Compositions and methods for treating tissue ischemia

1 . A method of treating tissue ischemia comprising administering to a subject a therapeutically effective amount of a CXCR4 antagonist, wherein the CXCR antagonist elevates the peripheral blood endothelial progenitor cell (EPC) count of the subject, thereby treating the tissue ischemia in the subject.

2 . The method of claim 1 , further comprising administering a therapeutically effective amount of an agent that promotes EPC proliferation to the subject.

3 . The method of claim 2 , wherein the agent that promotes EPC proliferation is administered to the subject prior to the administration of the CXCR4 antagonist.

4 . The method of claim 2 , wherein the agent that promotes EPC proliferation is SDF-1.

5 . The method of claim 2 , wherein the agent that promotes EPC proliferation is selected from the group consisting of GRO-β, a Flt-3 ligand, a glutathione S-transferase inhibitor, angiotensin or an analog thereof, a CD26 inhibitor, a VLA4 inhibitor, and a kit ligand.

6 . The method of any of claims 1 - 5 , further comprising administering a therapeutically effective amount of an inhibitor of vascular endothelial growth factor-mediated vascular permeability to the subject.

7 . The method of any of claims 1 - 6 , further comprising:

a) removing EPCs from the subject,

b) contacting the EPCs with a therapeutically effective amount of an agent that promotes EPC proliferation, and

c) returning the EPCs to the subject.

8 . The method of any of claims 1 - 7 , wherein the subject has had or is having an acute myocardial infarction.

9 . The method of claim 8 , wherein the CXCR4 antagonist is administered to the subject less about 12 hours or less after suffering from an acute myocardial infarction.

10 . The method of any of claims 1 - 9 , wherein the subject is suffering from or at risk for developing restenosis.

11 . The method of any of claims 1 - 10 , wherein the subject has suffered or is suffering from a disorder or condition selected from the group consisting of arteriosclerosis, stroke, chronic ischemia of myocardium, chronic ischemia of lower extremities, and organ regeneration in mycoardium, limbs, brain, or liver.

12 . The method of any of claims 1 - 11 , wherein the CXCR4 antagonist is administered to the subject by an intravenous or subcutaneous route.

13 . The method of any of claims 1 - 12 , wherein the CXCR4 antagonist is administered to the subject in the dosage range of about 0.1 μg/kg-5 mg/kg of body weight.

14 . The method of any of claims 1 - 13 , wherein the CXCR4 antagonist is administered to the subject in a single dose or by continuous infusion.

15 . The method of any of claims 1 - 14 , wherein the CXCR4 antagonist has the formula:

Z-linker-Z′

or a pharmaceutically acceptable salt thereof

wherein Z is a cyclic polyamine containing 9-32 ring members of which 3-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;

wherein Z′ may be embodied in a form as defined by Z above, or alternatively may be of the formula

—N(R)—(CR 2 ) n —X  (1)

wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan; and

wherin “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.

16 . The method of claim 15 , wherein Z and Z′ are both cyclic polyamines.

17 . The method of any of claims 15 - 16 , wherein Z and Z′ are identical.

18 . The method of any of claims 15 - 16 , wherein Z contains 12-24 members and contains 4 nitrogen atoms.

19 . The method of any of claims 15 - 18 , wherein Z and Z′ are both 1,4,8,11-tetraazocyclotetradecane.

20 . The method of any of claims 15 - 19 , wherein the linker comprises an aromatic ring bracketed by two methylene moieties.

21 . The method of any of claims 15 - 20 , wherein the linker is 1,4-phenylene-bis-methylene.

22 . The method of any of claims 1 - 21 , wherein the CXCR4 antagonist is 1,1′-1,4-phenylene-bis-(methylene)-bis-1,4,8,11-tetraazacyclotetradecane (AMD-3100).

23 . The method of claim 15 , wherein the CXCR4 antagonist is selected from the group consisting of:

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-aminomethyl)pyridine;

7,7′-[1,4-phenylenebis(methylene)]bis-4,7,10,17-tetraazabicyclo-[13.3.1]heptadeca-1(17),13,15-triene;

7,7′-[1,4-phenylenebis(methylene)]bis-3,7,11,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-triene;

1,1′-[1,3-phenylenebis(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecane;

1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecane;

1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane;

1,1′-[1,3-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane;

11,11′-(1,2-propanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

N-[4-(1,4,7-triazacyclotetra-decane)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,7,10-triazabicyclo[13.3.1]heptadeca-[(17),13,15-triene)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,7,10,17-tetraazabicyclo[13.3.1]heptadeca-1 (17),13,15-triene)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine; and

N-[4-[4,7,10,17-tetraazabicyclo[13.3.1]heptadeca-1 (17),13,15-triene]-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine.

24 . The method of any of claims 15 - 23 , wherein formula (1) is in the form of a pharmaceutically acceptable salt.

25 . The method of claim 24 , wherein the pharmaceutically acceptable salt is an acid addition salt.