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.

Description

FIELD OF THE INVENTION [0001] The invention relates to pharmaceutically acceptable compositions for administration to humans to treat cystic fibrosis and also to methods for effectively utilizing these compositions. BACKGROUND OF THE INVENTION [0002] Cystic fibrosis (CF) is a systemic disorder that results when mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an apical membrane glycoprotein, lead to a reduction in apical membrane chloride transport. CFTR is a cAMP-dependent chloride channel that regulates fluid composition in the respiratory and gastrointestinal tracts. CF is a heritable disease that follows an autosomal recessive pattern of transmission. It is the most common invariably lethal genetic disease in the United States, with frequency among Caucasians being one in two thousand. One in twenty are carriers of the defective gene. CF is characterized by abnormal endocrine and exocrine gland function. In CF, unusually thick mucus leads chronic pulm...

AI Technical Summary

Problems solved by technology

In CF, unusually thick mucus leads chronic pulmonary disease and respiratory infections, insufficient pancreatic and digestive function, and abnormally concentrated sweat.

Lowered temperature results in the appearance of CFTR protein and channel activity at the cell surface, suggesting an intrinsic thermodynamic instability in ΔF508-CFTR at 37° C. that leads to recognition of the mutant protein by the ER quality control mechanism, prevents further trafficking, and results in protein degradation.

These treatments have a number of limitations, and do not address the illness directly, but rather attempt to treat the symptoms.

Some require continuous use at fairly high doses while others have short effective half-lives.

Tolerance to the active ingredient often develops rendering the composition functionally useless.

In addition to problems associated with tolerance, the substances themselves or their metabolic by-products or carriers can quickly reach toxic levels in the patient's system which impair kidney or liver function.

Consequently, in vivo retention times for active compounds are extremely short and the ability to achieve any sort of sustained biological effect becomes nearly impossible or, at least, impractical.

Gene therapy for cystic fibrosis has been attempted, but has not been successful to date for a number of reasons, including problems with delivery of the gene to airway cells, insufficient levels of gene expression, inadequate duration of gene expression, and toxicity of the gene therapy preparations.

These data argue against any beneficial or therapeutic effect of butyrate on cystic fibrosis.

In fact, some authors even stated that butyrate is likely too toxic to use clinically (Rubenstein et al.).

Moreover, 4PBA has been used in a few CF patients clinically, but was not well tolerated due to large number of pills required (i.e. very short half-life), and other side effects and, in consideration, that study was terminated.