Pharmacology and Therapeutics of Bronchodilators Revisited.

Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). There is therefore considerable interest in understanding how to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. However, new classes of bronchodilator have proved challenging to develop because many of these have no better efficacy than existing classes of bronchodilator and often have unacceptable safety profiles. Recent research has shown that optimization of bronchodilation occurs when both arms of the autonomic nervous system are affected through antagonism of muscarinic receptors to reduce the influence of parasympathetic innervation of the lung and through stimulation of ß 2-adrenoceptors (ß 2-ARs) on airway smooth muscle with ß 2-AR-selective agonists to mimic the sympathetic influence on the lung. This is currently achieved by use of fixed-dose combinations of inhaled long-acting ß 2-adrenoceptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs). Due to the distinct mechanisms of action of LAMAs and LABAs, the additive/synergistic effects of using these drug classes together has been extensively investigated. More recently, so-called "triple inhalers" containing fixed-dose combinations of both classes of bronchodilator (dual bronchodilation) and an inhaled corticosteroid in the same inhaler have been developed. Furthermore, a number of so-called "bifunctional drugs" having two different primary pharmacological actions in the same molecule are under development. This review discusses recent advancements in knowledge on bronchodilators and bifunctional drugs for the treatment of asthma and COPD. SIGNIFICANCE STATEMENT: Since our last review in 2012, there has been considerable research to identify novel classes of bronchodilator drugs, to further understand how to optimize the use of the existing classes of bronchodilator, and to better understand the role of bifunctional drugs in the treatment of asthma and chronic obstructive pulmonary disease.

A continuous-time Markov model approach for modeling myelodysplastic syndromes progression from cross-sectional data.

The integration of both genomics and clinical data to model disease progression is now possible, thanks to the increasing availability of molecular patients' profiles. This may lead to the definition of novel decision support tools, able to tailor therapeutic interventions on the basis of a "precise" patients' risk stratification, given their health status evolution. However, longitudinal analysis requires long-term data collection and curation, which can be time demanding, expensive and sometimes unfeasible. Here we present a clinical decision support framework that combines the simulation of disease progression from cross-sectional data with a Markov model that exploits continuous-time transition probabilities derived from Cox regression. Trajectories between patients at different disease stages are stochastically built according to a measure of patient similarity, computed with a matrix tri-factorization technique. Such trajectories are seen as realizations drawn from the stochastic process driving the transitions between the disease stages. Eventually, Markov models applied to the resulting longitudinal dataset highlight potentially relevant clinical information. We applied our method to cross-sectional genomic and clinical data from a cohort of Myelodysplastic syndromes (MDS) patients. MDS are heterogeneous clonal hematopoietic disorders whose patients are characterized by different risks of Acute Myeloid Leukemia (AML) development, defined by an international score. We computed patients' trajectories across increasing and subsequent levels of risk of developing AML, and we applied a Cox model to the simulated longitudinal dataset to assess whether genomic characteristics could be associated with a higher or lower probability of disease progression. We then used the learned parameters of such Cox model to calculate the transition probabilities of a continuous-time Markov model that describes the patients' evolution across stages. Our results are in most cases confirmed by previous studies, thus demonstrating that simulated longitudinal data represent a valuable resource to investigate disease progression of MDS patients.

The possible role of burden of therapy on the risk of myeloma extramedullary spread.

Extramedullary relapse (EMR) represents a poor prognostic marker in the course of multiple myeloma (MM). We reviewed data from 329 patients, diagnosed between 2000 and 2010, without extramedullary disease at onset to explore possible risk factors for EMR. The median overall survival of our study cohort was 6.4 years. The risk of EMR was 28 % with a median time from diagnosis to first EMR of 2.2 years (0.2-9.1 years). Patients with soft tissue masses located in extra-osseous organs (EMR-S) showed the worst outcome, compared to those with tumor masses arising from adjacent bone (EMR-B) (median OS 1.6 vs 2.4 years, p = 0.006). In addition, patients with EMR-S showed a significant trend for further development of extramedullary masses in a very short time (3.7 vs 5.7 months for EMR-B, p = 0.043). Multivariate analysis failed to identify any clinically presenting features predictive for EMR. The occurrence of EMR was higher in patients with more complex treatment history, defined on the basis of longer treatment duration (≥6 vs <6 months) and on elevated number of treatment lines administered (>2 vs ≤2 lines) (HR = 4.5, p < 0.001 and HR = 9.0, p < 0.001, respectively, when one or both factors are present).In conclusion, increasing burden of treatment might be a possible risk factor for EMR. MM patients with multiple relapses should be comprehensively investigated including, when possible, a whole-body-targeted radiologic technique to accurately detect EMR. Treatment choice should take into account the very poor outcome for patients with soft tissue involvement.

Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts.

BACKGROUND: Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODS: We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTS: We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONS: Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.).

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Physiopathology of pain in rheumatology.

Pain is the main manifestation of many rheumatic diseases (be they overtly inflammatory such as rheumatoid arthritis or dysfunctional such as fibromyalgia) but, at least initially, the mechanisms involved in the genesis, amplification and chronicisation of the persistent pain characterising the various conditions can be very different. The main peripheral mechanism underlying acute nociceptive pain is a change in the activity of the nociceptors located in the affected anatomical structures (joints, tendons and ligaments), which makes them more sensitive to normally painful stimuli (hyperalgesia) or normally non-painful stimuli (allodynia). This physiopathological mechanism of peripheral sensitisation plays a primary role in rheumatic diseases characterised by acute inflammation, such as the arthritides due to microcrystals. In the case of chronic rheumatic diseases that do not regress spontaneously, functional and structural central nervous system changes cause a generalised reduction in the pain threshold that is not limited to the anatomical structures involved, thus leading to the appearance of hyperalgesia and allodynia in many, if not all body districts. This is the physiopathological basis of chronic, widespread musculoskeletal pain.

Three-dimensional morphological condylar and mandibular changes in a patient with juvenile idiopathic arthritis: interdisciplinary treatment.

Temporomandibular joint (TMJ) involvement is common but usually delayed in patients with juvenile idiopathic arthritis (JIA). We describe the case of a JIA patient with bilateral TMJ involvement, mandibular retrognathia, bone erosion, and severely restricted mouth opening. The use of cone beam computed tomography and a 3D diagnostic protocol in young patients with JIA provides reliable, accurate and precise quantitative data and images of the condylar structures and their dimensional relationships. Analgesics and conventional disease modifying antirheumatic drugs were ineffective, but interdisciplinary treatment with etanercept and a Herbst functional appliance improved functional TMJ movement and bone resorption.

Pain in fibromyalgia and related conditions.

Pain is the hallmark symptom of fibromyalgia (FM) and other related syndromes, but quite different from that of other rheumatic diseases, which depends on the degree of damage or inflammation in peripheral tissues. Sufferers are often defined as patients with chronic pain without an underlying mechanistic cause, and these syndromes and their symptoms are most appropriately described as "central pain", "neuropathic pain", "nonnociceptive pain" or "central sensitivity syndromes". The pain is particular, regional or widespread, and mainly relates to the musculoskeletal system; hyperalgesia or allodynia are typical. Its origin is currently considered to be distorted pain or sensory processing, rather than a local or regional abnormality. FM is probably the most important and extensively described central pain syndrome, but the characteristics and features of FM-related pain are similar in other disorders of particular interest for rheumatologists, such as myofascial pain syndromes and temporo-mandibular joint disorders, and there is also an intriguing overlap between FM and benign joint hypermobility syndrome. This suggests that the distinctive aspects of pain in these idiopathic or functional conditions is caused by central nervous system hypersensitivity and abnormalities. Pharmacological and non-pharmacological therapies have been suggested for the treatment of these conditions, but a multidisciplinary approach is required in order to reduce the abnormal cycle of pain amplification and the related maladaptive and self-limiting behaviours.

Costs of pain in rheumatology.

Chronic pain has been identified as an important issue related to various rheumatic diseases. At the time of a major government spending review, it is appropriate to discuss the pain characterising rheumatic diseases and its related costs. It is clearly essential for healthcare authorities to rationalise their policies on the basis of the increasing expectations of the users of healthcare services while simultaneously balancing their books. There are few published studies concerning the costs of pain of any kind, and the same is true of the costs of the chronic pain associated with diseases such as rheumatoid arthritis, osteoarthritis, and fibromyalgia.

Pain in rheumatoid arthritis: a critical review.

Patients with rheumatoid arthritis (RA) are frequently afflicted by pain, which may be caused by joint inflammation (leading to structural joint damage) or secondary osteoarthritis, and may be increased by central sensitisation. Non-inflammatory pain may also confuse the assessment of disease activity, and so the aim of treatment is not only to combat inflammatory disease, but also relieve painful symptoms. In order to ensure effective treatment stratification, it is necessary to record a patients medical history in detail, perform a physical examination, and objectively assess synovitis and joint damage. The management of pain requires various approaches that include pharmacological analgesia and biological and non-biological treatments. Although joint replacement surgery can significantly improve RA-related pain, it may only be available to patients with the most severe advanced disease.

Chronic widespread pain in spondyloarthritis.

The pain associated with spondyloarthritis (SpA) can be intense, persistent and disabling. It frequently has a multifactorial, simultaneously central and peripheral origin, and may be due to currently active inflammation, or joint damage and tissue destruction arising from a previous inflammatory condition. Inflammatory pain symptoms can be reduced by non-steroidal anti-inflammatory drugs, but many patients continue to experience moderate pain due to alterations in the mechanisms that regulate central pain, as in the case of the chronic widespread pain (CWP) that characterises fibromyalgia (FM). The importance of distinguishing SpA and FM is underlined by the fact that SpA is currently treated with costly drugs such as tumour necrosis factor (TNF) inhibitors, and direct costs are higher in patients with concomitant CWP or FM than in those with FM or SpA alone. Optimal treatment needs to take into account symptoms such as fatigue, mood, sleep, and the overall quality of life, and is based on the use of tricyclic antidepressants or selective serotonin reuptake inhibitors such as fluoxetine, rather than adjustments in the dose of anti-TNF agents or disease-modifying drugs.

Prolonged-release pirfenidone in patients with pulmonary fibrosis as a phenotype of post-acute sequelae of COVID-19 pneumonia. Safety and efficacy.

INTRODUCTION: One of the major concerns with post-acute sequelae of COVID-19 (PASC) is the development of pulmonary fibrosis, for which no approved pharmacological treatment exists. Therefore, the primary aim of this open-label study was to evaluate the safety and the potential clinical efficacy of a prolonged-release pirfenidone formulation (PR-PFD) in patients having PASC-pulmonary fibrosis. METHODS: Patients with PASC-pulmonary fibrosis received PR-PFD 1800 mg/day (1200 mg in the morning after breakfast and 600 mg in the evening after dinner) for three months. Blood samples were taken to confirm the pharmacokinetics of PR-PFD, and adverse events (AEs) were evaluated monthly using a short questionnaire. Symptoms, dyspnea, and pulmonary function tests (spirometry, diffusing capacity for carbon monoxide, plethysmography, and 6-min walk test [6MWT]) were evaluated at baseline, and one and three months after having started the PR-PFD treatment. RESULTS: Seventy subjects with mild to moderate lung restriction were included. The most common AEs were diarrhea (23%), heartburn (23%), and headache (16%), for which no modifications in the drug study were needed. Two patients died within the first 30 days of enrolment, and three opted not to continue the study, events which were not associate with PR-PFD. Pulmonary function testing, 6MWT, dyspnea, symptoms, and CT scan significantly improved after three months of treatment with PR-PFD. CONCLUSION: In patients with PASC pulmonary fibrosis, three months' treatment with PR-PFD was safe and showed therapeutic efficacy. Still, it remains to be seen whether the pulmonary fibrotic process remains stable, becomes progressive or will improve.

Preliminary identification of key clinical domains for outcome evaluation in fibromyalgia using the Delphi method: the Italian experience.

OBJECTIVE: Fibromyalgia (FM) is a complex syndrome that, in Italy, affects at least 2% of the adult population. It is characterized by chronic widespread musculoskeletal pain often accompanied by multiple other symptoms. The aim of this study was to identify a set of clinical domains for FM considered relevant by both clinicians and patients using a consensus process. METHODS: Consensus was achieved using the Delphi method based on questionnaires and systematic, controlled opinion feedback. The Delphi exercise involved a panel of 252 rheumatologists and 86 patients with FM as defined by the American College of Rheumatology criteria. All of the patients and clinicians were asked to rank the relative different domains of FM in order of priority. The content validity index (CVI) was used to establish the percentage agreement. The importance of each item was ranked on a 0-3 Likert scale. The frequency, mean relevance scores, and frequency importance product were also calculated. RESULTS: The Delphi exercise showed that the domains ranked highest by patients were similar to those of the clinicians, with the exception of tender point intensity (considered relevant by the clinicians but not by the patients) and environmental sensitivity (considered important by the patients but not by the clinicians). A final 8-item model was developed which was considered to demonstrate adequate validity. CONCLUSIONS: The Delphi exercises identified and ranked relevant key clinical domains that need to be assessed in FM research. On the basis of these results, a new patient-reported composite outcome index can be developed and used in clinical trials.

Asthma and comorbid medical illness.

Asthma is associated with several comorbidities but the magnitude of the association has not been clearly defined. We aimed to examine the relationship between asthma and comorbidities using information obtained from the Health Search Database (HSD) owned by the Italian College of General Practitioners (Società Italiana Medici Generici, Florence, Italy). We conducted a population-based retrospective study using information obtained from the HSD. The software system used codes of all the diagnostic records using the 9th revision of the International Classification of Diseases. Asthma appeared to be weakly associated with cardiovascular and hypertensive diseases. Intriguingly, the odds ratio of acute or old myocardial infarction was 0.84 (95% CI 0.77-0.91). Asthma was also weakly associated with depression, diabetes mellitus, dyslipidaemia, osteoporosis and rhinosinusitis. In contrast, it was strongly associated with gastro-oesophageal reflux disease (GORD) and, particularly, allergic rhinitis. Age did not influence the association of asthma with comorbidities whereas sex had a different impact according to the specific comorbidity. Our results indicate that asthma is weakly associated with several comorbidities, whereas its association with allergic rhinitis or GORD is stronger.

Symptom variability in patients with severe COPD: a pan-European cross-sectional study.

In between exacerbations, chronic obstructive pulmonary disease (COPD) is usually regarded as a stable condition, but there is increasing recognition of variability in this state. This cross-sectional study assessed patients' perception of symptom variability. Participants were outpatients > 45 yrs old with COPD, current or ex-smokers, forced expiratory volume in 1 s (FEV1) <50% predicted, FEV1/forced vital capacity < 0.7 and no exacerbation leading to therapeutic intervention in the previous 3 months. Patients' perceptions of COPD symptoms and their impact on daily life activities were recorded. Alterations in therapy use in response to COPD worsening were also recorded. COPD symptoms were experienced by 2,258 (92.5%) out of 2,441 patients during the 7 days before interview. Breathlessness was the most common symptom (72.5%). Daily and/or weekly symptom variability was reported by 62.7% of symptomatic patients; the morning was the worst time of day. Factors associated with perception of variability of breathlessness included younger age, symptom severity and recruitment to the study by general practitioners. The perception of variability was significantly different between European countries or regions. Patient-perceived COPD symptoms vary over the day and the week, and impact on daily activities; morning being the worst time of day. The majority of patients appear not to adjust treatment when symptoms worsen.

Chronic widespread pain and fibromyalgia: could there be some relationships with infections and vaccinations?

Chronic widespread pain (CWP) is a common symptom within the community, and may be part of or arise as a result of various diseases or conditions. Fibromyalgia (FM) is probably the most common and best known disease whose cardinal symptom is CWP. Many authors, however, indistinctively describe pain as 'widespread', 'diffuse' or 'generalised', and this may lead to misunderstandings about true clinical or scientific significance. Widespread pain has been variously defined, over the years, beginning from the American College of Rheumatology (ACR) classification criteria for FM in 1990, and the CWP Manchester definition in 1996. A comprehensive and brief core sets for CWP was developed in 2003, by the WHO International Classification of Functioning Consensus Conference, and finally, the ACR proposed new preliminary diagnostic criteria for FM in 2010. Research into CWP and/or FM is therefore difficult and can lead to conflicting results. CWP and (particularly) FM are multifactorial disorders. There is increasing evidence that they may be triggered by environmental factors, and many authors have highlighted a relationship with various infectious agents and some have suggested that vaccinations may play a role. This review analyses the available data concerning the relationships between FM and widespread pain (in its various meanings) with infections and vaccinations, from the earliest report to the most recent contributions. Considering all scientific papers, various levels of possible associations emerge. There is no clear-cut evidence of FM or CWP due to infections or vaccinations, no correlations with persistent infection, and no proven relationship between infection, antimicrobial therapies and pain improvement. A higher prevalence of FM and chronic pain has been found in patients with Lyme disease, and HIV or HCV infection, and, perhaps, also in patients with mycoplasmas, HBV, HTLV I, and parvovirus B19 infections. Some unconfirmed evidence and case reports suggest that vaccinations may trigger FM or chronic pain.

Psychometric properties of the Fibromyalgia Assessment Status (FAS) index: a national web-based study of fibromyalgia.

Fibromyalgia (FM) is a generalized chronic pain condition that is often accompanied by symptoms such as fatigue, sleep disturbances, psychological and cognitive alterations, headache, migraine, variable bowel habits, diffuse abdominal pain, and urinary frequency. Its key assessment domains include pain, fatigue, disturbed sleep, physical and emotional functioning, and patient global satisfaction and health-related quality of life (HRQL). A number of evaluation measures have been adapted from the fields of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and others such as the Fibromyalgia Assessment Status (FAS) index and the Fibromyalgia Impact Questionnaire (FIQ) have been specifically developed. The aim of this study was to assess the impact of FM on HRQL by comparing the performance of the FAS index, the FIQ and the Health Assessment Questionnaire [HAQ] in 541 female and 31 male FM patients (mean age 50 years; mean disease duration 7.7 years) entered in the database of a web-based survey registry developed by the Italian Fibromyalgia Network (IFINET). Tests of convergent validity showed that the FAS index and FIQ significantly correlated with each other (rho=0.608, p<0.0001), but there were also significant correlations between the FAS index and other clinical measures of disability, including the HAQ (rho=0.423, p<0.0001), anxiety (rho=0.138, p=0.0009), depression (rho=0.174, p<0.0001) and, especially, the number of comorbidities (rho=0.147, p=0.0004). The FAS index revealed a statistically significant difference between males and females (p=0.048), analysed using the Mann-Whitney U-test for all pair wise comparisons. The FAS index is a valid three-item instrument (pain, fatigue and sleep disturbances) that performs at least as well as the FIQ in FM patients, and is simpler to administer and score. Both questionnaires may be useful when screening FM patients, with the choice of the most appropriate instrument depending on the setting.

Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data.

UNLABELLED: Erdosteine, a drug approved for the treatment of acute and chronic pulmonary diseases, has been shown to be an effective treatment for chronic bronchitis or COPD (CB/COPD) in several studies, although marked differences in the perception of its usefulness still remain. AIM: to test the available evidence for the efficacy of erdosteine in adults with stable or exacerbated CB/COPD. METHODS: Meta-analysis of individual patient data from both published and unpublished randomized controlled trials (RCTs) comparing erdosteine with placebo/mucolytics, given for up to 10 days in association with standard therapy (RCTs used for regulatory drug approval). Individual patient data were provided by the manufacturer of erdosteine, Edmond Pharma (Milano, Italy). Endpoints were symptom scores (cough frequency and intensity, sputum viscosity and purulence, difficulty to expectorate, catarrh rhonchi at auscultation, dyspnoea), a cumulative global efficacy index (cGEI), and an overall physician efficacy assessment (OA). RESULTS: individual data from 1046 patients from 15 RCTs (12 on exacerbated and 3 on stable CB/COPD) were obtained. Erdosteine induced a significant reduction of cGEI vs comparators (-1.02; 95% CI: from -1.60 to -0.44; p=0.0006), both placebo and mucolytics. On individual symptoms, it positively impacted on cough frequency (-0.19; 95% CI: from -0.34 to -0.03) and intensity (-0.30; 95% CI: from -0.44 to -0.17), sputum viscosity (-0.28; 95% CI: from -0.49 to -0.07), difficulty to expectorate (-0.24; 95% CI: from -0.40 to -0.08), and catarrh ronchi at auscultation (-0.35; 95% CI: from -0.60 to -0.10). The effects on dyspnoea were only significant vs placebo, whereas sputum purulence was not significantly modified. The OA also favoured erdosteine, doubling the chance of success compared with placebo and mucolytics: OR (odds ratio) 2.06; (95% CI: from 1.27 to 3.33). The treatment with erdosteine was well tolerated. Adverse events, mainly gastrointestinal, were reported by 10.2% of patients compared to 11.0% in the reference groups. CONCLUSIONS: Treatment with erdosteine is associated with a significant benefit in terms of symptom amelioration both vs placebo and mucolytics in patients with CB/COPD. Although with some limitations (e.g. not fully validated scores) this review reinforces the use of erdosteine, in combination with standard therapy, in respiratory diseases characterized by increased expectoration, namely acute CB/COPD exacerbations.

Which kind of exercise is best in fibromyalgia therapeutic programmes? A practical review.

All of the specialists who deal in some way with fibromyalgia (FM) broadly agree that physical reconditioning programmes are useful, but it is not yet clear what type of physical activity is the most appropriate for different subsets of patients. The aim of this review was to examine the randomised controlled trials (RCTs) published between 1985 and August 2010 whose outcome measures indicate the effectiveness of different types of physical exercise (PE) on the main health domains affected by FM: pain, and physical and mental function. Studies that simultaneously used different types of PE or multimodal treatment strategies were excluded from the analysis, as were those in which the primary and secondary endpoints prevented any assessment of treatment efficacy in all three health domains. Twenty-seven studies were selected: 15 considered land-based physical aerobic exercise (PAE); seven exercises in water; and five muscle strengthening exercise (MSE). There was substantial uniformity in assessing the effectiveness of land- or water-based PAE and MSE in improving aerobic physical fitness (PF) and functional state. Water-based PAE offers some advantages over similarly intense land-based PAE in reducing spontaneous pain and improving depressive symptoms, but the data are insufficient to establish its overall superiority. Regardless of method, the latest findings concerning the neurophysiology of nociception indicate the fundamental importance of assigning workloads that do not exacerbate post-exercise pain.