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  • 2000-2004  (60)
  • 1985-1989  (4.529)
  • 1980-1984  (3.562)
  • Chemical Engineering  (6.138)
  • pharmacokinetics  (1.058)
  • Ultrastructure  (954)
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  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Journal of comparative physiology 186 (2000), S. 347-357 
    ISSN: 1432-1351
    Schlagwort(e): Key words Crustacean ; Sensorimotor ; Ultrastructure ; Multilamellar sheath ; Myelinated axons
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Notizen: Abstract Speed of nerve impulse conduction is greatly increased by myelin, a multi-layered membranous sheath surrounding axons. Myelinated axons are ubiquitous among the vertebrates, but relatively rare among invertebrates. Electron microscopy of calanoid copepods using rapid cryofixation techniques revealed the widespread presence of myelinated axons. Myelin sheaths of up to 60 layers were found around both sensory and motor axons of the first antenna and interneurons of the ventral nerve cord. Except at nodes, individual lamellae appeared to be continuous and circular, without seams, as opposed to the spiral structure of vertebrate and annelid myelin. The highly organized myelin was characterized by the complete exclusion of cytoplasm from the intracellular spaces of the cell generating it. In regions of compaction, extracytoplasmic space was also eliminated. Focal or fenestration nodes, rather than circumferential ones, were locally common. Myelin lamellae terminated in stepwise fashion at these nodes, appearing to fuse with the axolemma or adjacent myelin lamellae. As with vertebrate myelin, copepod sheaths are designed to minimize both resistive and capacitive current flow through the internodal membrane, greatly speeding nerve impulse conduction. Copepod myelin differs from that of any other group described, while sharing features of every group.
    Materialart: Digitale Medien
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  • 2
    ISSN: 1437-773X
    Schlagwort(e): Key words Mitogen-activated protein kinase (MAPK) ; Ischemia reperfusion injury ; Heart ; Ultrastructure ; Immunohistochemistry
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The mitogen-activated protein kinase (MAPK) family is considered to be activated by stress, but the role of the MAPK family is still unknown in cardiac pathology. In the present study, not only the localization of MAPKs such as the extracellular responsive kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK (p38), but also ultrastructural changes were investigated in the ischemia-reperfusion model of Wistar rats. At 5, 10, 30, 60, and 180 min reperfusion after 30 min ischemia by occluding the coronary artery, the expression of these MAPKs was increased in blood vessels and cardiomyocytes by Western blotting and immunohistochemical methods. In addition, after ischemia reperfusion, various ultrastructural changes such as decreased glycogen granules, mitochondrial swelling, and myolysis were observed in the blood vessels and cardiomyocytes. These results suggest that protein kinases may regulate numerous biological processes, including the regulation of contraction and ion transport.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1437-773X
    Schlagwort(e): Key words Gonadotroph adenoma ; FSH ; Childhood ; Ultrastructure ; Immunohistochemistry
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Female gonadotroph adenomas with endocrinological symptoms are uncommon. Six cases of such adenomas have been reported in the literature: two were girls who presented with precocious puberty and four were premenopausal women with accompanying multiple ovarian cysts. We describe here a 10-year-old Japanese girl with a gonadotroph macroadenoma and present detailed morphological findings of the tumor. The patient's chief complaints were nausea, abdominal distention, and abdominal pain. Abdominopelvic ultrasonography and magnetic resonance imaging (MRI) revealed bilateral multiple ovarian cysts. Endocrinological assays showed elevated serum follicle-stimulating hormone (FSH) (33.7 mIU/ml) and estradiol (3840 pg/ml). MRI of the head showed a large pituitary tumor. Two transsphenoidal operations and subsequent radiation therapy were performed. Immunohistochemically, more than half the tumor cells were positive for anti-FSH-β monoclonal antibody. Ultrastructurally, the tumor cells exhibited a fairly uniform picture of rounded cells. Their nuclei were slightly irregular and contained heterochromatin, and their cytoplasm contained many round, dense core granules, measuring 140–260 nm in diameter, together with well-developed organelles. An in vitro study showed that the tumor cells in primary culture produced FSH (1089.0 mIU/ml). To our knowledge, this is the first immunohistochemical and ultrastructural study of an FSH-secreting gonadotroph adenoma occurring in childhood.
    Materialart: Digitale Medien
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  • 4
    ISSN: 1437-773X
    Schlagwort(e): Key words Apoptosis ; Helicobacter pylori ; Fibroblasts ; Smooth muscle cells ; Ultrastructure ; Gastroduodenal ulcer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract It has been considered that Helicobacter pylori (H. pylori) infection is a major cause of human gastritis and gastroduodenal ulcers (G-DU). Many investigations of the relationship between H. pylori and apoptosis have been reported recently. However, these studies focused mostly on epithelium, using the TUNEL method. In the present study, we evaluated by electron microscopy the occurrence of apoptosis in the mesenchymal cells of lamina propria mucosae infected with H. pylori. Gastric biopsy specimens from 37 H. pylori-infected G-DU patients and 8 noninfected volunteers were examined with both light and electron microscopy and analyzed by the TUNEL method. The TUNEL method showed no significant difference between H. pylori-infected and noninfected cases. In contrast, electron microscopy revealed significant numbers of apototic fibroblasts and smooth muscle cells in H. pylori-infected lamina propria mucosae, with a diminished number of collagen fibers in surrounding areas. These areas showed edematous changes histopathologically. These results indicated that H. pylori infection induces apoptosis of fibroblasts and smooth muscle cells in lamina propria, with decrease in the numbers of collagen fibers, suggesting that these alterations may be affected by exaggerate acid secretion, decrease mucus protecting factors, and result in ulcer formation.
    Materialart: Digitale Medien
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  • 5
    Digitale Medien
    Digitale Medien
    Springer
    Medical electron microscopy 33 (2000), S. 109-114 
    ISSN: 1437-773X
    Schlagwort(e): Key words Ciliogenesis ; Ciliated cell ; Abnormal cilia ; Basal body ; Ultrastructure ; Human
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Cilia are motile processes extending from the basal bodies, playing important roles in the mucociliary clearance in the respiratory tract and the transport of the ovum from the ovary to the uterus in mammals. Ciliogenesis is divided into four stages: (1) duplication of centrioles; (2) migration of centrioles to the apical cell surface to become basal bodies; (3) elongation of cilia containing the axoneme; and (4) formation of accessory structures of basal bodies. The orderly course of ciliogenesis appears to be disturbed by various internal and external factors and, as a result, various unusual forms of the ciliary apparatus develop in the cell. Inhibition of basal body migration results in development of intracytoplasmic axonemes, cilia within periciliary sheaths, and intracellular ciliated cysts. Swollen cilia and the bulging type of compound cilia are formed during ciliary budding and elongation. This review also discusses the origin, composition, and function of the centriolar precursor structures.
    Materialart: Digitale Medien
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  • 6
    Digitale Medien
    Digitale Medien
    Springer
    Medical electron microscopy 33 (2000), S. 135-142 
    ISSN: 1437-773X
    Schlagwort(e): Key words Elastic system fiber ; Ultrastructure ; Fibrotic human liver ; Oxytalan fiber ; Elaunin fiber
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The network of elastic system fibers in human fibrotic liver was investigated by histological methods, immunohistochemical staining, and electron microscopy. Type III collagen was seen not only in regions of portal fibrosis but also in the sinusoidal wall. However, elastic system fibers were not found in the Disse space of the sinusoidal wall. Elastic system fibers including oxytalan, elaunin, and elastic fibers were found successively in the course of elastogenesis. A few normal oxytalan fibers and abnormal oxytalan fibers were observed in the periportal tracts. Few normal elaunin and abnormal elaunin fibers were observed in regions of portal fibrosis but not in the surrounding margin. Elastic fibers, only in scarce amounts, were observed around the portal veins in the case of chronic active hepatitis but not in acute hepatitis. Abnormal oxytalan fibers were seen as a bundle of wavelike microfibrils and had an irregular arrangement. Abnormal elaunin fibers were not associated with bundles of microfibrils. Abnormal elaunin fibers in large amounts were found interspersed with spiraled collagen, which most likely indicates that the oxytalan fibers degenerated in the course of elastogenesis. Thus, in a fibrotic liver it is possible that synthesis of normal elaunin and elastic fibers does not occur or that the quantity of such fibers synthesized may be small because of the effect of the degenerated oxytalan fibers. As a characteristic of liver fibrosis, the composition of abnormal elastic system fibers and spiraled collagen differs from that in other fibrotic organs.
    Materialart: Digitale Medien
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  • 7
    ISSN: 1437-773X
    Schlagwort(e): Key words Adenoid basal carcinoma ; Uterine cervix ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Adenoid basal carcinoma of the uterine cervix is a rare tumor with a favorable prognosis. A case of adenoid basal carcinoma (ABC) of the uterine cervix was studied using light and electron microscopy. The patient was a 74-year-old Japanese woman who had undergone hysterectomy due to cervical intraepithelial neoplasia 3. Incidentally, ABC was found in the resected uterus. The tumor cells made small nests and infiltrated the cervical portion of the uterus. In the nests, glands, cribriform patterns with glandlike structures, and squamous differentiation were seen. Immunohistochemically, the glandlike structures were positive for laminin and type IV collagen. Ultrastructurally, the tumor cells had irregular nuclei, scanty cytoplasm, and cribriform patterns in which glandlike structures were covered with basal lamina. No myoepithelial differentiation of the tumor cells was seen. These findings suggest a similarity between adenoid basal carcinomas and adenoid cystic carcinomas. Furthermore, both tumors are considered to originate in the reserve cells of the uterine cervix. Because their outcomes are different, they should be distinguished from each other.
    Materialart: Digitale Medien
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  • 8
    ISSN: 1432-2161
    Schlagwort(e): Key words Giant rice body ; Ultrastructure ; Immunohistochemistry ; Histogenesis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  Objective: To report four cases of rice bodies (RBs) showing remarkable size variations and discuss their pathogenesis. Design and patients: Based on analysis of the clinical data, we speculate on the pathogenesis of RBs using immunohistochemical and ultrastructural methods. The patients comprised three men and one woman, three with RBs in the subacromial bursae and one in the wrist synovial sheath, aged 28 (woman), 44, 50 and 81 (wrist) years, respectively. Results: There were no particular differences in clinical data among the patients. T2-weighted MR imaging was very useful for diagnosis of the RBs, allowing their clear delineation from the bursal fluid. The RBs consisted of a layered protein- aceous substance with vague targetoid cut surfaces. Much fibrin and a lesser amount of collagen fibers were recognized together with various mononuclear cells, which were few in number and predominantly T cells. The bursae and synovial sheath had multiple fibrinoid spheroids at the luminal surface. Conclusion: Fibrinoid nodular deposits probably became detached, forming the nuclei of RBs and growing to a giant RB 65 mm in diameter.
    Materialart: Digitale Medien
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  • 9
    ISSN: 1432-2307
    Schlagwort(e): Key words Arteriogenesis ; Collateral vessels ; Ultrastructure ; Cell adhesion molecules
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  Previous studies in the canine heart had shown that the growth of collateral arteries occurs via proliferative enlargement of pre-existing arteriolar connections (arteriogenesis). In the present study, we investigated the ultrastructure and molecular histology of growing and remodeling collateral arteries that develop after femoral artery occlusion in rabbits as a function of time from 2 h to 240 days after occlusion. Pre-existent arteriolar collaterals had a diameter of about 50 µm. They consisted of one to two layers of smooth muscle cells (SMCs) and were morphologically indistinguishable from normal arterioles. The stages of arteriogenesis consisted of arteriolar thinning, followed by transformation of SMCs from the contractile- into the proliferative- and synthetic phenotype. Endothelial cells (ECs) and SMCs proliferated, and SMCs migrated and formed a neo-intima. Intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) showed early upregulation in ECs, which was accompanied by accumulation of blood-derived macrophages. Mitosis of ECs and SMCs started about 24 h after occlusion, whereas adhesion molecule expression and monocyte adhesion occurred as early as 12 h after occlusion, suggesting a role of monocytes in vascular cell proliferation. Treatment of rabbits with the pro-inflammatory cytokine MCP-1 increased monocyte adhesion and accelerated vascular remodeling. In vitro shear-stress experiments in cultured ECs revealed an increased phosphorylation of the focal contacts after 30 min and induction of ICAM-1 and VCAM-1 expression between 2 h and 6 h after shear onset, suggesting that shear stress may be the initiating event. We conclude that the process of arteriogenesis, which leads to the positive remodeling of an arteriole into an artery up to 12 times its original size, can be modified by modulators of inflammation.
    Materialart: Digitale Medien
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  • 10
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 99 (2000), S. 310-316 
    ISSN: 1432-0533
    Schlagwort(e): Key words Ganglioglioma ; Ependymoma (tanycytic variant) ; Neurofibrillary tangle ; Immunohistochemistry ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract We studied a cystic ganglioglioma (GG) located in the right frontal lobe of the brain. Interestingly, the fibrillary spindle glial cells were often arranged in a fascicular pattern, and the generally uniform, round-to-oval delicate nuclei appeared to resemble those of ependymoma; and the neoplastic neurons often contained neurofibrillary tangles (NFTs). The glial component was positive for glial fibrillary acidic protein and occasionally contained granular or microvesicular structures positive for epithelial membrane antigen. Ultrastructural investigation revealed that the glial cells were ependymal in nature; intracytoplasmic lumina and intercellular microrosettes lined with cilia and microvilli, as well as long zonulae adherentes, were evident. In addition, chromogranin A-positive granular staining, neurosecretory-granule-like structures, and parallel arrays of microtubules were sometimes associated with the blood vessels. We considered the present case to be an unusual example of GG with an ependymoma, more precisely a tanycytic ependymoma, as the glial component; to our knowledge, the existence of ependymoma as the main glial component of this particular tumor has not been described before. The occurrence of NFTs, which has been reported in several cases of GG, was an additional, unusual feature.
    Materialart: Digitale Medien
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  • 11
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 99 (2000), S. 214-218 
    ISSN: 1432-0533
    Schlagwort(e): Key words Eosinophilic inclusion body ; Inclusion ¶body ; Ependymoma ; Microlumina ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract A study was undertaken to determine the pathological significance of previously unrecognized intracytoplasmic eosinophilic inclusions (IEIs) in ependymoma. The study group consisted of 58 ependymomas, all of which were pathologically characterized and graded according to the 1993 WHO classification. Electron microscopic studies were performed in 16 cases. The study showed that 33 (57%) ependymomas had IEIs and that in 8 cases these were abundant. Round and eosinophilic, their sizes varied from 10 μm to a tiny dot. Similar eosinophilic bodies were also observed between tumor cells. The inclusions were weakly PAS positive. On immunostains, IEIs were frequently positive for glial fibrillary acidic protein, less often for S-100 protein, and for epithelial membrane protein and CAM 5.2. They were negative for AE1/AE3, carcinoembryonic antigen and Ber-EP4. Ultrastructurally, IEIs represented intracytoplasmic lumens containing microvilli and cilia. These microlumina also frequently contained granulo-tubular materials. With reference to tumor subtypes, IEIs occurred most frequently in ordinary and clear cell ependymomas. IEIs were also present in 4 of 6 anaplastic ependymomas studied. In conclusion, IEIs represent microlumina and occur in more than a half of ependymomas including malignant examples. Their finding is a helpful diagnostic feature of ependymoma.
    Materialart: Digitale Medien
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  • 12
    Digitale Medien
    Digitale Medien
    Springer
    Anatomy and embryology 201 (2000), S. 51-61 
    ISSN: 1432-0568
    Schlagwort(e): Key words Female prostate (Skene gland) ; Ultrastructure ; Secretory (luminal) cells ; Basal (reserve) cells ; Intermediary cells
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  The predominant cells of female prostatic glands lining their lumen were found to be tall cylindrical secretory cells with short stubby microvilli, protuberances of the apical cytoplasm, and with bleb formation. Abundant secretory vacuoles and granules, rough endoplasmic reticulum, developed Golgi complexes and numerous mitochondria are characteristic of their active secretory configuration with apocrine (apical blebs) and merocrine (secretory vacuoles and granules) type of secretion. Basal (reserve) cells were seen to be located between the secretory (luminal) cells and the basement membrane. Their ground cytoplasm is dense with rough endoplasmic reticulum and mitochondria. Their nuclei, unlike those of secretory cells, possess more peripheral condensed chromatin, denser dispersed chromatin and sporadic nucleoli. Besides the two basic types of mature prostatic cells intermediary cells were also seen, located between the basal and secretory cells or in their close vicinity. Their cytoplasm exhibits numerous profiles of rough endoplasmic reticulum and free ribosomes. Secretory vacuoles and granules were mostly practically absent (type 1 intermediary cells) so that they resembled basal (reserve) cells. In some of them, however, as in secretory cells, such secretory elements do gradually appear (type 2 intermediary cells). The finding of intermediary cells in the lining of prostatic glands supports the role of basal (reserve) cells in the renewal of cells in glands of the female prostate. The first ultrastructural analysis of the normal female prostate performed by transmission electron microscopy showed that, as in the postpubertal male, the prostatic glands in the adult female display mature secretory and basal cells. The results of the presented study further corroborate the contemporary concept of the female prostate as a functional genitourinary organ.
    Materialart: Digitale Medien
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  • 13
    ISSN: 1432-0533
    Schlagwort(e): Key words Alzheimer disease ; Fibrillar amyloid-β ; Astrocytes ; Microglial cell ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Ultrastructural three-dimensional reconstruction of human classical plaques in different stages of development shows that microglial cells are the major factor driving plaque formation by fibrillar amyloid-β (Aβ) deposition. The amount of fibrillar Aβ released by microglial cells and the area of direct contact between amyloid and neuron determine the extent of dystrophic changes in neuronal processes and synapses. The volume of hypertrophic astrocytic processes separating fibrillar amyloid from neuron is a measure of the protective activation of astrocytes. On the bases of the volume of amyloid star, microglial cells, dystrophic neurites, and hypertrophic astrocytic processes, and spatial relationships between plaque components, three stages in classical plaque development have been distinguished: early, mature, and late. In early plaque, the leading pathology is fibrillar Aβ deposition by microglial cells with amyloid star formation. The mature plaque is characterized by a balance between amyloid production, neuronal dystrophy, and astrocyte hypertrophy. In late classical plaque, microglial cells retract and expose neuropil on direct contact with amyloid star, enhancing both dystrophic changes in neurons and hypertrophic changes in astrocytes. In late plaques, activation of astrocytes predominates. They degrade amyloid star and peripheral amyloid wisps. The effect of these changes is classical plaque degradation to fibrillar primitive and finally to nonfibrillar, diffuse-like plaques.
    Materialart: Digitale Medien
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  • 14
    ISSN: 1432-0533
    Schlagwort(e): Key words GM1-gangliosidosis ; Ultrastructure ; Electrospray ionisation tandem mass spectrometry ; Diagnosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The post-mortem diagnosis of lysosomal storage diseases can be confounded by the unavailability of suitable material. Here we report the diagnosis of GM1-gangliosidosis in a cross-bred dog, from which only formalin-fixed brain was available, by a combination of electron microscopy and the detection of elevated levels of GM1-ganglioside within the tissue using the novel technique of electrospray ionisation tandem mass spectrometry. Electron microscopic examination of ultrathin sections of resin-embedded tissue revealed cytoplasmic inclusions (membranous cytoplasmic and zebra bodies) in brain stem and cerebellar neurons that were characteristic of a gangliosidosis. Glycolipids were extracted from the fixed tissue and analysed by tandem mass spectrometry. Two major ions were detected, which corresponded to GM1 (d18:1–C18:0) and GM1 (d20:1–C18:0). Their identity was confirmed by comparison of their fragmentation patterns with those of authentic standards. The concentration of GM1 was approximately sixfold higher on a wet weight basis than in the brain of a normal control dog, confirming the diagnosis of GM1-gangliosidosis.
    Materialart: Digitale Medien
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  • 15
    Digitale Medien
    Digitale Medien
    Springer
    Virchows Archiv 436 (2000), S. 249-256 
    ISSN: 1432-2307
    Schlagwort(e): Key words Endothelial cells ; Cell culture ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  The aim of the present work was to examine and compare the ultrastructure of bovine retinal endothelial cells (BRECs) in vitro during several passages in a medium selective for endothelial cells. The identity of the endothelial cells was confirmed immunohistochemically, up to the tenth passage. Changes in their ultrastructure in comparison to endothelial cells in vivo occurred at the onset of culturing and not progressively with repeated passages. The cultured BRECs show high metabolic activity in all passages. While retaining their identity as endothelial cells, they modify their lipid metabolism, so that lipids are stored. This change in lipid metabolism was induced by the medium.
    Materialart: Digitale Medien
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  • 16
    ISSN: 1432-2013
    Schlagwort(e): Key words Pineal organ ; Photoreceptor cells ; Ultrastructure ; Proteus anguinus ; Regressive evolution
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract We studied ultrastructure of the photoreceptor cells in the pineal organ of blind, depigmented, neotenic cave salamander, Proteus anguinus. Unlike in epigean vertebrates the outer segments of most photoreceptor cells consists of concentrically arranged lamellae, however; in few cells, the outer segments contain 7-9 plasma membrane disks. In both types of photoreceptor cells the outer segments enclose lumps of vesicles of different sizes. The photoreceptor cells of Proteus anguinus are similar to those in other cavernicolous fish species.
    Materialart: Digitale Medien
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  • 17
    ISSN: 1569-8041
    Schlagwort(e): cisplatin ; pharmacokinetics ; phase I ; oral topotecan
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 18
    ISSN: 1569-8041
    Schlagwort(e): dosing ; inhibitor ; matrix metalloproteinase ; pharmacokinetics ; solid tumours ; toxicity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:This phase I study was performed to evaluatethe safety, tolerability, and efficacy of the oral matrixmetalloproteinase inhibitor BAY 12-9566 in patients with advanced solidtumours, and to identify the maximum tolerated dose and dose for use insubsequent studies. Patients and methods:BAY 12-9566 was administered to 29 patientsat doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days1–5, day 15 and days 29 and 30. Patients were continued on daily oraltreatment of BAY 12-9566 until a dose limiting toxicity or tumour progressionoccurred. Results:A maximum tolerated dose was not defined because plasmalevels of BAY 12-9566 could not be sufficiently increased, even withescalating doses of drug. Pharmacokinetic analysis suggested that absorptionwas saturable at higher doses. The predominant toxicities related to drug wereasymptomatic reversible effects on platelets and transaminases and mildanemia. There were no significant musculoskeletal toxicities. No objectiveresponses were seen at the doses tested, but stable disease was observed insome patients based on tumour measurements. Conclusions:The recommended dose of BAY 12-9566 for furtherstudies is 800 mg b.i.d. as this dose provides maximal plasma levels that canbe achieved with a convenient dosing schedule for a chronically administeredoral agent
    Materialart: Digitale Medien
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  • 19
    ISSN: 1569-8041
    Schlagwort(e): 776C85 ; bioequivalence ; dihydropyrimidine dehydrogenase inhibitor ; eniluracil ; 5-fluorouracil ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:This study was performed to evaluate thepharmacokinetics, bioequivalence, and feasibility of a combined oralformulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc.,Research Triangle Park, North Carolina), an inactivator of dihydropyrimidinedehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FUformulation oral dosing form is to simplify treatment with these agents, whichhas been performed using separate dosing forms, and decrease the probabilityof severe toxicity and/or suboptimal therapeutic results caused byinadvertently high or conversely insufficient 5-FU dosing. Patients and methods:The trial was a randomized, three-waycrossover bioequivalence study of three oral dosing forms of eniluracil/5-FUtablets in adults with solid malignancies. Each period consisted of two daysof treatment and a five- to seven-day washout phase. Eniluracil at a dose of20 mg, which results in maximal DPD inactivation, was administered twice dailyon the first day and in the evening on the second day of each of the threetreatments. On the morning of the second day, all patients received a totaleniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as eitherseparate tablets (treatment A) or combined eniluracil/5-FU tablets in twodifferent strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). Thepharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinaryexcretion of eniluracil, 5-FU, uracil, and α-fluoro-β-alanine (FBAL),were studied. To determine the bioequivalence of the combined eniluracil/5-FUdosing forms compared to the separate tablets, an analysis of variance onpharmacokinetic parameters reflecting eniluracil and 5-FU exposure wasperformed. Results:Thirty-nine patients with advanced solid malignancies hadcomplete pharmacokinetic studies performed during treatments A, B, and C. Thepharmacokinetics of eniluracil and 5-FU were similar among the three types oftreatment. Both strengths of the combined eniluracil/5-FU dosing form and theseparate dosing forms were bioequivalent. Mean values for terminal half-life,systemic clearance, and apparent volume of distribution for oral 5-FU duringtreatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and50.7/51.5/50.0 liters, respectively. The intersubject coefficient of variationfor pharmacokinetic variables reflecting 5-FU exposure and clearance intreatments ranged from 23% to 33%. The urinary excretion ofunchanged 5-FU over 24 hours following treatments A, B, and C averaged52.2%, 56.1%, and 50.8% of the administered dose of 5-FU,respectively. Parameters reflecting DPD inhibition, including plasma uraciland urinary FBAL excretion following treatments A, B, and C were similar.Toxicity was generally mild and similar following all three types oftreatments. Conclusions:The pharmacokinetics of 5-FU and eniluracil weresimilar and met bioequivalence criteria following treatment with the separateoral formulations of 5-FU and eniluracil and two strengths of the combinedformulation. The availability of a combined eniluracil/5-FU oral dosing formwill likely simplify dosing and decrease the probability of severe toxicityor suboptimal therapeutic results caused by an inadvertent 5-FU overdose orinsufficient 5-FU dosing in the case of separate oral formulations, therebyenhancing the overall feasibility and therapeutic index of oral 5-FU therapy.
    Materialart: Digitale Medien
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  • 20
    ISSN: 1569-8041
    Schlagwort(e): BBR3464 ; phase I ; platinum analog ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Objectives:To define the maximum tolerated dose (MTD), thetoxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods:Fourteen patients with advanced solid tumorsnot responsive to previous antitumor treatments received BBR 3464 on a daily× 5 schedule every twenty-eighth day. The drug was given as a one-hourinfusion with pre-and post-treatment hydration (500 ml in one hour) and noantiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. Amodified accelerated titration escalation design was used. Total and freeplatinum (Pt) concentrations in plasma and urine were assessed by ICP-MS ondays 1 and 5 of the first cycle. Results:Dose was escalated four times up to 0.17mg/m2/day. Short-lasting neutropenia and diarrhea of late onsetwere dose-limiting and defined the MTD at 0.12 mg/m2. Nausea andvomiting were rare, neither neuro- nor renal toxic effects were observed.BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-lifeof several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 werehigher than on day 1, indicating drug accumulation. Approximately 10%of the equivalent dose of BBR3464 (2.2%–13.4%) wasrecovered in a 24-hour urine collection. Conclusions:The higher than expected incidence of neutropenia andGI toxicity might be related to the prolonged half-life and accumulation oftotal and free Pt after daily administrations. Lack of nephrotoxicity and thelow urinary excretion support the use of the drug without hydration. Thesingle intermittent schedule has been selected for clinical development.
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  • 21
    ISSN: 1569-8041
    Schlagwort(e): interferon-α ; pharmacokinetics ; renal carcinoma ; retinoids
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Although advanced renal-cell carcinoma (RCC) responds poorly to standardtherapies, phase I–II trials have shown activity for combinations ofinterferon-α2b (IFN) with a retinoid. Alitretinoin (9-cis RA) isan endogenous retinoid with high binding affinity for both RAR and RXRreceptor families. This phase I–II study enrolled 38 patients with RCCin a dose-escalation study of tolerability, pharmacokinetics (PK), andefficacy of twice daily oral 9-cis RA with subcutaneous IFN. Incontrast to studies with similar doses of daily 9-cis RA, PK studiesfound a consistent reduction in 9-cis RA concentrations of about50% after multiple b.i.d. doses of 30 or 50 mg/m2,independent of cotreatment with IFN. In the phase I portion, toxicitiesincluded systemic symptoms typical of IFN and biochemical abnormalitiespreviously associated with retinoids. Two patients experienced dose-limitingtoxicity at 50 mg/m2 b.i.d. of 9-cis RA, thus therecommended phase II dose was 30 mg/m2 b.i.d. One of twenty-sixevaluable patients achieved a durable objective partial remission, andrepeated dosing with this regimen was poorly tolerated. This combination ofretinoid and interferon is not recommended for further study in RCC.
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  • 22
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; doxorubicin ; hepatocellular carcinoma ; liposome ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:There is lack of effective and safe chemotherapy foradvanced hepatocellular carcinoma. Polyethylene glycol-coated (pegylated)liposomal doxorubicin (PLD) has long circulation time and enhanced drugaccumulation in the tumor tissues. It has significant activity in Kaposi'ssarcoma, breast and ovarian cancers and the acute adverse effects of free drugare reduced. Patients and methods:A patient with advanced hepatocellularcarcinoma was treated with PLD and a pharmacokinetic study was performed.Initial serum total and direct bilirubin were 3.6 and 6.8 folds of uppernormal, respectively, and an indocyanine green clearance test at 15 minuteswas 26.3% (normal 〈 15%). Results:Compared to cases with normal liver function, increasedvolume of distribution of doxorubicin correlated with a large amount ofascites (P〈 0.05). The clearance of drug was unexpectedly higherthan in cases with normal liver function (P〈 0.05). According tothe pharmacokinetic studies, the disposition of PLD in this case has not beenretarded even in the presence of severe liver dysfunction. Only minimaltoxicities including grade 2 stomatitis and moderate leukopenia were observed.The tumor had a partial remission and the patient survived nine months afterPLD treatment. Conclusion:PLD could serve as a safe and effective treatment forhepatocellular carcinoma even in the presence of impaired liver function. Itsrole in treating advanced hepatocellular carcinoma is worthy of further study.
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  • 23
    ISSN: 1439-7609
    Schlagwort(e): Key words Septic arthritis ; Surface antigens ; Ultrastructure ; Burkholderia pseudomallei ; IEM
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Burkholderia pseudomallei is the causative agent of melioidosis, a disease that frequently runs a protracted course and is very difficult to eradicate. The mechanisms that this organism uses to escape from host defense mechanisms and antibiotics are not well understood. The aim of the study was to compare the morphological characteristics and surface antigen expression of B. pseudomallei in naturally infected human synovial tissues with the characteristics of bacteria grown in culture media. Immunoelectron microscopic study was performed in four synovial biopsies taken from four B. pseudomallei septic arthritis patients. Colonies of pathogenic B. pseudomallei collected from culture media were used as positive controls. Polyclonal antibody to whole cell B. pseudomallei was used as a primary antibody. Complete bacteria-like particles were demonstrated both extracellularly and intracellularly in all four synovial specimens. The intracytoplasmic location of B. pseudomallei and mononuclear phagosome containing microcolony-like structures were demonstrated. B. pseudomallei found in the synovial membrane samples were mostly atypical, with fewer cytoplasmic electron lucent granules. Immunogold staining of bacterial surface antigens was weaker than staining of positive controls. We demonstrated atypical forms of B. pseudomallei and evidence for suppression of its surface antigens in naturally infected human synovial tissues. This adaptation may help bacteria to survive despite host immune surveillance and treatment with antibiotics.
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  • 24
    Digitale Medien
    Digitale Medien
    Springer
    Mycorrhiza 10 (2000), S. 15-21 
    ISSN: 1432-1890
    Schlagwort(e): Anthoceros punctatus ; Arbuscular mycorrhiza ; Bryophytes ; Glomus ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Glomus claroideum (Schenck & Smith emend. Walker & Vestberg) were investigated for ability to form arbuscular mycorrhiza-like symbioses with the hornwort Anthoceros punctatus (L.). Spores were transferred to a cellulose acetate filter on water agar and a small portion of an Anthoceros thallus was placed directly upon the spores. Light-microscope observations 20 days after inoculation revealed branched hyphae growing within the thallus. After 45 days, arbuscules and vesicles were studied by light- and electron-microscopy. After 60 days in water agar culture, the colonised Anthoceros thalli were transferred to a low-nutrient medium agar. Hyphae spread in the agar and newly formed spores were observed 5 weeks after the transfer. After 4 months, about 1000 spores were formed in each Petri dish. This is the first report of an experimentally established arbuscular mycorrhiza-like symbiosis between an identified fungus belonging to the Glomales and a bryophyte.
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  • 25
    ISSN: 1432-5233
    Schlagwort(e): Key words Streptozotocin ; Diabetes ; Ventricular myocyte ; Cardiac muscle ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Contractile dysfunctions have been demonstrated in different experimental models of diabetes which have similar characteristics to many of the abnormalities found in the clinical setting. Administration of streptozotocin (STZ) to young adult rats induces β-cell necrosis of the pancreas which gives rise to hypoinsulinaemia and hyperglycaemia, features which are also seen in untreated type 1 clinical diabetes. We have investigated the chronic effects of STZ-induced diabetes on contraction in rat ventricular myocytes and ultrastructure of cardiac muscle. Diabetes was induced in male Wistar rats (230–270 g) with a single injection of STZ (60 mg kg−1). At 2 and 10 months after STZ treatment, the amplitude of contraction was larger in diabetic compared to control myocytes. Time to peak contraction was significantly longer at 2 months but appeared to normalise at 10 months after STZ treatment. In contrast, time to half relaxation of contraction was not significantly different after 2 months but was significantly reduced at 10 months after STZ treatment compared to control. Transmission electron microscope examination of cardiac muscle showed that the ultrastructure of cardiac muscle, especially structures associated with contraction, were not greatly altered after STZ treatment. Sarcomere lengths were not significantly different in papillary or ventricular muscle at 4 or 8 months after STZ treatment compared to control. Our data provide evidence that morphological defects in contractile myofilaments and associated structures cannot explain contractile dysfunctions seen in ventricular myocytes from STZ-treated animals.
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  • 26
    ISSN: 1615-6102
    Schlagwort(e): Arabidopsis thaliana ; Cryopreservation ; Dehydration ; Thermal analysis ; Sucrose ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Summary Arabidopsis thaliana suspension cells were preserved in liquid nitrogen for over three years, using embedding of cells in calcium-alginate prior to subculture in sucrose-enriched medium, air-drying, and direct quenching in liquid nitrogen. Survival of cells reached 34%, yielding regrowth at the surface of all cryopreserved beads in less than 7 days. Following pretreatment and dehydration, the water content dropped from 2300% to 34% with respect to dry weight. Differential scanning calorimetry showed that glass transition occurred on cooling, followed by a slight crystallization event on rewarming. The survival of cells was independent of the cooling rate. The tolerance of the acute dehydration step increased progressively with sucrose pretreatment duration, indicating the requirement for adaptative cellular alterations. Ultrastructural studies revealed several changes in cells after sucrose pretreatment prolonged from 1 to 7 days: reversal of the initially plasmolyzed state, microvacuolation, numerous autophagic structures, scarcity of ribosomes, increase in number and size of starch grains. No cell division seemed to occur during this period. After air-drying and after a freeze-thaw cycle, followed by 24 h rehydration, regenerating cells had recovered a high level of ultrastructural organization and contained numerous polysomes suggesting an intense metabolic activity. Trehalose, a cryoprotective disaccharide not considered to be a metabolic substrate, yielded only 70% regrowth after freezing. Biochemical analysis showed that soluble sugars accumulated during the pretreatment, essentially sucrose or trehalose; the monosaccharide content also increased. In the light of these results, the action of sucrose in inducing freezing tolerance is discussed.
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  • 27
    ISSN: 1615-6102
    Schlagwort(e): Beta vulgaris ; Cyst nematodes ; Histology ; Resistance mechanism ; Syncytium ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Summary Using susceptible and resistant sugar beet lines, comparative analyses of root histology and ultrastructure were made during invasion by nematodes and the induction and formation of specific feeding structures (syncytia).The resistant line carried the resistance geneHs1pro−1.Nematodes were able to invade and induce functional syncytia in roots of resistant and susceptible lines. However, syncytia in resistant roots were smaller and less hypertrophied. The vacuolar system of syncytia in susceptible plants contained many small vacuoles. In resistant plants vacuoles were larger but less numerous. Smooth endoplasmic reticulum prevailed in syncytial protoplasts of susceptible plants, whereas almost only rough endoplasmic reticulum occurred in syncytia in resistant plants. The most conspicuous and hitherto undescribed trait of syncytia in resistant roots was the initial appearance of loose, and later compact, aggregations of the endomembrane system which composed most of the endoplasmicreticulum system of syncytia at later stages. Syncytia in resistant plants usually degraded before the nematodes reached their adult stage. The appearance of membrane aggregations and the other resistance-specific features are discussed in relation to their possible effects on syncytium function and role in nematode resistance.
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  • 28
    Digitale Medien
    Digitale Medien
    Springer
    Protoplasma 211 (2000), S. 94-102 
    ISSN: 1615-6102
    Schlagwort(e): Androgenesis ; Embryogenesis ; Microspore culture ; Pollen ; Ultrastructure ; Wheat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Summary We have made a detailed cytological examination of the development of wheat embryoids, monitoring their initial divisions from two to ten cells by both light and electron microscopy. According to our observations the first embryogenic division is symmetrical. After the androgenesis induction treatment, there is a decrease in ribosome population with cells that have inactive nucleoli made up almost exclusively of a dense fibrillar component. This population is restored after initial embryogenic divisions. During the initial divisions the embryogenic pollen grains do not appear to change in size and the pollen wall remains intact. The exine undergoes no modification but the intine thickens, and we have observed that the thickness of the intine can be used as a cytological marker of androgenesis. The walls separating the cells obtained after embryogenic division contained numerous plasmodesmata. The beginnings of embryo polarization and cell differentiation could be made out in the very early pollen embryoids.
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  • 29
    Digitale Medien
    Digitale Medien
    Springer
    Investigational new drugs 18 (2000), S. 373-381 
    ISSN: 1573-0646
    Schlagwort(e): clinical pharmacology ; dihydropyrimdine dehydrogenase ; eniluracil ; oral 5-FU ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract The pharmacological inactivation of dihydropyrimidine dehydrogenase (DPD)represents one strategy to improve 5-FU therapy, which historically hasbeen associated with unpredictable pharmacological behavior andtoxicity. This is principally due to high interpatientdifferences in the activity of DPD, the enzyme that mediates theinitial and rate-limiting step in 5-FU catabolism. Byinactivating DPD and suppressing the catabolism of 5-FU,eniluracil has dramatically altered the pharmacological profileof 5-FU. The maximum tolerated dose of oral 5-FU given with oraleniluracil (1.0 to 25 mg/m2) is substantially lower thanconventional 5-FU doses. In the presence of eniluracil,bioavailability of 5-FU has increased to approximately 100%, thehalf-life is prolonged to 4 to 6 hours, and systemic clearanceis reduced 〉 20-fold to values comparable the glomerularfiltration rate (46 to 58 mL/min/m2). Renal excretion(∼ 45% to 75%), instead of DPD-related catabolism, is theprincipal route of elimination of oral 5-FU given witheniluracil. Chronic daily administration of oral 5-FU 1.0mg/m2 twice daily with eniluracil 20 mg twice dailyproduces 5-FU steady-state concentrations (8–38 ng/mL) similarto those achieved with protracted intravenous administration onclinically relevant dose-schedules. On a daily × 5regimen, higher 5-FU AUC values are related to neutropenia,whereas elevated 5-FU AUC and steady-state concentrations arerelated to diarrhea when oral 5-FU is given daily with eniluracilon a chronic schedule. The pharmacokinetic behavior of oraleniluracil is similar to that for oral 5-FU. Administration ofeniluracil 10 to 20 mg twice daily completely inactivates DPDactivity both in peripheral blood mononuclear cells and incolorectal tumor tissue, and prolonged inhibition of DPD afterdiscontinuation of eniluracil treatment has been noted. In thepresence of eniluracil, oral administration of 5-FU is feasibleand variation in 5-FU exposure is reduced, with the anticipationof further reduction in variation as dosing guidelines based onrenal function are formulated.
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  • 30
    Digitale Medien
    Digitale Medien
    Springer
    Veterinary research communications 24 (2000), S. 189-196 
    ISSN: 1573-7446
    Schlagwort(e): cattle ; dosage ; fluoroquinolone ; pefloxacin ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The disposition kinetics and urinary excretion of pefloxacin after a single intravenous administration of 5 mg/kg were investigated in crossbred calves and an appropriate dosage regimen was calculated. At 1 min after injection, the concentration of pefloxacin in the plasma was 18.95±0.892 μg/ml, which declined to 0.13±0.02 μg/ml at 10 h. The pefloxacin was rapidly distributed from the blood to the tissue compartment as shown by the high values for the initial distribution coefficient, α (12.1±1.21 h–1) and the constant for the rate of transfer of drug from the central to the peripheral compartment, K 12 (8.49±0.99 h–1). The elimination half-life and volume of distribution were 2.21±0.111 h and 1.44±0.084 L/kg, respectively. The total body clearance (ClB) and the ratio of the drug present in the peripheral to that in the central compartment (P/C ratio) were 0.454±0.026 L/kg h) and 5.52±0.519, respectively. On the basis of the pharmacokinetic parameters obtained in the present study, an appropriate intravenous dosage regimen for pefloxacin in cattle for most of the bacteria sensitive to it would be 6.4 mg/kg repeated at 12 h intervals.
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  • 31
    Digitale Medien
    Digitale Medien
    Springer
    Veterinary research communications 24 (2000), S. 245-260 
    ISSN: 1573-7446
    Schlagwort(e): anthelmintic ; antibiotic ; camel ; chemotherapy ; enzymes ; pharmacokinetics ; xenobiotic
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Recent publications dealing mainly with the kinetics of antiparasitic and antibacterial agents, NSAIDs, and other drugs in camels are briefly reviewed. The kinetic data for most of these drugs indicated that they have longer absorption and elimination half-lives and slower systemic clearance in the camel compared to other animals. This corroborates earlier reports that suggested that the activities of drug-metabolizing enzymes and the capacity to biotransform and eliminate xenobiotics is lower in camels than in other ruminants. There is a clear need to establish basic kinetic data for the camel in order to avoid extrapolation of drug dosage regimens and withdrawal times from data for other animals, as this may result in irrational use of drugs in camels.
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  • 32
    Digitale Medien
    Digitale Medien
    Springer
    Veterinary research communications 24 (2000), S. 339-348 
    ISSN: 1573-7446
    Schlagwort(e): anthelmintic ; benzimidazole ; chromatography ; enantiomer ; metabolism ; pharmacokinetics ; sex ; sheep
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Benzimidazole anthelmintic drugs are widely used in veterinary practice. Albendazole sulphoxide (ABZSO) is a benzimidazole drug with two enantiomers, as a consequence of a chiral centre in the sulphoxide group. The kinetics of these enantiomers were studied in male and female sheep. Plasma samples were obtained from the animals between 0.5 and 72 h after oral administration of 7.5 mg/kg of a racemic formulation of ABZSO (total-ABZSO). After a liquid–liquid extraction, the samples were analysed by HPLC to determine the concentrations of total-ABZSO and of the sulphone metabolite (ABZSO2). During the chromatographic analysis, the ABZSO peak was collected and reanalysed by an HPLC technique using a Chiral AGP column to quantify the enantiomeric proportion therein. After kinetic analysis, the AUCs obtained for the (+)-ABZSO were 5.8 and 4.0 times higher than those for the (–)-ABZSO in male and female animals, respectively. The mean residence times were 23.4 and 16.1 h for (+)-ABZSO and 22.2 and 17.4 h for (–)-ABZSO for male and female animals, respectively. The only significant difference between the sexes (p〈0.05) was in the T max of the (–)-ABZSO. Comparing both enantiomers within each sex, significant differences were found in all the kinetic parameters. Finally, no kinetic differences were found between sex for total-ABZSO or ABZSO2.
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  • 33
    ISSN: 1573-904X
    Schlagwort(e): allometric scaling ; interspecies scaling ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To evaluate (1) allometric scaling of systemic clearance (CL)using unbound drug concentration, (2) the potential usage of brainweight (BRW) correction in allometric scaling of both CL and oralclearance (CL/F). Methods. Human clearance was predicted allometrically (CLu = a ·Wbiv) using unbound plasma concentration for eight Parke-Daviscompounds and 29 drugs from literature sources. When the exponent bivwas higher than 0.85, BRW was incorporated into the allometricrelationship (CLu*BRW = a · Wbiv). This approach was also applied tothe prediction of CLu/F for 10 Parke-Davis compounds. Human oralt1/2, Cmax, AUC, and bioavailability were estimated based onallometrically predicted pharmacokinetic (PK) parameters. Results. Human CL and CL/F were more accurately estimated usingunbound drug concentration and the prediction was further improvedwhen BRW was incorporated into the allometric relationship. ForParke-Davis compounds, the predicted human CL and CL/F werewithin 50-200% and 50-220% of the actual values, respectively. Theestimated human oral t1/2, Cmax, and AUC were within 82-220%,56-240%, and 73-190% of the actual values for all 7 compounds,suggesting that human oral PK parameters of those drugs could bereasonably predicted from animal data. Conclusions. Results from the retrospective analysis indicate thatallometric scaling of free concentration could be applied to orallyadministered drugs to gain knowledge of drug disposition in man, and to helpdecision-making at early stages of drug development.
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  • 34
    ISSN: 1573-904X
    Schlagwort(e): pharmacokinetics ; recombinant human interleukin-11 ; absorption ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
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  • 35
    ISSN: 1573-904X
    Schlagwort(e): (R,S)-Ifosfamide ; R2-, R3-, S2-, S3-DCE-IFF ; iterative-two stage analysis ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To describe the pharmacokinetics of R- andS-Ifosfamide (IFF), and their respective 2 and 3 N-dechloroethylated (DCE)metabolites (R2-, R3-, S2, S3-DCE-IFF) in cancer patients. Methods. (R,S)-IFF was administered (1.5 g/m2)daily for 5 days in 13 cancer patients. Plasma and urine samples were collectedand analyzed using an enantioselective GC-MS method. An average of 97observations per patient were simultaneously fitted using apharmacokinetic-metabolism (PK-MB) model. A population PK analysis was performedusing an iterative 2-stage method (IT2S). Results. Auto-induction of IFF metabolism was observed over the 5day period. Increases were seen in IFF clearance (R: 4 vs 7 L/h; S: 5vs 10 L/h), and in the formation of DCE (R: 7 vs 9%; S: 14 vs 19%)and active metabolites (4-OHM-IFF; R: 71 vs 77%; S: 67 vs 71%). Anovel finding of this analysis was that the renal excretion of the DCEmetabolites was also induced. Conclusions. This population PK-MB model for (R,S)-IFF may beuseful in the optimization of patient care, and gives new insight intothe metabolism of (R,S)-IFF.
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  • 36
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 17 (2000), S. 782-787 
    ISSN: 1573-904X
    Schlagwort(e): stealth and remote loading proliposome ; doxorubicin ; pharmacokinetics ; acute toxicity ; anticancer effect
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The aim of the study was to prepare stealth and remoteloading proliposome (SRP-L) to carry doxorubicin (DXR) and evaluatethe pharmacokinetics, acute toxicity, and anticancer effect of DXRcarried with SRP-L. Methods. SRP-L was transparent solution. When SRP-L was injectedinto 0.9% NaCl aqueous solution containing DXR, liposomes formedand automatically loaded DXR (SRP-L-DXR). The long circulation ofSRP-L-DXR was evaluated using the pharmacokinetics ofSRP-L-DXR, cardiolipin liposomal DXR (CL-DXR) and free DXR (F-DXR).The acute toxicity and anticancer effect of SRP-L-DXR were evaluatedin C57BL/6 mice and murine hystocytoma M5076 tumor model. Results. The average diameter of SRP-L-DXR in pure water was112.9 ± 8.6 (nm) and the encapsulation efficiency of SRP-L-DXRwas 96.5 ± 0.2% in pure water, 95.5 ± 0.1% in 5% glucose and 98.01± 0.6% in 0.9% NaCl. The plasma concentration of SRP-L-DXR wasmuch higher than those of F-DXR and CL-DXR. Compared with thatof F-DXR, the SRP-L-DXR had lower acute toxicity and its anticancereffects depended upon the therapeutic treatment. Conclusions. A novel proliposome (SRP-L) was developed, whichcould automatically load DXR and form SRP-L-DXR with excellentcharacteristics. SRP-L-DXR had lower acute toxicity but was notalways more effective for the treatment of the ascitic M5076 thanF-DXR.
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  • 37
    ISSN: 1573-904X
    Schlagwort(e): morphine ; nociceptive effect ; electrical stimulation vocalisation method ; microdialysis ; retrodialysis by drug ; pharmacokinetics ; pharmacodynamics ; modelling ; blood-brain barrier transport
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To quantify the contribution of distributional processes across the blood-brain barrier (BBB) to the delay in antinociceptive effect of morphine in rats. Methods. Unbound morphine concentrations were monitored in venous blood and in brain extracellular fluid (ECF) using microdialysis (MD) and in arterial blood by regular sampling. Retrodialysis by drug was used for in vivo calibration of the MD probes. Morphine was infused (10 or 40 mg/kg) over 10 min intravenously. Nociception, measured by the electrical stimulation vocalisation method, and blood gas status were determined. Results. The half-life of unbound morphine in striatum was 44 min compared to 30 min in venous and arterial blood (p 〈 0.05). The BBB equilibration of morphine, expressed as the ratio of areas under the curve between striatum and venous blood, was less than unity (0.28 ± 0.09 and 0.22 ± 0.17 for 10 and 40 mg/kg), respectively, indicating active efflux of morphine across the BBB. The concentration-effect relationship exhibited a clear hysterisis with an effect delay half-life of 32 and 5 min based on arterial blood and brain ECF concentrations, respectively. Conclusions. Eighty five percent of the effect delay was caused by morphine transport across the BBB, indicating possible involvement of rate limiting mechanisms at the receptor level or distributional phenomena for the remaining effect delay of 5 min.
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  • 38
    ISSN: 1573-904X
    Schlagwort(e): bioequivalence ; dose proportionality ; mixed effects model ; pharmacokinetics ; power model
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs. Methods. Statistical estimation is used to derive a (1-α)% confidence interval (CI) for the ratio of dose-normalized, geometric mean values (Rdnm) of a pharmacokinetic variable (PK). An acceptance interval for Rdnm defining the clinically relevant, dose-proportional region is established a priori. Proportionality is declared if the CI for Rdnm is completely contained within the critical region. The approach is illustrated with mixed-effects models based on a power function of the form PK = β0 • Doseβ1; however, the logic holds for other functional forms. Results. It was observed that the dose-proportional region delineated by a power model depends only on the dose ratio. Furthermore, a dose ratio (ρ1) can be calculated such that the CI lies entirely within the pre-specified critical region. A larger ratio (ρ2) may exist such that the CI lies completely outside that region. The approach supports inferences about the PK response that are not constrained to the exact dose levels studied. Conclusion. The proposed method enhances the information from a clinical dose-proportionality study and helps to standardize decision rules.
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  • 39
    ISSN: 1573-904X
    Schlagwort(e): SK&F 107647 ; peptide ; pharmacokinetics ; hematore gulatory ; adenocarcinoma ; cytokines
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To describe the pharmacokinetics of SK&F 107647, a synthetichematoregulatory peptide, in healthy volunteers and in patientswith adenocarcinoma.Methods. SK&F 107647 pharmacokinetics were evaluated in 2dose-escalation studies. Volunteers received SK&F 107647 as single15-minute iv infusion doses of 1, 10, 100, 500, and 1000 μg/kg. Cancerpatients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1μg/kg once daily for 10 days. Drug concentrations were quantified in plasmaand urine of healthy volunteers and on days 1 and 10 in plasma ofcancer patients receiving the two top dose levels.Results. In volunteers, mean clearance (CL) ranged from 76.7 to 101ml/hour/kg; mean volume of distribution at steady-state (Vss)rangedfrom 175 to 268 ml/kg. Most of the administered dose was renallyexcreted as intact peptide within 24 hours postinfusion. In patients,mean CL was 57.6 ml/hour/kg, mean Vss ranged from 128 to 150ml/kg and terminal half-life from 2.1 to 3.4 hours. There was littleaccumulation of drug. In both studies, linear pharmacokinetics wasobserved. Clearance approached normal glomerular filtration rate(GFR) in volunteers and correlated with creatinine clearance incancer patients.Conclusions. SK&F 107647 exhibits linear pharmacokinetics, a smallVss, and clearance, primarily renal, approaching normal GFR.
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  • 40
    ISSN: 1573-904X
    Schlagwort(e): glycyrrhizic acid ; modeling ; enterohepatic cycling ; PBPK ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To analyze the role of the kinetics of glycyrrhizic acid (GD) in its toxicity. A physiologically-based pharmacokinetic (PBPK) model that has been developed for humans. Methods. The kinetics of GD, which is absorbed as glycyrrhetic acid (GA), were described by a human PBPK model, which is based on a rat model. After rat to human extrapolation, the model was validated on plasma concentration data after ingestion of GA and GD solutions or licorice confectionery, and an additional data derived from the literature. Observed interindividual variability in kinetics was quantified by deriving an optimal set of parameters for each individual. Results. The a-priori defined model successfully forecasted GA kinetics in humans, which is characterized by a second absorption peak in the terminal elimination phase. This peak is subscribed to enterohepatic cycling of GA metabolites. The optimized model explained most of the interindividual variance, observed in the clinical study, and adequately described data from the literature. Conclusions. Preclinical information on GD kinetics could be incorporated in the human PBPK model. Model simulations demonstrate that especially in subjects with prolonged gastrointestinal residence times, GA may accumulate after repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.
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  • 41
    ISSN: 1573-904X
    Schlagwort(e): luteinising hormone-releasing hormone (LH-RH) antagonist ; cetrorelix ; pharmacokinetics ; population PK/PD-modeling ; testosterone ; rat ; dog
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. Population models for thepharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasinghormone (LH-RH) antagonist, and the pharmacodynamic response ontestosterone production were investigated in rats and dogs. Methods. The plasma concentrations of CET and testosterone weredetermined after intravenous and subcutaneous injections. Thepopulation PK/PD-models were developed using P-PHARM software. Results. Absolute bioavailability of cetrorelix was 100% in rats and97% in dogs. In rats, the pharmacokinetics was explained by atwo-compartment model with saturable absorption, while athree-compartment model was used in dogs. Testosterone suppression in both specieswas described by a sigmoid Emax model with maximum effect (Emax)considered as total hormonal suppression. The duration of testosteronesuppression in rats was longer at higher doses. The populationelimination half-lifes after iv-dose were 3.0 h in rats and 9.3 h in dogs.Population mean estimates of IC50 were 1.39 and 1.24 ng/ml in ratsand dogs, respectively. Conclusions. A population pharmacokinetic model was developed toexplain the dissolution rate limited absorption from the injection site.The suppression of testosterone could be described by an indirectinhibitory sigmoid Emax model. In both species 1-2 ng/ml CET inplasma was necessary to suppress testosterone production.
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  • 42
    ISSN: 1573-904X
    Schlagwort(e): methylphenidate ; average bioequivalence ; individual bioequivalence ; human ; pharmacokinetics ; replicated design
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To determine the relative bioavailability of two marketed,immediate-release methylphenidate tablets. The study used a replicatedstudy design to characterize intrasubject variability, and determinebioequivalence using both average and individual bioequivalencecriteria. Methods. A replicated crossover design was employed using 20subjects. Each subject received a single 20 mg dose of the reference tableton two occasions and two doses of the test tablet on two occasions.Blood samples were obtained for 10 hr after dosing, and plasma wasassayed for methylphenidate by GC/MS. Results. The test product was more rapidly dissolved in vitro and morerapidly absorbed in vivo than the reference product. The mean Cmaxand AUC(0 − ∞) differed by 11% and 9%, respectively. Using anaverage bioequivalence criterion, the 90% confidence limits for theLn-transformed Cmax and AUC(0 − ∞), comparing the two replicatesof the test to the reference product, fell within the acceptable range of80–125%. Using an individual bioequivalence criterion the test productfailed to demonstrate equivalence in Cmax to the reference product. Conclusions. The test and reference tablets were bioequivalent usingan average bioequivalence criterion. The intrasubject variability of thegeneric product was greater and the subject-by-formulation interactionvariance was borderline high. For these reasons, the test tablets werenot individually bioequivalent to the reference tablets.
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  • 43
    ISSN: 1573-904X
    Schlagwort(e): 1,4-dihydropyridine calcium channel antagonist ; (+)-[3H]PN 200-110 ; senescence-accelerated prone mouse ; brain concentration ; pharmacokinetics ; in vivo receptor binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To characterize the in vivo specific binding andpharmacokinetics of a 1,4-dihydropyridine (DHP) calcium channel antagonist, PN200-110, in the senescent brain, using senescence-accelerated pronemice (SAMP8) and senescence-resistant mice (SAMR1). Methods. Blood, brain, and heart samples were taken periodically fromSAMR1 and SAMP8 following intravenous injection of (+)-[3H]PN200-110, and the concentration of (+)-[3H]PN 200-110 in the plasmaand tissues was determined. In addition, the in vivo specific bindingof (+)-[3H]PN 200-110 in the brains of SAMR1 and SAMP8 wasmeasured periodically after intravenous injection of the radioligand. Results. There was very little significant difference between SAMR1and SAMP8 in terms of the half-life (t1/2), total body clearance (CLtot),steady-state volume of distribution (Vdss), and AUC for the plasmaconcentration of (+)-[3H]PN 200-110 after intravenous injection ofthe radioligand. The brain concentration (AUCbrain) for (+)-[3H]PN200-110 and the brain/plasma AUC ratio (AUCbrain/AUCplasma) weresignificantly lower in SAMP8 than in SAMR1, and the heartconcentration (AUCheart) and the heart/plasma AUC ratio (AUCheart/AUCplasma)were similar in both strains. Also, the brain/plasma unbound AUCratio (AUCbrain/AUCplasma-free) for (+)-[3H]PN 200-110 wassignificantly lower in SAMP8 than in SAMR1. The in vivo specific binding(AUCspecific binding, maximal number of binding sites: Bmax) of(+)-[3H]PN 200-110 was significantly lower in brain particulate fractionsof SAMP8 than SAMR1. Conclusions. The concentration and in vivo specific binding of(+)-[3H]PN 200-110 was significantly reduced in the senescent brain. Thesimultaneous analysis of the concentrations of centrally acting drugsand the in vivo specific binding in the brain in relation to theirpharmacokinetics may be valuable in evaluating their CNS effects.
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  • 44
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 17 (2000), S. 903-905 
    ISSN: 1573-904X
    Schlagwort(e): P-glycoprotein ; hepatic metabolism ; pharmacokinetics ; first-pass metabolism ; drug interaction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
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  • 45
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 17 (2000), S. 127-134 
    ISSN: 1573-904X
    Schlagwort(e): in-situ head perfusion ; pharmacokinetics ; red blood cells ; water
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To develop a viable, single pass rat head perfusion modeluseful for pharmacokinetic studies. Methods. A viable rat head preparation, perfused with MOPS-bufferedRinger's solution, was developed. Radiolabelled markers (red bloodcells, water and sucrose) were injected in a bolus into the internalcarotid artery and collected from the posterior facial vein over 28minutes. The double inverse Gaussian function was used to estimatethe statistical moments of the markers. Results. The viability of the perfusion was up to one hour, with optimalperfusate being 2% bovine serum albumin at 37°C, pH 7.4. Thedistribution volumes for red blood cells, sucrose and water (from all studies,n = 18) were 1.0 ± 0.3ml, 6.4 ± 4.2ml and 18.3 ± 11.9ml, respectively.A high normalised variance for red blood cells (3.1 ± 2.0) suggestsa marked vascular heterogeneity. A higher normalised variance forwater (6.4 ± 3.3) is consistent with additional diffusive/permeabilitylimitations. Conclusions. Analysis of the physiological parameters derived fromthe moments suggested that the kinetics of the markers were consistentwith distribution throughout the head (weight 25g) rather than justthe brain (weight 2g). This model should assist in studying solutepharmacokinetics in the head.
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  • 46
    ISSN: 1573-904X
    Schlagwort(e): α1-acid glycoprotein ; protein binding ; dissociation rate ; species difference ; physiological model ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The extremely low clearance and small distribution volumeof UCN-01 in humans could be partly due to the high degree of bindingto hAGP (1,2). The quantitative effects of hAGP on the pharmacokineticsof UCN-01 at several levels of hAGP and UCN-01 were estimatedin rats given an infusion of hAGP to mimic the clinical situation anda physiological model for analysis was developed. Methods. The plasma concentrations of UCN-01 (72.5–7250 nmol/kgiv) in rats given an infusion of hAGP, 15 or 150 nmol/h/kg, weremeasured by HPLC. Pharmacokinetic analysis under conditionsassuming rapid equilibrium of protein binding and incorporating thedissociation rate was conducted. Results. The Vdss and CLtot of UCN-01 (725 nmol/kg iv) in ratsgiven an infusion of hAGP, 150 nmol/h/kg, fell to about 1/250 and 1/700that in control rats. The Vdss and CLtot following 72.5–7250nmol/kg UCN-01 to rats given 150 nmol/h/kg hAGP were 63.9–688ml/kg and 3.18–32.9 ml/h/kg, respectively, indicating non-linearitydue to saturation of UCN-01 binding. The CLtot estimated by thephysiological model assuming rapid equilibrium of UCN-01 bindingto hAGP, was six times higher than the observed value while the CLtotestimated by the model incorporating koff, measured using DCC, wascomparable with the observed value. Conclusions. These results suggest that the slow dissociation ofUCN-01 from hAGP limits its disposition and elimination.
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  • 47
    ISSN: 1573-904X
    Schlagwort(e): IVIVC ; racemate ; enantiomers ; metoprolol ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To investigate the ability of an IVIVC developedwith a racemate drug as well as each enantiomer in predicting the invivo enantiomer drug performance. Methods. Dissolution of metoprolol extended releasetablets with different release characteristics (e.g., fast (F),moderate (M), and slow (S)) was performed using USP ApparatusI, pH 1.2, 50 rpm. Metoprolol racemate tablets (S, M, and F, 100 mg) and 50mg oral solution were administered to healthy volunteers, blood samples werecollected over 24 (solution) and 48 (tablet) hours and assayed. IVIVC modelsdeveloped were: (1) Racemate-fraction of drug dissolved (FRD) vsRacemate-fraction of drug absorbed (FRA), (2) R-FRD vs R-FRA, and (3) S-FRDvs S-FRA for combinations of formulations (S/M/F, S/M, S/F, and M/F).Enantiomer Cmax and AUC prediction errors (PEs) were estimated for modelevaluation after convolution of in vivo release rates. Results. The R-IVIVC and S-IVIVC accurately predicted theR- and S-metoprolol pharmacokinetic profiles, respectively. The averagedprediciton errors (PE) for the enantiomer Cmax and AUC were less than10% for S/M/F, M/F, and S/F IVIVC models. Racemate-IVIVC (M/F) wasable to predict S-enantiomer with an average %PE of 2.52 for S-Cmaxand 4.3 for S-AUC. However, the racemate-IVIVC was unable to predict theR-enantiomer pharmacokinetic profile. Conclusions. Metoprolol racemate data cannot be used toaccurately predict R-enantiomer drug concentrations. However, the racematedata was predictive of the active stereoisomer.
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  • 48
    ISSN: 1615-6102
    Schlagwort(e): Glutathione ; Root ; Chromosomal aberration ; Ultrastructure ; Picea abies
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Summary Young spruce seedlings (Picea abies [L.] Karst.) grown in hydroponic culture were exposed to three different concentrations (50,100, and 500 μM) of reduced glutathione for 24 h. These physiologically relevant concentrations of glutathione had a multiple effect on the investigated tissue. Feeding of glutathione to roots increased the concentrations of thiols (glutathione, cysteine, and γ-glutamyl-cysteine) in roots, decreased the rate of cell divisions, induced mitotic abnormalities, and affected the cell ultrastructure. Electron micrographs showed effects such as advanced vacuolation, dilated rough-endoplasmic-reticulum cisternae, and separations of the plasma membrane from the cell wall.
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  • 49
    Digitale Medien
    Digitale Medien
    Springer
    Fish physiology and biochemistry 23 (2000), S. 225-232 
    ISSN: 1573-5168
    Schlagwort(e): methylisoborneol ; catfish ; cytochrome P450 ; biotransformation ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Abstract 2-Methylisoborneol (MIB) and structurally related terpenoid compounds are responsible for millions of dollars of lost revenue to catfish farmers. In an attempt to determine enzymatic pathways of biotransformation and elimination of MIB, the in vitro metabolism of MIB was examined in the Ulvade strain of channel catfish (Ictalurus punctatus). Although cytochrome P450 (CYP) activities were observed and correlated with expression of specific isoforms (i.e. steroid hydroxylation and CYP3A expression), no metabolites of MIB were observed. To determine whether extrahepatic biotransformation may be occurring the in vivo metabolism and disposition of 14C-MIB was examined in Uvalde, USDA-103 channel catfish, and a channel catfish X blue catfish (Ictalurus furcatus) hybrid species. Confirming in vitro hepatic studies, no metabolites were observed in plasma from animals treated with an intra-arterial dose of 14C-MIB. 14C-MIB elimination was predicted using a two compartment model in each strain of fish. There was no significant difference in terminal half-lives between strains but possible differences in total body clearance and apparent volumes of distribution which may be related to higher lipid content in the hybrids. Results of these studies indicate biotransformation has no involvement in MIB elimination and that other physiological processes may play a more significant role in MIB disposition within Ictalurid fish species.
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  • 50
    ISSN: 1573-7217
    Schlagwort(e): breast cancer ; 5-fluorouracil ; methotrexate ; pharmacodynamics ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract A novel approach is described to simulate effect site pharmacodynamics of anticancer drugs. This approach is based on (i) the in vivo measurement of unbound, interstitial drug pharmacokinetics (PK) in solid tumor lesions in patients and (ii) a subsequent pharmacodynamic (PD) simulation of the time versus drug concentration profile in an in vitro setting. For this purpose, breast cancer cells (MCF-7) were exposed in vitro to the time versus interstitial tumor concentration profiles of 5-fluorouracil (5-FU) and methotrexate (MTX) from primary breast cancer lesions in patients. This led to a maximal reduction in the viable cell count of 69 on day 4, and of 71 on day 7 for 5-FU and MTX, respectively. This effect was dependent on the initial cell count and was characterized by a high interindividual variability. For 5-FU there was a significant correlation between the maximum antitumor effect and the intratumoral AUC (r = 0.82, p = 0.0005), whereas no correlation could be shown for MTX (r = 0.05, p = 0.88). We conclude, that the in-vivo-PK / in-vitro-PD model presented in this study may provide a rational approach for describing and predicting pharmacodynamics of cytotoxic drugs at the target site. Data derived from this approach support the concept that tumor penetration of 5-FU may be a response-limiting event, while the response to MTX may be determined by events beyond interstitial fluid kinetics.
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  • 51
    ISSN: 1573-7241
    Schlagwort(e): colesevelam hydrochloride ; bile acid sequestrant ; drug interactions ; pharmacokinetics ; digoxin ; warfarin ; quinidine ; verapamil ; metoprolol ; valproic acid
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Colesevelam hydrochloride (colesevelam) is a novel, potent, bile acid–binding agent that has been shown to lower LDL cholesterol a mean of 19% at a dose of 3.8 g/d. We studied the pharmacokinetics of colesevelam coadministered with six drugs: digoxin and warfarin, agents with narrow therapeutic indices; sustained-release verapamil and metoprolol; quinidine, an antiarrhythmic with a narrow therapeutic index; and valproic acid, an antiseizure medication. Six individual studies were single-dose, crossover, with or without a 4.5-g dose of colesevelam. Plasma levels were determined using validated analytical methods. Values for the ratio of ln[AUC(0-t)] with and without colesevelam were 107% for quinidine, 102% for valproic acid, 89% for digoxin, 102% for warfarin, 82% for verapamil, and 112% for metoprolol. Values for the ratio of ln[Cmax] with and without colesevelam were 107% for quinidine, 92% for valproic acid, 96% for digoxin, 99% for warfarin, 69% for verapamil, and 112% for metoprolol. The 90% confidence intervals for these ratios and for values of ln[AUC(0-inf)] that could be determined were within the 80–125% range, with the exception of verapamil. In this study, verapamil had great interindividual variability, with a 28-fold range in Cmax and an 11-fold range in AUC(0-t). In summary, pharmacokinetic studies with colesevelam did not show clinically significant effects on absorption of six other coadministered drugs.
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  • 52
    ISSN: 1573-2568
    Schlagwort(e): azathioprine ; 6-mercaptopurine ; gastrointestinal ; pharmacokinetics ; bioavailability ; inflammatory bowel disease
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Azathioprine (AZA) is used in the treatment of patients with refractory inflammatory bowel disease; however, its use is limited because of systemic toxicity associated with long-term use. Ileocecal delivery of AZA might be advantageous if local intestinal therapeutic effects could be provided with decreased systemic side effects. Decreased cecal systemic absorption would allow higher dosages of AZA to be administered. A two-phase study was performed to compare the systemic exposure of AZA and 6-mercaptopurine (6-MP) following administration of AZA into the stomach, jejunum, and cecum and to compare the systemic exposure to AZA and 6-MP following administration of three different dosages of AZA into the cecum. In phase I, six healthy male volunteers received three 50 mg sequential doses of AZA via an oral tube directly placed into the stomach, jejunum, and cecum, respectively. In phase II, six healthy male volunteers received three different dosages (50, 300, 600 mg of AZA) into the cecum. Plasma concentrations of AZA and 6-MP at various times were quantified and area under the plasma concentration-time curve (AUC) and mean residence time (MRT) were determined. No significant differences in the AUC of AZA were seen at the different sites. The AUC of 6-MP following administration of AZA into the jejunum (67.0 ± 30.1 ng×hr/ml) was higher compared to the stomach (39.9 ± 38.1 ng/hr/ml) and cecum (29.2 ± 10.9 ng×hr/ml). Jejunal absorption was 68% higher than absorption from the stomach and 129% higher than that of the cecum. Gastric absorption was 27% higher than that of the cecum. Increased dosages given into the cecum resulted in increased AUCs of AZA and 6-MP. The AUCs of AZA following 50, 300, and 600 mg dosages were 16.9 ± 7.4, 52.3 ± 67.2, and 132 ± 151 ng×hr/ml, respectively, and the AUCs of 6-MP were 22.2 ± 14.9, 63.4 ± 50.6, and 104 ± 115 ng×hr/ml, respectively. Systemic exposure to 6-MP is reduced following administration of AZA into the cecum, most likely secondary to reduced absorption of 6-MP from the colon. Higher dosages of AZA presented to the cecum do result in increased systemic absorption, but may still allow more drug to be administered with less toxicity than the same dose received orally.
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  • 53
    Digitale Medien
    Digitale Medien
    Springer
    Neurological sciences 21 (2000), S. S27 
    ISSN: 1590-3478
    Schlagwort(e): Key words Neuronal ceroid lipofuscinoses ; Lipopigments ; Ultrastructure ; Classification ; Genes ; Neuronal loss
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Morphological aspects of the neuronal ceroid lipofuscinoses (NCL) encompass two main features: loss of nerve cells and accumulation of autofluorescent lipopigments within cellular compartments. The former requires histology and morphometry for assessment, while the latter necessitates fluorescence microscopy, electron microscopy, and immunohistochemistry. Accumulation of lipopigments is widespread throughout the central nervous system and extracerebrally. The latter feature enables diagnosis of NCL and its clinical subtype. Loss of neurons is most pronounced in cerebral and cerebellar cortices, in early childhood forms. In subcortical grey matter and in later-onset forms, juvenile and adult NCL, reduction in neurons and possible preceding dendritic pathology may only correctly be ascertained by age-matched, controlled morphometric investigations which, to date, have not yet completely assessed subcortical neuronal damage. Presently, clinical and morphological evaluations are mandatory for genetic analysis, genetic counselling, and prenatal diagnosis, the latter often being based on combined genetic and morphological studies.
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  • 54
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 17 (2000), S. 1426-1431 
    ISSN: 1573-904X
    Schlagwort(e): eplerenone ; selective aldosterone receptor antagonist ; dog ; pharmacokinetics ; absorption
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.
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  • 55
    ISSN: 1573-904X
    Schlagwort(e): amphotericin B ; liposomes ; pharmacokinetics ; toxicokinetics ; tissue distribution ; toxicity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated. Methods. Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated. Results. Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] ≤51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma; kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues. Conclusions. Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels 〉200 μg/ml and tissue levels 〉3000 μg/g.
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  • 56
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 17 (2000), S. 1236-1242 
    ISSN: 1573-904X
    Schlagwort(e): aspergillosis ; pharmacokinetics ; amphotericin B ; biodistribution ; liposomes ; cholesterol hemisuccinate
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. This study compared the biodistribution of two amphotericin B formulations in normal and Aspergillus infected mice. Amphotericin B cholesterol hemisuccinate vesicles (ABCV) which reduces the toxicity of amphotericin B and thereby enhances its therapeutic efficacy in a murine model of aspergillosis was compared with conventional amphotericin B deoxycholate suspension (AmBDOC). Methods. ABCV (12 mg/kg wt) and AmBDOC (2 mg/kg wt) were intravenously administered to normal and A.fumigatus infected mice. The concentration of amphotericin B in plasma and other organs was determined at different time points. Results. It was observed that ABCV had a significantly different pharmacokinetic profile compared to conventional amphotericin B. In comparison to AmBDOC significantly lower levels of amphotericin B were observed in kidneys and plasma, the major target organs of toxicity. Animals receiving ABCV demonstrated high levels of amphotericin B in liver (38% retention till 48 h) and spleen (2.6% retention till 48 h) in comparison to AmBDOC (7.3% and 0.21% retention in liver and spleen respectively till 48 h). Biodistribution studies of ABCV in infected mice demonstrated that there was a moderate enhancement in levels of amphotericin B in liver, spleen, lungs and kidneys as compared to normal mice and the plasma levels were reduced. However, such observations were not made after AmBDOC administration to infected mice except for kidneys in which there was a marked increase in uptake as compared to normal mice. Conclusions. Our results suggest that prolonged retention of high concentrations of ABCV in reticuloendothelial system organs is the reason for its reduced toxicity. Enhanced localization of the drug at the infected site may lead to improvement in therapeutic efficacy.
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  • 57
    ISSN: 1573-904X
    Schlagwort(e): oral absorption ; humans ; dogs ; rats ; interspecies scale-up ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To conduct a retrospective evaluation of using dog as ananimal model to study the fraction of oral dose absorbed (F) of 43drugs in humans and to briefly discuss potential factors that mighthave contributed to the observed differences in absorption. Methods. Mean human and dog absorption data obtained under fastedstate of 43 drugs with markedly different physicochemical andpharmacological properties and with mean F values ranging from 0.015 to1.0 were obtained from the literature. Correlation of F values betweenhumans and dogs was studied. Based on the same references, additionalF data for humans and rats were also obtained for 18 drugs. Results. Among the 43 drugs studied, 22 drugs were virtuallycompletely absorbed in both dogs and humans. However, the overallcorrelation was relatively poor (r2 = 0.5123) as compared to the earlier ratvs. human study on 64 drugs (r2 = 0.975). Several drugs showed muchbetter absorption in dogs than in humans. Marked differences in thenonliner absorption profiles between the two species were found forsome drugs. Also, some drugs had much longer Tmax values andprolonged absorption in humans than in dogs that might be theoreticallypredicted. Data on 18 drugs further support great similarity in F betweenhumans and rats reported earlier from our laboratory. Conclusions. Although dog has been commonly employed as ananimal model for studying oral absorption in drug discovery anddevelopment, the present study suggests that one may need to exercise cautionin the interpretation of data obtained. Exact reasons for the observedinterspecies differences in oral absorption remain to be explored.
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  • 58
    ISSN: 1573-904X
    Schlagwort(e): benzodiazepines ; pharmacokinetics ; EEG ; operational model of agonism ; receptor binding ; muscimol-induced Cl−uptake
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. A mechanism-based model is applied to analyse adaptivechanges in the pharmacodynamics of benzodiazepines upon chronictreatment in rats. Methods. The pharmacodynamics of midazolam was studied in ratswhich received a constant rate infusion of the drug for 14 days, resultingin a steady-state concentration of 102 ± 8 ng·ml−1. Vehicle treated ratswere used as controls. Concentration-EEG effect data were analysed onbasis of the operational model of agonism. The results were comparedto data obtained in vitro in a brain synaptoneurosomal preparation. Results. The relationship between midazolam concentration and EEGeffect was non-linear. In midazolam pre-treated rats the maximum EEGeffect was reduced by 51 ± 23 μV from the original value of 109 ±15 μV in vehicle treated group. Analysis of this change on basis ofthe operational model of agonism showed that it can be explained bya change in the parameter tissue maximum (Em) rather than efficacy(τ). In the in vitro studies no changes in density, affinity or functionalityof the benzodiazepine receptor were observed. Conclusions. It is concluded that the observed changes in theconcentration-EEG effect relationship of midazolam upon chronic treatmentare unrelated to changes in benzodiazepine receptor function.
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  • 59
    ISSN: 1573-8221
    Schlagwort(e): acylprolyldipeptide ; GVS-111 ; pharmacokinetics ; blood-brain barrier permeability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Notizen: Abstract Pharmacokinetics of GVS-111, a new acylprolyldipeptide with nootropic properties and its penetration across the blood-brain barrier were studied in rats using HPLC. It was found that the dipeptide is absorbed in the gastrointestinal tract, enters the circulation, and penetrates through the blood-brain barrier in an umodified state.
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  • 60
    Digitale Medien
    Digitale Medien
    Springer
    Brain tumor pathology 17 (2000), S. 15-19 
    ISSN: 1861-387X
    Schlagwort(e): Hemangioblastoma ; Supratentorial tumor ; Immunohistochemistry ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Supratentorial hemangioblastomas are rarely seen, especially in children and adolescents. We report the case of a 17-year-old male with supratentorial hemangioblastoma. Neuroimaging demonstrated a cystic lesion within the right parietal lobe. Systemic examination revealed no abnormality. The lesion was not attached to the dura and was not associated with von Hippel-Lindau disease. It was very difficult to confirm the final diagnosis of this case, in spite of extensive examination by light microscopy, immunohistochemical studies, and electron microscopy.
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  • 61
    Digitale Medien
    Digitale Medien
    Springer
    Virchows Archiv 414 (1989), S. 113-119 
    ISSN: 1432-2307
    Schlagwort(e): Gastric mucosa ; Intestinal metaplasia ; Ciliated cell ; Ciliated metaplasia ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
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  • 62
    Digitale Medien
    Digitale Medien
    Springer
    Virchows Archiv 414 (1989), S. 459-464 
    ISSN: 1432-2307
    Schlagwort(e): Sebaceous carcinoma ; Parotid gland ; Salivary gland ; Ultrastructure ; Immunohistochemistry
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 63
    Digitale Medien
    Digitale Medien
    Springer
    Virchows Archiv 415 (1989), S. 145-149 
    ISSN: 1432-2307
    Schlagwort(e): Paracrystalline inclusion ; Microtubule ; Ciliogenesis ; Gastric ciliated cell ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 64
    ISSN: 1432-2307
    Schlagwort(e): Malignant fibrous histiocytoma ; Ultrastructure ; Enzyme histochemistry ; Immunohistochemistry ; “Fibrohistiocytoid cell”
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 65
    Digitale Medien
    Digitale Medien
    Springer
    Virchows Archiv 415 (1989), S. 21-29 
    ISSN: 1432-2307
    Schlagwort(e): Alcoholic liver disease ; Ultrastructure ; Phagocytosis ; Cell shedding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 66
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 77 (1989), S. 599-604 
    ISSN: 1432-0533
    Schlagwort(e): Neuronal inclusions ; Leigh disease ; Tropomyosin ; Actin ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 67
    ISSN: 1432-0533
    Schlagwort(e): Cerebral hypoxia ; Cerebral ischemia ; Ultrastructure ; Neocortex ; Brain isolation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
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  • 68
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 79 (1989), S. 168-175 
    ISSN: 1432-0533
    Schlagwort(e): Muscular ; Dystrophy ; Ovine ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
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  • 69
    Digitale Medien
    Digitale Medien
    Springer
    Anatomy and embryology 180 (1989), S. 175-178 
    ISSN: 1432-0568
    Schlagwort(e): Paratympanic organ ; Reciprocal synapses ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 70
    ISSN: 1432-0568
    Schlagwort(e): Cecum ; Germ-free rat ; Microflora inoculation ; Morphometry ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
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  • 71
    Digitale Medien
    Digitale Medien
    Springer
    Anatomy and embryology 179 (1989), S. 435-442 
    ISSN: 1432-0568
    Schlagwort(e): Ultrastructure ; In vitro fertilization ; Bovine ; Ova ; Cortical granules
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
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  • 72
    Digitale Medien
    Digitale Medien
    Springer
    Anatomy and embryology 179 (1989), S. 497-501 
    ISSN: 1432-0568
    Schlagwort(e): Parotid gland ; Ultrastructure ; Amylase ; Secretion ; Isoproterenol
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 73
    ISSN: 1432-0568
    Schlagwort(e): Sympathetic ganglion ; Binucleate cells ; Ultrastructure ; Feulgen staining ; Computerized image analysis ; DNA
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 74
    Digitale Medien
    Digitale Medien
    Springer
    Anatomy and embryology 179 (1989), S. 591-604 
    ISSN: 1432-0568
    Schlagwort(e): Fetus ; Membranes ; Placenta ; Green monkey ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 75
    Digitale Medien
    Digitale Medien
    Springer
    Anatomy and embryology 180 (1989), S. 103-108 
    ISSN: 1432-0568
    Schlagwort(e): Ultrastructure ; Gut ; Endocrine cells ; Testudo graeca ; Chelonia
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 76
    ISSN: 1432-0568
    Schlagwort(e): Monkey ; Ultrastructure ; Pinealocytes ; Axon terminals ; Synapses
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 77
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 78 (1989), S. 72-85 
    ISSN: 1432-0533
    Schlagwort(e): 2,4-Dithiobiuret ; Thioimidodicarbonic diamide ; Motor endplate ; Neuromuscular junction ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 78
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 79 (1989), S. 336-339 
    ISSN: 1432-0533
    Schlagwort(e): AIDS ; Cytomembranous inclusions ; Tubuloreticular inclusions ; Ultrastructure ; Peripheral nerve
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 79
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 77 (1989), S. 654-658 
    ISSN: 1432-0533
    Schlagwort(e): Melanotic neuroectodermal tumor ; Immunohistochemistry ; Ultrastructure ; Pineal origin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 80
    ISSN: 1432-0533
    Schlagwort(e): Gangliocytoma ; Ganglioglioma ; Ultrastructure ; Immunohistochemistry ; Neuroendocrine markers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 81
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 77 (1989), S. 258-266 
    ISSN: 1432-0533
    Schlagwort(e): Neurofibrillary tangles ; Alzheimer's disease ; Pick bodies ; Immunohistochemistry ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 82
    Digitale Medien
    Digitale Medien
    Springer
    Acta neuropathologica 79 (1989), S. 86-93 
    ISSN: 1432-0533
    Schlagwort(e): Primary malignant CNS lymphoma ; Ultrastructure ; Intracytoplasmic tubuloreticular, membranous structures ; Intranuclear inclusions
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 83
    Digitale Medien
    Digitale Medien
    Springer
    Archives of dermatological research 281 (1989), S. 35-39 
    ISSN: 1432-069X
    Schlagwort(e): Pseudo-Kaposi's sarcoma ; Bluefarb-Stewart syndrome ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 84
    ISSN: 1432-0428
    Schlagwort(e): Islet amyloid polypeptide ; Pancreatic islets ; B cells ; Ultrastructure ; Immunocytochemistry
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 85
    Digitale Medien
    Digitale Medien
    Springer
    Development genes and evolution 198 (1989), S. 92-102 
    ISSN: 1432-041X
    Schlagwort(e): Vitellogenesis ; Xenopus oocyte ; Yolk-platelet membrane ; Ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: 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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  • 86
    ISSN: 1432-1106
    Schlagwort(e): Calcitonin gene-related peptide (CGRP) ; Bed nucleus of the stria terminalis ; Central nucleus of the amygdala ; Ultrastructure ; Rat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 87
    Digitale Medien
    Digitale Medien
    Springer
    Experimental brain research 76 (1989), S. 12-20 
    ISSN: 1432-1106
    Schlagwort(e): Distribution ; Ultrastructure ; Biopsy ; Catecholamines ; Interneurons
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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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  • 88
    Digitale Medien
    Digitale Medien
    Springer
    Sexual plant reproduction 2 (1989), S. 154-166 
    ISSN: 1432-2145
    Schlagwort(e): Helianthus annuus ; Unfertilized ovule culture ; Parthenogenesis ; Ultrastructure ; Proembryo
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: 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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  • 89
    Digitale Medien
    Digitale Medien
    Springer
    Sexual plant reproduction 2 (1989), S. 193-198 
    ISSN: 1432-2145
    Schlagwort(e): Polymorphism ; Ultrastructure ; Pollen grains ; Canna indica L ; Tannin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: 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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  • 90
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 36 (1989), S. 165-174 
    ISSN: 1432-1041
    Schlagwort(e): diflunisal ; pharmacokinetics ; healthy volunteers ; kidney failure ; rheumatoid arthritis ; aged subjects
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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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  • 91
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 36 (1989), S. 189-194 
    ISSN: 1432-1041
    Schlagwort(e): ipratropium bromide ; radioceptor assay ; pharmacokinetics ; inhalation ; systemic administration
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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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  • 92
    ISSN: 1432-1041
    Schlagwort(e): nabumetone ; rheumatoid arthritis ; pharmacokinetics ; old patients ; NSAID
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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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  • 93
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 36 (1989), S. 291-297 
    ISSN: 1432-1041
    Schlagwort(e): paracetamol ; renal failure ; drug disposition ; polar metabolites ; cumulation ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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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  • 94
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 37 (1989), S. 257-260 
    ISSN: 1432-1041
    Schlagwort(e): nifedipine ; propranolol ; indocyanine green ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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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  • 95
    ISSN: 1432-1041
    Schlagwort(e): ramipril ; renal insufficiency ; hypertension ; pharmacokinetics ; ramiprilat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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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  • 96
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 37 (1989), S. 279-283 
    ISSN: 1432-1041
    Schlagwort(e): ketoconazole ; terbinafine ; microsomal metabolism ; caffeine ; male volunteers ; pharmacokinetics ; drug interaction ; cytochrome P-450
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 97
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 37 (1989), S. 301-303 
    ISSN: 1432-1041
    Schlagwort(e): repirinast ; theophylline ; asthma ; drug interaction ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 98
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 37 (1989), S. 309-311 
    ISSN: 1432-1041
    Schlagwort(e): pyrazinamide ; haemodialysis ; pharmacokinetics ; uraemic patients ; drug metabolites ; anti-tuberculous chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 99
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 37 (1989), S. 375-379 
    ISSN: 1432-1041
    Schlagwort(e): dihydrocodeine ; pharmacokinetics ; young/elderly patients
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 100
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 37 (1989), S. 381-385 
    ISSN: 1432-1041
    Schlagwort(e): nicardipine ; first pass effect ; pharmacokinetics ; stable isotope assay
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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