Green Francis H Y, Leigh Richard, Fadayomi Morenike, Lalli Gurkeet, Chiu Andrea, Shrestha Grishma, ElShahat Sharif G, Nelson David Evan, El Mays Tamer Y, Pieron Cora A, Dennis John H
Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
Department of Medicine, University of Calgary, Calgary, AB, Canada.
Trials. 2016 Jul 28;17:361. doi: 10.1186/s13063-016-1489-8.
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 β-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.
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.
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.
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.
ClinicalTrials.gov NCT02616770 . Registered on 25 November 2015.
治疗急性哮喘加重的一个主要挑战是需要足够迅速地打开狭窄气道，以重新建立通气并使常规药物能够送达患病气道。解决方案需要一种新方法，该方法要同时考虑急性哮喘治疗中使用的生物物理和药理学方面。对几种制剂进行测试的结果是S - 1226：在雾化全氟溴烷（一种合成表面活性剂）中输送的富含二氧化碳的空气。这些药物协同作用，能在数秒内迅速重新打开关闭的气道。支气管扩张作用独立于β - 肾上腺素能和胆碱能介导的信号通路，提供了一种独特的作用机制。S - 1226具有低毒性特征，并且在哮喘动物模型中治疗支气管收缩有效。本研究的目的是评估S - 1226在健康人类受试者中的安全性和耐受性。
I期研究是在加拿大进行的一项单中心、随机、双盲、安慰剂对照、序贯、单剂量递增研究。36名受试者被分为三个队列。在每个队列中，受试者被随机分配接受单剂量的S - 1226或在2分钟雾化期内给予的匹配安慰剂。S - 1226由全氟溴烷和4%、8%或12%的二氧化碳配制而成。二氧化碳的剂量按队列依次递增。通过评估不良事件、生命体征、12导联心电图、临床实验室参数和体格检查来评估S - 1226的安全性和耐受性。
在所有三个二氧化碳水平（4%、8%和12%）下，S - 1226都是安全且耐受性良好的。共报告了28起不良事件，所有事件的严重程度均被判定为轻度。24起不良事件发生在S - 1226队列中，其中5起被认为与S - 1226有间接关联，6起可能与S - 1226有关。
S - 1226是一种正在研发用于治疗急性哮喘加重的新型药物。它由富含二氧化碳的空气和全氟溴烷组成，有潜力提供快速且强效的支气管扩张作用。研究结果表明S - 1226安全且耐受性良好。所有不良事件均为轻度、可逆的，并且可能是由于吸入二氧化碳的已知副作用所致。
ClinicalTrials.gov NCT02616770。于2015年11月25日注册。
