Impacts of residential indoor air quality and environmental risk factors on adult asthma-related health outcomes in Chicago, IL.

BACKGROUND: Residential environments are known to contribute to asthma. OBJECTIVE: To examine the joint impacts of exposures to residential indoor and outdoor air pollutants and housing risk factors on adult asthma-related health outcomes. METHODS: We analyzed >1-year of data from 53 participants from 41 homes in the pre-intervention period of the Breathe Easy Project prior to ventilation and filtration retrofits. Health outcomes included surveys of asthma control, health-related quality of life, stress, and healthcare utilizations. Environmental assessments included quarterly measurements of indoor and outdoor pollutants (e.g., HCHO, CO, CO2, NO2, O3, and PM), home walk-throughs, and surveys of environmental risk factors. Indoor pollutant concentrations were also matched with surveys of time spent at home to estimate indoor pollutant exposures. RESULTS: Cross-sectional analyses using mixed-effects models indicated that lower annual average asthma control test (ACT) scores were associated (p < 0.05) with higher indoor NO2 (concentration/exposure: ß = -2.42/-1.57), indoor temperature (ß = -1.03 to -0.94), and mold/dampness (ß = -3.09 to -2.41). In longitudinal analysis, lower ACT scores were also associated (p < 0.05) with higher indoor NO2 concentrations (ß = -0.29), PM1 (concentration/exposure: ß = -0.12/-0.24), PM2.5 (concentration/exposure: ß = -0.12/-0.26), and PM10 (concentration/exposure: ß = 10.14/-0.28). Emergency department visits were associated with poorer asthma control [incidence rate ratio (IRR) = 0.84; p < 0.001], physical health (IRR = 0.95; p < 0.05), mental health (IRR = 0.95; p < 0.05), higher I/O NO2 ratios (IRR = 1.30; p < 0.05), and higher indoor temperatures (IRR = 1.41; p < 0.05). SIGNIFICANCE: Findings suggest that residential risk factors, including indoor air pollution (especially NO2 and particulate matter), higher indoor temperature, and mold/dampness, may contribute to poorer asthma control. IMPACT: This study highlights the importance of residential indoor air quality and environmental risk factors for asthma control, health-related quality of life, and emergency department visits for asthma. Two timescales of mixed models suggest that exposure to indoor NO2 and particulate matter, higher indoor temperature, and mold/dampness was associated with poorer asthma control. Additionally, emergency department visits were associated with poorer asthma control and health-related quality of life, as well as higher I/O NO2 ratios and indoor temperatures. These findings deepen our understanding of the interrelationships between housing, air quality, and health, and have important implications for programs and policy.

First clinical trials of novel ENaC targeting therapy, SPX-101, in healthy volunteers and adults with cystic fibrosis.

BACKGROUND: ENaC inhibition has been investigated as a CF treatment; however, small molecule inhibitors of ENaC lack efficacy and/or have shown dose-limiting hyperkalemia. SPX-101 is a novel, investigational small peptide (SPLUNC1 mimetic) that regulates ENaC density with the potential for efficacy without systemic effects. METHODS: Two trials are presented: The first was a Phase 1, 2-part, randomized, double-blind, placebo-controlled, ascending-dose study of nebulized SPX-101 in healthy adults. Part 1 evaluated 4 single doses of SPX-101 ranging from 20 to 240 mg. Part 2 evaluated a 14-day regimen of SPX-101 at 4 doses of SPX-101 ranging from 10 to 120 mg BID. Pharmacokinetics, adverse events, spirometry, vital signs, electrocardiograms, pulse oximetry, and clinical laboratory values were assessed. The second trial was a tolerability-confirming, Phase 1b, open-label study conducted in 5 adult subjects with CF. Ascending doses of SPX-101 inhalation solution (10 mg-120 mg BID) were administered for 7 days. Safety was assessed as described above. RESULTS: All 64 healthy volunteers (32 in each Part) completed the single and multiple dose study. SPX-101 was well tolerated with little/no systemic exposure and with no hyperkalemia. Adverse events were generally mild with reported respiratory events associated with the purported pharmacological activity of SPX-101. Tolerability of SPX-101 was similarly observed in adults with CF; all 5 subjects treated with SPX-101 completed the study. CONCLUSIONS: SPX-101 was well-tolerated across a range of doses and had little/no systemic exposure in healthy adults and adults with CF, thus supporting further study in patients with CF. CLINICALTRIAL. GOV REGISTRATION: NCT03056989.

Nonclinical safety assessment of SPX-101, a novel peptide promoter of epithelial sodium channel internalization for the treatment of cystic fibrosis.

BACKGROUND: ENaC inhibition has long been an attractive therapeutic target for the treatment of cystic fibrosis. However, previous attempts at developing ENaC inhibitors have been unsuccessful due to complications arising from systemic circulation of the compounds. Here, we describe the preclinical toxicology assessment of a new inhaled peptide promoter of ENaC internalization delivered as a nebulized aerosol. METHODS: Preclinical assessment of SPX-101 safety was determined using an in vitro hERG assay, bolus injection of SPX-101 in a canine cardiovascular and respiratory safety pharmacology model and 28-day inhalation toxicology studies of nebulized drug in rats and dogs. RESULTS: SPX101 had no effects on the respiratory, cardiac or central nervous systems. The 28-day inhalation toxicology studies of nebulized SPX-101 in rats and dogs revealed no drug-related adverse events. Plasma levels of SPX-101 peaked less than 1 h after the end of treatment in rats and were below the limit of detection in canine models. CONCLUSIONS: SPX-101, a novel peptide promoter of ENaC internalization, elicited no adverse effects at doses up to the MFD and in excess of the highest preclinical efficacious and expected clinical doses. In contrast to channel blockers like amiloride and derivative small molecules, SPX-101 does not achieve significant systemic circulation, thus doses are not limited due to toxic side effects like hyperkalemia and weight loss.

SPX-101 Is a Novel Epithelial Sodium Channel-targeted Therapeutic for Cystic Fibrosis That Restores Mucus Transport.

RATIONALE: Cystic fibrosis (CF) lung disease is caused by the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) combined with hyperactivation of the epithelial sodium channel (ENaC). In the lung, ENaC is responsible for movement of sodium. Hyperactivation of ENaC, which creates an osmotic gradient that pulls fluid out of the airway, contributes to reduced airway hydration, causing mucus dehydration, decreased mucociliary clearance, and recurrent acute bacterial infections. ENaC represents a therapeutic target to treat all patients with CF independent of their underlying CFTR mutation. OBJECTIVES: To investigate the in vitro and in vivo efficacy of SPX-101, a peptide mimetic of the natural regulation of ENaC activity by short palate, lung, and nasal epithelial clone 1, known as SPLUNC1. METHODS: ENaC internalization by SPX-101 in primary human bronchial epithelial cells from healthy and CF donors was assessed by surface biotinylation and subsequent Western blot analysis. SPX-101's in vivo therapeutic effect was assessed by survival of ß-ENaC-transgenic mice, mucus transport in these mice, and mucus transport in a sheep model of CF. MEASUREMENTS AND MAIN RESULTS: SPX-101 binds selectively to ENaC and promotes internalization of the α-, ß-, and γ-subunits. Removing ENaC from the membrane with SPX-101 causes a significant decrease in amiloride-sensitive current. The peptide increases survival of ß-ENaC-transgenic mice to greater than 90% with once-daily dosing by inhalation. SPX-101 increased mucus transport in the ß-ENaC mouse model as well as the sheep model of CF. CONCLUSIONS: These data demonstrate that SPX-101 promotes durable reduction of ENaC membrane concentration, leading to significant improvements in mucus transport.

Rapid at-line pharmaceutical cleaning verification using a novel light induced fluorescence (LIF) sensor.

A novel light emitting diode (LED) array-based light induced fluorescence (LIF) sensor is presented as an analytical methodology for at-line cleaning verification within the pharmaceutical industry. This sensor differs from conventional LIF sensors through the ability to dynamically control both the LED excitation array and detection parameters, enabling the exploitation of the optical power and detection sensitivity to rapidly detect trace concentrations of residual drug. This feature makes this sensor an ideal alternative to conventional cleaning verification analytical methodologies. In this study, the LIF sensor was validated as an analytical technique through the analysis of specificity, precision, linearity, limit of quantitation, and accuracy, with respect to solutions and swab extracts of a single pharmaceutical compound (Compound A). The validated system was then utilized for cleaning process optimization and subsequent routine cleaning process verification following three manufacturing campaigns. The LIF sensor enabled a significant improvement in the analysis time for quantitative detection of Compound A; individual swab and rinsate extracts were analyzed in less than 1 min. The results presented herein effectively demonstrate the ability of the novel LIF sensor to efficiently function as a valid at-line analytical methodology for cleaning verification.

Formulation of a dry powder influenza vaccine for nasal delivery.

The purpose of this research was to prepare a dry powder vaccine formulation containing whole inactivated influenza virus (WIIV) and a mucoadhesive compound suitable for nasal delivery. Powders containing WIIV and either lactose or trehalose were produced by lyophilization. A micro-ball mill was used to reduce the lyophilized cake to sizes suitable for nasal delivery. Chitosan flakes were reduced in size using a cryo-milling technique. Milled powders were sieved between 45 and 125 microm aggregate sizes and characterized for particle size and distribution, morphology, and flow properties. Powders were blended in the micro-ball mill without the ball. Lyophilization followed by milling produced irregularly shaped, polydisperse particles with a median primary particle diameter of approximately 21 microm and a yield of approximately 37% of particles in the 45 to 125 microm particle size range. Flow properties of lactose and trehalose powders after lyophilization followed by milling and sieving were similar. Cryo-milling produced a small yield of particles in the desired size range (<10%). Lyophilization followed by milling and sieving produced particles suitable for nasal delivery with different physicochemical properties as a function of processing conditions and components of the formulation. Further optimization of particle size and morphology is required for these powders to be suitable for clinical evaluation.

Formulation of a dry powder influenza vaccine for nasal delivery.

The purpose of this research was to prepare a dry powder vaccine formulation containing whole inactivated influenza virus (VIIV) and a mucoadhesive compound suitable for nasal delivery. Powders containing WIIV and either lactose or trehalose were produced by lyophilization. A micro-ball mill was used to reduce the lyophilized cake to sizes suitable for nasal delivery. Chitosan flakes were reduced in size using a cryo-milling technique. Milled powders were sieved between 45 and 125 µm aggregate sizes and characterized for particle size and distribution, morphology, and flow properties. Powders were blended in the micro-ball mill without the ball. Lyophilization followed by milling produced irregularly shaped, polydisperse particles with a median primary particle diameter of ≈21 µm and a yield of ≈37% of particles in the 45 to 125 µm particle size range. Flow properties of lactose and trehalose powders after lyophilization followed by milling and sieving were similar. Cryo-milling produced a small yield of particles in the desired size range (<10%). Lyophilization followed by milling and sieving produced particles suitable for nasal delivery with different physicochemical properties as a function of processing conditions and components of the formulation. Further optimization of particle size and morphology is required for these powders to be suitable for clinical evaluation.

Highly reproducible powder aerosolisation for lung delivery using powder-specific electromechanical vibration.

Dry powder inhalers (DPIs) have been in use since the 1970s, but it is only within the past few years that their use has constituted > approximately 10% of the inhaler units sold worldwide. Similarly, active DPIs have been in development for more than a decade, but no active device has yet been approved. Oriel is developing an active DPI technology that uses a very simple physical design coupled with a complex knowledge of powder flow and dispersion characterisation. The DPI uses electromechanical vibration with frequencies determined through the analysis of powder flow properties. Results so far have shown highly reproducible, efficient performance. The technology lends itself to both unit-dose and multidose platforms in a targeted cost-effective DPI.

A novel dry powder influenza vaccine and intranasal delivery technology: induction of systemic and mucosal immune responses in rats.

Intranasal (i.n.) vaccination represents an attractive non-invasive alternative to needle-based injection and provides superior protection at mucosal surfaces. However, new formulations are needed to improve efficacy and reduce the refrigerated storage and distribution requirements associated with standard liquid vaccines. Here, we describe a powder formulation of whole inactivated influenza virus and a novel i.n. delivery platform. The powder-formulated vaccine elicited a significant serum antibody response in rats that was at least as strong as that provided by the liquid vaccine administered i.n. or via intramuscular (i.m.) injection. Significant nasal IgA responses were also observed solely after i.n. delivery. This study demonstrates for the first time the generation of potent nasal mucosal and systemic immune responses using an i.n. delivered influenza vaccine powder and suggests an alternative approach to vaccination against influenza and other infectious diseases.

Factors affecting the deposition of inhaled porous drug particles.

Recent findings indicate that the inhalation of large manufactured porous particles may be particularly effective for drug delivery. In this study, a mathematical model was employed to systematically investigate the effects of particle size, particle density, aerosol polydispersity, and patient ventilatory parameters on deposition patterns of inhaled drugs in healthy human lungs. Aerodynamically similar particles with densities of 0.1, 1.0, and 2.0 g/cm(3) were considered. Particle size distributions were defined with mass median aerodynamic diameters (MMADs) ranging from 1 to 3 microm and geometric standard deviations ranging from 1.5 to 2.5, representing particles in the respirable size range. Breathing rates of 30 and 60 L/min with tidal volumes of 500 to 3000 mL were assumed, simulating shallow to deep breaths from a dry powder inhaler. Particles with a high density and a small geometric diameter had slightly greater deposition fractions than particles that were aerodynamically similar, but had lower density and larger geometric size (typical of manufactured porous particles). This can be explained by the fact that particles with a small geometric diameter deposit primarily by diffusion, which is a function of geometric size but is independent of density. As MMAD increased, the effect of density on deposition was less pronounced because of the decreased efficiency of diffusion for large particles. These data suggest that polydisperse aerosols containing a significant proportion of submicron particles will deposit in the pulmonary airways with greater efficiency than aerodynamically similar aerosols comprised of geometrically larger porous particles.

Fundamental effects of particle morphology on lung delivery: predictions of Stokes' law and the particular relevance to dry powder inhaler formulation and development.

Key factors that contribute to the aerodynamic properties of aerosol particles are found in Stokes' law. These factors may be monitored or controlled to optimize drug delivery to the lungs. Predictions of the aerodynamic behavior of therapeutic aerosols can be derived in terms of the physical implications of particle slip, shape and density. The manner in which each of these properties have been used or studied by pharmaceutical scientists to improve lung delivery of drugs is readily understood in the context of aerosol physics. Additional improvement upon current aerosol delivery of particulates may be predicted by further theoretical scrutiny.