Cytokine modulation

Abstract

The inventions relate to the use of hemichannel blockers to modulate cytokine levels in a subject, including the angiogenic cytokine, VEGF, and their production, secretion and/or release, and to the use of hemichannel blockers to reduce or level cytokine activity, including in conditions characterized in whole or in part by angiogenesis and/or vessel leak.

We claim: 
     
         1 . A method for modulating cytokine activity in a subject, comprising administering an effective amount of a hemichannel blocker to said subject. 
     
     
         2 . The method of  claim 1 , wherein the presence or amount of said cytokine is decreased. 
     
     
         3 . The method of  claim 1 , wherein an increase in the presence or amount of said cytokine is inhibited. 
     
     
         4 . The method of  claim 1 , wherein the cytokine is selected from the group consisting of interleukin-6 (IL-6), an interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and soluble intracellular adhesion molecule-1 (sICAM-1). 
     
     
         5 . The method of  claim 1 , wherein the cytokine is a vascular endothelial growth factor. 
     
     
         6 . The method of  claim 5 , wherein the vascular endothelial growth factor is vascular endothelial growth factor-A. 
     
     
         7 . The method of  claim 1 , wherein the hemichannel blocker is a connexin 43 hemichannel blocker. 
     
     
         8 . The method of  claim 1 , wherein the hemichannel blocker is a small molecule hemichannel blocker. 
     
     
         9 . The method of  claim 8 , wherein the small molecule hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). 
     
     
         10 . The method of  claim 1 , wherein the hemichannel blocker is a connexin peptidomimetic. 
     
     
         11 . The method of  claim 10 , wherein the hemichannel blocker is VDCFLSRPTEKT (SEQ ID NO:1). 
     
     
         12 . The method of  claim 10 , wherein the hemichannel blocker consists essentially of SRPTEKT (SEQ ID NO:2). 
     
     
         13 . The method of  claim 10 , wherein the hemichannel blocker is selected from the group consisting of peptides that consist essentially of ADCFLSRPTEKT (SEQ ID NO:3), VACFLSRPTEKT (SEQ ID NO:4), VDCFLSRPTAKT (SEQ ID NO:5), VDCFLSRPTEAT (SEQ ID NO:6), CFLSRPTEKT (SEQ ID NO:7), and “LSRPTEKT (SEQ ID NO:8). 
     
     
         14 . The method of  claim 1 , wherein the method further comprises administering a VEGF antagonist or a VEGF receptor antagonist. 
     
     
         15 . The method of  claim 14 , wherein the VEGF is VEGF-A. 
     
     
         16 . The method of  claim 1 , wherein the method further comprises administering an IL-6 antagonist or an IL-6 receptor antagonist. 
     
     
         17 . The method of  claim 1 , wherein the method further comprises administering one or more of an IL-8 antagonist, a MCP-1 antagonist or a sICAM-1 antagonist. 
     
     
         18 . The method of  claim 15 , wherein the hemichannel blocker is a connexin 43 hemichannel blocker. 
     
     
         19 . The method of  claim 18 , wherein angiogenesis is reduced or attenuated. 
     
     
         20 . The method of  claim 1 , wherein said hemichannel blocker is administered by injection. 
     
     
         21 . The method of  claim 1 , wherein said hemichannel blocker is administered orally. 
     
     
         22 . The method of  claim 1 , wherein the hemichannel blocker is administered administered PRN or on a predetermined schedule or both. 
     
     
         23 . The method of  claim 1 , wherein the subject is a human. 
     
     
         24 . The method of  claim 10 , wherein the hemichannel blocker is a modified peptidomimetic. 
     
     
         25 . The method of  claim 25 , wherein the modification comprises C12-C12-VDCFLSRPTEKT (SEQ ID NO: 171). 
     
     
         26 . The method of  claim 1 , wherein said subject has a pathological, abnormal, unwanted or undesired amount of cytokine activity.