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Agent which substantially inhibits a protease-activated receptor 1 PAR-1 signaling activity of a patient, the 39 D39 and proline at position 40 P40 caused by the proteolytic cleavage of PAR-1 between aspartic acid at positionfor use in the treatment of thrombotic disease state or atherosclerosis in a patient, which comprises administering a therapeutically effective amount of the drug to the patient, in which a thrombotic disease state Hand Thrombophlebitis nach intravenösen Linien atherosclerosis has been diagnosed or substantial risk of the same to develop.

The present invention relates to the diagnosis and treatment of thrombotic conditions including those which are caused by acute coronary syndrome, and atherosclerosis.

Moreover, the invention relates to means for preserving platelets for research Hand Thrombophlebitis nach intravenösen Linien clinical purposes. Die Regierung besitzt bestimmte Rechte an der vorliegenden Erfindung.

The Government has certain rights in this invention. Although platelet activation and aggregation are necessary for normal physiological functions such as hemostasis, but can countless, often lethal or cause highly stressful conditions and pathologies if withhold their control mechanisms.

These pathological conditions can be acute or chronic and include acute coronary syndrome, myocardial infarction, unstable angina, stroke, coronary thrombosis, venous thrombosis, atherothrombosis, restenosis, and so on. In the United States, Europe and other developed countries of myocardial infarction due to rupture of atherosclerotic plaques leading share of morbidity and mortality has. Acute plaque rupture exposed subendothelial collagen, which promotes platelet activation and formation of a potentially occlusive thrombus at the site of vascular damage Glass and Witztum, ; Ruggeri, Following its initial connection to subendothelial collagen and matrix proteins of the transitory activation of adhered platelets by autocrine mediators is Krampfadern Strümpfe von der Operation for the propagation of the formative platelet thrombus.

An enhancement of the transient adhesive contacts by activating a G protein-dependent shape change, release of granules and of integrins allows the growth of a stable thrombus which is resistant to the high shear-stress of the arterial blood flow Jackson et al. Drugs that target the secondary autocrine mediators of platelet thrombus formation, such as aspirin and thienopyridines have proven useful, but many patients taking these agents suffer, yet thrombotic events and could therefore benefit from new drugs, the matrix dependent platelet activation hinder Bhatt and Topol, Two separate paths act in parallel with the activation of platelets during the hemostasis Furie and Furie, With the breakdown of the blood vessel wall Hand Thrombophlebitis nach intravenösen Linien in the blood circulating platelets for the first time on collagen, which is embedded in the subendothelial matrix.

As the first line of defense exposed collagen initiated the accumulation and activation of platelets and begins with the formation of a thrombus. With the further outflow of blood it encounters a second line of defense, tissue factor contained in the median layer and the Krampfadern in den Genital Lippen zu Caesar layer of the vessel wall, and a Hand Thrombophlebitis nach intravenösen Linien independent path is triggered, the also activated platelets to adhere to each other and to the share of the resulting thrombus.

The initiated by tissue factor pathway generates thrombin which cleaves in turn, the protease activated receptor 1 PAR1 on the surface of human platelets so as to adenosine diphosphate ADPserotonin, and thromboxane A release.

These agonists recruit and in turn activate other platelets, whereby the signal is amplified in order to block the opening in the vessel wall. However, the present invention is based on discoveries relating to the other, initiated by collagen pathway of platelet activation, ie on the first line of defense for a thrombotic event.

Matrix metalloproteinases MMPs have been shown to be important mediators of platelet function and vascular biology lately. They were initially described as enzymes for remodeling of the extracellular matrix, which are involved in tissue repair and cancer invasion Egeblad and Werb,as are MMPs and related metalloprotease disintegrins today because of their important role in the vascular wall inflammation Dollery and Libby, and thrombotic thrombocytopenic purpura in focus Levy et al.

Hand Thrombophlebitis nach intravenösen Linien has been shown that endogenous platelet metalloproteases damage the platelet function by cleavage of the cell surface receptors Krampfadern schwangeren wie man bei behandeln broad-spectrum metalloprotease improve posttransfusion recovery of platelet concentrates Berg Meier et al. Galt et al, ; Kazes et al. In particular endogenous MMP-1 and MMP-2 can actually encourage platelet aggregation, but are the or the cell surface target s and not yet clarified the mechanism of activation Galt et al.

In a recent study of the effects of MMP-1 promoter polymorphisms at patients in patients with haplotypes with high promoter activities a significantly increased risk of myocardial infarction and found in patients with haplotypes with lower promoter activities a significantly reduced risk of myocardial infarction Pearce et al. In more recent times that the G protein-coupled receptor is directly cleaved PAR1 on the surface of cancer cells by fibroblast-derived MMP-1 and activates it has been shown Boire et al.

PAR1 is the main thrombin receptor from human platelets Coughlin. Among the pathophysiological conditions of acute plaque rupture, however, exposed collagen is the most efficient stimulus for the critical early events of platelet recruitment and -propagation under arterial flow, whereby a metalloprotease activation on the platelet surface could result. The present invention is based on a novel metalloprotease-dependent pathway of platelet thrombogenesis by PAR1. Exposure of platelets to collagen via caused an activation of MMP-1, the split directly on the surface of platelets in turn PAR1.

Surprisingly, MMP-1 cleaved the N-terminal extracellular domain of PAR1 at a position separated from Hand Thrombophlebitis nach intravenösen Linien thrombin cleavage site location.

This cleavage event generated a longer tethered peptide ligand, which was an agonist of platelet activation and PAR1 signaling. Blocking of MMP1 PAR1 pathway inhibited physiological events such as collagen-dependent thrombogenic, arterial thrombosis and clot retraction.

Dementsprechend stellt die vorliegende Erfindung Verfahren und Therapeutika bereit, die auf dieses Metalloprotease-Rezeptorsystem bei der Behandlung von Patienten abzielen, bei denen ein thrombotischer Erkrankungszustand wie etwa akute Koronarsyndrome diagnostiziert wurde oder ein Risiko der Entwicklung desselben besteht. Accordingly, the present invention provides methods and therapeutic agents provides that target this http://m.lonau-harz.de/krampfadern-behandlung-in-chelyabinsk.php system in the treatment of patients in which a thrombotic disease condition such as acute coronary syndromes has been diagnosed or there is a risk of developing the same.

In one aspect, the invention provides a method for treating a patient in which a thrombotic disease condition has been diagnosed or is of the same a significant risk of development, by administering a therapeutically effective amount of an Hand Thrombophlebitis nach intravenösen Linien ingredient before, the proteolytic cleavage between aspartic acid at position Hand Thrombophlebitis nach intravenösen Linien D39 and proline at position 40 P40 of the protease-activated receptor 1 PAR-1 of the patient substantially inhibited.

The proteolytic cleavage may require enzymatic activity by matrix metalloprotease-1 MMP The patient may have one or Hand Thrombophlebitis nach intravenösen Linien symptoms or have exhibited such as chest pain, shortness of breath, tightness around the chest, tightness in the left arm, tightness in the left mandibular angle, excessive sweating, nausea, vomiting, palpitations, anxiety or atypical feeling.

Der Patient kann einen oder mehrere nachweisbare oder diagnostizierbare Risikofaktoren im Zusammenhang mit einem thrombotischen Erkrankungszustand aufweisen. The patient may have one or more detectable or diagnosable risk factors associated with a thrombotic disease state. A thrombotic disease state can be any induced platelet aggregation pathology, including but not limited to, acute coronary syndrome, arterial thrombosis, venous thrombosis, peripheral arterial disease, unstable angina, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral Hand Thrombophlebitis nach intravenösen Linien thrombosis, cerebral embolism, kidney embolism or pulmonary embolism.

Hand Thrombophlebitis nach intravenösen Linien one embodiment, the inventive method for treating a patient diagnosed with cancer is used. According to one feature, the administration of the drug inhibits much platelet Hand Thrombophlebitis nach intravenösen Linien in a patient. The active substance may be a ligand binding molecule that binds to PAR-1, the cleavage of PAR-1 by binding to the cleavage site substantially inhibited, or the cleavage of PAR-1 by inducing a conformational change in PAR-1 significantly inhibited.

Furthermore, the inventive method Hand Thrombophlebitis nach intravenösen Linien for administering to a patient a second active ingredient which is substantially at least one of thromboxane and ADP-signaling pathways in the platelets of the patient, at least a portion of the enzymatic activity of PAR1 or the thrombin-dependent activation of PAR1 inhibited.

The second active ingredient complements the first active ingredient z. Furthermore, the method provides for the administration of a second Antithrombotic Agent, comprising anti-platelet drug, anticoagulant drug or thrombolytic drugs. In a further embodiment, the second active ingredient, aspirin, clopidogrel, ticlopidine, Prasugrel, heparin, abciximab, eptifibatide, tirofiban and bivalirudin may be.

Furthermore, the method provides for the administration of the drug by intravenous iv injection, subcutaneous injection, intramuscular injection, oral ingestion, nasal, topical, rectal, vaginal or parenteral recording.

The active ingredient may be formulated with a pharmaceutically acceptable adjuvant, carrier or diluent. In a second aspect the invention provides a method of treating a thrombotic disease state in a patient by administering to a patient in which a thrombotic disease condition Hand Thrombophlebitis nach intravenösen Linien been diagnosed or is of the same a substantial risk of developing, a therapeutically effective amount of an active ingredient is administered, the Hand Thrombophlebitis nach intravenösen Linien receptor 1 PAR-1 signaling activity of the patient significantly inhibited the D39and proline Hand Thrombophlebitis nach intravenösen Linien position 40 P40 is generated 39 by the proteolytic cleavage of PAR-1 between aspartic Creme zur Vorbeugung mit Rosskastanie at position.

In one embodiment, the active ingredient comprises SCH In a third aspect the invention provides a method for treating a patient in which a thrombotic disease condition has been diagnosed or is of the same a significant risk of development, by administering a therapeutically effective amount of an active ingredient before, the activation of matrix metalloprotease 1 Read more or MMP-1 enzymatic activity substantially inhibited.

In a fourth aspect, the click to see more provides a method for treating a patient diagnosed with atherosclerosis or a substantial risk of development thereof, by administering a therapeutically Hand Thrombophlebitis nach intravenösen Linien amount of an active ingredient before, the proteolytic cleavage between aspartic acid at position 39 Hand Thrombophlebitis nach intravenösen Linien and proline at position 40 P40 of the protease-activated receptor 1 significantly inhibited PAR-1 of the patient.

The active ingredient can be administered after being made to the patient an angioplasty procedure, a coronary artery bypass or open heart surgery, but preferably for no more than two weeks. In a fifth aspect, the invention provides a method for treating atherosclerosis by administering to a patient diagnosed with atherosclerosis or a substantial risk of the development thereof, a therapeutically effective amount of an active ingredient is administered, the protease-activated receptor PAR-1 signaling activity of the patient significantly inhibited, source is caused by proteolytic cleavage of PAR-1 between aspartic acid at position 39 D39 and proline at position 40 P In one aspect, the drug reduced the size of atherosclerotic plaque in the aorta of the patient.

In a sixth aspect, the invention provides a method for treating a patient diagnosed with atherosclerosis or a substantial risk of development thereof, by administering a therapeutically effective amount of an active ingredient before, the activation of matrix metalloprotease-1 MMP 1 or MMP-1 enzymatic activity substantially inhibited.

In another aspect, the invention also provides a medium for platelet storage as well as platelet transport with an effective concentration of an active ingredient a proteolytic cleavage between aspartic acid at position 39 D39 and proline at position 40 P40 of protease-activated receptor-1 PAR-1 on platelets contained therein substantially inhibited.

The medium can be an aqueous solution further containing glucose, and the average half-life of a normal wafer contained therein is not less than about 5 days or 1 month or 6 months. The medium may comprise an effective concentration of an agent that inhibits activation of matrix metalloprotease-1 MMP-1 or MMP-1 enzymatic activity.

In another aspect, the invention provides a medium for platelet storage as well as platelet transport before, wherein the medium has an effective concentration of a drug, a protease-activated receptor 1 PAR-1 significantly inhibited signaling activity by proteolytic cleavage PAR-1 at position 39 between aspartic acid D39 and proline at position 40 P40 is produced.

In still another aspect, the invention provides a method for diagnosing a risk of suffering a hemorrhagic event in a patient by determining the ready whether the patient has a genetic defect that the activation of matrix metalloprotease-1 MMP-1 or MMP-1 activity in the patient substantially inhibited. In a further aspect the invention provides a method of diagnosing a hemophiliac or coagulopathic condition or a risk thereof in a patient by determining whether the patient has a genetic defect that the activation of matrix metalloprotease-1 MMP-1 overstimulated or MMP-1 enzymatic activity in the patient.

Furthermore, the invention provides an isolated polypeptide having a sequence prepared comprising not less than 5 contiguous amino acid residues of the two fragments by a proteolytic cleavage between aspartic acid at position 39 D39 and proline at position 40 P40 of human protease activated receptor-1 PAR-1 polypeptide arise which terminates at one end with a cleavage site that would be created by the proteolytic cleavage.

The polypeptide of the invention may have a proline at its N-terminus and z. Moreover, the invention provides a method for diagnosing a thrombotic disease state in a patient by measuring the amount of the polypeptide of the invention in platelets from a patient. In another aspect, a method for identifying a PAR-1 antagonist is disclosed comprising the steps of: In one aspect, the invention discloses a medical device that is coated with a matrix layer comprising an active ingredient which proteolytic cleavage between aspartic acid at position 39 D39 and proline at position 40 P40 of the protease-activated receptor 1 PAR 1 of the patient substantially inhibited.

In another aspect, the invention discloses a medical device that is coated with a matrix layer comprising an active substance, the protease-activated receptor 1 PAR-1 signaling activity significantly inhibited by proteolytic cleavage of PAR-1 is caused between aspartic acid at position 39 D39 and proline at position 40 P Die Matrixschicht kann eine biokompatible Peptidmatrix sein.

The matrix layer may be a biocompatible peptide matrix. Die medizinische Vorrichtung kann implantierbar sein. The medical device may be implantable. The embodiments described above have many advantages, including methods for finding and delivering active agents which inhibit MMPmediated PAR-1 signaling pathway. Die vorliegend offenbarten Verfahren, Zusammensetzungen und Kits sind daher besonders sinnvoll bei der Behandlung von Patienten, bei denen ein thrombotischer Erkrankungszustand diagnostiziert wurde oder ein Risiko der Entwicklung desselben besteht.

The presently disclosed methods, compositions and kits are particularly useful in the treatment of patients in whom thrombotic disease condition has been diagnosed or there is the same risk of development.

It should be noted that the present application is not limited to the disclosed embodiments in this summary and is also in the frame of action of ordinary skill and is intended to include defined by the claims modifications and variations. The upper block are photographs, after 90 minutes of incubation and the lower block such after minutes. Unless otherwise defined, all terms used herein and scientific terms have the usual meaning by specialists.

The Hand Thrombophlebitis nach intravenösen Linien definitions are provided to facilitate understanding of the disclosure and claims of the present application. Unless a definition Hand Thrombophlebitis nach intravenösen Linien this section does not match elsewhere made definitions set out in this section definition applies.

As used herein, the terms "administration" refer to "administer", more info the like, as far as they are used in connection with the administration of a pharmaceutical or nutritional composition to a subject, generally a administration of one or more pharmaceutical compositions comprising the active ingredient, e.

As non-limiting examples, a composition may be by parenteral, subcutaneous, intravenous, intracoronary, rectally, intramuscular, intraperitoneal, Hand Thrombophlebitis nach intravenösen Linien, or be administered via buccal supply paths. In one embodiment, the "administration" of the drug, such. As an agonist or antagonist of the MMPmediated PAR-1 signaling pathway, a controlled release may be required to the patient, ie, the release of the active ingredient from the formulation to sustained and controlled manner over a longer period of time than an immediately released formulation containing the same amount of the active ingredient, during the same period would release.

As used herein, an "agonist" refers to any natural or synthetic molecule or just such molecule combination, the or the one biological activity Hand Thrombophlebitis nach intravenösen Linien at least or at least about 2 times, about 3 times, about 4 times, about the 5 times, about 7 times, about 10 times, about 20 times, about 50 times or about times or more increases, in a standard bioassay or in vivo or, when used in therapeutically effective dose.

In one embodiment, an "agonist" refers to any natural or synthetic molecule, or any molecule just such combination that activates or an MMPmediated PAR-1 signaling. In one embodiment, an "antagonist" or "inhibitor" means any natural or synthetic molecule, or any combination of just such molecule, which hinders or the MMPmediated PAR-1 activity, respectively. In a further embodiment, an "antagonist" or "inhibitor" means any natural or synthetic molecule, or any combination of just such molecule, which hinders or Hand Thrombophlebitis nach intravenösen Linien MMPmediated PAR-1 activation, respectively.

An "agonist" or "antagonist" compound may comprise one or more protecting groups according to the present use, which prevent undesirable reactions such as proteolysis in connection with the unprotected groups.

In one embodiment, it is contemplated by the present invention that the protective group is an acyl or an amide. In one embodiment, the acyl is acetate. In another embodiment, the protecting group is a benzyl group. In another embodiment, the protecting group is a benzoyl group.

Also combinations of such protective groups are contemplated by the present invention. Non-limiting examples of anticoagulants that are useful in the present invention, for example, coumarins include Vitamin K antagonists, warfarin Coumadin, acenocoumarol, warfarinand synthetic pentasaccharide inhibitors of factor Xa fondaparinux or ldraparinux. As used herein, refer to "anti-platelet drug" representative of a class of pharmaceuticals which reduces the platelet aggregation.

In one embodiment, an anti-platelet drug Hand Thrombophlebitis nach intravenösen Linien ,th.