US 20090226407A9 (19) United States (10) Pub. No.: US 2009/0226407 A9 (12) Patent Application Publication (48) Pub. Date: Sep. 10, 2009 L0ScalZ0 et al. CORRECTED PUBLICATION (54) METHODS OF TREATING VASCULAR (60) Provisional application No. 60/179,020, filed on Jan. DISEASES CHARACTERIZED BY NITRC 31, 2000. Provisional application No. 60/162,230, OXIDE INSUFFICIENCY filed on Oct. 29, 1999. Provisional application No. 60/179,020, filed on Jan. 31, 2000. Provisional appli (76) Inventors: Joseph Loscalzo, Dover, MA (US); cation No. 60/162,230, filed on Oct. 29, 1999. Joseph A. Vita, Hingham, MA (US); Michael D. Loberg, Boston, MA (US); Publication Classification Manuel Worcel, Boston, MA (US) (51) Int. Cl. Correspondence Address: A6II 38/43 (2006.01) WILMERHALEANTROMED AOIN 43/04 (2006.01) 1875 PENNSYLVANIAAVE, NW (52) U.S. Cl. .............................................. 424/94.1: 514/23 WASHINGTON, DC 20006 (US) (21) Appl. No.: 10/692,724 (57) ABSTRACT (22) Filed: Oct. 27, 2003 The invention provides methods of treating and/or preventing vascular diseases characterized by nitric oxide insufficiency Prior Publication Data by administering atherapeutically effective amount of at least one nitrosated angiotensin-converting enzyme inhibitor, nit (15) Correction of US 2004/0105850 A1 Jun. 3, 2004 rosated beta-adrenergic blocker, nitrosated cholesterol reducer, nitrosated calcium channel blocker, nitrosated See (60) Related U.S. Application Data. endothelin antagonist, nitrosated angiotensin II receptor (65) US 2004/0105850 A1 Jun. 3, 2004 antagonist, nitrosated renin inhibitor, and optionally at least one compound used to treat cardiovascular diseases and/or at Related U.S. Application Data least one antioxidant, or a pharmaceutically acceptable salt thereof, and/or at least one compound that donates, transfers (60) Continuation-in-part of application No. 10/679,257. or releases nitric oxide, elevates endogenous levels of endot filed on Oct. 7, 2003, now Pat. No. 7,556,824, which is helium-derived relaxing factor, stimulates endogenous syn a division of application No. 09/697.317, filed on Oct. thesis of nitric oxide or is a substrate for nitric oxide synthase. 27, 2000, now Pat. No. 6,635,273. The antioxidant may preferably be a hydralazine compound Continuation of application No. 10/687,706, filed on or a pharmaceutically acceptable salt thereof. The compound Oct. 20, 2003, now Pat. No. 7,537,785, which is a that donates, transfers or releases nitric oxide, elevates endog continuation of application No. 10/415,136, filed on enous levels of endothelium-derived relaxing factor, stimu Apr. 25, 2003, now Pat. No. 7,235,237, filed as 371 of lates endogenous synthesis of nitric oxide or is a Substrate for international application No. PCT/US01/14245, filed nitric oxide synthase may preferably be isosorbide dinitrate on May 2, 2001, which is a continuation-in-part of and/or isosorbide mononitrate. The vascular diseases charac application No. PCT/US00/29582, filed on Oct. 26, terized by nitric oxide insufficiency include a cardiovascular 2OOO. disease and a disease resulting from oxidative stress. Patent Application Publication Sep. 10, 2009 Sheet 1 of 3 US 2009/0226407 A9 FIG. 1 Decreased Renin Release NO Insufficiency Salt/Water Retention Increased Intracellular Increased Sensitivity to Sodium & Calcium Catecholamines and Angiotensin II - Increased Vascul DecreasedLVH Capillary Density increasedC vascularascular Tonetone Myocardial Fibrosis Microvascular Increased LV Mass Cardiac Ischemi Diastolic Dysfunction -o-White hypertensives -o-Black Hypertensives Basetne 0.3 O 3.0 10 Methachottne Dose (glnin) Patent Application Publication Sep. 10, 2009 Sheet 2 of 3 US 2009/0226407 A9 FIG. 3A -o-White nomotensives -e-Black nomotensives gC 15 2. NE to 21 5h 5 - 41 El O PCO,05 Basettine 0.3 10 3.O. 10 Nitroprusside Dose (gfmin) FIG. 3B -O-White nomotensives mile- Blacknomotensives Baseline os to so do Methachotine Dose (gfmtn) Patent Application Publication Sep.10, 2009 Sheet 3 of 3 US 2009/0226407 A9 FIG. 4A -o- Satt Resistant (n=25) S -e - Satt Sensitive (n=6) O - s Basettle O.3 .0 3.0 O Methachottne Dose (g/min) FIG. 4B -O-Satt Resistant (n=25) -e-Satt Sensttive (n=6) Baseline os to so to Nitroprusside Dose (glnin) US 2009/0226407 A9 Sep. 10, 2009 METHODS OF TREATING VASCULAR DISEASES that donates, transfers or releases nitric oxide, elevates endog CHARACTERIZED BY NITRC OXDE enous levels of endothelium-derived relaxing factor, stimu INSUFFICIENCY lates endogenous synthesis of nitric oxide or is a Substrate for nitric oxide synthase, and, optionally, at least one nitrosated RELATED APPLICATIONS angiotensin-converting enzyme inhibitor, nitrosated beta adrenergic blocker, nitrosated calcium channel blocker, nit 0001. This application is (i) a continuation-in-part of U.S. rosated endothelin antagonist, nitrosated angiotensin II application Ser. No. 10/679.257 filed Oct. 7, 2003, which is a receptor antagonist, nitrosated renin inhibitor, and/or at least continuation of U.S. application Ser. No. 09/697.317, filed one compound used to treat cardiovascular diseases. The Oct. 27, 2000, issued as U.S. Pat. No. 6,635,273, which present invention also provides Sustained release formulation claims priority to U.S. Provisional Application No. 60/179, comprising at least one antioxidant or a pharmaceutically 020 filed Jan. 31, 2000, and U.S. Provisional Application No. acceptable salt thereof, and at least one nitric oxide donor, 60/162.230 filed Oct. 29, 1999; and is (ii) a continuation of and, optionally, at least one nitrosated compound. U.S. Application No. 10/ filed Oct. 20, 2003, which is a continuation of U.S. application Ser. No. 10/415,136 filed BACKGROUND OF THE INVENTION Apr. 25, 2003, which is a S 371 of PCT/US01/14245 filed May 2, 2001 which claims priority to PCT/US00/29582 filed 0003. The decline in cardiovascular morbidity and mor Oct. 27, 2000. tality in the United States over the past three decades has been the result of significant advances in research on cardiovascu FIELD OF THE INVENTION lar disease mechanisms and therapeutic strategies. The inci dence and prevalence of myocardial infarction and death 0002 The present invention provides methods of treating from myocardial infarction, as well as that from cerebrovas and/or preventing vascular diseases characterized by nitric cular accident, have decreased significantly over this period oxide insufficiency by administering a therapeutically effec largely owing to advances in prevention, early diagnosis, and tive amount of at least one antioxidant or a pharmaceutically treatment of these very common diseases. acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, elevates endog 0004 Analysis of outcomes by race, however, paints quite enous levels of endothelium-derived relaxing factor, stimu a different picture: life expectancy and cardiovascular mor lates endogenous synthesis of nitric oxide or is a Substrate for bidity rates have improved far less for blacks than whites. nitric oxide synthase, and, optionally, at least one nitrosated Available data show that the likelihood of dying from cardio angiotensin-converting enzyme inhibitor, nitrosated beta vascular disease is far greater among black Americans than adrenergic blocker, nitrosated calcium channel blocker, nit among white Americans. In this decade, the death rate from rosated endothelin antagonist, nitrosated angiotensin II cardiovascular disease for black males was 353 per 100,000 receptor antagonist, nitrosated renin inhibitor, and/or at least population, while that for white males was 244 per 100,000; one compound used to treat cardiovascular diseases. The the rate for black females was 226 per 100,000; while that for antioxidant may preferably be a hydralazine compound or a white females was 135 per 100,000. Consonant with this pharmaceutically acceptable salt thereof. The compound that important demographic parameter is the observation that donates, transfers or releases nitric oxide, elevates endog there is a higher prevalence of several of the important risk enous levels of endothelium-derived relaxing factor, stimu factors for cardiovascular disease, e.g., hypertension, Smok lates endogenous synthesis of nitric oxide or is a Substrate for ing, diabetes mellitus, obesity, and left ventricular hypertro nitric oxide synthase may preferably be isosorbide dinitrate phy, among blacks compared with whites. In addition, out and/or isosorbide mononitrate. The present invention also comes of cardiovascular events are worse for blacks than provides methods of treating and/or preventing vascular dis whites. Following myocardial infarction, blacks have a 50% eases characterized by nitric oxide insufficiency by adminis higher annual mortality rate than whites, and their five year tering a therapeutically effective amount of at least one nit survival is only 70%. Thus, the many advances in cardiovas rosated angiotensin-converting enzyme inhibitor, nitrosated cular medicine that account for the overall improvement in beta-adrenergic blocker, nitrosated calcium channel blocker, cardiovascular health in the general population have failed to nitrosated endothelin antagonist, nitrosated angiotensin II translate into comparable racial benefits. receptor antagonist and/or nitrosated renin inhibitor, and, 0005. There is a need in the art for new and more effective optionally, at least one antioxidant and/or at least one com compositions and methods for treating vascular diseases. The pound