On the effects of the ocean on atmospheric CFC-11 lifetimes and emissions.

The ocean is a reservoir for CFC-11, a major ozone-depleting chemical. Anthropogenic production of CFC-11 dramatically decreased in the 1990s under the Montreal Protocol, which stipulated a global phase out of production by 2010. However, studies raise questions about current overall emission levels and indicate unexpected increases of CFC-11 emissions of about 10 Gg ⋅ yr-1 after 2013 (based upon measured atmospheric concentrations and an assumed atmospheric lifetime). These findings heighten the need to understand processes that could affect the CFC-11 lifetime, including ocean fluxes. We evaluate how ocean uptake and release through 2300 affects CFC-11 lifetimes, emission estimates, and the long-term return of CFC-11 from the ocean reservoir. We show that ocean uptake yields a shorter total lifetime and larger inferred emission of atmospheric CFC-11 from 1930 to 2075 compared to estimates using only atmospheric processes. Ocean flux changes over time result in small but not completely negligible effects on the calculated unexpected emissions change (decreasing it by 0.4 ± 0.3 Gg ⋅ yr-1). Moreover, it is expected that the ocean will eventually become a source of CFC-11, increasing its total lifetime thereafter. Ocean outgassing should produce detectable increases in global atmospheric CFC-11 abundances by the mid-2100s, with emission of around 0.5 Gg ⋅ yr-1; this should not be confused with illicit production at that time. An illustrative model projection suggests that climate change is expected to make the ocean a weaker reservoir for CFC-11, advancing the detectable change in the global atmospheric mixing ratio by about 5 yr.

Excision of Prominent Bony Mass due to Skeletal Fluorosis: A Case Report.

CASE: A 72-year-old man presented for evaluation of bony prominences over extremities. Radiographic imaging demonstrated masses of varying sizes extending from the cortical surfaces without medullary continuity. The patient had a history of Freon inhalation abuse and was diagnosed with skeletal fluorosis due to elevated serum fluoride levels. He underwent an uncomplicated excision of a left fibular mass that was threatening skin breakdown. CONCLUSIONS: This is the first reported surgical case of skeletal fluorosis demonstrating continued enlargement of bony prominences throughout the body. Skeletal fluorosis not only causes diffuse mineralization but may also lead to protruding lesions throughout the body.

Sustainability in Inhaled Drug Delivery.

Asthma and chronic obstructive pulmonary disease (COPD) are amongst the most common chronic diseases worldwide, and are largely preventable by improving the quality of the air we breathe. The most commonly deployed treatment, the metered dose inhaler (MDI), uses hydrofluorocarbon propellants, which are powerful greenhouse gases that contribute disproportionately to the climate crisis. Alternative treatment strategies are required if we are to avoid contributing to the worst effects of climate change. These strategies include promoting non-pharmacological therapies like smoking cessation and pulmonary rehabilitation; empowering patients to gain better disease control through written management plans and encouraging preventer, rather than reliever therapies. Pharmacological strategies include: improving inhaler technique and spacer use; minimising propellant release by using smaller volume MDIs and simpler dosing regimes; dose counters to prevent waste; switching to low global warming potential inhalers; and inhaler recycling. There are also opportunities to improve disease control alongside reduced greenhouse gas emissions, including better matching of patients' devices to inhaler technique rather than defaulting to MDIs, stopping unnecessary inhaled steroids in COPD and maintenance and reliever therapy in asthma. New, lower global warming potential propellants are on the horizon, and their introduction could offer a golden opportunity to enhance MDIs usability and sustainability by making them refillable, integrating whistles to optimise inhalation technique, adding integrated caps, optimising materials for recycling and adding dose counters to all MDIs.

Use of Ozone-Depleting Substances. Direct final rule.

The Food and Drug Administration (FDA, the Agency, or we) is amending its regulation on uses of ozone-depleting substances (ODSs), including chlorofluorocarbons (CFCs), to remove the designation for certain products as "essential uses" under the Clean Air Act. Essential-use products are exempt from the ban by FDA on the use of CFCs and other ODS propellants in FDA-regulated products and from the ban by the Environmental Protection Agency (EPA) on the use of ODSs in pressurized dispensers. The products that will no longer constitute an essential use are: Sterile aerosol talc administered intrapleurally by thoracoscopy for human use and metered-dose atropine sulfate aerosol human drugs administered by oral inhalation. FDA is taking this action because alternative products that do not use ODSs are now available and because these products are no longer being marketed in versions that contain ODSs.

Developing an in vitro understanding of patient experience with hydrofluoroalkane-metered dose inhalers.

As a result of the Montreal Protocol on Substances that Deplete the Ozone Layer, manufacturers of metered dose inhalers began reformulating their products to use hydrofluoroalkanes (HFAs) as propellants in place of chlorofluorocarbons (CFCs). Although the new products are considered safe and efficacious by the US Food and Drug Administration (FDA), a large number of complaints have been registered via the FDA's Adverse Events Reporting System (FAERS)-more than 7000 as of May 2013. To develop a better understanding of the measurable parameters that may, in part, determine in vitro performance and thus patient compliance, we compared several CFC- and HFA-based products with respect to their aerodynamic performance in response to changes in actuator cleaning interval and interactuation delay interval. Comparison metrics examined in this study were: total drug delivered ex-actuator, fine particle dose (<5 µm), mass median aerodynamic diameter, plume width, plume temperature, plume impaction force, and actuator orifice diameter. Overall, no single metric or test condition distinguishes HFA products from CFC products, but, for individual products tested, there were a combination of metrics that differentiated one from another.

Efficacy and safety of eco-friendly inhalers: focus on combination ipratropium bromide and albuterol in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and its treatment is critical to improve quality of life, reduce symptoms, and diminish the frequency of COPD exacerbations. Due to the harmful environmental effects of pressurized metered-dose inhalers (pMDIs) containing chlorofluorocarbons (CFCs), newer systems for delivering respiratory medications have been developed. METHODS: A search of the literature in the PubMed database was undertaken using the keywords "COPD," "albuterol," "ipratropium bromide," and "Respimat® Soft Mist Inhaler™"; pertinent references within the identified citations were included. The environmental effect of CFC-pMDIs, the invention of the Respimat® Soft Mist Inhaler™ (SMI) (Boehringer Ingelheim, Ingelheim, Germany), and its use to deliver the combination of albuterol and ipratropium bromide for the treatment of COPD were reviewed. RESULTS: The adverse environmental effects of CFC-pMDIs stimulated the invention of novel delivery systems including the Respimat SMI. This review presents its development, internal mechanism, and use to deliver the combination of albuterol and ipratropium bromide. CONCLUSION: CFC-pMDIs contributed to the depletion of the ozone layer and the surge in disorders caused by harmful ultraviolet B radiation. The banning of CFCs spurred the development of novel delivery systems for respiratory medications. The Respimat SMI is an innovative device that produces a vapor of inhalable droplets with reduced velocity and prolonged aerosol duration that enhance deposition within the lower airway and is associated with improved patient satisfaction. Clinical trials have demonstrated that the Respimat SMI can achieve effects equivalent to pMDIs but with lower medication doses. The long-term safety and efficacy remain to be determined. The Respimat SMI delivery device is a novel, efficient, and well-received system for the delivery of aerosolized albuterol and ipratropium bromide to patients with COPD; however, the presence of longer-acting, less frequently dosed respiratory medications provide patients and providers with other therapeutic options.

Therapeutic equivalence of triamcinolone acetonide hydrofluoroalkane and chlorofluorocarbon nasal inhalers in patients with seasonal allergic rhinitis.

BACKGROUND: Triamcinolone acetonide (TAA) has been reformulated as an hydrofluoroalkane (HFA) aerosol for intranasal use in patients with seasonal allergic rhinitis (SAR). This study compared the TAA HFA formulation with the previously available chlorofluorocarbon (CFC) nasal inhaler in a dose-ranging study. METHODS: This was a double-blind, parallel-group, multicenter study in 780 adults with SAR. Patients had a history of fall seasonal rhinitis and positive skin tests to ragweed. After meeting minimum symptom requirements during the run-in phase, patients were randomized to one of eight groups: TAA CFC or HFA at 14, 110, or 440 micrograms once daily or matching placebo. Treatment was continued for two weeks and patient completed a daily diary for reflective and instantaneous rating of nasal and ocular allergy symptoms. RESULTS: All active treatment groups were statistically superior to placebo with respect to the primary outcome variable, total nasal symptoms. Furthermore, the TAA HFA and TAA CFC formulations were statistically comparable over the dose range. Within each formulation, there was a significant mean reduction from baseline in the symptoms of rhinitis that increased with increasing dose. Ocular symptoms were also reduced with both formulations. Both preparations were well tolerated without any safety concerns. CONCLUSION: In conclusion, a new formulation of TAA with a HFA propellant was found to be effective in the treatment of SAR and comparable with the previously available TAA CFC formulation. There was a dose response to TAA, with doses as low as 7 micrograms per nostril once daily producing statistically significant improvement in rhinitis symptoms.

The president speaks: prevention is best: lessons from protecting the ozone layer.

The Montreal Protocol was signed 25 years ago. As a result, the irreversible destruction of the ozone layer was prevented. However, stratospheric ozone will not recover completely until 2060 and the consequent epidemic in skin cancer cases will persist until 2100. Many millions of patients with asthma and chronic obstructive pulmonary disease have safely switched from chlorofluorocarbon (CFC)-powered metered-dose inhalers (MDIs) to either hydrofluorocarbon (HFC) or DPIs. China will be the last country to phase out CFCs by 2016. HFCs are global warming gases which will be controlled in the near future. HFCs in MDIs may be phased out over the next 10-20 years.

Short-term lower leg growth in 5- to 11-year-old asthmatic children using beclomethasone dipropionate inhalers with chlorofluorocarbon or hydrofluoroalkane propellants: a 9-week, open-label, randomized, crossover, noninferiority study.

BACKGROUND: Beclomethasone dipropionate-hydrofluoroalkane (BDP-HFA) is a non-chlorofluorocarbon (CFC)-propelled metered dose inhaler. Data is needed to support the registration of BDP-HFA in pediatric populations for countries in the European Union. OBJECTIVE: The aim of the study was to assess short-term lower leg growth in children with asthma during treatment with BDP-HFA 100 µg BID compared with BDP-CFC 200 µg BID. METHODS: Children with asthma were included in this open-label, randomized, crossover study with 2-week run-in, active treatment, and washout periods. Lower leg length was measured every second week. As a secondary outcome parameter, 24-hour urine was collected for assessment of free cortisol. Interventions were inhaled BDP-HFA 100 µg BID with AeroChamber Plus spacer and BDP-CFC 200 µg BID with Volumatic spacer. RESULTS: In 63 patients with asthma aged 5 to 11 years, BDP-HFA 100 µg BID was noninferior to BDP-CFC 200 µg BID, as the lower margin of CI (-0.03 to 0.10 mm/wk) of the estimated difference (0.03 mm/wk) was greater than the prespecified lower limit for noninferiority of -0.12 mm/wk. Mean (SD) lower leg growth rate during run-in, BDP-HFA 100 µg BID, and BDP-CFC 200 µg BID was 0.36 (0.17), 0.27 (0.21), and 0.23 (0.18) mm/wk, respectively (BDP-HFA estimate of difference, -0.09 [95% CI, -0.16 to -0.03 mm/wk; P < 0.01]; BDP-CFC estimate of difference, -0.13 [95% CI, -0.19 to -0.06 mm/wk; P < 0.001]). No statistically significant differences were seen in urinary free cortisol assessments. Eight and 6 mild to moderate adverse events in 10 children were reported during treatment with BDP-HFA and BDP-CFC, respectively. One event in each group was judged to be probably related to the study medication; no others were judged to be related. CONCLUSIONS: No statistically significant differences were found in lower leg growth between BDP-HFA 100 µg BID with AeroChamber Plus spacer and BDP-CFC 200 µg BID with Volumatic spacer during 2-week treatment. Evidence of differences in systemic activity between the treatments was not found. EudraCT registration: 2007-007455-14.

Use of ozone-depleting substances; removal of essential-use designation (flunisolide, etc.). Final rule.

The Food and Drug Administration (FDA), after consultation with the Environmental Protection Agency (EPA), is amending FDA's regulation on the use of ozone-depleting substances (ODSs) in self-pressurized containers to remove the essential-use designations for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil used in oral pressurized metered-dose inhalers (MDIs). The Clean Air Act requires FDA, in consultation with the EPA, to determine whether an FDA-regulated product that releases an ODS is an essential use of the ODS. FDA has concluded that there are no substantial technical barriers to formulating flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil as products that do not release ODSs, and therefore they will no longer be essential uses of ODSs as of the effective dates of this rule. MDIs for these active moieties containing an ODS may not be marketed after the relevant effective date.

Uncontrolled occupational exposure to 1,1-dichloro-1-Fluoroethane (HCFC-141b) is associated with acute pulmonary toxicity.

BACKGROUND: The toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b), a hydrochlorofluorocarbon (HCFC), is low according to animal studies. However, pulmonary manifestations associated with acute HCFC exposure by inhalation have not been reported as yet in man. We evaluated the pulmonary effects of HCFC-141b inhalation, caused by an accident, in previously healthy individuals. METHODS: The subjects in this study were 15 workers in whom unpleasant symptoms developed after inhaling HCFC-141b at work. Clinical manifestations, radiologic findings, and changes in pulmonary function and airway hyperresponsiveness (AHR) over time were assessed, and BAL fluid analyses findings for four subjects were compared with those of four healthy volunteers (control subjects). RESULTS: (1) Cough, shortness of breath, and malaise developed in most patients, but only two patients complained of a sore throat. (2) A high-resolution CT scan of the chest revealed bilateral diffuse ground-glass opacities that were predominant in upper lung zones. (3) The mean (+/- SD) FVC was 71.4 +/- 18.86% predicted, and the mean FEV(1)/FVC ratio was 92.9 +/- 4.25%. Eleven patients (73%) showed restrictive ventilatory impairments during the initial tests. FVC gradually improved, and the FEV(1)/FVC ratio gradually decreased with time. (4) AHR was observed in four subjects during the initial tests. (5) BAL fluid samples revealed significantly higher neutrophil counts than those in control subjects. CONCLUSIONS: Overexposure to HCFC-141b was associated with parenchymal lung injury that was characterized by ground-glass opacities, elevated BAL neutrophil counts, and restrictive ventilatory impairment. Restrictive impairments improved with time after exposure.

Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydrofluoroalkane-134a.

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluoroalkane-134a (HFA) has been designed to be equivalent in terms of safety to chlorofluorocarbon (CFC)-formulated metered dose inhalers (MDI). The aim was to assess whether BDP HFA MDI 100 microg twice daily was equivalent to BDP CFC MDI 100 microg twice daily in terms of effects on short-term lower leg growth rate (LLGR) and measures of hypothalamic-pituitary-adrenal (HPA) function. The study consisted of a randomized double-blind cross-over trial with three active, a run-in and two wash-out periods each consisting of 2 wk. The place of study was a secondary referral outpatient clinic. The subjects involved were 14 boys and 10 girls with asthma, aged 7-12 yr. They were all administered BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily. The outcome measures included LLGR and 24-h urine-free cortisol (UFC) and total cortisol metabolites (TCM). Mean (SD) LLGR during run-in and BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily periods were 0.43 (0.23), 0.09 (0.29), 0.10 (0.45) and 0.08 (0.27) mm/wk. The one-sided 97.5% confidence interval for the difference in LLGR between BDP HFA 100 microg and BDP CFC 100 microg was 0.24, thus, below the predefined criterion of 0.20 mm/week. Inter-period comparisons of active treatments showed no differences between means of LLGR, UFC or TCM. Though non-inferiority between BDP HFA and CFC 100 microg twice daily in terms of effects on LLGR was not found, equivalence was suggested by comparisons of LLGR during run-in and active treatments and by HPA function measures.

Use of ozone-depleting substances; removal of essential-use designations. Final rule.

The Food and Drug Administration (FDA) is amending its regulation on the use of ozone-depleting substances (ODSs) in self-pressurized containers to remove the essential-use designations for albuterol used in oral pressurized metered-dose inhalers (MDIs). Under the Clean Air Act, FDA, in consultation with the Environmental Protection Agency (EPA), is required to determine whether an FDA-regulated product that releases an ODS is an essential use of the ODS. Two albuterol MDIs that do not use an ODS have been marketed for more than 3 years. FDA has determined that the two non-ODS MDIs will be satisfactory alternatives to albuterol MDIs containing ODSs and is removing the essential-use designation for albuterol MDIs as of December 31, 2008. Albuterol MDIs containing an ODS cannot be marketed after this date.

Low incidence of paradoxical bronchoconstriction with bronchodilator drugs administered by Respimat Soft Mist inhaler: results of phase II single-dose crossover studies.

BACKGROUND AND OBJECTIVES: Respimat Soft Mist Inhaler (SMI) is an innovative device that offers improved lung deposition and is an environmentally friendly alternative to conventional, chlorofluorocarbon-containing metered-dose inhalers (CFC-MDIs). The aqueous formulations of bronchodilator drugs administered from Respimat SMI contain low concentrations of ethylene diamine tetra-acetic acid (EDTA), a stabilising agent, and benzalkonium chloride (BAC), an antibacterial agent, both of which have been associated with bronchoconstriction when administered via nebulisers. The aim of this retrospective analysis was to compare the incidence of paradoxical bronchoconstriction with bronchodilator drugs administered via Respimat SMI or a CFC-MDI in patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS: Nine randomised, active- and/or placebo-controlled, double-blind, crossover studies, in which asthmatic and COPD patients (n = 444 and n = 216, respectively) received a beta(2)-agonist and/or anticholinergic or placebo via Respimat SMI or CFC-MDI, were included in the analysis. The incidence of conditions indicative of paradoxical bronchoconstriction were collated and divided into four categories: (1) 'bronchospasm'; (2) two or more of the following events: 'other respiratory adverse events', 'rescue medication use' or 'asymptomatic drop in forced expiratory volume in one second' (FEV(1)); (3) either 'rescue medication use' or 'other respiratory adverse event'; (4) 'asymptomatic drop in FEV(1)'. RESULTS: The incidence of adverse events indicative of paradoxical bronchoconstriction was low in those patients using the Respimat SMI device, and similar to that seen in the CFC-MDI group. In addition, the incidence of adverse events indicative of paradoxical bronchoconstriction observed in the Respimat SMI group was similar for BAC + EDTA and BAC-only drug formulations. CONCLUSIONS: These studies demonstrate that, due to the extremely low absolute amounts of BAC and EDTA delivered to the lungs by the device, Respimat SMI is safe with regard to paradoxical bronchoconstriction in patients with asthma or COPD.

Formula for a new foam.

As the 2010 phaseout date for chlorofluorocarbons draws nearer, materials engineers are working to find replacements for these ozone-depleting chemicals in the production of plastics and other products. One team of engineers is focusing on a combination of two low-cost and environmentally benign substances--supercritical carbon dioxide and clay nanoparticles--to meet these needs. The result is a strong yet lightweight alternative that retains all the beneficial qualities of solid plastic.