Treatment Of Chronic Asthma Research Articles

Ojeok-san, a traditional Korean herbal medicine attenuates airway inflammation and pulmonary fibrosis induced by repeated ovalbumin challenge

Ethnopharmacological evidenceOjeok-san, a traditional Korean herbal medicine, is widely used in China, Japan and Korea for treatment of the common cold, pain and fever. Aim of the studyIn this study, we investigated the protective effects of Ojeok-san aqueous extract (OJS) against pulmonary fibrosis using a chronic asthma murine model. MethodsMice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed 1 weeks later by an airway challenge with OVA delivered three times a week for 4 weeks. OJS (50mg/kg or 100mg/kg) was also administered by oral gavage once a day for 4 weeks. ResultsOJS significantly reduced interleukin (IL)-4, IL-13, eotaxin, immunoglobulin E and the number of inflammatory cells in bronchoalveolar lavage fluid; in addition, it reduced inflammatory cell infiltration and mucus production in the respiratory tract. We found that OJS also attenuated the OVA-induced increase in vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1 and Smad3 protein in lung tissue, as determined by Western analysis and immunohistochemistry. These inhibitory effects of OJS were accompanied by a reduction in pulmonary fibrosis, consistent with the histopathology of lung tissue stained with Masson's trichrome. ConclusionAdministration of OJS reduced the airway inflammation and pulmonary fibrosis, as well as the level of T helper type 2 cytokines and VEGF and TGF-β1/Smad3 expressions in lung tissue. These results suggest that OJS might represent a useful new oral therapy for the treatment of chronic asthma.

Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and γ-scintigraphic techniques

Objective: To evaluate the in vivo behavior of controlled and pulsatile release pastilles for chronic treatment of asthma and chronic obstructive pulmonary disease (COPD) and for the chronotherapeutic management of nocturnal asthma, respectively.Research design & methods: The prepared immediate release and controlled release pastilles were subjected to in vivo pharmacokinetic studies in rats. Whereas, pulsatile release formulation was subjected to γ-scintigraphic study in rats to study the gastrointestinal transit of the formulations and its results were correlated with the previous pharmacokinetic data.Results: The in vivo pharmacokinetic study of controlled release pastille formulation showed significant decrease in Cmax with increase in tmax, which indicates that the effect of dosage form would last for longer duration. Thus, the prepared formulation can be useful for the chronic treatment of asthma and COPD. The γ-scintigraphic study and pharmacokinetic data indicated that the pastilles coated with the enteric coat and the additional floating coat were effective in significantly delaying the in vivo drug release (by 4–5 h) required for the chronotherapeutic treatment of nocturnal asthma.Conclusion: This study opens a new alternative to the conventional tablet or capsule dosage form for the development of both immediate and modified release drug delivery systems.

Long‐term macrolide treatment of chronic inflammatory airway diseases: risks, benefits and future developments

Macrolide antibiotics were discovered over 50years ago and following their use as antimicrobials it became apparent that this group of antibiotics also possessed anti-inflammatory properties. Subsequent clinical trials showed benefits of macrolides as long-term adjuncts in the treatment of a spectrum of chronic inflammatory respiratory diseases, particularly diffuse panbronchiolitis, cystic fibrosis, post-transplant bronchiolitis obliterans and more recently chronic obstructive pulmonary disease (COPD). The evidence for efficacy of macrolides in the long-term treatment of chronic asthma and bronchiectasis is less well established. The mechanism(s) of action of macrolides in the treatment of these diseases remains unexplained, but may be due to their antibacterial and/or anti-inflammatory actions, which include reductions in interleukin-8 production, neutrophil migration and/or function. Macrolides have additional potentially beneficial properties including anti-viral actions and an ability to restore corticosteroid sensitivity. The increased prescribing of macrolides for long-term treatment could result in the development of microbial resistance and adverse drug effects. New macrolides have been developed which do not possess any antimicrobial activity and hence lack the ability to produce microbial resistance, but which still retain immunomodulatory effects. Potentially novel macrolides may overcome a significant barrier to the use of this type of drug for the long-term treatment of chronic inflammatory airway diseases.

Liposome: A Novel Aerosol Carrier of Doxophylline in Treatment of Chronic Asthma & Chronic Obstructive Pulmonary Disease

The aim of the present research work is to develop liposomal dry powder inhaler of doxophylline by double hydration method to increase the entrapment efficiency of this hydrophilic drug. In this formulation, PVP coated mannitol and the mannitol were used as a cryoprotectant and a carrier respectively. Doxophylline, a new methylxanthine derivative, chemically designated as 7-(1,3-dixolan-2-yl-methyl) theophylline, is a more potent bronchodilator than theophylline, which is associated with a wide range of adverse effects accounting for poor compliance and high dropout rates. Powder inhaler formulation of the drug was characterized by angle of repose, compressibility index and in vitro aerosolization properties using Anderson cascade impactor including fine particle dose (212.9 + 7.2), fine particle fraction (21.69 + 1.21), % dispersibility (62.34 + 3.5) and % emission (72.1 + 0.13) at a flow rate of 28.3 lit/m for 10 seconds using 10 capsules for each determinations. The optimized formulations were subjected to stability studies at 2-8 o C, RT, and 40 o C for 3 months. The stability studies of LDPI were determined in terms of their visual appearance (surface characteristics and colour changes) and PDRE. The in vivo study was carried out by gamma scintigraphy and that showed better retention of doxophylline in liposomal formulation as compared to the controlled release formulation.

Azithromycin for Bronchial Asthma in Adults: An Effectiveness Trial

Macrolides have antimicrobial and anti-inflammatory properties that may be useful in the treatment of chronic asthma. We performed a randomized, placebo-controlled, double-blinded effectiveness trial of 12 weekly doses of adjunctive azithromycin, with follow-up to 1 year after randomization, in adults with persistent asthma. Measurements included overall asthma symptoms, asthma quality of life (AQL), and asthma control. Eligible subjects who declined to participate in randomization were offered enrollment into a parallel open-label (OL) azithromycin treatment arm. Of 304 adult asthma patients screened, 97 (32%) were enrolled: 38 were randomized to azithromycin, 37 were randomized to placebo, and 22 opted in as OL subjects. OL subjects had higher rates of severe persistent asthma compared with randomized subjects (32% vs 8%, respectively; P = .012). At 1 year, compared with the placebo arm, subjects randomized to azithromycin were more likely to have an AQL score ≥1 unit increase compared with baseline, but this difference was not statistically significant (36% vs 21% for placebo; P = .335). Compared with placebo, OL subjects had significant improvements in overall asthma symptoms from baseline (P = .0196), AQL (P = .0006), and asthma control (P = .0148). Adults with asthma who were randomized to azithromycin did not show statistically significant improvement in asthma outcomes, although the study was underpowered to detect clinical improvement in 15% (number needed to treat = 7). Adults with severe persistent asthma who elected OL treatment documented clinical improvements in asthma symptoms, AQL, and asthma control that persisted after completion of OL azithromycin (number needed to treat = 2).

Role of antileukotrienes in acute asthma exacerbations

Acute asthma exacerbations are one of the most frequent reasons to visit the emergency department or general practitioner. Although current standard treatments for acute asthma – including supplemental oxygen, short-acting β2-agonists, systemic corticosteroids and anticholinergics – are quite effective in most patients, they are inadequate for rapid and sustained improvement in a significant proportion. The antileukotrienes, a relatively new class of drugs, have a role in the treatment of chronic asthma. Their relatively rapid onset of action after endovenous or oral administration and their additive effect to β2-agonists led to the hypothesis that they might be of benefit in acute asthma. This review examines the efficacy of antileukotrienes in the treatment of acute asthma.

Role of antileukotrienes in acute asthma exacerbations

Acute asthma exacerbations are one of the most frequent reasons to visit the emergency department or general practitioner. Although current standard treatments for acute asthma – including supplemental oxygen, short-acting β2-agonists, systemic corticosteroids and anticholinergics – are quite effective in most patients, they are inadequate for rapid and sustained improvement in a significant proportion. The antileukotrienes, a relatively new class of drugs, have a role in the treatment of chronic asthma. Their relatively rapid onset of action after endovenous or oral administration and their additive effect to β2-agonists led to the hypothesis that they might be of benefit in acute asthma. This review examines the efficacy of antileukotrienes in the treatment of acute asthma.

Bioequivalence study of montelukast 5 mg chewable tablets

The importance of generic drugs is the possibility of reduced costs in the national health system without sacrificing quality of service and the efficacy and safety of treatments. However, bioequivalence studies must show that the pharmacokinetic profiles of the test product and reference product are similar and interchangeable. Montelukast sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age or older. It is generally well tolerated, although adverse reactions are more frequent in patients treated with the drug than in those treated with placebo. To compare the bioavailability of Amisped® (5 mg montelukast chewable tablets) manufactured by Sanofi-Aventis and 5 mg chewable tablet montelukast (Singulair®) developed by Merck. Materials and methods. The magnitude and rate of absorption of montelukast was compared in 18 healthy volunteers using a randomized complete crossover design. The bioassay was performed by high performance liquid chromatography. Results are indicated for the generic and innovator, respectively: Tmax (h) 2.17±0.73, 2.28±0.88; Cmax (ng/mL) 607.4±122.9, 627.7±134.2; AUC0-t (ng*h/ml) 3,316±861, 3,545±1,070; AUC0-∞ (ng*h/ml) 3,450±904, 3,722±1121; Ke (1/h) 0.25±0.05, 0.23±0.04 in the confidence range of 0.99-1.00 for lnCmax and 0.94-1.06 for lnAUC0-∞. The formula tested in Amisped® from Sanofi-Aventis is bioequivalent to the reference formulation of Merck Singulair®.

Estudio de bioequivalencia de Montelukast tabletas masticables de 5 mg

Introduction. The importance of generic drugs is the possibility of reduced costs in the national healthsystem without sacrificing quality of service and the efficacy and safety of treatments.However, bioequivalence studies must show that the pharmacokinetic profiles of the test product andreference product are similar and interchangeable. Montelukast sodium is indicated for the prophylaxisand chronic treatment of asthma in adults and pediatric patients 12 months of age or older. It is generallywell tolerated, although adverse reactions are more frequent in patients treated with the drug than inthose treated with placebo.Objectives. To compare the bioavailability of Amisped® (5 mg montelukast chewable tablets)manufactured by Sanofi-Aventis and 5 mg chewable tablet montelukast (Singulair®) developed by Merck.Materials and methods. The magnitude and rate of absorption of montelukast was compared in 18healthy volunteers using a randomized complete crossover design. The bioassay was performed byhigh performance liquid chromatography.Results.Results are indicated for the generic and innovator, respectively: Tmax (h) 2.17±0.73, 2.28±0.88;Cmax (ng/mL) 607.4±122.9, 627.7±134.2; AUC0-t (ng*h/ml) 3,316±861, 3,545±1,070; AUC0-∞ (ng*h/ml) 3,450±904, 3,722±1121; Ke (1/h) 0.25±0.05, 0.23±0.04 in the confidence range of 0.99-1.00 for lnCmaxand 0.94-1.06 for lnAUC0-∞.Conclusions. The formula tested in Amisped® from Sanofi-Aventis is bioequivalent to the referenceformulation of Merck Singulair®.doi: http://dx.doi.org/10.7705/biomedica.v32i3.708

Similarities And Differences Between Lung Ligands For Mouse Siglec-f And Human Siglec-8

S A T U R D A Y 185 Pro-fibrotic Effect Of Dexamethasone In Human Airway Fibroblasts W. Manuyakorn, D. Davies, P. Howarth; Faculty of Medicine, University of Southampton, Southampton, UNITED KINGDOM, Faculty of Medicine, Ramathobodi Hospital, Mahidol University, Bangkok, THAILAND. RATIONALE: Airway remodelling in asthma is characterized by deposition of extracellular matrix proteins (ECMs). Collagen is the most abundant ECMprotein in the airways and its cross-linking by lysyl oxidase (LOX) influences its strength and stability. Inhaled corticosteroids are the standard treatment for chronic asthma. We hypothesized that corticosteroids may have a role in regulating the production of LOX by fibroblasts from asthmatic airways. METHODS: Bronchial fibroblasts fromnormal or asthmatic subjectswere treated with dexamethasone in the presence and absence of TGFb2. LOX and collagen I mRNA expression was measured using RT-qPCR. The level of LOX in culture supernatants was measured using western blot analysis. RESULTS: TGFb2 significantly up-regulated collagen I mRNA expression. In contrast, dexamethasone had no effect on collagen I mRNA expression. TGFb2 also up-regulated LOX mRNA expression in fibroblasts from both healthy and asthmatic subjects (p50.002). In fibroblasts from asthmatic donors only, dexamethasone up-regulated LOX mRNA expression and had an additive effect with TGFb2 (p50.02). Both TGFb2 and dexamethasone enhanced the production of pro-LOX and active LOX in fibroblasts from normal or asthmatic donors (p50.03). CONCLUSIONS: TGFb2 and dexamethasone up-regulated LOX expression by bronchial fibroblasts with the potential for increased cross-linking of collagen in the airways. These findings suggest that apart from their immediate anti-inflammatory effects, corticosteroids may have a long term detrimental effect on collagencross-linking, affecting airwaywallmechanics. Should suchanactionbeevident invivo this couldhave adetrimental effect on decline in lung function and disease persistence in asthma.

Acute severe childhood asthma

Asthma is the most common chronic disease of South African children, affecting 10-20% of the population. Correct treatment of chronic asthma with regular antiinflammatory controller therapy prevents symptoms, asthma exacerbations, hospitalisation and mortality.

Complementary anti-inflammatory effects of a β-blocker and a corticosteroid in an asthma model.

Glucocorticosteroids are the mainstay treatment for chronic asthma; however, adverse effects can limit their usefulness. We previously determined in experimental asthma that chronic administration of β₂-adrenoceptor inverse agonists reduced airway hyperresponsiveness and indexes of inflammation. However, the effect of co-administration of glucocorticosteroids with β₂-adrenoceptor inverse agonists is unknown. Therefore, we evaluated the anti-inflammatory effect of co-administration of dexamethasone, a glucocorticosteroid, and nadolol, a β₂-inverse agonist, in a murine asthma model. We measured eosinophils and cytokines in bronchoalveolar lavage fluid and mucin content in epithelial cells after exposure to different concentrations of dexamethasone and nadolol. Dexamethasone was administered for 3 days and nadolol for 24 days prior to ovalbumin challenge. Both drugs were continued during five daily intranasal challenges with ovalbumin. Independent administration of dexamethasone (0.4 mg/kg/day) or nadolol (25 ppm) reduced bronchoalveolar lavage eosinophils by 58% and 36%, respectively (P < 0.05). Co-administration of both drugs yielded an additive reduction in eosinophils (81%, P < 0.05). Co-administration of both drugs (dexamethasone 0.4 mg/kg/day and nadolol 25 ppm) also yielded a greater reduction in mucin volume density (83%) than either drug alone (18% for dexamethasone and 62% for nadolol) and greater than high-dose dexamethasone (71%) alone (P < 0.05). Similarly, co-administration of both drugs (dexamethasone 0.4 mg/kg/day and nadolol 25 ppm) yielded an additive effect on the reduction of type 2 cytokines in bronchoalveolar lavage fluid equivalent to the administration of a 10-fold higher dose of dexamethasone. In Summary, the simultaneous administration of a glucocorticosteroid and a β₂-adrenoceptor inverse agonist was more effective at reducing indexes of airway inflammation than either drug given alone; suggesting nadolol may possess "glucocorticoid-sparing" properties.

Improved activity and mental function related to proper antiasthmatic treatment in elderly patients with Alzheimer's disease

Alzheimer's disease (AD) and bronchial asthma are common diseases in elderly patients. Untreated chronic diseases, such as chronic obstructive pulmonary disorder, diabetes, heart failure, and asthma can be associated with declining cognitive function. The objective of this study was to evaluate the influence of asthma therapy performed according to Global Initiative for Asthma (GINA) guidelines (GINA. Global strategy for asthma management and prevention. Report. Available online at http://www.ginasthma.com/Guidelineitem.asp??l1=2&l2=1&intId=60 last accessed Oct. 2009) on cognitive function and functional status in patients diagnosed with AD. A total of 302 participants who were diagnosed with bronchial asthma and mild or moderate AD (138 women and 164 men) with a mean age of 68.2 ± 5.1 years were included in the study. Cognitive function was assessed based on the Mini-Mental State Examination (MMSE) and the clock drawing test at the beginning of the study, after 6 months, and after 1 year. Results were compared with a control group of patients with AD but not asthma. Several patients (68.9%) had uncontrolled asthma (confirmed at the beginning of the study) and AD. After 1 year of antiasthmatic treatment, the mean MMSE score increased significantly from the baseline values of 17.2 ± 3.2 to 19.5 ± 2.1 (mean ± SD; p < 0.05). This change was significant compared with the control group. Significant improvement in instrumental activity was observed after 1 year of treatment in patients with asthma. Finally, 63.6% of patients met the criteria of well-controlled asthma. Adequate treatment of chronic asthma could improve some cognitive and instrumental activities. Asthma in patients with AD is commonly underdiagnosed and undertreated.

In vitro transdermal permeation of fenoterol hydrobromide

The aim of this study was to determine if transdermal penetration of fenoterol, a β-agonist drug, could be enhanced and controlled by formulation modification and formulation of transdermal patches. Pre-formulation studies were performed to determine the feasibility of a transdermal dosage form of fenoterol. Penetration of fenoterol was determined using the hairless guinea pig skin with unjacketed Franz diffusion cell. Transdermal patches were formulated using drug in-adhesive technique. Several enhancers were investigated for fenoterol skin penetration. Transcutol–oleic acid co-solvent gives the highest drug flux among all tested liquid formulations. Pretreatment of the skin with oleic acid 2h before patch application significantly increases drug diffusion. Cis-oleic acid gives best results compared to oleic acid. Azone derivative (1-dodecyl-2-pyrrolidinone) gives the highest drug diffusion amongst all tested enhancers. Results of this study show the feasibility of using fenoterol formulated in transdermal delivery system in the treatment of chronic asthma to improve patient compliance, bioavailability and reduce the inter-subject variability.

Effect of inhaled corticosteroids on small airway inflammation in patients with bronchial asthma

Bronchial asthma is a chronic inflammatory disease affecting the bronchial mucosa. In asthma patients, the highest number of inflammatory cells, including eosinophils, are found in the small bronchi. According to the most recent 2006 report of the Global Initiative for Asthma, inhaled corticosteroids (ICS) remain the first-line treatment of chronic asthma. They are characterized by high lung deposition and good distribution in the small bronchi, which makes them particularly efficient in reducing chronic inflammatory infiltrate in the small airways. Good pulmonary distribution of ICS in patients with mild asthma is reflected by a better control of the disease, improvement in the quality of life, improvement in the results of pulmonary function tests, decreased levels of exhaled proinflammatory nitric oxide, lower number of inflammatory cells (including eosinophils) in the induced sputum, decrease in bronchial hyperreactivity, and decrease in exhaled air trapping observed in the computed tomographic scanning of the lungs.

Prescribing of β-adrenoceptor antagonists in asthma: an observational study

Backgroundβ-Antagonists have recently been proposed for the treatment of chronic asthma; however, concerns regarding risk of acute bronchoconstriction in clinical trials remain.ObjectiveTo determine the frequency of oral β-blocker prescribing in...

Anti-Inflammatory Effects of the Neurotransmitter Agonist Honokiol in a Mouse Model of Allergic Asthma

Chronic airway inflammation is a hallmark of asthma, an immune-based disease with great societal impact. Honokiol (HNK), a phenolic neurotransmitter receptor (γ-aminobutyric acid type A) agonist purified from magnolia, has anti-inflammatory properties, including stabilization of inflammation in experimentally induced arthritis. The present study tested the prediction that HNK could inhibit the chronic inflammatory component of allergic asthma. C57BL/6 mice sensitized to and challenged with OVA had increased airway hyperresponsiveness to methacholine challenge and eosinophilia compared with naive controls. HNK-treated mice showed a reduction in airway hyperresponsiveness as well as a significant decrease in lung eosinophilia. Histopathology studies revealed a marked drop in lung inflammation, goblet cell hyperplasia, and collagen deposition with HNK treatment. Ag recall responses from HNK-treated mice showed decreased proinflammatory cytokines in response to OVA, including TNF-α-, IL-6-, Th1-, and Th17-type cytokines, despite an increase in Th2-type cytokines. Regulatory cytokines IL-10 and TGF-β were also increased. Assessment of lung homogenates revealed a similar pattern of cytokines, with a noted increase in the number of FoxP3(+) cells in the lung. HNK was able to alter B and T lymphocyte cytokine secretion in a γ-aminobutyric acid type A-dependent manner. These results indicate that symptoms and pathology of asthma can be alleviated even in the presence of increased Th2 cytokines and that neurotransmitter agonists such as HNK have promise as a novel class of anti-inflammatory agents in the treatment of chronic asthma.

Targeting Interleukin (IL) 5 for Asthma and Hypereosinophilic Diseases

Although glucocorticosteroids are still the first line of treatment for chronic asthma, over the last two decades great advances have been made in understanding the pathogenesis of asthma that enabled the identification of new therapeutic targets for asthma treatment. The interleukin (IL) 5: eosinophil axis is a hallmark pathway of allergic inflammation that has received much attention. Indeed, IL-5 is known to regulate eosinophil differentiation, proliferation, priming and activation. Therefore, therapeutic agents targeting IL-5 have been generated. In this review we will discuss the effects of IL-5 on eosinophils and outline the signaling mechanism involved in IL-5-mediated effects. Furthermore, recent results from clinical trials targeting IL-5 in asthma and hypereosinophilic syndrome will be discussed and an overview of newly developed patents aimed to target IL-5 will be reviewed.

Synthesis of Enantiomerically Pure 2,5-Disubstituted 3-Oxygenated Tetrahydrofurans

The synthesis of enantiomerically pure 2,5-disubstituted 3-oxygenatedtetrahydrofurans has been achieved from cheap and commercially available L-malic acid. This method was used to preparean advanced intermediate toward CMI-977, a promising candidate forthe treatment of chronic asthma.

Salmeterol use and risk of hospitalization among emergency department patients with acute asthma

The safety of inhaled long-acting beta2-agonists (LABAs) in the treatment of chronic asthma remains controversial and has not been evaluated in emergency department (ED) patients with acute asthma. To determine whether ED patients undergoing long-term LABA therapy would have increased risk of asthma-related hospitalization compared with those not undergoing LABA therapy and whether concurrent long-term inhaled corticosteroid (ICS) therapy would mitigate this risk. Prospective cohort study of patients aged 12 to 54 years with acute asthma in 115 EDs. Four patient groups were created based on their asthma regimen: no ICS or salmeterol (group A), salmeterol monotherapy (group B), ICS monotherapy (group C), and combination ICS and salmeterol (group D). Of the 2,236 included patients, group A had 1,221 patients (55%), group B had 48 patients (2%), group C had 787 patients (35%), and group D had 180 patients (8%); 489 patients (22%) required hospitalization. In a multivariable model controlling for 20 factors and using group A as the reference, group B had an increased risk of hospitalization (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.0-4.9), whereas groups C (OR, 1.1; 95% CI, 0.8-1.5) and D (OR, 1.2; 95% CI, 0.8-1.9) did not. Among ED patients with acute asthma, those undergoing salmeterol monotherapy had an increased risk of hospitalization; however, this risk was not seen among patients undergoing combination ICS-salmeterol therapy. Our findings provide data from a unique ED population on clinical response to acute asthma treatment among patients undergoing long-term LABA therapy.