Salmeterol Research Articles

Lung myofibroblasts as targets of salmeterol and fluticasone propionate: inhibition of α-SMA and NF-κB

Lung myofibroblasts play a major role in the pathophysiology of asthma, contributing not only to tissue remodelling but also to airway inflammation. Nevertheless, only recently, attention has been focused on these cells as potential targets for anti-allergic drugs. Herein, we analysed the pharmacological response of lung myofibroblasts to beta2-agonists associated or not to inhaled corticosteroids, investigating their effects on (i) the constitutive and transforming growth factor-beta (TGF-beta)-induced expression of alpha-smooth muscle actin (alpha-SMA), the main functional marker of myofibroblastic differentiation and contractility; (ii) isometric contraction and (iii) tumour necrosis factor-alpha (TNF-alpha)-induced nuclear translocation of the pro-inflammatory transcription factor nuclear factor-kappaB (NF-kappaB). The beta2-agonist salmeterol (SMl) has on human lung myofibroblasts new direct anti-contractile/anti-inflammatory effects that are amplified by the combined use of low concentrations of the glucocorticoid fluticasone propionate (FP). First, SMl and/or FP (10(-12) M) inhibits the constitutive and TGF-beta-induced expression of alpha-SMA. Second, the two drugs block the TNF-alpha-induced nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. Finally, SMl decreases TNF- alpha-induced production of the inflammatory cytokine IL-6. The complementary anti-inflammatory/ anti-contractile effects displayed by SMl and FP on lung myofibroblasts in vitro may be related to the improvement in lung function and symptom control obtained in vivo by the early use of low doses of glucocorticoids in combination with long-acting beta2-agonists.

EFFECT OF FLUTICASONE PROPIONATE/SALMETEROL 250/50 ON LUNG HYPERINFLATION AND EXERCISE ENDURANCE IN PATIENTS WITH COPD

PURPOSE: To evaluate the effect of fluticasone propionate (FP)/salmeterol Diskus (FSC) 250/50 BID and placebo (PLA) on lung hyperinflation and exercise endurance. A preliminary comparison of FSC and salmeterol (SAL) was included, allowing for initial evaluation of the contribution of FP to FSC.

Surface roughness contribution to the adhesion force distribution of salmeterol xinafoate on lactose carriers by atomic force microscopy

Adhesion force distributions of silica spheres (5 and 20 µm) and salmeterol xinafoate (4 µm) particles with inhalation grade lactose surfaces and spin coated lactose films were determined by atomic force microscopy (AFM) to investigate the influence of surface roughness on the force distributions. The roughness of lactose particles and films was determined by both AFM and confocal microscopy (CM); the lactose particles showed RMS Rq values between 0.93 and 2.2 µm. The adhesion force distributions for silica and SX probes were significantly different for the different lactose carriers and broad, e.g., the adhesion force distribution between a 5 µm silica sphere and lactose particles ranged from 5 to 105 nN. This contrasted with distributions on smooth spin coated lactose films (RMS Rq of 0.28nm) which were not significantly different and were narrow, e.g., the adhesion force distribution between a 5 µm silica sphere and spin coated lactose films was between 42 and 68 nN. In addition, no significant difference in adhesion force distribution occurred with silica probe size on the lactose carrier surface. The use of X-ray photoelectron spectroscopic analysis confirmed that the lactose surfaces were free of impurities that might contribute to variation in adhesion. Although the almost atomically flat films showed some adhesion variability, the surface roughness of the lactose particles was a major contributing factor to the broad distributions seen in this study. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association.

An improved thermoanalytical approach to quantifying trace levels of polymorphic impurity in drug powders

Accurate quantification of impurities existing as separate crystalline phases at trace levels in drug materials is an important issue in the pharmaceutical industry. In the present study, a thermoanalytical approach previously developed for quantifying trace levels of polymorphic impurity (form II metastable nuclei) in commercial salmeterol xinafoate powders has been successfully applied with slight modifications to ribavirin, an antiviral drug exhibiting roughly similar polymorph-dependent crystallization kinetics in melts to that of salmeterol xinafoate. Essentially, the approach involved modeling of the crystallization kinetics of both tested and reference drug materials in melts using the Avrami-Erofe’ev (AE) rate expression, derivation of a mathematical equation for relating the AE kinetic constant to the composition of reference polymorph mixtures, and the use of this derived equation (in the form of a calibration curve) to calculate the impurity contents of the tested samples from their computed AE constants. For ribavirin, modification of the latter equation by incorporation of an empirical exponent was found necessary to account for the composition-dependent changes in crystallization kinetics of the reference mixtures. Such modification has made possible the determination of polymorphic impurity content of as low as 0.004% (w/w) in ribavirin samples induced by different forms of grinding treatment.

A comparison of the risk of hospitalizations due to chronic obstructive pulmonary disease in medicaid patients with various medication regimens, including ipratropium, inhaled corticosteroids, salmeterol, or their combination

Objective: The aim of this study was to compare therisk of hospitalizations related to chronic obstructive pulmonary disease (COPD) among Medicaid patients prescribed various medication regimens. Methods: This was an observational, retrospective study set in the Texas Medicaid program. Eligible patients were aged 40 to 65 years, had a primary or secondary diagnosis of COPD, and had ≥1 prescription for ipratropium (IPR), inhaled corticosteroids (ICS), or salmeterol (SAL) between January 1, 1998, and August 31, 2000. Five index therapy groups were included in the risk analysis: IPR alone, ICS alone, SAL alone, ICS + IPR, and ICS + SAL. Results: A total of 4447 patients were included in the study (IPR alone, n = 2435; ICS alone, n = 1088; SAL alone, n = 299; ICS + IPR, n = 410; and ICS + SAL, n = 215). After adjusting for baseline characteristics, ICS + SAL was associated with a 35% lower risk of COPD-related hospitalization (hazard ratio [HR], 0.653 [95% CI, 0.428–0.997]) versus IPR alone. ICS alone was associated with a 16% lower risk (HR, 0.844 [95% CI, 0.693–1.028]) and SAL alone was associated with a 24% lower risk (HR, 0.756 [95% CI, 0.539–1.060]) versus IPR alone, but neither of these was statistically significant. There was no decrease in risk with ICS + IPR versus IPR alone (HR, 1.111 [95% CI, 0.870–1.420]). Variables that indicated increased risk were as follows: increasing age (HR, 1.015 [95% CI, 1.003–1.027]); number of preindex emergency department visits (HR, 1.189 [95% CI, 1.080–1.309]); number of preindex hospitalization visits (HR, 1.342 [95% CI, 1.220–1.477] ); number of nonrespiratory comorbid diagnoses (HR, 1.046 [95% CI, 1.012–1.081]); and having a diagnosis of influenza/pneumonia (HR, 1.276 [95% CI, 1.062–1.533]) or other respiratory diseases (HR, 1.356 [95% CI, 1.134-1.622]). Comorbid asthma was not associated with increased risk. Conclusions: ICS + SAL was associated with a significantly lower risk of COPD-related hospitalization compared with IPR alone during the initial 12 months of therapy in a Medicaid population. Additional studies are needed to confirm these findings across different populations.

Surface characterization of salmeterol xinafoate powders by inverse gas chromatography at finite coverage

In our previous studies, surface analysis by inverse gas chromatography (IGC) at infinite dilution (zero coverage) was performed on four salmeterol xinafoate (SX) powdered samples, viz, two supercritical CO2‐processed Form I (SX‐I) and Form II (SX‐II) polymorphs, a commercial granulated SX (GSX) raw material and its micronized product (MSX). Both GSX and MSX are also of the same Form I polymorph. To further probe the differences in surface properties between the samples, the present study has extended the IGC analysis to the finite concentration range of selected energy probes. The adsorption isotherms of the SX samples were constructed using (nonpolar) octane, (polar acidic) chloroform, and (polar basic) tetrahydrofuran as liquid probes. Type II adsorption isotherms with weak knees were observed with each probe for all SX Form I samples. The extents of probe adsorption by the samples at various relative pressures follow the rank order: SX‐II > GSX ≈ MSX > SX‐I, indicating that the SX‐I has fewer high‐energy adsorption sites than GSX and MSX. Type III isotherms were observed for SX‐II with the two polar probes, indicative of weak adsorbate–adsorbent interactions. The additional information generated shows that IGC analysis at finite coverage is a valuable complementary tool to that at infinite dilution. © 2005 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:695–700, 2005

Salmeterol HFA is as effective as salmeterol CFC in children and adults with persistent asthma

In accordance with the Montreal Protocol 1987, initiatives to phase out and replace ozone-depleting chlorofluorocarbon (CFC) propellants with non-ozone-depleting propellants in metered-dose inhalers (MDIs) in the treatment of asthma and chronic obstructive pulmonary disease are underway. In view of this, two multi-centre, randomised, parallel-group, double-blind studies were conducted to compare the safety and efficacy of salmeterol xinafoate delivered by an MDI using the hydrofluoroalkane (HFA) 134a propellant with the licensed CFC formulation (Serevent) in asthmatic populations of children (4-11 years) and adults (12 years). Patients on a stable dose of inhaled corticosteroids with a scope for improvement based on mean morning peak expiratory flow (PEF) and symptoms were randomised to receive salmeterol HFA MDI 50 microg twice daily or salmeterol CFC MDI 50 microg twice daily for 12 weeks. The primary efficacy variable was mean morning PEF and secondary variables included other lung function parameters, symptom scores, use of relief medication and safety assessments. The difference between the treatments in adjusted mean morning PEF (salmeterol HFA-salmeterol CFC) were 2.5 and -3.2 L/min for per-protocol populations of children and adults, respectively. The lower limit of 95% confidence intervals for both populations was within the pre-defined limit (-15 L/min) set for non-inferiority. Similar results were observed in intent-to-treat (ITT) populations. In children, the two formulations resulted in a lack of any statistically significant difference in secondary efficacy parameters. A significant difference at endpoint in clinic forced expiratory volume in 1s was reported in favour of the HFA formulation in the adult population, although the magnitude of this effect was not considered clinically significant. The incidences of adverse events (AEs) were similar for both formulations and populations, and no safety concerns were generated. Together these data demonstrate salmeterol HFA MDI to be as effective as salmeterol CFC MDI in adults and children.

Comparison of the systemic pharmacodynamic effects and pharmacokinetics of salmeterol delivered by CFC propellant and non-CFC propellant metered dose inhalers in healthy subjects

This was a randomised, double-blind, placebo-controlled, cross-over study comparing the systemic pharmacodynamic effects (heart rate and serum potassium) and pharmacokinetics of salmeterol delivered by the non-CFC hydrofluoralkane (HFA) propellant 134a and the CFC propellant (propellant 11/12) metered dose inhalers (MDI) in healthy subjects. At the therapeutic dose (50 microg), salmeterol-mediated systemic pharmacodynamics were equivalent for the HFA and CFC MDIs. Higher doses of salmeterol (150 and 300 microg) produced dose-related beta-agonist pharmacodynamic effects irrespective of the propellant. However, these effects were lower with salmeterol HFA MDI than with the salmeterol CFC MDI at all dose levels. Overall, salmeterol Cmax and AUC(0-t) values were lower for salmeterol HFA compared with salmeterol CFC MDI. At the highest dose (300 microg), where a full pharmacokinetic profile was obtained, exposure to salmeterol delivered by the HFA MDI compared with the salmeterol CFC MDI was 27% and 30% lower for Cmax and AUC(0-t), respectively. Maximum plasma concentrations were generally seen in the first plasma samples taken 5 min after the start of dosing. Salmeterol HFA was well-tolerated. At supratherapeutic doses, adverse events were typical for high-dose salmeterol with fewer adverse events occurring with the HFA compared with the CFC formulation. These data indicate that the salmeterol HFA MDI would not be associated with a significantly different pharmacodynamic, safety and tolerability profile compared with the salmeterol CFC MDI.

“Stepping Down” from Fluticasone Propionate/Salmeerol 100/50mcg Diskus® Results in Loss of Asthma Control: Lack of Effect of Ethnic Origin

PURPOSE: To determine if asthma subjects of different ethnic origin adequately controlled on fluticasone propionate (FP)/salmeterol (SAL) 100/50mcg (FSC) differ in maintenance of control when therapy is stepped-down to FP, SAL, or montelukast (MON) compared with continuing FSC.

Additive blockade of beta 2-integrin adhesion of eosinophils by salmeterol and fluticasone propionate.

Migration of human eosinophils is regulated by integrin expression, conformational change, and activation of cytosolic phospholipase A2 (cPLA2). Corticosteroids have been shown to inhibit cPLA2 hydrolysis in human eosinophils. The objective of this study was to determine the mechanisms of fluticasone propionate (FP) alone or in combination with salmeterol (SM) in blocking adhesion mediated by beta 2-integrin in human eosinophils. Human eosinophils were isolated by negative magnetic selection. beta 2-integrin-mediated eosinophil adhesion was measured by residual eosinophil peroxidase activity. Eosinophils were pretreated for 12 h to 24 h with FP and with or without SM for 30 min. Both SM alone and FP alone inhibited eosinophil adhesion in concentration- and time-dependent manner. SM alone modestly (approximately 30%) inhibited interleukin (IL)-5-induced eosinophil adhesion. Blockade of IL-5-induced eosinophil adhesion caused by 10(-7) M FP at 24 h was augmented by 10(-7) M SM from 41.5% to 72.5%. Similar blockade was also observed for eotaxin-induced eosinophil adhesion. Neither SM, FP, nor FP + SM blocked either: 1) upregulation of CD11b surface expression; or 2) phosphorylation of cPLA2. Blockade of beta 2-integrin-mediated eosinophil adhesion by fluticasone propionate is augmented by salmeterol. Decreased adhesion results from augmented blockade of nuclear translocation of cytosolic phospholipase A2 caused by addition of salmeterol to fluticasone.

Effect of carrier size on the dispersion of salmeterol xinafoate from interactive mixtures

The objective of this study was to determine the influence of lactose carrier size on drug dispersion of salmeterol xinafoate (SX) from interactive mixtures. SX dispersion was measured by using the fine particle fractions determined by a twin stage impinger attached to a Rotahaler®. The particle size of the lactose carrier in the SX interactive mixtures was varied using a range of commercial inhalation-grade lactoses. In addition, differing size fractions of individual lactose samples were achieved by dry sieving. The dispersion of SX appeared to increase as the particle size of the lactose carrier decreased for the mixtures prepared from different particle size commercial samples of lactose and from different sieve fractions of the same lactose. Fine particles of lactose (<5μm) associated with the lactose carrier were removed from the carrier surface by a wet decantation process to produce lactose samples with low but similar concentrations of fine lactose particles. The fine particle fractions of SX in mixtures prepared with the decanted lactose decreased significantly (analysis of variance, p<0.001) and the degree of dispersion became independent of the volume mean diameter of the carriers (analysis of variance, p<0.05). The dispersion behavior is therefore associated with the presence of fine adhered particles associated with the carriers and the inherent size of the carrier itself has little influence on dispersion.

Lactose surface modification by decantation: are drug-fine lactose ratios the key to better dispersion of salmeterol xinafoate from lactose-interactive mixtures?

The role of fine lactose in the dispersion of salmeterol xinafoate (SX) from lactose mixtures was studied by modifying the fine lactose concentration on the surface of the lactose carriers using wet decantation. Fine lactose was removed from lactose carriers by wet decantation using ethanol saturated with lactose. Particle sizing was achieved by laser diffraction. Fine particle fractions (FPFs) were determined by Twin Stage Impinger using a 2.5% SX mixture, and SX was analyzed by a validated high-performance liquid chromatography method. Adhesion forces between probes of SX and silica and the lactose surfaces were determined by atomic force microscopy. FPFs of SX were related to fine lactose concentration in the mixture for inhalation grade lactose samples. Reductions in FPF (2-tp 4-fold) of Aeroflo 95 and 65 were observed after removing fine lactose by wet decantation; FPFs reverted to original values after addition of micronized lactose to decanted mixtures. FPFs of SX of sieved and decanted fractions of Aeroflo carriers were significantly different (p < 0.001). The relationship between FPF and fine lactose concentration was linear. Decanted lactose demonstrated surface modification through increased SX-lactose adhesion forces; however, any surface modification other than removal of fine lactose only slightly influenced FPF. Fine lactose played a key and dominating role in controlling FPF. SX to fine lactose ratios influenced dispersion of SX with maximum dispersion occurring as the ratio approached unity.

Asthma related ED/hospitalization risk and asthma costs of fluticasone propionate/salmeterol in a single inhaler compared to fluticasone propionate and salmeterol in separate inhalers

Rationale Compare asthma-related ED/hospitalizations, albuterol use (SABA) and direct asthma costs among patients prescribed fluticasone propionate (FP)/salmeterol (SL) from a single inhaler (FS) or from separate inhalers (FP + SL) as initial therapy. Method Retrospective observational study using data from four large managed care plans from 2000-2002. Subjects were >15 years of age with a diagnosis of asthma (ICD-9-CM=493.xx), at least one claim for FS or FP + SL and followed for 12 months after the initial prescription for FS or FP + SL. Patients with concomitant diagnosis of COPD or cystic fibrosis were excluded. Each subject had a 12-month pre-index period with no claims for any inhaled corticosteroid, salmeterol or leukotriene receptor antagonist. Multivariate generalized linear modeling and logistic regression was used to determine the influence of these therapies on post-index asthma related costs, SABA use and ED/hospitalizations. Outcomes were adjusted for age, gender, heath-plan, co-morbidities, pre-index asthma related medications, ED/hospitalization and costs. Results 1422 persons were identified, 1101 new FS user and 321 new FP + SL users. FS patients were associated with a 71% lower risk of an asthma related ED/hospitalization (95% CI 48%, 84%), 50% less SABA use (p<0.01), and 11% lower direct asthma related costs (p<0.03) compared to new FP + SL patients Conclusions The results of this analysis suggest that initiation FS, compared to initial treatment with FP + SL, was associated with a reduced risk for an asthma related ED/hospitalization, lower SABA utilization and lower direct asthma health care costs.

The effect of salmeterol (SAL) on the late phase response (LPR) to antigen challenge (AC), sputum eosinophilia and generation of IL-5 and IFN-gamma

Rationale The development of LPR to inhaled AC has been used to evaluate mechanisms of allergic inflammation in asthma and to test the effects of therapeutic interventions. Although SAL inhibits the immediate (IMM) response to AC, but not LPR despite its long-acting bronchodilating actions, the effects of SAL on the cellular mechanisms of inflammation are not defined and are the focus of this study. Methods 21 subjects with mild asthma were evaluated for the pulmonary response to AC (IMM and LPR), the appearance of sputum eosinophils and sputum cell generation of IL-5 and IFNγ in a double-blind, placebo-controlled trial in which each subject was treated with placebo, FP MDI (44 μg, 1 puff BID), SAL MDI (50 μg, 2 puffs BID), or FP+SAL (2 MDIs) in a 4-way crossover design. Results SAL significantly inhibited the IMM to AC but not the LPR, or sputum eosinophilia or sputum cell generation of IL-5 or IFNγ post AC. FP and FP+SAL inhibited the IMM to AC, LPR, sputum eosinophilia and the generation of IL-5 and IFNγ. Conclusion SAL alone did not modify inflammatory components of the airway and cellular response to AC, suggesting that, in the absence of corticosteroids, SAL does not appear to have anti-inflammatory actions under these conditions.

Cross-tolerance to albuterol occurs independently of β 2-adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol

Rationale We evaluated the Arg-16 and Gly-16 genotypes for the acute albuterol response following methacholine challenge, after the first and last doses of combination inhalers containing formoterol (FM) and salmeterol (SM). Methods Parallel groups of matched 10 homozygous Arg-16 and 10 homozygous Gly-16 asthmatics completed a randomized, double-blind, double-dummy, cross-over study. During a 1-week washout period prior to each randomized treatment, patients continued on their usual inhaled corticosteroid therapy. Patients received 2 weeks of either budesonide (BUD) 200 μg + FM 6 μg, 2 puffs bid, or fluticasone propionate (FP) 250 μg + SM 50 μg, 1 puff bid. After washouts and randomized treatments, 1 hour post first and last dose of combination inhalers, a methacholine challenge was performed followed by albuterol 200 μg, with recovery over 30 minutes (the primary outcome). Results Washout values for FEV 1, methacholine PC 20 and albuterol recovery were all similar for both treatments and genotypes. Pre-challenge FEV 1 values for both genotypes were not significantly different comparing first vs. last doses of each treatment. Albuterol recovery as area under the 30-minute time-response curve (%.min) was significantly delayed ( p<0.05) equally in both genotypes and treatments, comparing the first doses of BUD+FM (Arg-16: 386, Gly-16: 352) or FP+SM (Arg-16: 363, Gly-16: 289), vs. the last doses respectively of BUD+FM (Arg-16: 591, Gly-16: 491) or FP+SM (Arg-16: 529, Gly-16: 466). There were no differences in albuterol recovery comparing either genotypes or treatments. Conclusion Acute albuterol recovery in methacholine constricted airways was significantly delayed to a similar degree in both genotypes, due to cross-tolerance induced by FM or SM.

Control of T-cell responses by the combination of low dose steroids with beta2-agonists

Rationale Combination treatment of asthma with fluticasone propionate (FP), and long-acting beta2-agonist, salmeterol xinafoate, provides greater asthma control than increasing doses of steroids. Whether beta2-agonists can be beneficial not only for bronchodilation, but for suppression of inflammation in asthma is not defined. Methods Peripheral blood mononuclear cells (PBMC) from healthy controls and allergic asthmatics were stimulated with 2.5 μg/ml PHA in presence of FP (10-12-10-9 M) ± salmeterol (10-12-10-7 M) for 72h. The FP response was assessed by inhibition of T-cell proliferation, cytokine production and glucocorticoid receptor alpha (GCRalpha) translocation. Results Both groups showed similar degrees of inhibition of PHA induced T-cell proliferation by FP (IC50=10-9M). Addition of salmeterol (10-10-10-7M) facilitated proliferation inhibition with much lower concentrations of FP (10-12-10-11M), and provided greater inhibition as compared to FP alone in control group. Combinatory treatment revealed more efficient GCRalpha translocation within 1h ( p<0.01 as compared to 10-12M FP alone). However addition of salmeterol to low doses of FP did not provide any additional proliferation inhibition in asthma group. FP 10-12M/salmeterol 10-7M significantly inhibited TNFalpha and IFNgamma production ( p<0.05) (TNFalpha - 68.1 ± 10.8% inhibition, 62.6 ± 4.5%; IFNgamma - 77.1 ± 6.1%, 68.0 ± 10.3% in control and asthma groups, respectively), but failed to inhibit Th2 cytokine (IL-5, IL-13) production by allergic asthmatics. Addition of PDE4 inhibitor, rolipram (10-6M), to FP/salmeterol combination enhanced inhibition of T-cell proliferation in asthma group. Conclusions Beta2-agonists in combination with low doses of steroids can be beneficial for suppression of PBMC proliferation and cytokine production from healthy individuals, whereas suppression of inflammation in allergic asthmatics requires addition of phosphodiesterase inhibitor.

Effects of hydrofluoroalkane formulations of ciclesonide 320μg once daily versus fluticasone propionate 220μg twice daily on methacholine hyperresponsiveness in mild-to-moderate persistent asthma

Rationale We evaluated the comparative efficacy of HFA formulations of CIC and FP, assessing methacholine challenge, in addition to exhaled nitric oxide, lung function, diary cards and quality of life. Methods 19 mild-to-moderate asthmatics completed the study in randomized, double-blind, double-dummy, cross-over fashion. Patients stopped their inhaled corticosteroids during the study and were commenced instead on salmeterol (SM) 50μg 1puff bid + montelukast (ML) 10mg qd for 2-week washout periods prior to each randomized treatment. Patients received 4 weeks of either CIC 200μg ex-valve (160μg ex-actuator) 2puffs qd (8am) + CIC-placebo (PL) 2puffs qd (8pm) + FP-PL 2puffs bid (8am/8pm), or FP 125μg ex-valve (110μg ex-actuator) 2puffs bid (8am/8pm) + CIC-PL 2puffs bid (8am/8pm). SM+ML were withheld for 72hours prior to post-washout visits and CIC or FP was withheld for 24hours prior to study visits. Results There was no significant difference between CIC vs. FP for the primary outcome of methacholine PC 20 as doubling dilution (dd) shift from respective baseline; mean difference: 0.4dd (95%CI −0.4–1.2). Moreover, there was no difference between treatments for the sequence of CIC first vs. FP second; mean difference: 0.2dd (95%CI −1.3–1.7) or FP first vs. CIC second; mean difference: 0.9dd (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. Conclusion There were no differences between 4 weeks of CIC 320μg qd and FP 220μg bid on methacholine hyperresponsiveness in mild-to-moderate persistent asthma. Longer-term studies are indicated to evaluate their relative efficacy on asthma exacerbations.

Glucocorticoids suppress goblet cell metaplasia in natural and experimental asthma

Rationale To determine targets of glucocorticoid treatment in asthma, we examined goblet cell metaplasia and airway hyperreactivity in natural asthma and a mouse model of asthma. Methods For human studies, normal and asthmatic subjects were studied after treatment with fluticasone propionate (FP; 1760 μg/d) for 30 d and then after withdrawal of FP until peak flows decreased by 25%, FEV1 decreased by 15%, or 6 wk elapsed. To control for asthma triggers, genetic background, and treatment (e.g. β2-adrenergic receptor agonists), we studied a mouse model of persistent, asthma-like phenotypes induced by transient paramyxoviral infection (J. Clin. Invest. 110:165-175, 2002). Mice were treated with systemic dexamethasone (DEX), inhaled FP, or inhaled salmeterol xinafoate (SLM). Results In human studies, the group of asthmatic subjects exhibited decreased methacholine PC20 (by 1.2-fold) and increased numbers of endobronchial goblet cells (by 64%) after withdrawal of FP treatment, but the two parameters showed no correlation within individual subjects. In the murine model, systemic DEX or inhaled FP caused little change in airway reactivity, but each agent suppressed goblet cell metaplasia (by 86 and 68%, respectively). Addition of inhaled SLM to FP (or SLM alone) had no significant effect on either asthma-like phenotype. Conclusions Glucocorticoid treatment is sufficient to suppress goblet cell metaplasia but not necessarily airway hyperreactivity in natural and experimental asthma. The effect of glucocorticoids on mucus-producing cells may provide a therapeutic benefit in asthma and other hypersecretory states.

Efficacy and Safety of Inhaled Corticosteroids in Combination with a Long‐Acting Beta2‐Agonist in Asthmatic Children Under Age 5

The incidence of asthma in children under age 5 is higher than in any other segment of the population. Current NAEPP guidelines recommend treatment of some asthmatics in this age group with the combination of an inhaled corticosteroid and a long‐acting beta2‐agonist even though this practice has never been studied with children younger than 4. This retrospective study analyzes the efficacy and safety of a combination of fluticasone propionate (FP) and salmeterol (SA) in children under 5. Fifty patients who started using FP/SA before the age of 60 months were included in the analysis. To determine efficacy, we tracked the change in emergency room visits, hospitalizations, and the frequency of wheezing as a result of treatment. Emergency room visits were reduced from 78 to 5 (p < 0.001), hospitalizations were reduced from 43 to 2 (p < 0.001) and frequency of wheezing, daily, weekly, or monthly, was also reduced significantly (p < 0.003). In terms of safety, there was only a 3.4% reduction in height percentile (p = 0.37). Combination therapy is highly efficacious and safe for asthmatics under the age of 5. A well‐designed prospective study is necessary to further evaluate the benefits and risks of this treatment method.

Montelukast plus fluticasone is equivalent to salmeterol and fluticasone

Montelukast plus fluticasone is equivalent to salmeterol and fluticasone