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  • 1
    Electronic Resource
    Electronic Resource
    Low-Molecular-Weight Heparins in Thrombosis and Cancer: Emerging Links (2004)
    Oxford, UK : Blackwell Publishing Ltd
    Cardiovascular drug reviews 22 (2004), S. 0 
    Details
    ISSN: 1527-3466
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Heparin as well as low-molecular-weight heparins (LMWHs) have polypharmacological actions at various levels. Earlier studies focused on the plasma anti-Xa and anti-IIa pharmacodynamics (PD) for the different LMWHs. Other important PD parameters for heparin and LMWHs might explain the diverse clinical impacts of this class of agents in thrombosis and beyond: the release of the vascular tissue factor pathway inhibitor (TFPI), inhibition of key matrix-degrading enzymes, and other mechanisms. There is much evidence for the key role of LMWHs in hypercoagulation in thrombosis and cancer, angiogenesis, and inflammatory disorders. Many cancer patients reportedly have a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumor growth and metastasis. Clinical trials have suggested a clinically relevant and improved efficacy of LMWHs, as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Our laboratory has demonstrated a significant role for LMWHs and for LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis; we have also seen potent inhibition of matrix-degrading enzymes by LMWHs but not by TFPI. The antiangiogenesis effect of LMWHs or non-anticoagulant LMWH derivatives was shown to be reversed by anti-TFPI. Thus, modulation of tissue factor/Vila noncoagulant activities by LMWH-releasable TFPI and the inhibitory effects on matrix-degrading enzymes beside the anticoagulant efficacy have provided an expanded clinical utility for LMWHs in angiogenesis-associated disorders, including human tumor growth and metastasis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3466.2004.tb00135.x
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  • 2
    Electronic Resource
    Electronic Resource
    Ximelagatran, the New Oral Anticoagulant: Would Warfarin Survive the Challenge? (2005)
    Oxford, UK : Blackwell Publishing Ltd
    Cardiovascular drug reviews 23 (2005), S. 0 
    Details
    ISSN: 1527-3466
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The last decade witnessed major advances in the prevention and treatment of venous as well as of arterial thrombosis. Limitations of existing anticoagulants led to the development of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor (DTI) that is given orally, without the need for close monitoring. This compound was tried in the treatment of active venous thromboembolism, and the results were encouraging. Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective trials compared ximelagatran with low molecular weight heparin or warfarin in prevention of venous thromboembolism in patients undergoing major orthopedic procedures. The results of these clinical trials are reviewed in this article. Because of certain safety concerns (increased liver enzymes, potential hepatonecrosis, and increased coronary events) ximelagatran has not yet been approved by the FDA. Additional studies may be required to address these concerns. Ximelagatran has been approved, however, by the European regulatory authorities for short-term thromboprophylaxis. The success of ximelagatran or other oral antithrombin agents would provide significant proof of the concept for the long-term use of oral antithrombins in the prevention and treatment of both arterial and venous thrombosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3466.2005.tb00176.x
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  • 3
    Electronic Resource
    Electronic Resource
    The Low Molecular Weight Heparin, Tinzaparin, in Thrombosis and Beyond (2002)
    Oxford, UK : Blackwell Publishing Ltd
    Cardiovascular drug reviews 20 (2002), S. 0 
    Details
    ISSN: 1527-3466
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Standard unfractionated heparin (UFH) has been in clinical use for over 50 years. The commercial use of low molecular weight heparins (LMWHs) began in the mid 1980s for hemodialysis and the prophylaxis of deep vein thrombosis (DVT). Initially, the clinical development of LMWHs was concentrated on the European continent. Subsequently, LMWHs were introduced in North America as well. In the initial stages of development of these drugs only nadroparin, dalteparin and enoxaparin were used. Subsequently, several other LMWHs such as ardeparin, tinzaparin, reviparin and parnaparin were introduced. LMWHs constitute a group of important medications with total sales reaching nearly 2.5 billion dollars with expanded indications reaching far beyond the initial indications for the prophylaxis of post-surgical DVT. This review highlights the pharmacology of tinzaparin. Unlike other LMWHs, tinzaparin is prepared by enzymatic hydrolysis with heparinase, while various chemical depolymerization methods are used for the synthesis of other LMWHs. As compared with the standard heparin, LMWHs have different pharmacodynamic, and pharmacokinetic properties; they also differ in clinical benefits.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3466.2002.tb00087.x
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  • 4
    Electronic Resource
    Electronic Resource
    Orally Active Isoxazoline GPIIb/IIIa Antagonists (1998)
    Oxford, UK : Blackwell Publishing Ltd
    Cardiovascular drug reviews 16 (1998), S. 0 
    Details
    ISSN: 1527-3466
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3466.1998.tb00344.x
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  • 5
    Electronic Resource
    Electronic Resource
    An improved method for the quantitation of cellular migration: Role of αvβ3 integrin in endothelial and smooth muscle cell migration (1997)
    Springer
    Methods in cell science 19 (1997), S. 179-187 
    Details
    ISSN: 1573-0603
    Keywords: αvβ3 integrin ; Smooth muscle migration ; Endothelial cell migration ; Chemotaxis ; Quantitation ; Fluorescence measurement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The present study was undertaken to develop a simple and improvedmethod for the accurate quantitation of cellular migration and to examinethe role of αvβ3 integrins in different cellular migration. Usingour newly developed micro-volume chemotaxis assay, we developed an improvedquantitative method to measure in vitro chemotaxis of smooth muscle orendothelial cells toward different extracellular matrix proteins. Theconvenience in setup and counting of migrated cells using this methodallows for large capacity screening and for various research applicationswith other cells as well. The signal. to noise ratios were in the range of10/1, along with about 10–20% intra- or inter-assayvariabilities. Using this method, we have determined that eithervitronectin at 0.4 µg/well or osteopontin at 0.4 µg/well areselective αvβ3 chemoattractants for endothelial or smooth musclecells (0.5 × 105 cells/well). Additionally, a selective αvβ3small molecule peptiddomimetic, monoclonal antibody LM609, or an anti-β3 (αvβ3/αIIβ3) anti-body, c7E3 demonstratedmaximal inhibition of cellular migration toward vitronectin or osteopontin.These data suggest the potential utility of this method in assessing therole of various mechanisms in cellular migration and also suggests the potential implication of an αvβ3 antagonist in blocking pathologicalprocesses involving endothelial or smooth muscle cell adhesion/migration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009789416463
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  • 6
    Electronic Resource
    Electronic Resource
    Rapid and quantitative in vitro measurement of cellular chemotaxis and invasion (1997)
    Springer
    Methods in cell science 19 (1997), S. 189-195 
    Details
    ISSN: 1573-0603
    Keywords: Chemotaxis ; Fluorescence measurement ; Integrin ; Invasion ; In vitro migration ; Lung tumor ; Metastasis ; Quantitation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract An in vitro, fluorimetric method for cellular chemotaxis and invasion has been developed using a commercially available, disposable, 96-well chamber. This 4–18 hour microtiter chamber assay has a number of important advantages over existing methods. It does not require prior labeling of cells or radioactivity, and is rapid, automatable and quantitative. Cells are quantitated by a novel actin-based fluorescence tag as reported previously (Methods in Cell Science 17: 263–270, 1995). Following quantitation, cells are easily detectable by fluorescence microscopy. In addition, this assay conserves reagents due to its low volumes in the upper and lower chambers. The assay has been optimized using cultured human lung cancer cells to identify inhibitors or activators of directed cell migration. The effects of antibodies to αVβ3, αVβ5, and CD44 on the chemotaxis and invasion of A549 cultured lung tumor cells are reported.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009740100534
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  • 7
    Electronic Resource
    Electronic Resource
    Identification of novel peptide antagonists for GPIIb/IIIa from a conformationally constrained phage peptide library (1992)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 14 (1992), S. 509-515 
    Details
    ISSN: 0887-3585
    Keywords: phage peptide libraries ; conformationally constrained peptides ; IIb/IIIa peotide antagonists ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Methods have recently been developed to present vast libraries of random peptides on the surface of filamentous phage. To introduce a degree of conformational constraint into random peptides, a library of hexapeptides flanked by cysteine residues (capable of forming cyclic disulfides) was constructed. This library was screened using the platelet glycoprotein, IIb/IIIa, which mediates the aggregation of platelets through binding of fibrinogen. A variety of peptides containing the sequence Arg-Gly-Asp or Lys-Gly-Asp were discovered and synthesized. The cyclic, disulfide bonded forms of the peptides bound IIb/IIIa with dissociation constants in the nanomolar range, while reduced forms or an analogue in which Ser replaced the Cys residues bound considerably less tightly. These results demonstrate the feasibility for introducing conformational constraints into random peptide libraries and also demonstrates the potential for using phage peptide libraries to discover pharmacologically active lead compounds. © 1992 Wiley-Liss, Inc.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340140411
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