A novel breath-actuated integrated vortex spacer device increases relative lung bioavailability of fluticasone/salmeterol in combination.

BACKGROUND: Spacer devices facilitate respirable drug delivery. A novel breath-actuated antistatic spacer with integrated vortex chamber (Synchro-Breathe) device has been developed, which is compact,portable and user friendly as compared to conventional spacers which are bulky and cumbersome. The relative bioavailability to the lung of inhaled fluticasone and salmeterol combination is primarily dependent on respirable dose delivery and can be reliably quantified using adrenal suppression and early fall in serum potassium (marker of systemic beta-2 adrenoreceptor response) as surrogate markers for delivered lung dose. AIMS AND OBJECTIVES: To compare the in vivo relative bioavailability to the lung of Hydrofluoroalkane(HFA) Seretide delivered via Synchro-Breathe (SB); an optimally prepared 750 ml large volume plastic spacer, Volumatic (VM); and conventional Evohaler pMDI (EH). METHODS: Nineteen healthy volunteers completed the study using a randomised double blind, double dummy crossover design. Single doses of placebo or Seretide HFA 250 (total dose ex-valve: fluticasone 2000 mcg/salmeterol 200 mcg) were administered via SB, VM and EH. Overnight urinary cortisol creatinine (OUCC) and serum potassium (K) were measured at baseline and after each dose as systemic surrogates of relative respirable dose delivery for the fluticasone and salmeterol moieties, respectively. RESULTS: Significant suppression of OUCC and K occurred from baseline with SB and VM but not EH devices(geometric mean fold suppression, 95% CI, p and arithmetic mean fall mmol/L, 95% CI, respectively); EH:1.51(0.43-1.01), p 1/4 0.06; VM: 2.52(1.57-4.04), p < 0.001; SB: 2.66(1.57-4.49), p < 0.001(equating to 33.8%,60.2% and 62.3% falls, respectively). For K, the falls for EH were 0.09(0.25 to 0.07), p 1/4 0.69; VM: 0.27(0.46 to 0.08), p 1/4 0.003; SB: 0.32(0.53 to 0.11), p 1/4 0.002 (equating to 2.2%, 6.8%, and 8.06% fall,respectively). There were no significant differences between SB and VM. CONCLUSION: The breath-actuated Synchro-Breathe device was comparable to an optimally prepared Volumatic spacer, and resulted in commensurate improvement in relative lung bioavailability for both fluticasone and salmeterol moieties compared to pMDI.

In vivo comparison of the relative systemic bioavailability of fluticasone propionate from three anti-static spacers and a metered dose inhaler.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Conventional spacers help overcome problems with co-ordination and may improve lung deposition and decrease oropharyngeal impaction. Antistatic spacers eliminate electrostatic charge and may hence improve respirable dose delivery. The systemic bioavailability of inhaled fluticasone propionate is primarily dependent on delivery by the pulmonary route and hence the performance of antistatic spacers can be evaluated using adrenal suppression as a sensitive surrogate for relative bioavailability to the lung after an inhalation. WHAT THIS STUDY ADDS: This study compares the relative bioavailability to the lung of inhaled fluticasone delivered via conventional pressurized metered dose inhalers (pMDI) and three antistatic spacers (plastic Zerostat-V, plastic Aerochamber Max, and metal Nebuchamber) in patients with asthma. All three antistatic spacers when compared with pMDI significantly increased the relative bioavailability to the lungs of inhaled fluticasone in terms of relative adrenal suppression, and there were no significant differences between the plastic and metal antistatic spacers. AIMS: The systemic bioavailability of inhaled fluticasone propionate (FP) depends primarily on lung absorption and can be quantified by measuring suppression of overnight and early morning urinary cortisol/creatinine (OUCC and EMUCC, respectively). The aim of the study was to determine the relative bioavailability of hydrofluoroalkane (HFA) FP to the lungs via anti-static plastic (Zerostat-V and Aerochamber Max), metal (Nebuchamber) anti-static spacers and metered dose inhaler [Flixotide Evohaler (EH) (pMDI)]. METHODS: A randomized, double-blind, double-dummy, four-way crossover design was used. Eighteen mild to moderate asthmatics received single doses of placebo/HFA-FP 2 mg via the 280-ml Zerostat-V (ZS); 250-ml Nebuchamber (NC); 197-ml Aerochamber Max (AC); and pMDI (EH). Measurements of OUCC and EMUCC were made at baseline and 10 h after each dose. RESULTS: Significant suppression of OUCC and EMUCC occurred from baseline with all three spacers, but not Evohaler (geometric mean fold suppression, 95% confidence interval): ZS, 2.74 (1.75, 4.30), P < 0.001; NC, 3.31 (1.81, 6.06), P < 0.001; AC, 4.98 (3.39, 7.31), P < 0.001; and for EH this was 1.42 (0.92, 2.21), P= 0.169 (equating to a 64, 70, 80 and 30% fall in OUCC via the ZS, NC, AC and EH devices, respectively). There were significant differences between all three spacers vs. EH. When compared with the Evohaler, the Zerostat V resulted in 48% greater suppression (P= 0.009); the Nebuchamber 57% greater suppression (P= 0.001); and the Aerochamber Max 71% greater suppression of OUCC (P < 0.001). CONCLUSION: All three antistatic spacers significantly increased the relative systemic bioavailability of HFA-FP compared with the standard pMDI. --EudraCT Database trial registration number: 2005-005557-22.

Respirable dose delivery of fluticasone propionate from a small valved holding chamber, a compact breath actuated integrated vortex device and a metered dose inhaler.

AIMS: To compare the respirable dose delivery of the hydrofluroalkane fluticasone propionate (HFA-FP) via an optimally prepared Aerochamber Plus spacer (AP), via a Synchro-Breathe (SB) device, and pMDI Evohaler (EH). METHODS: Seventeen mild to moderate asthmatics completed the study using a randomized, double-blind, double-dummy, three way crossover design. Single doses of placebo or HFA-FP 2.0 mg were administered via the EH, AP, and SB devices. The overnight urinary cortisol : creatinine ratio (OUCC) was measured at baseline and after each dose. RESULTS: Significant suppression of OUCC occurred from baseline with AP and SB but not EH devices (geometric mean fold suppression, 95% CI): AP: 3.18 (2.29, 4.36), P < 0.001; SB: 1.79 (1.31, 2.40), P = 0.001; EH: 1.12 (0.69, 1.44), p = 0.37 (equating to 68%, 45% and 9% falls, respectively). Significant differences in OUCC between devices were as follows: (geometric mean fold difference, 95% CI): AP vs. EH. 2.83 (2.09, 3.82), P < 0.001; AP vs. SB: 1.78 fold (1.21, 2.60), P = 0.003; SB vs. EH: 1.59 (1.09, 2.31), P = 0.013 (equating to 65%, 44% and 37% differences, respectively). CONCLUSIONS: The use of an optimally prepared AP spacer and breath actuated SB device, when compared with pMDI, significantly increased the respirable dose of HFA-FP.

Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate.

AIM: Fluticasone propionate (FP) and mometasone furoate (MF) are inhaled corticosteroids that possess a high ratio of topical to systemic activity. The systemic bioavailability of MF has been claimed to be minimal (1%). FP has been shown to exhibit the same degree of systemic effects, but its systemic availability is between 13 and 17%. We hypothesize that FP and MF have comparable systemic availabilities that can explain their potential to cause systemic effects. METHODS: Steady-state FP and MF trough plasma samples were determined from a clinical study by Fardon et al. in patients with persistent asthma (forced expiratory volume in 1 s = 91%). The percent plasma protein binding of FP and MF was measured using ultracentrifugation. Free FP plasma concentrations were normalized for their differences in receptor binding affinity compared with MF and linked to overnight urinary cortisol/creatinine with an inhibitory E(max). RESULTS: A plot of steady-state FP and MF total trough plasma concentrations vs. dose showed that both drugs exhibit dose linearity. MF has comparable bioavailability to FP based on the steady-state concentrations observed for the different doses. The free plasma concentration producing 50% of urinary cortisol suppression (IC(50)) for MF was not statistically different from the free, normalized IC(50) for FP. CONCLUSION: FP and MF have similar pulmonary deposition and the same potential to cause systemic side-effects due to their similar IC(50) values. The observed urinary cortisol suppression of FP and MF is in agreement with their systemic availability, their differences in plasma protein binding and receptor binding affinity.

Respiratory symptoms, pulmonary function, and markers of inflammation among bar workers before and after a legislative ban on smoking in public places.

CONTEXT: Scotland prohibited smoking in confined public places on March 26, 2006. OBJECTIVE: To investigate the association of smoke-free legislation with symptoms, pulmonary function, and markers of inflammation of bar workers. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational study was conducted in Tayside, Scotland from February-June 2006. One hundred five nonasthmatic and asthmatic nonsmoking bar workers were initially enrolled, of whom 77 completed the study per protocol. MAIN OUTCOME MEASURES: Respiratory and sensory symptoms, spirometry measurements, serum cotinine levels, peripheral inflammatory cell count, asthma quality-of-life scores, and exhaled nitric oxide levels were evaluated before and after introduction of the smoking ban. RESULTS: For the per-protocol analysis, the percentage of bar workers with respiratory and sensory symptoms decreased from 79.2% (n = 61) before the smoke-free policy to 53.2% (n = 41) (total change, -26%; 95% confidence interval [CI], -13.8% to -38.1%; P<.001) and 46.8% (n = 38) (-32.5%; 95% CI, -19.8% to -45.2%; P<.001) 1 and 2 months afterward. Forced expiratory volume in the first second increased from 96.6% predicted to 104.8% (change, 8.2%; 95% CI, 3.9% to 12.4%; P<.001) and then 101.7% (change, 5.1%; 95% CI, 2.1% to 8.0%; P = .002), and serum cotinine levels decreased from 5.15 ng/mL to 3.22 ng/mL (change, -1.93 ng/mL; 95% CI, -2.83 to -1.03 ng/mL; P<.001) and then 2.93 ng/mL (-2.22 ng/mL; 95% CI, -3.10 to -1.34 ng/mL; P<.001). The total white blood cell and neutrophil count was reduced from 7610 to 6980 cells/microL at 2 months (-630 cells/muL; 95% CI, -1010 to -260 cells/microL; P = .002) and from 4440 to 4030 cells/microL (-410 cells/microL; 95% CI, -740 to -90 cells/microL; P = .03), respectively. Asthmatic bar workers also had less airway inflammation, with a reduction in exhaled nitric oxide from 34.3 parts per billion (ppb) to 27.4 ppb 1 month after the ban (0.8-fold change; 95% CI, 0.67 to 0.96 ppb; P = .04), and Juniper quality-of-life scores increased from 80.2 to 87.5 points (7.3 points; 95% CI, 0.1 to 14.6 points; P = .049). CONCLUSIONS: Smoke-free legislation was associated with significant early improvements in symptoms, spirometry measurements, and systemic inflammation of bar workers. Asthmatic bar workers also had reduced airway inflammation and improved quality of life.

Airway and systemic effects of hydrofluoroalkane formulations of high-dose ciclesonide and fluticasone in moderate persistent asthma.

BACKGROUND: There are no data comparing the relative effects of high-dose ciclesonide (CIC) and fluticasone propionate (FP) on airway and systemic outcomes in patients with moderate persistent asthma. OBJECTIVE: We elected to evaluate the relative effects of CIC and FP on the plasma cortisol response to stimulation with human corticotropin-releasing factor (hCRF) and bronchial hyperresponsiveness to methacholine as the primary outcome variables, in addition to secondary outcomes of overnight 10-h urinary cortisol (OUC) levels, exhaled nitric oxide levels, lung function, symptoms, and quality of life. METHODS: Fourteen patients with moderate persistent asthma (mean FEV(1), 67% predicted [prior to each randomized treatment]) completed the study, which had a randomized, double-blind, double-dummy, crossover design, per protocol. Patients stopped receiving their usual inhaled corticosteroids for the duration of the study and instead began receiving salmeterol, 50 mug twice daily, and montelukast, 10 mg once daily, for the 2-week washout periods prior to each randomized treatment, in order to prevent dropouts after withdrawal from inhaled corticosteroid therapy. Patients received 4 weeks of either CIC, 200 microg ex-valve (160 microg ex-actuator) four puffs twice daily, plus FP-placebo, four puffs twice daily, or FP, 250 microg ex-valve (220 microg ex-actuator) four puffs twice daily, plus CIC-placebo, four puffs twice daily. Salmeterol and montelukast were withheld for 72 h prior to each postwashout baseline visit, and CIC or FP was withheld for 12 h prior to each posttreatment visit. RESULTS: FP, but not CIC, when compared to respective baseline values, significantly suppressed (p < 0.05) plasma cortisol levels as follows: FP prior to receiving hCRF: geometric mean fold difference, 1.2; 95% confidence interval (CI), 1.1 to 1.3; CIC prior to receiving hCRF: geometric mean fold difference, 0.9; 95% CI, 0.8 to 1.0; FP 30 min after receiving hCRF: geometric mean fold difference, 1.2; 95% CI, 1.1 to 1.3; CIC 30 min after receiving hCRF: geometric mean fold difference, 1.0; 95% CI, 0.9 to 1.2; OUC after FP administration: geometric mean fold difference, 1.9; 95% CI, 1.4 to 2.6; OUC after CIC administration: geometric mean fold difference, 1.2; 95% CI, 0.9 to 1.5. There was also a significantly lower (p < 0.05) mean value for OUC levels after FP administration than after CIC administration (geometric mean fold difference, 1.5; 95% CI, 1.1 to 2.0). Therapy with CIC and FP, compared to respective baselines, significantly increased (p < 0.05) the provocative concentration of methacholine causing a 20% fall in FEV(1), as follows: CIC: doubling dilution difference, 0.8; 95% CI, 0.1 to 1.6; FP: doubling dilution difference, 1.0; 95% CI, 0.1 to 2.0. It also significantly reduced (p < 0.05) exhaled nitric oxide levels, as follows: CIC: geometric mean fold difference, 1.2; 95% CI, 1.1 to 1.3; FP: geometric mean fold difference, 1.9; 95% CI, 1.3 to 2.8. There was no effect on other secondary efficacy outcomes. CONCLUSION: FP, 2,000 microg daily, but not CIC, 1,600 microg daily, significantly suppressed hypothalamic-pituitary-adrenal axis outcomes, with OUC levels being lower after FP administration than after CIC administration. Both drugs significantly improved airway outcomes in terms of methacholine bronchial hyperresponsiveness and exhaled nitric oxide levels. The present results would therefore suggest that CIC might confer a better therapeutic ratio than FP when used at higher doses.

Effects of high-dose inhaled fluticasone propionate on the hypothalamic-pituitary-adrenal axis in asthmatic patients with severely impaired lung function.

BACKGROUND: The effects of high-dose fluticasone propionate therapy on dynamic cortisol stimulation in severe asthma are unknown. OBJECTIVE: To evaluate the human corticotropin-releasing factor (hCRF)-stimulated plasma cortisol response to fluticasone propionate therapy in severe asthmatic patients with impaired airway caliber (forced expiratory volume in 1 second [FEV1] < 60% of predicted) and in control subjects. METHODS: Ten severe asthmatic patients (mean FEV1, 47% of predicted) and 10 controls (mean FEV1, 104% of predicted) received fluticasone propionate, 2,000 microg/d, via a 750-mL primed spacer for 2 weeks. Plasma cortisol levels before and after hCRF stimulation and overnight 10-hour urinary cortisol excretion corrected for creatinine concentration (OUCC) were measured at baseline after washout and 12 hours after the last dose of fluticasone propionate. RESULTS: Baseline values before fluticasone propionate use were not significantly different in asthmatic patients vs controls for plasma cortisol before and after hCRF stimulation and OUCC. Comparing values at baseline vs after fluticasone propionate use, there was no significant suppression of plasma cortisol levels before (378.2 vs 357.4 nmol/L) or after (510.5 vs 507.9 nmol/L) hCRF stimulation or OUCC (8.2 vs 7.5 nmoL/mmoL) in asthmatic patients. In controls, all outcomes were significantly suppressed comparing values before vs after fluticasone propionate therapy: plasma cortisol levels before (423.5 vs 200.2 nmol/L; P = .002) and after (503.5 vs 291.1 nmol/L; P = .001) hCRF stimulation and OUCC (6.5 vs 2.4 nmol/mmol; P = .002). CONCLUSION: Patients with severe persistent asthma and impaired airway caliber seem to be protected from developing systemic adverse effects with high-dose fluticasone propionate therapy, as evaluated by basal and dynamic measures of hypothalamic-pituitary-adrenal axis activity.

Adrenal suppression with dry powder formulations of fluticasone propionate and mometasone furoate.

Mometasone furoate (MF) and fluticasone propionate (FP) are high potency inhaled corticosteroids. The systemic bioavailability of MF is claimed to be negligible, leading to a minimal potential for systemic adverse effects. We assessed the overnight urinary cortisol/creatinine as the primary outcome of adrenal suppression in 21 patients with persistent asthma (mean FEV1 = 91%). Patients were randomized in a crossover fashion to receive 2 weekly consecutive doubling incremental doses of either FP Accuhaler (500, 1,000, and 2,000 microg/day) or MF Twisthaler (400, 800, and 1,600 microg/day). For the 21 per protocol completed patients, there was significant suppression of overnight urinary cortisol/creatinine with high and medium doses of both drugs-as geometric mean fold suppression (95% confidence interval) from baseline: FP 2,000 microg, 1.85 (1.21-2.82, p = 0.002); FP 1,000 microg, 1.45 (1.07-1.96, p = 0.02); MF 1,600 microg, 1.92 (1.26-2.93, p = 0.001); and MF 800 microg, 1.39 (1.04-1.88, p = 0.02). For secondary outcomes of 8:00 A.M. plasma cortisol, serum osteocalcin, and early morning urinary cortisol/creatinine, there was significant suppression with MF and FP at the highest dose. Our data refute the assertion that MF has negligible systemic bioavailability and a lower potential for systemic adverse effects compared with FP.

Systemic bioactivity of intranasal triamcinolone and mometasone in perennial allergic rhinitis.

AIMS: To evaluate the systemic bioactivity of triamcinolone acetonide (TA) 220 micro g or mometasone furoate (MF) 200 micro g over 3 weeks in perennial allergic rhinitis. METHODS: Twenty-seven patients received TA 220 micro g or MF 200 micro g once daily for 3 weeks with a 2 week placebo washout period prior to each randomized treatment. Measurements were made at baseline after each washout and after each randomized treatment, comprising overnight 10-h urinary cortisol corrected for creatinine (OUCC), 08.00 h plasma cortisol and 08.00 h serum osteocalcin. RESULTS: There were no significant differences between baseline values prior to TA or MF, and for any outcome measures comparing randomized treatments to respective baseline values or comparing TA with MF. For OUCC compared with baseline, the geometric mean fold suppression (95% CI) was 1.02 (0.78, 1.33) for TA (2% decrease), 1.07 (0.80, 1.42) for MF (7% decrease), and 1.05 (0.79, 1.39) for TA vs MF (5% decrease). CONCLUSIONS: Standard doses of TA or MF over 3 weeks showed no differences in systemic bioactivity markers compared with respective baseline values after placebo washout, and there were no differences between TA vs MF.

Therapeutic ratio of hydrofluoroalkane and chlorofluorocarbon formulations of fluticasone propionate.

OBJECTIVES: To compare the therapeutic ratio of chlorofluorocarbon (CFC) and hydrofluoroalkane-134a (HFA) formulations of fluticasone propionate (FP). METHODS: We performed a randomized, placebo-controlled, crossover study comparing 6 weeks of treatment with FP using 500 micro g/d and 1,000 microg/d formulations of CFC and HFA. The primary end points were provocative dose of methacholine causing a 20% fall in FEV1 (PD20) and overnight urinary cortisol/creatinine excretion. RESULTS: Eighteen patients with mild-to-moderate asthma and geometric mean (SEM) PD20 of 82.3 micro g (19.2 micro g) completed the study. All treatments significantly improved PD20 values and morning peak expiratory flow vs placebo, while 1,000 microg/d was significantly better than 500 microg/d for the CFC formulation of FP (CFC-FP) but not the HFA formulation of FP (HFA-FP). Only 1,000 microg/d of CFC-FP caused significant suppression of overnight urinary cortisol/creatinine compared to placebo. There were no differences between formulations at either dose. CONCLUSIONS: The increased airway benefit with CFC-FP > 500 microg/d was offset by greater systemic effects. Although HFA-FP had fewer systemic effects than CFC-FP at 1,000 microg/d, there was no benefit to increasing HFA-FP to > 500 microg/d.