Reducing myocardial damage and the incidence of arrhythmia arising from loss, reduction or interruption in coronary blood flow

Abstract

A method is disclosed for reducing the extent of myocardial cell damage or cell death arising from hypoxia or a loss, reduction or interruption in coronary blood flow comprising administering a pharmaceutical composition which includes riluzole or a pharmaceutically acceptable salt or derivative thereof. The method further discloses administering the pharmaceutical composition to reduce the incidence and severity of arrhythmias arising from the hypoxia or loss, reduction or interruption in coronary blood flow. The method also discloses treating a sequence of pathological events with the pharmaceutical composition wherein the sequence involves a cellular influx of sodium via persistent sodium channels, and the development of myocardial cellular damage or myocardial cellular death.

We claim: 
     
         1 . A method of reducing the extent of myocardial cell damage or cell death in a mammalian heart arising from hypoxia or a loss, reduction or interruption in coronary blood flow comprising administering to the mammal a pharmaceutical composition which includes riluzole or a pharmaceutically acceptable salt or derivative thereof. 
     
     
         2 . The method of  claim 1  wherein the mammal is human. 
     
     
         3 . The method of  claim 2  wherein the myocardial cell damage or cell death arises in a region of the heart, and the pharmaceutical composition reduces the extent of myocardial cell damage or cell death in the region. 
     
     
         4 . The method of  claim 2  wherein the myocardial cell damage or cell death arises in a region of the heart, and the pharmaceutical composition reduces the size of the region. 
     
     
         5 . The method of  claim 2  wherein the myocardial cell damage or cell death arises in a region of the heart and the region is bounded by a border zone, and the pharmaceutical composition reduces one or more of the extent of myocardial cell damage or cell death in the border zone, the size of the inside border, the size of the outside border, and the volume of the border zone. 
     
     
         6 . The method of  claim 2  wherein the myocardial cell damage or cell death is reperfusion injury. 
     
     
         7 . The method of  claim 2  wherein arrhythmias may also arise from the hypoxia or loss, reduction or interruption in coronary blood flow, and wherein the pharmaceutical composition reduces the incidence of the arrhythmias. 
     
     
         8 . The method of  claim 2  wherein arrhythmias may arise from the myocardial cell damage or cell death, and wherein the pharmaceutical composition reduces the incidence of the arrhythmias by reducing the extent of the myocardial cell damage or cell death. 
     
     
         9 . The method of  claim 4  wherein the pharmaceutical composition reduces the size of the region to a size smaller than that which is required to maintain a re-entrant circuit thereby either reducing or eliminating the incidence of re-entrant arrhythmias from arising from the hypoxia or loss, reduction or interruption in coronary blood flow, or causing arising re-entrant arrhythmias to self-terminate. 
     
     
         10 . The method of  claim 7  wherein the arrhythmias are non-lethal, and the pharmaceutical composition reduces or eliminates the incidence of the non-lethal arrhythmias converting to, or initiating, lethal arrhythmias. 
     
     
         11 . The method of  claim 7  wherein the arrhythmias are reperfusion arrhythmias. 
     
     
         12 . The method of  claim 2  wherein the myocardial cell damage or cell death causes haemodynamic compromise, and wherein the pharmaceutical composition reduces the level of haemodynamic compromise by reducing the extent of the myocardial cell damage or cell death. 
     
     
         13 . The method of  claim 2  wherein the pharmaceutical composition is administered prophylactically. 
     
     
         14 . A method for treating, ameliorating or preventing a sequence of pathological events, said sequence of pathological events occurring in mammalian cardiac tissue and including a loss, reduction or interruption to the blood supply or oxygen supply in one or more coronary vessels or regions of the heart, an onset of hypoxia, and a cellular influx of sodium via persistent sodium channels, wherein the influx of sodium leads to the development of myocardial cellular damage or myocardial cellular death, wherein the method involves the step of administering to the mammal an effective amount of one or more pharmaceutical compositions which include one or more compounds which when used individually or in combination block or partially block persistent sodium channels in mammalian cardiac cell membranes, and further wherein one of the compounds is riluzole or a pharmaceutically acceptable salt or derivative thereof. 
     
     
         15 . The method of  claim 14  wherein the influx of sodium or the development of myocardial cellular damage or cellular death leads to the development of one or more cardiac arrhythmias from the group: automatic arrhythmias, re-entrant arrhythmias, triggered activity arrhythmias, one or more beats in the form of any one or more of premature contractions, ectopic beats, bigeminy, trigeminy or any other single or multiple or alternating group of beats or any other sustained or non-sustained lethal or non-lethal cardiac arrhythmia, and wherein the pharmaceutical compositions reduce or eliminate the incidence of the one or more cardiac arrhythmias. 
     
     
         16 . The method of  claim 14  wherein the pharmaceutical compositions reduce or eliminate the extent of the myocardial cellular damage or cellular death, or reduce the size of the inside or outside border of a border zone surrounding a region of myocardial cellular damage or cellular death, or reduce the volume of such a border zone. 
     
     
         17 . The method of  claim 14  wherein the pharmaceutical compositions are administered in multiple doses either via a single route or via different routes. 
     
     
         18 . The method of  claim 14  wherein the pharmaceutical compositions have at least a 10-fold selectivity or preferably a 20-fold, a 50-fold or most preferably a 100-fold selectivity for cardiac persistent sodium currents relative to cardiac transient sodium currents. 
     
     
         19 . The method of  claim 15  wherein the pharmaceutical compositions reduce or avert a decrease in quality of life by reducing or eliminating the extent or the occurrence of the myocardial cellular damage or cellular death, or the incidence of the cardiac arrhythmias. 
     
     
         20 . A method for providing cardio-protection against arrhythmias and myocardial cell damage or cell death in a mammalian heart arising from hypoxia or a loss, reduction or interruption in coronary blood flow comprising administering to the mammal a pharmaceutical composition which includes riluzole or a pharmaceutically acceptable salt or derivative thereof.