A randomized, comparative study of formoterol and terbutaline dry powder inhalers in the treatment of mild to moderate asthma exacerbations in the pediatric acute care setting

Background: Formoterol is a fast-acting, long-acting beta-agonist. Its on-demand use by outpatients has been beneficial in controlling asthma. Objective: To evaluate the efficacy of formoterol as rescue medication for pediatric asthma exacerbation. Methods: A randomized, double-blind study was conducted on parallel groups involving 79 pediatric patients (mean [SD] age, 9.92 [2.5] years) with mild to moderate asthma exacerbations. They were treated with up to 3 doses of formoterol aerolizer, 12 mu g, or terbutaline Turbuhaler, 0.5 mg (dry powder inhalers). Respiratory rate, clinical score, pulse oximetry, and spirometry were analyzed at baseline and 15 minutes after administration of each bronchodilator dose. All the patients received oral prednisolone, 1 mg/kg, at study entry, followed by a single daily dose for 4 days. Forty-one patients were treated with formoterol and 38 with terbutaline. The groups were comparable in age and in severity of asthma exacerbation. Results: Both treatments resulted in similar clinical and functional improvement; 37 patients (47%) required 1 bronchodilator dose. Increases of 19.5% and 1.5.3% occurred in forced expiratory volume in 1 second in the formoterol and terbutaline groups, respectively. Therapeutic failures occurred in 2 patients. No adverse effects were observed. At 1-week follow-up, patients were stable, with pulmonary function close to normal. Conclusion: Formoterol therapy was at least as effective as terbutaline therapy in children and adolescents with mild and moderate asthma exacerbations. Ann Allergy Asthma Immunol. 2009; 103:248-253.

Analysis of body posture in children with mild to moderate asthma

The mechanical alterations related to the excessive use of accessory respiratory muscles and the mouth breathing observed in children with asthma may lead to the development of alterations in head posture, shoulders, thoracic region and, consequently, in alterations of body posture. The purpose of this study was to assess body posture changes of children with asthma compared to a non-asthmatic control group matched for gender, age, weight, and height. Thirty children with asthma and 30 non-asthmatic children aged 7 to 12 years were enrolled in this study. Digital photographic records were obtained for analysis of the body posture of the children by computed photogrammetry. The intraclass correlation coefficient and Student`s t test (p < 0.05) were used for statistical analysis. There were no significant differences between groups for the angles analyzed, except for the knee flexor angle. These results demonstrate that children with asthma did not present postural alterations compared to non-asthmatic controls since the only angle for which there was a significant difference between groups showed weak reproducibility. The findings of this study do not support the notion that children with asthma present alterations in body posture.

Exhaled nitric oxide as a predictor of exacerbation in children with moderate-to-severe asthma: a prospective, 5-month study

Background: Inhaled corticosteroids (ICSs) are recommended as the first line of treatment in children with moderate-to-severe asthma. Exhaled nitric oxide (ENO) has been proposed as a clinically useful marker of control that might help identify patients in whom ICS dose may be safely reduced. Objective: To evaluate the ability of ENO to predict future asthma exacerbations in children with moderate-to-severe asthma undergoing ICS tapering. Methods: This is an observational study with no control group. ENO was measured biweekly for 14 weeks in 32 children with moderate-to-severe asthma who were undergoing ICS tapering. Clinical evaluations and spirometry were performed concomitantly, and families kept daily diaries to record symptoms between visits. We used generalized estimating equations to model the In (odds) of an asthma exacerbation in the subsequent 2-week interval as a function of ENO level at the start of the interval while adjusting for age, sex, asthma severity, and current medication use. Results: We were able to successfully lower ICS doses in 10 (56%) of the 18 children with moderate asthma and in 3 (21%) of the 14 children with severe asthma. In 83 of the 187 follow-up clinical evaluations, children were determined to have had an exacerbation during the preceding 2 weeks. ENO levels, whether expressed as a continuous variable or dichotomized, were not associated with future risk for exacerbations in either unadjusted or adjusted models. Conclusion: ENO was not a useful clinical predictor of future asthma exacerbations for children with moderate-to-severe asthma undergoing ICS tapering. Ann Allergy Asthma Immunol. 2009; 103:206-211.

Impacts of coexisting bronchial asthma on severe exacerbations in mild-to-moderate COPD : results from a national database

Acknowledgments The authors would like to thank Kyungjoo Kim for the confident statistical analyses in this work. This study was supported by a grant (2014P3300300) from the Korea Centers for Disease Control and Prevention. The abstract of this paper was presented at the Asian Pacific Society of Respirology 20th Congress as an oral presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in Respirology

Craniocervical posture and hyoid bone position in children with mild and moderate asthma and mouth breathing

Introduction The objective of the present study was to assess the craniocervical posture and the positioning of the hyoid bone in children with asthma who are mouth breathers compared to non-asthma controls. Methods The study was conducted on 56 children, 28 of them with mild (n = 15) and moderate (n = 13) asthma (14 girls aged 10 79 +/- 1 31 years and 14 boys aged 9 79 +/- 1.12 years), matched for sex, height, weight and age with 28 non-asthma children who are not mouth breathers The sample size was calculated considering a confidence interval of 95% and a prevalence of 4% of asthma in Latin America. Eighteen variables were analyzed in two radiographs (latero-lateral teleradiography and lateral cervical spine radiography), both obtained with the head in a natural position The independent t-test was used to compare means values and the chi-square test to compare percentage values (p < 0 05) Intraclass correlation coefficient (ICC) was used to verify reliability. Results. The Craniovertebral Angle (CVA) was found to be significantly smaller in asthma than in control children (106.38 +/- 766 vs. 111 21 +/- 7.40. p = 0 02) and the frequency of asthma children with an absent or inverted hyoid triangle was found to be significantly higher compared to non-asthma children (36% vs 7%, p = 0.0001). The values of the inclination angles of the superior cervical spine in relation to the horizontal plane were significantly higher in moderate than in mild asthma children (CVT/Hor 85 10 +/- 725 vs. 90 92 +/- 6.69, p = 0 04 and C1/Hor. 80 93 +/- 5.56 vs 85 00 +/- 4 20, p = 0 04) Conclusions These findings revealed that asthma children presented higher head extension and a higher frequency of changes in hyoid bone position compared to non-asthma children and that greater the asthma severity greater the extension of the upper cervical spine. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Comparative effectiveness of long term drug treatment strategies to prevent asthma exacerbations: network meta-analysis

Objective To determine the comparative effectiveness and safety of current maintenance strategies in preventing exacerbations of asthma. Design Systematic review and network meta-analysis using Bayesian statistics. Data sources Cochrane systematic reviews on chronic asthma, complemented by an updated search when appropriate. Eligibility criteria Trials of adults with asthma randomised to maintenance treatments of at least 24 weeks duration and that reported on asthma exacerbations in full text. Low dose inhaled corticosteroid treatment was the comparator strategy. The primary effectiveness outcome was the rate of severe exacerbations. The secondary outcome was the composite of moderate or severe exacerbations. The rate of withdrawal was analysed as a safety outcome. Results 64 trials with 59 622 patient years of follow-up comparing 15 strategies and placebo were included. For prevention of severe exacerbations, combined inhaled corticosteroids and long acting β agonists as maintenance and reliever treatment and combined inhaled corticosteroids and long acting β agonists in a fixed daily dose performed equally well and were ranked first for effectiveness. The rate ratios compared with low dose inhaled corticosteroids were 0.44 (95% credible interval 0.29 to 0.66) and 0.51 (0.35 to 0.77), respectively. Other combined strategies were not superior to inhaled corticosteroids and all single drug treatments were inferior to single low dose inhaled corticosteroids. Safety was best for conventional best (guideline based) practice and combined maintenance and reliever therapy. Conclusions Strategies with combined inhaled corticosteroids and long acting β agonists are most effective and safe in preventing severe exacerbations of asthma, although some heterogeneity was observed in this network meta-analysis of full text reports.

Can certain genotypes predispose to poor asthma control in children? A pharmacogenetic study of 9 candidate genes in children with difficult asthma

Objective - We tested the hypothesis that patients with difficult asthma have an increased frequency of certain genotypes that predispose them to asthma exacerbations and poor asthma control. Methods - A total of 180 Caucasian children with confirmed asthma diagnosis were selected from two phenotypic groups; difficult (n = 112) versus mild/moderate asthma (n = 68) groups. All patients were screened for 19 polymorphisms in 9 candidate genes to evaluate their association with difficult asthma. Key Results - The results indicated that LTA4H A-9188>G, TNFα G-308>A and IL-4Rα A1727>G polymorphisms were significantly associated with the development of difficult asthma in paediatric patients (p<0.001, p = 0.019 and p = 0.037, respectively). Haplotype analysis also revealed two haplotypes (ATA haplotype of IL-4Rα A1199>C, IL-4Rα T1570>C and IL-4Rα A1727>G and CA haplotype of TNFα C-863>A and TNFα G-308>A polymorphisms) which were significantly associated with difficult asthma in children (p = 0.04 and p = 0.018, respectively). Conclusions and Clinical Relevance - The study revealed multiple SNPs and haplotypes in LTA4H, TNFα and IL4-Rα genes which constitute risk factors for the development of difficult asthma in children. Of particular interest is the LTA4H A-9188>G polymorphism which has been reported, for the first time, to have strong association with severe asthma in children. Our results suggest that screening for patients with this genetic marker could help characterise the heterogeneity of responses to leukotriene-modifying medications and, hence, facilitate targeting these therapies to the subset of patients who are most likely to gain benefit.

Cardiovascular adaptive responses in rats submitted to moderate resistance training

The present study investigated the effects of 8 week of resistance training (RT) on hemodynamic and ventricular function on cardiac myosin ATPase activity, and on contractility of papillary muscles of rats. Groups: control (CO), electrically stimulated (ES), trained at 60% (TR 60%) and 75% of one repetition maximum (1RM) (TR 75%). Exercise protocol: 5 sets of 12 repetitions at 60 and 75% of 1RM, 5 times per week. The CO and ES groups had similar values for parameters analyzed (P > 0.05). Blood pressure (BP), heart rate (13%), left ventricle systolic pressure (LVSP 13%) decreased and cardiac myosin ATPase activity increased in the TR 75% group (90%, P < 0.05). The contractile performance of papillary muscles increased in trained rats (P < 0.05). Eight weeks of RT was associated with lowering of resting BP, heart rate and LVSP, improvements in contractility of the papillary muscle and an increase of cardiac myosin ATPase activity in rats.

Extracellular matrix components and regulators in the airway smooth muscle in asthma

There is an intimate relationship between the extracellular matrix (ECM) and smooth muscle cells within the airways. Few studies have comprehensively assessed the composition of different ECM components and its regulators within the airway smooth muscle (ASM) in asthma. With the aid of image analysis, the fractional areas of total collagen and elastic fibres were quantified within the ASM of 35 subjects with fatal asthma (FA) and compared with 10 nonfatal asthma (NFA) patients and 22 nonasthmatic control cases. Expression of collagen I and III, fibronectin, versican, matrix metalloproteinase (MMP)-1, -2, -9 and -12 and tissue inhibitor of metalloproteinase-1 and -2 was quantified within the ASM in 22 FA and 10 control cases. In the large airways of FA cases, the fractional area of elastic fibres within the ASM was increased compared with NFA and controls. Similarly, fibronectin, MMP-9 and MMP-12 were increased within the ASM in large airways of FA cases compared with controls. Elastic fibres were increased in small airways in FA only in comparison with NFA cases. There is altered extracellular matrix composition and a degradative environment within the airway smooth muscle in fatal asthma patients, which may have important consequences for the mechanical and synthetic functions of airway smooth muscle.

Inflammatory and functional effects of increasing asthma treatment with formoterol or double dose budesonide

Adding a long-acting beta(2)-agonist to inhaled corticosteroids (ICS) for asthma treatment is better than increasing ICS dose in improving clinical status, although there is no consensus about the impact of this regimen on inflammation. In this double-blind, randomized, parallel group study, asthmatics with moderate to severe disease used budesonide (400 mcg/day) for 5 weeks (run-in period); then they were randomized to use budesonide (800 mcg/day - BUD group) or budesonide plus formoterol (400 mcg and 24 mcg/day, respectively - FORMO group) for 9 weeks (treatment period). Home PEF measurements, symptom daily reporting, spirometry, sputum induction (for differential cell counts and sputum cell cultures), and hypertonic saline bronchial challenge test were performed before and after treatments. TNF-alpha, IL-4 and eotaxin-2 levels in the sputum and cell culture supernatants were determined. Morning and night PEF values increased in the FORMO group during the treatment period (p < 0.01), from 435 +/- 162 to 489 +/- 169 and 428 +/- 160 to 496 +/- 173 L/min, respectively. The rate of exacerbations in the FORMO group was lower than in the BUD group (p < 0.05). Neutrophil counts in sputum increased in both groups (p < 0.05) and leukocyte viability after 48 h-culture increased in the FORMO group (p < 0.05). No other parameter changed significantly in either group. This study showed that adding formoterol to budesonide improved home PEF and provided protection from exacerbations, although increase of leukocyte viability in cell culture may be a matter of concern and needs further investigation. (C) 2008 Elsevier Ltd. All rights reserved.

Antihypertensive effects exerted by enalapril in mild to moderate hypertension are not associated with changes in the circulating levels of nitric oxide-related markers

The antihypertensive effects of angiotensin-converting enzyme inhibitors (ACEi) are explained, at least in part, by enhanced bradykinin-dependent nitric oxide (NO) formation and decreased angiotensin II-induced oxidative stress and vasoconstriction. We examined for the first time whether treatment with enalapril increases the plasma levels of markers of NO formation and decreases oxidative stress in mild to moderate hypertensive patients. Eighteen untreated hypertensive patients were treated with enalapril 10 mg/day (n = 10) or 20 mg/day (n = 8) for 60 days. Eighteen normotensive healthy controls were followed for the same period. Venous blood samples were collected at baseline and after 30/60 days of treatment with enalapril. Plasma NOx (nitrites + nitrates) concentrations were determined by using the Griess reaction. Plasma nitrite and whole blood nitrite concentrations were determined by using an ozone-based chemiluminescence assay. Plasma thiobarbituric acid-reactive species (TBARS) and 8-isoprostane concentrations were determined by a fluorimetric method and by ELISA, respectively. Treatment with enalapril decreased blood pressure in hypertensive patients. However, we found no significant changes in plasma NOx, nitrite, whole blood nitrite, and in the levels of markers of oxidative stress in both normotensive controls and hypertensive patients treated with enalapril. Our data show that enalapril 10-20 mg/day does not affect the concentrations of relevant markers of NO formation or markers of oxidative stress in mild to moderately hypertensive subjects, despite satisfactory blood pressure control. Our findings do not rule out the possibility that ACEi may produce such effects in more severely hypertensive patients treated with higher doses of ACEi.

Brazilian multicenter study on efficacy and tolerability of trandolapril in mild-to-moderate essential arterial hypertension. EMBATHE substudy with ambulatory blood pressure monitoring

OBJECTIVE: A double-blind, placebo-controlled multicenter study involving 34 centers from different Brazilian regions was performed to evaluate the antihypertensive efficacy and tolerability of trandolapril, an angiotensin I converting enzyme inhibitor, in the treatment of mild-to-moderate systemic arterial hypertension. METHODS: Of 262 patients enrolled in this study, 127 were treated with trandolapril 2 mg/day for 8 consecutive weeks, and the remaining 135 patients received placebo for the same period of time. Reduction in blood pressure (BP) and the occurrence of adverse events during this period were evaluated in both groups. RESULTS: Significant reductions in both systolic and diastolic pressures were observed in patients treated with trandolapril when compared with those on placebo. Antihypertensive efficacy was achieved in 57.5% of the patients on trandolapril and in 42% of these normal values of BP were obtained. The efficacy of trandolapril was similar in all centers, regardless of the area of the country. In a subset of 30 patients who underwent ABPM, responders showed a significant hypotensive effect to trandolapril throughout the 24 hour day. The adverse event profile was similar in both trandolapril and placebo groups. CONCLUSION: Our results demonstrate, for the first time in a large group of hypertensive patients from different regions in Brazil, good efficacy and tolerability of trandolapril during treatment of mild-to-moderate essential systemic hypertension.

A multicenter, open-label study of the efficacy and safety of telmisartan in mild to moderate hypertensive patients

OBJECTIVE: To evaluate the efficacy and tolerability of telmisartan, given once a day to patients with mild to moderate hypertension, as well as to assess the 24-hour blood pressure profile with ABPM. METHODS: Initially, 163 patients over 18 were selected, regardless of sex, with blood pressure levels >140/90mmHg at visit 1, which was confirmed at visit 2. One hundred thirty-four patients completed the study. After a 4-week placebo run-in phase, telmisartan 40mg/daily was given for 6 weeks. In those patients whose blood pressure (BP) levels were lower than 140/90mmHg, the same dosage was kept for an additional period of 6 weeks. For those who had BP higher than 140/90mmHg, the dosage was increased to 80mg/daily. Sixty-two patients were included in a subgroup that underwent ABPM 3 different times during the study. RESULTS: In the overall group, blood pressure reduction ranged from 162.3±14.5/101.3±5.75 mmHg (baseline) to 147.3±20.1/90.8±10.9 mmHg (week 12) (p<0.05). Mean blood pressure decreases were 14.4mmHg for systolic BP and 10.3mmHg for diastolic BP, after 12 weeks of active treatment. A subanalysis showed that 47 (35%) patients took telmisartan 40mg throughout the study and 81 (65%) had the dosage increased to 80mg daily. Using ABPM, an 8-mmHg reduction in systolic BP as well as a 5-mmHg reduction in diastolic BP were observed, when compared with baseline values in the final 6 hours (18-24 hours after the last dose of study medication). CONCLUSION: Our results confirm that telmisartan given once a day is effective in reducing blood pressure levels in mild to moderate hypertensive patients. This reduction occurs in a sustained and gradual manner during a 24-hour period confirmed by ABPM.

Detection of incipient left ventricular hypertrophy in mild to moderate arterial hypertension with normal electrocardiogram and echocardiogram: a new use for signal-averaged electrocardiography

OBJECTIVE: To assess signal-averaged electrocardiogram (SAECG) for diagnosing incipient left ventricular hypertrophy (LVH). METHODS: A study with 115 individuals was carried out. The individuals were divided as follows: GI - 38 healthy individuals; GII - 47 individuals with mild to moderate hypertension and normal findings on echocardiogram and ECG; and GIII - 30 individuals with hypertension and documented LVH. The magnitude vector of the SAECG was analyzed with the high-pass cutoff frequency of 40 Hz through the bidirectional four-pole Butterworth high-pass digital filter. The mean quadratic root of the total QRS voltage (RMST) and the two-dimensional integral of the QRS area of the spectro-temporal map were analyzed between 0 and 30 Hz for the frequency domain (Int FD), and between 40 and 250 Hz for the time domain (Int TD). The electrocardiographic criterion for LVH was based on the Cornell Product. Left ventricular mass was calculated with the Devereux formula. RESULTS: All parameters analyzed increased from GI to GIII, except for Int FD (GII vs GIII) and RMST log (GII vs GIII). Int TD showed greater accuracy for detecting LVH with an appropriate cutoff > 8 (sensitivity of 55%, specificity of 81%). Positive values (> 8) were found in 56.5% of the G II patients and in 18.4% of the GI patients (p< 0.0005). CONCLUSION: SAECG can be used in the early diagnosis of LVH in hypertensive patients with normal ECG and echocardiogram.

Local transient myocardial liposomal gene transfer of inducible nitric oxide synthase does not aggravate myocardial function and fibrosis and leads to moderate neovascularization in chronic myocardial ischemia in pigs.

Microcirculation (2010) 17, 69-78. doi: 10.1111/j.1549-8719.2010.00002.x Abstract Background: This study was designed to explore the effect of transient inducible nitric oxide synthase (iNOS) overexpression via cationic liposome-mediated gene transfer on cardiac function, fibrosis, and microvascular perfusion in a porcine model of chronic ischemia. Methods and Results: Chronic myocardial ischemia was induced using a minimally invasive model in 23 landrace pigs. Upon demonstration of heart failure, 10 animals were treated with liposome-mediated iNOS-gene-transfer by local intramyocardial injection and 13 animals received a sham procedure to serve as control. The efficacy of this iNOS-gene-transfer was demonstrated for up to 7 days by reverse transcriptase-polymerase chain reaction in preliminary studies. Four weeks after iNOS transfer, magnetic resonance imaging showed no effect of iNOS overexpression on cardiac contractility at rest and during dobutamine stress (resting ejection fraction: control 27%, iNOS 26%; P = ns). Late enhancement, infarct size, and the amount of fibrosis were similar between groups. Although perfusion and perfusion reserve in response to adenosine and dobutamine were not significantly modified by iNOS-transfer, both vessel number and diameter were significantly increased in the ischemic area in the iNOS-treated group versus control (point score: control 15.3, iNOS 34.7; P < 0.05). Conclusions: Our findings demonstrate that transient iNOS overexpression does not aggravate cardiac dysfunction or postischemic fibrosis, while potentially contributing to neovascularization in the chronically ischemic heart.