Compositions and methods for the treatment of cystic fibrosis

Abstract

The invention is directed to novel pharmaceutical compositions comprising chemicals agents that are useful in the treatment and prevention of cystic fibrosis and the prevention of signs and symptoms of this disease. These pharmaceutical compositions are surprisingly successful in the treatment disorders related to cystic fibrosis including disorders of blood production. Many of these compositions of the invention are even more effective when administered to a patient in pulses. Pulse therapy is not a form of discontinuous administration of the same amount of a composition over time, but comprises administration of the same dose of the composition at a reduced frequency or administration of reduced doses.

1 . A method for the treatment or prevention of cystic fibrosis comprising the administration of a composition comprising a physiologically-effective amount of one or more agents selected from the group consisting of butyric acid ethyl ester, 2,2-dimethyl butyric acid, 2,2-diethyl butyric acid, 3,3-dimethyl butyric acid, 3,3-diethyl butyric acid, 2,3-dimethyl succinic acid, methoxy acetic acid, phenoxyacetic acid, 2- and 3-thiophenoxy propionic acid, 2- and 3-phenoxy propionic acid, 2- and 3-phenyl propionic acid, 4-chlorophenoxy-2-propionic acid, methoxy acetic acid, or 2-thiophenoxy acetic acid, or a chemical compound of the structure phenyl-R 9 —R 10  wherein R 9  is CH x , CO, NH x , OX x , SH x , or a branched or linear aryl chain; R 10  is CH x , CO, H x , NH x , OH x , SH x , CONH x , COOH, COSH x , COOR x , COR x , CO or OR 11 ; and R 11  is CH x , CO, H x , NH x , OH x , SH x  or a branched or linear alkyl chain; wherein x is 0, 1, 2 or 3.  
   
   
       2 . The method of  claim 1  wherein the chemical compound of the structure phenyl-R9-R10 is selected from the group consisting of acids, amines and amides of cinnamic acid, hydrocinnamic acid, dihydrocinnamic acid, a-methyl hydrocinnamic acid, dihydro cinnamic acid, 2,3-dimethyl hydrocinnamic, dihydrocinnamic acid, phenyl acetate ethyl ester, 2-phenoxypropionic acid, phenoxy acetic acid, or 3-phenyl butyric acid.  
   
   
       3 . The method of  claim 1  wherein the one or more agents is substituted with one or more halogens.  
   
   
       4 . The method of  claim 3  wherein the halogen is selected from the group consisting of chlorine, fluorine, iodine, bromine or mixtures or combinations thereof.  
   
   
       5 . The method of  claim 1  wherein administration is pulsed administration or timed-release administration.  
   
   
       6 . The method of  claim 5  wherein the pulsed administration comprises a plurality of individual pulses delivered to a patient continuously over a period of 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours 16 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, two weeks, three weeks or four weeks.  
   
   
       7 . The method of  claim 5  wherein the pulsed administration comprises a plurality of individual pulses delivered at regular intervals measuring from between 3 to 9 hours.  
   
   
       8 . The method of  claim 1  wherein the composition further comprises a pharmaceutically acceptable carrier.  
   
   
       9 . The method of  claim 1  wherein the composition further comprises a compound that positively affects expression of a CFTR molecule.  
   
   
       10 . The method of  claim 9  wherein the compound that positively affects expression of the CFTR increases the extent or magnitude of CFTR function, increases the expression of the CFTR molecule, increases transport of the CFTR molecule to the cell surface, increases half-life of the CFTR molecule, increases expression from a CFTR gene, increases CFTR transcript levels, increases post-transcriptional processes which increases CFTR transcript levels in the cell, or increases translation post-translational processing of a CFTR gene product.  
   
   
       11 . The method of  claim 1  wherein the agent treats defective chloride ion transport.  
   
   
       12 . A method for the therapy of cystic fibrosis comprising administering to a patient a quantity of an agent, or pharmaceutically acceptable derivatives thereof, effective for said therapy, said agent selected from the group consisting of butyric acid ethyl ester, 2,2-dimethyl butyric acid, 2,2-diethyl butyric acid, 3,3-dimethyl butyric acid, 3,3-diethyl butyric acid, 2,3-dimethyl succinic acid, methoxy acetic acid, phenoxyacetic acid, 2- and 3-thiophenoxy propionic acid, 2- and 3-phenoxy propionic acid, 2- and 3-phenyl propionic acid, 4-chlorophenoxy-2-propionic acid, methoxy acetic acid, 2-thiophenoxy acetic acid, or a chemical compound f the structure phenyl-R 9 —R 10  wherein R 9  is CH x , CO, NH x , OH x , SH x , or a branched or linear aryl chain; R 10  is CH x , CO, H x , NH x , OH x , SH x , CONH x , COOH, COSH x , COOR 11 , COR 11 , CO or OR 11 ; and R 11  is CH x , CO, H x , NH x , OH x , SH x  or a branched or linear alkyl chain; wherein x is 0, 1, 2 or 3.  
   
   
       13 . The method of  claim 12  wherein the chemical compound of the structure phenyl-R9-R10 is selected from the group consisting of acids, amines and amides of cinnamic acid, hydrocinnamic acid, dihydriocinnamic acid, a-methyl hydrocinnamic acid, dihydro cinnamic acid, 2,3-dimethyl hydrocinnamic, dihydrocinnamic acid, phenyl acetate ethyl ester, 2-phenoxypropionic acid, phenoxy acetic acid, and 3-phenyl butyric acid.  
   
   
       14 . A method for enhancing expression of CFTR comprising the administration of a physiologically effective amount of one or more agents or pharmaceutically acceptable derivatives thereof, said agents selected from the group consisting of butyric acid ethyl ester, 2,2-dimethyl butyric acid, 2,2-diethyl butyric acid, 3,3-dimethyl butyric acid, 3,3-diethyl butyric acid, 2,3-dimethyl succinic acid, methoxy acetic acid, phenoxyacetic acid, 2- and 3-thiophenoxy propionic acid, 2- and 3-phenoxy propionic acid, 2- and 3-phenyl propionic acid, 4-chlorophenoxy-2-propionic acid, methoxy acetic acid, 2-thiophenoxy acetic acid, and chemical compounds of the structure phenyl-R 9 —R 10  wherein R 9  is CH x , CO, NH x , OH x , SH x , or a branched or linear aryl chain; R 10  is CH x , CO, H x , NH x , OH x , SH x CONH x , COOH, COSH x , COOR 11 , COR 11 , CO or OR 11 ; and R 11  is CH x , CO, H x , NH x , OH x , SH x  or a branched or linear alkyl chain; wherein x is 0, 1, 2 or 3.  
   
   
       15 . The method of  claim 14  wherein the chemical compounds of the structure phenyl-R 9 —R 10  are selected from the group consisting of acids, amines and amides of cinnamic acid, hydrocynnamic acid, dihydrocinnamic acid, a-methyl hydrocinnamic acid, dihydro cinnamic acid, 2,3-dimethyl hydrocinnamic, dihydrocinnamic acid, phenyl acetate ethyl ester, 2-phenoxypropionic acid, phenoxy acetic acid, and 3-phenyl butyric acid.  
   
   
       16 . The method of  claim 14  wherein administration is pulsed administration.  
   
   
       17 . The method of  claim 14  wherein enhancement of the expression of CFTR comprises increasing the expression of CFTR genes, increasing the number of CFTR-expressing cells or increasing the function or activity of CFTR.  
   
   
       18 . The method of  claim 14  wherein CFTR expression is enhanced greater than about 30%.  
   
   
       19 . The method of  claim 14  wherein CFTR expression is enhanced greater than about 100%.  
   
   
       20 . The method of  claim 14  wherein CFTR expression is enhanced greater than about 200%.