Pulse oximeters to self monitor oxygen saturation levels as part of a personalised asthma action plan for people with asthma.

BACKGROUND: We became aware through talking with people with asthma that some are using pulse oximeters to monitor their own blood oxygen levels during an asthma attack. Pulse oximeters are marketed by some suppliers as essential equipment for the home medicine cabinet. We wanted to find out if reliable evidence is available on use of pulse oximeters to self monitor asthma exacerbations at home. We decided to include only trials that used pulse oximeters as part of a personalised asthma action plan because it is important that decisions are made on the basis of symptoms as well as oxygen saturation, and that patients have a clear protocol to follow when their asthma worsens. OBJECTIVES: To determine whether pulse oximeters used as part of a personalised asthma action plan for people with asthma are safer and more effective than a personalised asthma action plan alone. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR), which includes reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED) and PsycINFO, and by handsearching. We also searched ClinicalTrials.gov and the World Health Organization (WHO) trials portal. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs). Participants would have included adults, children or both with a diagnosis of asthma. We planned to include trials in which investigators compared participants who used pulse oximeters to monitor oxygen levels at home during an asthma exacerbation as part of a personalised asthma action plan (PAAP) versus those who used a PAAP without a pulse oximeter. We planned to include studies involving people receiving any treatment regimen provided that no medicine was included as part of the randomisation schedule. DATA COLLECTION AND ANALYSIS: We planned to use standard methods as recommended by The Cochrane Collaboration. MAIN RESULTS: We found no studies and no evidence to support or refute the use of home pulse oximetry in self management of asthma; therefore, we can make no recommendations about use of a pulse oximeter as part of a PAAP. AUTHORS' CONCLUSIONS: We found no reliable data to support or refute patient use of pulse oximeters to monitor oxygen saturation levels when experiencing an asthma attack. People should not use a pulse oximeter without seeking advice from a qualified healthcare professional.We identified no compelling rationale for home monitoring of oxygen levels in isolation for most people with asthma. Some people have a reduced perception of the severity of their own breathlessness when exposed to hypoxia. If trials on self monitoring of oxygen levels in the blood by pulse oximeter at home by people with asthma are conducted, the pulse oximeter must be given as part of a personalised asthma action plan.

Interventions for bronchiectasis: an overview of Cochrane systematic reviews.

BACKGROUND: Bronchiectasis is a chronic respiratory disease characterised by abnormal dilatation of the bronchi, and presents typically with a chronic productive cough (or chronic wet cough in children) and recurrent infective exacerbations. It significantly impacts daily activities and quality of life, and can lead to recurrent hospitalisations, severe lung function impairment, respiratory failure and even death. OBJECTIVES: To provide an overview of the efficacy and safety of interventions for adults and children with bronchiectasis from Cochrane reviews.To identify gaps in the evidence base that will inform recommendations for new research and reviews, and to summarise information on reported outcomes and make recommendations for the reporting of standard outcomes in future trials and reviews. METHODS: We included Cochrane reviews of non-cystic fibrosis (CF) bronchiectasis. We searched the Cochrane Database of Systematic Reviews. The search is current to 11 February 2015. We also identified trials that were potentially eligible for, but not currently included in, published reviews to make recommendations for new Cochrane reviews. We assessed the quality of included reviews using the AMSTAR criteria. We presented an evidence synthesis of data from reviews alongside an evidence map of clinical trials and guideline data. The primary outcomes were exacerbations, lung function and quality of life. MAIN RESULTS: We included 21 reviews but extracted data from, and rated the quality of, only nine reviews that reported results for people with bronchiectasis alone. Of the reviews with no usable data, two reviews included studies with mixed clinical populations where data were not reported separately for people with bronchiectasis and 10 reviews did not contain any trials. Of the 40 studies included across the nine reviews, three (number of participants nine to 34) included children. The studies ranged from single session to year-long studies. Each review included from one to 11 trials and 28 (70%) trials in the overview included 40 or fewer participants. The total number of participants included in reviews ranged from 40 to 1040. The age range of adult participants was from 36 to 73 years and children ranged from six to 16 years. The proportion of male participants ranged from 21% to 72%. Where reported, mean baseline forced expiratory volume in one second (FEV1) ranged from 1.17 L to 1.66 L and from 47% to 88% predicted. Most of the reviews had search dates older than two years.We have summarised the published evidence as outlined in Cochrane reviews, but it was not possible to draw definitive conclusions. There was inconclusive evidence on the use of long-term antibiotics and nebulised hypertonic saline for reducing exacerbation frequency and evidence that human deoxyribonuclease (RhDNase) increases exacerbation frequency. Improvements in lung function were reported for inhaled corticosteroids (ICS) though this was small and not clinically relevant. Evidence of benefit for hyperosmolar agents and mucolytics was inconclusive. There was limited evidence of improvements in quality of life with airway clearance techniques and physical therapy but evidence of benefit for hyperosmolar agents was inconclusive. Secondary outcomes were not clearly reported in all trials in the included reviews. Improvements in dyspnoea, wheeze and cough-free days were reported for small trials of ICS and LABA (long-acting beta2-agonsts)/ICS and cough reduction was also reported for a small bromhexine trial. Reduction in sputum production was reported for long-term antibiotics and airway clearance techniques but evidence of benefit for hyperosmolar agents was inconclusive.Adverse events were included as outcomes in seven reviews. The review of long-term (four weeks to one year) prophylactic courses of antibiotics reported significantly more cases of wheeze (Peto odd ratio (OR) 8.56, 95% confidence intervals (CI) 1.63 to 44.93), dyspnoea (12 versus three, P value = 0.01) and chest pain (seven versus zero, P value = 0.01) from the same trial (74 participants) but no differences in occurrence of diarrhoea, rash or number of withdrawals. In the review of mucolytics versus placebo, relevant outcomes were not reported for erdosteine comparisons and no significant adverse effects were reported for bromhexine, though adverse events were associated with RhDNase (OR 28.19, 95% CI 3.77 to 210.85, 1 study). Of the remaining five reviews, adverse events were not reported in the single trials included in the ICS review or the physical therapy review and the impact of adverse events in the single trial included in the inhaled LABA/ICS combination versus ICS review were unclear. The reviews of short-term courses of antibiotics and inhaled hyperosmolar agents reported no significant differences in occurrence of adverse events. Fewer admissions to hospital were reported for long-term antibiotics, but this outcome was not reported in all reviews. No reviews reported differences in mortality, but again this outcome was not included in all reviews.We did not explicitly include antibiotic resistance as an outcome in the review, but this was unclear in the Cochrane reviews and evidence from other trials should be considered.We rated all reviews as high quality (AMSTAR), though opportunities for improved reporting (e.g. summary of findings and GRADE evaluation of the evidence) were identified for inclusion in future updates of the reviews. However, the majority of trials were not high quality and confidence in the effects of treatments, therefore, requires additional evidence from larger and more methodologically robust trials. We evaluated the overall coverage of important topics in bronchiectasis by mapping the quality of the current evidence base against published guidelines and identifying high priority areas for new research on; use of short-course and long-term antibiotics, ICS and oral corticosteroids, inhaled hyperosmolars, mucolytics, and use of airway clearance techniques. AUTHORS' CONCLUSIONS: This overview clearly points to significant opportunities for further research aimed at improving outcomes for people with bronchiectasis. We have highlighted important endpoints for studies (particularly exacerbations, quality of life and lung function), and areas of clinical practice that are in most urgent need of evidence-based support (including long-term antibiotics, ICSs and mucolytics).As the evidence is confined to small trials of short duration, it is not currently possible to assess the balance between the benefits and potential harms of treatments for bronchiectasis.

Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma.

BACKGROUND: In acute asthma inhaled beta(2)-agonists are often administered by nebuliser to relieve bronchospasm, but some have argued that metered-dose inhalers with a holding chamber (spacer) can be equally effective. Nebulisers require a power source and need regular maintenance, and are more expensive in the community setting. OBJECTIVES: To assess the effects of holding chambers (spacers) compared to nebulisers for the delivery of beta(2)-agonists for acute asthma. SEARCH METHODS: We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies to identify additional trials. Date of last search: February 2013. SELECTION CRITERIA: Randomised trials in adults and children (from two years of age) with asthma, where spacer beta(2)-agonist delivery was compared with wet nebulisation. DATA COLLECTION AND ANALYSIS: Two review authors independently applied study inclusion criteria (one review author for the first version of the review), extracted the data and assessed risks of bias. Missing data were obtained from the authors or estimated. Results are reported with 95% confidence intervals (CIs). MAIN RESULTS: This review includes a total of 1897 children and 729 adults in 39 trials. Thirty-three trials were conducted in the emergency room and equivalent community settings, and six trials were on inpatients with acute asthma (207 children and 28 adults). The method of delivery of beta(2)-agonist did not show a significant difference in hospital admission rates. In adults, the risk ratio (RR) of admission for spacer versus nebuliser was 0.94 (95% CI 0.61 to 1.43). The risk ratio for children was 0.71 (95% CI 0.47 to 1.08, moderate quality evidence). In children, length of stay in the emergency department was significantly shorter when the spacer was used. The mean duration in the emergency department for children given nebulised treatment was 103 minutes, and for children given treatment via spacers 33 minutes less (95% CI -43 to -24 minutes, moderate quality evidence). Length of stay in the emergency department for adults was similar for the two delivery methods. Peak flow and forced expiratory volume were also similar for the two delivery methods. Pulse rate was lower for spacer in children, mean difference -5% baseline (95% CI -8% to -2%, moderate quality evidence), as was the risk of developing tremor (RR 0.64; 95% CI 0.44 to 0.95, moderate quality evidence). AUTHORS' CONCLUSIONS: Nebuliser delivery produced outcomes that were not significantly better than metered-dose inhalers delivered by spacer in adults or children, in trials where treatments were repeated and titrated to the response of the participant. Spacers may have some advantages compared to nebulisers for children with acute asthma.

Drug therapy for obstructive sleep apnoea in adults.

BACKGROUND: The treatment of choice for moderate to severe obstructive sleep apnoea (OSA) is continuous positive airways pressure (CPAP) applied via a mask during sleep. However, this is not tolerated by all individuals and its role in mild OSA is not proven. Drug therapy has been proposed as an alternative to CPAP in some patients with mild to moderate sleep apnoea and could be of value in patients intolerant of CPAP. A number of mechanisms have been proposed by which drugs could reduce the severity of OSA. These include an increase in tone in the upper airway dilator muscles, an increase in ventilatory drive, a reduction in the proportion of rapid eye movement (REM) sleep, an increase in cholinergic tone during sleep, an increase in arousal threshold, a reduction in airway resistance and a reduction in surface tension in the upper airway. OBJECTIVES: To determine the efficacy of drug therapies in the specific treatment of sleep apnoea. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials. Searches were current as of July 2012. SELECTION CRITERIA: Randomised, placebo controlled trials involving adult patients with confirmed OSA. We excluded trials if continuous positive airways pressure, mandibular devices or oxygen therapy were used. We excluded studies investigating treatment of associated conditions such as excessive sleepiness, hypertension, gastro-oesophageal reflux disease and obesity. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by The Cochrane Collaboration. MAIN RESULTS: Thirty trials of 25 drugs, involving 516 participants, contributed data to the review. Drugs had several different proposed modes of action and the results were grouped accordingly in the review. Each of the studies stated that the participants had OSA but diagnostic criteria were not always explicit and it was possible that some patients with central apnoeas may have been recruited.Acetazolamide, eszopiclone, naltrexone, nasal lubricant (phosphocholinamine) and physiostigmine were administered for one to two nights only. Donepezil in patients with and without Alzheimer's disease, fluticasone in patients with allergic rhinitis, combinations of ondansetrone and fluoxetine and paroxetine were trials of one to three months duration, however most of the studies were small and had methodological limitations. The overall quality of the available evidence was low.The primary outcomes for the systematic review were the apnoea hypopnoea index (AHI) and the level of sleepiness associated with OSA, estimated by the Epworth Sleepiness Scale (ESS). AHI was reported in 25 studies and of these 10 showed statistically significant reductions in AHI.Fluticasone in patients with allergic rhinitis was well tolerated and reduced the severity of sleep apnoea compared with placebo (AHI 23.3 versus 30.3; P < 0.05) and improved subjective daytime alertness. Excessive sleepiness was reported to be altered in four studies, however the only clinically and statistically significant change in ESS of -2.9 (SD 2.9; P = 0.04) along with a small but statistically significant reduction in AHI of -9.4 (SD 17.2; P = 0.03) was seen in patients without Alzheimer's disease receiving donepezil for one month. In 23 patients with mild to moderate Alzheimer's disease donepezil led to a significant reduction in AHI (donepezil 20 (SD 15) to 9.9 (SD 11.5) versus placebo 23.2 (SD 26.4) to 22.9 (SD 28.8); P = 0.035) after three months of treatment but no reduction in sleepiness was reported. High dose combined treatment with ondansetron 24 mg and fluoxetine 10 mg showed a 40.5% decrease in AHI from the baseline at treatment day 28. Paroxetine was shown to reduce AHI compared to placebo (-6.10 events/hour; 95% CI -11.00 to -1.20) but failed to improve daytime symptoms.Promising results from the preliminary mirtazapine study failed to be reproduced in the two more recent multicentre trials and, moreover, the use of mirtazapine was associated with significant weight gain and sleepiness. Few data were presented on the long-term tolerability of any of the compounds used. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend the use of drug therapy in the treatment of OSA. Small studies have reported positive effects of certain agents on short-term outcomes. Certain agents have been shown to reduce the AHI in largely unselected populations with OSA by between 24% and 45%. For donepezil and fluticasone, studies of longer duration with a larger population and better matching of groups are required to establish whether the change in AHI and impact on daytime symptoms are reproducible. Individual patients had more complete responses to particular drugs. It is possible that better matching of drugs to patients according to the dominant mechanism of their OSA will lead to better results and this also needs further study.

Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease.

BACKGROUND: Combination therapy (inhaled corticosteroids and long-acting beta2-agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments. OBJECTIVES: To compare the relative effects of inhaled combination therapy and tiotropium on markers of exacerbations, symptoms, quality of life, lung function, pneumonia and serious adverse events in patients with chronic obstructive pulmonary disease. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (November 2012) and reference lists of articles. We also contacted authors of the studies. SELECTION CRITERIA: We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta2-agonist against inhaled tiotropium bromide. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. We resolved discrepancies through discussion. MAIN RESULTS: One large, two-year trial (INSPIRE) and two smaller, shorter trials on a total of 1528 participants were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data were not collected for patients who withdrew, raising concerns about the reliability of data from this study.In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto odds ratio (OR) 0.55; 95% confidence interval (CI) 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was 11 times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all-cause hospital admissions in patients on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium when compared as either an odds ratio or a rate ratio (mean number of exacerbations per patient per year). Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (rate ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (rate ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than in those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew. AUTHORS' CONCLUSIONS: Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long-term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled long-acting beta2-agonist/steroid combination therapies with tiotropium are also required.

Home-based educational interventions for children with asthma.

BACKGROUND: While guidelines recommend that children with asthma should receive asthma education, it is not known if education delivered in the home is superior to usual care or the same education delivered elsewhere. The home setting allows educators to reach populations (such as the economically disadvantaged) that may experience barriers to care (such as lack of transportation) within a familiar environment. OBJECTIVES: To perform a systematic review on educational interventions for asthma delivered in the home to children, caregivers or both, and to determine the effects of such interventions on asthma-related health outcomes. We also planned to make the education interventions accessible to readers by summarising the content and components. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials, which includes the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearched respiratory journals and meeting abstracts. We also searched the Education Resources Information Center database (ERIC), reference lists of trials and review articles (last search January 2011). SELECTION CRITERIA: We included randomised controlled trials of asthma education delivered in the home to children, their caregivers or both. In the first comparison, eligible control groups were provided usual care or the same education delivered outside of the home. For the second comparison, control groups received a less intensive educational intervention delivered in the home. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials, assessed trial quality and extracted the data. We contacted study authors for additional information. We pooled dichotomous data with fixed-effect odds ratio and continuous data with mean difference (MD) using a fixed-effect where possible. MAIN RESULTS: A total of 12 studies involving 2342 children were included. Eleven out of 12 trials were conducted in North America, within urban or suburban settings involving vulnerable populations. The studies were overall of good methodological quality. They differed markedly in terms of age, severity of asthma, context and content of the educational intervention leading to substantial clinical heterogeneity. Due to this clinical heterogeneity, we did not pool results for our primary outcome, the number of patients with exacerbations requiring emergency department (ED) visit. The mean number of exacerbations requiring ED visits per person at six months was not significantly different between the home-based intervention and control groups (N = 2 studies; MD 0.04; 95% confidence interval (CI) -0.20 to 0.27). Only one trial contributed to our other primary outcome, exacerbations requiring a course of oral corticosteroids. Hospital admissions also demonstrated wide variation between trials with significant changes in some trials in both directions. Quality of life improved in both education and control groups over time.A table summarising some of the key components of the education programmes is included in the review. AUTHORS' CONCLUSIONS: We found inconsistent evidence for home-based asthma educational interventions compared to standard care, education delivered outside of the home or a less intensive educational intervention delivered at home. Although education remains a key component of managing asthma in children, advocated in numerous guidelines, this review does not contribute further information on the fundamental content and optimum setting for such educational interventions.

Formoterol versus short-acting beta-agonists as relief medication for adults and children with asthma.

BACKGROUND: Formoterol is a long-acting beta(2)-agonist but because it has a fast onset of action it can also be used as a relief medication. OBJECTIVES: To asses the efficacy and safety of formoterol as reliever therapy in comparison to short-acting beta(2)-agonists in adults and children with asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register and websites of clinical trial registers (for unpublished trial data), and we checked the Food and Drug Administration (FDA) submissions in relation to formoterol. The date of the most recent search was February 2010. SELECTION CRITERIA: Randomised, parallel-arm trials of at least 12 weeks duration in patients of any age and severity of asthma. Studies randomised patients to any dose of as-needed formoterol versus short-acting beta(2)-agonist. Concomitant use of inhaled corticosteroids or other maintenance medication was allowed, as long as this was not part of the randomised treatment regimen. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion in the review. Outcome data were extracted by one author and checked by the second author. We sought unpublished data on primary outcomes. MAIN RESULTS: This review includes eight studies conducted in 22,604 participants (mostly adults). Six studies compared formoterol as-needed to terbutaline whilst two studies compared formoterol with salbutamol as-needed. Background maintenance therapy varied across the trials. Asthma exacerbations and serious adverse events showed a direction of treatment effect favouring formoterol, of which one outcome reached statistical significance (exacerbations requiring a course of oral corticosteroids). In patients on short-acting beta(2)-agonists, 117 people out of 1000 had exacerbations requiring oral corticosteroids over 30 weeks, compared to 101 (95% CI 93 to 108) out of 1000 for patients on formoterol as-needed. In patients on maintenance inhaled corticosteroids there were also significantly fewer exacerbations requiring a course of oral corticosteroids on formoterol as-needed (Peto OR 0.75; 95% CI 0.62 to 0.91). There was one death per 1000 people on formoterol or on short-acting beta(2)-agonists. AUTHORS' CONCLUSIONS: In adults, formoterol was similar to short-acting beta(2)-agonists when used as a reliever, and showed a reduction in the number of exacerbations requiring a course of oral corticosteroids. Clinicians should weigh the relatively modest benefits of formoterol as-needed against the benefits of single inhaler therapy and the potential danger of long-term use of long-acting beta(2)-agonists in some patients. We did not find evidence to recommend changes to guidelines that suggest that long-acting beta(2)-agonists should be given only to patients already taking inhaled corticosteroids.There was insufficient information reported from children in the included trials to come to any conclusion on the safety or efficacy of formoterol as relief medication for children with asthma.

Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease.

BACKGROUND: Combination therapy (inhaled corticosteroids and long-acting beta(2)-agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments. OBJECTIVES: To assess the relative effects of inhaled combination therapy and tiotropium on patients with COPD. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials (March 2010) and reference lists of articles. We also contacted authors of the studies. SELECTION CRITERIA: We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta(2)-agonist against inhaled tiotropium bromide. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. Discrepancies were resolved through discussion. MAIN RESULTS: One large two year trial (INSPIRE) and two smaller, shorter trials (Dawber 2005; SCO40034) were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data was not collected for patients who withdrew, raising concerns about the reliability of data from this study.In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto OR 0.55; 95% CI 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was eleven times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all cause hospital admissions in patents on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium. Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (Rate Ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (Rate Ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew. AUTHORS' CONCLUSIONS: Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long-term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled LABA/steroid combination therapies with tiotropium are also required.

Caffeine for asthma.

BACKGROUND: Caffeine has a variety of pharmacological effects; it is a weak bronchodilator and it also reduces respiratory muscle fatigue. It is chemically related to the drug theophylline which is used to treat asthma. It has been suggested that caffeine may reduce asthma symptoms and interest has been expressed in its potential role as an asthma treatment. A number of studies have explored the effects of caffeine in asthma, this is the first review to systematically examine and summarise the evidence. OBJECTIVES: To assess the effects of caffeine on lung function and identify whether there is a need to control for caffeine consumption prior to either lung function or exhaled nitric oxide testing. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and the reference lists of articles (August 2009). We also contacted study authors. SELECTION CRITERIA: Randomised clinical trials of oral caffeine compared to placebo or coffee compared to decaffeinated coffee in adults with asthma. DATA COLLECTION AND ANALYSIS: Trial selection, quality assessment and data extraction were done independently by two reviewers. MAIN RESULTS: Seven trials involving a total of 75 people with mild to moderate asthma were included. The studies were all of cross-over design .Six trials involving 55 people showed that in comparison with placebo, caffeine, even at a 'low dose' (< 5mg/kg body weight), appears to improve lung function for up to two hours after consumption. Forced expiratory volume in one minute showed a small improvement up to two hours after caffeine ingestion (SMD 0.72; 95% CI 0.25 to 1.20), which translates into a 5% mean difference in FEV1. However in two studies the mean differences in FEV1 were 12% and 18% after caffeine. Mid-expiratory flow rates also showed a small improvement with caffeine and this was sustained up to four hours.One trial involving 20 people examined the effect of drinking coffee versus a decaffeinated variety on the exhaled nitric oxide levels in patients with asthma and concluded that there was no significant effect on this outcome. AUTHORS' CONCLUSIONS: Caffeine appears to improve airways function modestly, for up to four hours, in people with asthma . People may need to avoid caffeine for at least four hours prior to lung function testing, as caffeine ingestion could cause misinterpretation of the results. Drinking caffeinated coffee before taking exhaled nitric oxide measurements does not appear to affect the results of the test, but more studies are needed to confirm this.

Structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2.

Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).