A 28-day clinical trial of aerosolized hyaluronan in alpha-1 antiprotease deficiency COPD using desmosine as a surrogate marker for drug efficacy.

INTRODUCTION: A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the unique elastin crosslinks, desmosine and isodesmosine (DID). To further assess the therapeutic efficacy of HA and the utility of DID as surrogate markers for the development of pulmonary emphysema, we have conducted a 28-day randomized, double-blind, placebo-controlled, phase 2 trial of HA involving 27 subjects with alpha-1 antiprotease deficiency COPD. METHODS: The study drug consisted of a 3 ml inhalation solution containing 0.03% HA with an average molecular weight of 150 kDa that was self-administered twice daily. DID levels were measured in urine, sputum, and plasma using tandem mass spectrometry. RESULTS: Free urine DID in the HA group showed a significant negative correlation with time between days 14 and 35 (r = -1.0, p = 0.023) and was statistically significantly decreased from baseline at day 35 (15.4 vs 14.2 ng/mg creatinine, p = 0.035). A marked decrease in sputum DID was also seen in the HA group between days 1 and 28 (0.96 vs 0.18 ng/mg protein), but the difference was not significant, possibly due to the small number of adequate specimens. Plasma DID remained unchanged following HA treatment and no significant reductions in urine, sputum, or plasma DID were seen in the placebo group. CONCLUSIONS: The results support additional clinical trials to further evaluate the therapeutic effect of HA and the use of DID as a real-time marker of drug efficacy.

Respiratory-swallow training in patients with head and neck cancer.

OBJECTIVE: To test a novel intervention to train swallowing to occur in the midexpiratory to low expiratory phase of quiet breathing to improve swallowing safety and efficiency. DESIGN: Safety and efficacy nonrandomized controlled trial with 1-month follow-up. SETTING: Ambulatory clinics. PARTICIPANTS: Patients (N=30) with head and neck cancer (HNC) and chronic dysphagia completed the intervention. Fifteen of these patients participated in a 1-month follow-up visit. INTERVENTIONS: Training protocol based on hierarchy of motor skill acquisition to encourage autonomous and optimal respiratory-swallowing coordination. Visual feedback of respiratory phase and volume for swallowing initiation was provided by nasal airflow and rib cage/abdomen signals. MAIN OUTCOME MEASURES: Respiratory-swallow phase pattern, Modified Barium Swallow Impairment Profile (MBSImP) scores, Penetration-Aspiration Scale (PAS) scores, and MD Anderson Dysphagia Inventory scores. RESULTS: Using visual feedback, patients were trained to initiate swallows during the midexpiratory phase of quiet breathing and continue to expire after swallowing. This optimal phase patterning increased significantly after treatment (P<.0001). Changes in respiratory-swallowing coordination were associated with improvements in 3 MBSImP component scores: laryngeal vestibular closure (P=.0004), tongue base retraction (P<.0001), and pharyngeal residue (P=.01). Significant improvements were also seen in PAS scores (P<.0001). Relative to pretreatment values, patients participating in 1-month follow-up had increased optimal phase patterning (P<.0001), improved laryngeal vestibular closure (P=.01), tongue base retraction (P=.003), and pharyngeal residue (P=.006) MBSImP scores and improved PAS scores (P<.0001). CONCLUSIONS: Improvements in respiratory-swallowing coordination can be trained using a systematic protocol and respiratory phase-lung volume-related biofeedback in patients with HNC and chronic dysphagia, with favorable effects on airway protection and bolus clearance.