Add-On Dextromethorphan Improves the Effects of Pirfenidone in Bleomycin-Treated Mice and Patients With Pulmonary Fibrosis.

Summary

In bleomycin-treated mice, ultralow-dose dextromethorphan (DM) alone or added to pirfenidone (PFD) reduced fibrosis and hydroxyproline, with benefits even when started 2 weeks after injury. Mechanistically, DM suppressed NOX4/ROS and increased SOD, restoring redox balance. In patients, adding DM to PFD attenuated pulmonary function decline and improved HRCT scores compared with PFD alone.

Key Findings

• In vivo, DM (alone/with PFD) reduced fibrotic area and hydroxyproline; efficacy persisted when initiated 2 weeks post-bleomycin.
• In vitro, DM restored redox balance by suppressing NOX4-derived ROS and upregulating SOD, limiting myofibroblast activation.
• Clinically, add-on DM improved HRCT scores and attenuated pulmonary function decline compared with PFD alone.

Clinical Implications

If validated in controlled trials, adding ultralow-dose dextromethorphan to pirfenidone could improve outcomes in pulmonary fibrosis with minimal additional toxicity.

Limitations

• Clinical component appears nonrandomized with unspecified sample size, limiting causal inference
• Generalizability and optimal dosing require confirmation in controlled trials

Future Directions

Conduct randomized controlled trials to confirm efficacy and safety, define dosing, and validate redox biomarkers as pharmacodynamic readouts.