Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma.

BACKGROUND: The low toxicity of perfluorocarbons (PFCs), their high affinity for respiratory gases and their compatibility with lung surfactant have made them useful candidates for treating respiratory diseases such as adult respiratory distress syndrome. We report results for treating acute allergic and non-allergic bronchoconstriction in sheep using S-1226 (a gas mixture containing carbon dioxide and small volumes of nebulized perflubron). The carbon dioxide, which is highly soluble in perflubron, was used to relax airway smooth muscle. METHODS: Sheep previously sensitized to house dust mite (HDM) were challenged with HDM aerosols to induce early asthmatic responses. At the maximal responses (characterised by an increase in lung resistance), the sheep were either not treated or treated with one of the following; nebulized S-1226 (perflubron + 12% CO2), nebulized perflubron + medical air, 12% CO2, salbutamol or medical air. Lung resistance was monitored for up to 20 minutes after cessation of treatment. RESULTS: Treatment with S-1226 for 2 minutes following HDM challenge resulted in a more rapid, more profound and more prolonged decline in lung resistance compared with the other treatment interventions. Video bronchoscopy showed an immediate and complete (within 5 seconds) re-opening of MCh-constricted airways following treatment with S-1226. CONCLUSIONS: S-1226 is a potent and rapid formulation for re-opening constricted airways. Its mechanism(s) of action are unknown. The formulation has potential as a rescue treatment for acute severe asthma.

Efficacy of a Peruvian Botanical Remedy (Sabell A4+) for Treating Liver Disease and Protecting Gastric Mucosal Integrity.

The purpose of this study was to determine the efficacy of a Peruvian botanical formulation for treating disorders of hepatic function and gastric mucosal integrity. The formulation A4+ (Sabell Corporation) contains extracts of Curcuma longa rhizome, Cordia lutea flower, and Annona muricata leaf. Individually these plants have been used as traditional remedies for liver disease. We report the efficacy of A4+ and its components using a variety of in vitro and in vivo disease models. The methods used included tests for antioxidant, anti-inflammatory, and antiviral activity as well as mouse models of liver disease, including Concanavalin A-induced immune-mediated hepatitis and a bile duct ligation model for evaluating sickness behaviour associated with liver disease. Rat models were used to evaluate the gastric mucosal protective property of A4+ following indomethacin challenge and to evaluate its anti-inflammatory action in an "air pouch" model. In all tests, A4+ proved to be more effective than placebo. A4+ was antioxidant and anti-inflammatory and diminished Hepatitis C virus replication in vitro. In animal models, A4+ was shown to protect the liver from immune-mediated hepatitis, improve behavioural function in animals with late stage liver disease, and protect the rat gastric mucosa from ulceration following NSAID exposure. We conclude that A4+ ameliorated many aspects of liver injury, inhibited hepatitis C virus replication, and protected the gastric mucosa from NSAIDs. These varied beneficial properties appear to result from positive interactions between the three constituent herbs.

A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma.

BACKGROUND: This study evaluates a novel bronchodilator, S1226, for its efficacy in reversing allergen-induced bronchoconstriction in subjects with mild, allergic asthma. S1226 is a new class of bronchodilator that is an aerosol/vapor/gas mixture combining pharmacological and biophysical principles for a novel mode of action. It contains a potent bronchodilator gas (carbon dioxide or CO2) and nebulized perflubron (a synthetic surfactant possessing mucolytic properties). It has demonstrated rapid reversal of allergen-induced bronchoconstriction in an ovine study model. METHODS: This was a phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover single-dose clinical trial to evaluate the safety, tolerability, and efficacy of S1226 (8% CO2) administered by nebulization following an allergen-induced early asthmatic response in 12 subjects with mild, allergic asthma. Primary safety endpoints were adverse events, vital signs, pulse oximetry, and spirometry. Efficacy endpoints included bronchodilator response (measured as the forced expiratory volume in 1 s or FEV1) over time, the area under the curve of FEV1 for the early asthmatic response over time, and achievement of responder status, defined as a 12% improvement after the allergen challenge. RESULTS: No significant safety issues were observed. All adverse events were non-serious, mild, and transient. There was a statistically significant decrease in peripheral blood oxygenation levels over time in the placebo group following allergen inhalation, whereas blood oxygenation was maintained at normal levels in the S1226-treated subjects (P = 0.028). This effect was greatest 5 min after start of treatment (P < 0.001). The recovery rate was faster but not significantly so (P = 0.272) for S1226 compared to the placebo at earlier time points (5, 10, and 15 min), as assessed by ≥12% reversal of FEV1. The recovery of FEV1 over time was significantly greater (P = 0.04) with S1226 compared to the placebo. CONCLUSIONS: S1226 was safe, tolerated well, and provided bronchodilation and improved blood oxygenation in subjects with mild atopic asthma following allergen-induced bronchoconstriction. Additional studies to optimize the therapeutic response are indicated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02334553 . Registered on 12 November 2014.

Myofibroblasts are increased in the lung parenchyma in asthma.

BACKGROUND: Increased airway smooth muscle is observed in large and small airways in asthma. Semi-quantitative estimates suggest that cells containing alpha smooth muscle actin (α-SMA) are also increased in the lung parenchyma. This study quantified and characterized α-SMA positive cells (α-SMA+) in the lung parenchyma of non-asthmatic and asthmatic individuals. METHODS: Post-mortem sections of peripheral lung from cases of fatal asthma (FA), persons with asthma dying of non-respiratory causes (NFA) and non-asthma control subjects (NAC) were stained for α-SMA, quantified using point-counting and normalised to alveolar basement membrane length and interstitial area. RESULTS: α-SMA+ fractional area was increased in alveolar parenchyma in both FA (14.7 ± 2.8% of tissue area) and NFA (13.0 ± 1.2%), compared with NAC (7.4 ± 2.4%), p < 0.05 The difference was greater in upper lobes compared with lower lobes (p < 0.01) in both asthma groups. Similar changes were observed in alveolar ducts and alveolar walls. The electron microscopic features of the α-SMA+ cells were characteristic of myofibroblasts. CONCLUSIONS: We conclude that in asthma there is a marked increase in α-SMA+ myofibroblasts in the lung parenchyma. The physiologic consequences of this increase are unknown.

Pulmonary surfactant dysfunction in pediatric cystic fibrosis: Mechanisms and reversal with a lipid-sequestering drug.

BACKGROUND: Airway surfactant is impaired in cystic fibrosis (CF) and associated with declines in pulmonary function. We hypothesized that surfactant dysfunction in CF is due to an excess of cholesterol with an interaction with oxidation. METHODS: Surfactant was extracted from bronchial lavage fluid from children with CF and surface tension, and lipid content, inflammatory cells and microbial flora were determined. Dysfunctional surfactant samples were re-tested with a lipid-sequestering agent, methyl-ß-cyclodextrin (MßCD). RESULTS: CF surfactant samples were unable to sustain a normal low surface tension. MßCD restored surfactant function in a majority of samples.Mechanistic studies showed that the dysfunction was due to a combination of elevated cholesterol and an interaction with oxidized phospholipids and their pro-inflammatory hydrolysis products. CONCLUSION: We confirm that CF patients have impaired airway surfactant function which could be restored with MßCD. These findings have implications for improving lung function and mitigating inflammation in patients with CF.

A phase I, placebo-controlled, randomized, double-blind, single ascending dose-ranging study to evaluate the safety and tolerability of a novel biophysical bronchodilator (S-1226) administered by nebulization in healthy volunteers.

BACKGROUND: A major challenge in treating acute asthma exacerbations is the need to open constricted airways rapidly enough to reestablish ventilation and allow delivery of conventional medication to diseased airways. The solution requires a new approach that considers both biophysical and pharmacological aspects of treatments used in acute asthma. The result of testing several formulations was S-1226: carbon dioxide-enriched air delivered in nebulized perflubron, a synthetic surfactant. These agents act synergistically to rapidly reopen closed airways within seconds. The bronchodilator effect is independent of ß-adrenergic and cholinergic mediated-signaling pathways, offering a unique mechanism of action. S-1226 has a low toxicity profile and was effective in treating bronchoconstriction in animal models of asthma. The goal of the present study was to evaluate the safety and tolerability of S-1226 in healthy human subjects. METHODS: The phase I study was a single-center, randomized, double-blind, placebo-controlled, sequential, single-ascending-dose study conducted in Canada. Thirty-six subjects were distributed into three cohorts. Within each cohort, subjects were randomized to receive a single dose of S-1226 or a matching placebo administered over a 2-minute nebulization period. S-1226 was formulated with perflubron and 4 %, 8 %, or 12 % CO2. The dose of CO2 was sequentially escalated by cohort. The safety and tolerability of S-1226 were evaluated through assessment of adverse events, vital signs, 12-lead electrocardiograms, clinical laboratory parameters, and physical examinations. RESULTS: S-1226 was safe and well tolerated at all three CO2 levels (4 %, 8 %, and 12 %). A total of 28 adverse events were reported, and all were judged mild in severity. Twenty-four adverse events occurred in the S-1226 cohort, of which five were considered remotely related and six possibly related to S-1226. CONCLUSIONS: S-1226 is a novel drug being developed for the treatment of acute asthma exacerbations. It consists of CO2-enriched air and perflubron and has potential to offer rapid and potent bronchodilation. The results of the study indicate that S-1226 is safe and well tolerated. All adverse events were mild, reversible, and likely due to known side effects of CO2 inhalation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02616770 . Registered on 25 November 2015.