Model Systems for the Evaluation of Mucolytic Drugs: Acetylcysteine and S-Carboxymethylcysteine

Abstract

The therapeutic place of mucolytic drugs remains uncertain; clinical studies have seldom demonstrated significant benefit and the activity of such agents is poorly understood. In this study the effects of the mucolytic agents acetylcysteine (AC) and S-carboxymethylcysteine (SCMC) have been assessed in-vitro, using purified mucus gels and tracheal explant systems and in-vivo, in the mini-pig tracheal pouch model, in order to elucidate their mechanisms of action. A reduction in the elastic modulus (up to 70% over the frequency range 0.2-20 Hz) was apparent after treatment of mucus gels in-vitro with AC (P less than 0.05), but not with SCMC. Gel chromatography indicated that AC reduced the mucus glycoprotein to smaller subunits and a breakdown of gel structure was apparent when visualized using a cryofracture technique. SCMC treated gels were comparable with control samples. Mucus production was assessed in isolated rat trachea by monitoring the uptake and release of [3H] glucosamine. AC (5-15 mM) did not affect secretion whereas SCMC (5 and 10 mM) reduced the production of radiolabelled material (24 and 37%, respectively) over 24 h (P less than 0.05). Single oral doses of SCMC and AC (20 mg kg-1) were administered to mini-pigs and mucus collected from tracheal pouches; no significant changes in the rheological or biochemical properties of the secretion could be determined. The in-vitro mucolytic activity of AC depends upon a direct action on the secretion, SCMC appears able to reduce production of the mucus glycoprotein. Wide inter- and intra-individual variation in the properties of the secretion would suggest that such effects are not readily demonstrated in-vivo.