US6147109A
Expired / Lapsed
US
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Upregulation of Type III endothelial cell Nitric Oxide Synthase by HMG-CoA reductase inhibitors
Assignee: The Brigham and Women's Hospital Inc
•
Filing: 1998-08-11
•
Granted: 2000-11-14
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Expires: 2018-08-11
Abstract
Abstract A new use for HMG-CoA reductase inhibitors is provided. In the instant invention, HMG-CoA reductase inhibitors are found to upregulate endothelial cell Nitric Oxide Synthase activity through a mechanism other than preventing the formation of oxidative-LDL. As a result, HMG-CoA reductase inhibitors are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include pulmonary hypertension, ischemic stroke, impotence, heart failure, hypoxia-induced conditions, insulin deficiency, progressive renal disease, gastric or esophageal motility syndrome, etc. Subjects thought to benefit mostly from such treatments include nonhyperlipidemics and nonhypercholesterolemics, but not necessarily exclude hyperlipidemics and hypercholesterolemics.
Inventors
- 👤 James K. Liao
- 👤 Ulrich Laufs
- 👤 Matthias Endres
- 👤 Michael A. Moskowitz
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 05:51
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/33; A61K31/335; A61K31/35; A61P; A61P1/00; A61P11/00; A61P13/00; A61P13/12; A61P15/00; A61P15/10; A61P43/00; A61P9/00
Claims Analysis
Total Claims: 61
Claim 1
Independent Claim
54 words
A method for treating a nonhypercholesterolemic subject to increase endothelial cell Nitric Oxide Synthase activity in a tissue of the subject, comprising: administering to a nonhypercholesterolemic subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in said tissue of the subject.
Claim 2
Independent Claim
54 words
A method for treating a nonhypercholesterolemic subject to increase endothelial cell Nitric Oxide Synthase activity in a tissue of the subject, comprising: administering to a nonhypercholesterolemic subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in said tissue of the subject.
Claim 3
Dependent Claim
10 words
The method of claim 1 wherein the subject is nonhyperlipidemic.
Claim 4
Dependent Claim
25 words
The method of claim 2 wherein the amount is less than an amount which alters the blood LDL cholesterol levels in the subject by 10%.
Claim 5
Dependent Claim
22 words
The method of claim 2 wherein the amount is sufficient to increase endothelial cell Nitric Oxide Synthase activity above normal baseline levels.
Claim 6
Dependent Claim
26 words
The method of claim 2 wherein the subject has a condition comprising an abnormally low level of endothelial cell Nitric Oxide Synthase activity which is hypoxia-induced.
Claim 7
Dependent Claim
27 words
The method of claim 2 wherein the subject has a condition comprising an abnormally low level of endothelial cell Nitric Oxide Synthase activity which is cytokine induced.
Claim 8
Dependent Claim
16 words
The method of claim 2 wherein the subject has an abnormally elevated risk of pulmonary hypertension.
Claim 9
Dependent Claim
11 words
The method of claim 2 wherein the subject has pulmonary hypertension.
Claim 10
Dependent Claim
17 words
The method of claim 2 wherein the subject has an abnormally elevated risk of an ischemic stroke.
Claim 11
Dependent Claim
13 words
The method of claim 2 wherein the subject has experienced an ischemic stroke.
Claim 12
Dependent Claim
14 words
The method of claim 2 wherein the subject is chronically exposed to hypoxic conditions.
Claim 13
Dependent Claim
27 words
The method of claim 1 wherein the subject has a condition comprising an abnormally low level of endothelial cell Nitric Oxide Synthase activity which is chemically induced.
Claim 14
Dependent Claim
18 words
The method of claim 1 wherein the inhibitor is selected from the group consisting of simvastatin and lovastatin.
Claim 15
Dependent Claim
22 words
A The method of claim 1 further comprising co-administering a nonHMG-CoA reductase inhibitor agent that increases endothelial cell Nitric Oxide Synthase activity.
Claim 16
Independent Claim
65 words
A method for increasing endothelial cell Nitric Oxide Synthase activity in a subject to treat a nonhyperlipidemic condition favorably affected by an increase in endothelial cell Nitric Oxide Synthase activity in a tissue comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in said tissue of the subject.
Claim 17
Independent Claim
65 words
A method for increasing endothelial cell Nitric Oxide Synthase activity in a subject to treat a nonhyperlipidemic condition favorably affected by an increase in endothelial cell Nitric Oxide Synthase activity in a tissue comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in said tissue of the subject.
Claim 18
Dependent Claim
11 words
The method of claim 15 wherein the nonhyperlipidemic condition is hypoxia-induced.
Claim 19
Dependent Claim
12 words
The method of claim 15 wherein the nonhyperlipidemic condition is pulmonary hypertension.
Claim 20
Dependent Claim
13 words
The method of claim 15 wherein the nonhyperlipidemic condition is an ischemic stroke.
Claim 21
Dependent Claim
11 words
The method of claim 15 wherein the nonhyperlipidemic condition is impotence.
Claim 22
Dependent Claim
12 words
The method of claim 15 wherein the nonhyperlipidemic condition is heart failure.
Claim 23
Dependent Claim
13 words
The method of claim 15 wherein the nonhyperlipidemic condition is progressive renal disease.
Claim 24
Dependent Claim
16 words
The method of claim 15 wherein the nonhyperlipidemic condition is a gastric or esophageal motility disorder.
Claim 25
Dependent Claim
27 words
The method of claim 15 wherein the HMG-CoA reductase inhibitor is administered in an amount which is insufficient to alter blood cholesterol levels by more than 10%.
Claim 26
Dependent Claim
13 words
The method of claim 15 wherein the HMG-CoA reductase inhibitor is administered acutely.
Claim 27
Dependent Claim
13 words
The method of claim 15 wherein the HMG-CoA reductase inhibitor is administered prophylactically.
Claim 28
Dependent Claim
20 words
The method of claim 15 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin and lovastatin.
Claim 29
Dependent Claim
21 words
The method of claim 15 further comprising co-administering a nonHMG-CoA reductase inhibitor agent that increases endothelial cell Nitric Oxide Synthase activity.
Claim 30
Independent Claim
47 words
A method for reducing brain injury resulting from a stroke comprising: administering to a subject having an abnormally high risk of an ischemic stroke, a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the brain tissue of the subject.
Claim 31
Independent Claim
47 words
A method for reducing brain injury resulting from a stroke comprising: administering to a subject having an abnormally high risk of an ischemic stroke, a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the brain tissue of the subject.
Claim 32
Dependent Claim
13 words
The method of claim 28 wherein the HMG-CoA reductase inhibitor is administered prophylactically.
Claim 33
Dependent Claim
13 words
The method of claim 28 wherein the HMG-CoA reductase inhibitor is administered acutely.
Claim 34
Dependent Claim
20 words
The method of claim 28 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin and lovastatin.
Claim 35
Dependent Claim
21 words
The method of claim 28 further comprising co-administering a nonHMG-CoA reductase inhibitor agent that increases endothelial cell Nitric Oxide Synthase activity.
Claim 36
Independent Claim
39 words
A method for treating pulmonary hypertension comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the pulmonary tissue of the subject.
Claim 37
Independent Claim
39 words
A method for treating pulmonary hypertension comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the pulmonary tissue of the subject.
Claim 38
Dependent Claim
26 words
The method of claim 33 wherein the HMG-CoA reductase inhibitor is administered prophylactically to a subject who has an abnormally elevated risk of developing pulmonary hypertension.
Claim 39
Dependent Claim
19 words
The method of claim 33 wherein the HMG-CoA reductase inhibitor is administered to a subject who has pulmonary hypertension.
Claim 40
Dependent Claim
14 words
The method of claim 33 wherein the subject is chronically exposed to hypoxic conditions.
Claim 41
Dependent Claim
20 words
The method of claim 33 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin and lovastatin.
Claim 42
Dependent Claim
21 words
The method of claim 33 further comprising co-administering a nonHMG-CoA reductase inhibitor agent that increases endothelial cell Nitric Oxide Synthase activity.
Claim 43
Independent Claim
39 words
A method for treating heart failure comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the heart tissue of the subject.
Claim 44
Independent Claim
39 words
A method for treating heart failure comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the heart tissue of the subject.
Claim 45
Dependent Claim
13 words
The method of claim 39 wherein the HMG-CoA reductase inhibitor is administered prophylactically.
Claim 46
Dependent Claim
13 words
The method of claim 39 wherein the HMG-CoA reductase inhibitor is administered acutely.
Claim 47
Dependent Claim
20 words
The method of claim 39 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin and lovastatin.
Claim 48
Dependent Claim
10 words
The method of claim 39 wherein the subject is nonhyperlipidemic.
Claim 49
Dependent Claim
21 words
The method of claim 39 further comprising co-administering a nonHMG-CoA reductase inhibitor agent that increases endothelial cell Nitric Oxide Synthase activity.
Claim 50
Independent Claim
40 words
A method for treating progressive renal disease comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the kidney tissue of the subject.
Claim 51
Independent Claim
40 words
A method for treating progressive renal disease comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the kidney tissue of the subject.
Claim 52
Dependent Claim
13 words
The method of claim 45 wherein the HMG-CoA reductase inhibitor is administered prophylactically.
Claim 53
Dependent Claim
13 words
The method of claim 45 wherein the HMG-CoA reductase inhibitor is administered acutely.
Claim 54
Dependent Claim
20 words
The method of claim 45 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin and lovastatin.
Claim 55
Dependent Claim
10 words
The method of claim 45 wherein the subject is nonhyperlipidemic.
Claim 56
Dependent Claim
21 words
The method of claim 45 further comprising co-administering a nonHMG-CoA reductase inhibitor agent that increases endothelial cell Nitric Oxide Synthase activity.
Claim 57
Independent Claim
48 words
A method for treating a subject to increase blood flow in a tissue of the subject, comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the tissue of the subject.
Claim 58
Independent Claim
48 words
A method for treating a subject to increase blood flow in a tissue of the subject, comprising: administering to a subject in need of such treatment a HMG-CoA reductase inhibitor in an amount effective to increase endothelial cell Nitric Oxide Synthase activity in the tissue of the subject.
Claim 59
Dependent Claim
20 words
The method of claim 51 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin and lovastatin.
Claim 60
Dependent Claim
10 words
The method of claim 51 wherein the subject is nonhyperlipidemic.
Claim 61
Dependent Claim
53 words
The method of claim 51 further comprising co-administering a second agent to the subject with a condition treatable by the second agent in an amount effective to treat the condition, whereby the delivery of the second agent to a tissue of the subject is enhanced as a result of the increased blood flow.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2003-11-14 | 2004-05-15 | 2004-11-14 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2007-11-14 | 2008-05-15 | 2008-11-14 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2011-11-14 | 2012-05-15 | 2012-11-14 | $7700.00 | Window Closed / Lapsed |