COMPOSITIONS AND METHODS FOR REDUCING PROLIFERATION AND VIABILITY OF LYMPHOBLASTOID CELLS

• US 20110281950A1
• Filed: 05/11/2011
• Published: 11/17/2011
• Est. Priority Date: 05/11/2010
• Status: Abandoned Application

• Current Assignee: Robert A. Baiocchi
• Original Assignee: Robert A. Baiocchi
• Inventors: Baiocchi, Robert A.
• Application Number:
  US13/105,576
• Publication Number:
  US 20110281950A1
• Time in Patent Office: Days
• US Class Current: 514/575
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Pharmaceutical compositions including an HDAC inhibitor and a pharmaceutically acceptable carrier wherein the HDAC inhibitor is present in an amount sufficient to achieve a plasma concentration from about 100 nM to about 2 uM and methods of treatment using the same. Pharmaceutical compositions including an HDAC inhibitor and a pharmaceutically acceptable carrier wherein the HDAC inhibitor is present in an amount from 0.1 mg to 100 mg. Pharmaceutical compositions including an HDAC inhibitor and a pharmaceutically acceptable carrier, wherein the concentration of the HDAC inhibitor is sufficient to decrease the relative viability of lymphoblastoid cells by at least about 50 percent and/or is sufficient to decrease the proliferation of lymphoblastoid cells by at least about 60 percent and/or is sufficient to decrease the relative viability of peripheral blood mononuclear cells by less than about 50 percent and methods of treatment using the same.

Claims

1. A pharmaceutical composition comprising an HDAC inhibitor and a pharmaceutically acceptable carrier, wherein the HDAC inhibitor is present in an amount sufficient to achieve a plasma concentration from about 100 nM to about 2 uM in a mammal after administration of the HDAC inhibitor to the mammal.

2. The pharmaceutical composition of claim 1, wherein the HDAC inhibitor is N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide.

3. The pharmaceutical composition of claim 1, wherein the plasma concentration is from about 100 nM to about 1000 nM.

4. The pharmaceutical composition of claim 1, wherein the plasma concentration achieved is from about 250 nM to about 750 nM.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises about 20 mg to about 40 mg of the HDAC inhibitor.

6. A pharmaceutical composition comprising an HDAC inhibitor and a pharmaceutically acceptable carrier, wherein the HDAC inhibitor is present in an amount from about 0.1 mg to about 100 mg.

7. The pharmaceutical composition of claim 6, wherein the HDAC inhibitor is present in an amount from about 10 mg to about 50 mg.

8. The pharmaceutical composition of claim 6, wherein the HDAC inhibitor is present in an amount from about 20 mg to about 40 mg.

9. A pharmaceutical composition comprising an HDAC inhibitor and a pharmaceutically acceptable carrier, wherein the concentration of the HDAC inhibitor is sufficient to decrease the relative viability of lymphoblastoid cells by at least about 50 percent.

10. The pharmaceutical composition of claim 9, wherein the HDAC inhibitor is N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide.

11. The pharmaceutical composition of claim 9, wherein the HDAC inhibitor is present in an amount sufficient to achieve a plasma concentration of about 250 nM in a mammal after administration of the HDAC inhibitor to the mammal.

12. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises about 20 mg to about 40 mg of the HDAC inhibitor.

13. A pharmaceutical composition comprising an HDAC inhibitor and a pharmaceutically acceptable carrier, wherein the concentration of the HDAC inhibitor is sufficient to decrease the proliferation of lymphoblastoid cells by at least about 60 percent.

14. The pharmaceutical composition of claim 13, wherein the HDAC inhibitor is N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide.

15. The pharmaceutical composition of claim 13, wherein the HDAC inhibitor is present in an amount sufficient to achieve a plasma concentration of about 100 nM in a mammal after administration of the HDAC inhibitor to the mammal.

16. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises about 20 mg to about 40 mg of the HDAC inhibitor.

17. A pharmaceutical composition comprising an HDAC inhibitor and a pharmaceutically acceptable carrier, wherein the concentration of the HDAC inhibitor is sufficient to decrease the relative viability of peripheral blood mononuclear cells by less than about 50 percent.

18. The pharmaceutical composition of claim 17, the concentration of the HDAC inhibitor is sufficient to decrease the relative viability of peripheral blood mononuclear cells by less than about 30 percent.

19. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises about 20 mg to about 40 mg of the HDAC inhibitor.

20. A method of decreasing the relative viability of lymphoblastoid cells by at least about 50 percent comprising administering an HDAC inhibitor to a mammal in an amount sufficient to achieve a plasma concentration of about 250 nM in the mammal.

21. The method of claim 20, wherein relative viability of peripheral blood mononuclear cells is decreased by less than about 50 percent.

22. The method of claim 20, wherein relative viability of peripheral blood mononuclear cells is decreased by less than about 30 percent.

23. The method of claim 20, wherein the HDAC inhibitor is N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide.

24. A method of decreasing the proliferation of lymphoblastoid cells'"'"' by at least about 60 percent comprising administering an HDAC inhibitor to a mammal in an amount sufficient to achieve a plasma concentration of about 100 nM in the mammal.

25. The method of claim 24, wherein the relative viability of peripheral blood mononuclear cells is decreased by less than about 50 percent.

26. The method of claim 24, wherein the relative viability of peripheral blood mononuclear cells is decreased by less than about 30 percent.

27. The method of claim 24, wherein the HDAC inhibitor is N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide.

28. A method of treating a lymphoproliferative disease comprising administering an HDAC inhibitor and a pharmaceutically acceptable carrier to a mammal in need of treatment, wherein the HDAC inhibitor is administered in an amount sufficient to achieve a plasma concentration of about 100 nM to about 2 uM in the mammal.

29. The method of claim 28, wherein the plasma concentration is about 100 nM to about 250 nM.

30. The method of claim 28, wherein the plasma concentration is about 250 nM to about 500 nM.

31. The method of claim 28, wherein the plasma concentration is about 500 nM to about 750 nM.

32. The method of claim 28, wherein the plasma concentration is about 750 nM to about 1000 nM.

33. The method of claim 28, wherein the relative viability of peripheral blood mononuclear cells in the mammal is decreased by less than about 50 percent.

34. The method of claim 28, wherein the relative viability of peripheral blood mononuclear cells in the mammal is decreased by less than about 30 percent.

35. The method of claim 28, further comprising terminating or reducing administration of the HDAC inhibitor to the mammal wherein the plasma concentration of the HDAC inhibitor is reduced.

36. The method of claim 35, wherein about 24 hours after terminating or reducing the administration of the HDAC inhibitor, interferon-gamma (IFNγ

) release levels increase by at least 50 percent as compared to interferon-gamma (IFNγ

) release levels during administration of the HDAC inhibitor.

37. The method of claim 35, wherein about 24 hours after terminating or reducing administration of the HDAC inhibitor, granzyme B (GzB) release levels increase by at least 25 percent as compared to granzyme B (GzB) release levels during administration of the HDAC inhibitor.

38. The method of claim 35, wherein about 24 hours after terminating or reducing administration, relative cytotoxicity levels increase by at least 50 percent as compared to relative cytotoxicity levels during administration of the HDAC inhibitor.

39. The method of claim 35, wherein the HDAC inhibitor is N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide.

40. The method of claim 35, wherein the method includes administering and terminating administration of the HDAC inhibitor on alternating days.

41. The method of claim 40, wherein administering and terminating administration of the HDAC inhibitor on alternating days allows washout of the HDAC inhibitor to occur between each administration thereof.