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.

A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma.

We conducted a double blind, randomised, placebo-controlled, crossover study evaluating the effects of halving inhaled steroid dosage plus salmeterol, or salmeterol and tiotropium. Eighteen life-long non-smoking severe asthmatics [mean FEV(1) 1.49 l (51%)] were run-in for 4 weeks on HFA-fluticasone propionate 1000 microg daily, and were subsequently randomised to 4 weeks of either (a) HFA-fluticasone propionate 500 microg BD/salmeterol 100 microg BD/HFA-tiotropium bromide18 microg od; or (b) fluticasone propionate 500 microg BD/salmeterol 100 microg BD matched placebo. Measurements of spirometry and body plethysmography were made. Adding salmeterol to half the dose of fluticasone led to a mean improvement (95% CI) vs. baseline in morning PEF of 41.5 (14.0-69.0)l/min [p<0.05]; and RAW of 0.98 (0.14-1.8)cm H(2)O/l/s [p<0.05]. Adding salmeterol/tiotropium produced similar improvements in PEF and RAW, but also improved FEV(1) by 0.17 (0.01-0.32)l [p<0.05]; FVC 0.24 (0.05-0.43)l [p<0.05] and reduced exhaled NO by 2.86 (0.12-5.6)ppb [p<0.05]. RV and TLC were not altered by either treatment; there were no significant changes in symptoms or quality of life compared with baseline. Addition of salmeterol/tiotropium to half the dose of fluticasone afforded small, but significant improvements in pulmonary function. These effects were not associated with commensurate changes in subjective symptoms or 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.

Reproducibility of response to nasal lysine-aspirin challenge in patients with aspirin-induced asthma.

BACKGROUND: Peak nasal inspiratory flow (PNIF) and acoustic rhinometry objectively measure the effects of nasal provocation testing. Although the latter is conventionally used in nasal lysine-aspirin challenge, use of the former in aspirin-induced asthma (AIA) has never been evaluated. OBJECTIVE: To evaluate the reproducibility of PNIF and acoustic rhinometry following nasal lysine-aspirin challenge in AIA. METHODS: Fourteen patients with a clear-cut history of AIA underwent nasal lysine-aspirin challenge at 2 separate visits 1 week apart. Both PNIF and minimum cross-sectional area (MCA) were measured using acoustic rhinometry for 120 minutes following standard nasal lysine-aspirin challenge (25 mg). RESULTS: Prechallenge values were not significantly different at visit 1 vs visit 2 for mean [SEM] PNIF (128 [13] vs 127 [9] L/min) and MCA (6.89 [0.51] vs 6.94 [0.57] cm2). The mean (SEM) maximum percent PNIF change from baseline for visit 1 and visit 2 was -42 (5) and -42 (6), respectively, and the mean (SEM) average percent PNIF change from baseline was -25 (4) and -25 (6), respectively. The mean (SEM) maximum percent MCA change from baseline for visit 1 and visit 2 was -49 (4) and -48 (3), respectively, and the mean (SEM) average percent MCA change from baseline was -25 (8) and -24 (4), respectively. Coefficients of variation for maximum and average responses were 2.3% and 6.5%, respectively, for PNIF and 7.4% and 16.1% for MCA. CONCLUSIONS: Measurement of PNIF following nasal lysine-aspirin challenge is a simple and reproducible alternative to acoustic rhinometry, with maximum response being a more reproducible outcome measure than average response.

Effects of butterbur treatment in intermittent allergic rhinitis: a placebo-controlled evaluation.

BACKGROUND: Butterbur (Petasites hybridus) contains the active ingredient petasin, which exhibits antileukotriene and antihistamine activity. Previous studies of intermittent allergic rhinitis (IAR) have demonstrated a comparable response to butterbur compared with a histamine H1-receptor antagonist on the 36-Item Short-Form Health Survey quality-of-life score. However, there has been no placebo-controlled study of the effects of butterbur use on objective and subjective outcomes in IAR. OBJECTIVE: To evaluate the effects of treatment with butterbur vs placebo on objective and subjective outcomes in IAR. METHODS: A double-blind, placebo-controlled, crossover study was carried out during the grass pollen season in Tayside, Scotland. Thirty-five patients (14 men and 21 women) with IAR received butterbur, 50 mg twice daily, or placebo for 2 weeks. Domiciliary measurements were taken in the morning and evening for peak nasal inspiratory flow (PNIF) (the primary outcome variable), nasal and eye symptoms, and rhinoconjunctivitis-specific quality-of-life score. RESULTS: Butterbur treatment had no significant effect on PNIF, total nasal symptom score, eye symptom score, or quality of life compared with placebo use. Mean (SEM) morning and evening PNIF values were 107 (6) and 114 (6) L/min, respectively, for butterbur vs 105 (6) and 117 (6) L/min for placebo. Mean (SEM) morning and evening total nasal symptom scores (maximum total score, 12) were 3.4 (0.4) and 3.5 (0.4), respectively, for butterbur vs 3.7 (0.3) and 3.8 (0.4) for placebo. CONCLUSIONS: There was no significant clinical efficacy of butterbur use vs placebo use on objective and subjective outcomes in IAR. Further studies are now indicated to investigate the use of butterbur in persistent allergic rhinitis.

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.

Effects of hydrofluoroalkane formulations of ciclesonide 400 microg once daily vs fluticasone 250 microg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma.

AIMS: There are no data comparing the relative efficacy of hydrofluoroalkane (HFA) formulations of ciclesonide (CIC) and fluticasone propionate (FP) on airway hyper-responsiveness, in mild-to-moderate persistent asthma. We therefore elected to evaluate the comparative efficacy of HFA pressurized metered-dose inhaler formulations of CIC and FP, assessing methacholine challenge, in addition to exhaled nitric oxide, lung function, diary cards and quality of life. METHODS: Nineteen mild-to-moderate asthmatic patients completed the study per protocol in randomized, double-blind, double-dummy, crossover fashion. Patients were required to stop their usual inhaled corticosteroid therapy for the duration of the study. Patients were commenced instead on salmeterol (SM) 50 microg one puff twice daily + montelukast (ML) 10 mg once daily for 2-week washout periods prior to each randomized treatment, in order to prevent dropouts. Patients received 4 weeks of either CIC 200 microg two puffs once daily (08.00 h) + CIC-placebo (PL) two puffs once daily (20.00 h) + FP-PL two puffs twice daily (08.00 h and 20.00 h), or FP 125 microg two puffs twice daily (08.00 h and 20.00 h) + CIC-PL two puffs twice daily (08.00 h and 20.00 h). SM + ML were withheld for 72 h prior to post-washout visits and CIC or FP was withheld for 24 h prior to study visits. RESULTS: There was no significant difference between CIC vs. FP for the primary outcome of methacholine PC20 as doubling dilution (dd) shift from respective baseline; mean difference: 0.4 dd (95% CI -0.4, 1.2). Moreover, there was no difference between treatments for the sequence of CIC first vs FP second; mean difference: 0.2 dd (95% CI -1.3, 1.7) or FP first vs CIC second; mean difference: 0.9 dd (95% CI -0.1, 1.8). There were also no differences for other secondary outcomes between treatments, either respective or irrespective of sequence, as change from baseline. CONCLUSIONS: There were no differences between 4 weeks of CIC 400 microg once daily and FP 250 microg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma. Longer-term studies are indicated to evaluate their relative efficacy on asthma exacerbations.

Repeated dosing effects of mediator antagonists in inhaled corticosteroid-treated atopic asthmatic patients.

BACKGROUND: The anti-inflammatory effects of repeated dosing with mediator antagonists as add-on therapy to that with inhaled corticosteroids (ICSs) in patients with asthma remain to be fully established. OBJECTIVE: We elected to evaluate the effects of repeated dosing with fexofenadine (FEX) and montelukast (ML) at clinically recommended doses in ICS-treated asthmatic patients using adenosine monophosphate (AMP) bronchial challenge as the primary outcome. METHODS: Eighteen atopic asthmatic patients receiving a mean (+/- SEM) dose of 631 +/- 104 micro g daily of ICSs, which remained unchanged throughout the entire study, were randomized in double-blind, cross-over fashion to receive FEX, 180 mg, ML, 10 mg, or placebo (PL) for 1 week. There was a 1-week washout period prior to each randomized treatment. Measurements of the provocative concentration of a substance (ie, AMP) causing a 20% fall in FEV(1) (PC(20)) were made after each washout period and randomized treatment period. RESULTS: The values for AMP PC(20) after the washout period prior to each randomized treatment were not significantly different (FEX, 74 +/- 15 mg/mL; ML, 73 +/- 18 mg/mL; PL, 71 +/- 19 mg/mL). There were significant improvements (p < 0.05) in AMP PC(20) with the use of FEX (127 +/- 38 mg/mL) and ML (121 +/- 27 mg/mL) compared to PL (78 +/- 23 mg/mL). Spontaneous recovery after AMP challenge, as determined by area under the 60-min time-response curve, was significantly enhanced (p < 0.05) with the use of ML (352 +/- 95%.min [corrected]) compared to FEX (758 +/- 140%.min) and PL (683 +/- 134%.min [corrected]). Both FEX and ML significantly suppressed (p < 0.05) the levels of exhaled nitric oxide, while only ML significantly reduced (p < 0.05) the peripheral blood eosinophil count compared to PL. Morning and evening peak expiratory flow were significantly higher (p < 0.05), and the frequency of salbutamol rescue was significantly reduced (p < 0.05) with FEX and ML compared to PL. CONCLUSION: Repeated dosing with FEX and ML as add-on therapy improved AMP PC(20) and other surrogate inflammatory markers along with asthma diary outcomes in ICS-treated atopic asthmatic patients. Further studies are indicated to evaluate the long-term add-on effects of FEX on asthma exacerbations.

The effects of histamine and leukotriene receptor antagonism on nasal mannitol challenge in allergic rhinitis.

AIMS: It is unclear as to which mediators are involved in mediating the response to nasal mannitol challenge, a novel osmotic stimulus. METHODS: A double-blind, randomized, placebo-controlled, crossover design was employed. Nine patients with allergic rhinitis were randomized to receive a single-dose of desloratadine 5 mg, montelukast 10 mg or placebo, and underwent nasal mannitol challenges with nasal peak inspiratory flow recordings over 60 min. The change in peak nasal inspiratory flow was calculated as percentage change from baseline as the peak response and area under the time-response curve (AUC). RESULTS: Desloratadine and montelukast conferred a significant degree of protection compared to placebo for peak and AUC response, but there were no significant differences between the two drugs. For the peak response as percentage fall, the mean difference (95% CI) vs placebo was 27.7 (8.0, 47.4)% for desloratadine and 17.6 (1.9, 33.3)% for montelukast. CONCLUSIONS: Our results suggest that histamine and cysteinyl-leukotrienes are involved in mediating the response to nasal mannitol in allergic rhinitis.

Effects of montelukast on surrogate inflammatory markers in corticosteroid-treated patients with asthma.

We evaluated whether montelukast conferred additive effects in patients with asthma receiving fluticasone/salmeterol (FP/SM) combination and FP alone. Twenty-two patients with mild to moderate asthma completed a double-blind, placebo-controlled study. After a 2-week run-in using FP 250 microg/SM 50 microg 1 puff twice daily, patients entered a randomized crossover period to receive additional montelukast 10 mg daily or placebo for 3 weeks each. For the first 2 weeks, they received FP/SM 1 puff BID, and then they received FP 250 microg 1 puff BID for the 3rd week. The primary outcome was adenosine monophosphate challenge threshold and recovery time; secondary outcomes included surrogate inflammatory markers and lung function. Compared with FP/SM run-in, adding montelukast to FP/SM was better (p < 0.05) than placebo for inflammatory markers but not for lung function. For adenosine monophosphate threshold, recovery, exhaled nitric oxide, and blood eosinophils, there were 1.4 (95% confidence interval, 1.1-1.8) geometric mean fold, 10 minutes (3-17 minutes), 2.1 parts per billion (0.2-3.9 parts per billion), and 88 (34-172) x 10(6)/L differences, respectively. The combination of FP plus montelukast was superior to FP/SM for inflammatory markers but was inferior for lung function. Thus, in patients taking FP/SM or FP, montelukast conferred complimentary effects on surrogate inflammatory markers, which were dissociated from lung function. Further studies are required to evaluate whether these effects of montelukast translate into clinical benefits.