Asthma-related hospitalizations after implementing SABA-free asthma management with a maintenance and anti-inflammatory reliever regimen.

Overreliance on short-acting ß2-agonists (SABA) has been a common feature of asthma management globally for at least 30 years. However, given the evidence against the long-term use of SABA, including potentially increased risk of exacerbations, emergency room visits, overall healthcare resource utilization, and mortality, the latest Global Initiative for Asthma report no longer recommends SABA only therapy. Since 2014, we implemented an ICS-containing reliever strategy at our asthma center at the G Baigorria Hospital in Argentina; we only administered budesonide/formoterol via a single inhaler device across the spectrum of asthma severity and completely eliminated the use of SABA therapy. In this article, we compare hospitalization data from our center, previously reported in the EAGLE study (when inhaled corticosteroids plus as-needed SABA was administered) for the years 1999 and 2004 with data from 2017 to 2018 (when budesonide/formoterol in a single inhaler device was administered as maintenance and/or anti-inflammatory reliever therapy [MART/AIR] without any SABA) from our center, to assess the impact of two distinct asthma management strategies on asthma-related hospitalizations. MART/AIR regimens in our SABA-free center reduced asthma hospitalizations from 9 (1999 and 2004) to 1 (2017 and 2018) (Fisher's exact test, p = 0.031; odds ratio = 0.11; 95% confidence interval [CI] = 0.013-0.98); the hospitalization rate was reduced by 92% (1.47% in 1999 and 2004 to 0.12% in 2017 and 2018). Our data provide preliminary real-world evidence that MART/AIR with budesonide/formoterol simultaneously with SABA elimination across asthma severities is an effective asthma management strategy for reducing asthma-related hospitalizations.

Position statement: asthma in Latin America. IS short-acting beta-2 agonist helping or compromising asthma management?

In Latin-America, with 603 million inhabitants, the average prevalence of asthma is estimated at 17%, but with wide fluctuations, ranging from 5% in some cities (Mexico) to 30% in Costa Rica. The risk of severe exacerbations seems to be higher in Latin America compared with other regions. A majority of patients uses daily quick-relief medication, with the belief that it is the most important treatment because of its rapid onset of action; without treating the underlying inflammation. Overuse of short-acting beta2 agonists (SABAs) is associated with increased risk of asthma deaths in a dose-response manner. Beta2 agonists increase the severity of asthma through enhanced bronchial hyperresponsiveness and reduced lung function. Also, it has been shown that overreliance on SABA delays recognition of a potentially life-threatening asthma attack. We believe that overreliance on SABA in asthma is also an important public health issue. The fact that SABA use in GINA is not supported by a randomized trial but by an anonymous paper; makes us guess that we use SABA just because we are used to do so. In 2019 GINA strategy introduces one of the most important changes in the management of Asthma in the past 30 years, highlighting anti-inflammatory reliever therapy. A combination of low dose ICS/fast action bronchodilator will not only treat symptoms, but more importantly the underlying inflammation, protecting patients from preventable asthma attacks. After 50 years of a SABA centric approach in asthma management, it is time to leave behind a treatment based just on the bronchodilation and tackle the inflammation.

Leptin does not enhance cell-mediated immune responses following mycobacterial antigen stimulation.

BACKGROUND: Tuberculosis (TB) is a infectious disease characterised by a profound immune-endocrine metabolic imbalance, including a diminution in leptin plasma levels. Leptin appears to be the link between nutritional status and the development of a protective immune response. OBJECTIVE: To examine the effects of leptin on the proliferation and production of interferon-gamma (IFN-γ) by peripheral blood mononuclear cells (PBMC) in TB patients and healthy controls stimulated with mycobacterial antigens with or without leptin. As macrophages are key cells in mycobacterial containment, the effect of leptin on the production of interleukin (IL) 1ß and IL-1Ra by the monocytic cell line THP-1 was also studied. RESULTS: Leptin diminished the proliferative capacity of PBMC on mycobacterial stimulation, and had no effect on IFN-γ production in terms of measurements in culture supernatants or intracytoplasmic analysis using flow cytometry. Real-time polymerase chain reaction studies of PBMC from TB patients revealed a preserved expression of leptin receptor. Furthermore, IL-1ß and IL-1Ra secretion by THP-1 cells was not modified by leptin treatment. CONCLUSION: The study results do not support the utility of treatment with leptin to correct immune imbalances due to TB.

Exhaled breath condensate pH in mechanically ventilated patients.

OBJECTIVES: In this prospective clinical trial we aimed to answer if spontaneous exhaled breath condensate (EBC) in the trap of the expiratory arm of the ventilator could replace EBC collected by coolant chamber standardized with Argon as an inert gas. Second, if EBC pH could predict ventilator associated pneumonia (VAP) and mortality. PATIENTS: We included 34 critically ill patients (males = 26), aged = 54.85 ± 19.86 (mean ± SD) yrs, that required mechanical ventilation due to non-pulmonary direct cause (APACHE II score = 23.58 ± 14.7; PaO(2)/FiO(2) = 240.00 ± 98.29). SETTING: ICU with 9 beds from a regional teaching hospital. INTERVENTION AND RESULTS: The patients were followed up until development of VAP, successful weaning or death. There were significant differences between mean EBC pH from the 4 procedures with the exception of spontaneous EBC de-aerated with Argon (n = 79; 6.74 ± 0.28) and coolant chamber deaerated with Argon (n = 79; 6.70 ± 0.36; p = NS by Tukey's Multiple Comparison Test). However, none of the procedures were extrapolated between each other according to Bland & Altman method. The mean EBC pH from the trap without Argon was 6.50 ± 0.28. From the total of 34 patients, 22 survived and were discharged and 12 patients died in the ICU. CONCLUSION: Spontaneous EBC pH could not be extrapolated to EBC pH from coolant chamber and it did not change in subjects who dead, neither subject with VAP in comparison with baseline data. The lack of other biomarker in EBC and the lack of a control group determinate the need for further studies in this setting.

Combined corticosteroid and long-acting beta-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease.

BACKGROUND: Long-acting beta-agonists and inhaled corticosteroids have both been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. Their co-administration in a combined inhaler may facilitate adherence to medication regimens, and improve efficacy. OBJECTIVES: To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations, compared to placebo, in the treatment of adults with chronic obstructive pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search is April 2007. SELECTION CRITERIA: Studies were included if they were randomised and double-blind. Studies could compare any combined inhaled corticosteroids and long-acting beta-agonist preparation with placebo. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. One author entered the data. MAIN RESULTS: Eleven studies met the inclusion criteria (6427 participants randomised). Two different combination preparations (fluticasone/salmeterol and budesonide/formoterol) were used. Study quality was good. Fluticasone/salmeterol and budesonide/formoterol both reduced the rate of exacerbations. Pooled analysis of both combination therapies indicated that exacerbations were less frequent when compared with placebo, Rate Ratio: 0.74 (95% CI 0.7 to 0.8). The clinical impact of this effect depends on the frequency of exacerbations experienced by patients. The patients included in these trials had on average 1-2 exacerbations per year which means that treatment with combination therapy would lead to a reduction of one exacerbation every two to four years in these individuals. There is an overall reduction in mortality, but this outcome is dominated by the results of TORCH and further studies on budesonide/formoterol are required. The three year number needed to treat to prevent one extra death is 36 (95% CI 21 to 258), using a baseline risk of 15.2% from the placebo arm of TORCH. Both treatments led to statistically significant improvement in health status measurements, although the clinical importance of the differences observed is open to interpretation. Symptoms and lung function assessments favoured combination treatments. There was an increase in the risk of pneumonia with combined inhalers. The three year number needed to treat for one extra case of pneumonia is 13 (95% CI 9 to 20), using a baseline risk of 12.3% from the placebo arm of TORCH. Fewer participants withdrew from studies assessing combined inhalers due to adverse events and lack of efficacy. AUTHORS' CONCLUSIONS: Compared with placebo, combination therapy led to a significant reduction of a quarter in exacerbation rates. There was a significant reduction in all-cause mortality with the addition of data from the TORCH trial. The increased risk of pneumonia is a concern, and better reporting of this outcome in future studies would be helpful. In order to draw firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, particularly in relation to the profile of adverse events and benefits in relation to different doses of inhaled corticosteroids.

Combined corticosteroid and long-acting beta-agonist in one inhaler versus inhaled steroids for chronic obstructive pulmonary disease.

BACKGROUND: Long-acting beta-agonists and inhaled corticosteroids have both been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens, and to improve efficacy. Two preparations are currently available, fluticasone/salmeterol (FPS) and budesonide/formoterol (BDF). OBJECTIVES: To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations, compared to inhaled corticosteroids, in the treatment of adults with chronic obstructive pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search is April 2007. SELECTION CRITERIA: Studies were included if they were randomised and double-blind. Studies compared combined inhaled corticosteroids and long-acting beta-agonist preparations with the inhaled corticosteroid component. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. The primary outcome were exacerbations, mortality and pneumonia. Health-related quality of life (measured by validated scales), lung function and side-effects were secondary outcomes. Dichotomous data were analysed as fixed effect odds ratios (OR), and continuous data as mean differences and 95% confidence intervals (CI). MAIN RESULTS: Seven studies of good methodological quality met the inclusion criteria randomising 5708 participants with predominantly poorly reversible, severe COPD. Exacerbation rates were significantly reduced with combination therapies (Rate ratio 0.91; 95% confidence interval 0.85 to 0.97, P = 0.0008). Data from two FPS studies indicated that exacerbations requiring oral steroids were reduced with combination therapy. Data from one large study suggest that there is no significant difference in the rate of hospitalisations. Mortality was also lower with combined treatment (odds ratio 0.77; 95% confidence interval 0.63 to 0.94). Quality of life, lung function and withdrawals due to lack of efficacy favoured combination treatment. Adverse event profiles were similar between the two treatments. No significant differences were found between FPS and BDP in the primary outcomes, but the confidence intervals for the BDP results were wide as smaller numbers of patients have been studied. AUTHORS' CONCLUSIONS: Combination ICS and LABA significantly reduces morbidity and mortality in COPD when compared with mono component steroid. Adverse events were not significantly different between treatments, although evidence from other sources indicates that inhaled corticosteroids are associated with increased risk of pneumonia. Assessment of BDF in larger, long-term trials is required. Dose response data would provide valuable evidence on whether efficacy and safety outcomes are affected by different steroid loads.

Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease.

BACKGROUND: The co-administration of inhaled corticosteroids and long-acting beta-agonists in a combined inhaler is intended to facilitate adherence to medication regimens, and to improve efficacy in COPD. In this review they are compared with mono component long-acting beta-agonists. OBJECTIVES: To assess the efficacy of combined inhaled corticosteroids and long-acting beta-agonists preparations with mono component long-acting beta-agonists in adults with chronic obstructive pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search is April 2007. SELECTION CRITERIA: Studies were included if they were randomised and double-blind. Studies could compare a combined inhaled corticosteroids and long-acting beta-agonist preparation with component long-acting beta-agonist preparation. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. The primary outcomes were exacerbations, mortality and pneumonia, with health-related quality of life (measured by validated scales), lung function and side-effects as secondary outcomes. Dichotomous data were analysed as fixed effect odds ratios (OR), and continuous data as mean differences and 95% confidence intervals (CI). Sensitivity analysis was performed by combining data with a random effects model. MAIN RESULTS: Ten studies of good methodological quality met the inclusion criteria, randomising 7598 participants with severe chronic obstructive pulmonary disease. Eight studies assessed fluticasone/salmeterol, and two studies budesonide/formoterol. The exacerbation rates with combined inhalers were reduced in comparison to long-acting beta-agonists alone (Rate Ratio 0.82, 95% CI 0.78 to 0.88). There was no significant difference in mortality between combined inhalers and long-acting beta-agonists alone. Pneumonia occurred more commonly with combined inhalers (OR 1.62; 95% CI 1.35 to 1.94). There was no significant difference in terms of hospitalisations, although the two studies contributing data to this outcome may have been drawn from differing populations. Combination was more effective than LABA in improving quality of life measured by the St George Respiratory Questionnaire, and the Chronic Respiratory Questionnaire, and predose and post dose FEV1. AUTHORS' CONCLUSIONS: Combination therapy was more effective than long-acting beta-agonists in reducing exacerbation rates, although the evidence for the effects on hospitalisations was mixed, and requires further exploration. No significant impact on mortality was found even with additional information from the TORCH trial. The superiority of combination inhalers should be viewed against the increased risk of side-effects, particularly pneumonia. Additional studies on BDF are required and more information would be useful of the relative benefits and adverse event rates with different doses of inhaled corticosteroids.

Breath-holding test in subjects with near-fatal asthma. A new index for dyspnea perception.

RATIONALE: Identification of asthmatic subjects with low perception of dyspnea (POD) that are at higher risk of hospitalization, near-fatal and fatal asthma could improve their management. OBJECTIVE: Create a simple procedure that facilitate the recognition of low POD. METHODS: We enrolled near fatal asthma (NFA) subjects and a wide spectrum of non-NFA subjects. Each subject was asked to stop breathing at end-expiration. Dyspnea was assesssed by a modified Borg scale. To design the new index, we combined the Borg score at the end of the voluntary breath-holding maneuver with the airway limitation. The equation was as follows: FEV(1)/FVC%/(breath-holding time in seconds/final Borg score minus basal Borg score). RESULTS: Eleven NFA subjects (4 females) aged 21-73yr and 55 non-NFA (14 severe, 18 moderate and 23 mild asthmatic subjects) completed the study. The threshold value of the index that could predict POD is <12. The mean (+/-sd) of the new index perception was significantly lower in NFA group (n=11; 5.21+/-3.59; vs. n=55; 13.67+/-11.08; P=0.006). This threshold value had 100% sensitivity and it best discriminated between mild and NFA groups. The negative likelihood ratio (when the index > or = 12) was zero. A result > or = 12 represented an almost null probability of poor POD. CONCLUSION: The breath-holding test is simple and rapid. Its negative likelihood ratio was zero. Accordingly, a test result of 12 or greater might exclude the probability of poor perception of dyspnea in subjects with stable asthma.

Combined corticosteroid and long acting beta-agonist in one inhaler for chronic obstructive pulmonary disease.

BACKGROUND: Long-acting beta-agonists and inhaled corticosteroids have both been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens, and to improve efficacy. OBJECTIVES: To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations, compared to placebo or the individual components, in the treatment of adults with chronic obstructive pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Airways Group chronic obstructive pulmonary disease (COPD) trials register. Date of last search April 2004. SELECTION CRITERIA: Studies were included if they were randomised and double-blind. Studies could compare a combined inhaled corticosteroids and long-acting beta-agonist preparation with either component preparation or placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. The primary outcome was exacerbations. MAIN RESULTS: Six randomised trials with 4118 participants were included. Two different combination preparations (fluticasone/salmeterol and budesonide/formoterol) were used. Combination treatment was more effective than placebo for mean exacerbation rates, quality of life and lung function. No trials were found comparing the combination of drugs in a single inhaler with the same drugs both given in separate inhalers. Exacerbations: Fluticasone/salmeterol did not significantly reduce exacerbations compared with either of its component treatments in one large study. There was no significant difference when budesonide/formoterol was compared with budesonide. Budesonide/formoterol was more effective than formoterol in reducing exacerbations (Rate ratio: 0.78 [0.68 to 0.90], two studies). A pooled analysis of both combination therapies indicated that exacerbations were less frequent when compared with either placebo or long-acting beta-agonist (versus placebo Rate ratio: 0.76 [0.68, 0.84], three studies, versus beta-agonist, Rate ratio: 0.85 [0.77, 0.95], three studies), but not when compared with steroid. The clinical impact of this effect depends on the frequency of exacerbations experienced by patients. One full exacerbation was prevented for every two to four years of treatment in the type of patients included in the trials. Quality of Life: There were conflicting findings in quality of life and symptoms when fluticasone/salmeterol was compared with inhaled steroids alone (three studies). There was no significant difference between fluticasone/salmeterol and long-acting beta-agonist in quality of life scores (three studies). Budesonide/formoterol improved symptoms when compared with budesonide but not with formoterol. There were conflicting findings in quality of life scores when budesonide/formoterol was compared with component inhaled corticosteroid or beta-agonist. These may be accounted for by different study design. Lung Function: Treatment with either combination led to small, significant differences in lung function compared with component steroid medication. Fluticasone/salmeterol led to small improvements in FEV1 compared with salmeterol, but budesonide/formoterol treatment did not increase FEV1 significantly when compared with formoterol. REVIEWERS' CONCLUSIONS: Compared with placebo, combination therapy led to clinically meaningful differences in quality of life, symptoms and exacerbations. However, there were conflicting results when the different combination therapies were compared with the mono-components alone. In order to draw firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, including the assessment of the comparative effects with separate administration of the two drugs in double-dummy trials.

Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease.

BACKGROUND: Long-acting beta-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. However, they have only been available until recently via separate administration. They have been developed in order to facilitate adherence to medication regimens, and to improve efficacy. OBJECTIVES: To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations in the treatment of adults with chronic obstructive pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Airways Group chronic obstructive pulmonary disease (COPD) trials register (March 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2003), LILACS (all years to March 2003) and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: Studies were included if they were randomised, with adequate blinding procedures in place. Studies could compare a combined inhaled corticosteroids and long-acting beta-agonist preparation with either component preparation or placebo. Studies comparing different members of each class of combined therapies were included DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Four randomised trials with 2986 participants were included. Two different combination preparations (fluticasone/salmeterol and budesonide/formoterol) were studied in the trials. No meta-analysis on clinical outcomes was possible due to different outcome assessment across studies. All studies demonstrated a reduction in exacerbation rates versus placebo. Budesonide/formoterol was more effective than formoterol in reducing exacerbations in one study from 1.84 to 1.42 exacerbations per year. Fluticasone/salmeterol did not significantly reduce exacerbations compared with either of its component treatments. Fluticasone/salmeterol led to better quality of life compared with placebo (two studies), although there were conflicting results when compared with inhaled corticosteroid alone (two studies). There was no significant difference between fluticasone/salmeterol and long-acting beta-agonist (two studies). Budesonide/formoterol led to statistically significant differences in quality of life compared with placebo, but not when compared with component inhaled corticosteroid or beta-agonist (one study). REVIEWER'S CONCLUSIONS: For the primary outcome of exacerbations, budesonide/formoterol had a modest advantage over a component medication, formoterol, in a single trial, but fluticasone/salmeterol did not result in a significant reduction in exacerbations compared to either of its components. The combination of steroids and long-acting beta-agonist in one inhaler was effective in improving symptoms compared with placebo and on certain clinical outcomes compared with one of the individual components alone. In order to draw firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, including the assessment of the comparative effects with separate administration of the two drugs in double-dummy trials.

[Effect of ipratropium bromide on histamine-induced bronchoconstriction in subjects with chronic airway obstruction]. / Efecto del bromuro de ipratropio sobre la broncoconstricción por histamina en sujetos con obstrucción crónica al flujo aéreo.

Ipratropium bromide (IB), a quaternary derivative of atropine has been extensively recommended as the first bronchodilator to be tried in chronic obstructive pulmonary disease (COPD). Despite the large information concerning IB use, a controversy still persists about the lack of non bronchodilator effects (preventive) of inhaled IB. Therefore, the purpose was: to study the effects of IB (80 micrograms) on histamine-induced bronchoconstriction in moderate airway obstruction due to COPD. From outpatient clinic 9 men aged (mean +/- SEM) 57.9 +/- 2.4 yr with smoking history of 54.6 +/- 5.1 pack-yrs and a mean FEV1 = 1.36 +/- 0.08 liters (47.2 +/- 3.8% predicted) were enrolled to participate in this randomized placebo-controlled double blind cross-over study. Each subject attended on 3 occasions (first visit was control day; logPC20 = -0.54 +/- 0.24 mg/ml; geometric mean [MG] = 0.27 mg/ml) for histamine challenge tests using the tidal breathing method after either 4 puffs of IB or placebo aerosol. IB significantly increased baseline FEV1. A correlation between baseline obstruction (FEV1; FEV1/FVC) and bronchodilation with airway hyperreactivity (logPC20) could not be demonstrated. The major finding was that IB attenuated the histamine-induced bronchoconstriction (logPC20 = -0.15 +/- 0.17 mg/ml; GM = 0.70 mg/ml) in comparison with placebo (logPC20 = -0.76 +/- 0.22 mg/ml; GM = 0.17 mg/ml; p = 0.018; doubling doses: IB = 2.02 +/- 0.68 vs placebo = -0.62 +/- 0.79; p = 0.024). The lack of correlation between bronchodilator response to IB and the shift in logPC20 might indicate an intrinsic protective role of IB against histamine. Both IB and fenoterol completely resolved the final fall in FEV1 after ending the histamine challenge test. In conclusion, IB diminished histamine-induced bronchoconstriction in these subjects with moderate COPD.

Efecto del bromuro de ipratropio sobre la broncoconstricción por histamina en sujetos con obstrucción crónica al flujo aéreo. / [Effect of ipratropium bromide on histamine-induced bronchoconstriction in subjects with chronic airway obstruction]

Ipratropium bromide (IB), a quaternary derivative of atropine has been extensively recommended as the first bronchodilator to be tried in chronic obstructive pulmonary disease (COPD). Despite the large information concerning IB use, a controversy still persists about the lack of non bronchodilator effects (preventive) of inhaled IB. Therefore, the purpose was: to study the effects of IB (80 micrograms) on histamine-induced bronchoconstriction in moderate airway obstruction due to COPD. From outpatient clinic 9 men aged (mean +/- SEM) 57.9 +/- 2.4 yr with smoking history of 54.6 +/- 5.1 pack-yrs and a mean FEV1 = 1.36 +/- 0.08 liters (47.2 +/- 3.8

predicted) were enrolled to participate in this randomized placebo-controlled double blind cross-over study. Each subject attended on 3 occasions (first visit was control day; logPC20 = -0.54 +/- 0.24 mg/ml; geometric mean [MG] = 0.27 mg/ml) for histamine challenge tests using the tidal breathing method after either 4 puffs of IB or placebo aerosol. IB significantly increased baseline FEV1. A correlation between baseline obstruction (FEV1; FEV1/FVC) and bronchodilation with airway hyperreactivity (logPC20) could not be demonstrated. The major finding was that IB attenuated the histamine-induced bronchoconstriction (logPC20 = -0.15 +/- 0.17 mg/ml; GM = 0.70 mg/ml) in comparison with placebo (logPC20 = -0.76 +/- 0.22 mg/ml; GM = 0.17 mg/ml; p = 0.018; doubling doses: IB = 2.02 +/- 0.68 vs placebo = -0.62 +/- 0.79; p = 0.024). The lack of correlation between bronchodilator response to IB and the shift in logPC20 might indicate an intrinsic protective role of IB against histamine. Both IB and fenoterol completely resolved the final fall in FEV1 after ending the histamine challenge test. In conclusion, IB diminished histamine-induced bronchoconstriction in these subjects with moderate COPD.

Magnesium sulfate as a vehicle for nebulized salbutamol in acute asthma.

PURPOSE: Magnesium sulfate is thought to be an effective bronchodilator when administered intravenously to patients with acute severe asthma, and it can be safely administered via inhalation to patients with stable asthma. Our goal was to determine if isotonic magnesium sulfate could be used as a vehicle for nebulized salbutamol for patients with acute asthma. METHODS: We enrolled 35 patients with acute asthma in a randomized, double-blind, controlled trial. After measurement of peak expiratory flow, patients received 2.5 mg salbutamol plus either 3 mL normal saline solution (n = 16) or isotonic magnesium sulfate (n = 19) through a jet nebulizer. Peak flow was reassessed 10 and 20 minutes after treatment. RESULTS: Peak flow at baseline was similar in the two groups. Ten minutes after baseline, the mean (+/- SD) percentage increase in peak flow was greater in the magnesium sulfate-salbutamol group (61% +/- 45%) than in the normal saline-salbutamol group (31% +/- 28%; difference = 30%; 95% confidence interval [CI] for the difference: 3% to 56%; P = 0.03). At 20 minutes, the percentage increase in peak flow was 57% greater in the magnesium sulfate group (95% CI: 4% to 110%, P = 0.04). There was a significant inverse correlation between baseline peak flow (percent of predicted) and the percentage increase in peak flow at 20 minutes in the magnesium sulfate group (r = -0.82, P <0.0001), but not in the saline group (r = -0.12, P = 0.67). CONCLUSION: In patients with acute asthma, isotonic magnesium sulfate, as a vehicle for nebulized salbutamol, increased the peak flow response to treatment in comparison with salbutamol plus normal saline.

Effect of inhaled furosemide in acute asthma.

We assessed the acute bronchodilator effect of nebulized furosemide when added to conventional therapy of acute emergency department (ED) asthma. Using a double-blind design, 42 patients with acute asthma were randomized to receive 2.5 mg nebulized salbutamol and either 40 mg of nebulized furosemide or saline solution. We recorded clinical variables (respiratory rate, heart rate, and pulsus paradoxus) and peak expiratory flow rates (PEFR) before and 15 and 30 min after therapy. We found no significant difference in PEFR between salbutamol/furosemide and salbutamol/saline-treated patients 15 and 30 min following inhalation. Other endpoints were equally unaffected. However, when we examined separately those patients whose exacerbations were of relative short duration (< 8 hr), PEFR improved significantly more in the furosemide-treated group. At 15 min, PEFR increased by 82 +/- 48% in the furosemide group compared to 35 +/- 40% in the control group (p = 0.03), an effect that was also evident at 30 min when PEFR had increased by 113 +/- 49% in the furosemide group versus 61 +/- 35% in the control group (p = 0.014). Respiratory rate, heart rate, and pulsus paradoxus improved with no differences between the groups. The beneficial effect of furosemide was not evident in patients who reported more prolonged duration (> 8 hr) of asthmatic symptoms. The response to furosemide appeared to be unrelated to concomitant ED therapy with corticosteroids, to baseline pulmonary function, or to patient demographic variables. We conclude that furosemide may offer additive bronchodilator benefits in acute naturally occurring asthma of relative short duration.

Galparan induces in vivo acetylcholine release in the frontal cortex.

The chimeric peptide galparan (galanin(1-13)-mastoparan) induced the in vivo release of acetylcholine in the frontal cortex of rats when injected intracerebroventricularly, i.c.v. The ACh-releasing effects of galparan are reversible, dose-dependent, and not exerted at galanin receptors or at sites where mastoparan acts. Pertussis toxin pretreatment (i.c.v.) of the rats for 96 h prior to injection of galparan or of mastoparan completely prevented the ACh-releasing effects of both galparan and mastoparan. It appears that galparan acts at a novel site in the release of ACh in the cerebral cortex in vivo.

Effect of inhaled magnesium sulfate on sodium metabisulfite-induced bronchoconstriction in asthma.

BACKGROUND: Inhaled magnesium (Mg) seemed to have a mild protective (nonbronchodilator) effect against histamine and methacholine. Inhaled sodium metabisulfite (MBS) causes bronchoconstriction in asthma through indirect mechanisms that involve sensory nerve stimulation, and it is extensively used to study airway hyperresponsiveness. We designed this double-blind, randomized, crossover, and placebo-controlled study to test the effect of nebulized Mg sulfate against indirect challenge with MBS. METHODS: Ten asthmatic subjects (three male) aged 38.8 (3.29, SEM) years came on three occasions to perform MBS challenges 5 min after inhalation of either normal saline solution as placebo or Mg sulfate (4 mL; 286 mOsm). Doubling increasing concentrations of MBS were administered by continuous nebulization at tidal breathing during 1 min starting at 0.3 to 80 mg/mL until a >20% fall in FEV1 (PC20) from post saline solution baseline value was achieved. PC20 values were logarithmically transformed before analysis. RESULTS: The mean baseline FEV1 at control day was 2.52 (0.14) L and 88.46 (4.28) percentage predicted, while the geometric mean MBS PC20 was 1.95 (1.38, geometric SEM) mg/mL. After placebo, the geometric mean PC20 was 2.26 (1.26) mg/mL. Inhaled Mg increased significantly the PC20 to 5.06 (1.52) mg/mL; p<0.05. Mg diminished the bronchoconstrictor response to MBS by 1.3 doubling doses (p=0.08). CONCLUSIONS: Inhaled Mg attenuates MBS-induced bronchoconstriction in these asthmatic subjects. This new feature of Mg, even modest in magnitude, emphasizes the necessity of studying the potential role of this cation in modulating airway response.

The cerebral cortex and parafascicular thalamic nucleus facilitate in vivo acetylcholine release in the rat striatum through distinct glutamate receptor subtypes.

Electrical stimulation (ten pulses of 0.5 ms, 10 V applied over 10 s at 10 Hz, 140 microA) delivered bilaterally to the prefrontal cortex or the parafascicular thalamic nucleus of freely moving rats facilitated acetylcholine release in dorsal striata, assessed by trans-striatal microdialysis. The facilitatory effects were blocked by coperfusion with 5 microM tetrodotoxin, suggesting that the release was of neuronal origin. The response of the striatal cholinergic neurons to prefrontal cortical stimulation was short-lived and required a longer period of stimulation (20 min) that the response to thalamic stimulation (4 min) to reach maximal effect. The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate glutamatergic receptor antagonist 6,7-dinitroquinoxaline-2,3-dione [DNQX; 12 nmol per side, intracerebroventricularly (i.c.v.)] and the AMPA antagonist 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (NBQX; 12 nmol per side, i.c.v. or 12.8 microM infused into the striatum), but not the NMDA-type receptor antagonist MK-801 (0.2 mg/kg, i.p.), abolished the facilitatory effect on striatal acetylcholine release evoked by stimulation of the prefrontal cortex. By contrast, DNQX or NBQX did not prevent the increase in striatal acetylcholine release evoked by parafascicular nucleus stimulation, but MK-801, in accordance with previous results, did so. MK-801 by itself lowered striatal acetylcholine output while DNQX and NBQX did not. The results provide in vivo evidence that the cerebral cortex facilitates cholinergic activity in the dorsal striatum apparently through the non-tonic activation of AMPA-type glutamatergic receptors while the parafascicular nucleus does this through tonic activation of NMDA receptors. Both glutamate receptor types are probably located in the striatum. The overall results suggest that the two pathways operate independently to regulate striatal cholinergic activity through distinct mechanisms.

Endogenous serotonin facilitates in vivo acetylcholine release in rat frontal cortex through 5-HT 1B receptors.

We characterized the role of endogenous serotonin (5-HT) in regulating in vivo acetylcholine (ACh) output in frontal cortex of freely moving rats using the microdialysis technique. Systemic (0.63, 1.25 and 2.5 mg/kg, i.p.) or local (20 and 40 microM, reverse dialysis) administration of the 5-HT releaser and uptake inhibitor, d-norfenfluramine, dose-dependently enhanced frontal cortex ACh output. The d-norfenfluramine-induced increase in cortical ACh release was tetrodotoxin sensitive and completely prevented by a 7-day chemical degeneration of the serotonergic afferents to the frontal cortex. Investigating the 5-HT receptors that might mediate the d-norfenfluramine cholinergic effect, we found that the 5-HT4 (GR 125487) and 5-HT2A/2C (ritanserin) receptor antagonists, at doses effective in other in vivo tests, did not prevent the increase in cortical ACh output induced by the maximal effective does of d-norfenfluramine. However, the 5-HT1A/1B receptor antagonists (-)-pindolol (8 mg/kg, s.c.) or (-)-propanolol (8.8 mg/kg, i.p.) antagonized the increasing effect of d-norfenfluramine although the selective 5-HT1A receptor antagonist WAY-100635 (1 and 2 mg/kg, s.c.) did not. In accordance with an involvement of the 5-HT1B receptor in the ACh facilitation induced by d-norfenfluramine is the finding that the selective 5-HT1B agonist, CP-93,129, given locally (2, 4 and 8 micrograms/side) does-dependently raised cortical ACh release. In conclusion, the overall regulatory control exerted by endogenous 5-HT in vivo is to facilitate frontal cortex ACh release through 5-HT1B receptors located in the frontal cortex. The 5-HT1B receptors may act indirectly to facilitate ACh release probably by inhibiting cortical inhibitory inputs onto the cholinergic neurons.