| Cystic fibrosis is a genetic disease inherited as an autosomal recessive trait. Clinically, it is manifested by increased viscosity of the exocrine secretions, especially those of the respiratory and gastrointestinal tracts. The biochemical basis for this abnormal rheological behavior is unknown.;It has long been suspected that the major macromolecular components of sputum, the mucins, are responsible for the rheological properties of sputum. However, the technical difficulties of working with crude sputum and the observation that sputum is rendered much less viscous by treatment with disulfide reducing agents has led to the routine pretreatment of sputum for biochemical analysis with disulfide reducing agents. This practice has precluded the biochemical and rheological examination of native mucin.;In the present investigation, mucins were isolated from the sputum of patients with cystic fibrosis, pneumococcal pneumonia, and chronic bronchitis without the use of disulfide reducing agents. Examination of native mucin has shown it to be a glycoprotein which is 80% carbohydrate by weight. This glycoprotein consists of a glycosylated portion (core glycoprotein) which is disulfide-linked to a 70,000 Dalton protein. The rheological behavior of this mucin mimics that of whole sputum. The propensity of mucin for aggregation is responsible for its high intrinsic viscosity. Disulfide reduction of mucin leads, not only to the cleavage of the molecule into its component parts, but to a decrease in soluble aggregate size, as well.;The rheological and biochemical characteristics of mucins form the basis for the rational design of mucolytic agents for use in cystic fibrosis. N-acetylcysteine has been used as an aerosol with limited success because of its irritative nature and its limited delivery to the small airways through an already compromised respiratory tract. We have developed the concept of an orally absorbed prodrug, a protected thiol, which would be delivered to the lungs and activated in vivo to the free thiol. WR 2721 is a thiophosphate whose free thiol analogue is an active in vitro mucolytic agent. It is converted in vivo to the free thiol, is delivered to the lungs, and can be shown to bind via mixed disulfide formation to plasma and sputum proteins. Clinical trials conducted to date indicate that WR 2721 is relatively non-toxic at doses of up to 20mg/kg/day p.o. for up to one month, and that it may be an effective in vivo mucolytic agent in patients with cystic fibrosis. These studies also suggest the possibility that the mucolytic effect of WR 2721 may decrease the rate of pulmonary function deterioration in patients with cystic fibrosis. |
