Methods for Administration and Methods for Treating Cardiovascular Diseases with Resiniferatoxin

Abstract

There is disclosed a method for administration of a formulation of resiniferatoxin (RTX) to provide cardiac sympathetic afferent denervation when applied in an amount and concentration sufficient to chemically denervate vanilloid 1 receptor (TRPV1)-expressing CSAR (cardiac sympathetic afferent reflex) afferents. There is further disclosed a method for treating heart failure or hypertension and its related indications selected from the group consisting of increased sympatho-excitation, cardiac hypertrophy, increased left ventricular end diastolic pressure (LVEDP), lung edema, and combinations thereof, comprising administering an effective amount of RTX directly to a tissue site selected from the group consisting of epicardium, a T1-T4 dorsal root ganglion and intrathecally to the T1-T4 region of the spinal column.

We claim: 
     
         1 . A method for administration of a formulation of resiniferatoxin (RTX) directly onto the epicardium, comprising applying a formulation of RTX directly onto the epicardium under the pericardial sac. 
     
     
         2 . The method for administration of a formulation of RTX of  claim 1 , wherein the concentration of RTX applied to the epicardium is from about 100 ng/ml to about 500 μg/ml. 
     
     
         3 . The method for administration of a formulation of RTX of  claim 1 , wherein the concentration of RTX applied to the epicardium is from about 5 μg/ml to about 80 μg/ml. 
     
     
         4 . The method for administration of a formulation of RTX of  claim 1 , wherein the concentration of RTX applied to the epicardium is from about from about 20 μg/ml to about 60 μg/ml. 
     
     
         5 . The method for administration of a formulation of RTX of  claim 1 , wherein, in a human, the administration of RTX is accomplished by a technique selected from the group consisting of pericardiocentesis and catheter based administration into the coronary artery circulation. 
     
     
         6 . A method for administration of RTX comprising a technique selected from the group consisting of pericardiocentesis, catheter based administration into the coronary artery circulation, intrathecal administration to a T1-T4 location and intraganglionic administration to a T1-T4 ganglion whereby the RTX provides cardiac sympathetic afferent denervation in an amount and concentration sufficient to chemically denervate vanilloid 1 receptor (TRPV1)-expressing CSAR (cardiac sympathetic afferent reflex) afferents. 
     
     
         7 . The method for the administration of RTX of  claim 6 , wherein the concentration of RTX administered is from about 100 ng/ml to about 500 μg/ml. 
     
     
         8 . The method for the administration of RTX of  claim 6 , wherein the concentration of RTX administered is from about 5 μg/ml to about 80 μg/ml. 
     
     
         9 . The method for the administration of RTX of  claim 6 , wherein the concentration of RTX administered is from about from about 20 μg/ml to about 60 μg/ml. 
     
     
         10 . A method for treating heart failure or hypertension and its related indications, comprising administering an effective amount of RTX directly to a tissue site selected from the group consisting of epicardium, dorsal root ganglion and intrathecally to the T1-T4 region of the spinal column, wherein the symptoms of heart failure are selected from the group consisting of increased sympatho-excitation, cardiac hypertrophy, increased left ventricular endodiasolic pressure (LVEDP), lung edema, and combinations thereof. 
     
     
         11 . The method for treating heart failure or hypertension and its related indications of  claim 10 , wherein the concentration of RTX administered is from about 100 ng/ml to about 500 μg/ml. 
     
     
         12 . The method for treating heart failure or hypertension and its related indications of  claim 10 , wherein the concentration of RTX administered is from about 5 μg/ml to about 80 μg/ml. 
     
     
         13 . The method for treating heart failure or hypertension and its related indications of  claim 10 , wherein the concentration of RTX administered is from about from about 20 μg/ml to about 60 μg/ml. 
     
     
         14 . The method for treating heart failure or hypertension and its related indications of  claim 10 , wherein, in a human, the administration of RTX is accomplished by a technique selected from the group consisting of pericardiocentesis, catheter based administration into the coronary artery circulation, intrathecal administration to a T1-T4 location and intraganglionic administration to a T1-T4 ganglion. 
     
     
         15 . A method for preventing cardiac fibrosis following an MI, comprising administering RTX as soon as possible following an MI. 
     
     
         16 . The method for preventing cardiac fibrosis following an MI of  claim 15 , wherein the concentration of RTX administered is from about 100 ng/ml to about 500 μg/ml. 
     
     
         17 . The method for preventing cardiac fibrosis following an MI of  claim 15 , wherein the concentration of RTX administered is from about 5 μg/ml to about 80 μg/ml. 
     
     
         18 . The method for preventing cardiac fibrosis following an MI of  claim 15 , wherein the concentration of RTX administered is from about from about 20 μg/ml to about 60 μg/ml. 
     
     
         19 . The method for preventing cardiac fibrosis following an MI of  claim 15 , wherein, in a human, the administration of RTX is accomplished by a technique selected from the group consisting of pericardiocentesis, catheter based administration into the coronary artery circulation, intrathecal administration to a T1-T4 location and intraganglionic administration to a T1-T4 ganglion. 
     
     
         20 . A method for reducing cardiac inflammation in an infracted heart, comprising administering RTX as soon as possible following an infarction. 
     
     
         21 . The method for reducing cardiac inflammation in an infracted heart of  claim 20 , wherein the concentration of RTX administered is from about 100 ng/ml to about 500 μg/ml. 
     
     
         22 . The method for reducing cardiac inflammation in an infracted heart of  claim 20 , wherein the concentration of RTX administered is from about 5 μg/ml to about 80 μg/ml. 
     
     
         23 . The method for reducing cardiac inflammation in an infracted heart of  claim 20 , wherein the concentration of RTX administered is from about from about 20 μg/ml to about 60 μg/ml. 
     
     
         24 . The method for reducing cardiac inflammation in an infracted heart of  claim 20 , wherein, in a human, the administration of RTX is accomplished by a technique selected from the group consisting of pericardiocentesis, catheter based administration into the coronary artery circulation, intrathecal administration to a T1-T4 location and intraganglionic administration to a T1-T4 ganglion.