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Objective We compared the efficacy of noninvasive ventilation with bilevel positive airway pressure added to usual care versus usual care alone in patients undergoing coronary artery bypass grafting. Methods We performed a 2-group, parallel, randomized controlled trial. The primary outcome was time until fit for discharge. Secondary outcomes were partial pressure of carbon dioxide, forced expiratory volume in 1 second, atelectasis, adverse events, duration of intensive care stay, and actual postoperative stay. Results A total of 129 patients were randomly allocated to bilevel positive airway pressure (66) or usual care (63). Three patients allocated to bilevel positive airway pressure withdrew. The median duration of bilevel positive airway pressure was 16 hours (interquartile range, 11-19). The median duration of hospital stay until fit for discharge was 5 days for the bilevel positive airway pressure group (interquartile range, 4-6) and 6 days for the usual care group (interquartile range, 5-7; hazard ratio, 1.68; 95% confidence interval, 1.08-2.31; P = .019). There was no significant difference in duration of intensive care, actual postoperative stay, and mean percentage of predicted forced expiratory volume in 1 second on day 3. Mean partial pressure of carbon dioxide was significantly reduced 1 hour after bilevel positive airway pressure application, but there was no overall difference between the groups up to 24 hours. Basal atelectasis occurred in 15 patients (24%) in the usual care group and 2 patients (3%) in the bilevel positive airway pressure group. Overall, 30% of patients in the bilevel positive airway pressure group experienced an adverse event compared with 59% in the usual care group. Conclusions Among patients undergoing elective coronary artery bypass grafting, the use of bilevel positive airway pressure at extubation reduced the recovery time. Supported by trained staff, more than 75% of all patients allocated to bilevel positive airway pressure tolerated it for more than 10 hours.

As cannabis use increases, physicians need to be familiar with the effects of both cannabis and tobacco on the lungs. However, there have been very few long-term studies of cannabis smoking, mostly due to legality issues and the confounding effects of tobacco. It was previously thought that cannabis and tobacco had similar long-term effects as both cause chronic bronchitis. However, recent large studies have shown that, instead of reducing forced expiratory volume in 1 s and forced vital capacity (FVC), marijuana smoking is associated with increased FVC. The cause of this is unclear, but acute bronchodilator and anti-inflammatory effects of cannabis may be relevant. Bullous lung disease, barotrauma and cannabis smoking have been recognised in case reports and small series. More work is needed to address the effects of cannabis on lung function, imaging and histological changes.

Importance: Guidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use.Objective: To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit.Design, Setting, and Participants: The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom-based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids.Interventions: Azithromycin 500 mg daily or matched placebo for 3 days.Main Outcomes and Measures: The primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of -0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score.Results: Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference, -0.166; 95% CI, -0.670 to 0.337), nor on any day between exacerbation and day 10. No significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score.Conclusions and Relevance: In this randomized population, azithromycin treatment resulted in no statistically or clinically significant benefit. For each patient randomized, more than 10 were excluded because they had already received antibiotics.Trial Registration: clinicaltrials.gov Identifier: NCT01444469.

Reduction in total lung capacity (TLC) in obese men is associated with restricted expansion of the thoracic cavity at full inflation. We hypothesized that thoracic expansion was reduced by the load imposed by increased total trunk fat volume or its distribution. Using MRI, we measured internal and subcutaneous trunk fat and total abdominal and thoracic volumes at full inflation in 14 obese men [mean age: 52.4 yr, body mass index (BMI): 38.8 (range: 36–44) kg/m2] and 7 control men [mean age: 50.1 yr, BMI: 25.0 (range: 22–27.5) kg/m2]. TLC was measured by multibreath helium dilution and was restricted (

Adenosine deaminase (ADA) deficiency is an inherited disorder which leads to elevated cellular levels of\ud deoxyadenosine triphosphate (dATP) and systemic accumulation of its precursor, 2-deoxyadenosine. These\ud metabolites impair lymphocyte function, and inactivate S-adenosylhomocysteine hydrolase (SAHH) respectively,\ud leading to severe immunodeficiency. Enzyme replacement therapy with polyethylene glycol-conjugated\ud ADA is available, but its efficacy is reduced by anti-ADA neutralising antibody formation. We report\ud here carrier erythrocyte encapsulated native ADA therapy in an adult-type ADA deficient patient. Encapsulated\ud enzyme is protected from antigenic responses and therapeutic activities are sustained. ADA-loaded\ud autologous carrier erythrocytes were prepared using a hypo-osmotic dialysis procedure. Over a 9-yr period\ud 225 treatment cycles were administered at 2–3 weekly intervals. Therapeutic efficacy was determined by\ud monitoring immunological and metabolic parameters. After 9 yr of therapy, erythrocyte dATP concentration\ud ranged between 24 and 44 lmol ⁄ L (diagnosis, 234) and SAHH activity between 1.69 and 2.29 nmol ⁄ h ⁄mg\ud haemoglobin (diagnosis, 0.34). Erythrocyte ADA activities were above the reference range of\ud 40–100 nmol ⁄ h ⁄mg haemoglobin (0 at diagnosis). Initial increases in absolute lymphocyte counts were not\ud sustained; however, despite subnormal circulating CD20+ cell numbers, serum immunoglobulin levels\ud were normal. The patient tolerated the treatment well. The frequency of respiratory problems was reduced\ud and the decline in the forced expiratory volume in 1 s and vital capacity reduced compared with the 4 yr\ud preceding carrier erythrocyte therapy. Carrier erythrocyte-ADA therapy in an adult patient with ADA\ud deficiency was shown to be metabolically and clinically effective.

OBJECTIVE: chronic obstructive pulmonary disease (COPD) prevalence steadily increases with age. However, the effectiveness of inhaled therapy in the elderly COPD population has rarely been formally evaluated. We studied a group of elderly patients with COPD with a range of severity, selected from one General Practice register to measure peak inspiratory flow (PIF) and assess patient perceived benefit. METHODS: we recruited 53 randomly selected elderly patients with COPD (36 males) with a mean age of 73.5 years (range 65-89 years). The evaluation consisted of (i) information obtained from directed questions and (ii) objective measurements of the ability to generate adequate PIF for a variety of inhalers. Patients answered questions regarding ease of use, perceived benefit from and specific problems encountered with their inhaler. Three recordings of PIF were measured at varying inhaled resistances using the 'In-Check Dial'. RESULTS: thirty-five were classified as mild, 17 moderate and 1 severe COPD. All patients used a metered dose inhaler (pMDI), and 12 of the patients also used a dry powder inhaler (DPI). Forty six per cent of patients using a pMDI and 17% of those using a DPI rated their device difficult to use. No patient used a nebuliser. Thirty-one of the 53 patients using just a pMDI felt they were able to perceive benefit in comparison to 4 of the 12 DPI users. Even though most DPI users (10/12) had rated their inhaler as easy to use, 50% were 'unsure' as to whether they received any clinical benefit. Most patients were unable to generate sufficient inspiratory flow to use the higher resistance DPI's and patients with COPD who were able to generate adequate PIF were invariably mild. A significant negative correlation was found between age and the PIF achieved when assessed using the high resistance device setting (R = 0.84, P

Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD 1 antigen presentation by hRTDC may contribute to asthma pathogenesis. Objective To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. Methods Sputum cells were induced from steroid-naive, allergen-challenged and allergen-naive subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. Results hRTDC stained HLA-DR + (negative for markers of other cell lineages) were predominantly myeloid and comprised ∼0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4 + naive T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P < 0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P < 0.05-P < 0.001), CD1c, CD1d and langerin (P < 0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24h; P < 0.05). CD11c - CD123 high hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. Conclusion Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD 1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.

The skeletal effects of low-dose methotrexate (MTX), in glucocorticoid-dependent asthmatics (GCDA), are unknown.We studied 9 patients from a total of 26 chronic GCDA who completed 28 weeks of MTX (15 mg weekly, intramuscularly). Prednisolone dose was not altered during the first 12 weeks, and was then reduced between 12 and 28 weeks. Mean (S.E.M.) age of the patients was 54 (4.0) years. They had normal bone mineral density (BMD), were not taking medication that affected bone metabolism (except prednisolone and inhaled corticosteroids) and all achieved at least 50% reduction in prednisolone dose at 28 weeks. Blood and urine samples were obtained at baseline, 12, 28 and 40 weeks for measurement of serum osteocalcin (OC) and bone alkaline phosphatase (Bone-ALP) as formation markers and urinary deoxypyridinoline (DPD) and N-terminal cross-linked telopeptide of type I collagen (NTX-I) as resorption markers.Concurrently with the changes in prednisolone dosage serum OC levels increased significantly at 28 weeks (p0.008) (8.1+/-1.0 ng/ml) compared to baseline (4.7+/-0.6 ng/ml) and 12 weeks (5.1+/-0.6 ng/ml), but trended back by 40 weeks (6.6+/-0.6 ng/ml). No significant changes were observed for the other bone markers between baseline and the other time points.The beneficial effects of steroid reduction on bone metabolism do not appear to be impaired by concomitant MTX treatment at least over 12 weeks.

The present study compared the safety of 4.5 microg formoterol with 0.5 mg terbutaline, both by Turbuhaler and used as needed, in addition to regular formoterol in moderate asthma. In this double-blind parallel-group study, 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d. over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital signs and lung function were assessed monthly; peak expiratory flow and severe asthma exacerbations were recorded daily. Patients used 2.16 (range 0.0-6.3) formoterol and 2.34 (range 0.1-7.5) terbutaline relief inhalations x day(-1). No clinically significant differences in safety variables were found between treatments. Statistically greater increases in cardiac frequency (2.6 beats x min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline, respectively, with no significant difference in time to first exacerbation. There was also no difference between treatments for other efficacy measures (peak expiratory flow, forced expiratory volume in one second and morning/evening symptom scores). Formoterol 4.5 microg as needed was at least as safe, well tolerated and effective as terbutaline 0.5 mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking formoterol plus inhaled corticosteroids regularly over 12 weeks.

BACKGROUND: Salbutamol is the most widely prescribed short acting beta 2 agonist and salmeterol is the first long acting inhaled beta 2 agonist. The dose equivalence of salmeterol and salbutamol is disputed. Estimates of weight-for-weight dose ratio have ranged from 1:2 to 1:16. A study was undertaken to clarify the true dose ratio. METHODS: The bronchoprotection afforded against repeated methacholine challenge by inhaled salmeterol 25 micrograms and 100 micrograms and salbutamol 100 micrograms and 400 micrograms was compared in a randomised, double blind, placebo controlled, crossover trial. Subjects were 16 stable asthmatics with a baseline forced expiratory volume in one second (FEV1) of > or = 65% predicted, screening concentration provoking a fall in FEV1 of 20% (PC20FEV1) of < or = 8mg/ml, and a shift in PC20FEV1 of more than two doubling concentration steps following inhalation of salbutamol 400 micrograms. On five separate occasions subjects underwent methacholine challenge before and 30 and 120 minutes after drug administration. PD20FEV1 was calculated for each challenge. FEV1 at 90 minutes after drug administration was also recorded. RESULTS: Bronchoprotection afforded by salmeterol was increased at 120 minutes compared with 30 minutes and protection by salbutamol was decreased. Protection by both doses of salmeterol was similar to salbutamol 100 micrograms at 30 minutes but significantly greater at 120 minutes. FEV1 at 90 minutes was significantly greater after salmeterol 100 micrograms than after placebo, but there were no other significant differences between treatments. Maximal observed protection was equivalent for salmeterol 100 micrograms and salbutamol 400 micrograms. CONCLUSIONS: The data are compatible with a weight-for- weight dose ratio for salmeterol:salbutamol of < or = 1:4.

Pulmonary renal syndrome (PRS) describes the occurrence of renal failure in association with respiratory failure, characterised by autoimmune-mediated rapidly progressive glomerulonephritis (RPGN) and diffuse alveolar haemorrhage (DAH), respectively. PRS is associated with significant morbidity and mortality, and prompt diagnosis and treatment significantly improve outcomes. Prompt diagnosis of PRS requires a high index of suspicion, as clinical features are non-specific, and immunological testing aids the diagnosis in many cases. The diagnostic evaluation of DAH and RPGN is outlined in the context of the important differential diagnoses. The commonest causes of PRS include antineutrophil cytoplasm antibody (ANCA)-associated vasculitis and antiglomerular basement membrane disease. As such, more emphasis has been placed on these two conditions in addition to an overview of the less common causes of PRS. We provide a practical review of the diagnostic evaluation, current treatment strategies and clinical outcomes of PRS for renal, respiratory and general physicians.

Inhaled steroids are increasingly advocated as first line treatment for mild asthma. Some studies suggest that inhaled steroids suppress bone formation as reflected by a fall in plasma osteocalcin. Spacers have been shown to increase the proportion of inhaled aerosol that is deposited in the lungs and to reduce the amount swallowed. We measured plasma osteocalcin levels to determine the effect on bone formation of inhaled beclomethasone dipropionate (BDP) with and without a 750 ml spacer in a double-blind, randomised, placebo-controlled, cross-over study. Twenty-six healthy male volunteers took BDP 500 micrograms (two puffs of Becloforte) together with two puffs of placebo, inhaled twice daily for seven days. One inhaler was taken directly while the other was inhaled through a 750 ml spacer. After a two week washout period, the inhalers were exchanged so that BDP was taken by the alternate route for a further seven days. Fasting plasma osteocalcin levels were measured at 09.00 h before and at the end of each week. After a week of BDP taken directly (without a spacer), osteocalcin levels fell from 11.8 (SEM 0.6) ng/ml to 9.5 (SEM 0.5) ng/ml (p < 0.001). After a week of BDP taken through a spacer, osteocalcin levels fell from 12.1 (SEM 0.5) ng/ml to 11.1 (SEM 0.5) ng/ml (p < 0.001). The fall in osteocalcin when a spacer was used was significantly less than when BDP was taken directly (p < 0.005). This is likely to be because the systemic effects on bone are caused by swallowed rather than inhaled BDP, and this is limited by the use of a spacer. Spacers should be more widely prescribed with inhaled steroids. Further prospective studies are indicated to evaluate whether spacers protect bone mass.

Bronchial inflammation in mild asthma has been investigated using bronchoscopical techniques. The safety of bronchoscopy in patients with more severe asthma has been questioned. We have used the non-invasive technique of hypertonic saline (HS) inhalation to induced sputum samples for cellular analysis whilst simultaneously yielding a measure of bronchial responsiveness. Ten normal subjects and a heterogenous group of 24 asthmatic patients (range % predicted FEV1 43.3-111.5) underwent HS challenge. Sputum samples induced were analysed. Total and differential cell counts between the two groups were compared. The association between bronchial responsiveness to HS and sputum cell counts was examined in the asthma group. Mean maximum fall in FEV1 for normal subjects was 4.0 (2.1-5.9, 95% CI)% after saline. Geometric mean PD20HS for asthma patients was 7.7 (range 0.68-40.92)ml. Adequate sputum samples were obtained from 9/10 normals and 23/24 asthmatic patients. Sputum from normal subjects contained a median of 3.8 (2.8-8.1, interquartile range)% eosinophils compared with 17.6 (8.9-34.1)% in sputum from asthma patients (P < 0.001). Sputum from asthma patients contained fewer of all other cell types compared with normals, with the difference in macrophages reaching significance. There was no correlation between PD20HS and cell count for any cell type in asthma subjects. Analysis of induced sputum represents a simple, safe, non-invasive and well-tolerated method of assessment of bronchial inflammation, suitable for use in patients with a range of asthma severity. There was no relationship between inflammation, as assessed by sputum cell counts and a measure of 'indirect' bronchial responsiveness.

BACKGROUND: Platelet activating factor (PAF) is a potent mediator of inflammation. Inhalation of PAF causes acute bronchoconstriction and a transient fall in white blood cell count in humans. Salmeterol inhibits pulmonary inflammation induced by PAF in guinea pigs. METHODS: The effect of salmeterol on effects induced by PAF was investigated in eight normal subjects who inhaled salmeterol (50 micrograms) twice daily or a matched placebo for one week before challenge with PAF. Blood samples were taken from a forearm catheter for total white cell and neutrophil counts before and for 30 minutes after administration of PAF (48 micrograms) through a Mefar dosimeter. Blood films were stained for unsegmented neutrophils before and after treatment with PAF on a placebo day. RESULTS: Mean baseline total white cell counts and neutrophil counts did not differ on the two days. Mean baseline sGaw was significantly higher after inhaled salmeterol (1.84 (95% C1 1.45-2.23) s-1kPa-1) than after placebo (1.53 (1.24-1.82)). After placebo mean total white cell counts, neutrophil counts, and sGaw were reduced to 60 (43-78)%, 39 (14-64)%, and 82 (71-93)% of baseline respectively five minutes after inhaled PAF. After salmeterol treatment mean reductions five minutes after inhaled PAF were 59 (45-73)%, 40 (19-61)%, and 82 (71-93)% of baseline respectively. At 30 minutes after treatment with PAF the neutrophil count rebounded to 143 (82-204)% of baseline after placebo and to 127 (93-161)% after inhaled salmeterol. There was no significant difference in the percentage of immature neutrophils before and after treatment with PAF (2.0 (0.5-2.6)% compared with 3.9 (2.2-5.6)%. CONCLUSIONS: Treatment with salmeterol did not inhibit reduction in total white cell count or neutrophil count, rebound neutrophilia, acute bronchoconstriction, or transient flushing after inhalation of PAF. These results conflict with the inhibitory effect of salmeterol on lung inflammation in guinea pigs but are consistent with the lack of effect of salbutamol in humans. Salmeterol does not have an anti-PAF effect in vivo in humans.

1. The effect of inhaled frusemide and high dose inhaled ipratropium bromide on bronchoconstriction induced by inhaled metabisulphite was studied in 10 atopic volunteers. 2. Frusemide (40 mg), ipratropium bromide (0.5 mg) or saline placebo were administered by nebuliser in a double-blind fashion, prior to construction of a dose-response curve to metabisulphite (2.5-100 mg ml-1). 3. Geometric mean of the provocative dose of metabisulphite that caused a 35% fall in specific airways resistance (sGaw) after placebo was 13 (95% confidence intervals CI 4-36 mumol) compared with 36 (16-78) mumol after ipratropium bromide and 45 (22-94) mumol after frusemide. 4. Mean maximum fall in sGaw was 49 (40-57)% after placebo, 11 (0-22)% after frusemide and -1 (-25-22)% after ipratropium bromide. 5. Frusemide significantly protected against metabisulphite induced bronchoconstriction (P less than 0.005). The protection from high dose ipratropium bromide was also significant (P less than 0.05), but the response was more variable between subjects.

Background. A single deep inspiration (DI) is known to be a potent bronchodilator but it is not known if repeated DI can accelerate sustained recovery from bronchoconstriction. Methods. We induced sustained bronchoconstriction using increasing concentrations of nebulized methacholine (Mch) during tidal breathing and assessed airway narrowing by measuring respiratory resistance (Rrs) using forced oscillation in six healthy subjects. On separate days we examined the effects of DI every 3 minutes and of prohibition of DI on recovery of Rrs for 30 minutes after the end of Mch nebulization. Results. Bronchoconstriction (Rrs ∼ 150% above baseline) was induced. DI during recovery had a transient bronchodilator effect but no cumulative effect. At 30 minutes after end of nebulization (and 2 minutes after the last DI) Rrs was 87% above baseline compared to 93% above baseline when DI was prohibited. Conclusion. Recovery from induced bronchoconstriction with methacholine was slow (∼ 2%/min) and not accelerated by fre...

Summary Background Concomitant methotrexate (MTX) therapy of oral corticosteroid (CS)–dependent asthmatics has been shown to spare CS therapy, but the mechanism is unknown. In a previous report, we showed that MTX increases T cell inhibition by CS. In this report we focus on effects of MTX on immunoglobulin concentrations and their possible clinical relevance. Objective To monitor changes in circulating leucocytes and Ig in a group of these patients during MTX therapy, and to relate these changes to clinical ‘response’ as defined by oral CS reduction. Methods Sixteen severe asthmatics dependent on oral prednisolone 15 (7.5–25) mg/day in addition to high dose inhaled CS were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. Prednisolone dosages were maintained constant for 12 weeks then reduced systematically over the next 16 weeks provided that asthma control did not deteriorate. Patients were classified a priori as ‘responders’ or ‘non-responders’ to MTX (reduction of initial oral prednisolone requirement by 50% or

Atrial natriuretic peptide (ANP) causes mast cell degranulation in rats in vivo and in vitro but is bronchodilator in humans. The aim of this study was to investigate the wheal and flare dose-response to intradermal injection of alpha-human ANP in normal humans. Eight normal subjects received five 30 microliters injections containing 1, 10, 39, 78, 117 pmol ANP and one each of normal saline, histamine 675 pmol and substance P 30 pmol. Maximum ANP flare response was greater but not significantly than that to saline at 1.55 +/- 0.6 (mean +/- s.e. mean) compared with 0.42 +/- 0.17 cm2, but much less than to histamine 9.86 +/- 0.97 or to substance P 12.5 +/- 1.2. Maximum ANP wheal response was significantly greater than that to saline at 0.38 +/- 0.08 compared with 0.18 +/- 0.05 cm2 (difference between means 0.20, 95% CI 0.05, 0.35), but much less than to histamine 0.75 +/- 0.06 or to substance P 1.05 +/- 0.08 cm2. No dose-response to ANP was demonstrated, though responses to the highest dose differed significantly from those to the lowest dose studied. We conclude that human cutaneous responses to ANP differ from those of animals and that the skin is less responsive than other tissues in humans.

Concomitant methotrexate (MTX) therapy of severe, oral corticosteroid-dependent asthmatics has been shown to be corticosteroid sparing, but the mechanism is unknown. We hypothesized that MTX therapy of these patients increases the susceptibility of their T cells to corticosteroid inhibition.To measure prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells from a group of these patients before, during and following MTX therapy.Eighteen severe asthmatics (median (range) age 56 (33-68) years, FEV1 61 (38-69)% predicted, dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high-dose, inhaled corticosteroids) were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. After 12 weeks of MTX, oral prednisolone dosages were reduced systematically over 16 weeks, provided that asthma control did not deteriorate. Patients were followed for a further 12 weeks after MTX withdrawal. Concentration-dependent, prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells was measured just prior to MTX therapy (week 1) and at weeks 12, 28 and 40, and IC50 concentrations were interpolated.By week 28 of MTX therapy, patients were able to reduce oral prednisolone dosages from (median, SIQR) 15 (10-20.5) to 5.9 (1.4-9.4) mg/day (P0.01) without alteration of lung function and symptoms, while median IC50 values for prednisolone inhibition of peripheral blood T cell proliferation were reduced from 49 (21-144) to 4 (1-9) nm (P0.0001). These increased again to 15 (9.4-25.7) mg/day and 36 (18-67) nm, respectively, following MTX withdrawal. A correlation (P0.01) was observed between percentage reductions in prednisolone dosages in vivo and fold changes in prednisolone IC50in vitro between weeks 12 and 28.This effect of MTX may at least partly account for its oral corticosteroid-sparing effect in severe asthma.

Viozan, (Sibenadet HCl, AR-C68397AA) is a dual D2 dopamine receptor, beta2-adrenoceptor agonist that combines bronchodilator activity with the sensory afferent modulating effects associated with D2-receptor agonism. Investigation in animal models of key chronic obstructive pulmonary disease (COPD) symptoms has demonstrated that sibenadet effectively inhibits sensory nerve activity, thereby reducing reflex cough, mucus production and tachypnoea. The results of the early clinical evaluation of this novel agent are reported. An initial proof of concept study (Study 1) aimed to determine the clinical potential of this novel agent by assessing the effects of three doses of sibenadet therapy relative to placebo, with two commonly used bronchodilators, intended to provide a benchmark against which sibenadet activity could be judged. In all, 701 patients were randomized to one of three sibenadet dose groups (400, 600 or 1000 microg ex valve), salbutamol 200 microg, ipratropium bromide (IB) 40 microg or placebo, all three times daily via pressurized metered dose inhaler (pMDI) for 4 weeks. Once the results of Study 1 had been evaluated, a dose-ranging, study (Study 2) involving 872 patients randomized to receive sibenadet (45, 270, or 495 microg ex actuator), or placebo all three times daily via pMDI, for 6 weeks commenced. Both studies were preceded by a 2-week baseline phase and followed by a 2-week follow up period.The primary efficacy variable identified changes in key COPD symptoms over the treatment period (compared with baseline data) as determined by the novel Breathlessness, Cough and Sputum Scale (BCSS). In addition, data on lung function, health-related quality of life and adverse events were collected. Patients receiving sibenadet therapy three times daily exhibited statistically significantly greater improvements in BCSS total score than those receiving placebo or bronchodilator therapy alone. A clear dose-response was evident in Study 2. Symptom improvement in this study was also accompanied by improved lung function and health-related quality of life. Sibenadet therapy was well tolerated with an adverse events profile comparable to current bronchodilator therapy. These data were viewed as extremely encouraging, warranting further, large-scale clinical investigation.

A large mediastinal bronchogenic cyst presented acutely with paroxysmal atrial fibrillation and severe airflow obstruction. The patient had experienced identical symptoms on two other occasions over the previous 24 years. These had been previously misdiagnosed as due to a mediastinal lymphoma. Percutaneous extrapleural aspiration successfully decompressed the cyst with substantial improvement in lung function. Recurrent swelling of the cyst occurred that could not be relieved surgically. After repeat aspiration percutaneous instillation of bleomycin and alcohol has been used to prevent further increase in the size of the cyst.

1. The effects of salmeterol hydroxynaphthoate (50 micrograms, 8.3 x 10(-8) M) and salbutamol (200 micrograms, 3.5 x 10(-7) M) on sGaw were compared in a double-blind, placebo-controlled, randomised study in 10 normal subjects. 2. SGaw increased by 29% (14-43) (mean (CI)), 5 min after salmeterol and by 35% (19-51) at 15 min compared with an increase of 32% (14-51) and 37% (10-63) after salbutamol and 4% (-3-11) and 8% (0-16) after placebo. 3. The mean area under the sGaw-time curve (AUC480) after salmeterol inhalation was 22,500 kPa-1 (10,100-39,500) compared with 14100 kPa-1 (8020-24,500) after salbutamol and 5300 kPa-1 (1500-10,400) after placebo. 4. Salmeterol produced a significantly prolonged bronchodilator effect compared with salbutamol in normals.

Tachyphylaxis to the cardiac effects of beta-adrenoceptor stimulation after long-term beta2-agonist administration is well recognized, but the influence on global cardiac beta-adrenoceptor density has not been previously investigated in vivo. Positron emission tomography (PET) has made possible the noninvasive quantification of regional receptor density. This study assesses the effect of long-term beta2-agonist dosing on cardiac beta-adrenoceptors.Beta-adrenoceptors in the hearts of 29 healthy male subjects aged 35 +/- 8 years were imaged and quantified in vivo by means of PET and compared with the receptor density in the same subjects' lung tissue. Mononuclear leukocyte (MNL) beta-receptor density was determined in vitro by means of a radioligand binding assay. Beta-receptor density was 8.41 +/- 2.03 pmol/gm tissue in heart, 10.81 +/- 1.91 pmol/gm tissue in lung, and 38.0 +/- 17.5 fmol/mg protein on MNLs. There was a weak relationship between cardiac and pulmonary beta-receptor densities (r = 0.45, p0.02) but not between cardiac and MNL receptor density. In seven subjects, the measurements were repeated after 2 weeks of albuterol treatment (4 mg orally twice daily and 200 microg inhaled four times daily in the first week, with doubling of the dose during the second week). After the albuterol treatment, beta-receptor density fell on average by 19% (p0.05) in the heart compared with 22% (p0.05) in the lung and 42% (p0.05) in MNLs. Correlations were found between the percentage changes in receptor density in heart and lung (r = 0.98, p0.001) and in heart and MNLs (r = 0.99, p0.002).Two weeks of high-dose albuterol results in equivalent downregulation of beta-receptors in vivo, both in the lung and in the heart.

The aims of this study were to (1) record the changes of (arterial oxygen partial pressure) PaO2, (arterial carbon dioxide partial pressure) PaCO2, (percentage saturation of haemoglobin with oxygen in arterial blood) SaO2 and alveolar-arterial (A-a) oxygen gradiant resulting from bronchoalveolar lavage (BAL) in asthmatic and normal subjects; (2) measure changes in forced expiratory volume in 1 s (FEV1), vital capacity forced (FVC) associated with BAL; and (3) assess possible predictive factors for the degree of hypoxaemia and impairment of spirometry resulting from BAL. Bronchoscopy and BAL (150 ml) were performed in 24 asthmatics and 15 healthy subjects. Serial arterial blood samples (radial artery) were obtained in all subjects: T1 and before T2 after local anaesthesia; T3 at end of bronchoscopy; T4 after BAL and 5 min, 15 min, 1 h, 2 h, 8 h and 24 h (T5-T10) after the procedure, FEV1 and FVC were measured immediately before and 5 min afer bronchoscopy. Baseline PaO2 was lower in asthmatics (10.2 +/- 0.8 kPa) than in healthy subjects (10.8 +/- 0.8). Both groups showed a significant decrease in PaO2, and a significant widening in (A-a) oxygen tension gradiant at T3-9, with respect to T1 (P0.05). PaO2 reached a significantly lower value in asthmatics (7.1 +/- 0.6 kPa) than in HS (7.7 +/- 0.5; P0.05). In asthmatics, FEV1, FVC and the ratio FEV1/FVC decreased significantly after BAL (P0.001). In healthy subjects, FEV1 and FVC decreased significantly (P0.001), whereas FEV1/FVC did not. The fall in FEV1 after BAL was significantly greater in asthmatics (32.4 +/- 10.0%) than in healthy subjects (17.7 +/- 4.6; P0.001). Severity of asthma, basline FEV1 or initial PaO2 did not predict the degree of hypoxaemia or the fall of FEV1. It is concluded that BAL causes more severe hypoxaemia and a greater decrease in FEV1 in asthmatics compared to healthy subjects, strongly supporting the recommendation of special caution and careful monitoring when BAL is undertaken in asthmatics.

Summary Background Infiltration of the airways mucosa with activated inflammatory cells appears to be a major factor in the pathogenesis of asthma and other airway diseases. Examination of sputum provides a direct method to investigate airway inflammation non-invasively. Objectives The aim of the present study was to evaluate the reproducibility of cell counts on cytospins and fluid phase (eosinophil cationic protein, ECP) measurements in a selected portion of induced sputum. We aimed to confirm the validity of the tecnique by comparing measurements between stable asthmatics, allergic rhinithis and healthy subjects. Methods Sputum was induced with hypertonic saline (4.5%) twice within one week in 53 stable asthmatics, 16 subjects with seasonal rhinitis (out of the pollen season), and 19 healthy subjects. Reproducibility was examined within sample (two different plugs of the same sample) between sample (two specimens of induced sputum obtained within one week) and between examiners on stable subjects taking into account sample size, number of examinations per patients and Confidence Interval (CI) of the estimates. Results We have found that the method is highly reproducible within sample and between examiners for all types of cells and fluid phase measurements of ECP. It is reproducible between sample for eosinophils, macrophages, neutrophils and ECP, but not for lymphocytes and weakly for epithelial cells. Sputum from asthmatics, in comparison with the sputum of healthy subjects and subjects with rhinitis had higher eosinophils (asthmatics: 12.2%± 12.9, rhinitis: 0.4 ± 0.8, normals: 0.4 ± 0.7(%) and ECP (asthmatics: 827 ± 491 μg/L, rhinitis: 127 ± 82 normals: 157 ± 203). No significant differences were found between healthy subjects and subjects with rhinitis. Eosinophil counts were inversely correlated with FEV1 (r=−0.37) expressed as percentage of predicted, but not significantly correlated with PC20 methacholine (r =−0.28) or blood eosinophils (r = 0.26). Conclusions The importance of this study is the confirmation, within important statistical guidelines for a study of reproducibility, that the methods examined are reproducible and valid.

The in vivo regional distribution of pulmonary beta-adrenoceptors was imaged and quantified in humans with the hydrophilic beta-adrenoceptor antagonist (S)-CGP-12177 labeled with carbon-11 [(S)-[11C]CGP-12177] and positron emission tomography (PET). Six normal male volunteers and eight patients with hypertrophic cardiomyopathy were studied. PET scanning consisted of transmission (tissue density), C15O (blood volume), and (S)-[11C]CGP-12177 (beta-adrenoceptor) emission scans. High-specific-activity (S)-[11C]-CGP-12177 (7.1 +/- 2.0 micrograms, 6.5 +/- 2.1 GBq/mumol) was given intravenously followed by a low-specific-activity (S)-[11C]CGP-12177 injection (34.0 +/- 4.8 micrograms, 2.3 +/- 0.8 GBq/mumol). Binding capacity (Bmax) was calculated in each region of interest as picomoles per gram by normalizing it to the local extravascular tissue density. In normal subjects, average Bmax for all regions of interest was 14.8 +/- 1.6 (SD) pmol/g, which is similar to previously reported in vitro values. In both groups there were no differences in beta-adrenoceptor density between peripheral and central regions nor between right and left lungs. In patients with hypertrophic cardiomyopathy, extravascular tissue density was 24% higher than in normal subjects; Bmax per milliliter thoracic volume was correspondingly higher but was not different from that in normal subjects when expressed per gram tissue (15.8 +/- 2.6 pmol/g). These data suggest that in vivo beta-adrenoceptor density may be quantifiable in humans with the use of PET. This should offer a means to study physiological regulation through repeat measurements.

1. The effects of nedocromil sodium and sodium cromoglycate on bronchoconstriction induced by inhaled sodium metabisulphite have been studied in eight atopic subjects, three of whom had mild asthma. 2. Nedocromil sodium (4 mg, 7.8 X 10(-6) M), sodium cromoglycate (10 mg, 24.1 X 10(-6) M) and matched placebo were administered by identical metered dose inhalers 30 min before a dose-response to sodium metabisulphite (5-100 mg ml-1) was performed. 3. Maximum fall in sGaw after placebo pre-treatment was -43.9 +/- 3.3% baseline (mean +/- s.e. mean). At the same metabisulphite concentration maximum fall in sGaw after sodium cromoglycate was -13.0 +/- 3.6% and after nedocromil sodium was +4.3 +/- 6.8%. Nedocromil sodium prevented any significant fall in sGaw even after higher concentrations of metabisulphite. 4. Both nedocromil sodium, 4 mg, and sodium cromoglycate, 10 mg, inhibited sodium metabisulphite induced bronchoconstriction but nedocromil sodium was significantly more effective. Relative in vivo potency of the two drugs is broadly in line with other in vivo and in vitro studies.

Lactose is commonly used as a carrier for inhaled drugs. Twenty healthy volunteers without respiratory symptoms inhaled seven different doses of lactose and a placebo (empty) dose through the four place Diskhaler device, in order to determine the lowest dose that could be reliably sensed. The minimum dose for which all subjects reported taste or feel sensations was 10 mg. This has implications regarding the amount of carrier used in future drug delivery systems.

A man presented with frank haematuria and a grossly prolonged prothrombin time. He was later found to have taken an overdose of difenacoum — a 'superwarfarin' rodenticide. The diagnosis was confirmed by a serum concentration of difenacoum of 0.6 μg ml-1. Overdosage with superwarfarins is discussed and the need for prolonged treatment with vitamin K1 highlighted.

The effect of salbutamol on bronchoconstriction induced by inhaled sodium metabisulphite has been studied in 12 atopic subjects. Salbutamol (200 micrograms, 3.5 x 10(-7) M) and matched placebo were administered by identical metered dose inhaler 15 min before a dose-response to sodium metabisulphite (1.25-100 mg ml-1) was performed. Geometric mean provocative dose of metabisulphite causing a 35% fall in sGaw after placebo pretreatment was 12.8 [5.75-28.1, 95% Cl] mumol, and after salbutamol was 75.9 [46.5-126] mumol. Mean maximum fall in sGaw after placebo pre-treatment was 47.4 [41-53.9]%. At the same metabisulphite concentration mean maximum fall in sGaw after salbutamol was 2.9 [-8.2-14.1]%.

The concentration of plasma histamine may provide an index of mast cell activation (degranulation) and can be measured by a sensitive radioenzymatic assay based on its specific conversion to (3H)-methylhistamine in the presence of histamine-N-methyltransferase and (3H)-S-adenosyl-L-methionine. In this assay, the separation of excess (3H)-S-adenosyl-L-methionine from (3H)-methylhistamine requires several steps, for which a correction factors is necessary to maintain precision. In the present modification, duplicate 50-microliters aliquots of each plasma sample were incubated with histamine-N-methyltransferase and (3H)-S-adenosyl-L-methionine. A further aliquot, with an added standard of 200 ng/ml histamine, was incubated with histamine-N-methyl-transferase and (14C)-S-adenosyl-L-methionine. This standard was converted to (14C)-methylhistamine, and its recovery at the end of the assay corrected both for varying efficiency of methylation among plasma samples and for losses during the subsequent extraction and separation stages. The sensitivity of the assay was 25 pg/ml. The intra-assay and interassay coefficients of variation were 7.2% and 11.6%, respectively. In five asthmatics, antigen challenge caused a 28% fall in FEV1, and this was associated with a twofold to threefold rise in plasma histamine concentration. This assay may thus prove a useful method for assessing the role of mast cell release of mediators in vivo.

Non-adrenergic inhibitory nerves may have an important role in regulating airway calibre. A recently discovered peptide, peptide histidine valine, is a potent relaxer of airway smooth muscle in vitro and has been proposed as a possible neurotransmitter in this tissue. The cardiovascular and respiratory effects of graded infusions of this peptide (2.5-10 pmol kg-1 min-1) have been examined in six normal subjects in a placebo controlled, randomised double blind study. The mean (SEM) peak plasma concentration of peptide histidine valine during the highest infusion rate was 2392 (170) pmol/l, representing a 29 fold increase above the basal concentration. This was accompanied by flushing, a significant increase in heart rate of 28 (3.7) beats/min and skin temperature of 1.8 degrees (0.16 degrees) C, but no effect on systolic or diastolic blood pressure. Despite these high plasma concentrations of the peptide and the substantial tachycardia and increase in skin blood flow, there was no change in partial expiratory flow at 40% of vital capacity (Vp40) or in the airway response to inhaled histamine (geometric PD40 9.37 and 9.73 mumol during saline and peptide histidine valine infusion respectively). Although these findings provide no support for a physiological role of peptide histidine valine in controlling airway function in healthy subjects, important effects of locally released peptides in the vasoactive intestinal peptide family cannot be excluded.

Plasma histamine concentration in the circulation has been proposed as an index of mast cell degranulation occurring in vivo but there are problems with this approach in practice. Local elevations in plasma histamine occur in blood draining the site of antigen challenge in forearm skin. We have compared changes in plasma histamine concentration with time following intradermal injection of antigen, codeine or histamine to produce matched wheal and flare responses in 4 atopic subjects. Less histamine appears to be released after non-immunological challenge.

The intrahepatic kinetics of 111indium-labelled platelets have been studied using dynamic gamma camera scintigraphy immediately following injection. Platelets labelled in saline with 111In-oxine or 111In-acetylacetonate underwent rapidly reversible hepatic sequestration, indicating that they were "activated". Platelets labelled in plasma with 111In-tropolonate, however, did not display this phenomenon. On the assumption that plasma-labelled platelets display a normal initial bio-distribution, mean intrahepatic platelet transit time, as a factor of the transit time of 99m-Tc labelled red cells, was 1.45 +/- SE 0.12 (n = 6), implying the normal presence of a small intrahepatic platelet pool. Unlike the liver, transit through the spleen was not sensitive to the labelling medium; thus the mean intrasplenic transit time of plasma-labelled platelets was 9.3 +/- SE 0.7 min (n = 10), and of saline-labelled platelets 9.5 +/- SE 0.3 min (n = 8).

The effect of a prolonged warm-up period of exercise on subjects with exercise-induced asthma (EIA) has been studied. Seven asthmatic subjects with known EIA were exercised according to two different protocols on two separate days, which were randomized. On Day A, subjects performed a standard 6-min treadmill run (S1A), which increased heart rate to 98% predicted maximum, followed 45 min later by an identical run (S2A). Refractoriness was demonstrated on the second exercise test, with a mean maximal fall in FEV1 of 29 +/- 3.1% and a PEFR of 32 +/- 2.8% after S2A, compared with a mean maximal fall in FEV1 of 46 +/- 2.6% and a PEFR of 51 +/- 4.0% after S1A. On Day B, subjects performed a 30-min treadmill run at a lower gradient (W1B), followed 21 min later by another standard 6-min treadmill test (S2B). W1B was followed by significantly less EIA (mean maximal fall in FEV1 of 17 +/- 5.4% and a PEFR of 21 +/- 6.3%) than followed S1A. Nevertheless, when subjects subsequently performed a standard 6-min run (S2B), significant refractoriness to bronchoconstriction, comparable to that observed after S2A, developed, with a mean maximal fall in FEV1 of 26 +/- 3.6% and a PEFR of 27 +/- 2.3% (p less than 0.05). We conclude that a warm-up period of exercise can induce refractoriness to EIA without itself inducing marked bronchoconstriction.

Histamine was infused in six normal volunteers at rates of 16, 32, 64 and 96 ng/kg/min increasing at 5-min intervals followed by 128 ng/kg/min for 45 min. Heart rate increased, diastolic blood pressure decreased and skin temperature increased in a dose-dependent fashion. Mean heart rate increased by 15.6 +/- 5.7 beats/min, mean diastolic pressure fell by 8.8 +/- e.2 mmHg and mean skin temperature increased by 1.2 +/- 0.3 degrees C at the highest infusion rate. Mean plasma histamine rose from a basal level of 0.20 +/- 0.03 ng/ml to 1.97 +/- 0.25 ng/ml at the end of the highest infusion rate. The threshold infusion rate for physiological effects was 64-96 ng/kg/min corresponding to 0.77-0.97 ng/ml. Salivary flow was stimulated by 21% after 30 min at the highest dose infusion (P = 0.05). Plasma adrenaline increased 132% but plasma noradrenaline was unchanged. There was a linear decline in heart rate after terminating the histamine infusion with a half time of 82 sec. The half life of infused histamine in the plasma was 102 sec. The clearance of histamine from the plasma was 6.1 %/- 0.2 l/min or 83 ml/kg/min. These concentration effect relationships in normals throw doubt on some of the high endogenous plasma histamine values in the literature.

Prazosin, a potent and selective alpha-adrenergic antagonist, was given by inhalation to nine asthmatic subjects aged 25-48 years (six with positive skin tests). Prazosin 0.5 mg, salbutamol 1 mg, or placebo were given by nebuliser in randomised double-blind fashion on separate days. Although all subjects showed a significant increase in FEV1, vital capacity, and maximum expiratory flow at 70% of total lung capacity after salbutamol, there was no significant difference between prazosin and placebo. This suggests that alpha-adrenergic receptors are not important in the control of bronchial tone in asthma. The weak bronchodilatation ascribed to alpha-antagonists in previous studies could be explained by other pharmacological actions of the drugs used.

Plasma histamine concentration was measured in venous blood draining the site of antigen-induced wheal and flare responses in the forearm skin of seven atopic volunteers. Concentrations were measured using a double isotope radioenzymatic method. The mean +/- s.e. mean resting plasma concentration was 0.18 +/- 0.01 ng/ml. In all subjects an increase was detected in local plasma histamine concentration after intradermal antigen challenge. The peak histamine concentration occurred between 2 and 15 min after challenge, and represented an increase of three- to 20-fold above the resting concentration. Plasma histamine concentration remained significantly elevated for at least 60 min after challenge. A 30 min incubation at 37 degrees C of blood taken at the time of peak plasma concentration caused a fall in histamine concentration. This suggests that histamine release from basophils during the sampling procedure was not a significant problem. This method is less invasive than skin chamber or blister techniques for the demonstration of mediator release in cutaneous inflammation and allows a simultaneous assessment of tissue response.

We have explored in man the hypothesis that histamine released from dermal mast cells by neurotransmitters from afferent nerves contributes to vasodilatation of the axon reflex. The ability of substance P to release histamine from human skin in vivo, and the effects of a histamine H1-receptor antagonist on capsaicin-induced axon reflex flares were studied. Intradermal injections of substance P (50 pmol) produced a weal and flare response which was associated with increased histamine concentration in blood draining the site (mean plasma histamine concentration before injection 0.17 +/- 0.02 ng ml-1 (+/- s.e.mean), concentration one minute after injection 1.26 +/- 0.28 ng ml-1, n = 6). Terfenadine, an H1-receptor antagonist, had no effect on the flare response to intradermal injection of capsaicin at a dose which inhibited by more than 60% the flare response to exogenous histamine and to histamine released from dermal mast cells by substance P. Substance P releases histamine from human skin in vivo. However, whatever the nature of the neurotransmitter released from afferent nerves during the axon reflex, it does not produce vasodilatation through release of histamine from dermal mast cells. Histamine may still contribute to the flare by initiation of the reflex.

Cold urticaria is a rare condition characterized by abnormal wealing following exposure to cold. It has been suggested that lipid-derived mediators may be involved in the pathogenesis of this condition. We have investigated whether the inflammatory reaction in cold urticaria is associated with the release of cysteinyl-leukotrienes. Leukotriene E4 (LTE4; a stable metabolic product of LTC4 and LTD4) and histamine were measured in the blood draining the site of a cold-challenge in five patients with clinical histories of cold urticaria. Three of the patients showed a typical clinical response to the challenge, and this was associated with an increase in the concentration of LTE4 and histamine. No increase in LTE4 or histamine levels were observed following cold challenge in the non-responding individuals.