Efficiency of Ipratropium Bromide and Albuterol Deposition in the Lung Delivered via a Soft Mist Inhaler or Chlorofluorocarbon Metered-Dose Inhaler.

The propellant-free Combivent Respimat Soft Mist Inhaler (CVT-R) was developed to replace the chlorofluorocarbon-propelled Combivent metered-dose inhaler (CVT-MDI). This steady-state pharmacokinetic (PK) substudy evaluated drug lung-delivery efficiency, using data from two phase III safety and efficacy trials. PK parameters were obtained from well-controlled population PK analyses. Area under the plasma concentration-time curve (AUC), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) showed systemic exposure to ipratropium bromide and albuterol delivered via the CVT-R was proportional to ex-mouthpiece delivered dose. Although the labeled dose of ipratropium bromide in the CVT-R was half that in the CVT-MDI, the systemic exposure was comparable. No PK interaction for the ipratropium bromide and albuterol Respimat drug components was demonstrated. Ipratropium bromide alone resulted in similar exposure to the combination of ipratropium bromide and albuterol. These results show that CVT-R delivers drug more efficiently to the lung than CVT-MDI.

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.

The acute, genetic, developmental and inhalation toxicology of trans-1-chloro,3,3,3-trifluoropropene (HCFO-1233zd(E)).

Trans-1-chloro,3,3,3-trifluoropropene (HCFO-1233zd(E)) is being developed as a foam blowing agent, refrigerant and solvent because it has a very low global warming potential (<10), as contrasted to the hydrofluorocarbons (>500). The toxicology profile is described. The acute 4-hour 50% lethal concentration value in rats receiving HCFO-1233zd(E) was 120 000 ppm. The no observed effect level (NOEL) in cardiac sensitization studies in dogs was 25 000 ppm. In a 2-week range-finding study, rats were exposed to HCFO-1233zd(E) at levels of 0, 2000, 7500 and 20 000 ppm 6 hours/day for 5 days/week. Histopathological changes in the heart described as multifocal mononuclear infiltrates were observed in males (mid- and high-exposure group) and females (high-exposure group), suggesting this organ was the target for HCFO-1233zd(E) toxicity. In a 4-week study, rats were exposed to 0, 2000, 4500, 7500 and 10 000 ppm. The only finding was an increase in potassium (mid- and high-exposure males). No increase was observed after a 2-week recovery period, nor in a subsequent 13-week toxicity study. In a 13-week study, rats were exposed to 4000, 10 000 and 15 000 ppm 6 hours/day for 5 days/week. Findings consisted of multifocal mononuclear cell infiltrates in the heart with a NOEL/lowest observed adverse effect level of 4000 ppm. No genetic toxicity was observed in a battery of genetic toxicity studies. In a rat prenatal developmental toxicity study, dilated bladders were observed in the high-exposure group fetuses (15 000 ppm), a finding of unclear significance. HCFO-1233zd(E) was not a developmental toxin in rabbits, even at exposure levels up to 15 000 ppm.

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.

Biotransformation of trans-1-chloro-3,3,3-trifluoropropene (trans-HCFO-1233zd).

trans-1-Chloro-3,3,3-trifluoropropene (trans-HCFO-1233zd) is a novel foam blowing and precision cleaning agent with a very low impact for global warming and ozone depletion. trans-HCFO-1233zd also has a low potential for toxicity in rodents and is negative in genotoxicity testing. The biotransformation of trans-HCFO-1233zd and kinetics of metabolite excretion with urine were assessed in vitro and in animals after inhalation exposures. For in vitro characterization, liver microsomes from rats, rabbits and humans were incubated with trans-HCFO-1233zd. Male Sprague Dawley rats and female New Zealand White rabbits were exposed to 2,000, 5,000 and 10,000ppm for 6h and urine was collected for 48h after the end of the exposure. Study specimens were analyzed for metabolites using (19)F NMR, LC-MS/MS and GC/MS. S-(3,3,3-trifluoro-trans-propenyl)-glutathione was identified as predominant metabolite of trans-HCFO-1233zd in all microsomal incubation experiments in the presence of glutathione. Products of the oxidative biotransformation of trans-HCFO-1233zd were only minor metabolites when glutathione was present. In rats, both 3,3,3-trifluorolactic acid and N-acetyl-(3,3,3-trifluoro-trans-propenyl)-l-cysteine were observed as major urinary metabolites. 3,3,3-Trifluorolactic acid was not detected in the urine of rabbits. Quantitation showed rapid excretion of both metabolites in both species (t1/2<6h) and the extent of biotransformation of trans-HCFO-1233zd was determined as approximately 0.01% of received dose in rabbits and approximately 0.002% in rats. trans-HCFO-1233zd undergoes both oxidative biotransformation and glutathione conjugation at very low rates. The low extent of biotransformation and the rapid excretion of metabolites formed are consistent with the very low potential for toxicity of trans-HCFO-1233zd in mammals.

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.

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide.

AIMS: A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS: Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC(24h) [area under the concentration-time curve (0-24 h)], budesonide AUC(0-12h) and C(max) . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC(20) (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS: In the pharmacokinetic study, there were no differences in cortisol, AUC(0-12h) [area under the concentration-time curve (0-12 h)], T(max) (time to maximum concentration) or C(max) (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC(24h) was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC(0-12h) was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC(20) (provocative concentration of methacholine needed to produce a 20% fall in FEV(1) ) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS: Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.

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.

Fluid and thermal dynamics of cryogen sprays impinging on a human tissue phantom.

Cryogen spray cooling (CSC) protects the epidermis from unintended heating during cutaneous laser surgery. The present work investigated the time-dependent flow characteristics of cryogen sprays and correspondent thermal dynamics at the surface of a human tissue phantom. First, a numerical analysis was carried out to evaluate an epoxy block substrate as a human tissue phantom. Next, the velocity and diameter of cryogen droplets were measured simultaneously and correlated with surface temperature of the human tissue phantom during CSC. Finally, velocity and diameter measurements were used to compute the spray number, mass, and kinetic energy fluxes, and temperature measurements were used to compute the surface heat flux. Numerical modeling showed that the thermal response of our phantom was qualitatively similar to that of human stratum corneum and epidermis; quantitatively, thermal responses differed. A simple transformation to map the temperature response of the phantom to that of tissue was derived. Despite the relatively short spurt durations (10 ms, 30 ms, and 50 ms), cryogen delivery is mostly a steady state process with initial and final fluid transients mainly due to the valve dynamics. Thermal transients (16 ms) are longer than fluid transients (4 ms) due to the low thermal diffusivity of human tissues; steady states are comparable in duration ( approximately 10 ms, 30 ms, and 50 ms) although there is an inherent thermal delay ( approximately 12 ms). Steady state temperatures are the lowest surface temperatures experienced by the substrate, independent of spurt duration; hence, longer spurt durations result in larger exposures of the tissue surface to the same lower, steady state temperature as in shorter spurts. Temperatures in human tissue during CSC for the spray system and parameters used herein are estimated to be approximately -19 degrees C at the stratum corneum surface and >0 degrees C across the epidermis.

Part III: Location of asthma inflammation and the distal airways: clinical implications.

Accumulating evidence suggests that the airway inflammation and remodeling characteristic of asthma occur not only in the central airways, but also in the distal lung and the lung parenchyma. The distal airways are increasingly being recognized as important sites of airflow obstruction. Research indicates that distal inflammation may play a crucial role in airway hyperresponsiveness, nocturnal asthma, and spontaneous exacerbations of asthma symptoms. Although the effectiveness of inhaled corticosteroids in improving asthmatic symptoms and preventing exacerbations is well established, the ability of conventional formulations to reach the distal airways is limited. The impaired ability of these formulations to reach the distal airways may contribute to the observation that inhaled corticosteroids do not always provide adequate control of asthma symptoms. Newer formulations of inhaled corticosteroids that use hydrofluoroalkane (HFA) propellants in solution have greater access to the distal airways and produce beneficial changes in lung function. Due to their highly targeted delivery systems, newer HFA-based formulations have the potential to effectively treat asthma at reduced doses.

Differential anti-inflammatory effects of large and small particle size inhaled corticosteroids in asthma.

BACKGROUND: Extra-fine particle formulations of hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) exhibit clinical effects comparable with conventional particle formulations of chlorofluorocarbon beclometasone dipropionate (CFC-BDP) at half the dose. There is little data comparing their effects on inflammation. We have evaluated the effects of HFA-BDP and CFC-BDP on pulmonary and systemic markers of asthmatic inflammation. METHODS: A double-blind randomized crossover trial was undertaken comparing the anti-inflammatory effects of HFA-BDP (100 and 400 microg/day) and CFC-BDP (200 and 800 microg/day). Treatment with montelukast was evaluated as add-on to the higher dose of BDP. RESULTS: Compared with baseline after withdrawal of usual asthma therapy, 100 microg of HFA-BDP significantly attenuated serum eosinophilic cationic protein levels (0.61-fold change, 95% CI 0.49-0.77; a 39% reduction, P < 0.001), but 200 microg of CFC-BDP did not (0.87-fold change, 95% CI 0.63-1.23; P = 1). A dose of 800 microg of CFC-BDP and 400 microg of HFA-BDP led to reductions in exhaled nitric oxide (0.57-fold change, 95% CI 0.44-0.73; a 43% reduction, P < 0.001 and 0.65-fold change, 95% CI 0.47-0.91; a 35% reduction, P = 0.008, respectively); and peripheral eosinophils (-74 cells/microl, 95% CI -146 to -2; P = 0.020 and -77 cells/microl, 95% CI -140 to -14; P = 0.012, respectively). Montelukast further reduced exhaled nitric oxide (0.81-fold change, 95% CI 0.66-0.98; P = 0.028) with 400 microg HFA-BDP and eosinophils (-44 cells/microl, 95% CI -80 to -8; P = 0.012) with 800 microg CFC-BDP, but not vice versa. CONCLUSION: Chlorofluorocarbon beclometasone dipropionate and HFA-BDP have differential effects on pulmonary and systemic inflammation, which dictate the additive effects of montelukast.

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.

Optimizing aerosol delivery by pressurized metered-dose inhalers.

The modern era of aerosol therapy began with the introduction of the Medihaler Epi in 1956, after a 13-year-old asthmatic told her father, an officer in the Riker company, that asthma medications should be as convenient to use as hair spray and she complained that the bulb atomizer leaked in her school bag. Since then, advances in technology have made aerosol delivery much more efficient, so that it is now the most widely used mode of medication delivery for chronic airways diseases. Today the pressurized metered-dose inhaler (pMDI) is a metal canister containing a mixture of propellants, surfactants, preservatives, and drug. However, pMDIs are underused in the United States. One barrier to use is the misconception related to pMDI effectiveness relative to small-volume nebulizers, especially among pediatricians. This is despite the strongest evidence of pMDI superiority, from well-controlled pediatric studies. In this manuscript we discuss ways to optimize the use of medications given via pMDI and examine recent changes in pMDI technology that will make drug delivery more efficient and consistent.

Hydrofluoroalkane-134A beclomethasone or chlorofluorocarbon fluticasone: effect on small airways in poorly controlled asthma.

Inflammation in asthma extends into the small airways (< 2 mm diameter). Most inhaled corticosteroids are suspensions with a particle size > 2 mm. Therefore, inflammation in the small airways of patients with asthma may not be adequately treated with these preparations. Some inhaled corticosteroids, on the other hand, are compounded with alcohol, resulting in a solution producing an aerosol that has a mean particle diameter of < 2 mm. This study was designed to compare the addition of equivalent amounts of two inhaled corticosteroids (one a suspension and one a solution) to the treatment of patients with asthma, which was uncontrolled despite treatment with moderate to high doses of inhaled corticosteroids and usually additional controller medications. The study was performed with 30 patients, > or = 18 years of age. Subjects were randomized in a single-blind fashion to receive, in addition to their current asthma therapy, either CFC-FP 220 microg each morning and 110 microg each evening (n = 10) or HFA-BDP 160 mcg twice daily (n = 20). Pre- and postbronchodilator spirometry, single breath nitrogen washout for closing volume and residual volume by plethysmography were assessed before and after 3 months of therapy. In the subjects who received HFA-BDP, the ratio of closing volume (CV) to vital capacity (VC) and residual volume (RV) decreased significantly (p = 0.0214 and 0.0433, respectively), whereas forced expiratory flow over 25-75% of the vital capacity (FEF25-75%), forced expiratory volume in 1 second (FEV1), and morning peak flow improved significantly (p = 0.0014, 0.0184, and 0.0321). Improvements from baseline of CV, CV/VC, and postbronchodilator FEF25-75%, were statistically significant in the HFA-BDP group compared with the CFC-FP group (p = 0.0049, 0.0194, and 0.0355, respectively). These preliminary findings suggest that the addition of HFA-BDP, compared with CFC-FP in patients with poorly controlled asthma despite receiving moderate to high doses of inhaled steroids, has a greater effect on parameters reflecting small airway patency presumably secondary to reduction in inflammation.

Effects of mometasone furoate dry powder inhaler and beclomethasone dipropionate hydrofluoroalkane and chlorofluorocarbon on the hypothalamic-pituitary-adrenal axis in asthmatic subjects.

STUDY OBJECTIVES: Mometasone furoate dry powder inhaler (MF-DPI) [400 mug] is an inhaled corticosteroid (ICS) that is effective in the treatment of asthma. MF-DPI has a low potential for suppression of the hypothalamic-pituitary-adrenal (HPA) axis at its clinical dose. The effect of MF-DPI, 400 microg qd, on the HPA axis was compared to that of beclomethasone dipropionate (BDP) using hydrofluoroalkane (HFA) and chlorofluorocarbon (CFC) propellants via metered-dose inhalers (MDIs) twice daily. DESIGN AND INTERVENTIONS: This randomized, third-party blind, parallel-group study compared the effects of MF-DPI 400 mug one puff qd in the morning (n = 18), HFA-BDP 200 microg two puffs MDI bid (n = 18), and CFC-BDP 400 microg two puffs MDI bid (n = 17) for 14 days on the area under the 24-h serum cortisol concentrations curve (AUC(0-24)) and on total 24-h urinary free cortisol excretion in mild asthmatic subjects. Effects on morning/evening peak expiratory flow (PEF) and on inhaled albuterol use were also assessed. Adverse events that occurred during or > or = 30 days after the study were recorded. RESULTS: The mean decrease from baseline in the serum cortisol concentrations AUC(0-24) in the MF-DPI group was significantly less than in either the HFA-BDP (p = 0.024) or the CFC-BDP (p = 0.011) groups. Decreases in serum cortisol concentrations AUC(0-24) in the two BDP groups did not differ from one another. The MF-DPI group trended toward higher morning and evening PEF than either BDP group. Treatment-associated adverse events were reported by seven subjects in the MF-DPI group, vs one subject in the HFA-BDP and three subjects in the CFC-BDP groups; these were mild, and no subject discontinued treatment due to an adverse event. CONCLUSIONS: Fourteen days of treatment with MF-DPI 400 microg qd was associated with a significantly lesser decrease in the serum cortisol concentrations AUC(0-24) compared with HFA-BDP 200 microg MDI or CFC-BDP 400 microg MDI bid.

Effects of HFA- and CFC-beclomethasone dipropionate on the bronchial response to methacholine (MCh) in mild asthma.

Metered inhalers using chlorofluorocarbon (CFC) propellents have been gradually replaced by new devices that use hydrofluoroalkanes (HFAs) as their propellents, which are less harmful to the environment. This reformulation led to a substantial improvement of the previous technologies applied to inhalation devices and of the physical characteristics of drugs delivered. In particular, inhaled corticosteroids, such as beclomethasone dipropionate (BDP) which is of fundamental importance in the long-term management of bronchial asthma, took advantage of this reformulation. Unlike the preparation beclomethasone dipropionate and chlorofluorocarbon (BDP-CFC) which was a suspension, that of beclomethasone dipropionate and a hydrofluoroalkane (BDP-HFA) is a solution and produces an aerosol with a mean aerodynamic particle size of 1.1 microm, which is much smaller than the particle size of 3.5-4.0 microm, obtained with the BDP-CFC. The particles of BDP-HFA can then deposit in the lungs in a larger amount, and particularly in the more peripheral airways where the inflammatory process starts in the case of bronchial asthma. A 12-week use of BDP-HFA ensured a significant better control of the bronchial response to methacholine (MCh) than the corresponding use of BDP-CFC for the same duration. The therapeutic performance of BDP-HFA proved much higher and allowed the substantial reduction of the therapeutic daily dose for the clinical asthma management, being the increased and more peripheral deposition of BDP-HFA is presumed to play a crucial role.

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.

Effects of droplet velocity, diameter, and film height on heat removal during cryogen spray cooling.

Cryogen spray cooling (CSC) is an effective method to reduce or eliminate epidermal damage during laser treatment of various dermatoses. This study sought to determine the effects of specific cryogen properties on heat removal. Heat removal was quantified using an algorithm that solved an inverse heat conduction problem from internal temperature measurements made within a skin phantom. A nondimensional parameter, the Weber number, characterized the combined effects of droplet velocity, diameter, and surface tension. CSC experiments with laser irradiation were conducted on ex vivo human skin samples to assess the effect of Weber number on epidermal protection. An empirical relationship between heat removal and the difference in droplet temperature and the substrate, droplet velocity, and diameter was obtained. Histological sections of irradiated ex vivo human skin demonstrated that sprays with higher Weber numbers increased epidermal protection. Results indicate that the cryogen film acts as an impediment to heat transfer between the impinging droplets and the substrate. This study offers the importance of Weber number in heat removal and epidermal protection.