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US 201300.95095A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0095095 A1 Lines (43) Pub. Date: Apr. 18, 2013

(54) METHOD FORTREATING THROMBOTIC A613 L/42 (2006.01) DSORDERS USING A63L/38 (2006.01) QUERCETIN-CONTAINING COMPOSITIONS A613 L/4439 (2006.01) A 6LX3/397 (2006.01) (76) Inventor: Thomas Christian Lines, Wayland, MA A613 L/7II (2006.01) (US) A613 L/403 (2006.01) A6IP 7/02 (2006.01) (21) Appl. No.: 13/272,508 A613 L/4985 (2006.01) 1-1. (52) U.S. Cl. (22) Filed: Oct. 13, 2011 USPC ...... 424/133.1: 514/249; 514/456; 514/301; 514/56; 514/457; 514/13.8: 514/331; 514/161; Publication Classification 514/418; 514/332: 514/312: 514/377: 514/444; (51) Int. Cl. 514/314: 514/341; 514/210.17: 514/44 R: A 6LX39/395 (2006.01) 51474 11 A6 IK3I/352 (2006.01) A6 IK3I/4365 (2006.01) (57) ABSTRACT A 6LX3L/727 (2006.01) A method for treating thrombotic disorders using a compo A6 IK3I/353 (2006.01) sition containing quercetin, together with one or more of A6 IK38/36 (2006.01) Vitamin B vitamin C, and folic acid. Also disclosed is a A6 IK3 L/452 (2006.01) method of improving the efficacy of a blood thinning medi A6 IK3I/60 (2006.01) cation by co-administering a composition containing querce A6 IK3I/404 (2006.01) tin, together with one or more of vitamin B. vitamin C, and A6 IK3I/444 (2006.01) folic acid to a subject being treated with a blood thinning A 6LX3L/24709 (2006.01) . US 2013/0095095 A1 Apr. 18, 2013

METHOD FOR TREATING THROMBOTC thrombotic disorder using a composition containing querce DISORDERS USING tin, vitamin B3, vitamin C, and folic acid as the only active QUERCETIN-CONTAINING COMPOSITIONS ingredients. 0008. The invention also features a method for improving BACKGROUND the efficacy of a blood thinning medication, in which an effective amount of the above-mentioned composition is 0001. refers to the formation of a blood clot administered to a Subject taking a blood thinning medication. within the vascular system. Clot formation is a normal In still another aspect, the invention features a method for response to hemorrhage and helps to maintain . If reducing the level of D-dimer in a Subject by administering thrombosis occurs at the wrong place or at the wrong time, it the above-mentioned composition. can lead to reduced blood flow to critical organs such as the 0009. The composition, either in dry form (e.g., powder or brain (), lungs (pulmonary embolism), and myocar tablet) or in liquid form (e.g., beverage, syrup, or Solution), dium (). Venous thrombosis, which can be a dietary Supplement or a pharmaceutical formulation. occurs mainly in the deep veins of the leg, often results in The dietary Supplement or the pharmaceutical formulation pulmonary embolism, when a portion of the clot flows can be in the form of a tablet, a capsule, a soft chew, a gel, or through the circulation to the lungs. Atherothrombosis, or a sterile injectable solution. The composition can also be a clots that form in arteries, lead to acute coronary syndrome, food product. Examples include tea (e.g., a tea drink and the ischemic stroke, and limb . contents of a tea bag), Soft drinks, juice (e.g., a fruit extract 0002 formation involves several sequential and a juice drink), milk, coffee, jelly, ice cream, yogurt, steps that typically begin following a skin laceration or a cookies, cereals, chocolates, and Snack bars. vascular injury. Circulating first adhere to the site of 0010. The details of one or more embodiments of the injured endothelial cells and a series of events occurs that invention are set forth in the description below. Other fea allows activation of these platelets. Activated platelets then tures, objects, and advantages of the invention will be appar recruit additional platelets to the site of injury, where they ent from the description and from the claims. aggregate to form a plug until a stable clot forms. Inactive factors, which are always present and circulating DETAILED DESCRIPTION in the bloodstream, are then sequentially activated in a pro 0011. This invention is based, at least in part, on the unex cess known as the coagulation cascade. The coagulation cas pected findings that quercetin, together with one or more of cade ultimately leads to a stable fibrin-containing clot. vitamin B. vitamin C, and folic acid, exhibits synergistic 0003. Thrombotic disorders are a group of inherited and inhibition of PDI activity and venous or arterial thrombus acquired disorders that cause abnormal activation of the formation without leading to excessive bleeding following hemostatic system, leading to an increased risk of venous and administration of a composition containing these ingredients arterial thrombosis. Cancer is among the acquired disorders to a subject. that greatly increase the risk of thrombosis. Tumor cells, by 0012. Accordingly, the present invention features a expressing high levels of tissue factor on their Surface, cause method for treating a subject Suffering from a venous or a hypercoagulable state. Tissue factoris required for initiating arterial thrombotic disorder by administering an effective the just-mentioned coagulation cascade. amount of a composition containing quercetin and folic acid. 0004 Among the factors involved in thrombus formation In another embodiment, quercetin, Vitamin B, and, option is protein disulfide isomerase (PDI). PDI is secreted by acti ally, folic acid may be used to treat a venous or arterial vated endothelial cells and platelets, after which it plays a thrombotic disorder. In still another embodiment, quercetin, critical role in thrombus formation. PDI can activate tissue Vitamin C, and, optionally, folic acid may be used to treat a factor, which leads to activation of the coagulation cascade, venous or arterial thrombotic disorder. Further, a venous or ultimately resulting in fibrin deposition and thrombus forma arterial thrombotic disorder may be treated using a composi tion that includes quercetin, vitamin B, Vitamin C, and, tion. optionally, folic acid. In a preferred embodiment, a compo 0005. It is known that certain natural antioxidants, such as sition described above contains quercetin in the form of iso quercetin, inhibit both acute and chronic phases of free-radi quercetin or rutin. In an additional preferred embodiment, a cal induced diseases. Further, some natural antioxidants venous or arterial thrombotic disorder is treated by co-admin exhibit synergy in their reactions with biologically relevant istering bisulfate and a composition containing oxygen species, e.g., hydroxyl radicals, Superoxides, oxysul quercetin, isoquercetin, or rutin, together with one or more of furs, Sulfur dioxide, and nitrogen dioxide. Vitamin B vitamin C, and folic acid. 0006 Quercetin, in addition to its effects on free-radical 0013 The present invention also features a method for induced diseases, is known to inhibit aggregation in improving the efficacy of a blood thinning medication by vitro. Quercetin administration is also known to reduce blood administering an effective amount of the above-described pressure in hypertensive patients. compositions to a subject being treated with a blood thinning medication. SUMMARY 0014. In one aspect, improving the efficacy of a blood thinning medication according to the present invention will 0007. The present invention features a method for treating allow for a subject to be treated with lower doses of blood a thrombotic disorder by administering to a subject in need thinners. For example, a subject being treated with a 75 mg thereof an effective amount of a quercetin-containing com per day dose of clopidogrel bisulfate, a blood thinning medi position, which also includes one or more of vitamin B. cation, can be treated with a lower dose (e.g., 50 mg, 25 mg. Vitamin C, folic acid, and a blood thinning medication. In 10 mg. or less) if concurrently administered one of the above another aspect, the invention features a method for treating a described compositions. The ability to treat a subject using US 2013/0095095 A1 Apr. 18, 2013

lower doses of blood thinning medication can, for example, 0020. The term “thrombotic disorder” refers to many dis advantageously reduce the time needed prior to Surgery to tinct conditions that cause or increase the risk of a venous or withdraw blood thinning treatment, and can also reduce the arterial thrombotic event, including but not limited to, atrial time needed to restore anti-thrombotic activity post-Surgery fibrillation, thrombosis due to a mechanical heart valve, myo after treatment is resumed. Improving the efficacy of a blood cardial infarction, unstable angina, deep vein thrombosis, thinning medication also refers to reducing the side effects acute ischemic stroke, pulmonary embolism, atherosclerosis, associated with the blood thinning medication, e.g., reducing factor V Leiden, III deficiency, defi the amount of bleeding that occurs while a Subject is being ciency, protein S deficiency, prothrombin gene mutation treated with the blood thinning medication. (G20210A), hyperhomocysteinemia, antiphospholipid anti 0.015. Further, the invention includes a method for reduc body syndrome, anticardiolipin antibody, thrombosis Syn ing the level of D-dimer in a subject with a higher than normal drome, lupus syndrome, malignancy, major D-dimer level by administering the above-mentioned compo Surgery, immobilization, oral contraceptive use, thalidomide sitions. In addition, the composition can also be used to use, especially in combination with dexamethasone, reduce the risk of a venous or arterial thrombotic event by induced thrombocytopenia, pregnancy, myeloproliferative prophylactic treatment of a Subject at risk for a venous or disorders, inflammatory bowel disease, nephrotic syndrome, arterial thrombotic event. paroxysmal nocturnal hemoglobinuria, hyperviscosity Syn 0016. Without being bound by theory, the above described drome, Waldenstrom's macroglobulinemia, and trauma. The compositions may function to ameliorate thrombotic disor term “thrombotic disorder also refers to thrombosis induced ders by the following mechanisms. by cancer, e.g., multiple myeloma and other hematologic 0017 Quercetin, together with one or more of vitamin B, cancers, adenocarcinoma, cancer of the pancreas, stomach, Vitamin C, and folic acid, synergistically inhibits the ovaries, prostate, colon, lung, brain, breast, kidney, skin, cer activity of protein disulfide isomerase (PDI). As mentioned vix, and ear-nose-throat cancer. above, PDI plays a critical role in the initiation of the coagul 0021. The efficacy of quercetin is enhanced by vitamin B, lation cascade. By blocking this critical enzyme activity, Vitamin C, or both. For example, a combination of quercetin, quercetin can prevent thrombus formation. The antithrom vitamin B, and vitamin C maintains quercetin levels in botic activity of quercetin can be evaluated in humans by plasma up to five times those of quercetin alone or a combi measuring D-dimer levels in plasma samples from patients nation of quercetin and vitamin B. Further, a combination of treated with quercetin. D-dimer, a small protein fragment quercetin, vitamin B, and vitamin C results in a quercetin present in the blood, is a fibrin degradation product. The level halflife in plasma twice as long as that of quercetin alone and of D-dimer in the blood increases after athrombotic event due about one and a halftimes that of a combination of quercetin to its release from blood clots via . Quercetin and vitamin B. See U.S. Pat. Nos. 7,745,486 and 7,745.487. administration to hypertensive patients results in a reduction in the level of D-dimer in their blood, Suggesting that quer 0022 Typically, a subject who has or is at risk for devel cetin reduces thrombus formation in these patients. Hyper oping a thrombotic disorder can be administered, once or tensive patients are prone to thrombotic events. periodically per day, with the composition in an amount that 0018. Additionally, quercetin, together with one or more provides 20 mg to 3 g (preferably, 250 mg to 1 g) of quercetin. of vitamin B vitamin C, and folic acid, synergistically low When vitamin B vitamin C, or folic acid is included in a ers the of a subject. High blood pressure is a composition of this invention, it is preferred that each dose or major risk factor for cardiovascular complications, including serving contain 20 Jug-3 g vitamin B, 200 ug-3 g vitamin C, stroke, myocardial infarction, and . High blood or 40-3000 ug of folic acid. pressure can also lead to deep vein thrombosis as well as 0023 The term "quercetin” refers to both quercetin agly peripheral vascular disease, including both peripheral arterial con and quercetin derivatives, e.g., quercetin-3-O-glucoside disease and chronic venous insufficiency. Quercetin, together (isoquercetin), quercetin-5-O-glucoside, quercetin-7-O-glu with one or more of vitamin B, Vitamin C, and folic acid, can coside, quercetin-9-O-glucoside, quercetin-3-O-rutinoside therefore reduce the risk of developing the just-mentioned (rutin), quercetin-3-O-O-rhamnosyl-(1->2)-a-rhamnosyl conditions by lowering blood pressure. (1->6)-3-glucoside, quercetin-3-O-galactoside, quercetin 0019. The term “blood thinning medication” refers to an 7-O-galactoside, quercetin-3-O-rhamnoside, and quercetin , e.g., clopidogrel bisulfate, heparin, war 7-O-galactoside. After digestion, quercetin derivatives are farin, enoxaparin, , , , prasug converted to quercetin aglycon and other active derivatives, rel, , , , , , which are absorbed in the body. The quantity of quercetin , , , , , mentioned above refers to that of quercetin aglycon or the , , , , cloric quercetin moiety of a quercetin derivative. Quercetin can be romen, ; or an anticoagulant, e.g., , added to the composition either in a pure form or as an , , , phenproc ingredient in a mixture (e.g., a plant extract). Examples of oumon, , , , tiocloma commercially available quercetin include QU995 (containing rol, bemiparin, certoparin, dalteparin, nadroparin, parna 99.5% quercetin) and QU985 (containing 98.5% quercetin) parin, reviparin, tinzaparin, , , from Quercegen Pharma LLC (Newton, Mass.) and Merck , , , , betrixa KGaA (Brazil). “Vitamin B” mentioned herein includes ban, , , , , lepiru Vitamin B in its various forms, including niacinamide, nico din, desirudin, , , melagatran, Ximela tinic acid, nicotinamide, inositol hexaniacinate. “Vitamin C gatran, regimen 1 (REG1; a combination of RB-006, a Factor mentioned herein includes vitamin C (i.e., L-ascorbic acid, IXa antagonist, and its oligonucleotide active control agent D-ascorbic acid, or both) and its salts (e.g., sodium ascor RB-007), , , antithrombin III, or bate). “Folic acid mentioned herein includes vitamin Bo. . folate, pteroylglutamic acid, and L-methyl folate. US 2013/0095095 A1 Apr. 18, 2013

0024. The composition administered in the methods of solution. The term "parenteral refers to subcutaneous, intra this invention can be in various forms. For example, it can be cutaneous, intravenous, intramuscular, intraarticular, intraar a softchew composition that includes quercetin, niacinamide, terial, intrasynovial, intrasternal, intrathecal, intralesional, ascorbic acid, Sodium ascorbate, folic acid, Sugar, corn Syrup, and intracranial injection, as well as various infusion tech Sucralose, Soy lecithin, corn Starch, glycerin, palm oil, Xylitol, niques. An “effective amount” refers to a dose of the compo carrageenan, FD&C Yellow #6, FD&C Yellow #5, and natural sition that is sufficient to provide a therapeutic benefit (e.g., and/or artificial flavors. An exemplary serving of this soft reducing the levels of PDI activity in the serum). Both in vivo chew composition (5.15g) includes 250 mg of quercetin, 12.9 and in vitro studies can be conducted to determine optimal mg of vitamin B (i.e., niacinamide), and 382.8 mg of vitamin administration routes and doses. C (i.e., L-ascorbic acid and Sodium ascorbate). A subject can 0029. The compositions described above can be prelimi take one to eight servings (e.g., 4 servings) of this soft chew narily screened for their efficacy in treating the above-de composition daily. The amounts taken can vary depending on, scribed conditions by in vitro assays and then confirmed by for example, the disorder or condition to be treated and the animal experiments and clinic trials. Other Suitable analytical physical states of the Subject. Another exemplary composi and biological assays are apparent to those of ordinary skill in tion of this soft chew includes 5.25 wt % of quercetin, 0.25 wt the art. For example, the effectiveness of the compositions % of vitamin B, and 7.81 wt % of vitamin C (i.e., L-ascorbic described above can be measured by conducting in vivo or in acid and Sodium ascorbate) plus 200g offolic acid per chew. vitro studies of PDI enzymatic activity. 0025. When the above-described composition is in pow der form, it can be used conveniently to prepare beverage, Other Embodiments paste, jelly, capsules, or tablets. Lactose and corn starch are 0030 All of the features disclosed in this specification commonly used as diluents for capsules and as carriers for may be combined in any combination. Each feature disclosed tablets. Lubricating agents, such as magnesium Stearate, are in this specification may be replaced by an alternative feature typically included in tablets. serving the same, equivalent, or similar purpose. Thus, unless 0026. The oral of quercetin in the above expressly stated otherwise, each feature disclosed is only an mentioned capsule or tablet formulations can be improved by example of a generic series of equivalent or similar features. the use of certain additives. For example, a capsule or tablet 0031. From the above description, one skilled in the art can include acid treated gelatin, citrate, potassium hydroxide, can easily ascertain the essential characteristics of the present and/or a cyclodextrin. A preferred amount of these additives invention, and without departing from the spirit and scope per mg of quercetin is 0.01-0.5 mg potassium hydroxide, thereof, can make various changes and modifications of the 0.01-0.7 mg acid treated gelatin, 0.1-1 mg citrate, and 0.01-1 invention to adapt it to various usages and conditions. Thus, mg of a cyclodextrin. Quercetin, in the presence of the addi other embodiments are also within the scope of the following tives, can have a solubility in an aqueous solution of 2-5%. claims. Additionally, the pH of a quercetin-containing formulation What is claimed is: with improved oral bioavailability can be between pH 7 and 1. A method for treating a thrombotic disorder, the method pH 12. comprising administering to a subject in need thereof an 0027. The composition administered in the methods of effective amount of a composition that includes quercetin and this invention can be a dietary Supplement or a pharmaceuti vitamin B3, vitamin C, or folic acid. cal formulation. As a dietary Supplement, additional nutri 2. The method of claim 1, wherein the composition ents, such as minerals or amino acids may be included. A includes folic acid. pharmaceutical formulation can be a sterile injectable or 3. The method of claim 1, wherein the composition infusible solution that contains the composition together with includes vitamin B3. pharmaceutically acceptable excipients. The composition 4. The method of claim 1, wherein the composition can also be a food product. As used herein, the term “food includes vitamin C. broadly refers to any kinds of liquid and solid/semi-solid 5. The method of claim 4, wherein the composition materials that are used for nourishing humans and animals, includes vitamin B3. for Sustaining normal or accelerated growth, or for maintain 6. The method of claim 5, wherein the composition ing stamina or alertness. Examples of human food products includes folic acid. include, but are not limited to, tea-based beverages, juice, 7. The method of claim 1, wherein the composition is coffee, milk, jelly, cookies, cereals, chocolates, Snack bars, co-adminstered with a blood thinning medication. herbal extracts, dairy products (e.g., ice cream, and yogurt), 8. The method of claim 7, wherein the blood thinning Soybean product (e.g., tofu), and rice products. medication is clopidogrel bisulfate. 0028. The terms “improving.” “treating,” and “reducing 9. The method of claim 8, wherein the quercetin is in the refer to the administration of an effective amount of a com form of isoquercetin or rutin. position of the invention to a subject, who needs to improve 10. The method of claim 1, wherein the thrombotic disor one or more of the above-mentioned conditions or has one or der is , thrombosis due to a mechanical heart more of the just-mentioned disorders, or a symptom or a valve, myocardial infarction, unstable angina, deep vein predisposition of one of more of the disorders or conditions, thrombosis, acute ischemic stroke, pulmonary embolism, with the purpose to improve one or more of these conditions, atherosclerosis, factor V Leiden, antithrombin III deficiency, or to prevent, cure, alleviate, relieve, remedy, or ameliorate protein C deficiency, protein S deficiency, prothrombin gene one or more of these disorders, or the symptoms or the pre mutation (G20210A), hyperhomocysteinemia, antiphospho dispositions of one or more of them. The term “administra antibody syndrome, anticardiolipin antibody, thrombo tion' covers oral or parenteral delivery to a Subject a compo sis syndrome, lupus anticoagulant syndrome, major Surgery, sition of the invention in any suitable form, e.g., food product, immobilization, oral contraceptive use, thalidomide use, hep beverage, tablet, capsule, Suspension, and sterile injectable arin-induced thrombocytopenia, pregnancy, myeloprolifera US 2013/0095095 A1 Apr. 18, 2013

tive disorders, inflammatory bowel disease, nephrotic Syn 18. The method of claim 17, wherein the antiplatelet drug drome, paroxysmal nocturnal hemoglobinuria, is clopidogrel bisulfate, heparin, , enoxaparin, abcix hyperviscosity syndrome, Waldenstrom's macroglobuline imab, eptifibatide, tirofiban, , ticlopidine, beraprost, mia, trauma, or cancer. prostacyclin, iloprost, treprostinil, aspirin, aloxiprin, car 11. A method for improving the efficacy of a bloodthinning basalate calcium, indobufen, triflusal, dipyridamole, picota medication, comprising administering to a subject taking a mide, terutroban, cilostazol, , or ditazole. blood thinning medication an effective amount of a compo 19. The method of claim 17, wherein the anticoagulant is sition that includes quercetin and vitamin B3, vitamin C, or acenocoumarol, coumatetralyl, dicoumarol, ethyl biscou folic acid. macetate, , clorindione, diphenadione, phen 12. The method of claim 11, wherein the composition indione, , bemiparin, certoparin, dalteparin, includes folic acid. nadroparin, parnaparin, reviparin, tinzaparin, fondaparinux, 13. The method of claim 11, wherein the composition idraparinux, danaparoid, Sulodexide, dermatan Sulfate, apixa includes vitamin B3. ban, , edoxaban, otamixaban, rivaroXaban, biva 14. The method of claim 11, wherein the composition lirudin, , desirudin, argatroban, dabigatran, melagat includes vitamin C. ran, , regimen 1, defibrotide, ramatroban, antithrombin III, or drotrecogin alfa. 15. The method of claim 14, wherein the composition 20. A method for reducing the level of D-dimer in a subject, includes vitamin B3. comprising administering to a Subject that has an elevated 16. The method of claim 15, wherein the composition level of D-dimer an effective amount of a composition that includes folic acid. includes quercetin and vitamin B3, Vitamin C, or folic acid. 17. The method of claim 11, wherein the blood thinning medication is an antiplatelet drug or an anticoagulant. k k k k k