CYSTIC FIBROSIS

Cystic Fibrosis

Cystic Fibrosis

Introduction

Cystic fibrosis (CF) is an auto somal recessive disorder that affects approximately 1 in 3000 Caucasian births, or 30,000 individuals in the US and 70,000 worldwide. It is the most common life-shortening genetic disorder in the White population, and less frequently other racial and ethnic groups. Mutations of the cystic fibrosis trans membrane regulator (CTFR) gene account for the clinical manifestations of the disease; about 1500 mutations in CFTR are described, but only 22 occur with significant frequency and the pheno typical distribution varies considerably. The most common mutation, occurring in 70% of patients is the F508del, which results in an abnormal protein that is largely ubiquitinated in the endoplasmic reticulum and degraded in the proteasome (Boehler, 2003).

CFTR is found on apical membranes of epithelial cells and functions as a chloride channel. A non functioning CFTR restricts chloride secretion and increases sodium reabsorption, limiting the amount of water that can passively move across the epithelium. This depletes the airway surface liquid, which in turn impairs mucociliary clearance. The result is impaired host defenses and chronic bacterial airway infection. CF is also characterized by a hyperactive airway inflammatory response which cannot be fully accounted for by chronic bacterial infections. CF patients usually present in infancy or childhood with failure to thrive due to pancreatic insufficiency, chronic cough and sputum production, persistent lung and sinus infections, nasal polyps, and digital clubbing. Other presenting manifestations include biliary cirrhosis, rectal prolapse, hypoproteinemia, salt loss syndrome and obstructive azoospermia. Respiratory failure accounts for over 90% of deaths. Classic CF is the result of two mutations that cause severe disease. Non classic disease has at least one mutant CFTR allele that confers partial function and these patients are generally diagnosed later in life. There is great variability in phenotype and survival in CF. This variability exists even in patients homozygous for F508del and is likely due to modifier genes and poorly understood environmental factors. These include aggressive treatment with antibiotics and drugs targeted to slow the decline of lung function. Indeed, survival in CF improved markedly over the years, manifested by a growing number of adults with this disease. In this article a review would be made for the drugs approved for CF and describe other therapies in development (Davis, 2006).

Inhaled antibiotics

In the early stages of disease, Staphylococcus aureus and Haemophilus influenzae are the most common organisms found in the lungs of patients with CF; Pseudomonas aeruginosa (PA) becomes more dominant later in life, and emerges as the most common microbe causing illness in adult patients. Initial infection may be related to increased adherence of PA to the receptors in CF airways. Once PA airway infection is established, eradication becomes extremely difficult. Most patients respond clinically to antibiotics even though sputum cultures remain positive. Infection with the mucoid form of PA is associated with more rapid decline of lung function and poorer survival than infection with nonmucoid strains (Gershman, 2006).

FDA-approved agents

Inhaled aminoglycosides have a high therapeutic index because ...