US5216025A
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Nitric oxide synthesis inhibitors for potentiating the action of pressor agents in certain hypotensive patients
Assignee: Cornell Research Foundation Inc
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Filing: 1991-07-01
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Granted: 1993-06-01
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Expires: 2011-07-01
Abstract
Abstract A method for treatment of an animal for systemic hypotension induced by internal nitric oxide production caused by endotoxin or cytokines. The method involves administering an α 1 adrenergic agonist and an amount of an inhibitor of nitric oxide formation from argi Research relating to the development of this invention was supported by the United States Public Health Service grants which gives the United States government certain rights to use of the present invention.
Inventors
- 👤 Steven S. Gross
- 👤 Robert G. Kilbourn
- 👤 Roberto Levi
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-03 00:29
CPC Classifications
A; A61; A61K; A61K38/00; A61K38/04; A61K38/08; A61K38/085; A61K31/00; A61K31/185; A61K31/19; A61K31/195; A61K31/197; A61K31/198; A61K31/21; A61K31/215; A61K31/22; A61K31/223; A61K45/00; A61K45/06; A61P; A61P9/00; A61P9/02
Claims Analysis
Total Claims: 39
Claim 1
Independent Claim
68 words
A method for treatment of a patient having systemic hypotension induced by administration of gamma-interferon, tumor necrosis factor, interleukin-1 or interleukin-2, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an inhibitor of nitric oxide synthesis from arginine to the patient, wherein the amount of nitric oxide synthesis inhibitor restores vascular sensitivity to effects of the α 1 adrenergic agent.
Claim 2
Independent Claim
68 words
A method for treatment of a patient having systemic hypotension induced by administration of gamma-interferon, tumor necrosis factor, interleukin-1 or interleukin-2, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an inhibitor of nitric oxide synthesis from arginine to the patient, wherein the amount of nitric oxide synthesis inhibitor restores vascular sensitivity to effects of the α 1 adrenergic agent.
Claim 3
Dependent Claim
15 words
The method of claim 1 wherein the nitric oxide synthesis inhibitor is an arginine derivative.
Claim 4
Dependent Claim
53 words
The method of claim 2 wherein the arginine derivative is an N G -substituted arginine or an N G ,N G -disubstituted arginine and the N G -substituted arginine or N G ,N G -disubstituted arginine has at least one nitro, amino, lower alkyl, hydroxyalkyl or alkenyl substituent replacing a guanidino amino hydrogen.
Claim 5
Independent Claim
62 words
A method for treatment of a patient for systemic hypotension induced by exposure to endotoxin or other bacterial toxins, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an inhibitor of a nitric oxide synthesis from arginine, wherein the amount of nitric oxide synthesis inhibitor restores vascular sensitivity to the α 1 adrenergic agent.
Claim 6
Independent Claim
62 words
A method for treatment of a patient for systemic hypotension induced by exposure to endotoxin or other bacterial toxins, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an inhibitor of a nitric oxide synthesis from arginine, wherein the amount of nitric oxide synthesis inhibitor restores vascular sensitivity to the α 1 adrenergic agent.
Claim 7
Dependent Claim
12 words
The method of claim 4 wherein the inhibitor is an arginine derivative.
Claim 8
Dependent Claim
54 words
The method of claim 4 wherein the nitric oxide synthesis inhibitor is an N G -substituted arginine or N G ,N G -disubstituted arginine and the N G -substituted arginine or N G ,N G -disubstituted arginine has at least one nitro, amino, lower alkyl, hydroxyalkyl or alkenyl substituent replacing a guanidino amino hydrogen.
Claim 9
Dependent Claim
33 words
The method of claim 3 or 6 wherein the N G -substituted arginine is N G -aminoarginine, N G -nitroarginine, N G -methylarginine, N G -ethylarginine, N G -propylarginine or N G -butylarginine.
Claim 10
Dependent Claim
31 words
The method of claim 3 or 6 wherein the N G -substituted arginine or N G ,N G -disubstituted arginine is an N G -alkylarginine or N G ,N G -dialkylarginine.
Claim 11
Dependent Claim
24 words
The method of claim 2, 3 or 6 wherein the N G -substituted arginine or N G ,N G -disubstituted arginine are L-arginine derivatives.
Claim 12
Independent Claim
66 words
A method for treatment of a patient for systemic hypotension caused by induced production, by cytokine administration or exposure to endotoxin, of nitric oxide, said method involving administering to a patient an α 1 adrenergic agonist and an arginine derivative in an amount inhibiting production of nitric oxide from arginine, this inhibition being effective to restore vascular sensitivity to effects of the α 1 adrenergic agonist.
Claim 13
Independent Claim
66 words
A method for treatment of a patient for systemic hypotension caused by induced production, by cytokine administration or exposure to endotoxin, of nitric oxide, said method involving administering to a patient an α 1 adrenergic agonist and an arginine derivative in an amount inhibiting production of nitric oxide from arginine, this inhibition being effective to restore vascular sensitivity to effects of the α 1 adrenergic agonist.
Claim 14
Independent Claim
51 words
A method for treatment of a patient for systemic hypotension caused by nitric oxide production induced by gamma-interferon, tumor necrosis factor, interleukin-1, or interleukin-2, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an arginine derivative inhibiting production of nitric oxide from arginine.
Claim 15
Independent Claim
51 words
A method for treatment of a patient for systemic hypotension caused by nitric oxide production induced by gamma-interferon, tumor necrosis factor, interleukin-1, or interleukin-2, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an arginine derivative inhibiting production of nitric oxide from arginine.
Claim 16
Independent Claim
64 words
A method for treatment of a patient for systemic hypotension induced by therapy with gamma-interferon, tumor necrosis factor, interleukin-1 or interleukin-2, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of N G -alkylarginine, N G ,N G -dialkylarginine, N G -aminoarginine or N G -nitroarginine effective to restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 17
Independent Claim
64 words
A method for treatment of a patient for systemic hypotension induced by therapy with gamma-interferon, tumor necrosis factor, interleukin-1 or interleukin-2, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of N G -alkylarginine, N G ,N G -dialkylarginine, N G -aminoarginine or N G -nitroarginine effective to restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 18
Dependent Claim
33 words
The method of claim 12 wherein the N G -alkylarginine and N G ,N G -dialkylarginine have at least one alkyl substituent selected from the group consisting of methyl, ethyl, propyl and butyl.
Claim 19
Dependent Claim
32 words
The method of claim 12 wherein the alkyl of the N G -alkylarginine and N G ,N G -dialkylarginine are derivatized and selected from the group consisting of hydroxyalkyl, carboxyalkyl and aminoalkyl.
Claim 20
Independent Claim
66 words
A method for treatment of a patient for systemic hypotension induced by exposure to endotoxin or other bacterial toxins, the method involving administering to the patient an α 1 adrenergic agonist and an amount of N G -alkylarginine, N G ,N G -dialkylarginine, N G -aminoarginine or N G -nitroarginine effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 21
Independent Claim
66 words
A method for treatment of a patient for systemic hypotension induced by exposure to endotoxin or other bacterial toxins, the method involving administering to the patient an α 1 adrenergic agonist and an amount of N G -alkylarginine, N G ,N G -dialkylarginine, N G -aminoarginine or N G -nitroarginine effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 22
Independent Claim
52 words
A method for treatment of a patient for systemic hypotension caused by induced production, by an administered cytokine or endotoxin exposure, of nitric oxide from arginine, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an inhibitor of production of nitric oxide from arginine.
Claim 23
Independent Claim
52 words
A method for treatment of a patient for systemic hypotension caused by induced production, by an administered cytokine or endotoxin exposure, of nitric oxide from arginine, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an inhibitor of production of nitric oxide from arginine.
Claim 24
Independent Claim
63 words
A method for treatment of a patient for systemic hypotension caused by nitric oxide production induced by exposure to endotoxin or other bacterial toxins, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an arginine derivative inhibiting production of nitric oxide from arginine being effective to restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 25
Independent Claim
63 words
A method for treatment of a patient for systemic hypotension caused by nitric oxide production induced by exposure to endotoxin or other bacterial toxins, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of an arginine derivative inhibiting production of nitric oxide from arginine being effective to restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 26
Independent Claim
82 words
A method for treatment of a patient with systemic hypotension caused by nitric oxide production induced by endotoxin or other bacterial toxins, said method involving intravascularly administering to the animal an α 1 adrenergic agonist and an amount of an arginine derivative effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist, said arginine derivative being arginine with at least one N G substituent selected from the group consisting of amino, nitro, alkyl, hydroxyalkyl and alkenyl.
Claim 27
Independent Claim
82 words
A method for treatment of a patient with systemic hypotension caused by nitric oxide production induced by endotoxin or other bacterial toxins, said method involving intravascularly administering to the animal an α 1 adrenergic agonist and an amount of an arginine derivative effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist, said arginine derivative being arginine with at least one N G substituent selected from the group consisting of amino, nitro, alkyl, hydroxyalkyl and alkenyl.
Claim 28
Independent Claim
57 words
A method for treatment of a patient for systemic hypotension induced by treatment with gamma-interferon, tumor necrosis factor, interleukin-1 or interleukin-2 said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of N G -methylarginine effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 29
Independent Claim
57 words
A method for treatment of a patient for systemic hypotension induced by treatment with gamma-interferon, tumor necrosis factor, interleukin-1 or interleukin-2 said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of N G -methylarginine effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 30
Independent Claim
62 words
A method for treatment of a patient for systemic hypotension caused by production of a nitrogen oxide induced by exposure to endotoxin or other bacterial toxins, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of N G -methylarginine effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 31
Independent Claim
62 words
A method for treatment of a patient for systemic hypotension caused by production of a nitrogen oxide induced by exposure to endotoxin or other bacterial toxins, said method involving intravascularly administering to the patient an α 1 adrenergic agonist and an amount of N G -methylarginine effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist.
Claim 32
Dependent Claim
20 words
The method of claim 19 or 20 wherein the effective amount is between about 0.1 mg/kg and about 100 mg/kg.
Claim 33
Dependent Claim
17 words
The method of claim 19 or 20 wherein the N G -methylarginine is N G -methyl L-arginine.
Claim 34
Independent Claim
95 words
A method for treatment of a patient for systemic hypotension induced by chemotherapeutic treatment with tumor necrosis factor or interleukin-2, said method involving administering to the patient an α 1 adrenergic agonist and an amount of N G -substituted arginine or an N G ,N G -disubstituted arginine effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist, wherein the N G -substituted or N G ,N G -disubstituted arginine has a nitro, amino, alkyl, hydroxyalkyl or alkenyl substituent replacing at least one hydrogen of a guanidino amino group.
Claim 35
Independent Claim
95 words
A method for treatment of a patient for systemic hypotension induced by chemotherapeutic treatment with tumor necrosis factor or interleukin-2, said method involving administering to the patient an α 1 adrenergic agonist and an amount of N G -substituted arginine or an N G ,N G -disubstituted arginine effective to inhibit nitric oxide production and restore vascular sensitivity to the α 1 adrenergic agonist, wherein the N G -substituted or N G ,N G -disubstituted arginine has a nitro, amino, alkyl, hydroxyalkyl or alkenyl substituent replacing at least one hydrogen of a guanidino amino group.
Claim 36
Dependent Claim
10 words
The method of claim 23 wherein the administering is parenteral.
Claim 37
Dependent Claim
11 words
The method of claim 24 wherein the parenteral administering is intravascular.
Claim 38
Dependent Claim
38 words
The method of claim 1, 4, 10, 11, 12, 15, 16, 17, 18, 19, 20 or 23 wherein the α 1 adrenergic agonist is selected from the group consisting of epinephrine, norepinephrine, dopamine, metaraminol, methoxamine, ephedrine and mephentermine.
Claim 39
Dependent Claim
34 words
The method of claim 1, 4, 10, 11, 12, 15, 16, 17, 18, 19, 20 or 23 wherein the α 1 adrenergic agonist is selected from the group consisting of phenylephrine and angiotensin II.
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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) | 1996-05-31 | 1996-11-30 | 1997-06-01 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2000-05-31 | 2000-11-30 | 2001-06-01 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2004-05-31 | 2004-11-30 | 2005-06-01 | $7700.00 | Window Closed / Lapsed |