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.

Intentional self-inflicted and peer-inflicted aerosol skin injuries called 'frosties': Cohort series and systematic literature review.

BACKGROUND AND OBJECTIVES: 'Frosties' are deliberate cold skin burns caused by an aerosol device. The aim of this article was to examine our own cohort, and those previously published, to identify the key features of patients presenting with frosties and inform appropriate early clinical interventions. METHOD: We compared cases in our dataset that occurred between 1 January 2013 and 30 June 2017 with those reported in the literature, focusing on seven domains: sex, age at injury, days to presentation, first aid, depth of injury and outcome. RESULTS: The median patient age was 13 years; 70.5% were female. Adequate first aid was not reported in any patient. Where recorded, the median time to presentation to a health service was six days. Where severity of injury was recorded, 13 of 37 cases (35.1%) were full thickness, and 10 patients received a split thickness skin graft. Two subgroups were identified: cluster injuries and psychological distress. DISCUSSION: Cluster injuries occur as the result of a mutual 'test of courage'. Solo injuries may point to underlying psychological distress. Frosties frequently result in significant burn injuries and often require skin grafting. The severity of frosties is underappreciated and, as a consequence, treatment, through first aid or presentation to a health service, is delayed or absent. General practitioners should be familiar with the appearance of frosties in order to identify them in unrelated consultations.

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.

Efficacy and safety of ipratropium bromide/salbutamol sulphate administered in a hydrofluoroalkane metered-dose inhaler for the treatment of COPD.

BACKGROUND: The use of chlorofluorocarbons (CFCs) has contributed to the depletion of the stratospheric ozone layer resulting in serious health concerns. Ipratropium bromide/salbutamol sulphate CFC-pressurized metered-dose inhalers (IB/SAL-CFC pMDI) have been in widespread use for many years without any apparent ill consequences. This combination has now been reformulated using the hydrofluoroalkane (HFA) propellant. This study sought to establish the clinical noninferiority of a new HFA-containing IB/SAL pMDI to the conventional IB/SAL-CFC pMDI in subjects with mild/moderate COPD. METHODS: This was a randomized, double-blind, parallel-group, multicenter study in two consecutive periods: a 14-day run-in period followed by a 85-day treatment period. Eligible mild-to-moderate stable COPD subjects aged 40-75 years were enrolled into the study and entered the run-in period during which subjects withdrew all the bronchodilators, except for salbutamol as rescue medication. Subjects were randomized to 85 days treatment with either IB/SAL-HFA or IB/SAL-CFC, 20 µg qid. RESULTS: Of the 290 randomized patients, 249 completed the study. The primary efficacy variable was the change in forced expiratory volume in one second from predose to 60 minutes after dosing on day 85. At the end of the treatment period, the adjusted mean change in forced expiratory volume in one second at 60 minutes was 123 mL in the IB/SAL-HFA pMDI group and 115 mL in the IB/SAL-CFC pMDI group. Because the lower limit of the 95% confidence interval for the between-group difference (-62 mL) was well within the noninferiority margin (-100 mL), the HFA formulation was deemed clinically noninferior to the CFC formulation. This finding was supported by secondary efficacy assessments. Both formulations of IB/SAL were well tolerated during the prolonged multiple dosing. CONCLUSION: It is concluded that IB/SAL-HFA pMDI provides effective bronchodilation of similar degree to that achieved with IB/SAL-CFC pMDI. Therefore, IB/SAL-HFA pMDI is a valuable alternative to IB/SAL-CFC pMDI.

R-134a (1,1,1,2-Tetrafluoroethane) Inhalation Induced Reactive Airways Dysfunction Syndrome.

R-134a (1,1,1,2-tetrafluoroethane) is widely used as a refrigerant and as an aerosol propellant. Inhalation of R-134a can lead to asphyxia, transient confusion, and cardiac arrhythmias. We report a case of reactive airways dysfunction syndrome secondary to R-134a inhalation. A 60-year-old nonsmoking man without a history of lung disease was exposed to an air conditioner refrigerant spill while performing repairs beneath a school bus. Afterward, he experienced worsening shortness of breath with minimal exertion, a productive cough, and wheezing. He was also hypoxic. He was admitted to the hospital for further evaluation. Spirometry showed airflow obstruction with an FEV1 1.97 L (45% predicted). His respiratory status improved with bronchodilators and oral steroids. A repeat spirometry 2 weeks later showed improvement with an FEV1 2.5 L (60% predicted). Six months after the incident, his symptoms had improved, but he was still having shortness of breath on exertion and occasional cough.

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.

Diffuse alveolar haemorrhage associated with aerosol propellant use.

Diffuse alveolar haemorrhage (DAH) is a clinical syndrome resulting from injury to the alveolar microcirculation, most commonly associated with not only autoimmune disorders or connective tissue disease, but also a variety of infections, neoplasms and toxins. We report here a case of an otherwise healthy young man with DAH attributable to an inhalation injury resulting from use of aerosol spray paint.

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.

Nitrogenous subcutaneous emphysema caused by spray application of fibrin glue during retroperitoneal laparoscopic surgery.

We report a case of a patient treated by retroperitoneoscopic partial nephrectomy who developed nitrogenous subcutaneous emphysema (SCE) as a complication. The use of a nitrogen gas-pressured fibrin tissue adhesive applied as a spray caused excessively increased pressure in the closed retroperitoneal space and resulted in widespread SCE with protracted clinical course. To the best of our knowledge, this is the first report of nitrogenous SCE associated with pneumoperitoneum. The clinical significance of nitrogenous SCE is emphasized, and the risks associated with the use of fibrin glue as a spray during laparoscopic surgery are discussed.

Extrinsic allergic alveolitis with eosinophil infiltration induced by 1,1,1,2-tetrafluoroethane (HFC-134a): a case report.

A 22-year-old woman was admitted with symptoms of dyspnea and fever with pulmonary infiltrates noted on her chest X-ray study. She developed these symptoms in the workplace; her job included the removal of body hair using a diode-laser with 1,1,1,2-tetrafluoroethane (HFC134a, an alternative to chlorofluorocarbon) as a coolant. A chest X-ray examination revealed ground-glass opacities in the lower lung fields, and a chest computed tomographic study showed diffuse centrilobular opacities. An examination of the bronchoalveolar lavage fluid revealed increased lymphocytes with a slight increase in the number of eosinophils. An examination of the transbronchial biopsy specimens revealed eosinophil infiltration. A peripheral blood eosinophilia was also seen. The patient's symptoms, chest X-ray findings, and arterial blood gas analysis all returned to normal within a week. A challenge test of 1,1,1,2-tetrafluoroethane (HFC134a) inhalation was performed, which resulted in an elevation of body temperature, the development of a cough, and laboratory data indicating increased inflammation. We then determined the patient's diagnosis to be extrinsic allergic alveolitis with eosinophil infiltration, caused by HFC134a.

A modified prescription-event monitoring study to assess the introduction of Seretide Evohaler in England: an example of studying risk monitoring in pharmacovigilance.

INTRODUCTION: Monitoring was required for the introduction of non-chlorofluorocarbon (CFC) propellants in metered dose inhalers (MDIs) to ensure that there were no unexpected adverse events due to the new products. A postmarketing surveillance study has been conducted to evaluate the introduction of the MDI Seretide Evohaler (hydrofluoroalkane-134a inhaler containing salmeterol and fluticasone propionate). OBJECTIVES: To summarise the modified prescription-event monitoring (PEM) study conducted to evaluate the introduction of Seretide Evohaler and discuss the relevance of this type of study towards pharmacovigilance risk-management planning. METHODS: Modified PEM methodology was used to examine the introduction of Seretide Evohaler into general practice in England. Patients were identified from the first National Health Service prescriptions dispensed in England for Seretide Evohaler. One postal questionnaire was sent to the prescribing doctor, requesting demographic information, severity of the indication, concomitant medication for this condition, smoking history, event data 3 months prior to and 3 months after the first prescription for Seretide Evohaler and also reason for stopping if it had been stopped. Pregnancies, deaths and selected events were followed up. Incidence density ratios were calculated to compare event rates 3 months prior to and 3 months after the introduction of Seretide Evohaler. A matched cohort analysis examined oral corticosteroid use and hospital admissions between the pre- and post-exposure periods. RESULTS: The cohort comprised 13,464 patients prescribed Seretide Evohaler, with a response rate of 62%. There was no significant difference in the length of courses of oral corticosteroid use when the pre- and post-exposure periods were compared. A matched cohort analysis showed there was no increase in the use of oral corticosteroids (relative risk [RR] 0.95; 95% CI 0.90, 0.99) or hospital admissions in the post-exposure period (RR 0.87; 95% CI 0.73, 1.04). When the number of patients with events were compared for the periods 3 months before and 3 months after exposure, fewer events were reported in the post-exposure period. There were 64 patients who experienced adverse events within an hour of using Seretide Evohaler, including one report of paradoxical bronchospasm and one of myocardial infarction with fatal outcome that were both assessed as possibly related to treatment. DISCUSSION: The results of the study suggest that the introduction of Seretide Evohaler was generally well tolerated. The modified methodology has allowed a comparison of the event rates before and after the introduction of this CFC-free inhaler into general practice.

Efficacy of beclomethasone dipropionate HFA 200 microg once daily in chronic obstructive pulmonary disease and bronchial asthma.

The efficacy and safety of once-daily beclomethasone dipropionate (BDP; 200 microg), in combination with the propellant hydrofluoroalkane-134a (HFA) was compared with that of budesonide turbuhaler (BUD-TH) 400 microg twice daily and fluticasone propionate inhaler (FP-IH) 250 microg twice daily in 40 patients with bronchial asthma or chronic obstructive pulmonary disease. All patients had used inhaled corticosteroids for at least 1 month. On randomization, 20 patients were switched to HFA-BDP and 20 patients remained on their existing BUD-TH or FP-IH treatment. After 8 weeks, HFA-BDP demonstrated a greater improvement in spirometric values, respiratory symptoms and beta2-agonist use. No significant local adverse effects were observed. Blood cortisol levels remained in the normal range in both groups. We conclude that HFA-BDP (200 microg once-daily) offered more benefit in terms of clinical and spirometry indices than BUD-TH (400 microg twice daily) or FP-IH (250 microg twice daily) in patients with moderate asthma and chronic obstructive pulmonary disease.

Fluticasone propionate hydrofluoroalkane inhalation aerosol in patients receiving inhaled corticosteroids.

BACKGROUND: Inhaled corticosteroids (ICSs) delivered by metered-dose inhalers that contain chlorofluorocarbon propellants are being discontinued because of the harmful effects of chlorofluorocarbon on the ozone layer. Therefore, some metered-dose inhaler products are being reformulated with "ozone-friendly" hydrofluoroalkane propellants. OBJECTIVE: To evaluate treatment with fluticasone propionate hydrofluoroalkane inhalation aerosol, 88, 220, and 440 microg twice daily, vs placebo in patients with asthma receiving an ICS. METHODS: Randomized, double-blind, parallel-group, 12-week study. RESULTS: Mean morning predose percent predicted forced expiratory volume in 1 second increased by 2.2%, 3.2%, and 4.6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, compared with an 8.3% decrease for placebo (P < .001 vs placebo for all groups). Secondary pulmonary function end points and asthma symptoms showed similar improvements compared with placebo. Discontinuation from the study due to lack of efficacy was 50% in the placebo group and 11%, 10%, and 6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively. At week 12, the probability of remaining in the study was 0.89, 0.90, and 0.94 for the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, vs 0.45 for the placebo group (P < .001 for all). Changes in 24-hour urinary cortisol excretion rates were similar among treatment groups. CONCLUSIONS: Fluticasone propionate hydrofluoroalkane, previously shown to be a clinically suitable alternative to fluticasone propionate chlorofluorocarbon, was effective and well tolerated. The ability to switch from fluticasone propionate chlorofluorocarbon and other chlorofluorocarbon-containing ICSs to fluticasone propionate hydrofluoroalkane without sacrificing asthma control or tolerability will facilitate a smooth transition to this nonchlorofluorocarbon-containing medicinal.