Bronchial asthma is recognized as a highly prevalent health problem in the developed and developing world with significant social and economic consequences. Increased asthma severity is not only associated with enhanced recurrent hospitalization and mortality but also with higher social costs. The pathogenetic background of allergic-atopic bronchial asthma is characterized by airway inflammation with infiltration of several cells (mast cells, basophils, eosinophils, monocytes, and T-helper (Th)2 lymphocytes). However, in atopic asthma the trigger factors for acute attacks and chronic worsening of bronchial inflammation are aeroallergens released by pollens, dermatophagoides, and pets, which are able to induce an immune response by interaction with IgE antibodies. Currently anti-inflammatory treatments are effective for most asthma patients, but there are asthmatic subjects whose disease is not completely controlled by inhaled or systemic corticosteroids and who account for a significant portion of the healthcare costs of asthma. A novel therapeutic approach to asthma and other allergic respiratory diseases involves interference in the action of IgE, and this antibody has been viewed as a target for novel immunological drug development in asthma. Omalizumab is a humanized recombinant monoclonal anti-IgE antibody approved for treatment of moderate to severe IgE-mediated (allergic) asthma. This non-anaphylactogenic anti-IgE antibody inhibits IgE functions, blocking free serum IgE and inhibiting their binding to cellular receptors. By reducing serum IgE levels and IgE receptor expression on inflammatory cells in the context of allergic cascade, omalizumab represents a new class of mast cells stabilizing drugs; it is a novel approach to the treatment of atopic asthma. Omalizumab therapy is well tolerated and significantly improves symptoms and disease control, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids. Moreover, omalizumab improves quality of life of patients with severe persistent allergic asthma which is inadequately controlled by currently available asthma medications. In conclusion omalizumab may fulfil an important need in patients with moderate to severe asthma.
airway hyper-reactivity; asthma; allergic respiratory diseases; atopic respiratory diseases; anti-IgE therapy; hypersensitivity; monoclonal anti-IgE antibody; omalizumab
BACKGROUND: The allergen-induced late asthmatic reaction (LAR) is associated with mucosal inflammation involving several cell types including activated T lymphocytes and eosinophils. In contrast, the early asthmatic reaction (EAR) is considered to results from rapid allergen-induced release of bronchoconstrictor mediators from IgE sensitised mast cells. Cyclosporin A has efficacy in chronic severe corticosteroid-dependent asthma and is believed to act principally by inhibiting cytokine mRNA transcription in T lymphocytes. However, it has effects on other cell types in vitro, including the inhibition of exocytosis/degranulation events in mast cells. It was therefore hypothesised that cyclosporin A would attenuate both the EAR and LAR in subjects with mild asthma. METHODS: Twelve sensitised atopic asthmatic subjects with documented dual asthmatic responses were studied in a double blind, placebo controlled, crossover trial. On two separate study visits subjects received two oral doses of either cyclosporin A or matched placebo before inhaled allergen challenges. The forced expiratory volume in one second (FEV1) was measured half hourly for eight hours and blood eosinophil counts were analysed three, six, and 24 hours after the challenge. Treatment effects on blood eosinophil counts as well as the EAR and LAR, respectively defined as the areas under the curve (AUC) of FEV1 changes from baseline between 0-1 and 4-8 hours after challenge, were compared by non-parametric crossover analysis. RESULTS: Cyclosporin A reduced both the LAR (median AUC -41.9 1.h (interquartile range -82.7 to -12.4) for cyclosporin A and -84.5 1.h (-248.9 to -39.1) for placebo; p = 0.007) and the late increase in blood eosinophils (median 0.2 x 10(9)/1 (0.15 to 0.4) for cyclosporin A and 0.4 x 10(9)/1 (0.25 to 0.55) for placebo; p = 0.024) but had no effect on the EAR. The reduction of the LAR by cyclosporin A correlated significantly with prechallenge blood concentrations of cyclosporin A (r = 0.6, p = 0.028). CONCLUSIONS: These data are consistent with the concept that cyclosporin A has anti-inflammatory actions in asthma resulting from inhibition of mRNA transcription of eosinophil-active cytokines, predominantly in T lymphocytes. Cyclosporin A, possibly in its inhaled form, or other agents which prevent cytokine gene transcription may therefore have potential in ameliorating the inflammatory component of asthma.
Ulcerative colitis (UC) is a chronic inflammatory condition of the colon characterized by episodes of disease activity and symptom-free remission. There is paucity of evidence regarding the efficacy and safety of complementary or alternative medicines for the management of UC. Curcumin, an anti-inflammatory agent, has been used in many chronic inflammatory conditions such as rheumatoid arthritis, esophagitis and post-surgical inflammation. The efficacy of this agent for maintenance of remission in patients with UC has not been systematically evaluated.
The primary objective was to systematically review the efficacy and safety of curcumin for maintenance of remission in UC.
A computer-assisted literature search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Specialized Trial Register was performed on July 11, 2012 to identify relevant publications. Proceedings from major gastroenterology meetings and references from published articles were also searched to identify additional studies.
Randomized placebo-controlled trials (RCT) of curcumin for maintenance of remission in UC were included. Studies included patients (of any age) who were in remission at the time of recruitment. Co-interventions were allowed.
Data collection and analysis
Two authors independently extracted data and assessed the methodological quality of the included studies using the Cochrane risk of bias tool. Data were analyzed using Review Manager (RevMan 5.1). We calculated the relative risk (RR) and 95% confidence interval (95% CI) for each dichotomous outcome. For continuous outcomes we calculated the mean difference (MD) and 95% CI.
Only one trial (89 patients) fulfilled the inclusion criteria. This trial randomized 45 patients to curcumin and 44 patients to placebo. All patients received treatment with sulfasalazine or mesalamine. The study was rated as low risk of bias. Curcumin was administered orally in a dose of 2 g/day for six months. Fewer patients relapsed in the curcumin group than the placebo group at six months. Four per cent of patients in the curcumin group relapsed at six months compared to 18% of patients in the placebo group (RR 0.24, 95%CI 0.05 to 1.09; P = 0.06). There was no statistically significant difference in relapse rates at 12 months. Twenty-two per cent of curcumin patients relapsed at 12 months compared to 32% of placebo patients (RR 0.70, 95% CI 0.35 to 1.40; P = 0.31). A total of nine adverse events were reported in seven patients. These adverse events included sensation of abdominal bulging, nausea, transient hypertension, and transient increase in the number of stools. The authors did not report which treatment group the patients who experienced adverse events belonged to. The clinical activity index (CAI) at six months was significantly lower in the curcumin group compared to the placebo group (1.0 ± 2.0 versus 2.2 ± 2.3;MD −1.20, 95%CI −2.14 to −0.26). The endoscopic index (EI) at six months was significantly lower in the curcumin group than in the placebo group (0.8 ± 0.6 versus 1.6 ± 1.6; MD −0.80, 95% CI −1.33 to −0.27).
Curcumin may be a safe and effective therapy for maintenance of remission in quiescent UC when given as adjunctive therapy along with mesalamine or sulfasalazine. However, further research in the form of a large scale methodologically rigorous randomized controlled trial is needed to confirm any possible benefit of curcumin in quiescent UC.
Anti-Inflammatory Agents, Non-Steroidal [*therapeutic use]; Colitis, Ulcerative [*drug therapy]; Curcumin [*therapeutic use]; Drug Therapy, Combination [methods]; Maintenance Chemotherapy [*methods]; Mesalamine [therapeutic use]; Randomized Controlled Trials as Topic; Recurrence; Sulfasalazine [therapeutic use]; Humans
Curcumin has shown considerable pharmacological activity, including anti-inflammatory, but its poor bioavailability and rapid metabolization have limited its application. The purpose of the present study was to formulate curcumin-solid lipid nanoparticles (curcumin-SLNs) to improve its therapeutic efficacy in an ovalbumin (OVA)-induced allergic rat model of asthma. A solvent injection method was used to prepare the curcumin-SLNs. Physiochemical properties of curcumin-SLNs were characterized, and release experiments were performed in vitro. The pharmacokinetics in tissue distribution was studied in mice, and the therapeutic effect of the formulation was evaluated in the model. The prepared formulation showed an average size of 190 nm with a zeta potential value of −20.7 mV and 75% drug entrapment efficiency. X-ray diffraction analysis revealed the amorphous nature of the encapsulated curcumin. The release profile of curcumin-SLNs was an initial burst followed by sustained release. The curcumin concentrations in plasma suspension were significantly higher than those obtained with curcumin alone. Following administration of the curcumin-SLNs, all the tissue concentrations of curcumin increased, especially in lung and liver. In the animal model of asthma, curcumin-SLNs effectively suppressed airway hyperresponsiveness and inflammatory cell infiltration and also significantly inhibited the expression of T-helper-2-type cytokines, such as interleukin-4 and interleukin-13, in bronchoalveolar lavage fluid compared to the asthma group and curcumin-treated group. These observations implied that curcumin-SLNs could be a promising candidate for asthma therapy.
airway hyperresponsiveness; pharmacokinetics; curcumin; solid lipid nanoparticles
Current therapy for allergic bronchopulmonary aspergillosis (ABPA) uses oral corticosteroids, exposing patients to the adverse effects of these agents. There are reports of the steroid-sparing effect of anti-IgE therapy with omalizumab for ABPA in patients with cystic fibrosis (CF), but there is little information on its efficacy against ABPA in patients with bronchial asthma without CF.
To examine the effects of omalizumab, measured by asthma control, blood eosinophilia, total serum immunoglobulin E (IgE), oral corticosteroid requirements, and forced expiratory volume spirometry in patients with ABPA and bronchial asthma.
A retrospective review of charts from 2004–2006 of patients treated with omalizumab at an academic allergy and immunology practice in the Bronx, New York were examined for systemic steroid and rescue inhaler usage, serum immunoglobulin E levels, blood eosinophil counts, and asthma symptoms, as measured by the Asthma Control Test (ACT).
A total of 21 charts were screened for the diagnosis of ABPA and bronchial asthma. Four patients with ABPA were identified; two of these patients were male. The median monthly systemic corticosteroid use at 6 months and 12 months decreased from baseline usage. Total serum IgE decreased in all patients at 12 months of therapy. Pre-bronchodilator forced expiratory vital capacity at one second (FEV1) was variable at 1 year of treatment. There was an improvement in Asthma Control Test (ACT) symptom scores for both daytime and nighttime symptoms.
Treatment with omalizumab creates a steroid-sparing effect, reduces systemic inflammatory markers, and results in improvement in ACT scores in patients with ABPA.
allergic bronchopulmonary aspergillosis; omalizumab; asthma
Asthma guidelines recommend reducing the dose of inhaled corticosteroids after establishing control.
To identify predictors of loss of control and the kinetics of symptoms, and inflammatory and physiological measurements when inhaled corticosteroids are reduced in patients with stable asthma.
PATIENTS AND METHODS
In a single-blind study, the daily dose of inhaled corticosteroid was reduced by one-half at intervals of 20±2 days in 17 adults with controlled asthma until loss of asthma control occurred or until the corticosteroid was replaced with placebo for 20 days. The patients recorded symptoms and peak expiratory flow each day, and forced expiratory volume in 1 s (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), exhaled nitric oxide, and eosinophils in sputum and blood were measured every 10 days. A loss of asthma control was defined as a worsening of the symptoms score of at least 20%, and either a decrease in FEV1 of at least 15% or a decrease in PC20 of at least fourfold.
Two patients had a respiratory infection and were withdrawn from the study. In eight patients, asthma became uncontrolled after a mean of 33 days (range 13 to 48 days). This was accurately reflected by a worsening of all parameters. The first parameter to change was the sputum eosinophil percentage (20 days before the loss of asthma control). Significant changes in exhaled nitric oxide, FEV1 and methacholine PC20 were observed only when the symptoms became uncontrolled. A high blood eosinophil count at baseline (risk ratio of 2.5, 95% CI 1.0 to 6.5) and an increase in sputum eosinophil count after the reduction of corticosteroids were predictors of loss of asthma control.
In patients whose asthma is controlled on inhaled corticosteroid, it is prudent not to reduce the dose further if the blood eosinophils are increased or if the sputum eosinophils increase by as little as 1% after the reduction of corticosteroids.
Asthma exacerbation; Eosinophils; Induced sputum; Inhaled corticosteroid
Specific antibody deficiency (SAD) is a humoral immunodeficiency characterized by normal levels of IgG, IgA, IgM and IgG subclasses but a failure to polysaccharide antigens, manifested with recurrent bacterial respiratory infections. To establish the SAD diagnosis an inadequate IgG antibody response to more than 50% of pneumococcal serotypes after unconjugated pneumococcal immunization are needed. An adequate response is defined as a post-immunization titre of ≥1.3 μg/mL or ≥4 times the preimmunization value.1,2
The record of 1 patient was review and relevant clinical data was collected. A review of the literature about SAD was made.
A 4-year old male with family history of atopic disease, esophageal reflux at 3-months, he began with recurrent upper respiratory tract infections at 1-year old, 1 to 2 events per month, fever (39–40° C), persistent cough and hyaline rhinorrhea, nasal itching and sneezing he was treated with multiple antibiotics, inhaled and oral corticosteroids with mild clinical recovery between episodes. A normal blood cell count and normal levels of IgG 1219 mg/dL, IgA 146 mg/dL, IgM 98 mg/dL and IgG subclasses were determined. Allergic rhinitis and asthma were diagnosed at 3-years old, percutaneous prick skin test was positive to Dermatophagoides farinae, Salsola pestifer, Phleum pratense, Heliantus sp. and specific immunotherapy was started. Despite of treatment he continued with recurrent infections so specific antibody response to polysaccharide pneumococcal antigens was evaluated, he responded less than 50% to 14 pneumococcal serotypes after 23-valent unconjugated pneumococcal vaccine, so SAD was diagnosed and treated with prophylactic antibiotic, pneumococcal polysaccharide conjugated vaccine (10-valent) and specific immunotherapy. He showed clinical improvement, with few mild infections, and controlled rhinitis and asthma.
There are several Primary Immunodeficiency Diseases related to allergic diseases as IgA deficiency and SAD. In the atopic patient that does not improve in spite of specific immunotherapy further investigations are needed to exclude them.
Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.
We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.
Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).
Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.
ClinicalTrials.gov Identifier: NCT00099710.
Various mutant forms of Escherichia coli heat-labile enterotoxin (LT) have been used as a mucosal adjuvant for vaccines, as it enhances immune responses to specific antigens including antigen-specific IgA antibodies when administrated intranasally or orally. We hypothesized that a detoxified mutant form of LT, LTS61K, could modulate dendritic cell (DC) function and alleviate allergen-induced airway inflammation. Two protocols, preventative and therapeutic, were used to evaluate the effects of LTS61K in a Dermatophagoides pteronyssinus (Der p)-sensitized and challenged murine model of asthma. LTS61K or Der p-primed bone marrow-derived dendritic cells (BMDCs) were also adoptively transferred into Der p-sensitized and challenged mice. Intranasal inoculations with LTS61K or LTS61K/Der p decreased allergen-induced airway inflammation and alleviated systemic TH2-type immune responses. Bronchoalveolar lavage fluid (BALF) and sera from LTS61K/Der p-treated mice also had higher concentrations of Der p-specific immunoglobulin (Ig) A than those of other groups. In vitro, BMDCs stimulated with Der p underwent cellular maturation and secreted proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)α In contrast, Der p-stimulated BMDCs that were pretreated with LTS61K showed decreased IL-6 and TNFα production and were less mature. Intratracheal adoptive transfer of LTS61K- or LTS61K/Der p-primed BMDCs into Der p-sensitized mice reduced inflammatory cell infiltration and TH2-type chemokines in BALF and alleviated airway inflammation in treated mice. LTS61K influenced DC maturation and decreased inflammatory cytokine production. Moreover, LTS61K/Der p induced increased Der p-specific IgA production to decrease allergic TH2 cytokine responses and alleviated airway inflammation in Der p-sensitized mice. These results suggest that the immunomodulatory effects of LTS61K may have clinical applications for allergy and asthma treatment.
Addition of the long acting β2 agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids. However, little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process, control of which is considered important for the long term outcome of asthma.
After a 4 week fluticasone run‐in period, 54 patients with allergic asthma were randomised to receive twice daily treatment with fluticasone 250 μg with or without salmeterol 50 μg for 1 year in a double blind, parallel group design (total daily dose of fluticasone 500 μg in both treatment groups). Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations. Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker. The effects on allergen induced changes were determined before and at the end of the treatment period.
Adding salmeterol to fluticasone resulted in improved peak expiratory flow, symptom scores, rescue medication usage, and bronchial hyperresponsiveness (p<0.05 for all). There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment (p>0.05). However, adding salmeterol significantly reduced sputum ratios of α2‐macroglobulin and albumin during the treatment period (p = 0.001).
The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane. This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting β2 agonist is combined with inhaled corticosteroids.
asthma; inflammation; sputum; bronchodilator agents; anti‐inflammatory agents
Common medications used to treat mild persistent asthma are glucocorticoids, leukotriene receptor antagonists and theophylline. The aim of the study was to evaluate monotherapy with either inhaled steroids, oral leukotriene receptor antagonist or theophylline in Egyptian children with mild persistent asthma by determining their clinical, laboratory and spirometric responses to treatment.
Material and methods
Thirty-nine mild asthmatic children between 8 and 13 years of age were included in the study. Patients were classified according to therapy received into four groups: oral leukotriene receptor antagonist (montelukast), inhaled corticosteroid (fluticasone propionate), sustained-release (SR) theophylline, and no treatment. Pulmonary function testing was performed at the start of therapy and 8 weeks later using spirometry. Eosinophil count and serum nitric oxide were estimated in the blood. Minitab statistical package was used for analysis of data.
Follow-up after 8 weeks revealed significant improvement in FEV1% in groups 1 (p < 0.01) and 3 (p < 0.05), significant improvement in PEFR in groups 1 (p < 0.05) and 2 (p < 0.01), significant decline in serum NO levels in groups 1 (p < 0.05) and 2 (p < 0.05), as well as significant improvement in eosinophil count in groups 1, 2 and 3 (p < 0.01, < 0.001, < 0.01 respectively). There was a statistically significant positive correlation between the decline in serum NO and the decline in blood eosinophil % in group 2 (p < 0.05).
Inhaled corticosteroids and montelukast have a significant role in controlling the pulmonary functions and the inflammatory process in children with mild persistent asthma, although inhaled corticosteroids seem to yield a better response. Children with mild persistent asthma should receive a controller medication, and SR theophylline may be a good cost-benefit alternative for low socio-economic groups of patients.
asthma; inhaled corticosteroids; montelukast; slow-release theophylline
BACKGROUND: Current guidelines on the management of asthma advocate the use of anti-inflammatory treatment in all but mild disease. They define disease control in terms of clinical criteria such as lung function and symptoms. However, the relationship between the clinical control of the disease and inflammation of the airways is not clear. A cross sectional study was therefore undertaken to investigate the relationship between airways inflammation and measures of clinical control and bronchial hyperresponsiveness in asthmatic patients treated with inhaled steroids. METHODS: Twenty six atopic adults (19-45 years) with mild to moderate asthma (baseline forced expiratory volume in one second (FEV1) > or = 50% predicted, concentration of histamine causing a 20% fall in FEV1 (PC20) 0.02-7.6 mg/ml) on regular treatment with inhaled steroids entered the study. Diary card recordings during the two weeks before a methacholine challenge test and bronchoscopic examination were used to determine peak flow variability, symptom scores, and use of beta 2 agonists. Biopsy specimens were taken by fibreoptic bronchoscopy from the carina of the right lower and middle lobes, and from the main carina. Immunohistochemical staining was performed on cryostat sections with monoclonal antibodies against: eosinophil cationic protein (EG1, EG2), mast cell tryptase (AA1), CD45, CD22, CD3, CD4, CD8, CD25, and CD45RO. The number of positively stained cells in the lamina propria was counted twice by using an interactive display system. RESULTS: There were no differences in cell numbers between the three sites from which biopsy specimens were taken. The PC20 for methacholine was inversely related to the average number of total leucocytes, EG1+, and EG2+ cells, mast cells, CD8+, and CD45RO+ cells in the lamina propria. These relationships were similar for each of the biopsy sites. Symptom scores, beta 2 agonist usage, FEV1, and peak flow variability were not related to any of the cell counts. CONCLUSIONS: Infiltration of inflammatory cells in the lamina propria of the airways seems to persist in asthmatic outpatients despite regular treatment with inhaled steroids. The number of infiltrating leucocytes such as mast cells, (activated) eosinophils, CD8+, and CD45RO+ cells in bronchial biopsy specimens from these patients appears to be reflected by airway hyperresponsiveness to methacholine, but not by symptoms or lung function. These findings may have implications for the adjustment of anti-inflammatory treatment of patients with asthma.
Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing.
In a 52-week, randomized, double-blind, placebo-controlled study, 911 subjects with moderate-to-severe COPD managed without ICS received MF-DPI 800 μg QD PM, MF-DPI 400 μg BID, or placebo. The change from baseline in postbronchodilator forced expiratory volume in 1 second (FEV1), total COPD symptom scores, and health status as well as the percentage of subjects with a COPD exacerbation were assessed. Adverse events were recorded.
Mometasone furoate administered via a dry powder inhaler 800 μg QD PM and 400 μg BID significantly increased postbronchodilator FEV1 from baseline (50 mL and 53 mL, respectively, versus a 19 mL decrease for placebo; P < 0.001). The percentage of subjects exacerbating was significantly lower in the pooled MF-DPI groups than in the placebo group (P = 0.043). Subjects receiving MF-DPI 400 μg BID reported a statistically significant (19%) reduction in COPD symptom scores compared with placebo (P < 0.001). Health status as measured with St. George's Respiratory Questionnaire (SGRQ) improved significantly in all domains (Total, Activity, Impacts, and Symptoms) in the pooled MF-DPI groups versus placebo (P ≤ 0.031). MF-DPI treatment was well tolerated.
Once-daily MF-DPI improved lung function and health status in subjects with moderate-to-severe COPD and was comparable to BID MF-DPI.
No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.
To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment–based adjustment in preventing treatment failure in adults with mild to moderate asthma.
Design, Setting, and Participants
A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n=114 assigned to physician assessment–based adjustment [101 completed], n=115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n=113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.
For physician assessment–based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.
Main Outcome Measure
The primary outcome was time to treatment failure.
There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).
Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment–based adjustment of inhaled corticosteroids in time to treatment failure.
clinicaltrials.gov Identifier: NCT00495157
Curcumin has been shown to have many potentially health beneficial properties in vitro and in animal models with clinical studies on the toxicity of curcumin reporting no major side effects. However, curcumin may chelate dietary trace elements and could thus potentially exert adverse effects. Here, we investigated the effects of a 6 month dietary supplementation with 0.2% curcumin on iron, zinc, and copper status in C57BL/6J mice. Compared to non-supplemented control mice, we observed a significant reduction in iron, but not zinc and copper stores, in the liver and the spleen, as well as strongly suppressed liver hepcidin and ferritin expression in the curcumin-supplemented mice. The expression of the iron-importing transport proteins divalent metal transporter 1 and transferrin receptor 1 was induced, while hepatic and splenic inflammatory markers were not affected in the curcumin-fed mice. The mRNA expression of other putative target genes of curcumin, including the nuclear factor (erythroid-derived 2)-like 2 and haem oxygenase 1 did not differ between the groups. Most of the published animal trials with curcumin-feeding have not reported adverse effects on iron status or the spleen. However, it is possible that long-term curcumin supplementation and a Western-type diet may aggravate iron deficiency. Therefore, our findings show that further studies are needed to evaluate the effect of curcumin supplementation on iron status.
A 6 month dietary supplementation with 0.2% curcumin in C57BL/6J mice led to a significant reduction in iron, but not zinc and copper stores, in the liver and the spleen, and suppressed liver hepcidin and ferritin expression. Furthermore, the expression of the iron-importing transport proteins divalent metal transporter (DMT) 1 and transferrin receptor (TfR) 1 was induced in the curcumin-fed mice. These data suggest that long-term curcumin supplementation and a Western-type diet may aggravate iron deficiency.
•0.2% dietary curcumin for 6 months reduced iron stores in murine liver and spleen.•Curcumin chelated iron but not zinc and copper in vivo.•Liver hepcidin and ferritin expression was strongly suppressed in curcumin-fed mice.•Curcumin induced expression of hepatic iron transporters DMT1 and TfR1.•Curcumin did not affect hepatic and splenic inflammatory and oxidative markers.
γ-GCS, γ-glutamyl cysteine synthetase; DMT1, divalent metal transporter 1; FPN, ferroportin; HO1, haem oxygenase; IL, interleukin; NQO1, NAD(P)H quinone oxidoreductase; NRF2, nuclear factor (erythroid-derived 2)-like 2; qRT-PCR, quantitative real-time polymerase chain reaction; TBS, tris buffered saline; TfR1, transferrin receptor 1; TNFα, tumour necrosis factor α; Curcumin; Iron store; Liver minerals; Safety; Enlarged spleen; Toxicity
This study aimed to evaluate the clinical efficacy and mucosal/systemic antibody response changes after sublingual immunotherapy (SLIT) using Dermatophagoides pteronyssinus (Dpt) allergens with or without bacterial extracts in mite-allergic Brazilian children.
One-hundred and 2 patients presenting allergic rhinitis with or without asthma were selected for a randomized double-blind, placebo-controlled trial and distributed into 3 groups: DPT (Dpt allergen extract, n = 34), DPT + MRB (Dpt allergen plus mixed respiratory bacterial extracts, n = 36), and Placebo (n = 32). Clinical evaluation and immunological analyses were carried out before and after 12 and 18 months of treatment, including rhinitis/asthma symptom and medication scores, skin prick test (SPT) to Dpt extract, and measurements of Dpt-, Der p 1-, Der p 2-specific IgE, IgG4, and IgG1 in serum and -specific IgA in saliva and nasal lavage fluid.
Clinical results showed a significant decline in rhinitis/asthma symptom scores in all groups, but medication use decreased only in active DPT group at 12 months. SPT results showed no significant changes and SLIT was generally safe, with no severe systemic reactions. SLIT using Dpt allergen alone induced increased serum IgG4 levels to Dpt, Der p 1 and Der p 2, and increased serum IgG1 and salivary IgA levels to Dpt and Der p 1. SLIT using DPT+MRB was able to decrease IgE levels, particularly to Der p 2, to increase salivary IgA levels to Der p 1, but had no changes on specific IgG4 and IgG1 levels.
Therefore, SLIT seems to be effective in ameliorating clinical symptoms, but only active SLIT was able to modulate the mucosal and systemic antibody responses. These findings support the role of specific serum IgG4 and IgG1, in addition to salivary IgA, as protective or blocking antibodies as well as biomarkers of tolerance that may be useful for monitoring activation of tolerance-inducing mechanisms during allergen immunotherapy.
Many children with persistent asthma use inhaled corticosteroids on a periodic basis. Clinical trials in adults suggest that periodic use of inhaled corticosteroids may be effective for patients with mild persistent asthma. However, scant information exists on the clinical outcomes of children with asthma who are using inhaled corticosteroids on a periodic basis in real-world settings.
This prospective cohort study compared clinical outcomes during a 12-month follow-up period between children with persistent asthma whose parents believed that they were supposed to use inhaled steroids either (a) periodically or (b) daily year-round at the start of the period. The clinical outcomes studied were (1) asthma-related emergency department (ED) visits or hospitalizations, (2) uncontrolled asthma based on health care and medication use, and (3) outpatient visits for asthma.
Patients and methods
The study population included children with persistent asthma from two health plans whose parents reported that they were using inhaled corticosteroids during a baseline telephone interview. The interviews collected information on whether the children’s parents believed they were supposed to use inhaled corticosteroids on a periodic or daily basis, as well as baseline asthma symptom status, sociodemographic, and behavioral variables. We used computerized databases to identify clinical events for each child during the 12 months after their baseline interview. Uncontrolled asthma was defined as any asthma-related ED visit or hospitalization, two or more oral steroid prescription fills, or four or more beta-agonists canisters filled during the 12-month period. We compared these outcomes between the periodic versus daily users of inhaled corticosteroids using logistic regression analyses. We conducted both (1) a traditional logistic regression analysis in which we adjusted for selection bias by including covariates such as age, asthma physical status, sociodemographic and behavioral variables, and history of asthma-related health care use during the year before interview and (2) an analysis using propensity scores to more fully adjust for selection bias.
Of a total of 476 children in the study, 55% of parents believed their children were supposed to be using inhaled corticosteroids on a periodic basis and 45% believed their children were supposed to be using them daily year-round based on the baseline parent interview. At baseline, periodic inhaled corticosteroid users had less severe asthma than daily users based on several measures including better asthma physical status scores on the Children’s Health Survey for Asthma (mean 87 ± 16.0 vs. 81 ± 17.4, p = < 0.0001). During the year before the baseline interview, periodic users compared with daily users were less likely to have an ED visit or hospitalization (10% vs. 23%, p = 0.0001) and less likely to have had five or more albuterol prescription fills (13% vs. 31%, p < 0.0001). During the follow-up year, those who believed inhaled steroids were for periodic use were less likely than those who believed inhaled steroids were for daily use to have an ED visit or hospitalization for asthma (OR 0.36, 95% CI: 0.18–0.73), even after adjusting for baseline asthma status and other covariates. Similarly, those who believed inhaled steroids were for periodic use were less likely to have uncontrolled asthma, OR 0.38 (95% CI: 0.24–0.62). Analyses using propensity score adjustment yielded similar results to the logistic regression analyses.
Children whose parents believed they were supposed to use inhaled corticosteroids on a periodic basis had less severe asthma at baseline than those whose parents believed they were supposed to be using them daily. Periodic users were less likely than daily users to have adverse asthma outcomes during 1-year follow-up. This suggests that clinicians may be applying appropriate selection criteria by choosing patients with less severe asthma for periodic inhaled corticosteroid regimens.
asthma; periodic inhaled corticosteroids; children
Oxidative stress as a result of cigarette smoking is an important etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic steroid-insensitive inflammatory disease of the airways. Histone deacetylase-2 (HDAC2), a critical component of the corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity. We demonstrate here that curcumin (diferuloylmethane), a dietary polyphenol, at nanomolar concentrations specifically restores cigarette smoke extract (CSE)- or oxidative stress–impaired HDAC2 activity and corticosteroid efficacy in vitro with an EC50 of approximately 30 nM and 200 nM, respectively. CSE caused a reduction in HDAC2 protein expression that was restored by curcumin. This decrease in HDAC2 protein expression was reversed by curcumin even in the presence of cycloheximide, a protein synthesis inhibitor. The proteasomal inhibitor, MG132, also blocked CSE-induced HDAC2 degradation, increasing the levels of ubiquitinated HDAC2. Biochemical and gene chip analysis indicated that curcumin at concentrations up to 1 μM propagates its effect via antioxidant-independent mechanisms associated with the phosphorylation-ubiquitin-proteasome pathway. Thus curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity induced by either CSE or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.
cigarette smoke; corticosteroid; macrophages; chronic obstructive pulmonary disease; polyphenols
There is evidence that humanized monoclonal antibody against IgE (Omalizumab) is effective in severe allergic asthma. In this study, we examined the effectiveness of omalizumab on asthma and nasal symptoms in Japanese patients with severe allergic asthma and rhinitis.
An open-label study that enrolled 7 patients with both severe allergic asthma and rhinitis who visited Allergy Center, Saitama Medical University was performed. All patients presented uncontrolled asthma despite medication including high-dose inhalational corticosteroids, long-acting beta2-agonist, leukotriene receptor antagonist, theophylline, and oral predonisolone. Omalizumab was added on their treatments and symptoms score using Asthma Contol Test (ACT), peak expiratory flow rate (PEFR), exhaled nitric oxide (eNO), sputum eosinophils and nasal symptoms were evaluated before and 12 to 16 weeks after omalizumab.
Omalizumab significantly improved ACT scores especially dose of rescue use of short-acting beta2-agonist (P < 0.05) and PEFR (P < 0.05). Furthermore, omalizumab significantly decreased exhaled both eNO (P < 0.05) and the percentage of eosinophils in induced sputum. On the other hand, nasal symptoms were not change following induction of omalizumab.
Clinical effectiveness of omalizumab was confirmed in Japanese population of severe allergic asthma, but not rhinitis. The therapeutic potency of omalizumab on asthma likely involves anti-inflammatory properties such as decreasing eNO or airway eosinophilia.
Background and aim
Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.
Systematic literature review.
No significant increase in the number of patients requiring rescue oral corticosteroid for an exacerbation of asthma has been observed after initiation of β-blocker treatment. Patients with mild to moderate reactive airway disease, probably both asthma and chronic obstructive pulmonary disease, may have a limited fall in forced expiratory volume in 1 second (FEV1) following single-dose administration of β-blocker, whereas no change in FEV1 has been reported following long-term administration. In a murine model of asthma, long-term administration of β-blockers resulted in a decrease in airway hyperresponsiveness, suggesting an anti-inflammatory effect. In keeping with this, long-term administration of a nonselective β-blocker to steroid-naïve asthma patients has shown a dose-dependent improvement in airway hyperresponsiveness, and either an asymptomatic fall in FEV1 or no significant change in FEV1. Furthermore, available studies show that bronchoconstriction induced by inhaled methacholine is reversed by salbutamol in patients on regular therapy with a β-blocker. On the other hand, a recent placebo-controlled trial of propranolol and tiotropium bromide added to inhaled corticosteroids revealed no effect on airway hyperresponsiveness and a small, not statistically significant, fall in FEV1 in patients classified as having mild to moderate asthma.
The available, although limited, evidence suggests that a dose-escalating model of β-blocker therapy to patients with asthma is well tolerated, does not induce acute bronchoconstriction, and, not least, may have beneficial effects on airway inflammation and airway hyperresponsiveness in some patients with asthma. Further studies addressing the potential role of β-blocker therapy for asthma are clearly needed, but careful selection of the target population is warranted.
asthma; beta-blockers; lung function; airway responsiveness
BACKGROUND: Long term administration of oral corticosteroids in patients with asthma may be associated with serious side effects. Non-steroidal anti-inflammatory drugs, including gold salts, have been shown to reduce the need for systemic corticosteroid treatment in uncontrolled studies. The effect of oral gold (auranofin) on asthma symptoms, lung function, and the need for oral prednisone treatment was investigated. METHODS: A 26 week randomised, double blind, placebo controlled, parallel group trial of auranofin was performed in 32 patients with moderately severe chronic asthma who required an oral corticosteroid dose of at least 5 mg prednisone a day (or equivalent) or 2.5 mg/day prednisone plus more than 800 micrograms/day inhaled corticosteroids. Auranofin was given orally in a dose of 3 mg twice daily. Asthma symptoms, lung function, and adverse effects were assessed at regular intervals. After 12 weeks of treatment prednisone dosage was tapered down by 2.5 mg every two weeks if the patient was clinically stable. Asthma exacerbations were treated with short courses of high doses of oral steroids. RESULTS: Twenty eight of the 32 patients, 13 in the placebo group and 15 in the auranofin group, completed the study. The total corticosteroid reduction achieved after 26 weeks of treatment was significantly greater (4 mg) in the auranofin group than in the placebo group (0.3 mg). The number of exacerbations requiring an increase of steroids was greater in the placebo group (2.1) than in the active group (0.9). A significant increase in FEV1 of 6.4% predicted occurred in the auranofin group during the study and there was a reduction of asthma symptoms such as wheezing and cough. There was no difference between the groups in peak flow measurements or in the number of asthma attacks. The incidence of side effects of auranofin was low, but exacerbations of constitutional eczema were noticeable. CONCLUSION: Auranofin provides an effective adjunct to treatment for steroid dependent asthma, leading to a reduction of oral steroid dose.
Anti IgE treatment with omalizumab is efficacious in the treatment of patients suffering from allergic asthma, improving asthma control and improving quality of life. Furthermore, this approach could be beneficial for patients with concomitant atopic dermatitis. We assessed quality of life and asthma control in atopic patients with allergic asthma and concomitant atopic dermatitis versus those with asthma and without atopic dermatitis treated with omalizumab.
A total of 22 patients with severe allergic asthma were treated with omalizumab for 12 months. 13 patients with allergic asthma without concomitant atopic dermatitis (IgE 212 ± 224 IU/ml) and 9 patients with concomitant allergic asthma and atopic dermatitis (IgE 3,528 ± 2,723 IU/ml) were included. Asthma-related quality of life (AQLQ), atopic dermatitis related quality of life (DLQI), and asthma-related treatment were compared between both groups at baseline and after initiating omalizumab treatment.
DLQI was significantly in favor of omalizumab after 2 months in the atopic dermatitis/asthma group (P = 0.01); AQLQ was improved after 6 months in the asthma group (P = 0.01), while no change was seen in AQLQ in the atopic dermatitis/asthma group (P = 0.12). Omalizumab controlled oral corticosteroid use more effective (P < 0.01) in patients with asthma and atopic dermatitis (in 9/9 cases) compared to patients with asthma alone (9/13). Baseline IgE as well as other factors do not predict response to omalizumab.
Omalizumab is effective in improving atopic dermatitis-related quality of life scores and modulates oral corticosteroid use in patients with concomitant asthma and atopic dermatitis in a positive fashion.
allergic asthma; anti-IgE; atopic dermatitis; omalizumab; quality of life
Background: The use of anti-allergic mattress covers in patients with asthma can result in a large reduction in the level of house dust mite allergen in dust samples. Apart from a reduction in histamine induced bronchial hyperresponsiveness, there are few data on the effect of mattress covers on clinical efficacy and quality of life in patients with moderate to severe asthma.
Methods: Thirty patients with asthma and house dust mite allergy were studied in a randomised, double blind, placebo controlled study. Before and after using anti-allergic covers for 1 year, dust was collected from the mattresses to determine concentrations of Dermatophagoides pteronyssinus (Der p 1), and bronchial hyperresponsiveness and quality of life were measured. The patients scored their symptoms (lungs and nose), morning and evening peak flow values, and rescue medication for 14 days before and after the intervention period.
Results: There was a significant reduction in the concentration of Der p 1 in the dust collected from the mattresses in the actively treated group after 1 year compared with before treatment; no change was found in the placebo group. In both the actively treated and placebo groups there was no significant improvement in PC20 histamine. Quality of life improved similarly in both groups. The symptom score of the lower airways did not significantly change in either group. A significant decrease in nasal symptom score was seen in the actively treated group compared with before treatment, but there was no significant difference between the groups. No changes in morning and evening peak flow values, peak flow variability, nor in the use of rescue medication were found in either group.
Conclusion: The use of anti-allergic mattress covers results in significant reductions in Der p 1 concentrations in carpet-free bedrooms. However, in patients with moderate to severe asthma, airways hyperresponsiveness and clinical parameters are not affected by this effective allergen avoidance.
Rationale: One-quarter to one-third of individuals with asthma smoke, which may affect response to therapy and contribute to poor asthma control.
Objectives: To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke.
Methods: In a multicenter, placebo-controlled, double-blind, double-dummy, crossover trial, 44 nonsmokers and 39 light smokers with mild asthma were assigned randomly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast.
Measurements and Main Results: Primary outcome was change in prebronchodilator FEV1 in smokers versus nonsmokers. Secondary outcomes included peak flow, PC20 methacholine, symptoms, quality of life, and markers of airway inflammation. Despite similar FEV1, bronchodilator response, and sensitivity to methacholine at baseline, subjects with asthma who smoked had significantly more symptoms, worse quality of life, and lower daily peak flow than nonsmokers. Adherence to therapy did not differ significantly between smokers and nonsmokers, or between treatment arms. Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein (ECP) in both smokers and nonsmokers, but increased FEV1 (170 ml, p = 0.0003) only in nonsmokers. Montelukast significantly increased a.m. peak flow in smokers (12.6 L/min, p = 0.002), but not in nonsmokers.
Conclusions: In subjects with mild asthma who smoke, the response to inhaled corticosteroids is attenuated, suggesting that adjustments to standard therapy may be required to attain asthma control. The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting. Larger prospective studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke.
antiasthmatic agents; smoking adverse effects; corticosteroids; leukotrienes
Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation and airway inflammation, accompanied by decreased health status. It is still unknown which factors are responsible for the impaired health status in COPD. We postulated that airway inflammation negatively contributes to health status in COPD.
In 114 COPD patients (99 male, age: 62 ± 8 yr, 41 [31–55] pack-years, no inhaled or oral corticosteroids, postbronchodilator FEV1: 63 ± 9% pred, FEV1/IVC: 48 ± 9%) we obtained induced sputum and measured health status (St. George's respiratory questionnaire (SGRQ)), postbronchodilator FEV1, hyperinflation (RV/TLC), and airway hyperresponsiveness to methacholine (PC20). Sputum was induced by hypertonic saline and differential cell counts were obtained in 102 patients.
Univariate analysis showed that SGRQ total and symptom score were positively associated with % sputum macrophages (r = 0.20, p = 0.05; and r = 0.20, p = 0.04, respectively). Multiple regression analysis confirmed these relationships, providing significant contributions of % sputum macrophages (B = 0.25, p = 0.021) and RV/TLC (B = 0.60, p = 0.002) to SGRQ total score. Furthermore, SGRQ symptom score was associated with % sputum macrophages (B = 0.30, p = 0.03) and RV/TLC (B = 0.48, p = 0.044), whilst SGRQ activity score was associated with % sputum macrophages (B = 0.46, p = 0.002), RV/TLC (B = 0.61, p = 0.015), and PC20 (B = -9.3, p = 0.024). Current smoking and FEV1 were not significantly associated with health status in the multiple regression analysis.
We conclude that worse health status in COPD patients is associated with higher inflammatory cell counts in induced sputum. Our findings suggest that airway inflammation and hyperinflation independently contribute to impaired health status in COPD. This may provide a rationale for anti-inflammatory therapy in this disease.