Methods of treating vascular diseases characterized by nitric oxide insufficiency

a vascular disease and nitric oxide technology, applied in the field of vascular diseases characterized by nitric oxide insufficiency, can solve the problems of many advances in cardiovascular medicine, the overall improvement of cardiovascular health in the general population has not translated into comparable racial benefits, and the cardiovascular events are worse for blacks than whites, so as to improve the overall health of the general population, enhance the endogenous level, and stimulate endogenous synthesis

Inactive Publication Date: 2009-09-10
NITROMED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, outcomes of cardiovascular events are worse for blacks than whites.
Thus, the many advances in cardiovascular medicine that account for the overall improvement in cardiovascular health in the general population have failed to translate into comparable racial benefits.

Method used

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  • Methods of treating vascular diseases characterized by nitric oxide insufficiency
  • Methods of treating vascular diseases characterized by nitric oxide insufficiency
  • Methods of treating vascular diseases characterized by nitric oxide insufficiency

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0191] As described herein, NO deficiency is a central pathophysiologic mechanism for the black vascular diathesis. To examine this issue in forearm microvessels, the vasodilator responses to intra-arterial infusions of methacholine, sodium nitroprusside, and verapamil were examined using venous occlusion plethysmography in 36 white and black hypertensive patients. These patients had no other coronary factors, such as smoking, diabetes mellitus, or hypercholesterolemia, and the two groups were matched in terms of age, gender, lipid levels, blood pressure, and anti-hypertensive treatment. Similar to previous reports (Lang et al, N EngI J Med, 333:155-160 (1995); Panza et al, N Engl J Med, 323:22-27 (1990)), the dilator response to methacholine, but not nitroprusside, was significantly reduced in these hypertensive patients compared to age-matched normotensive controls (Sherman et al, Circulation, 98:1-376 (1998)). Regarding racial differences, as shown in FIG. 2, vasodilation in resp...

example 2

[0192] To investigate the issue of whether NO deficiency is a primary or secondary phenomenon in hypertensive black patients, 46 normotensive white and black patients who were matched for age and gender were compared. As shown in FIG. 3B, the vasodilator responses to methacholine were not significantly different in black and white normotensive patients. However, the response to sodium nitroprusside (FIG. 3A) was significantly lower in the black normotensive patients. This finding shows that there is an impairment in the vasodilator response exogenous source of NO in black patients even prior to the development of hypertension, an observation that would be consistent with a primary rather than secondary role in the black vascular diathesis. These findings are consistent with recently published results by other investigators (Lang et al, N EngI J Med, 333:155-160 (1995); Cardillo et al, Hypertension 31:1235-1239 (1998)).

example 3

[0193] Black patients have a preponderance of salt-sensitive hypertension, and the data described herein show that NO deficiency is a pathogenic mechanism of salt-sensitive hypertension in experimental models (Rudd et al, Am J Physiol, 277: H732-H739 (1999)). To explore the relation between salt-sensitivity and endothelium-derived NO action in black patients prior to the development of hypertension, the blood pressure response to salt-loading and salt-deprivation using an established inpatient protocol (Weinberger et al, Hypertension, 8:II-127-II-134 (1986)) in a group of normotensive black patients was assessed. Briefly, blood pressure was continuously monitored non-invasively during a salt load (sodium 458 mEq over 24 hours) and during a period of salt depletion (furosemide treatment and sodium intake 10 mEq over 24 hours). Patients were considered to be salt-sensitive if mean blood pressure was at least 10 mm Hg higher during the salt loading period (Weinberger et al, Hypertensio...

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Abstract

The invention provides methods of treating and / or preventing vascular diseases characterized by nitric oxide insufficiency by administering a therapeutically effective amount of at least one nitrosated angiotensin-converting enzyme inhibitor, nitrosated beta-adrenergic blocker, nitrosated cholesterol reducer, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angiotensin II receptor antagonist, nitrosated renin inhibitor, and optionally at least one compound used to treat cardiovascular diseases and / or at least one antioxidant, or a pharmaceutically acceptable salt thereof, and / or at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase. The antioxidant may preferably be a hydralazine compound or a pharmaceutically acceptable salt thereof. The compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase may preferably be isosorbide dinitrate and / or isosorbide mononitrate. The vascular diseases characterized by nitric oxide insufficiency include a cardiovascular disease and a disease resulting from oxidative stress.

Description

RELATED APPLICATIONS [0001] This application is (i) a continuation-in-part of U.S. application Ser. No. 10 / 679,257 filed Oct. 7, 2003, which is a continuation of U.S. application Ser. No. 09 / 697,317, filed Oct. 27, 2000, issued as U.S. Pat. No. 6,635,273, which claims priority to U.S. Provisional Application No. 60 / 179,020 filed Jan. 31, 2000, and U.S. Provisional Application No. 60 / 162,230 filed Oct. 29, 1999; and is (ii) a continuation of U.S. Application No. 10 / ______ filed Oct. 20, 2003, which is a continuation of U.S. application Ser. No. 10 / 415,136 filed Apr. 25, 2003, which is a § 371 of PCT / US01 / 14245 filed May 2, 2001 which claims priority to PCT / US00 / 29582 filed Oct. 27, 2000.FIELD OF THE INVENTION [0002] The present invention provides methods of treating and / or preventing vascular diseases characterized by nitric oxide insufficiency by administering a therapeutically effective amount of at least one antioxidant or a pharmaceutically acceptable salt thereof, and at least o...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/43A01N43/04A61K9/00A61K9/70A61K31/135A61K31/19A61K31/34A61K31/355A61K31/415A61K31/495A61K31/50A61K31/535A61K45/06
CPCA61K9/0056A61K9/7023A61K31/135A61K31/19A61K31/34A61K31/355A61K31/415A61K45/06A61K31/495A61K31/50A61K31/535A61K2300/00
Inventor LOSCALZO, JOSEPHVITA, JOSEPH A.LOBERG, MICHAEL D.WORCEL, MANUEL
Owner NITROMED
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