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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 14 (1997), S. 1422-1430 
    ISSN: 1573-904X
    Keywords: poly(glycolide-co-D,L-lactide) ; poly(D,L-lactide) ; granulocyte-macrophage colony-stimulating factor (GM-CSF) ; biodegradable microspheres ; pharmacokinetics ; resorbable polymer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study describes the preparation and characterization of a controlled release formulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) encapsulated in poly(glycolide-co-D,L-lactide) (PLGA) and poly(D,L-lactide) (PLA) microspheres. Methods. GM-CSF was encapsulated in PLGA/PLA microspheres by a novel silicone oil based phase separation process. Several different blends of PLGA and low molecular weight PLA were used to prepare the microspheres. The microspheres and the encapsulated GM-CSF were extensively characterized both in vitroand in vivo. Results. Steady release of GM-CSF was achieved over a period of about one week without significant 'burst' of protein from the microspheres. Analysis of microsphere degradation kinetics by gel permeation chromatography (GPC) indicated that low molecular weight PLA enhanced the degradation of the PLGA and thereby affected release kinetics. GM-CSF released from the microspheres was found to be biologically active and physically intact by bioassay and chromato-graphic analysis. Analysis of serum from mice receiving huGM-CSF indicated that the GM-CSF was biologically active and that a concentration of greater than 10 ng/mL was maintained for a period lasting at least nine days. MuGM-CSF was not detected followingin vivo administration of muGM-CSF microspheres. The tissues of mice receiving muGM-CSF microspheres were characterized by infiltration of neutrophils, and macrophages which were in significant excess of those found in mice administered with placebo controls (i.e. microspheres without GM-CSF). Conclusions. This study demonstrates the influence of formulation parameters on the encapsulation of GM-CSF in PLGA/PLA microspheres and its controlled release in biologically active form. The intense local tissue reaction in mice to muGM-CSF microspheres demonstrates the importance of the mode of delivery on the pharmacologic activity of GM-CSF.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Apoptosis 1 (1996), S. 243-246 
    ISSN: 1573-675X
    Keywords: Activation-induced cell death ; AICD ; APC ; APO-1 ; CD95 ; Fas ; FasL ; HIV ; T cells ; TNF ; TNFR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Springer seminars in immunopathology 19 (1998), S. 289-300 
    ISSN: 1432-2196
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Springer seminars in immunopathology 19 (1998), S. 289-300 
    ISSN: 1432-2196
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Conclusion The critical roles played by Fas/FasL and TNF/TNFR in AICD, peripheral T cell deletion and clonal downsizing have become increasingly apparent over the last few years. Consequently, new approaches have become possible for manipulation of T cell-mediated immune responses in either a positive or negative manner. For example, in disease states where excessive AICD involving FasL and TNF is observed there lies the possibility of intervention using specific inhibitors of these apoptotic pathways such as soluble forms of Fas and TNFR or neutralizing antibodies to TNF/TNFR or Fas/FasL interactions. Alternatively, the recent demonstration that the apoptotic pathways induced by FasL and TNF involve ICE-like caspases has revealed an opportunity to regulate apoptosis using inhibitors of this pathway. Indeed, in vivo treatment with a tripeptide inhibitor of ICE-like proteases (Z-VAD.fmk) protects mice from Fas-mediated hepatitis and death [53]. Thus, a multi-faceted approach to the treatment of depletion of T cells arising from HIV infection may in the future include not only inhibitors of viral replication but also inhibitors of host cell apoptosis. In addition, treatment of tumors that express FasL may be aided by use of an inhibitor of Fas to allow generation of an anti-tumor T cell response or, alternatively, T cells reactive with the tumor may be expanded in vitro in the presence of Fas and TNF antagonists for use in adoptive immunotherapy. In the area of transplantation biology, transfection of the tissue to be transplanted with the gene for FasL may in some cases help prevent rejection of the graft by host T cells, although recent studies have indicated that so-called “immune privilege” does not result from simple expression of FasL. Moreover, the ability to induce selective elimination of antigen-reactive T cells by immunization in immune privileged sites (ACAID) may allow for induction of tolerance to antigens implicated in autoimmune disease. Finally, the recent demonstration that monocytes may be stimulated via CD4 cross-linking or treatment with M-CSF to induce AICD in T cells raises the possibility of loading these cells with antigen to induce tolerance by adoptive immunotherapy. Again, a strategy such as this might be used for the treatment of autoimmune disease or in the prevention of allograft rejection. On a cautionary note, however, it has become clear from recent studies that we are not in a position at present to manipulate T cell-mediated immune responses at will. Several studies in which the gene for FasL was transfected into cells to induce a state of “immune privilege” produced the opposite of the predicted effect. Further understanding of the apoptotic pathways that control the expansion and survival of T cells will undoubtedly allow the development of novel strategies for treatment of infectious disease, cancer, immunodeficiency and autoimmune disease.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature America Inc.
    Nature medicine 5 (1999), S. 157-163 
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] To evaluate the utility of tumor necrosis factor–related apoptosis–inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing ...
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 60 (1996), S. 39-46 
    ISSN: 0730-2312
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: No abstract.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 373 (1995), S. 441-444 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] To address the possible role of Fas/Fas-ligand interactions in activation-induced apoptosis in T-cell hybridomas, we examined the expression of Fas and Fas-ligand in the hybridoma line Al. 1, which rapidly undergoes apoptosis following activation1'3. Al.l cells do not express cell-surface Fas ...
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 377 (1995), S. 348-351 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Resting lymph-node T cells (LNTC) from C3H/HeJ wild-type, Ipr (Fas-deficient), or gld (FasL-deficient) mice were primed for propriocidal apoptosis by concanavalin A and inter-leukin (IL)-2 treatment4'5. Dramatic cell death in wild-type LNTC was caused by crosslinking of the T-cell antigen receptor ...
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature medicine 3 (1997), S. 625-631 
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Daily treatment of mice with recombinant human Flt3 ligand (huFlt3L) results in a dramatic numerical increase in the number of dendritic cells (DCs) in vivo. Since DCs are pivotal in the induction of immune responses, we tested whether Flt3L treatment of mice challenged with a syngeneic ...
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