Effect of Traditional Chinese Medicine on Outcomes in Patients with Mild/Moderate Chronic Obstructive Pulmonary Disease: study protocol for a randomized placebo-controlled trial

ABSTRACT: BACKGROUND: Chronic obstructive pulmonary disease (COPD) has become a major public health problem worldwide because of its high and increasing prevalence, morbidity, and mortality. Little attention has been paid to earlier stages of COPD or before it has developed. It has reported that TCM may have some advantages in relieving symptoms, reducing the incidence of COPD exacerbations. It is hypothesis that in patients with COPD will benefit with the therapy with TCM treatment according to syndrome differentiation. Methods and design: A prospective, multi-center, double-blinded, double-dummy and randomized controlled method was conducted to test the therapeutic effects of TCM treatment with syndrome differentiation. A total of 504 patients will be enrolled into this study with 252 in each treatment group. Patients will receive medication according to their assigned group. TCM for COPD administered twice daily over 52 weeks, all patients followed 52 weeks. The FEV1 and exacerbations, will be used as the primary outcome measures. The quality of life and the modified medical research council dyspnea (MMRC) scale and The Six-Minute Walk Test (6MWD) will be used as the secondary outcome measures. DISCUSSION: It is hypothesis that in patients with COPD will benefit with the therapy with TCM treatment according to syndrome differentiation. Trial registration: This study is registered at ClinicalTrials.gov, NCT01486186 KEYWORDS: Chronic obstructive pulmonary disease, Traditional Chinese Medicine, treatment, Clinical trials.     

Microsomal epoxide hydrolase is not associated with COPD in a community-based sample

Microsomal epoxide hydrolase (EPHX1) is an important gene because of its role in the metabolism of components of cigarette smoke; thus it may be an important potential modifier of the risk of developing smoking-related lung disease, such as chronic obstructive pulmonary disease (COPD). Several studies have investigated EPHX1 and COPD, but some of these studies have potentially been affected by genotyping error. We investigated the influence of single nucleotide polymorphisms (SNPs) in EPHX1 on well-characterized COPD and intermediate phenotypes. A total of 1,232 participants completed a detailed respiratory questionnaire and spirometry. From this sample, 72 COPD cases (FEV1/FVC < 0.70 and FEV1 < 80% predicted) and 220 control subjects (no respiratory symptoms and normal lung function) were selected for analysis. The EPHX1 exon 3 and EPHX1 exon 4 polymorphisms were carefully genotyped to avoid error using several methods. We found that the EPHX1 exon 3 polymorphism was not associated with an increased risk of COPD, nor was the EPHX1 exon 4 polymorphism. In addition, none of the EPHX1 haplotypes were associated with an increased risk of any COPD phenotype. This finding, along with doubt shed on the accuracy of other studies that have demonstrated positive associations, suggests that a strong role for the EPHX1 polymorphisms in respiratory disease is unlikely.     

How Does Socioeconomic Development Affect COPD Mortality? An Age-Period-Cohort Analysis from a Recently Transitioned Population in China

Background

Chronic obstructive pulmonary disease (COPD) is a leading cause of death, particularly in developing countries. Little is known about the effects of economic development on COPD mortality, although economic development may potentially have positive and negative influences over the life course on COPD. We took advantage of a unique population whose rapid and recent economic development is marked by changes at clearly delineated and identifiable time points, and where few women smoke, to examine the effect of macro-level events on COPD mortality.

Methods

We used Poisson regression to decompose sex-specific COPD mortality rates in Hong Kong from 1981 to 2005 into the effects of age, period and cohort.

Results

COPD mortality declined strongly over generations for people born from the early to mid 20th century, which was particularly evident for the first generation to grow up in a more economically developed environment for both sexes. Population wide COPD mortality decreased when air quality improved and increased with increasing air pollution. COPD mortality increased with age, particularly after menopause among women.

Conclusions

Economic development may reduce vulnerability to COPD by reducing long-lasting insults to the respiratory system, such as infections, poor nutrition and indoor air pollution. However, some of these gains may be offset if economic development results in increasing air pollution or increasing smoking.     

Molecular mechanisms in chronic obstructive pulmonary disease: potential targets for therapy

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, antiinflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-beta, tumor necrosis factor-alpha, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-kappaB, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.     

Prospect of vasoactive intestinal peptide therapy for COPD/PAH and asthma: a review

There is mounting evidence that pulmonary arterial hypertension (PAH), asthma and chronic obstructive pulmonary disease (COPD) share important pathological features, including inflammation, smooth muscle contraction and remodeling. No existing drug provides the combined potential advantages of reducing vascular- and bronchial-constriction, and anti-inflammation. Vasoactive intestinal peptide (VIP) is widely expressed throughout the cardiopulmonary system and exerts a variety of biological actions, including potent vascular and airway dilatory actions, potent anti-inflammatory actions, improving blood circulation to the heart and lung, and modulation of airway secretions. VIP has emerged as a promising drug candidate for the treatment of cardiopulmonary disorders such as PAH, asthma, and COPD. Clinical application of VIP has been limited in the past for a number of reasons, including its short plasma half-life and difficulty in administration routes. The development of long-acting VIP analogues, in combination with appropriate drug delivery systems, may provide clinically useful agents for the treatment of PAH, asthma, and COPD. This article reviews the physiological significance of VIP in cardiopulmonary system and the therapeutic potential of VIP-based agents in the treatment of pulmonary diseases.     

Molecular mechanisms in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, anti-inflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-β, tumor necrosis factor-α, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-⦊B, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.     

Improving physical activity in COPD: towards a new paradigm

Chronic obstructive pulmonary disease (COPD) is a debilitating disease affecting patients in daily life, both physically and emotionally. Symptoms such as dyspnea and muscle fatigue, lead to exercise intolerance, which, together with behavioral issues, trigger physical inactivity, a key feature of COPD. Physical inactivity is associated with adverse clinical outcomes, including hospitalization and all-cause mortality. Increasing activity levels is crucial for effective management strategies and could lead to improved long-term outcomes. In this review we summarize objective and subjective instruments for evaluating physical activity and focus on interventions such as pulmonary rehabilitation or bronchodilators aimed at increasing activity levels. To date, only limited evidence exists to support the effectiveness of these interventions. We suggest that a multimodal approach comprising pulmonary rehabilitation, pharmacotherapy, and counselling programs aimed at addressing emotional and behavioural aspects of COPD may be an effective way to increase physical activity and improve health status in the long term.     

Future Impact of Various Interventions on the Burden of COPD in Canada: A Dynamic Population Model

Background

Chronic obstructive pulmonary disease (COPD) is a growing economic burden worldwide. Smoking cessation is thought to be the single most effective way of reducing the economic burden of COPD. The impact of other strategies such as interventions that predict risk of disease, reduce progression of disease, or reduce exacerbations has not been systematically studied.

Objectives

We estimated the economic and clinical burden of COPD over the next 25 years in Canada and the impact of three potential interventions (screening test for predisposition to COPD, new drugs to avoid progression into more severe disease stages, and predictive test for exacerbations) on COPD burden.

Methods

Using a dynamic simulation model, we projected the total burden of COPD (cost, morbidity, and mortality) from 2011 to 2035 using the population of Canada as a case study. The model stratified population based on sex, age, smoking status, respiratory symptoms, and their COPD stage. The cost and quality adjusted life years (QALYs) associated with each intervention were estimated.

Results

The model indicates that annual societal cost of COPD is $4.52 billion (B) Canadian dollars in 2011 and will reach $3.61B ($7.33B undiscounted) per year in 2035. Over the next 25 years, COPD will be responsible for approximately $101.4B in societal costs ($147.5B undiscounted) and 12.9 million QALYs lost (19.0 million undiscounted). Our results suggested that the best strategy to reduce the financial burden of COPD is by reducing exacerbations. Smoking cessation, while it is the cornerstone of COPD prevention, has only a modest effect in attenuating the financial burden of COPD over the next 25 years in Western countries such as Canada.

Conclusion

Our data suggest that any intervention that can reduce the number of exacerbations has a substantial impact on morbidity and costs of COPD and should be considered in conjunction with the ongoing efforts to reduce smoking rates.     

Chronic obstructive pulmonary disease: a novel risk factor for cardiovascular disease

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in Canada and elsewhere. It affects 5% of all adult Canadians and is the fourth leading cause of death. Interestingly, the leading causes of hospitalizations and mortality among COPD patients are cardiovascular events. In the Lung Health Study, over 5 800 patients with mild to moderate COPD were studied. Forty-two to 48% of all hospitalizations that occurred over the study's 5-year follow-up period were related to cardiovascular complications. Various population-based studies suggest that independent of smoking, age, and gender, COPD increases the risk of cardiovascular morbidity and mortality twofold. Alarmingly, some bronchodilators, which are commonly used to treat symptoms in COPD, may increase the risk of cardiovascular morbidity and even mortality among COPD patients. In this paper, we discuss the epidemiologic evidence linking COPD and cardiovascular events as well as the potential mechanism(s) which may be responsible for this association.     

Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and debilitating symptoms. For patients with moderate-to-severe COPD, long-acting bronchodilators are the mainstay of therapy; as symptoms progress, guidelines recommend combining bronchodilators from different classes to improve efficacy. Inhaled long-acting β₂-agonists (LABAs) have been licensed for the treatment of COPD since the late 1990s and include formoterol and salmeterol. They improve lung function, symptoms of breathlessness and exercise limitation, health-related quality of life, and may reduce the rate of exacerbations, although not all patients achieve clinically meaningful improvements in symptoms or health related quality of life. In addition, LABAs have an acceptable safety profile, and are not associated with an increased risk of respiratory mortality, although adverse effects such as palpitations and tremor may limit the dose that can be tolerated.Formoterol and salmeterol have 12-hour durations of action; however, sustained bronchodilation is desirable in COPD. A LABA with a 24-hour duration of action could provide improvements in efficacy, compared with twice-daily LABAs, and the once-daily dosing regimen could help improve compliance. It is also desirable that a new LABA should demonstrate fast onset of action, and a safety profile at least comparable to existing LABAs.A number of novel LABAs with once-daily profiles are in development which may be judged against these criteria. Indacaterol, a LABA with a 24-hour duration of bronchodilation and fast onset of action, is the most advanced of these. Preliminary results from large clinical trials suggest indacaterol improves lung function compared with placebo and other long-acting bronchodilators. Other LABAs with a 24-hour duration of bronchodilation include carmoterol, vilanterol trifenatate and oldaterol, with early results indicating potential for once-daily dosing in humans.The introduction of once-daily LABAs also provides the opportunity to develop combination inhalers of two or more classes of once-daily long-acting bronchodilators, which may be advantageous for COPD patients through simplification of treatment regimens as well as improvements in efficacy. Once-daily LABAs used both alone and in combination with long-acting muscarinic antagonists represent a promising advance in the treatment of COPD, and are likely to further improve outcomes for patients.     

Effective-components combination improves airway remodeling in COPD rats by suppressing M2 macrophage polarization via the inhibition of mTORC2 activity

BackgroundIn chronic obstructive pulmonary disease (COPD), M2 macrophages release multiple tissue repair-related factors, leading to airway remodeling, a significant pathological characteristic. Meanwhile, effective-components combination (ECC), derived from Bufei Yishen formula (BYF), is an effective treatment for COPD.PurposeTo determine the potential mechanisms of ECC in airway remodeling in COPD by suppressing M2 macrophage polarization.MethodsWe established a rat COPD Model using exposure to cigarette smoke and bacterial infection to investigate the efficacy of ECC. We also treated macrophages with IL-4 for 12 h to explore the in vivo effect of ECC on M2 macrophage polarization and mTORC2 signals.ResultsThe disease severity of COPD rats could be alleviated by ECC treatment, which improved pulmonary function and alleviated pathological injuries in lung tissue and the inflammatory cytokine levels. Meanwhile, ECC could ameliorate airway remodeling by reducing collagen deposition, hindering airway mucus hypersecretion and smooth muscle cell proliferation, and reducing the number of M2 macrophages in the lung tissues of COPD rats. Furthermore, with IL-4-induced macrophages, we found that ECC could suppress M2 macrophage polarization by decreasing the levels of M2 macrophage markers. Finally, we discovered that ECC inhibited mTORC2 activity by examining p-mTOR²⁴⁸¹ and its downstream protein p-Akt⁴⁷³.ConclusionsECC exerts beneficial effects on airway remodeling in COPD rats, likely by suppressing M2 macrophage polarization via the inhibition of mTORC2 activity.     

Polymorphisms of TNFalpha, IL1beta, and IL1RN genes in chronic obstructive pulmonary disease

It is recognized that genetic factors play a role in the susceptibility to COPD. COPD is characterized by airflow limitation. Chronic inflammation causes small airway disease and parenchymal destruction, leading to the airflow limitation. Polymorphisms in pro-inflammatory cytokine genes may confer a risk for the development of COPD. A case-control association study was performed in Japanese population (88 COPD patients and 61 controls) and Egyptian population (106 patients and 72 controls). Genotype and allele frequencies of the TNFalpha -308 G/A and +489 G/A polymorphisms, the IL1beta -511 C/T, -31 T/C, and +3954 C/T polymorphisms, and a VNTR polymorphism in intron 2 of the IL1RN gene were investigated. In addition, pairwise haplotype frequencies were analyzed. When studied independently, none of the polymorphisms were associated with the development of COPD in both populations. However, in the Egyptian population, the distributions of the haplotype (IL1beta -31 T/C : IL1beta +3954 C/T) were significantly different between the COPD patients and the controls (p(corr)=0.0037). Our findings suggest that this haplotype within the IL1beta gene may be involved in the pathogenesis of COPD and that the genetic factors of COPD susceptibility might be different between different populations.     

Fixed-Dose Combination Therapy in Type 2 Diabetes Mellitus

ObjectiveThe management of type 2 diabetes mellitus (T2DM) often requires combinations of antihyperglycemic medications with complementary mechanisms of action. Inadequate adherence to combination therapy, possibly related to pill burden (greater number of pills and higher administration frequency) and poor tolerability, may lead to suboptimal clinical outcomes. One potential means of addressing these problems is the use of fixed-dose combinations (FDCs) that simplify the treatment regimen by reducing pill burden compared with the same combination delivered as separate pills. The present study evaluates the efficacy and tolerability of FDCs in the treatment of T2DM patients and provides an overview of dosing, costs, and adherence.MethodsA review of FDCs, with particular attention to those that contain metformin extended-release (XR) and allow once-daily dosing.ResultsMany FDCs contain metformin as one of the component drugs. However, the standard immediate-release (IR) formulation of metformin requires twice-daily dosing and may have tolerability problems related to adverse gastrointestinal (GI) effects. The XR formulationsof metformin can be administered once daily and have been shown to reduce the occurrence of GI effects frequently observed with metformin IR; consequently, they may have significant advantages for inclusion in FDCs. The long-term cost-effectiveness of FDCs remains to be fully determined.ConclusionFor patients taking metformin, FDCs containing metformin XR offer equivalent efficacy with reduced dose frequency and, potentially, fewer GI events compared with standard IR formulation, as well as a reduced number of pills compared with separate-pill regimens. By reducing pill burden and improving tolerability, FDCs may improve adherence. (Endocr Pract. 2014;20: 1322-1332)     

Beta-blocker use and COPD mortality: a systematic review and meta-analysis

ABSTRACT: BACKGROUND: Despite the benefits of beta-blockers in patients with established or sub-clinical coronary artery disease, their use in patients with chronic obstructive pulmonary disease (COPD) has been controversial. Currently, no systematic review has examined the impact of beta-blockers on mortality in COPD. METHODS: We systematically searched electronic bibliographic databases including MEDLINE, EMBASE and Cochrane Library for clinical studies that examine the association between beta-blocker use and all cause mortality in patients with COPD. Risk ratios across studies were pooled using random effects models to estimate a pooled relative risk across studies. Publication bias was assessed using a funnel plot. RESULTS: Our search identified nine retrospective cohort studies that met the study inclusion criteria. The pooled relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%). CONCLUSION: The results of this review are consistent with a protective effect of beta-blockers with respect to all cause mortality. Due to the observational nature of the included studies, the possibility of confounding that may have affected these results cannot be excluded. The hypothesis that beta blocker therapy might be of benefit in COPD needs to be evaluated in randomised controlled trials.     

Disinfection procedures for controlling microorganisms in the semen and embryos of humans and farm animals

Semen and embryos generated by assisted reproductive techniques (ARTs) may be contaminated with numerous microorganisms. Contamination may arise from systemic or local reproductive tract infections in donors or the inadvertent introduction of microorganisms during ARTs, and may lead to disease transmission. This review describes sanitary procedures which have been investigated to ascertain whether they are effective in rendering semen and embryos free of pathogenic microorganisms, including internationally adopted washing procedures, which can be supplemented by antibiotics and enzymatic treatments. Other methods include treatment with antibodies or ozone, photoinactivation, acidification, and the use of novel antiviral compounds. In conclusion, despite the wide range of antimicrobial procedures available, none can be recommended as a universal disinfection method for rendering semen and embryos free from all potentially pathogenic microorganisms. However, some procedures are unsuitable, as they can compromise the viability of semen or embryos. In humans, washing by the gradient centrifugation method appears to be effective for reducing the microbial population in semen and is harmless to the spermatozoa. A useful procedure for embryos involving multiple washes in sterile medium has much to commend it for the prevention of disease transmission; furthermore, it is recommended by the International Embryo Transfer Society (IETS).     

Sub-clinical left ventricular diastolic dysfunction in early stage of chronic obstructive pulmonary disease

Sub-clinical cardiac dysfunction may be significantly associated with chronic obstructive pulmonary disease (COPD) with a different degree of severity. In a cross-sectional design we aimed to evaluate the frequency of left ventricular diastolic dysfunction (LVdd) and its correlation with lung function, pulmonary arterial pressure and systemic inflammation in a selected population of COPD at an early stage of their disease. Fifty-five COPD patients with no clinical signs of cardiovascular dysfunction were recruited and compared to 40 matched healthy controls. All the subjects underwent pulmonary function testing, doppler echocardiography, and interleukin-6 blood sampling. Presence of LVdd was defined according to the significant change in both the ratio between early and late diastolic transmitral flow velocity (E/A ratio), isovolumetric relaxation time (IVRT), and deceleration time (DT). The frequency of LVdd was higher in the COPD group (70.9 percent) compared to controls (27.5 percent). In these patients decreased E/A ratio, and prolonged IVRT and DT clearly pointed to left ventricular filling impairment, a condition we found to be especially severe in those patients suffering from lung static hyperinflation as expressed by inspiratory-to-total lung capacity ratio (IC/TLC) <0.25. Circulating levels of interleukin-6 were also higher among COPD patients compared to controls. The results of the present study suggest that subclinical left ventricular filling impairment is frequently found in COPD patients at the earlier stage of the disease even in the absence of any other cardiovascular dysfunction. Doppler echocardiography may help the early identification of LVdd in COPD patients.     

Level of daily physical activity in individuals with COPD compared with healthy controls

Background

Persons with Chronic Obstructive Pulmonary Disease (COPD), performing some level of regular physical activity, have a lower risk of both COPD-related hospital admissions and mortality. COPD patients of all stages seem to benefit from exercise training programs, thereby improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue. Physical inactivity, which becomes more severe with increasing age, is a point of concern in healthy older adults. COPD might worsen this scenario, but it is unclear to what degree. This literature review aims to present the extent of the impact of COPD on objectively-measured daily physical activity (DPA). The focus is on the extent of the impact that COPD has on duration, intensity, and counts of DPA, as well as whether the severity of the disease has an additional influence on DPA.

Results

A literature review was performed in the databases PubMed [MEDLINE], Picarta, PEDRO, ISI Web of Knowledge and Google scholar. After screening, 11 studies were identified as being relevant for comparison between COPD patients and healthy controls with respect to duration, intensity, and counts of DPA. Four more studies were found to be relevant to address the subject of the influence the severity of the disease may have on DPA. The average percentage of DPA of COPD patients vs. healthy control subjects for duration was 57%, for intensity 75%, and for activity counts 56%. Correlations of DPA and severity of the disease were low and/or not significant.

Conclusions

From the results of this review, it appears that patients with COPD have a significantly reduced duration, intensity, and counts of DPA when compared to healthy control subjects. The intensity of DPA seems to be less affected by COPD than duration and counts. Judging from the results, it seems that severity of COPD is not strongly correlated with level of DPA. Future research should focus in more detail on the relation between COPD and duration, intensity, and counts of DPA, as well as the effect of disease severity on DPA, so that these relations become more understandable.     

Blood and sputum protein biomarkers for chronic obstructive pulmonary disease (COPD)

ABSTRACT

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous set of disorders, characterized by airflow limitation, and reduced lung function. Despite increasing knowledge regarding its pathophysiology, there has been limited advancement in therapeutics and the current treatment strategy is symptom management and prevention of exacerbations.

Areas covered: Biomarkers represent important tools for the implementation of precision medicine. As fundamental molecules of all living processes, proteins could provide crucial information about how genes interact with the environment. Proteomics studies could act as important tools in identifying reliable biomarkers to enable a more precise therapeutic approach. In this review, we will explore the most promising blood and sputum protein biomarkers in COPD that have been consistently reported in the literature.

Expert commentary: Given the complexity of COPD, no single protein biomarker has been able to improve the outcomes of COPD patients. According to preliminary studies, precision medicine in COPD will likely require a combination of different proteins in a biomarker panel for clinical translation. With advancements in current mass spectrometry techniques, an enhancement in the identification of new biomarkers will be observed, and improvements in sequence database search can fill in potential gaps between biomarker discovery and patient care.