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(12) United States Patent (10) Patent No.: US 6,264,960 B1 Robins Et Al

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(12) United States Patent (10) Patent No.: US 6,264,960 B1 Robins Et Al USOO626496OB1 (12) United States Patent (10) Patent No.: US 6,264,960 B1 Robins et al. (45) Date of Patent: *Jul. 24, 2001 (54) TREATMENT OF WASCULAR EVENTS WO 97/35576 10/1997 (WO). USING LIPID-MODIFYING COMPOSITIONS WO 98/03069 1/1998 (WO). (76) Inventors: Sander J. Robins, 86 Framingham Rd., OTHER PUBLICATIONS Southboro, MA (US) 01772; Hanna Rubins, M.D., H.B., et al., “Gemfibrozil for the Secondary Bloomfield Rubins, 4101 Sunset Blvd., Prevention of Coronary Heart Disease in Men with Low St. Louis Park, Minneapolis, MN (US) Levels of High-Density Lipoprotein Cholesterol,” The New 55416; Dorothea Collins, 541 Nut England Journal of Medicine, 341: 410–418 (1999). Plains Rd., Guilford, CT (US) 06437 Rubins, H.B., et al., “Rationale and design of the Depart ment of Veterans Affairs High-Denisty Lipoprotein Choles (*) Notice: This patent issued on a continued pros terol Intervention Trial (HIT) for secondary prevention of ecution application filed under 37 CFR coronary artery disease in men with low high-density lipo 1.53(d), and is subject to the twenty year protein cholesterol and desirable low-density lipoprotein patent term provisions of 35 U.S.C. cholesterol.” Am. J. Cardiol. 71(1): 45–52 (1993). 154(a)(2). Fauci et al. “Harrison's Principles of Internal Medicine, 14th Ed.”, McGraw-Hill, Inc., New York, 2146-2148 (1998). Subject to any disclaimer, the term of this Rubenfire, et al. “Treatment Strategies for Management of patent is extended or adjusted under 35 Serum Lipids: Lessons Learned From Lipid Metabolism, U.S.C. 154(b) by 0 days. Recent Clinical Trials, and Experience With the HMG CoA Reductase Inhibitors.” Progress in Cardiovascular Diseases, (21) Appl. No.: 09/189,899 41(2), pp. 95–116 (1998). Wood et al., “Prevention of Coronary Heart Disease in (22) Filed: Nov. 10, 1998 Clinical Practice.” European Society of Cardiology, Euro (51) Int. Cl." ............................ A61K 9/00; A61K 31/19; pean Atherosclerosis Society, European Society of Hyper A61K 31/21 tension, International Society of Behavioural Medicine, (52) U.S. Cl. .......................... 424/400; 424/422; 424/434; European Society of General Practice/Family Medicine, 424/436; 514/568; 514/506; 514/510; 514/569; European Heart Network. Atherosclerosis, 140, #2, pp. 514/570; 514/824 199-270, 1998. (58) Field of Search ..................................... 424/400, 422, Belalcazar, et al., “Defining Specific Goals of Therapy in 424/434, 436, 43; 514/568, 506, 510,569, Treating Dyslipidemia in the Patient With Low High-Den 570, 824 sity Lipoprotein Cholesterol,” Progress in Cardiovascular Diseases, 41(2), pp 151-174 (1998). (56) References Cited National Cholesterol Education Program (“NCEP”), “Fibric Acid Derivatives” pp. III-10 and III-11, 1993. U.S. PATENT DOCUMENTS Primary Examiner-Gollamudi S. Kishore 3,674,836 7/1972 Creger .................................. 260/473 4,250,191 2/1981 Edwards .... ... 424/308 (74) Attorney, Agent, or Firm-Hamilton, Brook, Smith & 4,788,183 11/1988 Darrow ..... ... 514/166 Reynolds, P.C. 4,891.220 1/1990 Donzis ................................... 424/88 (57) ABSTRACT 4,933,165 6/1990 Brown .................................... 424/10 5,173,287 12/1992 Smith ..................................... 424/10 The claimed invention pertains to methods for treating a 5,211947 5/1993 Brannan et al. .. 424/94.63 patient who is at risk for a vascular (e.g., cardiovascular, 5,312,814 5/1994 Biller et al........ ... 514/39 cerebrovascular) event comprising administering to the 5,470,845 11/1995 Magnin et al. ... ... 514/121 patient an effective amount of a lipid-modifying drug. The 5,530,145 6/1996 Wang et al. ...... ... 549/328 claimed methods are particularly effective in patients having 5,593,971 1/1997 Tscholar et al. ...................... 514/39 a lipid profile comprising a low Low Density Lipoprotein FOREIGN PATENT DOCUMENTS and a low High Density Lipoprotein. 757911 2/1997 (EP). 793958 9/1997 (EP). 6 Claims, No Drawings US 6,264,960 B1 1 2 TREATMENT OF WASCULAR EVENTS High Density Lipoprotein-Cholesterol (HDL-C) and a low USING LIPID-MODIFYING COMPOSITIONS Low Density Lipoprotein-Cholesterol (LDL-C). AS defined herein a vascular event refers to a disease or BACKGROUND OF THE INVENTION disorder of a blood vessel and/or circulation of, for example, Vascular disorders, including heart disease and Stroke, the heart (e.g., cardiovascular event) or brain (e.g., cere persist as a leading cause of death in certain age and ethnic brovascular event). A cardiovascular and/or cerebrovascular groups. A need exists, therefore, for improved treatments for event can be a thrombotic disorder. A thrombotic disorder/ patients at risk for vascular disorders. In particular, a need event occurs, for example, when a clot forms and lodges exists to reduce the occurrence and/or Severity of Vascular within a blood vessel. The blockage may fully block or disorders. partially block the blood vessel causing a thrombotic disor SUMMARY OF THE INVENTION der. Other examples of cardiovascular and/or cerebrovascu lar events include a narrowing or constriction of a blood The invention pertains to methods for treating a patient vessel, myocardial infarction (MI), angina, Stroke, pulmo who is at risk for a vascular event (e.g., cardiovascular or 15 cerebrovascular event) comprising administering to the nary embolism, transient ischemic attack (TIA), deep vein patient an effective amount of a lipid or cholesterol modi thrombosis, thrombotic re-occlusion Subsequent to a coro fying drug. In particular, the patient is one having a lipid nary intervention procedure or disorders in which at least profile with a low High Density Lipoprotein-Cholesterol one major coronary artery exhibits greater than 50% Steno (HDL-C) and a low Low Density Lipoprotein-Cholesterol Sis. Two phases of a cardiovascular and/or cerebrovascular (LDL-C). A low HDL-C is less than about 40 mg/dL, and a event may exist, an ischemic Stage and a necrotic Stage. A low LDL-C is less than about 130 mg/dL. patient may Suffer from ischemia in which a decrease of The lipid?cholesterol modifying drug comprises a fibric blood flow may occur. This decrease in blood flow causes a acid or derivative thereof. Examples of fibric acid or deriva decrease in tissue oxygenation. After prolonged ischemia, tives thereof include gemfibrozil, fenofibrate, bezafibrate, 25 the tissue may undergo necrosis which is death of the tissue. ciprofibrate, clofibrate, clinofibrate, niacin and/or combina Therefore, patients who are at risk for a cardiovascular tions thereof. and/or cerebrovascular event may exhibit elevated levels of The claimed method implicates the treatment of various ischemic markers and/or necrosis markers. vascular events that can be characterized by a clot in the vessel (e.g., artery, vein) or narrowing of the vessel. A clot Patients who are at risk for a cardiovascular and/or which forms in a vessel can partially or fully block blood cerebrovascular event are patients who manifest at least one flow. Examples of Such diseases are a thrombotic disorder, Symptom indicative of a vascular disorder/event. Symptoms myocardial infarction, angina, Stroke, pulmonary embolism, that are indicative of a coronary-related vascular event, for transient ischemic attack, deep vein thrombosis, thrombotic example, include chest pain, abnormal electrocardiograms, re-occlusion Subsequent to a coronary intervention proce 35 elevated levels of ischemic markers, necrosis markers, or dure and a disorder in which at least one major coronary thrombin/fibrin generation markers. Such markers include, artery exhibits greater than 50% stenosis. The treatment but are not limited to, Creatine Kinase with Muscle and/or reduces the occurrence and/or Severity of these vascular Brain subunits (CKMB), D-Dimer, F1.2, thrombin anti eVentS. thrombin (TAT), soluble fibrin monomer (SFM), fibrin pep The claimed methods result in at least a 10% (e.g., 15% 40 tide A (FPA), myoglobin, thrombin precursor protein (TPP), or 20%) reduction of the patient’s triglyceride level, and/or platelet monocyte aggregate (PMA) and troponin. Patients at least a 5% (e.g., 7% or 10%) increase in the level of who are at risk also include patients having a history of a HDL-C. thrombotic event (e.g. disorder), including Coronary Heart The claimed invention also embodies methods for pre 45 venting a cardiovascular and/or cerebrovascular event in an Disease (CHD), stroke, or TIAs. A history of CHD can individual who has a lipid profile comprising a low HDL-C include, for example, a history of MI, coronary revascular level and a low LDL-C level, comprising administering an ization procedure, angina with ischemic changes, or a posi effective amount of fibric acid or derivative thereof in a tive coronary angiogram (e.g., showing greater than about 50% Stenosis of at least one major coronary artery). carrier (e.g., a pharmaceutically acceptable carrier). The 50 individual can also be at risk for a cardiovascular and/or In particular, the claimed invention involves patients who cerebrovascular event. are at risk for a cardiovascular and/or cerebrovascular event Advantages of the claimed invention include the ability to and have a low HDL-C and low LDL-C lipid profile. A low treat cardiovascular and/or cerebrovascular events with lipid HDL-C is less than about 40 mg/dL, and a low LDL-C is less modifying drugS/compositions, especially in patients who 55 than about 130 mg/dL. Lipoproteins are complexes which already have a low HDL-C and low LDL-C lipid profile. The contain both a lipid and protein. Most of the lipids in plasma claimed methods provide an effective way to treat, prevent, are present as lipoproteins and are transported as Such. and/or reduce the reoccurrence or Severity of these cardio Lipoproteins are characterized by their flotation constants vascular and/or cerebrovascular events. (e.g., densities). Various classes of lipoproteins exist and 60 include HDLS and LDLs.
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