Andrea Rizzi

Long-term effects of inhaled corticosteroids on sputum bacterial and viral loads in COPD

Inhaled corticosteroid-containing medications reduce the frequency of COPD exacerbations (mainly infectious in origin) while paradoxically increasing the risk of other respiratory infections. The aim was to determine the effects of inhaled corticosteroids on airway microbial load in COPD patients and evaluate the influence of the underlying inflammatory profile on airway colonisation and microbiome. This is a proof-of-concept prospective, randomised, open-label, blinded endpoint study. Sixty patients with stable moderate COPD were randomised to receive one inhalation twice daily of either a combination of salmeterol 50 μg plus fluticasone propionate 500 μg or salmeterol 50 μg for 12 months. The primary outcome was the change of sputum bacterial loads over the course of treatment. Compared with salmeterol, 1-year treatment with salmeterol plus fluticasone was associated with a significant increase in sputum bacterial load (p=0.005), modification of sputum microbial composition and increased airway load of potentially pathogenic bacteria. The increased bacterial load was observed only in inhaled corticosteroid-treated patients with lower baseline sputum or blood eosinophil (≤2%) levels but not in patients with higher baseline eosinophils. Long-term inhaled corticosteroid treatment affects bacterial load in stable COPD. Lower eosinophil counts are associated with increased airway bacterial load. Long term inhaled corticosteroids increase airway bacterial load in COPD patients with low eosinophil counts http://ow.ly/8nO530eMSza

The level of control of mild asthma in general practice: an observational community-based study

Abstract Objective: The aim of the present community-based study was to evaluate the level of asthma control in patients with mild asthma, regularly treated with inhaled steroids (ICS). Method: This observational cross-sectional study included patients registered in the general practitioner (GP) database and with at least three prescriptions of ICS in the last 12 months. Patients were asked to refer to the doctor’s office for a standardised interview. The level of asthma control was self-measured by the patients using the Asthma Control Test (ACT)™ (Quality Metric, Inc.). Results: The study included 950 asthmatic patients, referred by 540 GPs: 54.5% were females, mean age was 51 (±19.1) years; 59.5% were non-smokers, 22.5% were current smokers and 18.0% were former smokers; 81.1% of the patients were on ICS in the last 4 weeks. Only 38.6% of patients had a spirometry in the last 12 months. According to the ACT, 13.7% of the asthmatic patients were totally controlled, 51.0% well controlled, and 35.3% poorly controlled. Smoking habit, older age (>60) and living in Central or Southern Italy were associated with poorer control. In the last 12 months 4.5% of patients had an asthma-related hospitalisation, 5.3% an emergency visit and 18.9% a specialist visit. Conclusions: More than one of three patients had poor asthma control, despite being considered by their GPs as mild asthmatics and treated with ICS. Asthmatic patients need to be regularly re-evaluated. Treatment is often inadequate and should be targeted to improve control and reduce asthma morbidity (SAM104964).

Discovery and optimization of thiazolidinyl- and pyrrolidinyl- derivatives as inhaled PDE4 inhibitors for respiratory diseases

Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a number of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e and (S*,S**)-22e, in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an experimental animal model. The optimal biological profile as well as the excellent solid-state properties suggest that both compounds have the potential to be effective topical agents for treating respiratory inflammatory diseases.

Phenomenology of COPD: interpreting phenotypes with the ECLIPSE study.

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study was a large 3-year observational multicentre international study aimed at defining COPD phenotypes and identifying biomarkers and/or genetic parameters that help to predict disease progression. The study has contributed to a better understanding of COPD heterogeneity, with the characterization of clinically important subtypes/phenotypes of patients, such as the frequent exacerbators or patient with persistent systemic inflammation, who may have different prognosis or treatment requirements. Because of the big amount of information that is starting to be produced from metabolomic, proteomic and genomic approaches, one of the biggest challenges is the integration of data in a biological prospective such as clinical prognosis and response to medicinal products. In this article we highlight some of the progress in phenotyping the heterogeneity of the disease that have been made thanks to the analyses of this longitudinal study.

AIMAR survey on COPD phenotypes

BackgroundCOPD is characterized by considerable diversity in terms of clinical signs and symptoms, physiopathological mechanisms, response to treatment and disease progression. For this reason, the identification of different patient subgroups (or possible phenotypes) is important both for prognosis and for therapeutic objectives. Based on the foregoing, AIMAR has decided to conduct a survey on the perception of the prevalence of the different clinical COPD phenotypes/subtypes in the clinical practice of physicians who treat patients with chronic obstructive pulmonary disease, and on their therapeutic objectives.MethodsThe survey consisted of 19 multiple-choice questions, compiled through a form published online. All the data and answers entered into the system were checked for consistency and completeness directly online at the time they were entered, and each respondent could only complete the questionnaire once.ResultsThe survey took place from May through October 2012. A total of 1,434 questionnaires (60% of the sample approached) were eligible for analysis, broken down as follows: 537 pulmonologists, 666 general practitioners (GPs), 72 internal medicine specialists, 36 allergists, 30 geriatricians, 93 other specialists. The results show that a significant proportion of GPs (33%) identified more than 50 patients in their practices with a diagnosis of COPD. Although most patients are or have been in treatment with a long-acting bronchodilator, the most common reasons for seeing a GP or a specialist were exacerbations and worsening of the symptoms, suggesting the importance of an appropriate background therapy in order to reduce the risk of disease instability. The frequent exacerbator phenotype was the most commonly found phenotype in clinical practice (by 75% of specialists and 66% of GPs); patients with a prevalent phenotype of chronic bronchitis were reported more often by GPs, while specialists reported a higher number of patients with a prevalent phenotype of emphysema.A medical history of exacerbations and the extent of deterioration of the spirometry parameters were considered to be the major indicators for COPD severity and clinical risk. In managing the frequent exacerbator phenotype, the therapeutic objectives – both for GPs and for specialists – included reducing airway inflammation, improving bronchial dilation, and reducing pulmonary hyperinflation. For this type of patients at high clinical risk, specialists selected a first-line therapeutic option based on a predetermined combination of an inhaled corticosteroid (ICS) and a long-acting β2-agonist bronchodilator (LABA) and a second-line three-drug therapy (combination of ICS and two long-acting bronchodilators), while GPs’ choices are more diversified, without a clear-cut prevalence of one type of treatment. In patients with COPD and concomitant cardiovascular diseases, frequently observed in clinical practice by all physicians, the combination of ICS and LABA was considered the first-choice option by the highest proportion of GPs (43%) and specialists (37%), while a smaller number of specialists (35%) opted for the long acting muscarinic antagonists (LAMA). Both GPs and specialists believe that therapeutic continuity is of primary importance for the achievement of clinical outcomes with all classes of drugs.ConclusionsA good knowledge of COPD has been observed in a high percentage of GPs, indicating an increased awareness of this disease in Primary Health Care. The frequent exacerbator phenotype is viewed by all physicians as the most prevalent in clinical practice, bearing a high risk of hospitalization. For specialists, therapeutic measures aimed at reducing the number and severity of exacerbations are primarily based on the combination of inhaled corticosteroid and bronchodilator, presumably because of the complementary pharmacological action of its components, whereas while GPs’ choices tend to be more diversified. Adherence to medication regimens is of the essence for the achievement of clinical outcomes.