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.

Whole-body vibration of mice induces progressive degeneration of intervertebral discs associated with increased expression of Il-1ß and multiple matrix degrading enzymes.

OBJECTIVE: Whole-body vibration (WBV) is a popular fitness trend based on claims of increased muscle mass, weight loss and reduced joint pain. Following its original implementation as a treatment to increase bone mass in patients with osteoporosis, WBV has been incorporated into clinical practice for musculoskeletal disorders, including back pain. However, our recent studies revealed damaging effects of WBV on joint health in a murine model. In this report, we examined potential mechanisms underlying disc degeneration following exposure of mice to WBV. METHODS: Ten-week-old male mice were exposed to WBV (45 Hz, 0.3 g peak acceleration, 30 min/day, 5 days/week) for 4 weeks, 8 weeks, or 4 weeks WBV followed by 4 weeks recovery. Micro-computed tomography (micro-CT), histological, and gene expression analyses were used to assess the effects of WBV on spinal tissues. RESULTS: Exposure of mice to 4 or 8 weeks of WBV did not alter total body composition or induce significant changes in vertebral bone density. On the other hand, WBV-induced intervertebral disc (IVD) degeneration, associated with decreased disc height and degenerative changes in the annulus fibrosus (AF) that did not recover within 4 weeks after cessation of WBV. Gene expression analysis showed that WBV for 8 weeks induced expression of Mmp3, Mmp13, and Adamts5 in IVD tissues, changes preceded by increased expression of Il-1ß. CONCLUSIONS: Progressive IVD degeneration induced by WBV was associated with increased expression of Il-1ß within the IVD that preceded Mmp and Adamts gene induction. Moreover, WBV-induced IVD degeneration is not reversed following cessation of vibration.

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.

Repeated exposure to high-frequency low-amplitude vibration induces degeneration of murine intervertebral discs and knee joints.

OBJECTIVE: High-frequency, low-amplitude whole-body vibration (WBV) is being used to treat a range of musculoskeletal disorders; however, there is surprisingly limited knowledge regarding its effect(s) on joint tissues. This study was undertaken to examine the effects of repeated exposure to WBV on bone and joint tissues in an in vivo mouse model. METHODS: Ten-week-old male mice were exposed to vertical sinusoidal vibration under conditions that mimic those used clinically in humans (30 minutes per day, 5 days per week, at 45 Hz with peak acceleration at 0.3g). Following WBV, skeletal tissues were examined by micro-computed tomography, histologic analysis, and immunohistochemistry, and gene expression was quantified using real-time polymerase chain reaction. RESULTS: Following 4 weeks of WBV, intervertebral discs showed histologic hallmarks of degeneration in the annulus fibrosus, disruption of collagen organization, and increased cell death. Greater Mmp3 expression in the intervertebral disc, accompanied by enhanced collagen and aggrecan degradation, was found in mice exposed to WBV as compared to controls. Examination of the knee joints after 4 weeks of WBV revealed meniscal tears and focal damage to the articular cartilage, changes resembling osteoarthritis. Moreover, mice exposed to WBV also demonstrated greater Mmp13 gene expression and enhanced matrix metalloproteinase-mediated collagen and aggrecan degradation in articular cartilage as compared to controls. No changes in trabecular bone microarchitecture or density were detected in the proximal tibia. CONCLUSION: Our experiments reveal significant negative effects of WBV on joint tissues in a mouse model. These findings suggest the need for future studies of the effects of WBV on joint health in humans.