Dose of an angiogenic factor and method of administering to improve myocardial blood flow

Abstract

The present invention has multiple aspects. In one aspect, the present invention is directed to a unit dose pharmaceutical composition comprising from about 5 ng/dose to less than 135,000 ng of an angiogenic agent, typically from 5 ng to 67,500 ng. Preferably, the angiogenic agent is FGF, more preferably it is basic FGF (FGF-2). In its second aspect, the present invention is directed to a method for inducing angiogenesis, or increasing myocardial perfusion or vascular density in a patient's heart, comprising administering directly into the myocardium in an area in need, as a single injection or a series of injections, a unit dose of an angiogenic agent. It is also within the scope of the present invention that a plurality of unit dose compositions be administered directly into the myocardium at a plurality of sites in need of angiogenesis. In another aspect, the present invention is directed to a method for treating a patient for coronary artery disease, comprising administering directly into the myocardium in an area of need of angiogenesis in said patient, a unit dose (i.e., from about 5 ng to less than 135,000 ng) of an angiogenic agent. In yet another aspect, the present invention is directed to a method for treating a patient for a myocardial infarction, comprising administering directly into the myocardium in an area in need of angiogenesis in said patient, a unit dose (i.e., from about 5 ng to less than 135,000 ng) of an angiogenic agent.

What is claimed is:  
     
         1 . A pharmaceutical composition comprising an effective amount of an angiogenic agent in a pharmaceutically acceptable carrier, said effective amount of angiogenic agent being in the range from about 5 ng to less than about 135,000 ng of said angiogenic agent.  
     
     
         2 . The pharmaceutical composition of  claim 1  in lyophilized form.  
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein said angiogenic agent is platelet derived growth factor (PDGF), vascular endothelial growth factor-A (VEGF-A), VEGF-D, fibroblast growth factor (FGF) or an angiogenically active fragment or mutein thereof.  
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said angiogenic agent is VEGF-A, VEGF-D, FGF, or an angiogenically active fragment or mutein thereof.  
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein said VEGF-A is human VEGF-A 121 , VEGF-A 165 , VEGF-A 189 , or VEGF-A 206 .  
     
     
         6 . The pharmaceutical composition of  claim 4 , wherein said angiogenic agent is an FGF or an angiogenically active fragment or mutein thereof.  
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said FGF is an FGF-2 or an angiogenically active fragment or mutein thereof.  
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein said FGF is FGF-2 of SEQ ID NO: 2, 5 or 6.  
     
     
         9 . The pharmaceutical composition of  claim 2 , further comprising an amount of a chelating agent effective to inhibit oxidation of said angiogenic agent.  
     
     
         10 . The pharmaceutical composition of  claim 9 , further comprising an amount of a chelating agent effective to inhibit oxidation of said FGF-2 or said angiogenically active fragment or mutein thereof.  
     
     
         11 . The pharmaceutical composition of  claim 8 , wherein said effective amount of FGF-2 is in the range from 5 ng to 67,500 ng of said angiogenic agent.  
     
     
         12 . A method for increasing vascular perfusion in the myocardium comprising injecting an area of the myocardium in need of an increase in perfusion with an effective amount of an angiogenic agent, said effective amount being within the range of about 5 ng to less than 135,000 ng of an angiogenic agent.  
     
     
         13 . The method of  claim 12 , wherein said effective amount of angiogenic agent is 5 ng to 67,500 ng of PDGF, VEGF-A, VEGF-D, FGF, or an angiogenically active fragment or mutein thereof.  
     
     
         14 . The method of  claim 13 , wherein said angiogenic agent is VEGF-A, VEGF-D, FGF, or an angiogenically active fragment or mutein thereof.  
     
     
         15 . The method of  claim 14 , wherein said VEGF-A is human VEGF-A 121 , VEGF-A 165 , VEGF-A 189 , or VEGF-A 206 .  
     
     
         16 . The method of  claim 14 , wherein said angiogenic agent is an FGF or an angiogenically active fragment or mutein thereof.  
     
     
         17  The method of  claim 16 , wherein said FGF is FGF-2 or an angiogenically active fragment or mutein thereof.  
     
     
         18 . The method of  claim 17 , wherein said FGF-2 has the amino acid sequence of SEQ ID NO: 2, 5 or 6.  
     
     
         19 . A method for increasing vascular density in the myocardium comprising injecting an area of the myocardium in need of an increase in perfusion with an effective amount of an angiogenic agent, said effective amount being within the range of about 5 ng to less than 135,000 ng of an angiogenic agent.  
     
     
         20 . The method of  claim 19 , wherein said effective amount of angiogenic agent is 5 ng to 67,500 ng of PDGF, VEGF-A, VEGF-D, FGF, or an angiogenically active fragment or mutein thereof.  
     
     
         21 . A method for inducing angiogenesis in a heart of a patient, comprising injecting an effective amount of an angiogenic agent directly into the myocardium of said patient in one or more areas in need of angiogenesis, said effective amount of angiogenic agent being from about 5 ng to less than 135,000 ng of said angiogenic agent.  
     
     
         22 . The method of  claim 21 , wherein said effective amount of angiogenic agent is from 5 ng to 67,500 ng of said angiogenic agent.  
     
     
         23 . The method of  claim 22 , wherein said patient is a human patient.  
     
     
         24 . The method of  claim 22 , wherein said human patient has symptoms of coronary artery disease (CAD) or a myocardial infarction (MI).  
     
     
         25 . The method of  claim 23 , wherein said angiogenic agent is PDGF, VEGF-A, VEGF-D, FGF, or an angiogenically active fragment or mutein thereof.  
     
     
         26 . The method  claim 25 , wherein said angiogenic agent is VEGF-A, VEGF-D, FGF, or an angiogenically active fragment or mutein thereof.  
     
     
         27 . The method of  claim 26 , wherein said VEGF-A is human VEGF-A 121 , VEGF-A 165 , VEGF-A 189 , or VEGF-A 206 .  
     
     
         28 . The method of  claim 26 , wherein said angiogenic agent is an FGF or an angiogenically active fragment or mutein thereof.  
     
     
         29 . The method of  claim 28 , wherein said FGF is an FGF-2 or an angiogenically active fragment or mutein thereof.  
     
     
         30 . The method of  claim 29 , wherein said FGF-2 has the amino acid sequence of SEQ ID NO: 2, 5 or 6.  
     
     
         31 . A method for stimulating the production of FGF-2 and VEGF in human myocardial cells for up to three months, comprising injecting an effective amount of an angiogenic agent directly into the myocardium of said patient in one or more areas in need of angiogenesis, said effective amount of angiogenic agent being from about 5 ng to less than 135,000 ng of said angiogenic agent.  
     
     
         32 . The method of  claim 31 , wherein said effective amount of angiogenic agent is 6.75 μg to 67.5 μg of said angiogenic agent.  
     
     
         33 . A method for treating a human patient for coronary artery disease, comprising injecting an effective amount of an angiogenic agent directly into the myocardium in one or more areas in need of treatment for said disease, said effective amount of angiogenic agent being from about 5 ng to less than 135,000 ng of said angiogenic agent.  
     
     
         34 . The method of  claim 33 , wherein said effective amount of angiogenic agent is from 5 ng to 67,500 ng of said angiogenic agent.  
     
     
         35 . The method of  claim 34 , wherein said angiogenic agent is PDGF, VEGF-A, VEGF-D FGF, or is an angiogenically active fragment or mutein thereof.  
     
     
         36 . The method  claim 36 , wherein said angiogenic agent is VEGF-A, VEGF-D FGF, or is an angiogenically active fragment or mutein thereof.  
     
     
         37 . The method of  claim 37 , wherein said VEGF-A is human VEGF-A 121 , VEGF-A 165 , VEGF-A 189 , or VEGF-A 206 .  
     
     
         38 . The method of  claim 37 , wherein said angiogenic agent is an FGF or an angiogenically active fragment or mutein thereof.  
     
     
         39 . The method of  claim 38 , wherein said FGF is FGF-2 or an angiogenically active fragment or mutein thereof.  
     
     
         41 . The method of claim  40 , wherein said FGF-2 has amino acid sequence of SEQ ID NO:2, 5 or 6.