 ng·ml−1, Css,max; from 31 to 121 ng·ml−1, Css,min; and from 89 to 273 ng·ml−1, Cav). The decreased clearance of the diuretics in the elderly was believed due to deterioration of renal function, and there was a significant correlation between the plasma clearance of hydrochlorothiazide and creatinine clearance in both age groups (r=0.62, young;r=0.72, elderly). As a result of the pharmacokinetic findings caution may be indicated in the clinical dosage of the diuretics particularly when in fixed dose combination.
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  • 49
    ISSN: 1432-1041
    Keywords: felodipine ; metoprolol ; atenolol ; hypertension ; exercise ; pharmacokinetics ; adverse effects ; hypotensive action
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A study has been performed in thirteen patients with essential hypertension, WHO Class I–II, and a diastolic blood pressure ≥95 mm Hg, on beta-blocker (metoprolol or atenolol) monotherapy, who were also given felodipine 10 mg b.d. for 28 days. The acute and steady state blood pressure response at rest and during exercise, and the pharmacokinetics of felodipine and metoprolol, were examined. Felodipine in combination with the beta-blocker reduced the systolic and diastolic blood pressures acutely and at steady-state. The duration of the effect was longer at steady-state. There was a significant correlation between the plasma concentration of felodipine and the change in blood pressure. The increase in systolic blood pressure during exercise was of the same magnitude before and after felodipine administration. No change in resting supine heart rate was found after the administration of felodipine. There were no significant differences in the pharmacokinetics of felodipine during long-term treatment, except for the trough plasma concentration, which was increased at steady-state, even though cumulation of felodipine and its metabolite did not occur. There was a significant decrease in the maximal plasma concentration and AUC of metoprolol after 28 days of treatment with felodipine, but its elimination half-life was not changed. The adverse reactions reported during this study were those generally seen after dihydropyridines and, except for two patients who were withdrawn after the first study day, the effects were well tolerated.
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  • 50
    ISSN: 1432-1041
    Keywords: azathioprine ; 6-thiouric acid ; 6-mercaptopurine ; renal transplantation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The immunosuppressive activity of azathioprine (AZA) is unpredictable and depends on the formation of intracellular thiopurine ribonucleotides. However, the quantification of these active thiopurines presents difficult analytical problems. It has recently been postulated that plasma concentrations of 6-thiouric acid (6-TU) and 6-mercaptopurine (6-MP), metabolites of AZA, may provide more readily measurable indices of the pharmacologic activity of AZA. In order to evaluate the utility of 6-TU and 6-MP plasma concentrations in monitoring AZA therapy, we studied their pharmacokinetics in 6 renal transplant patients, and their in vitro immunosuppressive potency in a mixed lymphocyte proliferation assay. A peak plasma 6-TU concentration of 710.7 ng/ml was observed at 3.8 h after oral dosing. Good correlation was observed between the elimination t1/2 of 6-TU and serum creatinine, and between AUC over 24 h and serum creatinine. However, we did not observe a second peak in plasma 6-TU concentration that could be attributed to the degradation of active AZA metabolites. 6-MP plasma concentrations in the patients were low (mean peak concentration 36.0 ng/ml) and rapidly disappeared within 8 h. In vitro immunosuppressive activity could not be demonstrated for 6-TU over a concentration range of 1.25 ng/ml to 0.25 mg/ml. We conclude that 6-TU is pharmacologically inert and is primarily eliminated by the kidneys. Our findings currently do not support the use of plasma concentrations of 6-TU or 6-MP to monitor AZA therapy. In order to optimize AZA therapy, analytical techniques that are technically feasible and that can directly quantify the active intracellular thiopurines are being explored.
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  • 51
    ISSN: 1432-1041
    Keywords: meptazinol ; pregnant and non-pregnant women ; pharmacokinetics ; single and repeated i.v. dosing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the disposition of the centrally-acting analgesic meptazinol in a group of age-matched non-pregnant and pregnant (36–38 weeks gestation) women. Ten non-pregnant and nine multiparous pregnant volunteers each received a single i.v. dose of meptazinol hydrochloride (equivalent to 25 mg base). A further group of 9 non-pregnant (including four of the original participants) and 10 multiparous pregnant subjects were given repeated i.v. doses of meptazinol hydrochloride (each equivalent to 10 mg base) at 30-min intervals for 2.5 h. Meptazinol plasma concentrations were determined by HPLC using fluorescence detection and the pharmacokinetic variables investigated. After single dosing there were no statistical differences in half-life, clearance, or apparent volume of distribution between the two groups, suggesting that the disposition of meptazinol was not altered by pregnancy. This was confirmed in the repeated dose study, in which no significant differences occurred in either the plasma concentrations achieved or in areas under the curves between the non-pregnant and pregnant subjects. Furthermore, the steady-state concentrations were comparable with those predicted from the single dose results. This indicates that there should be no requirement for dosage alteration of meptazinol during pregnancy.
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  • 52
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    European journal of clinical pharmacology 36 (1989), S. 279-282 
    ISSN: 1432-1041
    Keywords: meptazinol ; rectal and oral administration ; pharmacokinetics ; first-pass metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of the centrally-acting analgesic meptazinol after oral and rectal administration to 15 healthy men. Each subject took a standard 200 mg tablet orally and Witepsol H12 suppositories containing 75, 100, and 150 mg of the drug in a cross-over design. Meptazinol plasma concentrations were measured by HPLC using fluorescence detection and the pharmacokinetics determined. The tmax values for the 100 mg and 150 mg suppositories (median =0.5 h) were statistically significantly shorter than for the tablet (median =1.13 h), suggesting that meptazinol was more rapidly absorbed via the rectal route. Despite substantial intersubject variation in Cmax the plasma concentrations after rectal dosage were higher than after oral administration. There was a statistically significant (p〈0.001) improvement in systemic availability for each of the suppository doses (mean approximately 15.5% compared with the oral tablet (mean approximately 4.5%).
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  • 53
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    European journal of clinical pharmacology 36 (1989), S. 283-290 
    ISSN: 1432-1041
    Keywords: ibuprofen ; enantiomers ; stereoselective protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have developed a novel and reproducible method for determining the plasma protein binding of the two ibuprofen enantiomers in the presence of each other. The method involves the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of the enantiomers to diastereomeric amides, high-performance liquid chromatography, and radiochemical analysis. We have determined the plasma protein binding of R(−)- and S(+)-ibuprofen in 6 healthy male volunteers after the oral administration of 800 mg racemic ibuprofen. The mean time-averaged percentage unbound of the R(−)-enantiomer, 0.419 was significantly less than that of the S(+)-enantiomer, 0.643, consistent with stereoselective plasma protein binding. The percentage unbound of each ibuprofen enantiomer was concentration-dependent over the therapeutic concentration range and was influenced by the presence of its optical antipode.
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  • 54
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    European journal of clinical pharmacology 36 (1989), S. 323-324 
    ISSN: 1432-1041
    Keywords: theophylline ; fluoroquinolones ; drug interaction ; renal excretion ; pharmacokinetics ; clearance ratio
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 55
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    European journal of clinical pharmacology 36 (1989), S. 407-409 
    ISSN: 1432-1041
    Keywords: oxazepam ; antipyrine ; glucuronidation ; drug metabolism ; very low calorie diet ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A very low calorie diet (Prodi) was administered to eleven otherwise healthy obese subjects for fourteen days. The daily intake of protein was 52.7 g and carbohydrate 25.7 g, corresponding to 360 kcal. The clearance of oxazepam and antipyrine was investigated before and after the diet period. Total oxazepam clearance was 1.04 ml·min−1·kg−1 and it decreased 0.88-fold after the diet. The mean clearance of unbound oxazepam was correspondingly reduced 0.88-fold. The elimination half-life increased to 1.22-times the control value, 7.9 h. No significant change was found in the volume of distribution or protein binding of oxazepam. Antipyrine clearance, estimated by the one-sample technique, was 52.4 and 51.8 ml·min−1, before and after the diet, respectively. It appears that a very low calorie diet with a sufficient protein and a very low carbohydrate content decreases the metabolism of oxazepam by glucuro-conjugation, whereas no effect was seen on the oxidative metabolism of antipyrine.
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  • 56
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    European journal of clinical pharmacology 36 (1989), S. 467-471 
    ISSN: 1432-1041
    Keywords: nitrendipine ; renal failure ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and plasma protein binding of nitrendipine in patients with terminal renal failure have been compared with those in subjects with normal renal function. Kinetic parameters were calculated after a single 40 mg oral dose, an i.v. injection of 3 mg and after a 15 mg i.v. infusion of nitrendipine. Steady-state plasma levels were determined after 5 days of oral treatment with 20 mg b.d. Pharmacokinetic parameters and steady-state plasma levels in patients with renal failure did not differ from those in subjects with normal renal function. Nitrendipine was as highly bound to plasma proteins in patients with renal failure, as in subjects with normal renal function. The plasma protein did not differ between the two. The dosage of nitrendipine need not be modified for kinetic reasons in patients with renal failure.
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  • 57
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    European journal of clinical pharmacology 36 (1989), S. 473-479 
    ISSN: 1432-1041
    Keywords: felodipine ; liver cirrhosis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nine patients (6 males, 3 females) with biopsy-proven liver cirrhosis participated in an open, cross-over, three centre study of the effect of impaired liver function on the pharmacokinetics of felodipine. Two of the nine patients had undergone porto-caval anastomosis. Each patient was given 0.75 mg i.v. and 10 mg p.o. on separate occasions. The results of this study have been compared with published data from younger subjects and elderly hypertensive patients. The mean peak plasma concentration normalized to a dose of 10 mg (Cmax 46 nmol/l) was twice as high in the cirrhotic patients as in the healthy subjects, but the bioavailability, f, (17.0%) was comparable. Subjects with a porto-caval shunt did not have higher f than the mean for the group. The volume of distribution at steady-state, Vss, was significantly lower than in the healthy subjects. Protein binding was significantly lower in the patients with cirrhosis: 99.46% compared to 99.64% in the healthy subjects. The weight-corrected clearance was 1/3 of the value in healthy subjects. No correlation between systemic availability and oral clearance was found, so it is proposed that felodipine is metabolized both in the liver and also in the gut wall. The results suggest that at least the starting dose should be reduced in patients with severe liver disease.
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  • 58
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    European journal of clinical pharmacology 36 (1989), S. 481-485 
    ISSN: 1432-1041
    Keywords: felodipine ; theophylline ; absorption ; metabolism ; pharmacokinetics ; blood pressure ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten healthy male volunteers (mean age 26 years) received 200 mg theophylline aminopropanol orally 8-hourly for 4 days, followed by 5 mg felodipine 8-hourly for 6 days, and then the combination of oral felodipine and theophylline for a further 4 days. Plasma concentrations of theophylline and felodipine were determined, and theophylline and its metabolites in urine were also measured. Felodipine led to a reduction in the plasma AUC of theophylline of 18.3%. The metabolic and renal clearances of theophylline remained unchanged, but the total recovery of theophylline-derived products was significantly reduced during felodipine treatment. No change in felodipine pharmacokinetics was observed during simultaneous treatment with theophylline. Compared to theophylline treatment alone, the diastolic blood pressure was significantly reduced during felodipine treatment alone and in combination with theophylline. It is concluded that felodipine slightly but significantly lowered the plasma theophylline concentration by interfering with its absorption. The interaction in most instances would probably be of minor clinical consequence.
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  • 59
    ISSN: 1432-1041
    Keywords: terodiline ; elderly patients ; metabolites ; pharmacokinetics ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elderly form an important target group for the treatment of urinary urge incontinence with drugs such as terodiline (Mictrol, Terolin). In order to evaluate its steady-state pharmacokinetics and tolerability in geriatric patients terodiline 12.5 mg b.d. was given to 28 hospitalized patients with urinary incontinence (mean age 85 years) for six weeks. The patients were monitored during the study and for 6 weeks afterwards, blood samples being taken at regular intervals. In addition to these multi-diseased and polymedicated patients, a small, homogenous group of healthy volunteers (mean age 40 years) was studied as a reference group, being given terodiline 12.5 mg b.d. for 2 weeks. Terodiline was generally well tolerated by the patients and no significant change in blood pressure or heart rate were found. One patient was withdrawn due to adverse effects. The mean terminal half-life of terodiline was 131 h and the clearance after oral administration (clearance/systemic availability) was 39 ml·min−1. The corresponding figures for the healthy volunteers were 57 h and 75 ml·min−1. The average steady-state serum concentration was 518 µg·l−1 in the geriatric patients and 238 µg·l−1 in the healthy volunteers. Steady-state was reached within 3 weeks in 20 of the 28 patients and within 5 weeks in 7 patients. In the geriatric patients the steady-state serum concentration of the main metabolite p-hydroxyterodiline, during the last three weeks on terodiline was 45 µg·l−1, 57 µg·l−1, and 45 µg·l−1, respectively, and a similar value was found in the healthy volunteers, 47 µg·l−1. The serum concentration of p-hydroxy-m-methoxyterodiline was 〈15 µg·l−1 both in the geriatric patients and in the healthy volunteers. Thus, terodiline 25 mg/day given to fragile elderly patients was well tolerated. It produced serum concentrations similar to those found after the standard dose of 37.5–50 mg given to younger, healthier patients.
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  • 60
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    European journal of clinical pharmacology 36 (1989), S. 507-512 
    ISSN: 1432-1041
    Keywords: indomethacin ; diflunisal ; drug interaction ; glucuronidation ; pharmacokinetics ; faecal blood loss
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of treatment with diflunisal on the steady-state pharmacokinetics of indomethacin has been studied in 16 healthy volunteers. The steady-state plasma concentration and AUC of indomethacin were significantly increased two- to threefold during treatment with diflunisal and its total clearance and total volume of distribution were significantly decreased. The urinary recovery of total indomethacin (unchanged+glucuronides) was significantly lower during administration of diflunisal, whereas excretion of the indomethacin metabolites desmethylindomethacin and desbenzoylindomethacin and their glucuronides was not significantly altered. The results can be explained by selective inhibition of glucuronidation of unchanged indomethacin by diflunisal. The interaction appears clinically relevant as potentially dangerous side effects of indomethacin are related to its plasma concentration.
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  • 61
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    European journal of clinical pharmacology 36 (1989), S. 513-516 
    ISSN: 1432-1041
    Keywords: dipyrone ; methylaminoantipyrine ; aging ; renal function ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the dipyrone metabolite, 4-metylaminoantipyrine (MAA) was evaluated, following the administration of a single oral dose of dipyrone 1.0 g to 12 young (21–30 years) and 9 elderly (73–90 years) healthy volunteers. Maximal concentration, time to peak and absorption rate of MAA were similar for both groups. The elimination half-life was 2.6 (0.2) h for the young and 4.5 (0.5) h for the elderly subjects. Total clearance of MAA, corrected for lean body mass (LBM), was lower in the elderly than in the young 2.65 vs 3.97 ml·min−1·k−1 LBM. There was no differences between the groups in the apparent volume of distribution. A good correlation was found between the total body clearance of MAA and the creatinine clearance, which was also reduced in the elderly (r=0.61).
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  • 62
    ISSN: 1432-1041
    Keywords: salbutamol ; sublingual ; oral ; inhaled ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Administration of drugs by the sublingual route provides rapid systemic absorption and avoids first-pass metabolism. The purpose of the present study was to assess the pharmacokinetics, efficacy and adverse effects of standard salbutamol tablets given by this route to patients with asthma. Seven asthmatic patients were given either sublingual salbutamol tablet 2 mg (SL), swallowed tablet 2 mg (O), metered dose inhaler 200 µg (MDI) or placebo (PL), in a randomized single-blind cross-over design. Airways responses (FEV1, FVC, PEFR), finger tremor (Tr), heart rate (HR), plasma potassium (K) and plasma salbutamol were measured over a 6 h period following drug administration. There were highly significant changes in FEV1 with MDI, O and SL routes compared with PL, although the response to MDI was greater and more rapid than with O or SL. There were similar findings for FVC and PEFR responses. There were no adverse effects with MDI, whereas both 0 and SL produced significant tremor responses. There were no differences between O and SL for any of the pharmacodynamic parameters. In addition, pharmacokinetic profiles for O and SL were also similar apart from an initial delay in absorption with SL. There were however, no significant differences in any of the pharmacokinetic parameters, between O and SL. This suggests that buccal absorption of salbutamol was negligible, and that systemic absorption occurred after swallowing of the dissolved sublingual tablet. These results show that sublingual administration of salbutamol tablet has no clinical benefit over the oral route.
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  • 63
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    European journal of clinical pharmacology 37 (1989), S. 577-580 
    ISSN: 1432-1041
    Keywords: cefoperazone ; cirrhosis ; ascites ; pharmacokinetics ; ascitic fluid content
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoperazone was studied in eleven cirrhotic patients with ascites after i.v. administration of a single dose of 15 mg·kg−1 (n=7) or after three doses of 15 mg·kg−1 given at 12 h intervals (n=4). The concentrations of cefoperazone in serum and ascitic fluid were determined by HPLC. The peak serum cefoperazone concentration after a single i.v. injection of 15 mg·kg−1 was 96.0 mg·l−1. The serum elimination half-life was longer (5.0 h) than in normal subjects. The penetration of cefoperazone into ascites was satisfactory (32.3% and 58.3% after single and repeated injections, respectively). Ascitic fluid concentrations of cefoperazone exceeded 5.4 mg·ml−1 from 0.5 to 6 h after the single i.v. injection, levels which are well above the MIC of most pathogens found in spontaneous bacterial peritonitis. Adjustment of the dose of cefoperazone in cases of severe hepatic insufficiency does not appear to be necessary provided that renal function is normal.
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  • 64
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    European journal of clinical pharmacology 37 (1989), S. 599-604 
    ISSN: 1432-1041
    Keywords: 4-methylpyrazole ; alcohol dehydrogenase inhibitor ; healthy volunteers ; pharmacokinetics ; saturable kinetics ; zero order elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to evaluate the pharmacokinetic profile of the alcohol dehydrogenase inhibitor 4-methylpyrazole 4-MP, a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose “Phase-I study” was performed in healthy male volunteers at dose levels of 10 (n=4), 20 (n=4), 50 (n=4) and 100 mg·kg−1 (n=3). In the 10 and 20 mg·kg−1 group, the elimination of 4-MP from the plasma followed non-linear kinetics with mean rates of concentration decline of 3.66 and 5.05 µmol·1−1·h−1, respectively. In the two highest dose groups, the elimination also appeared to be non-linear although the patterns were not followed long enough to confirm this, The mean rates of concentration decline at the higher doses were significantly increased, up to 14.9 µmol·l−1·h−1 at 100 mg·kg−1. The average renal clearance of 4-MP was low, 0.016 ml·min−1·kg−1, and only 3% of the administered dose was excreted unchanged in the urine, indicating metabolism as the major route of elimination. Because of the apparently unusual kinetics following single dose treatment, thorough multiple dose studies need to be carried out to determine a safe dosage regimen for 4-MP.
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  • 65
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    European journal of clinical pharmacology 37 (1989), S. 231-233 
    ISSN: 1432-1041
    Keywords: antipyrine ; terbinafine ; drug metabolism ; drug interaction ; enzyme induction/inhibition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The potential to inhibit drug metabolism of the new antifungal agent terbinafine has been studied using antipyrine (single oral dose of 10 mg/kg) as a probe drug. In a cross-over study in 8 healthy volunteers, antipyrine was administered prior to, during and after 8 days of oral terbinafine 125 mg b.d. Antipyrine, its major metabolites 4-hydroxyantipyrine (4-OH-AP), 3-hydroxymethylantipyrine (3-OH-CH3-AP) and norantipyrine (Nor-AP) were analyzed by specific HPLC assays in multiple plasma and urine samples. During all three parts of the study, the pharmacokinetics of antipyrine viz. t1/2 (11.7 h), total plasma (38.5 ml·h−1·kg−1) and renal clearance (1.6 ml·h−1·kg−1), and its clearance rates to metabolites (CLM), eg. CLM for 4-OH-AP (12.3 ml·h−1·kg−1), CLM for 3-OH-CH3-AP (4.2 ml·h−1·kg−1) and CLM for Nor-AP (6.7 ml·h−1·kg−1) did not differ from the control values. Thus, all the cytochrome P-450-dependent isozymes involved in the metabolism of antipyrine and many other drugs should not be affected by therapeutic doses of terbinafine.
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  • 66
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    European journal of clinical pharmacology 37 (1989), S. 245-248 
    ISSN: 1432-1041
    Keywords: breast milk ; zolpidem ; pharmacokinetics ; imidazopyridine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five, lactating, healthy white women were treated with a single 20 mg tablet of zolpidem 3–4 days after the delivery of a full term baby. The drug was administered at 20.00 h, 30 min after dinner, and milk samples were collected before and 3, 13 and 16 h. Venous blood 5 ml was taken before and 1.5, 3, 13, 16 h after zolpidem administration. The apparent elimination half life, estimated from plasma zolpidem concentrations was 2.6 h. The amount of zolpidem excreted in the milk at 3 h ranged between 0.76 and 3.88 µg, which represented 0.004 to 0.019% of the administered dose; no detectable (below 0.5 ng/ml) zolpidem was found in the milk at subsequent sampling times. The ratio of the zolpidem concentrations in breast milk and plasma at 3 h was 0.13. The apparent breast milk clearance of zolpidem, calculated from the ratio of the total amount of zolpidem excreted in milk to its AUC in plasma was 1.48 ml/h. The results show that the excretion of zolpidem in human milk is very low (below 0.02%) and that most of it takes place during the first 3 h following drug intake.
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  • 67
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    European journal of clinical pharmacology 37 (1989), S. 261-265 
    ISSN: 1432-1041
    Keywords: oflaxacin ; ascitic fluid ; cirrhosis ; drug penetration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and ascitic fluid concentrations of ofloxacin were determined in 12 cirrhotic patients after a single dose and repeated 200 mg oral doses. The single dose kinetics were compared to those obtained in 12 healthy volunteers. Mean plasma elimination half-life was 11.6 h in cirrhotics and 7.0 h in controls. Mean total clearance was 2.3 times lower in patients than in controls, due to a significant decrease of renal clearance of the drug, unrelated to creatinine clearance. Mean apparent volume of distribution was 1.2 l/kg in patients and 1.8 l/kg in controls. Estimated by the ratio of AUC in peritoneal fluid and plasma, ascitic fluid penetration was 80% after the first oral dose. Ascitic fluid concentrations equaled corresponding plasma concentrations after 10 h, without pronounced accumulation of ofloxacin in ascites. We may conclude that, in cirrhotic patients with normal serum creatinine, a significant impairment of renal tubular handling of ofloxacin could be observed and led to a delayed elimination half-life of the drug. Because of its broad sprectrum of activity, low side-effect profile, and large ascitic fluid penetration after oral administration, ofloxacin appears to be a new therapeutic approach of severe infections in cirrhotic patients, in particular spontaneous bacterial peritonitis.
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  • 68
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    European journal of clinical pharmacology 37 (1989), S. 267-272 
    ISSN: 1432-1041
    Keywords: midazolam ; pharmacokinetics ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A serum concentration profile study on midazolam in children was done. Fifty six children aged 3–10 years took part. The routes investigated were intravenous, intramuscular, rectal and oral at 0.15 mg·kg−1, and the oral at 0.45 mg·kg−1 and 1 mg·kg−1. Serum concentration levels for 5 h were studied using gas liquid chromatography. The volume of distribution, Vss, was 1.29 l·kg−1, the elimination half-life 1.17 h and the serum clearance 9.11 ml·kg−1·min−1. Peak serum concentrations for the intramuscular, rectal and oral routes were at 15 min, 30 min and 53 min respectively. Bioavailability was 87%, 18%, 27% respectively at a dose of 0.15 mg·kg−1. The oral route bioavailability halved to 15% at the two higher doses. Bioequivalence was present between the 0.15 mg·kg−1 intramuscular dose and the 0.45 mg·kg−1 oral dose from 45 to 120 min.
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  • 69
    ISSN: 1432-1041
    Keywords: nicotine ; transdermal delivery ; dose proportionality ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of nicotine delivered by a transdermal delivery system (TDS) was investigated in two separate studies, (A) a dose proportionality study and (B) a multiple dose study. In the dose range of 15–60 mg nicotine, the AUC and Cmax values were proportional to the dose. The levels achieved were in the same range as reported in smokers, following absorption from nicotine chewing gum. The TDS used in the present study produced sustained levels of nicotine for 24 h. No significant accumulation of nicotine was evident as a result of multiple dose administration using a 30-mg nicotine patch. Absorption of nicotine from the TDS was 80–90% and the rate of delivery was similar during both studies.
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  • 70
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    European journal of clinical pharmacology 37 (1989), S. 359-363 
    ISSN: 1432-1041
    Keywords: neuroleptics ; remoxipride ; pharmacokinetics ; urinary pH ; healthy volunteers ; overdose ; plasma prolactin ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of urinary pH on the plasma and urinary kinetics of remoxipride in man has been studied in an open crossover trial in ten healthy male volunteers. Ammonium chloride (urinary pH 5.2) and sodium hydrogen carbonate (urinary pH 7.8) were used as pretreatments on two occasions in randomized order. On each occasion remoxipride 50 mg solution was administered orally and plasma and urinary concentrations of the drug were determined by HPLC and plasma prolactin concentrations by RIA. Remoxipride was rapidly distributed in the body according to a one-compartment model. The mean plasma elimination half-life (t1/2) was 3.6 h in the ammonium chloride experiment and 6.2 h in the sodium hydrogen carbonate experiment. The mean plasma clearance of remoxipride was 141 and 89.9 ml·min−1 in the acidic and alkaline conditions, respectively, and the corresponding mean renal clearances were 58.5 ml·min−1 and 11.7 ml·min−1. The urinary excretion of remoxipride up to 72 h after drug administration was 43.1% and 12.3% following acidification and alkalinization, respectively. Remoxipride induced a similar rapid, transient elevation of plasma prolactin under both conditions. Thus, the urinary pH has a marked effect on the elimination kinetics of remoxipride. After an overdose, treatment with ammonium chloride might be valuable in hastening elimination of remoxipride from the body.
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  • 71
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    European journal of clinical pharmacology 36 (1989), S. 25-28 
    ISSN: 1432-1041
    Keywords: theophylline ; terbutaline ; asthma ; drug interaction ; hepatic metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic mechanism of the theophylline-terbutaline interaction has been studied. Sustained release theophylline 200–400 mg b.d. was given with placebo or terbutaline 2.5 mg t.d.s. to six adult asthmatic patients. Terbutaline decreased the serum trough theophylline levels from 8.1 to 7.3 µg/ml, improved daily the clinical score from 1.51 to 1.26 and increased the peak expiratory flow rate from 316 to 370 l/min. In a single dose study following the chronic therapy, it was shown that there was no change in the peak theophylline concentration or in the timing of the peak, but the t1/2 was reduced from 9.0 to 7.5 h, and the systemic clearance was increased from 20.2 to 24.8 ml·h−1·kg−1. Thus, terbutaline reduced the serum theophylline concentration by increasing its systemic clearance.
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  • 72
    ISSN: 1432-1041
    Keywords: pirenzepine ; hepatic insufficiency ; hepato-renal insufficiency ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady-state intravenous pharmacokinetics of pirenzepine has been investigated in patients with chronic liver disease and others with combined chronic liver disease and renal sufficiency. The plasma clearance (CL) of Pirenzepine, steady-state plasma concentration Cmin(ss) and dominant half life t1/2γ were not significantly altered in the chronic liver disease group. In patients with renal and hepatic insufficiency, CL was reduced, t1/2γ was prolonged from 11.1 to 19.4 h and Cmin(ss) was elevated from 36 ng/ml to 66 ng/ml compared to healthy controls. Plasma concentrations remained in the therapeutic range and the dosage regimen was well tolerated. Adjustment of the dose of pirenzepine need be considered only in cases of severe impairment of both renal and hepatic elimination.
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  • 73
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    European journal of clinical pharmacology 36 (1989), S. 67-70 
    ISSN: 1432-1041
    Keywords: diltiazem ; propranolol ; metoprolol ; atenolol ; pharmacokinetics ; drug interaction ; beta-adrenoceptor blockade ; healthy volunteers ; pharmacodynamic effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic interaction between diltiazem and three β-adrenoceptor blockers propranolol, metoprolol and atenolol was investigated in healthy volunteers given diltiazem 30 mg or placebo t.d.s. for 3 days, followed by a single dose of propranolol 20 mg, metoprolol 40 mg or atenolol 50 mg. The AUCs of propranolol and metoprolol were significantly increased after diltiazem and it significantly prolonged the elimination half-life of metoprolol. In contrast, it did not significantly affect the pharmacokinetics of atenolol. Propranolol significantly decreased the resting pulse rate after diltiazem pretreatment as compared to placebo. The results indicate that diltiazem impaired the clearance of propranolol and metoprolol, which are principally metabolized by an oxidative pathway, and that the kinetic interaction between diltiazem and propranolol may partly be related to the significant reduction in the pulse rate produced by the latter.
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  • 74
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    European journal of clinical pharmacology 36 (1989), S. 79-82 
    ISSN: 1432-1041
    Keywords: cefonicid ; paediatric infections ; pharmacokinetics ; single dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefonicid was studied in 17 children requiring antibiotic treatment for respiratory or urinary tract infections. After informed consent had been obtained from the parents, a single dose of cefonicid 50 mg/kg/body weight was given by intramuscular injection. The mean peak serum concentration of 212.63 µg/ml was reached at 1.00 h, as absorption occurred at a very fast rate with a mean constant of 3.24 h−1. Mean values for half-life, apparent volume of distribution (Vz), total body clearance (CL), and renal clearance (CLR) were 3.24 h, 0.21 l·kg−1, 16.67 ml·min−1 and 13.60 ml·min−1 respectively. There was an inverse relationship between age and Vz, whereas CL and CLR were positively correlated with age. Cefonicid concentrations in urine were many times higher than the MICs of susceptible strains of bacteria. The study demonstrated that i.m. cefonicid 50 mg·kg−1 gave serum concentrations well within the therapeutic range for susceptible bacteria, and that its pharmacokinetic properties allow single daily doses to be used to treat infections in children.
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  • 75
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    European journal of clinical pharmacology 36 (1989), S. 103-109 
    ISSN: 1432-1041
    Keywords: asthma ; chronopharmacology ; theophylline ; circadian rhythms ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 76
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    European journal of clinical pharmacology 36 (1989), S. 205-208 
    ISSN: 1432-1041
    Keywords: amlodipine ; pharmacokinetics ; renal-impairment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Amlodipine was administered as 14 single 5-mg oral daily doses to 27 male subjects with renal function ranging from normal to haemodialysis-dependent. Blood specimens were obtained for measurement of plasma amlodipine concentrations for 24 h following the first dose, for 168 h following the final dose and during daily administration of amlodipine. Amlodipine was well tolerated. Renal impairment had little effect on the pharmacokinetics of amlodipine. The elimination half-life was of the order of 50 h, similar to previously reported values and did not vary with renal function. Steady-state pre-dose concentrations were observed after the ninth dose. Accumulation of amlodipine was not significantly different from that expected on theoretical grounds and did not significantly change with renal function. These results suggest that once daily administration of amlodipine is suitable for all degrees of renal function and that dosage adjustment is not necessary in renal impairment.
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  • 77
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    European journal of clinical pharmacology 36 (1989), S. 209-211 
    ISSN: 1432-1041
    Keywords: naproxen ; transcutaneous absortion ; non-steroidal anti-inflammatory drug ; topical application ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of naproxen was studied in healthy volunteers after cutaneous application of gels containing 5 and 10% of the drug. Bioavailability was estimated from serum concentration and cumulative urinary metabolite excretion data, both determined up to 96 hours after drug administration. The mean bioavailability after the 10% gel was 1.1% (serum data) and 1.0% (urine data), and after the 5% gel it was 2.1% (serum data) and 1.8% (urine data). Despite the small amount of naproxen absorbed, a potential pharmacological effect, due to cutaneous accumulation of the drug following topical administration, may be suggested from the course of the serum concentration-time curves.
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  • 78
    ISSN: 1432-1041
    Keywords: nimodipine ; pharmacokinetics ; haemodynamics ; cardiopulmonary resuscitation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary As the pharmacokinetics of a drug may be altered in haemodynamically compromised patients, the plasma concentrations and haemodynamic effects of the calcium entry blocker nimodipine have been examined in patients resuscitated after out-of-hospital cardiac arrest. In 7 patients nimodipine was infused at increasing rates up to 30 µg·kg−1·h−1. The plasma concentrations increased with increasing dose; at the highest dose a mean steady-state plasma concentration of 22.1 ng·ml−1 was obtained, and the mean plasma clearance was 1.4 l·kg−1·h−1. There were no marked changes in mean arterial blood pressure or heart rate. In 9 other patients nimodipine was given as a bolus infusion of 10 µg·kg−1 over 3 min, followed by a continuous infusion of 30 µg·kg−1·h−1. A mean steady-state plasma concentration of 17.6 ng·ml−1 was obtained and the mean plasma clearance was 1.9 l·kg−1·h−1. Heart rate did not change significantly, but the mean arterial blood pressure fell. The data indicate that in patients resuscitated after cardiac arrest, the pharmacokinetics of nimodipine are not markedly different from patients with other conditions, e.g. subarachnoid haemorrhage. However, if a loading dose is given to obtain a steady-state concentration sooner, there will be a fall in arterial blood pressure.
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  • 79
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    European journal of clinical pharmacology 36 (1989), S. 361-367 
    ISSN: 1432-1041
    Keywords: cimetidine ; burned children ; stress ulceration ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the mechanisms of the increased dosage requirements of the H2-receptor antagonist cimetidine in paediatric burned patients in a pharmacokinetic and pharmacodynamic study. Cimetidine (10–15 mg·kg−1) was given to 21 burned children and multiple blood samples were obtained for determination of plasma cimetidine concentrations and pharmacokinetic analysis. The relation of gastric pH to plasma cimetidine concentrations was studied in five of these children who had nasogastric tubes. In an additional four patients the effects of cimetidine on gastric pH were studied during a continuous infusion of cimetidine, which maintained steady-state plasma cimetidine concentrations above 0.5 µg·ml−1. The mean (SEM) clearance of cimetidine in burned children was 16.22 ml·kg−1 and cimetidine half-life was 1.06 h. The cimetidine clearance and half-life values were significantly higher in burned children compared with our previously reported values for normal adult patients, 8.2 ml·min·kg−1 and 2.21 h respectively. Endogenous creatinine clearance normalized to 70 kg in burned children was 190 ml·min−1. In burned children 41% of the dose of intact cimetidine was excreted during 8 h of the study compared with 45% excretion during 24 h in healthy adult controls previously reported. The correlation coefficient between creatinine and cimetidine clearances was 0.93 (r 2=0.85). The plasma concentration of cimetidine needed to increase gastric pH to ≥4.0 was ≥1.0 µg·ml−1, which contrasts with the value of 〉0.5 µg·ml−1 required for adult burned patients. These findings support the hypothesis that the higher dosage requirements of cimetidine in burned children is due both to enhanced elimination kinetics and to alterations in target organ sensitivity, requiring higher than normal plasma concentrations for the desired effect. In burned children Cimetidine should be given in higher doses and/or more frequently.
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  • 80
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    European journal of clinical pharmacology 36 (1989), S. 375-378 
    ISSN: 1432-1041
    Keywords: mexiletine ; cimetidine ; ranitidine ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of mexiletine, a Class I antiarrhythmic drug, was investigated in 6 healthy volunteers after single oral doses and 15 min intravenous infusions of 3 mg/kg. Cimetidine and ranitidine are commonly used H2-receptor antagonists, which interact adversely with many drugs, e.g. inhibition of the metabolism of Class I antiarrhythmics such as lidocaine and quinidine by cimetidine. To investigate the effects of the two drugs on the kinetics of mexiletine, cimetidine 800 mg·day−1 or ranitidine 600 mg·day−1 were administered orally for one week. Neither H2-receptor antagonist altered the distribution and elimination of mexiletine, nor did they affect its overall kinetics, or excretion of the metabolites para- and 4-OH-methylmexiletine after oral and intravenous administration of mexiletine.
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  • 81
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    European journal of clinical pharmacology 36 (1989), S. 383-388 
    ISSN: 1432-1041
    Keywords: naproxen ; sustained-release formulation ; pharmacokinetics ; bioavailability ; efficacy ; tolerability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and clinical efficacy of a once-daily sustained-release formulation of naproxen (sodium salt) have been compared with those of conventional-release agents. In a single dose pharmacokinetic study, the rate of absorption of the sustained-release preparation was less than that of a conventional-release preparation but the extent of absorption was the same. As is the case with conventional-release naproxen, food decreased the rate but not the extent of absorption of the sustained-release formulation. On multiple dose administration for 7 days, the AUC and average concentrations of the sustained release preparation (1 g daily) were the same as those for conventional release preparations of naproxen sodium (250 mg four times daily) and naproxen free acid (500 mg daily). The conventional-release sodium salt was absorbed more quickly with no differences in bioavailability. A double-blind clinical comparison in patients with osteoarthritis showed the sustained-release preparation (1 g daily) to be equivalent in efficacy to conventional naproxen capsules (500 mg twice daily) but to have a significantly lower incidence of gastrointestinal side-effects. The results suggest that sustained-release naproxen sodium has potential for use as a once-daily treatment for inflammatory disease.
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  • 82
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    European journal of clinical pharmacology 36 (1989), S. 389-393 
    ISSN: 1432-1041
    Keywords: ornidazole ; haemodialysis ; pharmacokinetics ; renal function ; metabolism ; urine concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ornidazole was studied in 6 patients treated by haemodialysis and in 8 subjects with a creatinine clearance between 4 and 99 ml/min × 1.73 m2. Blood and urine collections were performed for 72 h after i.v. and oral administration of 1.0 g ornidazole. Total body clearance, half-life, volume of distribution and systemic availability were independent of renal function and did not differ from previously reported values in normal volunteers. The haemodialysis clearance of ornidazole was 〉100% higher than the total body clearance. The renal clearance of ornidazole accounted for less than 7% of the total body clearance. The percentage of the dose of ornidazole recovered in urine as parent compound or as the biologically active metabolites [α-(chloromethyl)-2 hydroxymethyl-5 nitroimidazole-1 ethanol and 3-(2 methyl-5 nitroimidazole-1-yl)1,2 propanediol] decreased linearly with decreasing renal function. Although the sum of those three compounds recovered in urine accounted for less than 10% of the total dose of ornidazole administered, they yielded therapeutic concentrations (〉4 µg/ml) in urine over 24 h after dosing. Due to the peculiar pharmacokinetic behaviour of ornidazole, i.e. high haemodialysis clearance in the absence of significant renal clearance, no dosage adjustment is necessary while renal function declines, but an increased dose is mandatory while patients are on dialysis.
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  • 83
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    European journal of clinical pharmacology 36 (1989), S. 395-400 
    ISSN: 1432-1041
    Keywords: pyrazinamide ; antituberculous chemotherapy ; pharmacokinetics ; xanthine oxidase ; microsomal deaminase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma and urine pharmacokinetic parameters of pyrazinamide and of its metabolites (pyrazinoic acid, 5-hydroxy-pyrazinamide, 5-hydroxy-pyrazinoic acid and pyrazinuric acid) have been studied after a single oral dose of pyrazinamide 27 mg · kg−1 in 9 healthy subjects. Pyrazinamide was rapidly absorbed (tmax ≤1 h) and showed a short distribution phase followed by an elimination phase of t1/2β=9.6 h. The close similarity of the apparent elimination rates of the metabolites led to a second trial of a single oral dose of pyrazinoic acid to evaluate the formation and elimination stages. The limiting factor was found to be the activity of a microsomal deamidase (pyrazinoic acid formation from pyrazinamide and 5-hydroxy-pyrazinoic acid formation from 5-hydroxy-pyrazinamide). In contrast, oxidation by xanthine oxidase occurred very rapidly (5-hydroxy-pyrazinamide formation and pyrazinoic acid catabolism to 5-hydroxy-pyrazinoic acid).
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  • 84
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    European journal of clinical pharmacology 36 (1989), S. 423-426 
    ISSN: 1432-1041
    Keywords: itraconazole ; antifungal drug ; pharmacokinetics ; systemic availability ; dose-dependency ; food effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the influence of food and dose (50, 100, 200 mg) on the oral systemic availability of the broad spectrum antifungal itraconazole and the pharmacokinetics after repeated dosing of 100 mg in six healthy volunteers. The relative systemic availability of itraconazole capsules compared with solution averaged 39.8% in the fasting state but 102% in the post-prandial state. Food did not significantly affect the tmax of the capsules. Itraconazole AUC at single doses of 50, 100, and 200 mg had a ratio of 0.3:1:2.7, and the steady-state AUC (0–24) after 15 days of 100 mg was five times the single-dose AUC. These findings suggest non-linear itraconazole pharmacokinetics in the range of therapeutically used doses. Furthermore, capsules should be given shortly after a meal to ensure optimal oral systemic availability.
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  • 85
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    European journal of clinical pharmacology 36 (1989), S. 433-437 
    ISSN: 1432-1041
    Keywords: nitrendipine ; renal failure ; haemodynamic effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In sixteen patients with arterial hypertension and differing degrees of renal function the pharmacokinetics and haemodynamic effects of nitrendipine have been studied after treatment for 7 days. The AUC (0–24) and the elimination half-life of nitrendipine were significantly increased; the AUC (0–24) in patients with renal failure (median creatinine clearance 27.1 ml × min−1) was 196 ng × ml−1 × h compared to 97.8 ng × ml−1 × h in control subjects (median creatinine clearance 94.4 ml × min−1). The corresponding elimination half-lives were 13.5 h in renal failure and 4.4 h in the controls. The haemodynamic effects of nitrendipine were not enhanced in the patients.
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  • 86
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    European journal of clinical pharmacology 37 (1989), S. 313-316 
    ISSN: 1432-1041
    Keywords: diprafenone ; pharmacokinetics ; bioavailability ; first-pass metabolism ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the antiarrhythmic drug diprafenone have been investigated in 6 healthy volunteers following single intravenous (50 mg) and oral doses (50 and 150 mg). Diprafenone was mainly eliminated by metabolism in the liver. Following i.v. infusion of 50 mg diprafenone, the terminal half-life of elimination was 1.50 h, the volume of distribution at steady-state was 1.23 l·kg−1, and the free fraction in plasma was 1.68%. Mean total plasma clearance was 741 ml·min−1·70 kg−1, which approaches normal liver blood flow after correction for the blood/plasma concentration ratio. Thus, diprafenone can be classified as a high extraction drug. Following oral administration, a dose-dependent increase in bioavailability from 10.9 (50 mg dose) to 32.5% (150 mg dose) was observed. The data suggest that diprafenone is subject to saturable hepatic first-pass metabolism.
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  • 87
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    European journal of clinical pharmacology 37 (1989), S. 321-322 
    ISSN: 1432-1041
    Keywords: cyclosporin ; synovial fluid ; rheumatoid arthritis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 88
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    European journal of clinical pharmacology 37 (1989), S. 387-389 
    ISSN: 1432-1041
    Keywords: salbutamol ; pharmacokinetics ; renal insufficiency ; biological effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Salbutamol was administered intravenously to 5 patients with renal function impairment for estimation its pharmacokinetic parameters. The mean terminal half-life was 256 min, similar to previously reported values in healthy adults. The mean clearance (167 ml/min) and the mean volume of distribution (55 l) were decreased. These parameters were not correlated with the creatinine clearance. A slight but significant decrease was observed in the plasma potassium level up to 125 min after the salbutamol infusion. The heart rate was significantly increased, and the increase in 3 patients was correlated with the salbutamol concentration. The biological effects of the drug were less marked than expected.
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  • 89
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    European journal of clinical pharmacology 36 (1989), S. 613-616 
    ISSN: 1432-1041
    Keywords: ceftriaxone ; cefotaxime ; cirrhosis ; pharmacokinetics ; ascites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have compared in two separate studies the kinetics of ceftriaxone and cefotaxime in 8 cirrhotic patients with ascites and 8 control subjects after a single 20 min intravenous infusion of 1 g of each drug. The apparent volumes of distribution (Vz) were found to be significantly higher in cirrhotics than in control subjects (0.87, versus 0.49, l·kg−1, for cefotaxime and 0.23 versus 0.13 for ceftriaxone). The elimination kinetics of ceftriaxone were similar in the two groups. In contrast, the total and non-renal clearances of cefotaxime were reduced in cirrhotic patients. The two drugs rapidly entered the ascitic fluid. Peritoneal concentrations of ceftriaxone were higher than 7 µg·ml−1 from the second hour after the infusion and were 8.9 µg·ml−1 at 24 h. Peritoneal concentrations of cefotaxime were higher than 4 µg·ml−1 from 0.5 to 8 h after the infusion.
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  • 90
    ISSN: 1432-1041
    Keywords: indomethacin ; diflunisal ; pharmacokinetics ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single-dose pharmacokinetics of indomethacin following 100 mg rectally was measured in two groups of 8 healthy subjects before and after diflunisal 500 mg p.o. once daily, or 500 mg in the morning and 1000 mg in the evening, until steady state conditions were reached. A further group of 8 healthy subjects was given 50 mg indomethacin rectally before and after diflunisal 500 mg p.o. twice daily. High dose diflunisal (1500 mg/day) decreased the renal clearance of indomethacin from 21.9 to 1.8 ml/min (92%) and reduced the renal excretion of both unchanged (63%) and conjugated (82%) indomethacin. The apparent total body clearance (0.12 l/h/kg), apparent volume of distribution (0.98 l/kg), and volume of distribution at steady state (0.80 l/kg) were decreased by 47%, 35% and 30%. The maximum plasma concentration (2.4 µg/ml) and total area under the curve (13.0 µg × h/ml) were increased by 40% and 119%, respectively. The terminal elimination half-life (5.7 h) and mean residence time (6.7 h) were slightly prolonged (7.0 h and 8.8 h) in the presence of diflunisal. The contribution of metabolism to the overall elimination of indomethacin was increased by only 2%. Similar results were obtained when the subjects were challenged with the low dose of diflunisal (500 mg/day), although the magnitude of the changes were smaller. The interaction between indomethacin and diflunisal may be due to competition both at the metabolic (conjugation) and the excretory (tubular secretion) levels. When the subjects were given 50 mg indomethacin and diflunisal 1000 mg/day simultaneously, the achieved maximum plasma concentration of indomethacin (2.53 µg/ml) was comparable to that seen after 100 mg in the absence of diflunisal (3.1 µg/ml), but the AUC was greater (21.7 µg × h/ml vs 13.0 µg × h/ml). Adverse central nervous reactions were more frequent and more pronounced at higher plasma indomethacin concentrations.
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  • 91
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    European journal of clinical pharmacology 37 (1989), S. 595-598 
    ISSN: 1432-1041
    Keywords: amitriptyline ; nortriptyline ; pharmacokinetics ; linear kinetics ; depressed patients ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The linearity of the (AMT) kinetics of amitriptyline has been tested in 135 depressed dosed twice daily by measuring plasma. Their (AMT) and nortriptyline (NT) levels under steady-state conditions. The AMT concentration/dose ratios at low and high dosages were not significantly different and there was a linear relationship between the dose ratios and the concentration ratios. No change in the metabolic ratio (AMT/NT) was observed between the two dosages. Although the results are consistent with linear AMT kinetics, there may have been nonlinear kinetics in some patients as the ratio between the concentration/dose ratios in them at low and high dosages was greater than one. Those patients were characterized by a low concentration/dose ratio at low dosage. No clinical adverse effect appeared in the study.
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  • 92
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    European journal of clinical pharmacology 37 (1989), S. 97-100 
    ISSN: 1432-1041
    Keywords: theophylline ; sex differences ; pharmacokinetics ; gender
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Theophylline pharmacokinetic parameters were compared in healthy males and healthy premenopausal females who were matched for age and smoking status. Twenty-four subjects (including five smokers and seven non-smokers of each sex) received a single dose of aminophylline 6 mg·kg−1, orally or by intravenous infusion. Theophylline half-life was significantly shorter in female non-smokers (FNS) versus male non-smokers (MNS), (FNS=6.0 h; MNS=9.3 h), and in female smokers (FS) versus male smokers (MS), (FS=4.6 h; MS=6.3 h). Total body clearance was significantly different in FNS versus MNS, (FNS=43.8 ml·min−1·−1.73 m−2; MNS=37.4 ml·min−1·1.73 m−2), but did not reach statistical significance in FS vs. MS, (FS=64.2 ml·min−1·l−1·1.73 m−2; MS=53.1 ml·min−1·1.73 m−2). Volume of distribution did not differ significantly between groups. Sex differences in theophylline pharmacokinetics exist and may reflect differences in drug metabolism.
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  • 93
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    European journal of clinical pharmacology 37 (1989), S. 173-180 
    ISSN: 1432-1041
    Keywords: frusemide ; nephrotic syndrome ; albumin ; dextran ; pharmacokinetics ; renin-angiotensin-aldosterone system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The renal handling and effects of an intravenous bolus of frusemide with and without plasma volume expansion with dextran or albumin, and with large variations in plasma albumin concentration, have been studied in five patients with the nephrotic syndrome. Decreased renal sensitivity to frusemide was found in only one patient, who also had hypovolaemia and an activated renin-angiotensin-aldosterone system. Plasma volume expansion increased the diuresis but not the saluresis, and slightly increased renal sensitivity to frusemide. An increase in albuminuria after albumin infusion did not reduce the sensitivity to frusemide. A decrease in plasma albumin concentration from 33 g·l−1 after albumin infusion to 23 g·l−1 after infusion of dextran caused a substantial increase in the renal clearance (from 84 to 123 ml·min−1), non-renal clearance (from 72 to 138 ml·min−1), and apparent volume of distribution (from 13 to 23 l) of frusemide, probably as a consequence of an increase in the unbound fraction. The rate of urinary excretion of frusemide was highest after albumin infusion, despite the fact that its renal clearance was lowest then.
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  • 94
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    European journal of clinical pharmacology 37 (1989), S. 181-184 
    ISSN: 1432-1041
    Keywords: baclofen ; renal function ; healthy subjects ; pharmacokinetics ; probenecid ; tubular secretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Baclofen, a centrally acting muscle relaxant, is used in the treatment of spasticity. Its pharmacokinetics has been derived from plasma and urine data in four healthy subjects, whose renal function was simultaneously measured. After oral administration of a single 40 mg dose, baclofen was mainly excreted unchanged by the kidney, 69 (14) %. The half-life, calculated from extended least squares modelling (ELSMOS) both of plasma and urine data was 6.80 (0.68) h, which is longer than reported in most studies based solely on plasma data. The renal excretion rate constant had the high mean value of 0.35 (0.24) h−1, and the apparent renal clearance of baclofen equalled the creatinine clearance. Passive tubular reabsorption is relatively unimportant, since no dependence was observed on variables urine flow or pH. Although active tubular secretion may contribute to its renal clearance, as shown by the effect of coadministration of probenecid, glomerular filtration appears to be the dominant transport mechanism.
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  • 95
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    European journal of clinical pharmacology 37 (1989), S. 193-194 
    ISSN: 1432-1041
    Keywords: urapidil ; digoxin ; blood drug level ; pharmacokinetics ; drug absorption/-interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open, randomized, two-period change-over study the effect of urapidil, an antihypertensive agent, on steady-state serum digoxin levels was investgated in 12 healthy male volunteers. The subjects were given digoxin 0.25 mg once daily for 4 days to produce a steady-state digoxin level in serum. At the end of that time the subjects received either digoxin monotherapy or digoxin and concomitant treatment with urapidil 60 mg b.d. for a further 4 days. Subsequently the treatments were changed over. The absorption characteristics Cmax and tmax of digoxin were not altered by concomitant urapidil treatment. The geometric mean and nonparametric 95% confidence limits of digoxin relative bioavailability were 97% (93%–103%). Therefore, concomitant administration of urapidil with digoxin treatments did not appear to alter the rate and extent of absorption of the glycoside.
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  • 96
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    European journal of clinical pharmacology 37 (1989), S. 185-189 
    ISSN: 1432-1041
    Keywords: nifedipine ; renal failure ; pharmacokinetics ; protein binding ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose. The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml−1) and maximum plasma concentration (75.0 ng·ml−1) were lower than in subjects with normal renal function (19300 ng·ml−1; 122 ng·ml−1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure. Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.
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  • 97
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    European journal of clinical pharmacology 37 (1989), S. 501-506 
    ISSN: 1432-1041
    Keywords: N-acetylcysteine ; paracetamol ; acetaminophen overdose ; pharmacokinetics ; liver damage ; adverse reactions ; dose modifications
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seventeen patients received standard treatment with intravenous N-acetylcysteine for 18 episodes of severe poisoning with paracetamol (acetaminophen). The dose of N-acetylcysteine was 150 mg/kg given in 15 min followed by 50 mg/kg in 4 h and 100 mg/kg over the next 16 h. Liver damage was absent or mild on 13 occasions (ALT〈500 µ/l) and severe on 5 (ALT〉1000 µ/l). Total plasma N-acetylcysteine was estimated by HPLC. The mean maximum plasma concentration after the initial loading dose was 554 mg/l. Concentrations then fell rapidly and after 12 h a mean steady-state level of about 35 mg/l was maintained. When the infusion was discontinued N-acetylcysteine disappeared with a half-life of 5.7 h. The mean steady-state volume of distribution, AUC, mean residence time and total clearance were 536 ml/kg, 1748 mg·h·l−1, 2.91 h and 3.18 ml·min−1·kg−1. These values are generally consistent with those previously reported with much smaller doses and the disposition of N-acetylcysteine does not appear to be dose-dependent. The elimination of N-acetylcysteine was not impaired in the patients with severe liver damage, and the pharmacokinetic variables and plasma concentrations were similar in patients with and without hepatotoxicity. The dosage schedule for intravenous N-acetylcysteine should probably be modified since adverse reactions invariably occur early when plasma concentrations are at their highest, and liver damage was prevented just as effectively at the lowest as at the highest Cmax. High initial concentrations of N-acetylcysteine can be avoided with simple alternative regimens based on the kinetic data of this study.
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  • 98
    ISSN: 1432-1041
    Keywords: oxitropium bromide ; pharmacokinetics ; radioreceptor assay ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Oxitropium bromide (OXBR) is a new anticholinergic drug, which is expected to be useful in the treatment of nocturnal asthma. The only pharmacokinetic data were obtained with the14C-labelled compound. A sensitive radioreceptor assay for the determination of unlabelled OXBR in plasma was developed, based on competition between OXBR and3H-N-methylscopolamine for binding to muscarinic receptors. OXBR was isolated from plasma by ion-pair extraction and re-extraction. Active metabolites present in significant amounts might interfere in the assay, but this was not the case for OXBR metabolites. Detection limits were 300 pg·ml−1 and 3 ng·ml−1 for plasma and urine, respectively. For the latter no extraction step was required. The single dose pharmacokinetics of OXBR was studied following inhalation (3 mg), oral (2 mg) and i.v. (1 mg) administration to 12 men, following an open, cross-over design. After i.v. administration the kinetic parameters were: Vc 38.4 l; t1/2α 5.3 min; t1/2β 142 min; AUC 8.9 h·ng·ml−1; renal excretion 50.2%, k10 3.5 l·h−1 and total clearance 1874 ml/min. The apparent bioavailabilities were 0.48% and 12.4% by the oral and inhalation routes, respectively, based on the cumulative renal excretion. There were moderate adverse reactions due to the anticholinergic properties of the drug.
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  • 99
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    European journal of clinical pharmacology 37 (1989), S. 533-536 
    ISSN: 1432-1041
    Keywords: bismuth ; absorption ; elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bismuth subcitrate were studied in plasma and urine under conditions of single and multiple dosing (28–56 days) using atomic absorption technique. Single dose plasma pharmacokinetics showed peak concentrations of 5.5–57.5 µg·l−1 (mean=24.7 µg·l−1), reached between 30 and 60 min post dosing with an apparent biphasic elimination pattern. Multiple dose studies showed a continuing rise in plasma concentration and urine excretion rate reaching apparent steady-state levels over 7–29 days (mean=18 days). Washout studies in 6 individuals reciprocated accumulation. Maximum equilibrated plasma levels of 7.6–58.3 µg·l−1 (mean=38.3 µg·l−1) were well below those associated with encephalopathy. The half-life of bismuth elimination was 20.7 days. Present patterns of intermittent dosing with bismuth are unlikely to be associated with bismuth accumulation despite slow accumulation and elimination.
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  • 100
    ISSN: 1432-1041
    Keywords: salbutamol ; asthma ; controlled-release formulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fifteen patients with asthma were given salbutamol controlled-release (SCR) 4 mg or 8 mg twice daily for seven days, in a randomised double-blind cross-over design. Plasma salbutamol levels were measured after the first and fifteenth doses for a 12 h period following drug ingestion. At steady-state the geometric mean values for Cmax were 8.2 ng/ml for 4 mg, and 16.1 ng/ml for 8 mg. Median tmax values were 300 and 240 min respectively. The geometric mean AUC (0–12) were 4507 ng·min·ml−1 and 8980 ng·min/ml. Peak to trough fluctuation ratios were 0.577 and 0.572. There were no significant differences between 4 mg or 8 mg formulations, for any of the parameters measured, after appropriate corrections for dose. The concentration-time profiles at steady-state showed little fluctuation in plasma salbutamol levels over the twelve hour dosing interval. These results show that 4 mg and 8 mg formulations of SCR provide smooth plasma profiles at steady-state with a twice daily dosing regime.
    Type of Medium: Electronic Resource
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