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1.
Respir Res ; 15: 98, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25355286

RESUMO

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.


Assuntos
Broncoconstrição/efeitos dos fármacos , Broncodilatadores/administração & dosagem , Dióxido de Carbono/administração & dosagem , Fluorocarbonos/administração & dosagem , Hipersensibilidade/tratamento farmacológico , Pulmão/efeitos dos fármacos , Administração por Inalação , Resistência das Vias Respiratórias/efeitos dos fármacos , Alérgenos , Animais , Broncodilatadores/química , Broncoscopia , Dióxido de Carbono/química , Modelos Animais de Doenças , Feminino , Fluorocarbonos/química , Gases , Hidrocarbonetos Bromados , Hipersensibilidade/imunologia , Hipersensibilidade/fisiopatologia , Proteínas de Insetos , Pulmão/imunologia , Pulmão/fisiopatologia , Tamanho da Partícula , Pyroglyphidae , Ovinos , Fatores de Tempo , Gravação em Vídeo
2.
Mil Med ; 183(suppl_1): 207-215, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29635617

RESUMO

Objectives: Acute respiratory distress syndrome (ARDS) is caused by many factors including inhalation of toxicants, acute barotrauma, acid aspiration, and burns. Surfactant function is impaired in ARDS and acute airway injury resulting in high surface tension with alveolar and small airway collapse, edema, hypoxemia, and death. In this study, we explore the mechanisms whereby surfactant becomes dysfunctional in ARDS and bronchiolitis and its repair with a cyclodextrin drug that sequesters cholesterol. Methods: We used in vitro model systems, a mouse model of ARDS, and samples from patients with acute bronchiolitis. Surface tension was measured by captive bubble surfactometry. Results: Patient samples showed severe surfactant inhibition even in the absence of elevated cholesterol levels. Surfactant was also impaired in ARDS mice where the cholesterol to phospholipid ratio (W/W%) was increased. Methyl-ß-cyclodextrin (MßCD) restored surfactant function to normal in both human and animal samples. Model studies showed that the inhibition of surfactant was due to both elevated cholesterol and an interaction between cholesterol and oxidized phospholipids. MßCD was also shown to have anti-inflammatory effects. Conclusions: Inhaled cyclodextrins have potential for the treatment of ARDS. They could be delivered in a portable device carried in combat and used following exposure to toxic gases and fumes or shock secondary to hemorrhage and burns.


Assuntos
Doenças Pulmonares Intersticiais/etiologia , Surfactantes Pulmonares/análise , Síndrome do Desconforto Respiratório/complicações , Adolescente , Alberta , Animais , Lavagem Broncoalveolar/métodos , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Lesão Pulmonar/metabolismo , Lesão Pulmonar/fisiopatologia , Masculino , Camundongos , Projetos Piloto , Surfactantes Pulmonares/isolamento & purificação
3.
Trials ; 19(1): 321, 2018 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-29914544

RESUMO

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.


Assuntos
Asma/tratamento farmacológico , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/administração & dosagem , Dióxido de Carbono/administração & dosagem , Expectorantes/administração & dosagem , Fluorocarbonos/administração & dosagem , Pulmão/efeitos dos fármacos , Doença Aguda , Administração por Inalação , Adolescente , Adulto , Alberta , Asma/sangue , Asma/diagnóstico , Asma/fisiopatologia , Broncodilatadores/efeitos adversos , Dióxido de Carbono/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Expectorantes/efeitos adversos , Feminino , Fluorocarbonos/efeitos adversos , Volume Expiratório Forçado , Humanos , Hidrocarbonetos Bromados , Pulmão/fisiopatologia , Masculino , Oxigênio/sangue , Estudo de Prova de Conceito , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
4.
Trials ; 17: 361, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27464582

RESUMO

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.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Dióxido de Carbono/uso terapêutico , Fluorocarbonos/administração & dosagem , Nebulizadores e Vaporizadores , Administração por Inalação , Adolescente , Adulto , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/efeitos adversos , Canadá , Dióxido de Carbono/efeitos adversos , Estudos de Coortes , Método Duplo-Cego , Sinergismo Farmacológico , Eletrocardiografia , Feminino , Fluorocarbonos/efeitos adversos , Voluntários Saudáveis , Humanos , Hidrocarbonetos Bromados , Masculino , Pessoa de Meia-Idade
5.
Can Respir J ; 21(2): 101-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24288700

RESUMO

BACKGROUND: Induced sputum cell counts are a noninvasive and reliable method for evaluating the presence, type and degree of airway inflammation in patients with asthma. Currently, standard nebulizer devices used for sputum induction in multiple patients are labelled as single-patient devices by the manufacturer, which conflicts with infection prevention and control requirements. As such, these devices cannot feasibly be used in a clinical sputum induction program. Therefore, there is a need to identify alternative nebulizer devices that are either disposable or labelled for multipatient use. OBJECTIVE: To apply validated rigorous, scientific testing methods to identify and validate commercially available nebulizer devices appropriate for use in a clinical sputum induction program. METHODS: Measurement of nebulized aerosol output and size for the selected nebulizer designs followed robust International Organization for Standardization methods. Sputum induction using two of these nebulizers was successfully performed on 10 healthy adult subjects. The cytotechnologist performing sputum cell counts was blinded to the type of nebulizer used. RESULTS: The studied nebulizers had variable aerosol outputs. The AeroNeb Solo (Aerogen, Ireland), Omron NE-U17 (Omron, Japan) and EASYneb II (Flaem Nuova, Italy) systems were found to have similar measurements of aerosol size. There was no significant difference in induced sputum cell results between the AeroNeb Solo and EASYneb II devices. DISCUSSION: There is a need for rigorous, scientific evaluation of nebulizer devices for clinical applications, including sputum induction, for measurement of cell counts. CONCLUSION: The present study was the most comprehensive analysis of different nebulizer devices for sputum induction to measure cell counts, and provides a framework for appropriate evaluation of nebulizer devices for induced sputum testing.


Assuntos
Aerossóis/administração & dosagem , Desenho de Equipamento/normas , Nebulizadores e Vaporizadores/normas , Doenças Respiratórias/diagnóstico , Administração por Inalação , Adulto , Broncodilatadores/administração & dosagem , Contagem de Células/instrumentação , Contagem de Células/métodos , Equipamentos Descartáveis , Feminino , Voluntários Saudáveis , Humanos , Masculino , Reprodutibilidade dos Testes , Escarro/citologia
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