Materials and methods for treatment and diagnosis of disorders associated with oxidative stress

• US 10,064,877 B2
• Filed: 12/05/2016
• Issued: 09/04/2018
• Est. Priority Date: 08/29/2003
• Status: Expired due to Fees

• Current Assignee: Therapeutic Research LLC
• Original Assignee: Therapeutic Research LLC
• Inventors: Pravda, Jay
• Primary Examiner(s): Pihonak, Sarah
• Assistant Examiner(s): DECK, JASON A
• Application Number:
  US15/369,182
• Publication Number:
  US 20170182067A1
• Time in Patent Office: 638 Days
• 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 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• 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 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/606 having amino groups
• CPC Class Codes: A61K 31/616 by carboxylic acids, e.g. acetylsalicylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Abstract

The subject invention pertains to materials and methods for the prevention and treatment of disease conditions associated with oxidative stress or a compromised reducing environment, including inflammatory bowel diseases such as Crohn'"'"'s disease and ulcerative colitis. Another aspect of the subject invention concerns compositions formulated for administration as an enema. In one embodiment, a composition suitable for administration as an enema comprises an effective amount of 5-ASA and a steroid such as budesonide or hydrocortisone. The subject invention also concerns compositions formulated for oral administration. In one embodiment, a composition comprises alpha-lipoic acid, and/or N-acetyl-L-cysteine (N-A-C), and/or L-glutamine. The alpha-lipoic acid can be racemic alpha-lipoic acid, R-lipoic acid, or R-dihydro-lipoic acid. Methods of the invention include administration of compounds or compositions of the invention. In one embodiment, compounds or compositions of the invention are rectally instilled in a patient. In another embodiment, compounds or compositions are orally administered. The subject invention also concerns methods for screening for, assessing risk of developing, and/or diagnosing conditions associated with oxidative stress, such as ulcerative colitis and other inflammatory bowel disorders.

Claims

1. A method of inducing clinical remission of ulcerative colitis in a mammal requiring such remission, comprising:

a) rectally administering to said mammal an enema comprising;

i) from about 500 mg to about 5000 mg of 5-ASA;

ii) from about 0.5 mg to about 10 mg of budesonide;

iii) from about 10 to about 1000 mg of cromolyn sodium; and

iv) from about 5 mmol to about 50 mmol of sodium butyrate; and

b) repeating said administering step a) daily until a clinical remission is observed.

2. The method of claim 1, wherein the enema is administered once daily, at about bedtime.

3. The method of claim 1, wherein the enema is retained for at least about 4 hours.

4. The method of claim 1, wherein the amount of 5-ASA is from about 750 mg to about 3000 mg.

5. The method of claim 4, wherein the amount of 5-ASA is about 2.7 g.

6. The method of claim 1, wherein the amount of budesonide is from about 1 mg to about 5 mg.

7. The method of claim 1, wherein the amount of cromolyn sodium is about 100 mg.

8. The method of claim 1, wherein the amount of sodium butyrate is about 15 mmol.

9. The method of claim 1, wherein the volume of the enema administered is from about 40 ml to about 80 ml.

10. The method of claim 1, wherein the amount of 5-ASA is about 2.67 g;

the amount of budesonide is about 5 mg;

the amount of cromolyn sodium is about 100 mg; and

the amount of sodium butyrate is about 15 mmol.

11. The method of claim 1, wherein the enema is administered once daily for about three to six weeks, and about twice weekly thereafter.

12. The method of claim 1, wherein the mammal is a human.

13. The method of claim 12, wherein the clinical remission is associated with a Mayo Score of ≤

2 after 6 weeks of treatment.

14. The method of claim 1, further comprising administering to said mammal orally, at least once daily, from about 100 mg to about 1,000 mg of an alpha-lipoic acid selected from the group consisting of racemic alpha-lipoic acid, R-lipoic acid, R-dihydro-lipoic acid and pharmaceutically acceptable salts thereof.

15. The method of claim 14, wherein the amount of alpha-lipoic acid is about 600 mg.

35. The method of claim 1, further comprising orally administering L-glutamine.

36. The method of claim 1, wherein said enema further comprises L-glutamine.

16. A method of inducing histological remission in a mammal with ulcerative colitis comprising administering to a mammal in need of such remission:

a) rectally administering to said mammal an enema comprising;

i) from about 500 mg to about 5000 mg of 5-ASA;

ii) from about 0.5 mg to about 10 mg of budesonide;

iii) from about 10 to about 1000 mg of cromolyn sodium; and

iv) from about 5 mmol to about 50 mmol of sodium butyrate; and

b) repeating said administering step a) daily until a histological remission is observed.

17. The method of claim 16, wherein the enema is administered once daily, at about bedtime.

18. The method of claim 16, wherein the enema is retained for at least about 4 hours.

19. The method of claim 18, wherein the histological remission is observed after about three to six weeks.

20. The method of claim 16, wherein the mammal is human.

21. A method of treating ulcerative colitis in a mammal requiring such treatment, comprising:

a) rectally administering to said mammal an enema comprising;

i) from about 500 mg to about 5000 mg of 5-aminosalicylic acid;

ii) from about 0.5 mg to about 10 mg of budesonide;

iii) from about 10 to about 1000 mg of cromolyn sodium; and

iv) from about 5 mmol to about 50 mmol of a short chain fatty acid; and

b) allowing the contents of the enema to be retained for at least about 4 hours.

22. The method of claim 21, wherein the enema is administered at about bedtime.

23. The method of claim 21, wherein the enema is retained for at least about 5 hours.

24. The method of claim 21, wherein the short chain fatty acid is selected from the group consisting of five, four, three, and two carbon fatty acids.

25. The method of claim 24 wherein the short chain fatty acid is selected from the group consisting of sodium butyrate, proprionate and acetate.

26. The method of claim 21, wherein the amount of 5-aminosalicylic acid is from about 750 mg to about 3000 mg, and the amount of budesonide is from about 1 mg to about 5 mg.

27. The method of claim 26, wherein the amount of cromolyn sodium is about 100 mg.

28. The method of claim 21, wherein the short chain fatty acid is sodium butyrate and the amount administered thereof is about 15 mmol.

29. The method of claim 21, wherein the volume of the enema administered is from about 40 ml to about 80 ml.

30. The method of claim 21, wherein the enema is administered once daily for about three to six weeks, and about twice weekly thereafter.

31. A method of decreasing an ulcerative colitis Mayo Score in a mammal in need of such treatment, comprising:

a) determining the ulcerative colitis Mayo Score of a mammal in need of treatment;

b) rectally administering to said mammal an enema comprising;

i) from about 500 mg to about 5000 mg of 5-aminosalicylic acid;

ii) from about 0.5 mg to about 10 mg of budesonide;

iii) from about 10 to about 1000 mg of cromolyn sodium; and

iv) from about 5 mmol to about 50 mmol of a short chain fatty acid;

c) allowing the contents of the enema to be retained for at least about 4 hours; and

d) repeating said administering step b) daily until a decrease in the ulcerative colitis Mayo Score of ≥

3 is observed.

32. The method of claim 31, wherein the decrease in the ulcerative colitis Mayo Score is observed after about three to six weeks.

33. The method of claim 31, wherein the short chain fatty acid is selected from the group consisting of five, four, three, and two carbon fatty acids.

34. The method of claim 31, wherein the short chain fatty acid is selected from the group consisting of sodium butyrate, proprionate and acetate.