Treatment for atherosclerosis and other cardiovascular and inflammatory diseases

• US 5,773,209 A
• Filed: 06/07/1995
• Issued: 06/30/1998
• Est. Priority Date: 10/30/1992
• Status: Expired due to Term

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Parthasarathy, Sampath, Khan, Bobby V., Medford, Russell M., Alexander, R. Wayne
• Primary Examiner(s): O SULLIVAN, PETER G
• Application Number:
  US08/484,059
• Time in Patent Office: 1,119 Days
• Field of Search: 424/9.1, 424/9.2, 436/71, 436/86, 436/129, 514/18, 514/423-478, 514/479, 514/484, 514/485, 514/487, 514/488, 514/489, 514/506, 514/513, 514/824, 514/825, 514/826, 514/861, 514/863, 530/331, 548/431, 558/230, 558/235, 564/76, 568/21, 568/25
• US Class Current: 435/7.24
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/145 having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) isothiourea A61K31/155
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/265 of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 333/04 having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 333/08 having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 333/16 Salts of dithiocarbamic acids
• CPC Class Codes: C07D 295/21 Radicals derived from sulfur analogues of carbonic acid
• CPC Class Codes: G01N 2333/70503 : Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
• CPC Class Codes: G01N 2333/7056 : Selectin superfamily, e.g. LAM-1, GlyCAM, ELAM-1, PADGEM
• CPC Class Codes: G01N 2500/00 : Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/323 : Arteriosclerosis, Stenosis
• CPC Class Codes: G01N 33/68 : involving proteins, peptides or amino acids involving lipoproteins G01N33/92
• CPC Class Codes: G01N 33/92 : involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743
• CPC Class Codes: Y10T 436/201666 : Carboxylic acid

Abstract

A method for the treatment of cardiovascular diseases and noncardiovascular inflammatory diseases that are mediated by VCAM-1 is provided that includes the removal, decrease in the concentration of, or prevention of the formation of oxidized polyunsaturated fatty acids, or interferes with a complex formed between a polyunsaturated fatty acid or an oxidized polyunsaturated fatty acid and a protein or peptide that mediates the expression of VCAM-1. A method is also provided for suppressing the expression of a redox-sensitive gene or activating a gene that is suppressed through a redox-sensitive pathway, that includes administering an effective amount of a substance that prevents the oxidation of the oxidized signal, and typically, the oxidation of a polyunsaturated fatty acid, or interferes with a complex formed between the oxidized signal and a protein or peptide that mediates the expression of the redox gene.

Claims

1. A method for the prediction or assessment of redox-sensitive gene mediated disease in vivo, comprising quantifying the level of oxidized polyunsaturated fatty acid in the tissue or blood.

3. The method of claim 1, wherein the oxidized polyunsaturated acid is selected from the group consisting of oxidized linoleic, linolenic, arachidonic and eicosatrienoic acids.

5. The method of claim 1, wherein the oxidized polyunsaturated fatty acid is oxidized linoleic acid.

6. The method of claim 1, wherein the oxidized polyunsaturated fatty acid is oxidized arachidonic acid.

13. The method of claim 1, wherein the oxidized polyunsaturated fatty acid is the hydroperoxide of linoleic acid.

14. The method of claim 1, wherein the oxidized polyunsaturated fatty acid is the hydroperoxide of arachidonic acid.

16. The method of claim 3, wherein the oxidized polyunsaturated fatty acid is the hydroperoxide of arachidonic acid.

2. A method for the prediction or assessment of redox-sensitive gene mediated disease in vivo, comprising quantifying a mediator of inflammation that is induced by polyunsaturated fatty or an oxidized polyunsaturated fatty acid.

4. The method of claim 2, wherein the oxidized polyunsaturated acid is selected from the group consisting of oxidized linoleic, linolenic, arachidonic and eicosatrienoic acids.

7. The method of claim 2, wherein the mediator is selected from the group consisting of IL-1β

, MCP-1, and IL-6.

8. The method of claim 2, wherein the mediator is a cytokine that initiates the immune response.

9. The method of claim 2, wherein the mediator is a chemoattractant that promotes the migration of inflammatory cells to a point of injury.

10. The method of claim 2, wherein the mediator is a growth factor.

11. The method of claim 2, wherein the mediator is an adhesion molecule.

12. The method of claim 2, wherein the mediator is a thrombin receptor.

15. The method of claim 2, wherein the oxidized polyunsaturated fatty acid is the hydroperoxide of linoleic acid.