| Use of radical-scavenging compounds for treatment and prevention of no-dependent microcirculation disorders -> Monitor Keywords |
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Use of radical-scavenging compounds for treatment and prevention of no-dependent microcirculation disordersRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The Cyclos, Polycyclo Ring System Having 1,3-diazine As One Of The Cyclos, A Ring Nitrogen Is Shared By The Two Cyclos Of The Bicyclo Ring System (e.g., Pyrrolo [1,2-a]pyrimidine, Imidazo[1,2-a]pyrimidine, Etc.),Use of radical-scavenging compounds for treatment and prevention of no-dependent microcirculation disorders description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080076786, Use of radical-scavenging compounds for treatment and prevention of no-dependent microcirculation disorders. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 11/565,142, filed Nov. 30, 2006 which is a continuation of U.S. application Ser. No. 11/347,896, filed Feb. 6, 2006, which is a continuation of U.S. application Ser. No. 10/121,496 (now U.S. Pat. No. 7,064,130) filed Apr. 12, 2002, which claims as does the present application priority to U.S. Provisional Application Ser. No. 60/288,605, filed on May 4, 2001 and DE 10119680, filed Apr. 20, 2001, the disclosure of all of which are incorporated by reference in their entirety. FIELD OF THE INVENTION [0002] This invention relates to a method of treatment of disorders of the microcirculation, particularly those where insufficient generation of NO seems to be the cause of the problem, using substances to scavenge free radicals such as Dipyridamole or Mopidamol in doses lower than those needed to directly inhibit platelet aggregation alone or in combination with substance to increase cellular Nitric oxide (NO) production such as HMG CoA reductase inhibitors at doses below the typical dose to lower serum lipids but sufficient to still enhance eNOS in cells of the vasculature. BACKGROUND OF THE INVENTION [0003] By laboratory models reflecting the complex physiology of the blood vessel it could be shown that the vasculature is not a passive conduit, but interacts profoundly with the blood through an intricate system of checks and balances to protect its integrity after vascular accident. Therefore the endothelium produces prostacyclin, a potent inhibitor of aggregation. The normal endothelium is not thrombogenic and prevents the attachment of platelets. Various stimulants precipitate the release of endothelium-derived relaxing factor (EDRF), which inhibits platelet adhesion and aggregation. At the same time, intracellular increase in cGMP was shown to be responsible for relaxation of smooth muscle cells following administration of nitro compounds. Thus the endothelium can provide maintenance of local perfusion of the vessels by several separate mechanisms, one being the local vasodilatation mediated by prostacyclin and Nitric Oxide (NO, also described in literature as EDRF) and another being the decreased interaction of blood cells with each other or the negative interaction of white blood cells or blood platelets with the cells of the vessel wall. Another would be the control of local fibrin accumulation by controlling the formation as well as lysis of already formed strands of fibrin. In larger vessels aggregation and adhesion of platelets to damaged parts of the vessel wall particularly after interventional therapy play an important role and have been shown to be treated with inhibitors of platelet aggregation (see WO 98/11896). The benefit of enhancing endothelial NO synthesis by HMG CoA reductase inhibitors has been described in U.S. Pat. No. 5,968,983 and WO 00/56403. [0004] In the past prevention and treatment of conditions causing reduced tissue perfusion have been focussed mainly on mechanical as well as pharmaceutical re-vasularisation of the larger arteries supplying blood to a larger area of tissue. The focus did lay on either preventing build-up of atherosclerotic plaques (lipid lowering therapy) or on the prevention of the thromboembolic occlusion triggered by rupturing plaque and activation of platelet aggregation leading often to an occlusive thrombus. This is the reason why major efforts have been focussed on inhibition of aggregation of platelets, ultimately by blocking the final common pathway of platelet aggregation, i.e. by inhibiting the receptor for fibrinogen on platelets, the final step of linking platelets together when forming a platelet rich thrombus. It therefore is also straight forward to combine lipid lowering therapy with potent platelet aggregation inhibitors of combinations of such as taught in WO 98/11896. [0005] In addition, procedures for fast and safe revascularisation of the occluded arteries have been developed such as pharmacological lysis of thrombi with thrombolytic agents such as r-tPA or mechanically by transcutaneous intravascular balloon angioplasty. Again here the major problem remaining is the acute rethrombosis of the reopened segment of the blood vessel, where strong inhibitors of platelet aggregation or the combination of platelet inhibition with inhibitors of fibrin formation have shown to be effective. [0006] In preventing reoccurrence of myocardial infarcts (MI), chronic application of mild platelet inhibitors such as Aspirin have shown only limited efficacy (published meta analysis agree to a reduction of the incidence by 18%). Using more potent platelet inhibitors such as various orally available inhibitors of the platelet fibrinogen receptor however have shown no improvement over the effect achieved by ASA. More than 37,000 patients have been subjects in major studies on the long term benefit of chronic administration of oral fibrinogen receptor antagonists in preventing cardiovascular events. All studies have been negative, in fact the treatment arm showed a higher risk for bleeding and increased mortality. [0007] This concludes that long term benefit can not be extrapolated from the clear short term benefit of very strong inhibition of platelet aggregation even when combined with therapy designed to reduce the build up of atherosclerotic plaques or the elevated risk related to elevated levels of plasma lipids as done by lipid lowering therapy. DESCRIPTION OF THE INVENTION [0008] Tissue perfusion is vital to the health and survival and function of any organ, particularly those organs with high oxygen and nutritive demand. Even after successful revascularisation of epicardial arteries the perfusion of the tissue, i.e. the properties of the microcirculation have been shown to significantly influence the mortality after MI at 90 days (Gibbson at all, Circulation 2000, 101:125-130), resulting in a reduction of mortality from 4.6% to 0.8%, in cases where tissue perfusion, was not reduced, i.e. microcirculation was not compromised. [0009] This present invention focuses on the importance of tissue perfusion on the level of smaller vessels downstream of the large vessels, supplying tissue with oxygen and nutrients by improving microcirculation. Microcirculation disorders, i.e. circulation disorders caused by microvascular dysfunction, can be caused by metabolic or oxidative stress leading to diseases where vascular dysfunction or damages are involved. [0010] The present invention provides a new approach for improving microcirculation by treatment and/or prevention of such disorders of microcirculation which are caused by reduced endogenous NO production by cells otherwise needed for local prevention of vessel spasm or loss of dilatory reactivity as well as prevention of cell mediated damage. The improvement of NO-dependent microvascular dysfunction is especially important in small vessels or capillary vessels where the ratio of vessel wall surface area to blood volume is high, and provides a new approach for treatment and prevention of disorders of the NO. Therefore, radical scavengers like Dipyridamole and Mopidamol alone or in combination with substance capable of increasing NO production may have therapeutic potential in a variety of diseases involving progressive dysfunction of medium and small-sized vessels. [0011] Accordingly, disorders of the microcirculation according to the present invention are meant to be those where by metabolic or genetic influence the cells of the vasculature are no longer able to produce sufficient amount of NO, the potent local regulator of homeostasis in the vascular system. Such disorders are named herein "NO-dependent microcirculation disorders". Examples of such disorders are diabetic angiopathy, especially diabetic microangiopathy, e.g. diabetic gangrene, diabetic retinopathy, diabetic neuropathy, [0012] or such as hyperhomocysteinemia, homocysteinuria, pulmonary hypertension, mucoviscidosis, neuro-degenerative disease, ulcus cruris, atrophic gastritis, colitis ulcerosa, or microcirculation disorders occurring after partial resection of stomach and/or bowels; [0013] furthermore re-establishment of blood flow upon insufficient tissue perfusion after revascularisation of large arteries such as after acute MI or Stroke or in peripheral artery disease in addition or following acute antiplatelet therapy to prevent acute reocclusion, e.g. as disclosed in WO 98/11896; similarly conditions where dysfunction is caused by re-perfusion injury after revascularisation or in transplant recipient; microcirculation disorders caused by inflammatory reactions, such as morbus crohn, colitis ulcerosa or acute respiratory dystress syndrome (ARDS); microcirculation disorders caused by autoimmune diseases, such as autoimmune chronic-active hepatitis (idiopathic hepatitis), primary-biliary cirrhosis or (autoimmune associated) multiple sclerosis; peripheral microcirculation disorders, Continue reading about Use of radical-scavenging compounds for treatment and prevention of no-dependent microcirculation disorders... 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