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Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation.

ABSTRACT: Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were produced by spray-drying, which generated generally spherical microparticles that were suitable for intramuscular injection. Multiple parameters were varied to produce formulations with a wide range of in vitro release kinetics. Testing of selected formulations in chlorine-exposed mice demonstrated efficacy against key aspects of acute lung injury. The results show the feasibility of developing microencapsulated formulations that could be used to treat chlorine-induced acute lung injury by intramuscular injection, which represents a preferred route of administration in a mass casualty situation.

SUBMITTER: Hoyle GW

PROVIDER: S-EPMC4821717 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation.

Hoyle Gary W GW Chen Jing J Schlueter Connie F CF Mo Yiqun Y Humphrey David M DM Rawson Greg G Niño Joe A JA Carson Kenneth H KH

Toxicology and applied pharmacology 20160304

Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were prod ...[more]

PMID: 26952014

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Project description:ObjectiveInhaled anticoagulation regimens are increasingly being used to manage smoke inhalation-associated acute lung injury. We systematically reviewed published and unpublished preclinical and clinical trial data to elucidate the effects of these regimens on lung injury severity, airway obstruction, ventilation, oxygenation, pulmonary infections, bleeding complications, and survival.Data sourcesPubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Relevant unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, MINDCULL.com, Current Controlled Trials, and Google.Study selectionInclusion criteria were any preclinical or clinical study in which 1) animals or subjects experienced smoke inhalation exposure, 2) they were treated with nebulized or aerosolized anticoagulation regimens, including heparin, heparinoids, antithrombins, or fibrinolytics (e.g., tissue plasminogen activator), 3) a control and/or sham group was described for preclinical studies, and 4) a concurrent or historical control group described for clinical studies. Exclusion criteria were 1) the absence of a group treated with a nebulized or aerosolized anticoagulation regimen, 2) the absence of a control or sham group, and 3) case reports.Data extractionNinety-nine potentially relevant references were identified. Twenty-seven references met inclusion criteria including 19 preclinical references reporting 18 studies and eight clinical references reporting five clinical studies.Data synthesisA systematic review of the literature is provided. Both clinical and methodological diversity precluded combining these studies in a meta-analysis.ConclusionsThe high mortality associated with smoke inhalation-associated acute lung injury results from airway damage, mucosal dysfunction, neutrophil infiltration, airway coagulopathy with cast formation, ventilation-perfusion mismatching with shunt, and barotrauma. Inhaled anticoagulation regimens in both preclinical and clinical studies improve survival and decrease morbidity without altering systemic markers of clotting and anticoagulation. In some preclinical and clinical studies, inhaled anticoagulants were associated with a favorable effect on survival. This approach appears sufficiently promising to merit a well-designed prospective study to validate its use in patients with severe smoke inhalation-associated acute lung injury requiring mechanical ventilation.

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Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation.

Publications

Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation.

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