Rheological Properties of Cystic Fibrosis Bronchial Secretion and <i>in Vitro</i> Drug Permeation Study: The Effect of Sodium Bicarbonate

Stigliani, Mariateresa; Manniello, Michele Dario; Zegarra‐Moran, Olga; Galietta, Luis J. V.; Minicucci, L.; Casciaro, R.; Garofalo, Emilia; Incarnato, Loredana; Aquino, Rita Patrizia; Gaudio, Pasquale Del; Russo, Paola

doi:10.1089/jamp.2015.1228

Cited by 33 publications

(30 citation statements)

References 24 publications

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“…Therefore, increasing the frequency of NaHCO 3 inhalations should be tested (every 4-6 h dosing); considering that most patients are prescribed airway clearance therapy two to three times per day, more frequent bicarbonate dosing may be feasible, but a search for alternative formulations that might allow a longer duration of action seems justifiable. A corroborating increase in pH due to NaHCO 3 in vitro has been described [15].…”

Section: Discussionmentioning

confidence: 60%

“…In a study on the effect of mixing NaHCO 3 solution directly with the sputum of CF patients in vitro, Stigliani et al [15] reported reductions in rheological moduli G′, G″, and G*. However, the present study evaluated native expectorated sputum.…”

Section: Discussionmentioning

confidence: 69%

“…Only relatively recently were the abnormalities of mucociliary transport in CF suggested to be caused by a HCO 3 − deficiency in ASL [8]. In vitro, NaHCO 3 was shown to change the rheological properties of sputum [15]. Thus, in CF, three factors seem to justify the therapeutic use of inhaled HCO 3 − aerosol: (1) HCO 3 − is critical in the extracellular processing of mucus to attain physiologically rheological properties [5,8,10,11,16]; (2) increased ASL pH decreases bacterial proliferation [13]; (3) hyperosmotic solutions of NaHCO 3 should help mobilize and remove airway surface debris [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Safety, Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis

et al. 2019

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Background Among the many consequences of loss of CFTR protein function, a significant reduction of the secretion of bicarbonate (HCO 3 −) in cystic fibrosis (CF) is a major pathogenic feature. Loss of HCO 3 − leads to abnormally low pH and impaired mucus clearance in airways and other exocrine organs, which suggests that NaHCO 3 inhalation may be a low-cost, easily accessible therapy for CF. Objective To evaluate the safety, tolerability, and effects of inhaled aerosols of NaHCO 3 solutions (4.2% and 8.4%). Methods An experimental, prospective, open-label, pilot, clinical study was conducted with 12 CF volunteer participants over 18 years of age with bronchiectasis and pulmonary functions classified as mildly to severely depressed. Sputum rheology, pH, and microbiology were examined as well as spirometry, exercise performance, quality-of-life assessments, dyspnea, blood count, and venous blood gas levels. Results Sputum pH increased immediately after inhalation of NaHCO 3 at each clinical visit and was inversely correlated with rheology when all parameters were evaluated: [G′ (elasticity of the mucus) = − 0.241; G″ (viscosity of the mucus) = − 0.287; G* (viscoelasticity of the mucus) = − 0.275]. G* and G′ were slightly correlated with peak flow, forced expiratory volume in 1 s (FEV 1), and quality of life; G″ was correlated with quality of life; sputum pH was correlated with oxygen consumption (VO 2) and vitality score in quality of life. No changes were observed in blood count, venous blood gas, respiratory rate, heart rate, peripheral oxygen saturation of hemoglobin (SpO 2), body temperature, or incidence of dyspnea. No adverse events associated with the study were observed. Conclusion Nebulized NaHCO 3 inhalation appears to be a safe and well tolerated potential therapeutic agent in the management of CF. Nebulized NaHCO 3 inhalation temporarily elevates airway liquid pH and reduces sputum viscosity and viscoelasticity.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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Safety, Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis

et al. 2019

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“…Micro-rheological properties of CF sputum [85] have been investigated using techniques such as diffusion rates or behavior of a tracer (molecules, peptides, nanospheres and microspheres) using fluorescence recovery after photobleaching, dynamic light scattering, fluorescence correlation spectroscopy and single-particle tracking in multi-particle tracking experiments [86]. These experiments and biochemical analyses have demonstrated that sputum microstructure is significantly altered by elevated mucin and extracellular DNA content.…”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

et al. 2016

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BackgroundThe airways of patients with cystic fibrosis (CF) are highly complex, subject to various environmental conditions as well as a distinct microbiota. Pseudomonas aeruginosa is recognized as one of the most important pulmonary pathogens and the predominant cause of morbidity and mortality in CF. A multifarious interplay between the host, pathogens, microbiota, and the environment shapes the course of the disease. There have been several excellent reviews detailing CF pathology, Pseudomonas and the role of environment in CF but only a few reviews connect these entities with regards to influence on the overall course of the disease. A holistic understanding of contributing factors is pertinent to inform new research and therapeutics.DiscussionIn this article, we discuss the deterministic alterations in lung physiology as a result of CF. We also revisit the impact of those changes on the microbiota, with special emphasis on P. aeruginosa and the influence of other non-genetic factors on CF. Substantial past and current research on various genetic and non-genetic aspects of cystic fibrosis has been reviewed to assess the effect of different factors on CF pulmonary infection. A thorough review of contributing factors in CF and the alterations in lung physiology indicate that CF lung infection is multi-factorial with no isolated cause that should be solely targeted to control disease progression. A combinatorial approach may be required to ensure better disease outcomes.ConclusionCF lung infection is a complex disease and requires a broad multidisciplinary approach to improve CF disease outcomes. A holistic understanding of the underlying mechanisms and non-genetic contributing factors in CF is central to development of new and targeted therapeutic strategies.

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“…However, in that early work, the donor compartment of the diffusion system contained a non-physiologic large volume of drug solution. Two decades later, the permeation of gentamicin sulfate [9] and ketoprofen lysinate [10] formulated as inhalation dry powders was reported to be significantly delayed in modified Franz cells when these incorporated a layer of artificial cystic fibrosis mucus or cystic fibrosis sputum, respectively. A common limitation of the three aforementioned studies is that the thickness of the mucus layers (~3 mm) was not clinically representative.…”

Section: Introductionmentioning

confidence: 99%

Development of an In Vitro System to Study the Interactions of Aerosolized Drugs with Pulmonary Mucus

et al. 2020

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Mucus is the first biological component inhaled drugs encounter on their journey towards their pharmacological target in the upper airways. Yet, how mucus may influence drug disposition and efficacy in the lungs has been essentially overlooked. In this study, a simple in vitro system was developed to investigate the factors promoting drug interactions with airway mucus in physiologically relevant conditions. Thin layers of porcine tracheal mucus were prepared in Transwell® inserts and initially, the diffusion of various fluorescent dyes across those layers was monitored over time. A deposition system featuring a MicroSprayer® aerosolizer was optimized to reproducibly deliver liquid aerosols to multiple air-facing layers and then exploited to compare the impact of airway mucus on the transport of inhaled bronchodilators. Both the dyes and drugs tested were distinctly hindered by mucus with high logP compounds being the most affected. The diffusion rate of the bronchodilators across the layers was in the order: ipratropium ≈ glycopyronnium > formoterol > salbutamol > indacaterol, suggesting hydrophobicity plays an important role in their binding to mucus but is not the unique parameter involved. Testing of larger series of compounds would nevertheless be necessary to better understand the interactions of inhaled drugs with airway mucus.

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Rheological Properties of Cystic Fibrosis Bronchial Secretion and in Vitro Drug Permeation Study: The Effect of Sodium Bicarbonate

Abstract: The interesting results confirm the previously reported bicarbonate. effectiveness in CF; this weak base seems to act by decreasing high viscosity of the CF bronchial secretion and, potentially, resulting in better mucus clearance and in fighting pulmonary infections.

Cited by 33 publications

References 24 publications

Safety, Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis

Safety, Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

Development of an In Vitro System to Study the Interactions of Aerosolized Drugs with Pulmonary Mucus

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