Dataset Information

An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases.

ABSTRACT:

Rationale

Airways obstruction with thick, adherent mucus is a pathophysiologic and clinical feature of muco-obstructive respiratory diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis (CF). Mucins, the dominant biopolymer in mucus, organize into complex polymeric networks via the formation of covalent disulfide bonds, which govern the viscoelastic properties of the mucus gel. For decades, inhaled N-acetylcysteine (NAC) has been used as a mucolytic to reduce mucin disulfide bonds with little, if any, therapeutic effects. Improvement of mucolytic therapy requires the identification of NAC deficiencies and the development of compounds that overcome them.

Objectives

Elucidate the pharmacological limitations of NAC and test a novel mucin-reducing agent, P3001, in preclinical settings.

Methods

The study used biochemical (e.g., Western blotting, mass spectrometry) and biophysical assays (e.g., microrheology/macrorheology, spinnability, mucus velocity measurements) to test compound efficacy and toxicity in in vitro and in vivo models and patient sputa.

Measurements and main results

Dithiothreitol and P3001 were directly compared with NAC in vitro and both exhibited superior reducing activities. In vivo, P3001 significantly decreased lung mucus burden in βENaC-overexpressing mice, whereas NAC did not (n = 6-24 mice per group). In NAC-treated CF subjects (n = 5), aerosolized NAC was rapidly cleared from the lungs and did not alter sputum biophysical properties. In contrast, P3001 acted faster and at lower concentrations than did NAC, and it was more effective than DNase in CF sputum ex vivo.

Conclusions

These results suggest that reducing the viscoelasticity of airway mucus is an achievable therapeutic goal with P3001 class mucolytic agents.

SUBMITTER: Ehre C

PROVIDER: S-EPMC6353008 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose Gender differences in the incidence, susceptibility and severity of many obstructive airway diseases (OADs) have been well recognized. However, gender differences in the inhaled pharmacotherapy profile are not well characterized. Methods We conducted a retrospective cohort study to investigate gender differences in new-users of inhaled corticosteroids (ICS), short-or long-acting beta2-agonist (SABA or LABA), ICS/LABA, short-or long-acting muscarinic antagonist (SAMA or LAMA) among patients with asthma, COPD or asthma-COPD overlap (ACO). We used Clinical Practice Research Datalink to identify OAD patients, 18 years and older, who were new-users (1-year washout period) from 01-January-1998 to 31-July-2018. Multivariable logistic regression was used to examine gender differences in each of the inhaled pharmacotherapies after controlling for potential confounders. Results A total of 242,079 new-users (asthma: 84.93%; COPD: 10.19%; ACO: 4.88%) of inhaled pharmacotherapies were identified. The multivariable analyses showed that males with COPD were more likely to be a new user of a LABA (odds ratio [OR] 1.29; 95% confidence interval [CI], 1.12–1.49), LAMA (OR 1.21; 95% CI 1.10–1.33), SAMA (OR 1.11; 95% CI 1.01–1.21) and less likely to be a new user of a SABA (OR 0.84; 95% CI, 0.80–0.89) compared to females. Similar patterns were also observed for patients with ACO; males were more likely to be prescribed with LABA (OR 1.26; 95% CI 1.03–1.55), LAMA (OR 1.28; 95% CI 1.11–1.48), SAMA (OR 1.28; 95% CI 1.11–1.48), and less likely to be a new user of a SABA (OR 0.89; 95% CI, 0.82–0.96). Also, males with asthma were more likely to be a new-user of ICS/LABA (OR 1.15; 95% CI, 1.08–1.23) and less likely to start an ICS (OR 0.97; 95% CI, 0.95–0.99) in comparison with females. Conclusion Our study showed significant gender differences in new-users of inhaled pharmacotherapies among OAD patients. Adjusting for proxies of disease severity, calendar year, smoking and socioeconomic status did not change the association by gender.