Methods and compositions for treating lupus

• US 8,748,475 B2
• Filed: 08/03/2011
• Issued: 06/10/2014
• Est. Priority Date: 01/12/2004
• Status: Expired due to Term

• Current Assignee: Natrogen Therapeutics International, Inc.
• Original Assignee: Natrogen Therapeutics International, Inc.
• Inventors: Wang, Longgui, Mencher, Simon K.
• Primary Examiner(s): Blanchard, David J
• Assistant Examiner(s): Gotfredson, Garen
• Application Number:
  US13/197,164
• Publication Number:
  US 20120058121A1
• Time in Patent Office: 1,042 Days
• Field of Search: None
• US Class Current: 514/414
• 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 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue

Abstract

The invention relates to compositions and methods for treating lupus. The methods typically comprise the step of administrating one or more compounds selected from isoindigo, indigo, indirubin, or derivatives thereof, such as, Meisoindigo and NATURA in an amount sufficient to treat the lupus; preferably by modulating cytokine expression. Preferably the compound is in an amount less than sufficient to substantially inhibit cyclin dependent kinases.

Claims

1. A method of treating an animal with lupus nephritis, the method comprising the step of administering to the animal in need of such treatment at least one compound selected from the group of:

Meisoindigo, tri-acetylated glyco-Meisoindigo (pro-drug) or 1-(β

-D-O-triacetyl-xylopyranosyl)-isoindigo, shown as Formulas (IV), (V), and (VI) respectively,

2. The method according to claim 1, wherein the amount administered is sufficient to inhibit pro-inflammatory cytokine expression and/or stimulate anti-inflammatory cytokine expression, but the amount is less than sufficient to substantially inhibit cyclin dependent kinases.

3. The method according to claim 1, wherein the amount administered is less than about 0.36 mmol/kg per day.

4. The method according to claim 3, wherein the compound administered is Meisoindigo and the amount administered is less than about 100 mg/kg per day.

5. The method according to claim 3, wherein the amount administered is between 0.036 mmol/kg and 0.288 mmol/kg per day.

6. The method according to claim 4, wherein the amount administered is between 10 mg and 80 mg per day.

7. The method according to claim 1, wherein the animal is a human.

8. The method according to claim 2, wherein the compound is administered in an amount sufficient to inhibit cytokine IL-1α

, β

, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, TNF-α

, LT, LIF, Oncostatin, or IFNc1α

, β

, γ

.

9. The method according to claim 2, where the compound is administered in an amount sufficient to stimulate expression of cytokine IL-4, IL-10, IL-11, W-13 or TGFβ

.

10. The method according to claim 2, where the compound is administered in an amount sufficient to modulate cytokines TNF-α

, IL-1β

, IL-6, and IL-10.

11. The method according to claim 1, where the compound is administered in an amount sufficient to reduce proteinuria levels and/or sufficient to modulate a humoral response.

12. The method according to claim 11, wherein modulation of a humoral response includes a decrease in total IgG antibody within the animal.

13. A method of treating lupus nephritis, the method comprising the step of administering to an animal in need of such treatment at least a first and a second compound, wherein the first compound is selected from the group of:

Meisoindigo, tri-acetylated glyco-Meisoindigo (pro-drug) or 1-(β

-D-O-triacetyl-xylopyranosyl)-isoindigo, shown as Formulas (IV), (V), and (VI) respectively,

14. The method according to claim 13, wherein the first compound is administered in an amount sufficient to inhibit pro-inflammatory cytokine expression and/or stimulate anti-inflammatory cytokine expression, but the amount is less than sufficient to substantially inhibit cyclin dependent kinases.

15. The method according to claim 13, wherein the compounds are administered concurrently within a single composition.

16. The method according to claim 13, wherein the compounds are administered sequentially.

17. The method according to claim 13, wherein the second compound is selected from the group of:

ibuprofen, corticosteroid, methotrexate, or BLyS-specific inhibitors.

18. The method according to claim 17, wherein the BLyS-specific inhibitor is belimumab.

19. The method according to claim 13, wherein the first compound is administered in an amount less than about 0.36 mmol/kg per day.

20. The method of claim 17, wherein the first compound is administered in an amount between 0.036 mmol/kg and 0.288 mmol/kg per day.

21. The method according to claim 13, wherein the animal is a human.

22. The method according to claim 13, wherein the first compound is administered in an amount sufficient to inhibit cytokine IL-1α

, β

, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, TNF-α

, LT, LIF, Oncostatin, or IFNc1α

, β

, γ

; and

/or sufficient to stimulate expression of cytokine IL-4, IL-10, IL-11, W-13 or TGFβ

.

23. The method according to claim 13, where the first compound is administered in an amount sufficient to modulate cytokines TNF-α

, IL-1β

, IL-6, and IL-10.

24. The method according to claim 13, where the first compound is administered in an amount sufficient to reduce proteinuria levels and/or sufficient to modulate a humoral response.

25. The method according to claim 24, wherein modulation of a humoral response includes a decrease in total IgG antibody within the animal.

26. A composition for treating lupus nephritis, the compositions comprising an active compound, an agent, and a pharmaceutically acceptable carrier, wherein the active compound is selected from the group of:

Meisoindigo, tri-acetylated glyco-Meisoindigo (pro-drug) or 1-(β

-D-O-triacetyl-xylopyranosyl)-isoindigo, shown as Formulas (IV), (V), and (VI) respectively,

27. The composition of claim 26, wherein the anti-inflammatory agent is ibuprofen, the immune suppressant agent is methotrexate, and the biologic drug is a BLyS-specific inhibitor.

28. The composition of claim 27, wherein the BLyS-specific inhibitor is belimumab.

30. The method of claim 27, wherein the nephritis is glomerulonephritis.

29. A method of treating an animal with nephritis, the method comprising the step of administering to the animal in need of such treatment at least one compound selected from the group of:

Meisoindigo, tri-acetylated glyco-Meisoindigo (pro-drug) or 1-(β

-D-O-triacetyl-xylopyranosyl)-isoindigo, shown as Formulas (IV), (V), and (VI) respectively,