Treatment for atherosclerosis and other cardiovascular and inflammatory diseases

• US 5,750,351 A
• Filed: 06/07/1995
• Issued: 05/12/1998
• Est. Priority Date: 10/30/1992
• Status: Expired due to Term

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Khan, Bobby V., Parthasarathy, Sampath, Medford, Russell M., Alexander, R. Wayne
• Primary Examiner(s): O SULLIVAN, PETER G
• Application Number:
  US08/474,530
• Time in Patent Office: 1,070 Days
• Field of Search: 424/9.1, 424/9.2, 436/71, 436/86, 436/129, 514/1 S, 514/423, 514/478, 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: 435/7.21
• 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 to assess a test compound for its ability to treat a disorder mediated by VCAM-1 comprising evaluating the ability of the compound to inhibit the oxidation of a polyunsaturated fatty acid by the steps of:

(i) challenging a host to a high level of a polyunsaturated fatty acid and;

(ii) determining the therapeutic efficacy of the test compound based on its ability to decrease the concentration of circulating or cell surface VCAM-1 concentration.

3. The method of claim 1, wherein the disorder is an inflammatory condition.

4. The method of claim 1, wherein the disorder is a cardiovascular disease.

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

2. A method to assess a test compound for its ability to treat a disorder mediated by VCAM-1 comprising the steps of:

(i) exposing a polyunsaturated fatty acid to a protein and the test compound in an in vitro solution in the presence of a substance that is known to oxidize the polyunsaturated fatty acid in the absence of the test compound and;

(ii) assessing the extent of interaction between the polyunsaturated fatty acid or oxidized polyunsaturated fatty acid and the protein.

6. A method to assess a test compound for its ability to treat a disorder mediated by VCAM-1 comprising evaluating the ability of the compound to inhibit the interaction of an oxidized polyunsaturated fatty acid with a protein comprising the steps of:

(i) exposing the oxidized polyunsaturated fatty acid to a protein and the test compound in an in vitro solution;

(ii) assessing the degree of reaction between the oxidized polyunsaturated fatty acid and the protein.

7. The method of claim 6, wherein the polyunsaturated fatty acid is selected from the group consisting of linoleic acid, linolenic acid, arachidonic acid and eicosatrienoic acid.

8. A method to assess a test compound for its ability to treat a disorder mediated by VCAM-1 comprising evaluating the ability of the compound to inhibit the oxidation of a polyunsaturated fatty acid by the steps of:

(i) exposing a polyunsaturated fatty acid to the test compound in an in vitro solution in the presence of a substance that is known to oxidize the polyunsaturated fatty acid in the absence of the test compound and;

(ii) assessing the degree of oxidation of the polyunsaturated fatty acid.

9. The method of claim 8 wherein the oxidizing substance is selected from the group consisting of a metal and an enzyme.

10. The method of claim 9 wherein the enzyme is selected from the group consisting of peroxidase, lipoxygenase, cyclooxygenase, and cytochrome P450.

11. The method of claim 8 wherein the metal is copper.