Effect of oral glycine on the clinical, spirometric and inflammatory status in subjects with cystic fibrosis: a pilot randomized trial

Abstract

Background: Patients with cystic fibrosis (CF) have airway inflammation that contributes to symptoms and to pulmonary function derangement. Current drugs used to diminish airway inflammation improve the clinical and spirometric status of patients with CF, but their use is limited due to their undesired side effects, for example, glucose intolerance, growth retardation, and cataracts with corticosteroids, gastrointestinal toxicity with ibuprofen, and macrolide resistance with azythromycin. Glycine is known to decrease activation of inflammatory cells, including alveolar macrophages and neutrophils, and is relatively inexpensive, palatable, and virtually devoid of untoward effects. These features make glycine a good candidate for antiinflammatory treatment of CF. Thus, we aimed to explore whether glycine can exert a beneficial effect in a population of patients with CF.

Methods: This was a randomized, double blinded, cross-over pilot clinical trial. Subjects with CF received, in random order, oral glycine (0.5 g/kg/day, dissolved in any liquid) and placebo (glass sugar), each during 8 weeks with an intermediate 2-week wash-out period.

Results: Thirteen subjects aged 6-23 years, 8 females, completed the two arms of the study. As compared with placebo, after glycine intake patients had better symptom questionnaire scores (p = 0.02), mainly regarding sputum features and dyspnea. While spirometric variables tended to decline during placebo intake, they remained stable or even increased during glycine treatment (p = 0.04 to p = 0.003). In this context, FEV₁ declined 8.6% after placebo and increased 9.7% at the end of the glycine period. Pulse oximetry improved after glycine intake (p = 0.04 vs. placebo). TNF-α in serum and IL-6 and G-CSF in sputum tended to decline at the end of the glycine period (p = 0.061, p = 0.068 and p = 0.04, respectively, vs placebo). Glycine was remarkably well tolerated.

Conclusions: The clinical, spirometric and inflammatory status of subjects with CF improved after just 8 weeks of glycine intake, suggesting that this amino acid might constitute a novel therapeutic tool for these patients. Thus, further studies are warranted.

Trial registration: www.clinicaltrials.gov , registration number: NCT01417481 , date of registration: March 12, 2012.

Keywords: Cystic fibrosis; Dyspnea; Forced expiratory volume at first second; Glycine; Inflammatory mediators; Peripheral oxygen saturation; Pulse oximetry.

Fig. 1

Flow diagram describing the selection process and follow up of participants

Fig. 2

Changes in symptom scores, main spirometric variables and pulse oximetry in subjects with cystic fibrosis during glycine and placebo intake. All data are expressed as percentage of their respective baseline values. Symbols correspond to mean ± standard error of 13 patients who received 0.5 g/kg/day glycine (filled circles) and placebo (empty circles) during 8 weeks in random order. Statistical significance was assessed through paired Student’s t-test. The symptoms total score, sputum features and dyspnea perception were assessed by a Liker-type scale ranging from 1 (better) to 5 (worse). SpO₂ = peripheral blood oxygen saturation; FEV₁ = forced expiratory volume at the first second; FVC = forced vital capacity

Fig. 3

Changes in selected serum and sputum cytokines in subjects with cystic fibrosis during glycine and placebo intake. All data are expressed as percentage of their respective baseline values. Symbols correspond to mean ± standard error of 9–12 subjects who received 0.5 g/kg/day glycine (filled circles) and placebo (empty circles) during 8 weeks in random order. Statistical significance was assessed through non-paired Student’s t-test. G-CSF = granulocyte colony stimulating factor; IL-6 = interleukin 6; TNF-α = tumor necrosis factor alpha

Fig. 4

Correlations between peripheral blood leukocytes and FEV₁ in subjects with cystic fibrosis. The scatter plots correspond either to all measures obtained at all visits (empty circles) or to the mean of the six visits for each patient (filled circles). The Pearson’s correlation coefficient (r) and its corresponding p value are shown in each panel

Fig. 5

Correlation between forced expiratory volume at first second (FEV₁) and peripheral oxygen saturation (SpO₂) in subjects with cystic fibrosis. The scatter plots correspond either to all measures obtained at all visits (empty circles) or to the mean of the six visits for each patient (filled circles). The hyperbolic function formula and its associated coefficient of determination (r²) are shown in each panel

Fig. 6

Relationship between selected cytokines and symptoms questionnaire, forced expiratory volume at first second (FEV₁) and peripheral oxygen saturation (SpO₂) in subjects with cystic fibrosis. Data correspond to all values observed at weeks 4 and 8, expressed as percentage of their respective baseline value at the beginning of the glycine or placebo period (week 0)