Zataria multiflora affects pulmonary function tests, respiratory symptoms, bronchodilator drugs use and hematological parameters in chronic obstructive pulmonary disease patients: A randomized doubled-blind clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora is employed as an antitussive, anti-spasmodic, analgesic and etc. Agent in traditional medicine. The modern medical studies are also confirmed effects of this plant for treatment of respiratory problems via anti-inflammatory, anti-oxidant and immunomodulatory properties. AIM OF STUDY: We evaluated efficacy of Z. multiflora on tests of pulmonary function, respiratory symptoms, inhaled bronchodilator drugs use, and hematological factors in COPD patients. METHODS: Patients (n = 45) were randomly grouped in the following three groups: placebo group (P), groups received Z. multiflora extract 3 and 6 mg/kg/day (Z3 and Z6). FEV1 and MEF25-75, respiratory symptoms, inhaled bronchodilator drugs use and hematological factors were evaluated before and 1-2 months after treatment. RESULTS: Z. multiflora led to significant enhancement of FEV1 (p < 0.05 to p < 0.01). Respiratory symptoms were also considerably ameliorated following treatment with extracts for 1 and 2 months compared to baseline values (p < 0.05 to p < 0.001). In groups received extract, inhaled bronchodilator drugs use was remarkably declined at the end of study (both, p < 0.05). Reduction of total WBC was observed 1-2 months after treatment in treated groups with extract compared to baseline values (p < 0.05 to p < 0.001). Neutrophils were remarkably declined in Z3 and Z6 groups after 2-monthes compared to 1-month treatment (p < 0.05 to p < 0.01). CONCLUSION: The evidence show therapeutic effect of this herb on COPD patients which could be result from properties that help to decrease inflammation.

Efficacy and safety of a proposed omalizumab biosimilar compared to the reference product in the management of uncontrolled moderate-to-severe allergic asthma: a multicenter, phase III, randomized, double-blind, equivalency clinical trial.

Background and aims: Allergic asthma has a considerable burden on the quality of life. A significant portion of moderate-to-severe allergic asthma patients need omalizumab, an anti-immunoglobulin-E monoclonal antibody, as an add-on therapy. In this phase III clinical trial P043 (Zerafil®, CinnaGen, Iran) efficacy, safety, and immunogenicity were compared with Xolair® (the originator omalizumab). The primary outcome was the rate of protocol-defined asthma exacerbations. Methods: Exacerbation rates, Asthma Control Test (ACT) results, spirometry measurements, immunogenicity, and safety were evaluated. Each subject received either medication with a dose ranging from 150 to 375 mg based on pre-treatment serum total IgE level (IU/mL) and body weight (kg) every two or four weeks for a duration of 28 weeks. Results: Exacerbation rates were 0.150 (CI: 0.079-0.220) in the P043 group, and 0.190 (CI: 0.110-0.270) in the omalizumab group (per-protocol). The least squares mean differences of predicted Forced Expiratory Volume in the First second (FEV1) were -2.51% (CI: -7.17-2.15, P=0.29) and -3.87% (CI: -8.79-1.04, P=0.12), pre- and post-bronchodilator use. The mean ± SD of ACT scores at the screening and the last visit were 10.62 ± 2.93 and 20.93 ± 4.26 in P043 and 11.09 ± 2.75 and 20.46 ± 5.11 in the omalizumab group. A total of 288 adverse events were reported for the 256 enrolled participants. Among all, "dyspnea" and "headache" were the most reported ones. The overall incidence of adverse events (P=0.62) and serious adverse events (P=0.07) had no significant differences between the two groups. None of the samples were positive for anti-drug antibodies. Conclusion: P043 was equivalent to omalizumab in the management of asthma in reduction of exacerbations. There was no significant difference in other efficacy and safety parameters. Clinical trial registration: www.clinicaltrials.gov (NCT05813470) and www.IRCT.ir (IRCT20150303021315N20).

Diagnosis of chronic obstructive pulmonary disease earlier than current Global Initiative for Obstructive Lung Disease guidelines using a feasible spirometry parameter (maximal-mid expiratory flow/forced vital capacity).

Some patients suffer from clinical symptoms of chronic obstructive pulmonary disease (COPD) but their pulmonary function tests are in the normal range (at risk group). The objective of this study was to discover a practical test to distinguish these patients from non-COPD subjects. A total of 77 subjects including 40 COPD patients, 37 subjects at risk for developing COPD, and 32 control subjects were entered in this study. The accuracy of maximal-mid expiratory flow (MMEF)/forced vital capacity (FVC) for the diagnosis of COPD in at risk patients and its capability to differentiate from early COPD and normal patients were evaluated. Body plethysmography was used for measurement of lung volume as the Global Initiative for Obstructive Lung Disease standard. MMEF/FVC in the at risk group of COPD (0.73±0.19) was significantly lower than the normal control group (0.9±0.24, respectively), and also, it was significantly higher than the COPD group (0.31±0.17). There was significant correlation between the MMEF/FVC and amount of smoking measured by pack year (r2=0.112, p=0.005) and stages of COPD (Spearman's ρ=0.82, p=0.0001). Early stage COPD (smoker subjects without spirometry derangement) can be diagnosed by MMEF/FVC. Using this tool we may be able to detect this highly preventable disease at an earlier stage.

Parietal Pleural Lymphatic Blockage by Anthracotic Nodule Laden Macrophage, Leading Cause of Pleural Effusion in Anthracosis.

Anthracosis of lung is assumed to be a disease that causes parenchymal accumulation of macrophage-laden anthracotic nodules, which leads to bronchial obstruction, lung mass, and lymphadenopathy. Pleural surface anthracosis involvement as extra-parenchymal involvement has been rarely reported. Still, due to presentation with a transudate pattern, pleural effusion is considered to be a side effect of lung collapse. I represent two subjects with patches of anthracosis in the presumptive place of anatomical fenestra of lymphatic vessels in the parietal pleural. It may cause inhibition of reabsorption of pleural fluid and finally accumulation of transudate pleural effusion. Involvement of the pleura by anthracosis, and black discoloration of the parietal pleura have already been discovered by physicians who perform pleuroscopy. The pleural involvement by anthracosis is usually diffuse. In these two subjects, pleural involvement was in the early stage of anthracosis, which helped me to introduce a new mechanism for transudative pleural effusion due to blockage of the pleural lymphatic channels entrance.

Comparison of Longevity in Patients with Idiopathic Pulmonary Fibrosis Using Pirfenidone Versus Triple Therapy with Prednisolone, Azathioprine, and Acetylcysteine.

Background: The effect of the combination of prednisolone, azathioprine, and acetylcysteine for the treatment of Idiopathic pulmonary fibrosis (IPF) is minimal. We aimed to investigate the effect of these drugs in case of intolerance to new anti-fibrotic drugs. Materials and Methods: This historical prospective study was performed on 91 patients with idiopathic pulmonary fibrosis who were referred to a pulmonologist in Mashhad during 2016-2020. Patients were divided into two groups, Pirfenidone which was prescribed for 46 subjects, and a combination of prednisolone, azathioprine, and acetylcysteine which was prescribed for 45 subjects. Patients were selected by convenience sampling and a life expectancy comparison between the two groups was performed by Cox regression. Results: There were no statistically significant differences between age, gender, and drug type in the two groups at the beginning of treatment. The death rate per year in the triple-drug treatment group was 44.44% (n = 20) and in the Pirfenidone treatment group was 11.08% (n=2). Of the 65 recovered population, 49% (22 patients) were in the triple-drug treatment group, and 78% (36 patients) were in the Pirfenidone treatment group which indicated that Pirfenidone has a significant impact on reducing death rate compared to triple-drug treatment (pvalue=0.003 <0.05). Pirfenidone decreased the risk of death, compared to triple therapy (0.23 when death was set up as one in the triple-therapy group). Conclusion: Pirfenidone has a favorable effect on increasing life expectancy and triple therapy should be considered as short-term only in subjects intolerant to anti-fibrotic.

Itraconazole Improved Bronchial Wall Thickness in Severe Persistent Asthma: A Double-blind Placebo-controlled Randomized Clinical Trial.

The purpose of this study was to evaluate the effect of 8 months of treatment with itraconazole on airway wall thickness in patients with severe persistent asthma. It was a double-blind, randomized, placebo-controlled clinical trial (IRCT20091111002695N9). Seventy-five subjects with severe persistent asthma received itraconazole (100 mg), prednisolone (5 mg), or placebo twice a day for eight months in three treatment groups (n=25 in each group). The primary objective was to improve the right upper lobe apical segmental bronchus (RB1) wall thickness percentage measured by high-resolution computed tomography scan of the lungs. Other morphometric measurements of RB1, asthma control test (ACT) score, presence of wheezing, dyspnea severity, rate of asthma exacerbation, fractional exhaled nitric oxide (FeNO), and expiratory volume in 1 second (FEV1) were set as the secondary outcomes. Wall thickness percentage reduced significantly from 46% to 43.7% from pre- to post-treatment in the itraconazole-treated subjects. Similarly, lumen area and radius increased significantly in both the prednisolone and itraconazole groups. Itraconazole led to a significant improvement in wheezing, dyspnea severity, FEV1, ACT score, and FeNO. Although prednisolone was also effective in improving pulmonary function tests and ACT scores, it was associated with significantly more side effects than itraconazole. Long-term treatment with itraconazole resulted in a significant reduction in bronchial wall thickness and improvements in clinical findings and pulmonary function tests. Thus, itraconazole could be a helpful add-on treatment option for severe persistent asthma patients to achieve better disease control.

Comparison of the effects of itraconazole and prednisolone on fibroblast growth factor-2 gene expression and clinical manifestations in patients with persistent severe asthma.

Background and Purpose: Considering the possible role of fungal sensitization in the treatment of resistant asthma, which may lead to the remodeling of bronchial structure, we theorized that itraconazole could result in better control of asthma. In this regard, this study aimed to compare the effects of itraconazole and prednisolone (routinely prescribed) on clinical, structural, and biomarker findings of the remodeling of asthma. Materials and Methods: This double-blind controlled randomized clinical trial was performed on 70 adult patients suffering from severe persistent asthma. The intervention group received 200 mg of itraconazole per day, and the control group received 10 mg of prednisolone per day, for 32 weeks, in addition to the classic treatment of asthma. The subjects were randomly divided into two groups, and assigned by sealed envelope. Blinding was performed by repacking the drug in a similar container. Primary outcomes were asthma control test score, fibroblast growth factor 2, and wall area percentage on RB1 bronchus measured by computed tomography. The outcomes were compared in subjects classified as allergic, eosinophilic, T2 low asthma, and four types of inflammatory cell classification in sputum. Results: Seventy subjects finished the 32-week trial (35 subjects in each group). Baseline data did not show significant differences between groups. A comparison of asthma variants showed significantly more severe cough and dyspnea in the allergic variant and higher spirometry results in T2-low asthma. Sputum cytology revealed a mixed pattern as the most frequent type (47%). After the trial, two groups improved in many parameters; however, FGF-2 improved more significantly by itraconazole (4.66±16.92 decreased to 1.14±2.98), and FEV1/FVC was significantly higher in the itraconazole group, compared to the control group. These results did not change in terms of asthma variants and sputum classification. Conclusion: Itraconazole was superior to prednisolone in the treatment of many clinical and spirometry aspects in severe persistent asthma.

Efficacy of Herbal Medicines on Lung Function in Asthma: a systematic review and meta-analysis of randomized controlled trials.

Objectives: The present study was designed to conduct a comprehensive systematic review and meta-analysis to assess the efficacy of herbal medicines as add-on therapy on lung function in asthmatic patients. Methods: A comprehensive search of online databases was performed up to December 2021 to identify randomized controlled trials that used orally herbal preparations for asthma as add-on therapy. Studies were assessed for methodological quality using the Cochrane Collaboration's Risk of Bias tool. The main outcome was percent predicted value of forced expiratory volume (% predicted FEV1). Pooled weighted mean difference (WMD) estimate with corresponding 95% confidence interval (CI) was calculated using inverse-variance weights method while random effects meta-analysis was used, taking into account clinical and conceptual heterogeneity. Results: As a result, 1,525 studies were identified. 169 studies were reviewed in-depth and 23 studies met our systematic review inclusion criteria. Finally, nine randomized controlled trials were included in the meta-analysis. Findings indicated that use of herbal medicines in patients with asthma significantly improved % predicted FEV1 (WMD 3.73, 95% CI 1.76-5.70), with no evidence for significant heterogeneity (p = 0.56 [Q statistic], I2 = 0.0%). In subgroup analysis by age, improvement in % predicted FEV1 was higher and significant in adults (WMD 5.16; 95% CI 2.68-7.63) compared to children (WMD = 1.27; 95% CI -1.98-4.51). Sensitivity analysis showed the significant effect of herbal medicine consumption on improving FEV1 was consistently (range of summary WMDs 3.27-4.59), indicating that the meta-analysis model was robust. There was no evidence of publication bias both visually and statistically. Conclusion: Findings support, the complementary use of herbal medicines resulted in significant improvement in the lung function compared to standard treatment in asthmatic patients with no considerable adverse events. This improvement is more likely to be observed amongst adults.

The association between MUC5AC and MUC5B genes expression and remodeling progression in severe neutrophilic asthma: A direct relationship.

BACKGROUND: MUC5 dysregulation is a hallmark of severe neutrophilic asthmatic patients. This study investigates the expression of MUC5AC and MUC5B at mRNA levels on asthma severity and airway wall thickness in severe neutrophilic asthmatic patients. METHOD: In this case-control clinical trial, twenty-five severe neutrophilic asthmatic patients and ten control subjects were enrolled. Subjects underwent ACT, pulmonary functions tests, and fractional exhaled nitric oxide (FENO). Also, induced sputum has been obtained to assess the expression of MUC5AC and MUC5B by the real-time PCR. In addition, the thickness of the airway wall was assessed by high-resolution computed tomography (HRCT), and bioinformatic analysis was implemented to approve the selection of the appropriate genes and for further investigations. RESULT: A significant difference was observed between the asthmatic and control in MUC5AC and MUC5B mRNA expression. Meanwhile, the expression of MUC5AC increased remarkably by asthma severity; also, it is associated with airway wall thickness (WT) (both P-value <0.05). The expression of MUC5B in asthmatic patients was lower than in control. There is no significant correlation between MUC5B mRNA level and WT and asthma severity. Notably, MUC5AC transcription level was correlated to sputum neutrophil percentage, while MUC5B transcription level had a positive correlation with sputum macrophages and a negative one with sputum neutrophils. CONCLUSION: In severe neutrophilic asthma, airway wall thickness increases with MUC5AC mRNA overexpression, which is probably related to asthma severity and the formation of mucus plugs. However, the expression of MUC5B was decreased, resulting in poor mucociliary clearance in the airways. TRIAL REGISTRATION: IR.IAU.MSHD.REC.1400.124.

Effect of verapamil on bronchial goblet cells of asthma: an experimental study on sensitized animals.

INTRODUCTION: Goblet cell hyperplasia (GCH) and mucus hypersecretion in the airway is recognized as an important contributor to morbidity and mortality in asthma and COPD. Verapamil is a calcium channel blocker that binds to the alpha-subunit of L-type calcium channels and inhibits the mucin gene via the calmodulin and CaM kinase pathway. The objective of this study was to determine the in vivo effect of verapamil on GCH and eosinophilic inflammation in sensitized mice. METHODS: Male BALB/c mice were sensitized to ovalbumin using the standard method. Two groups of animals were received verapamil via an intramuscular injection: 1-low dose (0.5 mg/kg/day for two weeks), 2-high dose (1.5 mg/kg/day for two weeks). Serum and bronchoalveolar lavage fluid (BALF) was collected and analyzed for inflammatory cells, interferon-γ and IL-4. The left lung was sent for histopathological evaluation, especially for periodic acid-Schiff (PAS), to identify goblet cells in the epithelium. The degree of inflammatory cell infiltration, including eosinophils, mucus plugging, and smooth muscle thickness of the airways were classified on a semi quantitative scale. RESULTS: Inflammatory cell infiltration in peribronchial and perivascular areas was observed in all sensitized groups. Eosinophils percentage in the BALF significantly decreased in verapamil-treated mice compared with sensitized mice (from 19.8% in asthmatic to 5.4% for low dose and 4.4% for high dose). The ratio of airway goblet cells per epithelial cells were significantly lower in verapamil-treated mice versus sensitized mice (1.57±1.30% for low dose; 1.50±0.93% for high dose versus 12.93±7.55%, P<0.05, respectively). Mucus production of goblet cells decreased significantly in verapamil-treated mice versus sensitized mice (mean score was 1.45±0.30 for low dose; 0.81±1.00 for high dose versus 2.85±0.86 in the sensitized control group, P<0.05, respectively). The concentration of serum and BALF-IFN-γ in verapamil-treated mice markedly increased by the verapamil treatment when compared to sensitized mice (15.1±0.43 versus 4.7±0.96, P<0.05 and 91.8±47.7 versus 14.8±4.6, P<0.01, respectively). CONCLUSION: Verapamil is a useful drug with therapeutic targeting on GCH and a potential way to limit mucous production and improve bronchial inflammation.

Effective Treatment of Chronic Cough with Tinidazole as the Newest Antiprotozoa against Lophomonas blattarum.

Background: Chronic cough is a common problem in the setting of family physicians. Recently, Lophomonas blattarum was considered a cause of respiratory symptoms in children and adults. Objective: This study is aimed at determining the effect of antiprotozoal treatment of Lophomonas in patients with a chronic cough in Mashhad during 2020-2021. Materials and Methods: This study was a randomized clinical trial. In this study, 60 patients with chronic cough and unremarkable imaging findings, who were unresponsive to three steps of standard treatment, were randomly assigned to the treatment, with 2 weeks of tinidazole and placebo. The tinidazole and placebo were prepared in a completely identical shape, and a random assignment was performed by a third party. The primary outcome was a complete resolution of cough. A follow-up of treatment was performed. Data were analyzed using the SPSS software version 25. Results: The basic demographic results showed no significant differences of sex and age between two groups. The results of this study showed a complete resolution of all respiratory symptoms in 40% (12), a complete improvement of cough in 40% (12), and a complete resolution of dyspnea in 50% (10) of the tinidazole group. The remaining showed significant improvement in the severity of cough and dyspnea. Postnasal drip, sputum, body temperature, and airway hyperresponsiveness were improved significantly. After tinidazole treatment, laboratory assessment of bronchial lavage and sputum revealed that 86 percent of smears were converted to negative. Conclusion: Tinidazole effectively resolved the chronic cough and most of the respiratory symptoms. Lophomonas blattarum is a potential mechanism for chronic cough.

The effect of two-month treatment with Zataria multiflora on inflammatory cytokines, pulmonary function testes and respiratory symptoms in patients with chronic obstructive pulmonary disease (COPD).

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora Boiss. (Z. multiflora) is a valuable medicinal plant that has been used in Iranian traditional and folk medicine as an antiseptic, carminative, diaphoretic, diuretic, anti-spasmodic and analgesic herbal medicine. This plant has been also used to relieve cough in common cold and respiratory tract disorders. The previous studies reported the pharmacological effects of Z. multiflora such as anti-inflammatory and anti-oxidant properties in respiratory disorders in animal models and clinical studies. AIM OF THE STUDY: The effects of Z. multiflora extract on inflammatory cytokines, pulmonary function tests (PFT), and respiratory symptoms in chronic obstructive pulmonary diseases (COPD) patients were investigated. MATERIALS AND METHODS: COPD patients (41 cases) were divided to three groups including placebo group (P) and groups received 3 and 6 mg/kg/day Z. multiflora extract (Z3 and Z6) for two months. Inflammatory cytokines, PFT values, and respiratory symptoms were assessed before treatment (stage 0), one (stage I) and two (stage II) months after treatment. RESULTS: Serum levels of TNF-α and IL-8 were significantly decreased after two months treatment compared to baseline values in Z3 and Z6 groups. The PFT values including forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were significantly increased during two months treatment with Z3 and Z6. The peak expiratory flow (PEF) was also significantly increased after one-month treatment with Z6. The respiratory symptoms including cough, chest tightness, modified medical research council (mMRC) dyspnea scale were significantly improved after one and two treatments with both doses of Z. multiflora compared to baseline values. CONCLUSION: The results suggest the potential therapeutic effect of Z. multiflora in COPD patients through reduction of inflammatory cytokines, increasing PFT values and improvement of respiratory symptoms.

The Effect of Glasthma Syrup in Asthma: a study protocol for a triple-blind randomized controlled trial.

Objectives: Asthma is a chronic disease, and the demand for herbal medicines in this field has increased in recent years. The new findings highlight the role of the gut-lung axis in the pathophysiology of asthma. Hence, this study will evaluate the safety and efficacy of Glasthma syrup, an herbal formula based on Persian medicine, in improving asthma and regulating intestinal permeability. The formula consists of five herbal ingredients that have anti-inflammatory effects on the respiratory tract, also known as gut tonics. Methods: The study will be conducted as a placebo-controlled, triple-blind, randomized trial. It will consist of a 4-week intervention followed by a 4-week follow-up period. The target sample size is 20 patients with moderate asthma aged 18 to 60 years. Eligible participants will be randomly assigned to either the experimental group or the control group in equal numbers. Patients in the experimental group will take Glasthma syrup (7.5 mL, twice a day), while patients in the control group will take a matching placebo. Both groups will receive a 4-week combination of a long-acting beta2 agonist and a leukotriene modulator as standard of care. Inhaled corticosteroids can be used as rescue medication as needed. Results: The primary outcomes are asthma symptom scale, lung function, and intestinal permeability. Secondary outcomes include quality of life, symptom recurrence rates, and blood tests. A safety assessment will also be conducted during the trial. Conclusion: In this trial, the effects of Glasthma syrup in patients with moderate asthma will be examined. The study will also assess the effects of the formulation on the gut-lung axis by simultaneously monitoring the gut permeability index, asthma symptoms, and lung function.

Effect of Propolis on moderate persistent asthma: A phase two randomized, double blind, controlled clinical trial.

OBJECTIVE: The aims of this study was to determine the effect of Propolis (resinous mixture that honey bees produce by mixing saliva and beeswax) on clinical and physiological findings of moderate persistent asthma. MATERIALS AND METHODS: Fifty-two subjects aged 44.6±18.5 years old with moderate asthma and Forced expiratory volume in 1 second (FEV1) 60-79% of predicted, were enrolled in this clinical trial. We randomly allocated subjects to receive either propolis (75 mg three times a day) or a matched placebo for one month. Primary outcome was Asthma control test (ACT) score and secondary outcomes included dyspnea, spirometry, fractional exhaled nitric oxide (FENO) and sputum cytology including inflammatory cell. Sputum induction was done by hypertonic saline and cytology slides were stained by Papanicolaou stain. RESULTS: Clinical findings significantly improved after the treatment. ACT scores significantly increased by using propolis (12.8±5.5 before and 18.1±4.99 after the trial), which was significantly higher than the placebo group (14.4±6.6 after the trial). The most significant physiological improvements were significant increases in FEV1, FV1/Forced vital capacity and expiratory flows. FENO showed significant decreases in the propolis group but increases in the placebo group. Cytological examination of sputum showed that the pattern of inflammation was eosinophilic in 44% subjects with an average eosinophil of 7.2±1.01%. Eosinophilia significantly decreased (p<0.05) by using propolis (7.2±1.01 and 4.3±3.1%, before and after treatment, respectively), but it significantly increased (p<0.04) in the placebo group (5.5±2.8, and 11.1±6.6%, before and after treatment, respectively). CONCLUSION: Propolis improved the clinical and physiological findings of moderate persistent asthma, and it was able to suppress eosinophilic inflammation.

Effect of azithromycin on bronchial wall thickness in severe persistent asthma: A double-blind placebo-controlled randomized clinical trial.

BACKGROUND: Azithromycin reduced airway remodeling in animal models of asthma. However, its effect on human subjects has not been studied yet. This study aimed to investigate the effect of long-term treatment with azithromycin on airways wall thickness in patients with severe persistent asthma. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, patients with severe persistent asthma received azithromycin (250 mg, BID, three days a week), prednisolone (5 mg, BID), or placebo for eight months in three separate groups in addition to the standard therapy. The improvement in right upper lobe apical segmental bronchus (RB1) wall thickness obtained by high resolution computed tomography was set as the primary outcome. Secondary outcomes included: cough severity, dyspnea severity, asthma control test (ACT) score, asthma exacerbation rate, pulmonary function tests, and fractional exhaled nitric oxide (FENO). RESULTS: Seventy-eight out of ninety randomized subjects completed eight months of treatment with azithromycin (n = 25), prednisolone (n = 27), or placebo (n = 26). Bronchial wall thickness percentage did not change significantly in any of the groups. However, the inner radius and lumen area of azithromycin and prednisolone-treated subjects increased significantly (p < 0.05 for both). Azithromycin also significantly improved the dyspnea severity, ACT score, FENO, and FEV1, FEF25-75, and FEV1/FVC (p < 0.05 for all). Cough severity or asthma exacerbation rate did not change significantly after eight months of treatment with azithromycin. CONCLUSION: Long-term treatment with azithromycin increased lumen radius and lumen area in patients with severe persistent asthma. However, there was no significant change in wall thickness in any of the treatment groups. TRIAL REGISTRATION: IRCT.com (IRCT20091111002695N8).

A Randomized, Doubled-Blind Clinical Trial on the Effect of Zataria multiflora on Clinical Symptoms, Oxidative Stress, and C-Reactive Protein in COPD Patients.

The effects of Zataria multiflora on clinical symptoms, pulmonary function tests, oxidative stress, and C-reactive protein levels in chronic obstructive pulmonary disease (COPD) patients were evaluated. Forty-five patients were allocated to 3 groups: placebo group and 2 groups that received 3 and 6 mg/kg/day Z. multiflora extract (Z3 and Z6) for 2 months. Clinical symptoms, pulmonary function tests, oxidative stress, and serum C-reactive protein levels were evaluated pretreatment (step 0) and 1 (step I) and 2 (step II) months after treatment. Clinical symptoms including breathlessness and chest wheeze in Z3- and Z6-treated groups and sputum production only in the Z6-treated group were significantly improved 1 and 2 months after treatment compared with baseline values (P < .01 to P < .001). The FEV1 was significantly increased after 2 months of treatment with Z3 and Z6 (P < .05 to P < .01). Malondialdehyde and nitrite levels were significantly decreased after a 2-month treatment with Z6 compared with step 0 (P < .05 to P < .01). The thiol contents in the Z6 group as well as superoxide dismutase and catalase activities in both groups treated with the extract were significantly increased in step II compared with step 0 (P < .05 to P < .01). The C-reactive protein level at the end of the study was significantly reduced compared with the step 0 in both treated groups (P < .05 for both cases). Two-month treatment with Z. multiflora improved clinical symptoms, pulmonary function tests, oxidative stress, and C-reactive protein in COPD patients. The results suggest that this herbal medicine could be of therapeutic value as a preventive drug for the treatment of COPD.

Long-term effect of antifungal therapy for the treatment of severe resistant asthma: an active comparator clinical trial.

BACKGROUND AND PURPOSE: Itraconazole therapy has been reported to control asthma in severe therapy-resistant asthma with fungal sensitization. The aim of this study was to investigate the impact of anti-fungal therapy on the treatment of severe asthma, irrespective of sensitization. MATERIALS AND METHODS: This active comparator clinical trial was performed on 110 therapy-resistant asthmatic patients who were randomly assigned into two groups of case and control. The patients in the case group were administered 200 mg itraconazole twice a day and the control group received 10 mg prednisolone after breakfast for 4 months. The asthma control test (ACT) which was used as a marker for the global evaluation of treatment effectiveness (GETE) was applied as the primary endpoint parameter. Cough, dyspnea, and sleep disturbance were measured on a scale of 1-4, with 1 representing no symptom and 4 indicating severe exhausting disturbance. RESULTS: Based on the obtained results, 71% of the itraconazole group demonstrated a marked improvement in the GETE score after a four-month treatment. Itraconazole was able to suppress clinical symptoms, including cough, dyspnea, and night symptoms, and their physical exam was indicative of normalization in 60% of the patients. On the other hand, the patients in the parallel group "prednisolone" were only able to control dyspnea. The ACT score represented a notable improvement with itraconazole (mean: 14 before the trial and >20 after the trial) and spirometry parameters underwent a considerable change from obstructive pattern to normal. Furthermore, adverse effects were only detected in 6% of itraconazole users. CONCLUSION: The results of this clinical trial indicted the effectiveness of antifungal therapy for the control of the clinical condition of a subgroup of patients with severe steroid-refractory asthma.

Cromolyn, a New Hope for Limited Treatment of Neutrophilic Asthma: a Phase II Randomized Clinical Trial.

BACKGROUND: In this study, we aimed to determine the effects of cromolyn on the clinical outcomes and neutrophilic inflammation in patients with resistant cough-variant asthma. MATERIALS AND METHODS: Patients with cough-variant asthma, with normal physical examination and spirometry results, were treated by inhaled corticosteroids, antileukotrienes, antibiotics, and proton-pump inhibitors according to the Global Initiative for Asthma (GINA) guidelines. Seventy patients, who were resistant to these treatments, were enrolled in this double-blind randomized clinical trial. After randomization, eligible subjects received a cromolyn metered dose inhaler (MDI) or a placebo MDI, which was completely similar in appearance to the cromolyn inhaler. The primary outcomes included cough and Asthma Control Test (ACT) score. RESULTS: Based on the findings, cough significantly decreased with cromolyn therapy, compared to the placebo group. Other clinical findings, including dyspnea, sputum production, and nocturnal symptoms, also improved. The ACT score significantly improved to a nearly normal level (23.53±2.25) in the cromolyn group. Moreover, fractional exhaled nitric oxide (FeNO) significantly decreased with cromolyn treatment (14±9.31 ppm after treatment vs. 28.88±27.39 before treatment). The neutrophil count significantly decreased in the cromolyn group (from 44±24.2% before the trial to 34.08±16.7% after the trial), while it increased in the placebo group (from 39.67±26.47% to 56.71±27.22%). CONCLUSION: Cromolyn improved the clinical findings of resistant cough-variant asthma and could suppress neutrophilic inflammation.

Effect of Salmeterol-Fluticasone Combination and Tiotropium on Clinical and Physiological Improvement of Bronchial Anthracofibrosis: a Double Blind Randomized, Cross Over, Placebo Controlled, Clinical Trial.

BACKGROUND: Bronchial anthracosis is the black discoloration of bronchial mucosa that exhibits similar manifestations to Chronic Obstructive Pulmonary Disease ( COPD). The etiology of this obstructive lung disease has not been elucidated and standard therapy for this disease has not been introduced in the literature. The objective of this study is to determine the efficacy of the salmeterol-fluticasone inhaler and tiotropium as two safe treatments of obstructive lung disease for the treatment of symptomatic subjects of anthracofibrosis of the lung. MATERIALS AND METHODS: Twenty anthracofibrosis subjects who suffered from dyspnea were enrolled in this three-phase, cross over, placebo-controlled clinical trial. The primary outcome variable was quality of life (evaluated with the CAT questionnaire). Clinical findings and spirometry were the secondary outcome variables. Both of these drugs were delivered by an inhaler and were made identically by the reference manufacturer. Salmeterol-fluticasone was prescribed with a spacer and tiotropium by its special device, and the method of utilization was taught to the patients. RESULTS: Twenty anthracofibrosis subjects were enrolled in this three-phase, five-month course of treatment with either salmeterol-fluticasone or tiotropium inhalers. The response to therapy was not good; neither for salmeterol-fluticasone nor for tiotropium in the short course of the treatment. However, the overall results of 5 months of therapy with both of the drugs have shown improvement in 57% of the subjects. The most prominent results were found in the CAT score [25.1±5.54 before the trial, which decreased to 19.2±5.14 (Z score=2.7, P=0.007)] and clinical findings especially sputum, chest pain, and wheezing (81, 94 and 92% before the trial and 50, 56, 54% after the trial, respectively). Neither clinical findings nor spirometry was able to predict a good response to salmeterol-fluticasone or tiotropium. CONCLUSION: The combination of salmeterol-fluticasone and tiotropium inhaler was able to improve the clinical findings of symptomatic anthracofibrosis patients.

Effects of Rosmarinus officinalis and Platanus orientalis extracts on asthmatic subjects resistant to routine treatments.

OBJECTIVE: The present study aimed to determine the effects of Rosmarinus officinalis (R. officinalis) and Platanus orientalis (P. orientalis) extracts on asthma. MATERIALS AND METHODS: We conducted a randomized, double-blind, active-comparator study to evaluate the effect of P. orientalis and R. officinalis extracts on asthmatic patients resistant to routine treatment. The subjects were randomly divided into three groups receiving P. orientalis and R. officinalis extracts alone or in combination. The primary endpoints were clinical findings, spirometry, exhaled nitric oxide (FENO) and Asthma Control Test (ACT) assessed over the one-month treatment period. RESULTS: ACT score showed significant improvement after treatment with R. officinalis (p<0.05) but not with P. orientalis. Clinical evaluations showed that cough, sputum production and wheezing were significantly improved in R. officinalis group (p<0.05 to p<0.001) while in P. orientalis group only improvement of cough and chest tightness were shown. Spirometry results showed significant improving in FEV1/VC values for subjects treated with P. orientalis and those who received the combination of extracts as well as significant decrease in FEF25-75 value only for P. orientalis group (p<0.05 for all cases). FENO was decreased in both groups but the results were statistically significant only for R. officinalis group (p<0.05). Abdominal pain and skin rash were the most frequent side effects of the treatments which led to discontinuation of the intervention. CONCLUSION: R. officinalis extract showed promising results in treatment of resistant asthma. Further studies to find the most effective components of these herbal medicines are recommended.