❶Genetische Analyse Thrombophlebitis|Innere Medizin Grundlagen und Klinik innerer Krankheiten | Anisa Kondakçiu - m.webdesign-rahmen.de|Genetische Analyse Thrombophlebitis DEU1 - PAR-1 activation by metalloproteinase-1 (MMP-1) - Google Patents| Genetische Analyse Thrombophlebitis|Varikose und Thrombophlebitis Thomas Noppeney, Helmut Nüllen 44 Primäre Dyslipidämien. Wann ist eine genetische Analyse .|Innere Medizin in Frage Und Antwort|BROWSE BY CONTENT TYPE]
Thrombose oder Krankheiten oder Pathologien, die durch Verringerung von Plasmafibrinogen behandelbar sind. Use of a tumor necrosis factor antagonist for the manufacture of a medicament for the treatment of the following: Use according to claim 1, wherein the tumor necrosis factor antagonist is an antibody Antitumornekrosefaktor or an antigen-binding fragment Genetische Analyse Thrombophlebitis. Use according to claim 2, wherein the antibody is selected from the group consisting of a chimeric antibody or an antigen-binding fragment thereof, a humanized antibody or an antigen-binding fragment thereof, and provided with a modified surface Genetische Analyse Thrombophlebitis Use according to one of the preceding claims, wherein the tumor necrosis factor antagonist is a receptor molecule, derivative or a fragment thereof which binds to tumor necrosis factor.
Use according to claim 5, wherein the receptor molecule is selected from the group consisting of p55 tumor necrosis factor receptor, p75 tumor necrosis factor receptor or functional portions thereof, the extracellular domain of the p55 Turrlornekrosefaktor receptor, the extracellular domain of the p75 tumor necrosis factor receptora multimeric molecule of a tumor necrosis factor receptor or a functional part thereof, and an immunoreceptor fusion molecule or a functional part thereof.
Use according to claim 6, wherein the multimeric tumor necrosis factor receptor molecule all or a functional portion of two or more extracellular domains of tumor necrosis factor receptors contains that are connected to each other via one or more polypeptide linkers and the immunoreceptor fusion molecule the entire or a functional part of a including tumor necrosis factor receptor and an immunoglobulin chain.
Verwendung nach Check this out 1, wobei der Tumornekrosefaktor-Antagonist Tumornekrosefaktor-Synthese oder Tumornekrosefaktor-Freisetzung verhindert oder hemmt. Use according to claim 1, wherein the tumor necrosis factor antagonist tumor necrosis factor synthesis or tumor necrosis factor prevents or inhibits release.
Use according to claim 8, wherein the tumor necrosis factor antagonist is selected from the group consisting of a phosphodiesterase inhibitor, thalidomide, tenidap, an Genetische Analyse Thrombophlebitis adenosine receptor agonist and an A2b adenosine receptor enhancer.
Use according to claim 9, wherein the phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline and rolipram. Verwendung nach Anspruch 1, wobei der Tumornekrosefaktor-Antagonist Tumornekrosefaktor-Rezeptor-Signalisierung verhindert oder hemmt.
Use according to claim 1, wherein the tumor necrosis factor antagonist prevents tumor necrosis factor receptor signaling or inhibits. Platelets and fibrinogen play integral roles in the formation of blood clots thrombi.
Epidemiological studies have shown that elevated levels of plasma fibrinogen are associated with acute myocardial infarction, ischemic heart disease, coronary cardiac death, stroke in men, deep vein thrombosis and thrombophlebitis Trophischen ASD Bewertungen Geschwüren et al, Eur Heart J. Platelets play an important role in the development of Genetische Analyse Thrombophlebitis atherosclerotic lesions that typically coronary artery disease, aortic aneurysm, arterial disease of the lower extremities and cerebrovascular disease are based.
Zusammenfassung der Erfindung Summary of the Invention. The present invention is based on the surprising discovery that the inhibition of the biological activity of tumor necrosis factor a TNF fibrinogen and platelet Genetische Analyse Thrombophlebitis and lowers in patients with active rheumatoid arthritis.
As a result of the discovery of the applicant, the use of a tumor necrosis factor TNF chimera antibody CA2 is provided to you. Many patients with rheumatoid arthritis RA ultimately die from cardiovascular and cerebrovascular diseases.
Although other factors undoubtedly contribute to the to-observant in RA levels of cardiovascular and cerebrovascular Genetische Analyse Thrombophlebitis Wolfe et al, Arthritis Rheum. Typically, the formation of a blood clot begins with the adhesion of platelets to macromolecules in the subendothelial regions of the injured blood vessel.
The adhesion of platelets is mediated by platelet surface receptors that bind to extracellular matrix proteins in the exposed subendothelial such as von Willebrand factor, collagen, fibronectin, Genetische Analyse Thrombophlebitis and laminin. The adhesion of thrombocytes resulting in a monolayer of platelets. Then finds an activation of platelets in response to agonists such as epinephrine, adenosine diphosphate ADPcollagen and thrombin instead.
Thereafter, the platelets aggregate to form the primary hemostatic plug. The formation of подъехала Anschwellen von Krampfadern in den Beinen надеюсь fibrin clot results in reinforcement and stabilization of the Thrombozytenpfropfens at the site of vascular injury.
Under normal circumstances, blood clots serve to prevent the escape of blood cells from the vascular system, which is a desirable effect after the injury of a blood vessel. During certain disease states, however, clots can restrict blood flow or completely stop, leading to cell necrosis. The work described here clearly shows the surprising result that TNF blockade in the short Genetische Analyse Thrombophlebitis leads to normalization of fibrinogen levels in many patients and suggests that fibrinogen may be monitored or Genetische Analyse Thrombophlebitis by effective long-term TNF blockade.
Patents 5 10Davidsen SK click to see more al. Reducing Plasmafibrinogen- and platelet levels reduces the risk of developing many cardiovascular, cerebrovascular and thrombotic disorders. Thus, the formation or progression of these disorders can be prevented or slowed by Genetische Analyse Thrombophlebitis blockade of TNF.
Cardiovascular, Genetische Analyse Thrombophlebitis and thrombotic disorders can also be treated with Genetische Analyse Thrombophlebitis blockade of TNF. The present invention is directed to the use of a tumor necrosis factor antagonist in the form of a chimeric antibody CA2 for the preparation of a medicament for treating thrombosis or illnesses or pathologies treatable by decreasing plasma fibrinogen from.
Thus, as used herein, includes a a "cardiovascular disorder" acute myocardial infarction and cardiac thrombotic disorders, such as deep vein thrombosis and Genetische Analyse Thrombophlebitis. As it is used herein includes a "cerebrovascular disorder" vascular disorders, which are associated with the brain, such as stroke.
As it is used herein, a "thrombotic disorder" is a condition where thrombosis is a pathogenic component. For example, includes a "thrombotic disorder" thromboembolic disorders eg, pulmonary thromboembolism exampleischemic events eg. As transient ischemic attackstroke, acute myocardial infarction, deep vein thrombosis and thrombophlebitis one.
Die vorliegende Erfindung betrifft weiter ein Verfahren zum Verringern von Plasmafibrinogen in einem Individuum, das das Verabreichen einer therapeutisch wirksamen Menge eines TNF-Antagonisten an das Individuum umfasst.
The present invention further relates to a method for reducing plasma fibrinogen in an individual, comprising administering a therapeutically effective amount of a TNF antagonist to the individual. The TNF antagonist Genetische Analyse Thrombophlebitis with high affinity to TNF in the individual, resulting in a reduction in plasma fibrinogen in the individual. As shown in the example, leading for example, Genetische Analyse Thrombophlebitis administration of the chimeric antibody A2 cA2 to 49 patients with many of the patients to a signi ficant reduction of the plasma fibrinogen.
For example, the present invention can be used to thrombosis in pulmonary embolism, ischemic events eg. As transient ischemic attackdeep vein thrombosis, coronary bypass surgery, surgery to insert a prosthetic valve or vessel z. TNF, a pleiotropic cytokine released by activated 7 cells and macrophages, is Genetische Analyse Thrombophlebitis as a mature 17 kDa protein that is active as a trimer Smith, RA and Baglioni, C.
The TNF trimer binds the receptors on the cell surface, whereby local crosslinking of TNF receptors into clusters is caused, which are necessary for the transfer of signals. A "tumor necrosis factor antagonist", as it is used herein, reduced, blocked, inhibited, abrogates or interferes with TNF activity in vivo. Anti-TNF antibodies include thereof a monoclonal, chimeric, humanized, provided with modified surface engl.: The usable in the present invention, antibodies are characterized by their ability to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity.
An example of a monoclonal antibody with high affinity, is the mouse monoclonal antibody mAb A2 and antibodies which competitively inhibit the binding to Genetische Analyse Thrombophlebitis TNF of anti-TNF-MausmAb-A2 in vivo, or an antibody having substantially the has the same specific binding characteristics, as well as fragments and regions thereof.
Published on October 1, A second example of a monoclonal antibody with high affinity, is murine mAb and antibodies which competitively inhibit the binding to human TNF of anti-TNF-mouse in vivo, or an antibody which Genetische Analyse Thrombophlebitis the same specific binding characteristics substantially as as fragments Genetische Analyse Thrombophlebitis regions Genetische Analyse Thrombophlebitis. Other monoclonal antibodies having high affinity, which are useful in the methods of the present invention include murine mAb and murine mAb and antibodies which competitively in vivo the binding to human TNF of anti-TNF murine mAb or inhibit Genetische Analyse Thrombophlebitis or an antibody having the same specific binding characteristics of mAb or mAbin essence, as well as fragments and regions thereof.
Additional examples of monoclonal anti-TNF antibodies are described in the art see. Moller, et al, Cytokine 2: Chimeric antibodies are immunoglobulin molecules characterized by two or more segments or portions derived from different animal species. Generally, the variable region of a chimeric antibody is derived from a non-human mammalian antibody, such as a ist Krampfadern, oberflächliche was es Genetische Analyse Thrombophlebitis, and the immunoglobulin constant region is derived from a human immunoglobulin molecule.
Preferably, a variable region with low immunogenicity is selected and combined with a human constant Genetische Analyse Thrombophlebitis which also has low immunogenicity, the combination also preferably having low immunogenicity.
Just as you used herein, the term "chimeric antibodies" a monovalent, divalent or polyvalent immunoglobulins. A monovalent chimeric antibody is a dimer HL formed by a chimeric H Genetische Analyse Thrombophlebitis associated through disulfide bridges with a chimeric L chain.
A divalent chimeric antibody is a tetramer H2L2 formed by two HL dimers associated through at least one source bond with each other. A polyvalent chimeric antibody Genetische Analyse Thrombophlebitis be produced, for example, by using a CH region that aggregates eg. A chimeric L chain comprises an antigen binding region derived from the L chain of a non-human antibody specific for TNF that is linked to at least a portion of a human L chain C region CL is.
Juni ; Published June 11, ; Morrison et al. Mai ; Published May 7, ; Liu et al. The check this out also includes a fragment or a derivative of such an antibody, such as one or more portions of the antibody chain, such as constant or variable regions of the heavy chain constant or variable regions, or the light chain.
Humanization and oversight of the antibody with a modified surface Engl.: Winter See, eg, B. Winter US Patent Nr. EPA1 EP And Pedersen et al. Such antibodies and chimeric antibodies can include those generated by immunization using gerei nigtem recombinant TNF or peptide fragments thereof which have one or more epitopes, that. An example of such a chimeric antibody is cA2 and antibodies which competitively inhibit in vivo the binding to human TNF of anti-TNF murine mAb A2, chimeric mAb cA2, or an antibody which has the same specific binding Pilz gegen Krampfadern Creme substantially as as fragments and regions thereof.
Knight, DM et al. Chimeric A2 anti-TNF consists of the antigen binding variable region Genetische Analyse Thrombophlebitis neutralizing with high affinity mouse anti-human TNF IgG1 antibody, designated A2, and the constant regions of a human IgG1, kappa immunoglobulin.
The avidity and epitope specificity of the chimeric A2 is derived from the variable region of the murine A2. Chimeric A2 neutralizes the cytotoxic effect of both natural, such as recombinant human TNF in a Genetische Analyse Thrombophlebitis dependent manner. As it is used herein, it refers to the term "antigen binding region" refers to that portion of an antibody molecule which contains the Genetische Analyse Thrombophlebitis acid residues that interact with an antigen visit web page the antibody confers its specificity and affinity for the antigen.
The antibody region includes the "framework" amino acid residues necessary to obtain or maintain the proper conformation of the antigen-binding residues.
Im Allgemeinen stammt die Antigen-bindende Region von der Maus. In general, the antigen-binding region derived from the mouse. In other embodiments, the antigen-binding region may be derived from other species, such as Genetische Analyse Thrombophlebitis, rabbit, rat or hamster.
Preferred sources for the DNA encoding such a non-human antibody include cell lines which produce antibody, preferably hybrid cell lines commonly known as hybridomas. In one embodiment, the preferred hybridoma is the A2 hybridoma Genetische Analyse Thrombophlebitis. An "antigen" is a molecule or a portion of a molecule which is capable of being bound by an antibody and which is additionally capable of inducing an animal to produce an antibody that is capable Genetische Analyse Thrombophlebitis selectively to bind to an epitope of that antigen.
Ein Antigen kann ein oder mehrere Epitope aufweisen. An antigen Genetische Analyse Thrombophlebitis have one or more epitopes. The term "epitope" is meant to refer to that portion of the antigen that can be recognized by an antibody and bound by an antibody at one or more antigen-binding regions of the antibody.
Epitopes usually Genetische Analyse Thrombophlebitis of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics, as well as specific charge characteristics.
Epitopes of TNF have been within amino acids 1 to about 20, about Genetische Analyse Thrombophlebitis to about 77 identifies, from about to about and about to about Preferably, the antibody binds to an epitope containing at least 5 amino acids of TNF within TNF residues from about 87 to aboutabout 59 to Genetische Analyse Thrombophlebitis 80 or a combination thereof.
Generally, epitopes include at least about 5 amino acids and less than about 22 amino acids, which include or overlap one or more of these regions. J Biol Chem The preparation of antibodies using hybridomas The techniques for preparing antibodies to small peptide sequences that Genetische Analyse Thrombophlebitis sequences in the free or conjugated form or when they are presented as a native sequence in the context of a large protein recognize and bind, are Stand well known to the art.
Such antibodies can be produced by hybridoma or recombinant techniques known in the art. Die Zellfusionen werden durch Standardverfahren erreicht, die Fachleuten auf dem Gebiet der Immunologie gut bekannt sind. The cell fusions are accomplished by standard procedures, those skilled in the field of immunology are well known.