Co-administration of an agent linked to an internalization peptide with an anti-inflammatory

Abstract

The invention provides methods of delivering pharmacologic agents linked to an internalization peptide, in which an inflammatory response inducible by the internalization peptide is inhibited by co-administration of an anti-inflammatory or by linking the internalization peptide to biotin or similar molecule. Such methods are premised in part on the results described in the examples whereby administration of a pharmacological agent linked to tat at high dosages is closely followed by an inflammatory response, which includes mast cell degranulation, histamine release and the typical sequelae of histamine release, such as redness, heat, swelling, and hypotension.

1 . A method of inhibiting cerebral ischemia due to endovascular surgery, comprising:
 administering to a subject undergoing endovascular surgery a pharmacologic agent that inhibits binding of PSD95 to NDMAR 2B linked to an internalization peptide in a regime effective to inhibit cerebral ischemia; and   administering to the subject a mast cell degranulation inhibitor, whereby the mast cell degranulation inhibitor can inhibit an-anti-inflammatory response inducible by the internalization peptide and/or the mast cell degranulation inhibitor is administered within a period of 30 minutes before to 15 minutes after the pharmacological agent.   
     
     
         2 . A pharmacologic agent that inhibits binding of PSD95 to NDMAR 2B linked to an internalization peptide for use in inhibiting cerebral ischemia due to endovascular surgery in combination with a mast cell degranulation inhibitor to inhibit an inflammatory response inducible by the internalization peptide 
     
     
         3 . A mast cell degranulation inhibitor for use in inhibiting cerebral ischemia due to endovascular surgery in combination with a pharmacologic agent that inhibits binding of PSD95 to NDMAR 2B linked to an internalization peptide, wherein the mast cell degranulation inhibitor inhibits an inflammatory response inducible by the internalization peptide. 
     
     
         3 . The method, agent or inhibitor of  claim 1 , wherein the mast cell degranulation inhibitor is administered at the same time as or up to 15 minutes before the pharmacological agent. 
     
     
         4 . The method, agent or inhibitor of  claim 1 , wherein the mast cell degranulation inhibitor is co-formulated with the pharmacologic agent. 
     
     
         5 . The method, agent or inhibitor of  claim 1 , wherein the mast cell degranulation inhibitor is administered by a peripheral route. 
     
     
         6 . The method, agent or inhibitor of  claim 1 , wherein the mast cell degranulation inhibitor and pharmacologic agent are administered intravenously. 
     
     
         7 . The method, agent or inhibitor of  claim 1 , wherein the subject is suffering from an episode of a disease and the pharmacological agent and the mast cell degranulation inhibitor are administered once during the disease episode. 
     
     
         8 . The method, agent or inhibitor of  claim 1 , wherein the administration of the mast cell degranulation inhibitor does not comport with a recurring regime of administering the mast cell degranulation inhibitor to the patient without the pharmacologic agent. 
     
     
         9 . The method, agent or inhibitor of  claim 1 , wherein the internalization peptide is a tat peptide. 
     
     
         10 . The method, agent or inhibitor of  claim 9 , wherein the tat peptide has an amino acid sequence comprising RKKRRQRRR (SEQ ID NO:51) or GRKKRRQRRR (SEQ ID NO:1). 
     
     
         11 . The method, agent or inhibitor of  claim 10 , wherein the tat peptide has an amino acid sequence comprising YGRKKRRQRRR (SEQ ID NO:2). 
     
     
         12 . The method, agent or inhibitor of  claim 10  wherein the tat peptide has an amino acid sequence comprising of FGRKKRRQRRR (SEQ ID NO:3). 
     
     
         13 . The method, agent or inhibitor of  claim 10 , wherein the tat peptide has an amino acid sequence comprising GRKKRRQRRRP (SEQ ID NO:4). 
     
     
         14 . The method, agent or inhibitor of  claim 1 , wherein the pharmacologic agent is a peptide. 
     
     
         15 . The method or use of  claim 1 , wherein the pharmacologic agent is KLSSIESDV (SEQ ID NO:5). 
     
     
         16 - 47 . (canceled)