Effects of Direct Switching Dual Bronchodilators between Dry Powder and Soft Mist Inhalers in COPD Patients

Objective: Dual bronchodilation with long-acting muscarinic antagonist and long-acting β2-agonist combinations are available worldwide in COPD patients. However, the choice of agents remains under debate. We hypothesized that switching devices between dry powder and soft mist inhalers without a wash-out period to mimic clinical practice would improve clinical symptoms and lung function. The aim of this study was to examine the effects of switching between once-daily glycopyrronium/indacaterol (GLY/IND) or umeclidinium/vilanterol (UMEC/VI), dry powder inhalers, and tiotropium/olodaterol (TIO/OLO), a soft mist inhaler, in COPD patients. Methods: This was a prospective, open-label, 8-week, observational study with follow-up. Subjects included 57 COPD patients, who attended outpatient clinics at Shizuoka General Hospital for routine check-ups between February and December 2015, receiving GLY/IND (50/110 μg) or UMEC/VI (62.5/25 μg). After an 8-week run-in period, medications were switched to TIO/OLO (5/5 μg). Study outcomes included patient’s global rating (PGR), modified MRC (mMRC), COPD assessment test (CAT), and spirometric and forced oscillatory parameters after 8 weeks. PGR used in this study was a 7-point scale ranging from 1 to 7, with 4 in the middle. Patients who consented to switch from TIO/OLO to GLY/IND or UMEC/VI were followed-up thereafter. Results: In total, 53 patients completed the study (mean age, 75 years;48 males and 5 females;GOLD 1/2/3/4 = 19/27/6/1;mMRC 0/1/2/3/4 = 14/22/12/4/1;UMEC/VI 26, GLY/IND 27). PGR, mMRC, and CAT improved in 20 (38%), 9 (17%), and 15 patients (28%), respectively. Respiratory system resistance at 5 Hz (R5), 20 Hz (R20), and the difference between R5 and R20 (R5 - R20) significantly improved. In a follow-up of 16 patients after switching from TIO/OLO to UMEC/VI (9) or GLY/IND (7), PGR, mMRC, and CAT improved in 5 (31%), 3 (12%), and 4 patients (25%), respectively, and R20 significantly improved (p = 0.011). Conclusions: Switching dual bronchodilators between dry powder and soft mist inhalers improves symptoms and airway narrowing in some COPD patients.

Uniphyline-Induced Hypophosphatemia: A Rare Etiology of Severe Respiratory Failure

Hypophosphataemia is defined as low level of phosphate in the blood (normal range 0.8 - 1.4 mmol/l), which can be drug-induced such as uniphyline. We present a case of elderly female patient with known chronic obstructive pulmonary disease, admitted with acute respiratory failure and low serum phosphate level, her clinical signs and serum phosphate level did not improve with conventional therapy and intravenous phosphate replacement, until her recently commenced uniphyline was discontinued. This highlights the importance of awareness amongst the clinicians about this rare but potential side effect of uniphyline. We suggest monitoring phosphate levels in patients admitted with acute respiratory failure especially those on extended bronchodilator therapy.

Application of Inflammatory Markers in Induced Sputum in Stable Chronic Obstructive Pulmonary Disease Patients with Positive Bronchodilation Tests

Positive bronchodilation (BD) tests can be noticed in some stable chronic obstructive pulmonary disease (COPD) patients.The characteristics of airway inflammation in this entity remain unclear.Our study aimed to identify the characteristics of airway inflammation in stable COPD patients with positive BD tests.The airway inflammation was assessed in 88 patients with stable COPD using the examination of induced sputum in the aftermath of lung function and BD tests.Cellular counts and the levels of molecular markers including eosinophil cationic protein (ECP),myeloperoxidase (MPO),interleukin-5 (IL-5),and IL-8 were assayed by Wright's stain,Immuno-CAP system,and ELISA,RT-PCR.Among the 88 patients with stable COPD,20 (22.7%) showed positive BD tests.The values of eosinophils (4.7%±3.4%) and ECP (90.1±41.6 ng/mL) in induced sputum in stable COPD patients with positive BD tests were markedly elevated as compared with those in stable COPD patients with negative BD tests or in healthy controls (all P<0.05),but significantly lower than those in asthmatic patients (all P<0.01).The IL-5 in sputum supernatant was significantly decreased in stable COPD patients with positive BD tests as compared with the patients with asthma (12.5±7.8 vs.48.2±26.0 ng/mL;P<0.01).However,healthy controls exhibited similar concentrations of IL-5 in induced sputum with patients with stable COPD,whether with positive or negative BD tests (all P>0.05).Moreover,the values of neutrophils (61.8%±15.1%),MPO (574.0±111.8 ng/mL),and IL-8 (32.6±13.4 ng/mL) in induced sputum in stable COPD patients with positive BD tests were significantly higher than those in asthmatics or normal controls (all P<0.01).However,the values of the above inflammatory markers in induced sputum were similar among stable COPD patients with positive or negative BD tests (all P>0.05).The stable COPD patients with positive BD tests may present not only eosinophilic airway inflammation but also neutrophilic airway inflammation.

Phytopharmacological evaluation and anti-asthmatic activity of Ficus religiosa leaves

Objective:To discuss phytopharmacological potential and anti-asthmatic activity of Ficus religiosa(F.religiosa)(L.).Methods:Fresh leaves of F.religiosa were obtained from Vastrapur Lake,Ahmedabad,and dried to obtain powder.Histamine and acetylcholine were used to guinea pigs to establish bronchospasm model.In in vivo study,the aqueous extract of F.religiosa leaves (AEFR) at doses of 150 and 300 mg/ kg was administrated to guinea pigs,and the broncho-protective activity of AEFR was compared with aminophylline at 25 mg/kg.While in in vitro study,and 10 g/mL,20 g/mL,30 g/mL of AEFRL was administrated to guinea pigs,respectively, and mast cell stabilizing activity of AEFR was compared with ketotifen at 10 g/mL.Results: In the in-vivo model,pre-treatment with aminophylline(25 mg/kg,ip.) could significantly delay the onset of histamine induced pre-convulsive dyspnea,compared with vehicle control. Administration of AEFRL(150 and 300 mg/kg,ip.) also produced significant effect on latency to develop histamine & acetylcholine induced pre-convulsive dyspnea.In the mast cell stabilizing model,AEFRL at 10,20 and 30μg/mL could significantly increase the number of intact cells. Conclusions:It can be concluded that AEFRL is effective on histamine & acetylcholine induced bronchospasm in guinea pigs.In addition,AEFRL can potentiate the number of intact cells in the mast cell stabilizing model._____________________________________________________

Evaluation of antimicrobial activity and bronchodialator effect of a polyherbal drug-Shrishadi

Objective:To investigate antimicrobial and bronchodialator effect of hydroalcholic extract of polyherbal drug Shirishadi containing Shirisha(Albezzia lebbeck),Nagarmotha(Cyprus ratandus) & Kantakari(Solanum xanthocarpum).Methods:Antimicrobial activity was evaluated by discdiffusion method and MIC,MBC,MFC were calculated by micro dilution method.Hydroalcholic extract of this preparation was investigated for its phytochemical analysis,phenol and Oavonoid were determined by speclrophotometric method and in vivo bronchodilator effect was analysed by convulsion time.Results:The phytochemical tests revealed presence of alkaloids, anthraquinones,carbohydrates,flavonoids,saponins and tannins.The antimicrobial result showed the MIC of 6.25 mg/ml.against Staphylococcus aureus and 12.5 mg/mL.for Escherichia coli and 12.5 mg/mL against remaining bacteria tested,with strong antifungal activity.The maximum inhibition zone is found against Pseudomonas aeruginosa with MIC 16 mg/mL Drug showed significant bronchodilator effect with 27.86%& 36.13%increase in preconvulsion time of guinea pigs prebeated with 100 & 200 mg/kg body weight of extract.Conclusions:The study reveals that the extracts possess antibacterial activity and antifungal activity in a dose dependent manner. This antimicrobial property may be due to presence of several saponins,further studies are highly needed for the drug development.

Benefit of prophylactic bronchodilator withβ2 adrenergic agonist in ischemia-reperfusion-induced lung injury

Primary lung graft dysfunction could significantly attribute to ischemia-reperfusion lung injury(IRLI)during transplantation surgery.β2-adrenergic agonists were one of the bronchodilators that had been well-established in the management of asthma and chronic obstructive pulmonary disease(COPD)with anti-inflammatory potency.By applying the model of isolated rat lung,we evaluated the efficacy of short-actingβ2-agonist inhalation to ameliorate ischemia-reperfusion damage.The experiment protocol was 180 min of global ischemia and then reperfusion for 60 min.In theβ2-agonist inhalation group,aerosolized albuterol was administrated prior ischemia procedure.Increased weight ratios of wet to dry lung and microvascular permeability were characterized in the IRLI group.In contrast,pre-inhaledβ2-agonist significantly mitigated the severity of pulmonary edema.Bronchoalveolar lavage from theβ2-agonist group presented decreased leukocyte counts and cytokines production,including interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and macrophage inflammatory protein 2(MIP-2).Devastating oxidative stress was widely recognized during the ischemia-reperfusion process,whileβ2-agonist pretreatment revealed subsided H2O2,myeloperoxidase(MPO),and the cleavage of caspase-3.Western blotting from lung homogenates identified the blockade of NF-κB and MAPK activation in theβ2-agonist inhalation group.Currently,there was no specific pharmacotherapy in IRLI management.Our results elucidated the protective effect ofβ2-agonist bronchodilator against ischemia-reperfusion induced oxidative stress,inflammation reaction,and pulmonary edema.

The Clinical Role of Changes of Maximum Expiratory Flow at 25%and 50%of Vital Capacity before and after Bronchodilator Reversibility Test in Diagnosing Asthma

Summary:Changes of maximum expiratory flow at 25%and 50%of vital capacity(MEF2s and MEFso,respectively),and predominant parameters indicating small airways function in asthmatics before and after bronchodilator(BD)reversibility test have been less interpreted.Our study aimed to investigate the clinical role of changes of MEF2s and MEFso before and after BD reversibility test in diagnosing asthma.Forced expiratory volume in the first second(FEV),MEF2s,and MEFso were measured before and after BD reversibility test in 207 asthmatic patients using standard process.Forty healthy individuals were enrolled as controls.Receiver operating characteristic(ROC)curve was used to assess the diagnostic accuracy of reversibility of MEF2s and MEFgo before and after BD reversibility test(OMEF 2s%and AMEF so%,respectively)in diagnosing asthma.Among these functional criteria,AMEF2;%and 0MEFs%≥25%performed the best diagnostic performance.The sensitivity,specificity,and accuracy of AMEF 25%≥25%as an objcctive diagnostic test for asthma were 63.29%,87.50%,and 67.21%,and of AMEFs0%≥25%were 79.23%,85.00%,and 80.16%,respectively.The area under the ROC curve of the indicators was 0.8203 and 0.9104,respectively.By contrast,an increase in FEV≥12%and 200 mL demonstrated a sensitivity of 62.32%,specificity of 82.50%,and accuracy of 65.59%in diagnosing asthma.The changes of MEF2s and MEFso before and after BD reversibility test may be of additional value in the clinical diagnosis of asthma,with cutoff values of 25%being the most.

High-frequency electrical stimulation of cervical vagi reduces airway response to methacholine

AIM: To test whether high-frequency electrical stimulation(HES) of the bilateral cervical vagus nerves reduces the airway responses to methacholine(MCh).METHODS: Guinea pigs were pretreated with saline(Sal, n = 9) or ovalbumin(Ova, n = 10) aerosol for two weeks(5 min/d, 5 d/wk) and subsequently anesthetized, paralyzed, tracheotomized and artificially ventilated. Both total lung resistance(RL) and dynamic pulmonary compliance(Cdyn) were recorded. In addition, the effects of vagal low-frequency electrical stimulation(LES, monophasic, 50 Hz) and HES(monophasic and biphasic, 1 and 2.5 kH z) for about 10 s or 2 min on the responses of RL and Cdyn to MCh aerosol-induced bronchoconstriction were compared in both groups of guinea pigs. In a few guinea pigs, the impact of bivagotomy on the RL responses to MCh was assessed.RESULTS: Before MCh challenge, LES, but not HES, significantly increased RL by about 30%(P < 0.01) and decreased Cdyn by about 20%(P < 0.01) similarly in both groups. MCh aerosol for 2 min elevated RL and diminished Cdyn more in Ova- than Sal-treated animals(RL: 313% ± 52% vs 113% ± 17%, P < 0.01; Cdyn:-56% ± 7% vs-21% ± 3%, P < 0.01). During MCh-induced airway constriction, LES further enhanced, but HES decreased RL and this decrease was greater in Ova-(about 45%) than Sal-treated animals(about 34%, P < 0.01) with little change in cardiovascular activity. On the other hand, LES further reduced whereas HES increased Cdyn more in Ova-(about 20%) than Sal-treated animals(about 13%, P < 0.01). In addition, bivagotomy almost eliminated the RL and Cdyn responses to MCh. CONCLUSION: We conclude that vagal HES is able to alleviate the bronchoconstriction induced by MCh in anesthetized guinea pigs, likely via reversible inhibition/blockade of vagal conduction.

Pharmacological therapy for stable chronic obstructive pulmonary disease

In recent years,emphasis has shifted from preventing and treating chronic obstructive pulmonary disease(COPD)to early prevention,early treatment,and disease stabilization,with the main goal of improving patients’quality of life and reducing the frequency of acute exacerbations.This review summarizes pharmacological therapies for stable COPD.

Relationship among bacterial colonization,airway inflam-mation, and bronchodilator response in patients with stable chronic obstructive pulmonary disease

Bronchodilator reversibility, a response of airway to bronchodilator, occurred in 64% of stable patients with chronic obstructive pulmonary disease （COPD）. In patients with COPD who have a significant response to bronchodilators, a clinical and functional response to inhaled corticosteroids is similar to that in asthmatics.

A clinical study to determine the threshold of bronchodilator response for diagnosing asthma in Chinese children

Background There is few objective,clinically feasible and inexpensive test for diagnosing childhood asthma.We want to find an ideal way to solve it.Methods The control group was 301 non-asthmatic children,and the asthma group was 286 asthmatic children.The asthmatic children were divided into three groups according to the severity of their disease.Pre-and post-bronchodilator spirometer tests were performed,and the main spirometer parameters were compared.The bronchodilator response(BDR)[BDR is used to determine the reversibility of airway obstruction by measuring the changes of forced expiratory volume in the first second(FEV1)before and after inhalation of bronchodilators]was then determined,and the optimal threshold of BDR for diagnosing childhood asthma was found.Results 301 non-asthmatic children and 286 asthmatic children participated in the study,the demographics were similar.FEV 1 for pre-bronchodilator of asthmatic children was significantly lower than that of non-asthmatic children(P≤0.01).BDR of non-asthmatic children was 3.30±3.85%.BDR of asthmatic children was 9.45±9.15%.There was no significant difference in BDR for patients with different severities of asthma within the group.BDR had no statistical correlation with gender,age,height,weight in neither non-asthmatic children nor asthmatic children.On the receiver-operating characteristic curve,a BDR threshold of≥7.5%offered an optimal balance in asthma diagnosis with a sensitivity rate of 50.7%and specificity rate of 87.7%.Meanwhile,with a BDR threshold of≥12%,the sensitivity rate was 28.7%and the specificity rate was 96.3%.Conclusion A BDR threshold of≥7.5%has more value in childhood asthma diagnosis as compared to≥12%.

Effect of ipratropium bromide on airway and pulmonary muscarinic receptors in a rat model of chronic obstructive pulmonary disease

OBJECTIVE: To observe the level of muscarinic receptors in airway and lung tissues, and the effect of inhaled ipratropium bromide on these receptors in a rat model of chronic obstructive pulmonary disease (COPD). METHODS: This model was developed by exposure of rats to 250 ppm SO2 gas, 5 h/d, 5 d/wk, for a period of 7 wk. The COPD rats inhaled 0.025% aerosolized iratropium bromide for 20 min, 2 times daily, in an airtight chamber. Muscarinic receptors in airway and lung tissues of normal rats, ipratropium bromide-treated COPD rats and the recovering COPD rats were measured by the radio-ligand binding assay. RESULTS: Airway/lung pathology and pulmonary function tests showed that chronic SO2 exposure caused pathophysiologic changes similar to those observed in human COPD. The density (0.038 +/- 0.011, pmol/mg protein) and affinity (Kd, 23 +/- 11 pmol/L) of muscarinic receptors in airway and lung tissues of COPD rats were not changed compared with those of normal control rats (0.030 +/- 0.008 and 29 +/- 19, respectively, P > 0.05). Densities of the muscarinic receptors were not changed after inhalation of ipratropium bromide for 5 days, but increased significantly after inhalation for 30 days, as compared with those of the untreated COPD rats. The muscarinic receptors returned the normal levels at day 6 after cessation of ipratropium bromide treatment. There were no differences among different groups of rats in equilibrium dissociation constants (Kd). CONCLUSION: A rat model of COPD with pathophysiologic changes similar to the human counterpart was developed using chronic SO2 exposure. There was no significant change in the number and function of muscarinic receptors in airway and lung tissues of the COPD rats, but upregulation of the muscarinic receptors was observed after long-term inhalation of ipratropium bromide.

Determinants for asthma control, quality of life and use of complementary and alternative medicine in asthmatic pediatric patients in four cities

Background Asthma is a significant chronic health problem worldwide. Management aims at disease control by reducing functional impairment and exacerbations and improving quality of life (QoL). We report a multi-center study to survey asthma control and QoL in four cities in the Pearl River Delta. Methods The conjoint survey involved ten Hong Kong pediatric hospitals/units, two Shenzhen hospitals, two Macao hos-pitals, and two Guangzhou hospitals on asthma control (using Asthma Control Test) and QoL (Pediatric Allergic Disease Quality of Life Questionnaire, PADQLQ). Acceptability of a treatment is graded as very good/good/fair/poor. Results Good asthma control was only reported in 80% subjects in Hong Kong, but higher in sister cities (85–94%, P<0.001). Allergic rhinitis, 'incense burning', and 'smoker in family' were prevalent among the four cities. Logistic regres-sion showed better control of asthma was associated with better PADQLQ (B=?0.029, P < 0.001), better acceptability of bronchodilator (B=?1.488, P = 0.025), negatively with 'smoker in family' (B=?0.83, P = 0.015) and various PADQLQ domains. Conversely, worse PADQLQ was associated with allergic rhinitis severity (B=4.77, P <0.001), poor control of asthma (B=7.56, P <0.001), increased frequency of traditional Chinese medicine use (B=1.7, P < 0.05), increased fre-quency of bronchodilator usage (B=1.05, P < 0.05), 'smoker in family' (B=4.05, P < 0.05), and incense burning at home (B=3.9, P < 0.05). Conclusions There are some clinical and cultural differences among the four southern Chinese cities within the Guangdong province. This study identifies potentially modifiable environmental and treatment factors associated with poor asthma control and QoL for health-care interventions. Having a smoker in the family is independently associated with poor asthma control and QoL.