Gender differences in COPD management in a Sicilian general practice setting: a cohort study evaluating the impact of educational interventions.

AIM: The aim of this study was to measure gender differences among COPD patients' quality of care (QOC) before and after two educational interventions in Southern Italy. METHODS: In this prospective cohort study, COPD patients were identified from primary care electronic medical records (EMRs). Twelve process indicators concerning diagnosis, preventative measures and therapeutic processes were developed as a measure of QOC. Educational interventions consisted of clinical seminars and audits on COPD QOC at baseline, and at 12 and 24 months. QOC indicators were stratified by gender: odds ratios (ORs) (males as reference group) of having a good QOC indicator were calculated at baseline, 12 and 24 months, with 95% confidence intervals (CIs) using hierarchical generalised linear models. RESULTS: Of 46 326 people registered in the EMRs, 1463 COPD patients (3.1%) were identified, of which 37% were women. QOC indicators reflecting best practice 24 months after the educational programme were generally not different to baseline, often favouring men. On the other hand, the composite global QOC indicator suggested that while a good overall QOC at baseline was significantly higher in men than women (OR: 0.74; 95% CI: 0.57-0.96), it became nonsignificant at 24 months (OR: 0.96; 95% CI: 0.72-1.29). CONCLUSIONS: Specific QOC indicators among COPD patients often favoured men. However, several gender disparities seen at baseline disappeared at 24 months, suggesting that even general educational interventions which do not target gender can improve the gender disparity in QOC.

The effect of doxofylline in asthma and COPD.

Theophylline is still one of the most widely prescribed drugs for the treatment of asthma and COPD in developing countries because the majority of asthma and COPD medicines are largely unavailable and also because it is a cheap option. In any case, its anti-inflammatory effects and capacity to reverse corticosteroid resistance deserve consideration, but it can induce numerous side effects and drug-drug interactions and frequently requires measurement of drug levels in plasma. In order to overcome the problems posed by theophylline, other xanthines have been developed. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities and for this reason it has been called "novofylline". It differs substantially from theophylline at the pharmacological level. Clinical studies have shown substantial differences between doxofylline and theophylline. In particular, efficacy/safety profile of doxofylline is better than that of theophylline.

Inhalation therapy in the next decade: Determinants of adherence to treatment in asthma and COPD.

Proceedings of the European Seminars in Respiratory Medicine course, Inhalation therapy in the next decade: Determinants of adherence to treatment in asthma and COPD, held in Taormina, Italy, on 3-4 March, 2017.

LABA/LAMA combination in COPD: a meta-analysis on the duration of treatment.

When there are no randomised clinical trials directly comparing all relevant treatment options, an indirect treatment comparison via meta-analysis of the available clinical evidence is an acceptable alternative. However, meta-analyses may be very misleading if not adequately performed. Here, we propose and validate a simple and effective approach to meta-analysis for exploring the effectiveness of long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations in chronic obstructive pulmonary disease.14 articles with 20 329 patients (combinations n=9292; monocomponents n=11 037) were included in this study. LABA/LAMA combinations were always more effective than the monocomponents in terms of the improvement in trough forced expiratory volume in 1 s, transition dyspnoea index and St George's Respiratory Questionnaire scores after 3, 6 and 12 months of treatment. No significant publication bias was identified. Significant discrepancies with previous network meta-analyses have been found, with overall differences ranging from 26.7% to 43.3%.Results from previous network meta-analyses were misleading because no adequate attention was given to formulating the review question, specifying eligibility criteria, correctly identifying studies, collecting appropriate information and deciding what it would be pharmacologically relevant to analyse. The real gradient of effectiveness of LABA/LAMA fixed-dose combinations remains an unmet medical need; however, it can be investigated indirectly using a high-quality meta-analytic approach.

Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.

Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment of asthma.

INTRODUCTION: The pharmacokinetic (PK) and pharmacodynamic (PD) effects of long-acting ß2-agonists and mostly inhaled corticosteroids (ICSs) shape the efficacy and safety of these agents in the treatment of asthma. In fact, the PK and PD characteristics of the drug largely determine the degree of pulmonary targeting Areas covered. In this review, we summarize the PK and PD properties of inhaled fluticasone furoate (FF) and vilanterol trifenatate (VI) and their fixed-dose combination (FDC) for the treatment of asthma Expert opinion. It is difficult to interpret the data that we have described because the preclinical and clinical development of FF/VI FDC was not really based on solid information on quantitative PK/PD approach. Unfortunately, for both FF and VI we only know concentrations in systemic blood, a compartment that is downstream of both target and non-target respiratory tissue. This lack of information does not allow us to understand the temporal relationship between the delivered dose and the drug concentration at the sites of action within the lungs. In addition, all studies performed with FF and VI did not address the fundamental issue that asthma can significantly alter lung deposition, absorption and also clearance of inhaled medicines.

COPD: the patient perspective.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease characterized by nonreversible airway obstruction. Well-characterized symptoms such as exertional dyspnea and fatigue have a negative impact on patients' quality of life (QoL) and restrict physical activity in daily life. The impact of COPD symptoms on QoL is often underestimated; for example, 36% of patients who describe their symptoms as being mild-to-moderate also admit to being too breathless to leave the house. Additionally, early morning and nighttime symptoms are a particular problem. Methods are available to allow clinicians to accurately assess COPD symptoms, including patient questionnaires. Integrated approaches to COPD management, particularly pulmonary rehabilitation, are effective strategies for addressing symptoms, improving exercise capacity and, potentially, also increasing physical activity. Inhaled bronchodilators continue to be the mainstay of drug therapy in COPD, where options can be tailored to meet patients' needs with careful selection of the inhaled medication and the device used for its delivery. Overall, an integrated approach to disease management should be considered for improving QoL and subsequent patient outcomes in COPD.

Influence of ethnicity on response to asthma drugs.

INTRODUCTION: Understanding variability in the response to asthma medications is essential to ensure appropriate prescribing. Given that there are increased asthma treatment failures observed in ethnic minorities receiving asthma therapeutics, it is fundamental to understand the factors related to ethnicity that can modify the response to asthma therapy. AREAS COVERED: Race/ethnicity is an important determinant of drug response and therefore contributes to interindividual variability. It is generally recognized that its effects on drug response are determined by both genetic and environmental factors to a varying extent, depending on the ethnic groups and probe drugs studied. Also, adherence to therapy can influence pharmacological response to asthma therapeutics. EXPERT OPINION: Health-care professionals might never use the treatment in their patients irrespective of their ethnicity and thus inadvertently increase ethnic health inequality. However, our understanding of whether and/or how ethnicity influences pharmacological response to asthma therapeutics is still very scarce. A holistic, integrative systems biology approach that combines large-scale molecular profiling traits (e.g., transcriptomic, proteomic, metabolomic traits) and genetic variants could help to personalize the treatment of asthmatic patients regardless of race/ethnicity.

Pharmacological assessment of the onset of action of aclidinium and glycopyrronium versus tiotropium in COPD patients and human isolated bronchi.

Preclinical studies suggested that aclidinium and glycopyrronium might have a faster onset of action than tiotropium. In this study we assessed the onset of action of aclidinium and glycopyrronium versus tiotropium, all administered at the approved clinical doses, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and in human isolated bronchi by using different concentrations. Sixteen COPD patients inhaled single doses of aclidinium 400µg, glycopyrronium 50µg and tiotropium 18µg and FEV1 was measured to assess their onset of action. In human isolated bronchi the time to evoke half maximal relaxation of transmural stimulation was tested from 10nM to 1µM for each drug. Nine, eight and twelve patients did not achieve 15% increase of FEV1 after inhalation of aclidinium, glycopyrronium and tiotropium, respectively. Aclidinium (15.6±7.5min) and glycopyrronium (17.9±10.4min) enhanced 15% FEV1 more rapidly than tiotropium (42.5±19.4min), with no significant difference (P>0.05). In isolated airways, glycopyrronium elicited a dose-dependent onset of action (10nM: 8.2±1.3min, 100nM: 7.1±2.1min, 1µM: 3.4±0.4min) that was faster compared to that induced by aclidinium (1µM: 6.4±0.5min) and tiotropium (1µM: 8.4±1.1min) (P<0.05), that halved the contractile tone only at the highest concentration. Bronchodilation induced by aclidinium and glycopyrronium was faster than that induced by tiotropium, but since our analysis was restricted to the acute effect of these LAMAs and the inhaled doses were not isoeffective, the real differences in their impact on the onset of bronchodilation will be definitely determined after a long-term challenge of these treatments at isoeffective doses in COPD patients.

A review of the most common patient-reported outcomes in COPD--revisiting current knowledge and estimating future challenges.

Patient-reported outcome (PRO) measures that quantify disease impact have become important measures of outcome in COPD research and treatment. The objective of this literature review was to comprehensively evaluate psychometric properties of available PRO instruments and the ability of each of them to characterize pharmaceutical treatment effects from published clinical trial evidence. Identified in this study were several PRO measures, both those that have been used extensively in COPD clinical trials (St George's Respiratory Questionnaire and Chronic Respiratory Questionnaire) and new instruments whose full value is still to be determined. This suggests a great need for more information about the patient experience of treatment benefit, but this also may pose challenges to researchers, clinicians, and other important stakeholders (eg, regulatory agencies, pharmaceutical companies) who develop new treatment entities and payers (including but not limited to health technology assessment agencies such as the National Institute for Health and Care Excellence and the Canadian Agency for Drugs and Technologies in Health). The purpose of this review is to enable researchers and clinicians to gain a broad overview of PRO measures in COPD by summarizing the value and purpose of these measures and by providing sufficient detail for interested audiences to determine which instrument may be the most suitable for evaluating a particular research purpose.

Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.

PURPOSE: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. PATIENTS AND METHODS: A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). RESULTS: For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. CONCLUSION: For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.

Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages.

Energy expenditure and impact of bronchodilators in COPD patients.

28 Consecutive COPD patients performed four 6-minute walking tests (6-MWTs) in 2 different days before and 2, 4 and 6h after the inhalation of formoterol 12microg or tiotropium 18microg, respectively. Physical activity during each 6-MWT was assessed by the SenseWear Armband. At each time also spirometry was performed. Both formoterol and tiotropium induced a significantly sustained bronchodilation and influenced hyperinflation. Formoterol significantly increased distance walked in 6min at 2h and at 4h, whereas tiotropium significantly increased it at all time points. There was a trend to an increase in calories and metabolic equivalents of task (METs) after formoterol and a decrease after tiotropium, but changes were not statistically significant. Total energy expenditure for each 6-MWT was not changed by formoterol, but decreased in significant manner 6h after the inhalation of tiotropium. Active energy expenditure at physical activity level of more than 3 METs decreased significantly after tiotropium at each 6-MWT, but not after formoterol. We did not find any significant correlation between the changes in lung function and those of parameters recorded with SenseWear Armband. Our study seems to indicate that tiotropium, but not formoterol, is able to reduce energy expenditure in COPD patients, although both drugs elicit significant bronchodilation and are able to increase the distance walked in 6min.

Prognostic classification and risk assessment in myelodysplastic syndromes.

The clinical heterogeneity of myelodysplastic syndromes (MDS) is best illustrated by the observation that these disorders range from indolent conditions with a near-normal life expectancy to forms approaching acute myeloid leukemia (AML). A risk-adapted treatment strategy is mandatory for conditions showing a highly variable clinical course, and definition of the individual risk has been based so far on the use of prognostic scoring systems. The authors have developed a prognostic model that accounts for the World Health Organization (WHO) categories, cytogenetics, transfusion dependency, and bone marrow fibrosis. This WHO classification-based Prognostic Scoring System (WPSS) is able to classify patients into five risk groups showing different survivals and probabilities of leukemic evolution. WPSS predicts survival and leukemia progression at any time during follow-up, and may therefore be used for implementing risk-adapted treatment strategies.

Doppler echocardiographic assessment of the effects of inhaled long-acting beta2-agonists on pulmonary artery pressure in COPD patients.

Increase in pulmonary artery pressure (PAP), which is common in severe chronic obstructive pulmonary disease (COPD), is a predictor of mortality independent of airflow limitation. beta-agonists might slightly attenuate this increase because they exert a vasodilating effect on pulmonary circulation when systematically administered. We have investigated the acute effects of salmeterol and formoterol on echocardiographic systolic pulmonary artery pressure (sPAP) in 20 patients with COPD and a sPAP greater than 20mmHg at rest. Acute haemodynamic responses to inhaled formoterol or salmeterol were assessed in all patients, in a randomized, double-blind double-dummy fashion. On two consecutive days, patients received, in a randomized order, formoterol 12microg via Turbuhaler plus placebo via Diskus or salmeterol 50microg via Diskus plus placebo via Turbuhaler. Transthoracic Doppler echocardiography measurements of sPAP were made before and 15, 30, 60 and 180min after bronchodilator inhalation. Lung function, pulse oximetry and heart rate were also monitored at the same times. Mean sPAP significantly (p<0.05) decreased in comparison with baseline at 15, 30, and 60min post inhalation but returned towards control levels at 180min after both salmeterol and formoterol. There was no correlation between the maximum increase in FEV(1) and maximum decrease in sPAP either after inhalation of salmeterol (r(2)=0.071) or after that of formoterol (r(2)=0.0006). The increases in FEV(1) in comparison with baseline were always significant (p<0.05) from 15 to 180min post inhalation after either salmeterol or formoterol. Neither pulse oximetry nor heart rate changed in a significant manner (p>0.05). This study demonstrated that salmeterol and formoterol were equally beneficial for pulmonary haemodynamics in patients with COPD. A direct vasodilatation due to the activation of beta-adrenoceptors that are present in pulmonary vessels is a likely mechanism of their action in inducing the decrease in sPAP.

Novelties in the field of antimicrobial compounds for the treatment of lower respiratory tract infections.

Emergence of antimicrobial resistance is a growing problem and a public health threat. New drugs must be designed with emerging needs in mind: specific resistant and hard-to-treat organisms. But the difficulty to find real new drugs is a major problem. Only the oxazolidinones, the cationic peptides and the lipopeptide antibiotics can be truly regarded as structurally novel drugs, although the peptide deformylase inhibitors and, possibly, the pleuromutilins can be considered a potential advancement in the field. Obviously, these antibiotics must be reserved only to cases of documented ineffectiveness of the common antimicrobial agents.