L-Arginine supplementation in severe asthma

BACKGROUND. Dysregulation of L-arginine metabolism has been proposed to occur in patients with severe asthma. The effects of L-arginine supplementation on L-arginine metabolite profiles in these patients are unknown. We hypothesized that individuals with severe asthma with low fractional exhaled nitric oxide (FeNO) would have fewer exacerbations with the addition of L-arginine to their standard asthma medications compared with placebo and would demonstrate the greatest changes in metabolite profiles. METHODS. Participants were enrolled in a single-center, crossover, double-blind L-arginine intervention trial at UCD. Subjects received placebo or L-arginine, dosed orally at 0.05 mg/kg (ideal body weight) twice daily. The primary end point was moderate asthma exacerbations. Longitudinal plasma metabolite levels were measured using mass spectrometry. A linear mixed-effect model with subject-specific intercepts was used for testing treatment effects. RESULTS. A cohort of 50 subjects was included in the final analysis. L-Arginine did not significantly decrease asthma exacerbations in the overall cohort. Higher citrulline levels and a lower arginine availability index (AAI) were associated with higher FeNO (P = 0.005 and P = 2.51 x 10(-9), respectively). Higher AAI was associated with lower exacerbation events. The eicosanoid prostaglandin H-2 (PGH(2)) and N-alpha-acetyl-L-arginine were found to be good predictors for differentiating clinical responders and nonresponders. CONCLUSIONS. There was no statistically significant decrease in asthma exacerbations in the overall cohort with L-arginine intervention. PGH(2), N-alpha-acetyl-L-arginine, and the AAI could serve as predictive biomarkers in future clinical trials that intervene in the arginine metabolome.