Single inhaler triple therapy with extrafine beclomethasone,formoterol, and glycopyrronium for the treatment of chronic obstructive pulmonary disease

Introduction: Chronic obstructive pulmonary disease (COPD) management focuses on the alleviation of symptoms and prevention of exacerbations. Inhaled long acting bronchodilators and inhaled corticosteroids (ICS) are the main classes of treatment for COPD. Triple therapy with a long acting beta₂-agonist (LABA), long acting muscarinic antagonist (LAMA), and ICS is commonly prescribed for symptomatic COPD patients experiencing regular exacerbations. Triple therapy is usually administered using separate inhalers; there is little clinical trial evidence of an effect on exacerbation prevention with this approach.

Areas covered: This evaluation reviews the single inhaler extrafine combination containing beclometasone diproprionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) which has been developed as a simplified triple regime. BDP/FF/GB significantly reduced exacerbation rates in three clinical trials (1-year duration) compared against LAMA monotherapy (20% exacerbation reduction), ICS/LABA combination (23% exacerbation reduction), and LAMA/LABA combination (15% exacerbation reduction).

Expert opinion: The practical benefits of single inhaler triple therapy in the real world have not been studied. However, the robust clinical trial evidence that BDP/FF/GB reduces exacerbations compared to double combination treatments and LAMA monotherapy cements triple therapy positioning as an escalation step in COPD management pathways.     

A review of current and developing fixed-dose LABA/LAMA combinations for treating COPD

Introduction: The current GOLD (Global Initiative for Chronic Obstructive Lung Disease) recommendations suggest using long acting β2 agonists (LABA) and long acting muscarinic antagonists (LAMA) in combination for group B COPD patients with persistent symptoms, group C COPD patients with further exacerbations on LAMA therapy alone and for group D COPD patients with or without combination with inhaled corticosteroids (ICS). Thus, there is a lot of interest in developing LABA/LAMA combinations for maintenance therapy of chronic stable COPD.

Areas covered: Many LABA/LAMA combinations have successfully been approved through carefully designed pivotal clinical trials. The current clinical use of LABA/LAMA combinations in COPD will continue to evolve as new trials with and without inhaled corticosteroids are completed.

Expert opinion: Combining different classes of bronchodilators in a single inhaler is an attractive concept that can potentially improve patient adherence to therapy. Because LABA/LAMA combinations are the preferred treatment option for preventing COPD exacerbations in the updated GOLD guidelines for COPD, they will be clinically used. Future treatment of COPD should revolve around a personalized approach based on characterization of the COPD phenotype.     

Inhaled therapies and cardiovascular risk in patients with chronic obstructive pulmonary disease

Introduction: Chronic obstructive pulmonary disease (COPD) therapy includes a multi-dimensional approach, taking into account both symptoms of the patient and the number of acute exacerbations of COPD (AECOPDs). There are three main pharmaceutical classes currently available including long-acting muscarinic antagonists (LAMA), long-acting β₂-agonists (LABA) and inhaled corticosteroids (ICS). COPD is a major risk factor for most cardiovascular diseases, and cardiac comorbidities are very common in COPD patients. Both LAMA and LABA have a considerable impact on cardiac function by stimulating cardiac β2-adrenergic receptors or inhibiting the heart M₂ muscarinic receptors. ICS alone or in combination has never been associated with a real cardiovascular risk.

Areas covered: This review explores the data published on the safety of COPD therapy and the implications for current pharmacotherapy.

Expert opinion: Several studies have confirmed the good safety profile of bronchodilators available both in monotherapy and in association with other bronchodilators of different classes or with ICS despite the device used. Cardiovascular events in clinical trials are generally low and balanced between groups. The actual cardiovascular risk of fixed-dose combinations (FDCs) in an unselected COPD population will need to be investigated through post-marketing surveillance studies and observational studies.     

A re-evaluation of the role of inhaled corticosteroids in the management of patients with chronic obstructive pulmonary disease

Introduction: Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β₂-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary disease (COPD), outside their labeled indications and recommended treatment strategies and guidelines, despite having the potential to cause significant side effects.

Areas covered: Although the existence of asthma in patients with asthma–COPD overlap syndrome (ACOS) clearly supports the use of anti-inflammatory treatment (typically an ICS/LABA combination, as ICS monotherapy is usually not indicated for COPD), the current level of ICS/LABA use is not consistent with the prevalence of ACOS in the COPD population. Data have recently become available showing the comparative efficacy of fixed bronchodilator combinations (long-acting muscarinic antagonist [LAMA]/LABA with ICS/LABA combinations). Additionally, new information has emerged on ICS withdrawal without increased risk of exacerbations, under cover of effective bronchodilation.

Expert opinion: For patients with COPD who do not have ACOS, a LAMA/LABA combination may be an appropriate starting therapy, apart from those with mild disease who can be managed with a single long-acting bronchodilator. Patients who remain symptomatic or present with exacerbations despite effectively delivered LAMA/LABA treatment may require additional drug therapy, such as ICS or phosphodiesterase-4 inhibitors. When prescribing an ICS/LABA, the risk:benefit ratio should be considered in individual patients.     

Pharmacological basis and scientific rationale underlying the targeted use of inhaled corticosteroid/long-acting β2-adrenergic agonist combinations in chronic obstructive pulmonary disease treatment

Introduction: Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder, whose medical and socioeconomic burden as one of the main causes of morbidity and mortality is increasing worldwide. COPD pathophysiology includes chronic airway/lung inflammation and progressive airflow limitation. Therefore, anti-inflammatory and bronchodilator agents are key players in COPD treatment.

Areas covered: This review article discusses the complementary molecular interactions connecting the respective mechanisms of action of inhaled corticosteroids (ICS) and long-acting β₂-adrenergic agonists (LABAs). Moreover, attention is also focused on clinical trials, which have shown that ICS/LABA combinations are very effective in improving COPD symptoms and lung function, being also able to significantly reduce disease exacerbations.

Expert opinion: In selected subgroups of COPD patients, ICS/LABA combinations represent a very useful therapeutic approach for this widespread chronic respiratory disease. In addition to the well-known fixed-dose drug associations such as fluticasone propionate/salmeterol xinafoate and budesonide/formoterol fumarate, other newly developed ICS/LABA combinations are currently emerging as very interesting pharmacological options for COPD treatment.     

A safety comparison of LABA+LAMA vs LABA+ICS combination therapy for COPD

Introduction: LABA+LAMA and LABA+ICS combinations are key pharmacological approaches to the treatment of COPD. However, both combination types can induce adverse events (AEs).

Areas covered: Current literature on LABA+LAMA and LABA+ICS combinations has been reviewed with a specific focus on their safety profile in the treatment of COPD.

Expert opinion: Several meta-analyses have compared the pooled safety data from randomized clinical trials (RCTs) of LABA+LAMA combinations with LABA+ICS combinations. LABA+LAMA caused significantly less AEs and SAEs. However, this evidence in real life is less solid because of the lack of appropriate studies. A statistically significant reduction in the risk for pneumonia with LABA+LAMA compared with LABA+ICS has been repeatedly documented by various meta-analyses. The meta-analytic signal indicates that an equal number of patients would die or have cardiac SAEs on LABA+LAMA or LABA+ICS, and in an observational, real-life study the LABA+LAMA combination had similar or lower risk of these events in comparison to LABA+ICS. Nonetheless, since RCTs are conducted under widely varying conditions and, consequently, AE rates of a drug observed in a RCT cannot be directly compared with rates in the RCTs of another drug and may not reflect the rates observed in practice, we need more specific data.     

Healthcare utilization,medical costs and mortality associated with malnutrition in patients with chronic obstructive pulmonary disease: a matched cohort study

Objective: Although disease-related malnutrition has prognostic implications for patients with chronic obstructive pulmonary disease (COPD), its health-economic impact and clinical burdens are uncertain. We conducted a population-level study to investigate these questions.

Methods: We excerpted data relevant to malnutrition, prolonged mechanical ventilation and medications from claims by 1,197,098 patients which were consistent with COPD and registered by the Taiwan National Health Insurance Administration between 2009 and 2013. These patients were separated into cohorts with or without respiratory failure requiring long-term mechanical ventilation, and each cohort was divided to compare cases who developed malnutrition after their first diagnosis consistent with COPD, versus non-malnourished propensity-score matched controls.

Results: The prevalence of malnutrition was 3.8% overall (10,259/287,000 non-ventilator-dependent; 1198/15,829 ventilator-dependent). Propensity-score matched non-ventilator-dependent patients who became malnourished (N?=?10,242) had comparatively more hospitalizations, emergency room and outpatient visits, longer hospitalization (all p?<?.01), and higher mortality (HR?=?2.26, 95% CI 2.18–2.34) than non-malnourished controls (N?=?40,968). Malnourished ventilator-dependent patients (N?=?1197) had higher rates of hospitalization, emergency room and outpatient visits, but shorter hospitalization (all p?<?.001) and lower mortality (HR?=?0.85, 95% CI 0.80–0.93) than matched non-malnourished controls (N?=?4788). Total medical expenditure on malnourished non-ventilator-dependent COPD patients was 75% higher than controls (p?<?.001), whereas malnourished ventilator-dependent patients had total costs 7% lower than controls (p?<?.001).

Conclusions: Malnourishment among COPD patients who were not dependent on mechanical ventilation was associated with greater healthcare resource utilization and higher aggregate medical costs.     

Patient preference for chronic obstructive pulmonary disease (COPD) treatment inhalers: a discrete choice experiment in France

Objectives: Understanding inhaler preferences may contribute to improving adherence in COPD patients and improving long-term outcomes. This study aims to identify and quantify preferences for convenience-related inhaler attributes in French moderate-to-severe COPD patients, with discrete choice experiment (DCE) methodology.

Methods: Attributes were defined from a literature search, clinician and patient interviews: shape, dose insertion, dose preparation, dose release, dose confirmation, dose counter and reusability. An online DCE was conducted in respondents with self-reported COPD stage 2–4 recruited through a panel. The study questionnaire included twelve choice scenarios per respondent and questions on patient characteristics, treatment and disease severity. Statistical analyses used a mixed logit regression model with random effects. Utility scores were estimated for four types of inhalers: Inhaler A – soft mist inhaler; Inhaler B – reusable soft mist inhaler; Inhaler C – multi-dose dry powder inhaler; and Inhaler D – single dose dry powder inhaler.

Results: The study was completed by 153 patients (50 females); respondents were 50.4?years old on average; 13 different inhaler devices were reported. The most preferred inhaler is L-shaped, has dose preparation with capsule insertion and a dose counter, and is reusable. Inhaler profiles A and B had the highest utilities (mean of 1.2533 and 0.9578 respectively) compared to inhaler C (0.6315) and D (0.2200).

Conclusions: This study showed statistically significant results that the strongest drivers of preference in French users of inhalation devices for COPD are shape, dose counter and reusability. Convenience-related characteristics are important to patients and should be taken into account by clinicians prescribing these devices.     

Effect of coverage gap on healthcare utilization among Medicare beneficiaries with chronic obstructive pulmonary disorder

Objective: To evaluate the association between the Medicare coverage gap with hospitalization, emergency room (ER) visits, and time to hospitalization in chronic obstructive pulmonary disease (COPD) patients.

Methods: Retrospective cohort study using data from a Medicare Advantage (MA) plan. Patients with ≥1 claim for COPD at baseline, ≥65 years, continuous 24-months enrollment and without any cancer/end stage renal disease diagnosis were eligible. Patients not reaching the coverage gap (no coverage gap) were matched and compared to those reaching the coverage gap and those reaching catastrophic coverage in separate analyses. Chi-square tests and Cox proportional hazards model were used to compare outcomes across matched cohorts.

Results: In total, 3142 COPD patients were identified (79% no coverage gap, 10% coverage gap, and 11% catastrophic coverage). Compared to the no coverage gap group, a larger number of beneficiaries in the coverage gap group had ≥1 hospitalization (26% vs 32%, p?<?.05), ≥ 1 ER visits (43% vs 49%, p?<?.05), and ≥1 hospitalization/ER (total visit) (47% vs 54%, p?<?.05), respectively. Compared to the no coverage gap group, a greater number of beneficiaries in catastrophic coverage had ≥1 ER visit (45% vs 53%, p?<?.05) or ≥1 total visits (48% vs 56%, p?<?.05), respectively. Time to hospitalization was shorter among those entering the coverage gap as compared to the no coverage gap [Hazards Ratio (HR)?=?1.5; p?=?.040].

Conclusions: COPD patients entering the coverage gap and catastrophic coverage were associated with increased utilization of healthcare services. Entering the coverage gap was also associated with shorter time to hospitalization as compared to the no coverage gap.     

Revefenacin for the treatment of chronic obstructive pulmonary disease

Introduction: Acetylcholine is the predominant parasympathetic neurotransmitter in the airways, and plays a key role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Muscarinic receptors are found in smooth muscle cells and submucosal glands. Binding of acetylcholine to muscarinic receptors could trigger bronchoconstriction. Muscarinic antagonists prevent acetylcholine from binding to its receptors and produce bronchodilation. Revefenacin is the first once-daily dosed nebulized long-acting muscarinic antagonist indicated for the maintenance treatment of patients with COPD.

Areas covered: In this paper, the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy and safety of Revefenacin was introduced, and the evolution of muscarinic antagonists is also briefly described.

Expert commentary: Revefenacin is a new M₃ muscarinic receptor antagonist, which could prevent acetylcholine from binding with the muscarinic receptor, making bronchodilation and relieving COPD symptoms. Revefenacin has a rapid onset of action, and the curative effect is to maintain a long time. Clinical trials showed that Revefenacin could significantly increase forced expiratory volume in 1 s (FEV₁) in patients with COPD and improve their quality of life. The recommended dose of Revefenacin inhalation solution is 175 μg once daily. Adverse reactions were mild and the drug was well tolerated.     

Muscarinic antagonists in early stage clinical development for the treatment of asthma

Introduction: Parasympathetic neurons utilize the neurotransmitter acetylcholine to modulate and constrict airway smooth muscles at the muscarinic acetylcholine receptor. Inhaled agents that antagonize the muscarinic (M) acetylcholine receptor, particularly airway M3 receptors, have increasing data supporting use in persistent asthma.

Areas covered: Use of inhaled long-acting muscarinic antagonists (LAMA) in asthma is explored. The LAMA tiotropium is approved for maintenance in symptomatic asthma patients despite the use of inhaled corticosteroids (ICS), leukotriene receptor antagonists (LTRA) and/or long-acting beta₂ agonists (LABA). LAMA agents currently approved for chronic obstructive pulmonary disease (COPD) include tiotropium, glycopyrrolate/glycopyrronium, umeclidinium and aclidinium. These agents are reviewed for their pharmacological differences and clinical trials in asthma.

Expert opinion: Current guidelines place inhaled LAMAs as adjunctive maintenance therapy in symptomatic asthma not controlled by an ICS and/or a LTRA. LAMA agents will play an increasing role in moderate to severe symptomatic asthma patients. Additional LAMA agents are likely to seek a maintenance indication perhaps as a combined inhaler with an ICS or with an ICS and a LABA. These fixed-dose combination inhalers are being tested in COPD and asthma patients. Once-a-day dosing of inhaled LAMA agents in severe asthma patients will likely become the future standard.     

Next generation beta adrenoreceptor agonists for the treatment of asthma

Introduction: A fixed-dose inhalation of a long-acting β-agonist (LABA) and inhaled corticosteroids (ICS) is commonly recommended for moderate to severe asthmatic patients not adequately controlled by an ICS only. In order to improve the patients’ adherence and the control of disease there is a noteworthy interest for the next generation inhaled β adrenoreceptor agonists maintaining an over 24 hours bronchodilatation and used once-daily (ultra-LABAs).

This review focuses on the currently available evidences on the clinical role of any single ultra-LABAs in the treatment of asthmatic patients.

Areas covered: New ultra-LABAs have been developed in recent years for the treatment of asthma. In particular, several evidences in asthmatic patients include indacaterol, vilanterol, olodaterol, and abediterol.

Expert opinion: Pharmacologically, all new ultra-LABAs considered have demonstrated a good ability to maintain a true bronchodilatation for over 24 hours and a good safety profile. This aspect could be a key point to improve the patient’s perspective, the adherence to the treatment regimens and therefore the control of disease. At this time, however, limited data are available and no ultra-LABA+ICS may be recommended as preferred.     

Roflumilast in patients with advanced chronic obstructive pulmonary disease: towards a better-targeted use

Introduction: For patients with chronic obstructive pulmonary disease (COPD), one of the main goals in its management is to reduce the number of disease exacerbations. Roflumilast is an anti-inflammatory compound used in patients with advanced COPD and chronic bronchitis in order to fulfill this objective. However, this is not always easily achieved due to the heterogeneity of the population. Clinical trial data can allow more in-depth analysis in order to identify predictors for maximal efficacy in different patient populations.

Areas covered: A post hoc pooled data analysis derived from two large-scale randomized controlled trials helped to better define the disease subsets in which roflumilast would exert the maximal therapeutic effect. These are represented by patients with prior hospitalizations for COPD exacerbations and by patients with higher values for eosinophil blood count. This analysis is the focus of our key paper evaluation.

Expert opinion: This pooled data analysis suggests that a phenotype/endotype guided therapy has the potential to be impactful on overall survival by reducing the number of exacerbations and increase the life span of patients.     

Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

An evaluation of peripapillar choroidal thickness in patients receiving systemic isotretinoin treatment

Purpose: Oral isotretinoin (13-cis retinoic acid, 13-cis RA) was approved for severe acne treatment by the FDA in 1982. The ocular side effects associated with oral isotretinoin use are mostly dose-dependent. Numerous ocular pathologies affect peripapillary choroidal layer primarily or indirectly.

Objective: Evaluation of the peripapillary choroidal layer in the patients receiving oral isotretinoin therapy may aid in explaining the pathophysiology of ocular side effects.

Methods: In this study, peripapillary choroidal thickness was assessed in the patients receiving oral isotretinoin treatment via optical coherent tomography technique.

Results: Significant difference was found in the superotemporal and temporal areas.

Conclusion: Oral isotretinoin treatment may affect the thickness of the peripapillary choroidal layer.     

New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

Introduction: Inhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta₂-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic asthma. Additional drugs include leukotriene-receptor antagonists, slow-release theophylline and the long-acting muscarinic antagonist (LAMA) tiotropium (approved in 2015). There is a need for more effective therapies, as many patients continue to have poorly controlled asthma.

Areas covered: New and developing long-acting non-adrenoreceptor synthetic drugs for the treatment of symptomatic chronic asthma despite treatment with an ICS alone or combined with a LABA. Data was reviewed from studies published up until November 2016.

Expert opinion: Tiotropium improves lung function and has a modest effect in reducing exacerbations when added to ICS alone or ICS and LABA. The LAMAs umeclidinium and glycopyrronium are under development in fixed dose combination with ICS and LABA. Novel small molecule drugs, such as CRTH2 receptor antagonists, PDE₄ inhibitors, protein kinase inhibitors and nonsteroidal glucocorticoid receptor agonists and ‘off-label’ use of licensed drugs, such as macrolides and statins are under investigation for asthma, although their effectiveness in clinical practice is not established. To better achieve the goal of developing effective novel small molecule drugs for asthma will require greater understanding of mechanisms of disease and the different phenotypes and endotypes of asthma.     

Managing the safety of inhaled corticosteroids in COPD and the risk of pneumonia

Introduction: Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease. To estimate the association between ICS and pneumonia among users of ICS relative to non-ICS users and to examine whether this risk is dose related, class related and what’s its association with the pneumonia-mortality or overall mortality.

Areas covered: Through a comprehensive literature search of MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov from inception to February 2015, we identified randomized controlled trials of ICS therapy lasting at least 6 months. We conducted meta-analyses to generate summary estimates comparing ICS with non-ICS treatment on the risk of pneumonia.

Expert opinion: ICS alone or in combination with long-acting β-agonists are associated with an increased risk of pneumonia but have no effect on pneumonia related mortality. It is important to identify those patients to benefit the most from ICS, as those with frequent exacerbations, a severe airway obstruction, a positive bronchodilator test or a sputum eosinophilia despite treatment.     

An evaluation of roflumilast and PDE4 inhibitors with a focus on the treatment of asthma

Introduction: Asthma is a common chronic airway inflammatory disease characterized by diverse inflammatory events leading to airway hyperresponsiveness and reversible airflow obstruction. Corticosteroids have been the mainstay for asthma treatment due to their broad anti-inflammatory actions; however, other medications such as phosphodiesterase 4 inhibitors also demonstrate anti-inflammatory activity in the airways.

Areas covered: This review describes tissue expression of phosphodiesterase 4 in the airways, the different phosphodiesterase 4 isoenzymes identified, and the anti-inflammatory activities of phosphodiesterase 4 inhibition in asthma and related findings in chronic obstructive pulmonary disease (COPD). The authors further review clinical trials demonstrating that drugs such as roflumilast have an excellent safety profile and efficacy in patients with asthma and COPD.

Expert opinion: Phosphodiesterase 4 inhibitors suppress the activity of immune cells, an effect similar to corticosteroids although by acting through different anti-inflammatory pathways and uniquely blocking neutrophilic inflammation. Roflumilast and other phosphodiesterase 4 inhibitors have been shown to provide additive protection in asthma when added to corticosteroid and anti-leukotriene treatment. Developmental drugs with dual phosphodiesterase 3 and 4 inhibition are thought to be able to provide bronchodilation and anti-inflammatory activities and will consequently be pushed forward in their clinical development for the treatment of asthma and COPD.     

Association between asthma/chronic obstructive pulmonary disease overlap syndrome and healthcare utilization among the US adult population

Objectives: Asthma/chronic obstructive pulmonary disease (COPD) overlap (ACO) is a recently described phenomenon defined as the coexistence of both asthma and COPD. Both asthma and COPD are known to result in increased emergency department (ED) visits and hospitalizations, but it is unclear how the ACO population utilizes these same healthcare resources. The objective of this study was to compare healthcare utilization in the ACO population versus the general population, the asthma population and the COPD population.

Methods: We conducted a pooled cross-sectional statistical analysis using the 2012–2015 National Health Interview Survey (NHIS) data. We focused on adults 18 years of age and older and excluded pregnant women. We employed an adjusted logit regression model, where the primary outcomes were dichotomous indicators on healthcare utilizations including ED visits and hospital stays. A key covariate was a four-category variable: 1) no asthma or COPD; 2) asthma only; 3) COPD only; and 4) ACO. Other covariates included age, sex, race, education level, marital status, household income level, medical insurance status, smoking status, body mass index (BMI) category, region, year and comorbidities (cancer, diabetes, hypertension, coronary heart disease and ulcer).

Results: Adults with ACO were 134%, 53% and 21% more likely to have ED visits than the general population, asthma group and COPD group, respectively. For hospital stay, the ACO group was 120% and 86% more likely to be hospitalized than the general population and the asthma group respectively. In addition, adults with ACO were 61% and 130% more likely to have asthma exacerbations and asthma-related ED visits than the asthma group.

Conclusions: ACO is a considerable risk factor for healthcare utilization versus the general population, the asthma population and the COPD population. Future focus should be placed on the ACO population to identify ways to reduce their healthcare utilization.     

Impact of cigarette smoking on kidney inflammation and fibrosis in diabetic rats

Background: Cigarette smoking is a very common habit worldwide contributing to risk of kidney dysfunction and diabetes (DM). However, the mechanisms are unclear.

Aim: The goal of the present study was to assess the effects of cigarette smoking on kidney oxidative stress, inflammation, and remodeling in streptozotocin (STZ) rat model of diabetes.

Methods: Rats were randomized into control (intraperitoneal (i.p.) citrate buffer injection and exposure to fresh air), cigarette smoking (1?h daily for 6?d/week, citrate buffer), DM (single dose STZ 35?mg/kg i.p. and exposure to fresh air), and DM?+?smoking groups for a period of 4?weeks. Kidney biomarkers of inflammation, oxidative stress, and remodeling were measured.

Results: A significant increase in kidney to body weight ratio was observed in diabetic groups. Diabetes but not smoking increased blood urea nitrogen levels without changes in creatinine levels. Kidney levels of thiobarbituric acid substances, nitrite, endothelin-1, and C-reactive protein were increased significantly in the DM?+?smoking groups. Smoking induced GSH expression and activity of superoxide dismutase. A significant increase in kidney fibrosis was observed in the DM?+?smoking group coupled with a similar increase in transforming growth factor beta. Protein levels of matrix metalloproteinase-2, (MMP-2), mitogen-activated protein kinases, and c-Jun N terminal kinase were elevated in Smoking and DM?+?smoking groups.

Conclusion: Cigarette smoke might promote risk of kidney dysfunction in DM by augmentation of renal inflammation, oxidant radicals and fibrosis. The kidney promotes compensatory increase in MMP-2 in response to smoking probably to prevent pro-fibrotic factors induced-fibrosis.