Immunogenicity and tolerability in infants of a New Zealand epidemic strain meningococcal B outer membrane vesicle vaccine.

BACKGROUND: An outer membrane vesicle meningococcal vaccine (MeNZB), was developed for the New Zealand epidemic strain of Neisseria meningitidis B:4:P1.7-2,4. METHODS: A phase II, randomized, observer blind, controlled study evaluating the safety, reactogenicity, and immunogenicity of MeNZB administered with routine New Zealand immunizations at 6 weeks, 3 months, and 5 months of age (n = 375). Group 1 (n = 250) received 25 mug MeNZB and routine immunizations with a fourth MeNZB dose given at 10 months (n = 51). Group 2 (n = 125) received routine immunizations only. Sero-response was a > or =4-fold rise in vaccine strain serum bactericidal antibody titer compared with baseline or a titer of at least 1:8 for baselines <1:4. Reactogenicity was monitored for 7 days after vaccination. RESULTS: Sero-response in Group 1 was achieved in 53% (95% Confidence interval [CI]: 46-59, n = 239) and 69% (95% CI: 54-80, n = 45) with geometric mean antibody titers of 9 (95% CI: 7-10) and 22 (95% CI: 12-39) after the third and fourth doses, respectively. No negative interference by MeNZB on routine immunizations was detected. There were no serious adverse events judged to be vaccine related. CONCLUSIONS: In this group of New Zealand infants, 4 MeNZB doses were required to demonstrate titers comparable with those achieved after 3 doses in older children. MeNZB was safe when used concomitantly with routine New Zealand immunizations to 5 months of age.

Primary prevention of rheumatic fever in the 21st century: evaluation of a national programme.

Background: Acute rheumatic fever (ARF) has largely disappeared from high-income countries. However, in New Zealand (NZ) rates remain high in indigenous (Maori) and Pacific populations. In 2011, NZ launched an intensive and unparalleled primary Rheumatic Fever Prevention Programme (RFPP). We evaluated the impact of the school-based sore throat service component of the RFPP. Methods: The evaluation used national trends of all-age first episode ARF hospitalisation rates before (2009-11) and after (2012-16) implementation of the RFPP. A retrospective cohort study compared first-episode ARF incidence during time-not-exposed (23 093 207 person-days) and time-exposed (68 465 350 person-days) with a school-based sore throat service among children aged 5-12 years from 2012 to 2016. Results: Following implementation of the RFPP, the national ARF incidence rate declined by 28% from 4.0 per 100 000 [95% confidence interval (CI) 3.5-4.6] at baseline (2009-11) to 2.9 per 100 000 by 2016 (95% CI 2.4-3.4, P <0.01). The school-based sore throat service effectiveness overall was 23% [95% CI -6%-44%; rate ratio (RR) 0.77, 95% CI 0.56-1.06]. Effectiveness was greater in one high-risk region with high coverage (46%, 95% CI 16%-66%; RR 0.54, 95% CI 0.34-0.84). Conclusions: Population-based primary prevention of ARF through sore throat management may be effective in well-resourced settings like NZ where high-risk populations are geographically concentrated. Where high-risk populations are dispersed, a school-based primary prevention approach appears ineffective and is expensive.

Emil Fischer and the "art of chemical experimentation".

What did nineteenth-century chemists know? This essay uses Emil Fischer's classic study of the sugars in 1880s and 90s Germany to argue that chemists' knowledge was not primarily vested in the theories of valence, structure, and stereochemistry that have been the subject of so much historical and philosophical analysis of chemistry in this period. Nor can chemistry be reduced to a merely manipulative exercise requiring little or no intellectual input. Examining what chemists themselves termed the "art of chemical experimentation" reveals chemical practice as inseparable from its cognitive component, and it explains how chemists integrated theory with experiment through reason.

Chemical Identity Crisis: Glass and Glassblowing in the Identification of Organic Compounds.

This essay explains why and how nineteenth-century chemists sought to stabilize the melting and boiling points of organic substances as reliable characteristics of identity and purity and how, by the end of the century, they established these values as 'Constants of Nature'. Melting and boiling points as characteristic values emerge from this study as products of laboratory standardization, developed by chemists in their struggle to classify, understand and control organic nature. A major argument here concerns the role played by the introduction of organic synthesis in driving these changes. Synthetic organic chemistry vastly increased the number of known organic substances, precipitating the chemical identity crisis of my title. Successful natural product synthesis, moreover, depended on chemists' ability to demonstrate the absolute identity of synthetic product and natural target--something late nineteenth-century chemists eventually achieved by making reliable, replicable melting and boiling point measurements. In the period before the establishment of national standards laboratories, chemists and scientific glassblowers worked together to standardize melting and boiling points as physical constants, such collaborations highlighting the essential importance of chemical glassware and glassblowing skill in the development of nineteenth-century organic chemistry.

The "wonderful properties of glass": Liebig's Kaliapparat and the practice of chemistry in glass.

Everybody knows that glass is and always has been an important presence in chemical laboratories. Yet the very self-evidence of this notion tends to obscure a supremely important change in chemical practice during the early decades of the nineteenth century. This essay uses manuals of specifically chemical glassblowing published between about 1825 and 1835 to show that early nineteenth-century chemists began using glass in distinctly new ways and that their appropriation of glassblowing skill had profoundly important effects on the emerging discipline of chemistry. The new practice of chemistry in glass-exemplified in this essay by Justus Liebig's introduction of a new item of chemical glassware for organic analysis, the Kaliapparat--transformed not merely the material culture of chemistry but also its geography, its pedagogy, and, ultimately, its institutions. Moving chemistry into glass--a change so important that it warrants the term "glassware revolution"--had far-reaching consequences.

Second-line controller therapy for persistent asthma uncontrolled on inhaled corticosteroids: the step 3 dilemma.

The asthma syndrome is characterised by airway inflammation with associated bronchial hyperresponsiveness (BHR) and reversible airflow obstruction. Therapy has benefited from an enhanced understanding of the pathophysiology of asthma and the resulting guidelines that emphasise the pivotal role of anti-inflammatory inhaled corticosteroids (ICS) as first-line therapy. Most patients with mild-to-moderate asthma can be adequately controlled on low-to-medium dosages of ICS alone. For patients with moderate-to-severe asthma who are not adequately controlled by ICS, it is unclear which medication should be added on. The two principal drugs under consideration are long-acting beta(2)-agonists (LABAs) and leukotriene antagonists (LTAs). Although both LABAs and LTAs are both effective at improving lung function, reducing symptoms and decreasing exacerbations, important differences exist that may determine the selection of one over the other in particular circumstances. LABAs and LTAs are equally effective at reducing exacerbations and improving symptoms and quality of life when used as add-on therapy. LABAs tend to be more effective bronchodilators than LTAs. Although LABAs stabilise the airway smooth muscle, they do not affect the underlying inflammatory process. Their long-term use also leads to subsensitivity of response to both LABAs and short-acting beta(2)-agonists (SABAs). The subsensitivity of response to SABAs is more pronounced in the presence of acute bronchoconstriction, which could be relevant during an acute attack. When combined with an ICS, LTAs provide additive non-steroidal anti-inflammatory properties and alleviate associated BHR, but do not induce subsensitivity of response. Not only is the efficacy of LTAs maintained over time, but also they do not affect the response to SABAs as reliever therapy. LTAs also have beneficial effects in patients who have concomitant allergic rhinitis, thus treating the unified airway. The choice between LABA and LTA as add-on therapy will therefore be determined by the needs of the individual patient in terms of providing anti-inflammatory versus bronchodilatory control. For patients with poor lung function where bronchodilatation is required, then an LABA would seem to be a logical choice. For the patient whose lung function is less impaired, with evidence of ongoing BHR where bronchoprotection is needed (e.g. exercise, allergen, cold air), or when there is concomitant allergic rhinitis, then an LTA would be more suitable.

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.

Benefit-risk assessment of long-acting beta2-agonists in asthma.

The use of a regular long-acting beta2-adrenoceptor agonists (beta2-agonists; LABA) is now established in asthma guidelines as the preferred option for second-line controller therapy in addition to inhaled corticosteroids. This has been driven by data showing beneficial effects of LABAs on exacerbation rates, in turn suggesting a putative corticosteroid-sparing effect. As LABAs are devoid of any clinically meaningful anti-inflammatory activity in vivo, their effects on exacerbations are presumably due to a diurnal stabilising effect on airway smooth muscle. LABAs have marked effects on symptoms and lung function, and this may make it difficult to assess anti-inflammatory control with inhaled corticosteroids when used in a combination inhaler such as fluticasone propionate/salmeterol or budesonide/formoterol. The use of fixed-dose combination inhalers is in many respects counter-intuitive to conventional teaching regarding flexible dosage titration with inhaled corticosteroids. It would therefore seem prudent first to gain optimal control of inflammation with inhaled corticosteroids before considering adding a LABA. Increasing the dosage of inhaled corticosteroids will have a relatively greater effect on exacerbations than on symptoms and lung function, whereas the converse applies when adding a LABA. Another option is to add a leukotriene receptor antagonist, which confers additional anti-inflammatory activity and is as effective on exacerbations as adding a LABA. Despite in vitro and ex vivo data showing a ligand-independent effect of LABAs on glucocorticoid receptor activation, clinical data do not indicate any relevant synergy between LABAs and inhaled corticosteroids when used together in the same inhaler. In particular, there is no evidence of potentiation by LABAs of the in vivo anti-inflammatory activity of inhaled corticosteroids that would suggest any genuine corticosteroid-sparing activity. Nonetheless, the data support the additive effects of inhaled corticosteroids and LABAs when used together due to their separate effects on inflammation and smooth muscle, respectively. Tolerance with LABAs is a predictable pharmacological phenomenon that occurs despite concomitant therapy with inhaled corticosteroids. Moreover, cross-tolerance also develops to short-acting beta2-agonists used for protection against bronchoconstrictor stimuli as a result of LABA-induced down-regulation, desensitisation and prolonged occupancy of beta2-adrenoceptors. The exact role of beta2-adrenoceptor polymorphism in determining tolerance with LABAs requires further prospective clinical studies evaluating long-term effects on outcomes such as exacerbations in patients with relevant genotypes and haplotypes. The next decade will provide challenging issues for clinicians with respect to defining further the role of LABAs as add-on controller therapy, particularly in evaluating the long-term effects of combination inhalers on inflammatory outcomes and airway remodelling.

Chemistry as the defining science: discipline and training in nineteenth-century chemical laboratories.

The institutional revolution has become a major landmark of late-nineteenth century science, marking the rapid construction of large, institutional laboratories which transformed scientific training and practice. Although it has served historians of physics well, the institutional revolution has proved much more contentious in the case of chemistry. I use published sources, mainly written by chemists and largely focused on laboratories built in German-speaking lands between about 1865 and 1900, to show that chemical laboratory design was inextricably linked to productive practice, large-scale pedagogy and disciplinary management. I argue that effective management of the novel risks inherent in teaching and doing organic synthesis was significant in driving and shaping the construction of late-nineteenth century institutional chemical laboratories, and that these laboratories were essential to the disciplinary development of chemistry. Seen in this way, the laboratory necessarily becomes part of the material culture of late-nineteenth century chemistry, and I show how this view leads not only to a revision of what is usually known as the laboratory revolution in chemistry but also to a new interpretation of the institutional revolution in physics.

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Does bronchial hyperresponsiveness in asthma matter?

Bronchial hyperresponsiveness is a fundamental component of the asthmatic inflammatory process causing airway narrowing on exposure to a bronchoconstrictor stimulus. This in turn causes patients to experience symptoms of breathlessness, chest tightness, cough and wheeze. Bronchial challenge tests can be performed in the laboratory to establish the degree of bronchial hyperresponsiveness to both direct and indirect stimuli. The extent to which asthma pharmacotherapy attenuates bronchial hyperresponsiveness is therefore an important measure of efficacy. This review article discusses the effects of inhaled and oral asthma treatment upon bronchial hyperresponsiveness and highlights how, in conjunction with conventional measures of asthma control, it can be used as an aid to optimally manage patients.

Add-on therapy with montelukast or formoterol in patients with the glycine-16 beta2-receptor genotype.

AIMS: We assessed whether montelukast or formoterol provides additive effects to asthmatics not controlled on inhaled corticosteroids, by studying patients who were considered to be genetically susceptible to beta2-receptor down regulation and subsensitivity, and who expressed the homozygous glycine-16 beta2-receptor genotype. METHODS: Fifteen corticosteroid-treated, mild to moderate persistent asthmatics received montelukast 10 mg once daily or formoterol 9 micro g twice daily for 2 weeks, separated by a 2-week placebo run-in and washout, in a double-blind, double-dummy, randomized crossover design. Bronchoprotection against adenosine monophosphate (AMP) challenge (primary endpoint), spirometry and blood eosinophils were measured at trough after placebo, first and last doses. RESULTS: For AMP PC20vs placebo, there were sustained significant (P < 0.05) doubling dilution improvements following first (1.1; 95% CI 0.4, 1.9) and last (1.0; 95% CI 0.3, 1.8) doses of montelukast, and following first (1.3; 95% CI 0.1, 2.6) but not last (0.3; 95% CI -0.9, 1.6) doses of formoterol. Blood eosinophils (x 10(6) l(-1)) were significantly (P < 0.05) suppressed after the last dose of montelukast (-71; 95% CI -3, -140) compared with placebo, while formoterol exhibited a nonsignificant rise (20; 95% CI -92, 132). Neither treatment significantly improved FEV1, FEF25-75 or PEF after 2 weeks. CONCLUSIONS: In genetically susceptible patients with the homozygous glycine-16 genotype, montelukast, but not formoterol, conferred sustained anti-inflammatory properties in addition to inhaled corticosteroid, which were dissociated from changes in lung function after 2 weeks. Thus, assessing lung function may miss potentially beneficial anti-inflammatory effects of montelukast when used as add-on therapy.

The effects of butterbur on the histamine and allergen cutaneous response.

BACKGROUND: Butterbur or Petasites hybridus is an herbal remedy that exhibits antihistamine and antileukotriene activity and has been shown to attenuate the response to adenosine monophosphate challenge in patients with allergic rhinitis and asthma. However, no data are available regarding its effects on the histamine and allergen cutaneous response. OBJECTIVE: To evaluate the effects of butterbur compared with fexofenadine and montelukast on the histamine and allergen wheal and flare cutaneous responses. METHODS: Atopic patients were randomized into a double-blind, double-dummy, crossover study to receive for 1 week butterbur, 50 mg twice daily (8 AM and 10 PM); fexofenadine, 180 mg once daily (10 PM), and placebo once daily (8 AM); montelukast, 10 mg once daily (10 PM), and placebo once daily (8 AM); or placebo twice daily (8 AM and 10 PM). Patients attended the department at 10 AM and had measurements of the cutaneous wheal and flare responses to histamine, allergen, and saline control at 10-minute intervals for 60 minutes. RESULTS: Twenty patients completed the study. The mean +/- SE histamine wheal and flare responses, respectively, were significantly attenuated (P < .05) by fexofenadine (9.4 +/- 1.8 mm2 and 13.5 +/- 3.2 mm2) compared with placebo (15.5 +/- 3.3 mm2 and 179.8 +/- 74.3 mm2) but not by butterbur (16.4 +/- 2.1 mm2 and 297.7 +/- 121.2 mm2) or montelukast (19 +/- 1.9 mm2 and 240.2 +/- 66.6 mm2). The allergen wheal and flare responses, respectively, were also significantly attenuated (P < .05) by fexofenadine (31.1 +/- 6.3 mm2 and 256.9 +/- 86.5 mm2) compared with placebo (65.4 +/- 15.2 mm2 and 1,014.5 +/- 250.0 mm2) but not by butterbur (50.4 +/- 9.2 mm2 and 1,110.3 +/- 256.1 mm2) or montelukast (58.8 +/- 9.1 mm2 and 1,463.6 +/- 295.6 mm2). CONCLUSIONS: Butterbur did not produce any significant effects on the histamine and allergen cutaneous response compared with placebo, whereas mediator antagonism with fexofenadine but not montelukast produced significant attenuation. This finding would suggest that butterbur may not be effective in allergic skin disease.

Determinants of airway hyperresponsiveness in mild asthma.

BACKGROUND: Patients with mild asthma may have coexisting severe airway hyperresponsiveness (AHR), although the reasons for this are uncertain. OBJECTIVE: To evaluate the factors that determine AHR in mild asthma. METHODS: We performed a retrospective database evaluation of two groups of patients with mild asthma with forced expiratory volume in 1 second (FEV1) of 80% or more than predicted. Group A (n = 92; mean inhaled corticosteroid dose, 491 microg) had moderate-to-severe AHR to methacholine (provocative dose causing a 20% decrease in FEV1 [methacholine PD20], < or = 100 microg), whereas group B (n = 92; mean inhaled corticosteroid dose, 509 microg) had borderline AHR (methacholine PD20, > or = 800 microg). Both groups were matched for age, sex, inhaled corticosteroid use, and FEV1. RESULTS: From our database, we found 361 patients with an FEV1 of 80% or more than predicted of whom 123 (34%) had a methacholine PD20 of 100 microg or less and 138 (38%) had a methacholine PD20 of 800 microg or more. The methacholine PD20 geometric means (geometric SE) of groups A and B were 25 microg (3 microg) and 5,392 microg (295 microg), respectively. Despite matched mean values for FEV1, compared with group B, group A had a lower predicted forced expiratory flow between 25% and 75% (71% vs 81%, P = 0.007). A greater proportion of group A compared with group B patients were sensitized to house-dust mite (76% vs 54%, P = 0.002). No significant differences were found between groups in terms of presence of rhinitis and sensitization to other individual aeroallergens. CONCLUSIONS: Increased sensitization to house-dust mite and reduced small airway caliber were associated with moderate-to-severe AHR in mild asthma. Skin prick testing to common aeroallergens, especially house-dust mite, should be a routine part in the evaluation of asthmatic patients, including those patients with mild disease.

Effects of fluticasone plus salmeterol versus twice the dose of fluticasone in asthmatic patients.

OBJECTIVE: Current guidelines advocate adding a long acting beta(2)-agonist (LABA) to an inhaled corticosteroid as an alternative to increasing the dose of the latter. Since it is unclear how this translates into effects on surrogate inflammatory markers, we evaluated the anti-inflammatory activity of fluticasone plus salmeterol in combination versus twice the dose of fluticasone alone. METHODS: Fifteen mild-to-moderate asthmatics (mean FEV(1) 80% predicted) uncontrolled on inhaled corticosteroids (mean dose 470 microg) were randomised in a single-blind crossover fashion to receive 2 weeks each of fluticasone 250 microg plus salmeterol 50 microg in combination (FP+SM), 1 puff b.i.d., and fluticasone 500 microg (FP), 1 puff b.i.d. Prior to each randomised treatment, there was a 2-week run-in and washout period during which patients used their usual inhaled corticosteroid therapy. Measurements were made before and after randomised treatment periods. The primary outcome was airway hyper-responsiveness to adenosine monophosphate (AMP PC(20)), while secondary endpoints were exhaled tidal nitric oxide (NO), forced expiratory volume in 1 second (FEV(1)) and forced mid-expiratory flow (FEF(25-75)). RESULTS: For AMP PC(20), FP alone but not FP+SM conferred a significant ( P<0.05) improvement amounting to 3.27 (95% CI 1.46-7.32) and 1.44 (95% CI 0.64-3.23) geometric mean fold shifts, respectively, from baseline, while the difference between treatments was significantly ( P<0.05) greater with FP alone: a 2.26-fold (95% CI 1.01-5.07) difference. Both FP alone and FP+SM conferred significant ( P<0.05) falls in NO from baseline: 2.33 (95% CI 1.71-3.19) and 1.49 (95% CI 1.09-2.03) geometric mean fold changes, respectively, while between treatments the reduction was significantly ( P<0.05) greater with FP alone: a 1.57-fold (95% CI 1.15-2.14) difference. Neither treatment significantly improved FEV(1) or FEF(25-75). CONCLUSION: Double the dose of FP alone relative to FP+SM conferred superior effects on surrogate inflammatory markers but not on lung function. Long-term studies are required to evaluate whether these improvements on surrogate inflammatory markers translate into commensurate reductions in airway remodelling and exacerbations.

Effects of single or combined histamine H1-receptor and leukotriene CysLT1-receptor antagonism on nasal adenosine monophosphate challenge in persistent allergic rhinitis.

BACKGROUND: The effects of single or combined histamine H(1)-receptor and leukotriene CysLT(1)-receptor antagonism on nasal adenosine monophosphate (AMP) challenge in allergic rhinitis are unknown. OBJECTIVE: We elected to study the effects of usual clinically recommended doses of fexofenadine (FEX), montelukast (ML) and FEX + ML combination, compared with placebo (PL), on nasal AMP challenge in patients with persistent allergic rhinitis. METHODS: Twelve patients with persistent allergic rhinitis (all skin prick positive to house dust mite) were randomized in a double-blind cross-over fashion to receive for 1 week either FEX 180 mg, ML 10 mg, FEX 180 mg + ML 10 mg combination, or PL, with nasal AMP challenge performed 12 h after dosing. There was a 1-week washout period between each randomized treatment. The primary outcome measure was the maximum percentage peak nasal inspiratory flow (PNIF) fall from baseline over a 60-min period after nasal challenge with a single 400 mg ml(-1) dose of AMP. The area under the 60-min time-response curve (AUC) and nasal symptoms were measured as secondary outcomes. RESULTS: There was significant attenuation (P < 0.05) of the mean maximum percentage PNIF fall from baseline after nasal AMP challenge vs. PL, 48; with FEX, 37; 95% confidence interval for difference 2, 20; ML, 35 (4, 22); and FEX + ML, 32 (7, 24). The AUC (%.min) was also significantly attenuated (P < 0.05) vs. PL, 1893; with FEX, 1306 (30, 1143); ML, 1246 (214, 1078); and FEX + ML, 1153 (251, 1227). There were no significant differences for FEX vs. ML vs. FEX + ML comparing either the maximum or AUC response. The total nasal symptom score (out of 12) was also significantly improved (P < 0.05) vs. PL, 3.3; with FEX, 2.1 (0.3, 2.0); ML, 2.0 (0.5, 1.9); and FEX + ML, 2.5 (0.1, 1.4). CONCLUSION: FEX and ML as monotherapy significantly attenuated the response to nasal AMP challenge and improved nasal symptoms compared with PL, while combination therapy conferred no additional benefit.

Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma.

AIMS: Inhalers combining long acting beta2-adrenoceptor agonists (LABA) and corticosteroids (ICS) are indicated at Step 3 of current asthma guidelines. We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function, bronchoprotection, acute salbutamol recovery following methacholine bronchial challenge, and surrogate inflammatory markers in patients with moderate persistent asthma. METHODS: Twenty-nine patients with mean FEV1 (+/- SEM) of 78 +/- 3% predicted completed a randomized, double-blind, double-dummy, cross-over study. Patients received either 4 weeks of budesonide 400 microg + formoterol 12 microg (BUD + FM) combination twice daily followed by 1 week of BUD 400 microg alone twice daily, or 4 weeks of fluticasone propionate 250 microg + salmeterol 50 microg (FP + SM) combination twice daily followed by 1 week of FP 250 microg alone twice daily. Measurements were made at baseline and following each randomized treatment. RESULTS: FEV1 increase from pretreatment baseline as mean (+/- SEM) % predicted was significantly higher (P < 0.05) for BUD + FM (8 +/- 1%) vs BUD (2 +/- 1%), and for FP + SM (8 +/- 1%) vs FP (2 +/- 1%). The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups; BUD + FM (22 +/- 1%), BUD (24 +/- 1%), FP + SM (23 +/- 1%) and FP (23 +/- 1%). Salbutamol recovery over 30 min following methacholine challenge as area under curve (AUC %.min) was significantly blunted (P < 0.05) with BUD + FM (486.7 +/- 35.5) vs BUD (281.1 +/- 52.8), and with FP + SM (553.1 +/- 34.1) vs FP (368.3 +/- 46.7). There were no significant differences between respective combination inhalers or between respective ICS alone. Decreases in exhaled nitric oxide (NO) and serum eosinophilic cationic protein (ECP) from baseline were not significantly different between treatments. CONCLUSIONS: Combination inhalers improve pulmonary function without potentiating anti-inflammatory effects on exhaled NO and serum ECP as compared with ICS alone, but delay acute salbutamol recovery after bronchoconstriction.