Studies on the reduction of sputum viscosity in cystic fibrosis using an orally absorbed protected thiol.

The viscosity of cystic fibrosis fluids leads to clinical difficulties in adequate clearance of the respiratory and gastrointestinal tracts and in delivery of gases and nutrients to their respective sites. Various sulfhydryl agents are effective in reducing in vitro sputum viscosity. Present therapy for cystic fibrosis involves the aerosolization of N-acetylcysteine, presenting problems of toxicity and inadequate delivery to the small airways. We have been assessing various prodrugs which would liberate the free thiol in vivo and which would be orally absorbed. The free thiol of WR 2721, at a concentration of 1 mM, reduces sputum viscosity by 70% in 15 min. WR 2721 is hydrolyzed to the free thiol chemically at an acid pH and enzymatically by homogenates of the liver and gut. It is well absorbed (23%) after oral administration to rabbits. Clinical studies indicate that orally administered WR 2721 is without toxicity and reduces sputum viscosity in cystic fibrosis patients in 30 to 60 min after administration.