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Asthma and cardiovascular disease (CVD) often co-exist. When a patient has both conditions, management requires an approach that addresses the unique challenges of each condition separately, while also considering their potential interactions. However, specific guidance on the management of asthma in patients with CVD and on the management of CVD in patients with asthma is still lacking. Nevertheless, health care providers need to adopt a comprehensive approach that includes both respiratory and CVD health. The management of CVD in patients with asthma requires a delicate balance between controlling respiratory symptoms and minimising potential cardiovascular (CV) risks. In the absence of specific guidelines for the management of patients with both conditions, the most prudent approach would be to follow established guidelines for each condition independently. Careful selection of asthma medications is essential to avoid exacerbation of CV symptoms. In addition, optimal management of CV risk factors is essential. However, close monitoring of these patients is important as there is evidence that some asthma medications may have adverse effects on CVD and, conversely, that some CVD medications may worsen asthma symptoms. On the other hand, there is also increasing evidence of the potential beneficial effects of asthma medications on CVD and, conversely, that some CVD medications may reduce the severity of asthma symptoms. We aim to elucidate the potential risks and benefits associated with the use of asthma medications in patients with CVD, and the potential pulmonary risks and benefits for patients with asthma who are prescribed CVD medications. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusionsGlucagon-like peptide-1 receptor agonists (GLP1RAs), originally developed for the treatment of type 2 diabetes mellitus, have attracted attention for their potential therapeutic benefits in asthma due to their anti-inflammatory properties and effects on airway smooth muscle function. However, concerns have been raised about the possibility of GLP1RAs inducing or exacerbating asthma symptoms.We reviewed data from the US Food and Drug Administration’s (FDA) adverse event (AE) reporting system (FAERS) to examine reports of cases of asthma observed in the real-world during treatment with GLP1RAs.Analysis of the FAERS reporting system database has shown that certain GLP1RAs, particularly exenatide, semaglutide and liraglutide, were associated with a higher proportion of respiratory AEs, particularly asthma or asthma-like events. This association was statistically significant at least for semaglutide and liraglutide. Serious asthma-related events and deaths were also reported, with exenatide having the highest proportion of deaths.The reasons for the observed differences in the AE profiles of the GLP1RAs remain unclear and may involve various factors such as pharmacological properties, patient characteristics and reporting biases. The complex interplay between the therapeutic benefits of GLP1RAs and the potential respiratory risks requires careful monitoring by clinicians, underpinned by ongoing research efforts to improve patient care and safety. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) may coexist with type 2 diabetes mellitus (T2DM). Patients with COPD have an increased risk of developing T2DM compared with a control but, on the other side, hyperglycaemia and DM have been associated with reduced predicted levels of lung function. The mechanistic relationships between these two diseases are complicated, multifaceted, and little understood, yet they can impact treatment strategy. The potential risks and benefits for patients with T2DM treated with pulmonary drugs and the potential pulmonary risks and benefits for patients with COPD when taking antidiabetic drugs should always be considered. The interaction between the presence and/or treatment of COPD, risk of infection, presence and/or treatment of T2DM and risk of acute exacerbations of COPD (AECOPDs) can be represented as a vicious circle; however, several strategies may help to break this circle. The most effective approach to simultaneously treating T2DM and COPD is to interfere with the shared inflammatory substrate, thus targeting both lung inflammation (COPD) and vascular inflammation (DM). In any case, it is always crucial to establish glycaemic management since the reduction in lung function found in people with diabetes might decrease the threshold for clinical manifestations of COPD. In this article, we examine possible connections between COPD and T2DM as well as pharmacological strategies that could focus on these connections. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination. Main body: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS. Conclusions: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD. [ABSTRACT FROM AUTHOR]

A growing number of clinical trials are documenting that adding a long-acting muscarinic antagonist (LAMA) to established asthma treatment with an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABA) is a treatment option that improves the health of patients with uncontrolled severe asthma even when therapy is optimized. These favorable results are the reason why the leading guidelines recommend triple therapy with ICS + LABA + LAMA in patients with asthma uncontrolled by medium- to high-dose ICS-LABA. However, we suggest adding LAMAs to ICS-LABAs at an earlier clinical stage. Such action could positively influence airflow limitation, exacerbations, and eosinophilic inflammation, conditions that are associated with acetylcholine (ACh) activity. It could also interrupt the vicious cycle related to a continuous release of ACh leading to the progressive expansion of neuronal plasticity resulting in small airway dysfunction. The utility of an earlier use of triple therapy in asthma should, in any case, be confirmed by statistically powered trials. [ABSTRACT FROM AUTHOR]

A solid pharmacological rationale, a documented strong synergism of action on the human airway in vitro, and excellent clinical efficacy revealed by randomized controlled trials and real-world observational studies support the use of umeclidinium (UMEC)/vilanterol (VIL) combination in a single inhaler (Ellipta) in the treatment of chronic obstructive pulmonary disease (COPD). Robust evidence indicates that it is consistently more effective than UMEC or VIL alone in improving lung function, dyspnoea, and quality of life. There is also a signal, albeit not a very strong one, indicating the ability of UMEC/VIL to prevent or reduce the risk of COPD exacerbations. Several mechanisms explain why this combination may decrease the frequency of COPD exacerbations. Both UMEC and VIL, like all drugs that antagonise muscarinic receptors or stimulate β2-adrenergic receptors, have the potential to impact cardiac activity. However, UMEC/VIL combination has an acceptable cardiovascular safety profile, at least in the COPD population enrolled in randomized controlled trials. It has even been reported that it may exert a protective role against serious cardiovascular adverse events compared to its mono-components. Unfortunately, there are very few head-to-head studies comparing UMEC/VIL and the other LAMA/LABA combinations, but the available data seem to suggest that it should be understood as the most effective LAMA/LABA combination currently available. [ABSTRACT FROM AUTHOR]

Because there is a solid pharmacological rationale based on positive interactions between long‐acting muscarinic receptor antagonists (LAMAs) and long‐acting β‐agonists (LABAs) for their ability to relax human airway smooth muscle in vitro alongside several randomised controlled trials (RCTs) and real‐world observational studies that support the use of LAMA/LABA fixed‐dose combinations (FDCs) for the treatment of patients with chronic obstructive pulmonary disease (COPD), in this narrative review we discuss the preclinical and clinical proofs supporting the use of LAMA + LABA therapy in COPD and why this therapeutic approach optimises bronchodilation. Robust evidence indicates that all LAMA/LABA FDCs are consistently more effective than LAMA or LABA administered alone in improving lung function, dyspnoea, quality of life and exercise capacity in patients with COPD. However, the ability of dual bronchodilation with FDCs of LAMA/LABA to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large RCTs, despite several mechanisms explaining why such combinations should be of value in decreasing the frequency of COPD exacerbations. Both LABAs and LAMAs mechanistically can affect the cardiovascular system, but from clinical studies to date, LAMA/LABA FDCs have an acceptable cardiovascular safety profile, at least in the COPD population enrolled in RCTs. Indirect evidence suggests that some FDCs may even exert a protective role against serious cardiovascular adverse events compared to monotherapies. Consequently, several LAMA/LABA FDCs have been developed and approved for clinical use as treatments for patients with COPD. However, to date, there are unfortunately very few head‐to‐head studies comparing the safety and efficacy of different LAMA/LABA FDCs, making it difficult to choose the most appropriate combination, although the use of meta‐analyses has provided some information in this regard. Endurance time Exercise time until exhaustion measured by a standard endurance test. Inspiratory capacity The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. St George's Respiratory Questionnaire (SGRQ) A tool to measure health status in patients with respiratory disease. It has three domains: symptoms, activity and impacts. A total score is also calculated. A minimal important difference (range) of ∼4 (2.4‐5.6) units in the SGRQ total score is supported by published studies. Surface under the cumulative ranking curve analysis (SUCRA) A numerical representation of the overall rating that displays a single value for each treatment. SUCRA levels vary from 0% to 100%. The higher the SUCRA value and the closer it is to 100%, the more likely therapy is in the top rank or one of the top rankings; the lower the SUCRA value and the closer it is to 0%, the more likely therapy is in the bottom rank or one of the bottom ranks. Transition dyspnoea index (TDI) Widely used in clinical studies of COPD to measure shortness of breath, indicating change in response to an intervention. The total score ranges from −9 to 9; the negative value indicates deterioration, whereas a positive value indicates improvement. There is sufficient evidence to suggest that the minimal important difference for the TDI score is 1 unit. Trough FEV1 The mean volume of air that can be forced out in 1 second approximately 12 (with a twice‐daily agent) or 24 (with a once‐daily agent) hours after the last administration of bronchodilator. [ABSTRACT FROM AUTHOR]

There is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients [ABSTRACT FROM AUTHOR]

Involvement of small airways, those of <2 mm in internal diameter, is present in all stages of asthma and contributes substantially to its pathophysiologic expression. Therefore, small airways are a potential target to achieve optimal asthma control. Airway tone, which is increased in asthma, is mainly controlled by the vagus nerve that releases acetylcholine (ACh) and activates muscarinic ACh receptors (mAChRs) post‐synaptically on airway smooth muscle (ASM). In small airways, M3 mAChRs are expressed, but there is no vagal innervation. Non‐neuronal ACh released from the epithelial cells that may express choline acetyltransferase in response to inflammatory stimuli, as well as from other structural cells in the airways, including fibroblasts and mast cells, can activate mAChRs. By antagonizing M3 mAChR, the contraction of the ASM is prevented and, potentially, local inflammation can be reduced and the progression of remodeling may be averted. In fact, ACh also contributes to inflammation and remodeling of the airways and regulates the growth of ASM. Several experimental studies have demonstrated the potential benefit derived from the use of mAChR antagonists, mainly long‐acting mAChR antagonists (LAMAs), on small airways in asthma. However, there are several confounding factors that may cause a wrong estimation of the relationship between LAMAs and small airways in asthma. Further studies are needed to differentiate broncholytic and anti‐inflammatory effects of LAMAs and to better understand the interaction between LAMAs and corticosteroids, also in the context of a triple therapy that includes a β2‐AR agonist, at different levels of the bronchial tree. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous condition, but firm identification of heterogeneity-focused treatments is still lacking. Dividing patients into subgroups of asthma pheno-/endotypes based on combined clinical and cellular biological characteristics and linking them to targeted treatments could be a potentially useful approach to personalize therapy for better outcomes. Nonetheless, there are still many problems related to the identification and validation of asthma phenotypes and endotypes. Alternatively, a precision-medicine strategy for the management of patients with airways disease that is free from the traditional diagnostic labels and based on identifying "treatable traits" in each patient might be preferable. However, it would represent a quite unsophisticated approach because the definition of a treatable trait is too imprecise. In fact, there is still no understanding of the mechanisms underlying treatable traits that allow directing any targeted therapies against any particular treatable trait. Fortunately, in-depth identification of underlying molecular pathways to guide targeted treatment in individual patients is in progress thanks to the improvement in big data management obtained from '-omic' sciences that is greatly increasing knowledge concerning asthma. [ABSTRACT FROM AUTHOR]

The management of chronic obstructive pulmonary disease (COPD) is fundamentally still heavily dependent on the use of bronchodilators and corticosteroids. Therefore, there is a need for alternative, more effective and safer therapeutic approaches. In particular, since inflammation in COPD lungs is often poorly responsive to corticosteroid treatment, novel pharmacological anti-inflammatory approaches are needed to optimally treat COPD patients. There have been multiple attempts to develop drugs that inhibit recruitment and activation of inflammatory cells, such as macrophages, neutrophils and T-lymphocytes, in the lungs of patients with COPD or target inflammatory mediators that are important in the recruitment or activation of these inflammatory cells or released by such cells. This review article focuses on novel classes of anti-inflammatory drugs that have already been tested in humans as possible treatments for patients with COPD. [ABSTRACT FROM AUTHOR]

There is strong evidence to support the use of blood eosinophil counts (BECs) in chronic obstructive pulmonary disease (COPD). Post hoc, secondary-prespecified and data-modelling analyses have shown a better response to inhaled corticosteroids in patients with increased BECs. Consequently, experts have suggested that BECs may be a useful biomarker to predict a favourable response to corticosteroid therapy. However, the literature is rich in contrasting data and there are still fundamental points that need to be clarified before sound judgement can be made. In this narrative review, we examine the evidence that supports or denies the role of BECs in COPD. Based on the available literature, we believe that the role of BEC as a valuable biomarker to guide COPD treatment in clinical practice remains unsupported. [ABSTRACT FROM AUTHOR]

Erdosteine is a drug approved for the treatment of acute and chronic pulmonary diseases, originally developed as a mucolytic agent. It belongs to the thiol-based family of drugs that are known to also possess potentially important antioxidant and anti-inflammatory properties, and exhibit antibacterial activity against a variety of medically important bacterial species. Erdosteine is a prodrug that is metabolized to the ring-opening compound metabolite M1 (MET 1), which has mucolytic properties. Experimental studies have documented that erdosteine prevents or reduces lung tissue damage induced by oxidative stress and, in particular, that Met 1 also regulates reactive oxygen species production. The RESTORE study, which has been the only trial that investigated the effects of a thiol-based drug in chronic obstructive pulmonary disease (COPD) frequent exacerbators, documented that erdosteine significantly reduces the risk of acute exacerbations of COPD (AECOPDs), shortens their course, and also decreases the risk of hospitalization from COPD. The preventive action of erdosteine on AECOPDs was not affected by the presence or absence of inhaled corticosteroids (ICSs) or blood eosinophil count. These findings clearly contrast with the Global Initiative for Chronic Obstructive Lung Disease strategy's approach to use erdosteine only in those COPD patients not treated simultaneously with an ICS. Furthermore, they support the possibility of using erdosteine in a step-down approach that in COPD is characterized by the withdrawal of the ICS. [ABSTRACT FROM AUTHOR]

The article offers information on myelodysplastic syndromes (MDS), the morphologic abnormalities of the myeloid cell lines of hematopoiesis in preleukemic conditions. Topics discussed include mutation-derived genes in MDS, genetic complexity of MDS associated with mutations in SRSF2 or U2AF1, and molecular pathophysiology of three subtypes of MDS.

Guidelines are mainly based on evidence of well-designed randomized controlled trials (RCTs), but there are limitations to the transferability of conclusions of RCTs to usual care mainly because the patients enrolled in RCTs are selected and not representative of the population encountered in daily practice; moreover, the research environment is substantially different from that of the real world. Because of the scarcity of data generated in large unselected populations in everyday clinical practice, the possibility of using meta-analyses can be considered. Recently, several meta-analyses have attempted to clarify the role of triple therapy containing a long-acting β-agonist (LABA), a long-acting muscarinic antagonist (LAMA) and an inhaled corticosteroid (ICS) delivered from a single inhaler in chronic obstructive pulmonary disease (COPD), also considering that there is a big difference in the use of triple therapy between what is recommended by COPD guidelines or strategies and the prescriptive behaviour of clinicians. Taking into account the results of the most recent meta-analyses, we believe that triple therapy provides modest clinical benefit in the general COPD population, but in patients on LABA/LAMA combination therapy, who still experience acute exacerbations of COPD (AECOPDs) and have blood eosinophil counts ≥ 300 cells·μl−1, it is of clinical relevance. On the contrary, adding a LAMA to an ICS/LABA combination elicits relevant clinical benefit in the general COPD population, supporting the role of dual bronchodilation therapy for the treatment of COPD. The quantitative synthesis of the currently available clinical evidence seems to suggest that, in patients with COPD already on ICS/LABA combination, the therapy can be improved without an increase of cardiovascular severe adverse events (SAEs) when a LAMA is added to the combination. [ABSTRACT FROM AUTHOR]

In recent years, there has been a great deal of interest in the identification and validation of blood-based biomarkers for clinical use in chronic obstructive pulmonary disease (COPD). We now have panels of blood biomarkers that potentially hold great promise as they show statistically significant associations with COPD, but biomarkers for the diagnosis of COPD remain elusive. In fact, they are yet to demonstrate sufficient accuracy to be accepted in clinical use, and many are not specific to COPD but more related to inflammation (e.g. interleukin-6) or associated with other chronic diseases such as diabetes (e.g. soluble receptor for advanced glycation endproducts [sRAGE]). Although no single blood-based biomarker has demonstrated clinical utility for either the diagnosis or progression of COPD, it has been suggested that combinations of individual markers may provide important diagnostic or prognostic information; however, the interpretation of COPD biomarker results still requires thought and many questions remain unanswered. [ABSTRACT FROM AUTHOR]

Thiol-based drugs are considered as mucolytics because they decrease the viscosity and mostly decrease the elasticity of bronchial secretions by reducing disulfide bonds in proteins. However, they can also act as antioxidant drugs directly through free sulfhydryl groups that serve as a source of reducing equivalents, as well as indirectly through the replenishment of intracellular glutathione (GSH) levels. Modulation of neurokinin A levels may also be related to the effect of thiol drugs on oxidative stress. Moreover, thiol-based drugs interfere with inflammatory pathways and modulate human bronchial tone. They might also be considered as therapeutic agents against some types of infection because they reduce bacterial adhesion to the respiratory epithelial cell surface and inhibit biofilm formation, causing biofilm disruption and thereby improving the efficacy of antibiotic therapy. Thiol groups are common functional groups in protein structure. They stabilize the tertiary and quaternary structures of proteins by forming intra- and interchain disulfide bonds (S–S), play many roles in metabolism and homeostasis, and are important in several physiological and pathological processes. Drugs containing the thiol moiety (-SH) impact on a variety of biological systems. N -acetyl L-cysteine, S -carboxymethyl-L-cysteine, and erdosteine have been studied in the treatment of pulmonary diseases such as chronic obstructive pulmonary disease, bronchiectasis, and idiopathic pulmonary fibrosis. However, the implementation of these drugs in pulmonary medicine remains limited. Thiol-based drugs act as mucolytics and antioxidants. They also interfere with inflammatory pathways, modulate human bronchial tone, and should be considered in some infections because thiols reduce bacterial adhesion to the respiratory epithelial cell surface and inhibit biofilm formation, causing biofilm disruption and improving the efficacy of antibiotic therapy. [ABSTRACT FROM AUTHOR]

Background: Inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination is commonly prescribed to treat COPD; therefore, we performed a meta-analysis on the effect of adding a long-acting muscarinic receptor antagonist (LAMA) to ICS/LABA combination in COPD.Methods: Studies were identified by searching in different databases the randomized controlled trials that investigated the effect of ICS/LABA/LAMA combination in COPD. The primary end points were the effect of triple therapy on trough FEV1, risk of acute exacerbation of COPD (AECOPD), and risk of cardiovascular serious adverse events (SAEs), compared with ICS/LABA combination. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the quality of evidence.Results: Thirteen randomized controlled trials including 15,519 patients with COPD (ICS/LABA/LAMA combination, 53.1%; ICS/LABA combination, 46.9%) were meta-analyzed. ICS/LABA/LAMA combination improved trough FEV1 (mean difference, +104.86 mL; 95% CI, 86.74-122.99; high quality of evidence) and protected against AECOPD (relative risk, 0.78; 95% CI, 0.71-0.85; high quality of evidence) vs ICS/LABA combination. For every approximately four patients treated with triple therapy, one increased FEV1 > 100 mL, and approximately 26 patients had to be treated for 1 year with ICS/LABA/LAMA combination to prevent one AECOPD, compared with ICS/LABA combination. Adding a LAMA to ICS/LABA therapy did not modulate the risk of cardiovascular SAEs (moderate quality of evidence).Conclusions: Triple therapy provides significant clinical benefit in patients with COPD on ICS/LABA combination. ICS/LABA therapy can be escalated to triple therapy without a real risk to increase cardiovascular SAEs when a LAMA is added to the combination.Trial Registry: ClinicalTrials.gov; No.: CRD42018095300; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

The article discuses the Triple Therapy which is also Effective in Real-World when used in Chronic Obstructive Pulmonary Disease Patients who are Frequent Exacerbators. It mentions that this prescriptive behavior suggests that management of COPD patients does not generally follow the recommendations of many COPD guidelines or strategies that restrict the use of triple therapy to well-defined clinical conditions but is rather based on physicians' clinical experience.

Doxofylline is an effective bronchodilator for relieving airway obstruction in patients with asthma or chronic obstructive pulmonary disease (COPD), and displays a better safety profile with respect to theophylline. Herein, we performed a pairwise meta-analysis of the currently available data to provide consistent and homogeneous findings on the impact of this xanthine in COPD patients. Results obtained from 820 patients were selected from 20 clinical trials. Meta-regression was performed to examine the source of heterogeneity between-studies and identify potential confounder covariates. The quality of the evidence was assessed by the GRADE system. Doxofylline induced a significant (P < 0.001) increase in forced expiratory volume in 1 s (FEV 1 ) of 8.20% (95%CI 4.00–12.41; I 2 93%) and 317 ml (95%CI 19–439; I 2 87%) compared with baseline. The total administered dose of doxofylline significantly (P < 0.001) interacted with the size of the effect estimates detected for FEV 1 . Doxofylline induced a significant (P < 0.001), although moderate, increase in adverse events (AEs) frequency (proportion 0.03, 95%CI 0.02–0.04; I 2 88%), but only epigastralgia, nausea, dyspepsia and headache were statistically significant (P < 0.05). The GRADE analysis indicated high quality of evidence (++++) for the impact of doxofylline on FEV 1 , and moderate quality of evidence (+++) for the safety profile in COPD patients. Doxofylline is an effective and safe medicine when administered to patients with COPD and can be considered as an alternative to theophylline. [ABSTRACT FROM AUTHOR]

A previous meta-analysis suggested that the treatment with erdosteine was associated with significant amelioration of the cumulative global efficacy index and symptoms in comparison to placebo or other mucolytics. However, this conclusion was criticized because the meta-analysis, as it had been done, made it impossible to preclude the potential operation of selection biases within and across trials, and identify any realised benefits of an individual patient data approach. Taking into consideration these criticisms and also the publication of two further recent articles focused on the prevention of chronic obstructive pulmonary disease (COPD) exacerbations with erdosteine, we have carried out a quantitative synthesis via meta-analysis of the currently available data on the use of this drug. Our findings included data from ten studies involving 1278 patients and show that erdosteine is able to improve the clinical score of patients with chronic bronchitis and COPD, and also reduces the overall risk of chronic bronchitis/COPD exacerbations, and reduces the risk of experiencing at least one exacerbation. Furthermore, our data suggest that erdosteine can lengthen the time to the first COPD exacerbation, reduce the duration of a COPD exacerbation and the risk of hospitalization from COPD. The documented effect of erdosteine in reducing the occurence and/or influencing COPD exacerbations is important because it indicates that erdosteine can be added to the list of drugs that can be recommended for treating COPD. [ABSTRACT FROM AUTHOR]

Mucolytics are potentially useful for the management of chronic obstructive pulmonary disease (COPD), although there is conflicting advice on their use in different guideline documents. Furthermore, there is paucity of data comparing the efficacy of the different mucolytic agents in reducing the odds of COPD exacerbations. We performed pair-wise and network meta-analyses to evaluate the impact of mucoly-tics in COPD. Randomized clinical trials lasting at least 3 months and investigating the effects of mucolytics on COPD exacerbations were identified from published studies and repository databases. Mucolytics significantly reduced the odds of exacerbation vs. placebo (11 studies analyzed: odds ratio (OR) 0.51, 95% confidence interval (CI) 0.39–0.67;p< 0.001). The most effective drugs were carbocysteine, erdosteine, and N-acetylcysteine 1,200 mg/day (SUCRA 68.0–79.0%), whereas the OR was similar to placebo for ambroxol and N-acetylcysteine 600 mg/day. Only N-acetylcysteine 1,200 mg/day significantly protected against exacerbations vs. placebo (2 studies analyzed: OR 0.56, 95% CI 0.35–0.92;p< 0.05; high quality of evidence). A signal of effectiveness was detected for carbocysteine (2 studies analyzed: OR 0.45, 95% CI 0.20–1.01;p≥ 0.05; moderate quality of evidence). Specific differences in study designs and patient-related characteristics, such as history of exacerbations and ethnicity, were potential effect modifiers for our statistical models, whereas neither respiratory function nor the use of corticosteroids influenced the analysis. This meta-analysis demonstrates that mucolytics are useful in preventing COPD exacerbations as maintenance add-on therapy to patients with frequent exacerbations. The effectiveness of mucolytics is independent of the severity of airway obstruction and the use of inhaled corticosteroids. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) often coexist. The mechanistic links between these two diseases are complex, multifactorial, and not entirely understood, but they can influence the approach to treatment. Understanding whether COPD comes first followed by T2DM or vice versa, or whether the two diseases develop simultaneously due to common underlying mechanisms, is important for the development of novel therapeutic approaches to these two important diseases. In this review, we discuss the potential links between COPD and T2DM and pharmacological approaches that might target these links. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms ( MPNs) are generally acquired as a result of a somatic stem cell mutation leading to clonal expansion of myeloid precursors. In addition to sporadic cases, familial MPN occurs when one or several MPN affect different relatives of the same family. MPN driver mutations ( JAK2, CALR, MPL) are somatically acquired also in familial cases, so a genetic predisposition to acquire one of the MPN driver mutations would be inherited, even though the causative germline mutations underlying familial MPN remain largely unknown. Recently some germline variants [ ATG2B and GSKIP duplication, RBBP6 mutations, SH2B3 ( LNK) mutations], which can cause familial MPN, have been reported but these mutations are rare and do not explain most familial cases. Patients with familial MPN show the same clinical features and suffer the same complications as those with sporadic disease. This review aims to offer up-to-date information regarding the genetics of familial MPN. [ABSTRACT FROM AUTHOR]

Pheno-/endotyping chronic obstructive pulmonary disease (COPD) is really important because it provides patients with precise and personalized medicine. The central concept of precision medicine is to take individual variability into account when making management decisions. Precision medicine should ensure that patients get the right treatment at the right dose at the right time, with minimum harmful consequences and maximum efficacy. Ideally, we should search for genetic and molecular biomarker-based profiles. Given the clinical complexity of COPD, it seems likely that a panel of several biomarkers will be required to characterize pathogenetic factors and their course over time. The need for biomarkers to guide the clinical care of individuals with COPD and to enhance the possibilities of success in drug development is clear and urgent, but biomarker development is tremendously challenging and expensive, and translation of research efforts to date has been largely ineffective. Furthermore, the development of personalized treatments will require a much more detailed understanding of the clinical and biological heterogeneity of COPD. Therefore, we are still far from being able to apply precision medicine in COPD and the treatable traits and FEV-free approaches are attempts to precision medicine in COPD that must be considered still quite unsophisticated. [ABSTRACT FROM AUTHOR]

In all current guidelines and recommendations of the management of COPD, inhaled bronchodilators are the pillar of therapy at each stage of the disease. Dual bronchodilation with long-acting muscarinic antagonist (LAMA)/long-acting β-agonist (LABA) is always more effective than the LAMA or LABA alone in terms of the improvement in trough FEV, and transitional dyspnea index and St. George's Respiratory Questionnaire scores. Indacaterol/glycopyrronium has been the first LABA/LAMA to be developed and approved as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. It has received approval from numerous regulatory authorities around the world because of the results of the pivotal Phase III programs IGNITE, which explored indacaterol/glycopyrronium 110/50 μg once-daily across 52 countries, and EXPEDITION, which explored indacaterol/glycopyrronium 27.5/15.6 μg twice-daily in US. Although guidelines and recommendations suggest a 'slow' gradual therapeutic strategy, we advocate the need to start immediately, until the time of diagnosis, the treatment of COPD patients with indacaterol/glycopyrronium in order to optimize bronchodilation, because we strongly believe the rapid improvement in symptoms that it is able to elicit could help patients' adherence to treatment, which may be otherwise discouraged by a 'slow' gradual therapeutic approach. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases often coexist. The mechanistic links between these two diseases are complex, multifactorial and not entirely understood, but they can influence the therapeutic approach. Therapy can be primarily directed towards treating the respiratory symptoms and reducing lung inflammation. Smoking cessation, bronchodilators and inhaled corticosteroids are central to this therapeutic approach. The underlying pathophysiological mechanisms that are responsible for the increased cardiovascular risk in COPD remain unclear, but might include arterial stiffness, inflammation and endothelial dysfunction as a consequence of systemic exposure to chemicals in cigarette smoke or airborne pollution. Therefore, it is plausible that treatment of cardiovascular co-morbidities might reduce morbidity and mortality in patients with COPD and, consequently, therapy of COPD should be shifted to the treatment of cardiovascular diseases and systemic inflammation. In support of this approach, early data suggest that patients with COPD treated with angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, statins, anti-platelet drugs or β-adrenoceptor blockers may have improved survival and reduced hospitalisation from acute exacerbations of COPD. In this review, the potential impact of traditional therapies for COPD that are centred on treating the lungs and newer strategies potentially able to affect and mitigate cardiovascular risks in patients with COPD are discussed. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress is recognized to be one of predisposing factor in the pathogenesis of COPD. The oxidant/antioxidant imbalance is significantly pronounced in patients with COPD exacerbation. N-acetylcysteine (NAC) seems to be able to reduce COPD exacerbations by modulating the oxidative stress in addition to its well-known mucolytic activity, but there are discordant findings on the actual anti-oxidant activity of NAC.Methods: The anti-oxidant effect of NAC and its impact on the inflammatory response have been pharmacologically characterized on a human ex vivo model of COPD exacerbation induced by lipopolysaccharide (LPS).Results: NAC prevented the desensitization induced by LPS incubation on the contractile tone in linear concentration-response manner. Concentrations of NAC ≥1 μM reduced the pro-oxidant response (peroxidase activity, hydrogen peroxide, malondialdehyde, nitric oxide), and improved the anti-oxidant response (total anti-oxidant capacity, glutathione, superoxide dismutase) induced by LPS. Lower concentrations of NAC (<1 μM) did not modulate the bronchial oxidative imbalance. Concentrations of NAC ≥300 μM inhibited the inflammatory response (release of IL-1β, IL-8, and TNF-α) of human airways induced by the overnight stimulation with LPS, whereas lower concentrations of NAC (≥1 μM) were sufficient to reduce the release of IL-6 elicited by LPS. Both the anti-oxidant effect and the anti-inflammatory effect of NAC were inversely correlated with the release of NKA.Conclusions: The findings of this study suggest that NAC may have a role in modulating the detrimental effect induced by LPS in course of COPD exacerbation. It may elicit both anti-oxidant and anti-inflammatory effects when administered at high concentrations. [ABSTRACT FROM AUTHOR]

Essential thrombocythemia (ET) is an indolent myeloproliferative neoplasm that may be complicated by vascular events, including both thrombosis and bleeding. This disorder may also transform into more aggressive myeloid neoplasms, in particular into myelofibrosis. The identification of somatic mutations of JAK2, CALR, or MPL, found in about 90% of patients, has considerably improved the diagnostic approach to this disorder. Genomic profiling also holds the potential to improve prognostication and, more generally, clinical decision-making because the different driver mutations are associated with distinct clinical features. Prevention of vascular events has been so far the main objective of therapy, and continues to be extremely important in the management of patients with ET. Lowdose aspirin and cytoreductive drugs can be administered to this purpose, with cytoreductive treatment being primarily given to patients at high risk of vascular complications. Currently used cytoreductive drugs include hydroxyurea, mainly used in older patients, and interferon a, primarily given to younger patients. There is a need for disease-modifying drugs that can eradicate clonal hematopoiesis and/ or prevent progression to more aggressive myeloid neoplasms, especially in younger patients. In this article, we use a case-based discussion format to illustrate our approach to diagnosis and treatment of ET. [ABSTRACT FROM AUTHOR]

Myeloid neoplasms with ring sideroblasts are currently categorized within the myelodysplastic syndromes ( MDS) or myelodysplastic/myeloproliferative neoplasms ( MDS/ MPN) in the World Health Organization classification. Recent findings have identified that the presence of ring sideroblasts in these disorders has a unique molecular basis, i.e., the somatic mutation of SF3B1, a gene encoding a splicing factor. Mutations of SF3B1 occur in up to 90% of patients with refractory anaemia with unilineage dysplasia ( RARS) and 70% of those with refractory cytopenia with multilineage dysplasia and ring sideroblasts or RARS associated with marked thrombocytosis. Experimental evidence has shown that mutant SF3B1 results in the abnormal splicing of several genes, primarily due to misrecognition of 3′ splice sites. The resulting aberrant mRNAs undergo nonsense-mediated mRNA decay ( NMD), resulting in haploinsufficiency of canonical transcripts and protein expression. In addition, it is also possible that NMD-insensitive aberrant transcripts are translated into proteins with altered function. Patients with MDS carrying the SF3B1 mutation show a homogeneous disease phenotype characterized by isolated erythroid dysplasia and mild dysplasia in granulocytic or megakaryocytic lineages, supporting the notion that the SF3B1 mutation identifies a distinct entity within MDS. The available evidence suggests that these findings may have relevant impact on the diagnosis, classification and management of patients with these neoplasms. [ABSTRACT FROM AUTHOR]

Budesonide/formoterol (BF) is available in two delivery systems, the dry powder inhaler (DPI) Turbuhaler and a pressurized metered dose inhaler (pMDI) for use in patients with asthma or chronic obstructive pulmonary disease (COPD). Spiromax DPI was recently developed as an alternative to Turbuhaler DPI. In the present study, we examined whether there is a difference in the onset of bronchodilatation between BF 320/9 μg delivered by Spiromax and BF 320/9 μg delivered by Turbuhaler in 16 outpatients with stable moderate-to-severe COPD. Our results confirm the rapid onset of action of formoterol when combined with budesonide in patients with COPD and indicate that the onset of bronchodilation induced by BF Spiromax is faster than that elicited by BF Turbuhaler. Furthermore, they show that BF fixed-dose combination does not induce a decrease in SpO 2 or an increase in heart rate in patients with COPD, irrespective of the DPI used to deliver this combination. Given the evidence that both inhalers have an equal safety profile, BF Spiromax offers to prescribers and COPD patients an effective alternative to BF Turbuhaler depending also on their preference, availability and cost. [ABSTRACT FROM AUTHOR]

Background: Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between glycopyrronium bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction.Methods: The effects of glycopyrronium plus indacaterol on the contractile tone of medium and small human isolated bronchi were evaluated, and acetylcholine and cAMP concentrations were quantified. The interaction was assessed by Bliss Independence approach.Results: Glycopyrronium plus indacaterol synergistically inhibited the bronchial tone (medium bronchi, +32.51 % ± 7.86 %; small bronchi, +28.46 % ± 5.35 %; P < 0.05 vs. additive effect). The maximal effect was reached 140 min post-administration. A significant (P < 0.05) synergistic effect was observed during 9 h post-administration on the cholinergic tone, but not on the histaminergic contractility. Co-administration of glycopyrronium and indacaterol reduced the release of acetylcholine from the epithelium but not from bronchi, and enhanced cAMP levels in bronchi and epithelial cells (P < 0.05 vs. control), an effect that was inhibited by the selective KCa(++) channel blocker iberiotoxin. The role of cAMP-dependent pathway was confirmed by the synergistic effect elicited by the adenylate cyclase activator forskolin on glycopyrronium (P < 0.05 vs. additive effect), but not on indacaterol (P > 0.05 vs. additive effect), with regard of the bronchial relaxant response and cAMP increase.Conclusions: Glycopyrronium/indacaterol co-administration leads to a synergistic improvement of bronchodilation by increasing cAMP concentrations in both airway smooth muscle and bronchial epithelium, and by decreasing acetylcholine release from the epithelium. [ABSTRACT FROM AUTHOR]

The author discusses the 2016 changes of the World Health Organization (WHO) identification of tumors of hematopoietic and lymphoid tissues. Topics discussed include the revision of the 4th edition of "WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues," proposed revisions being revealed at the Clinical Advisory Committee meeting in Chicago, Illinois from March 31 to April 1, 2014, and changes to promote integration of morphology and genetics in cancer diagnosis.

Background To date there is emerging clinical evidence to add long-acting anti-muscarinic agents (LAMAs) with inhaled corticosteroid (ICSs) in asthma, but the pharmacological rationale that supports the use of such a combination has not yet been explained. The aim of this study was to pharmacologically investigate the interaction between the ICS beclomethasone and the LAMA glycopyrronium on the human airway smooth muscle (ASM) tone. Methods We investigated the rapid non-genomic bronchorelaxant effect of beclomethasone and glycopyrronium, administered alone and in combination, in human isolated bronchi and bronchioles. Experiments were carried out also in passively sensitized airways and the pharmacological analysis of drug interaction was performed by Bliss Independence method. Results The acute administration of beclomethasone and glycopyrronium induced a significant relaxation of passively sensitized ASM pre-contracted with histamine, by causing submaximal/maximal inhibition of the contractile tone in both medium bronchi and bronchioles. Beclomethasone was characterized by a rapid non-genomic and epithelium independent bronchorelaxant effect. In passively sensitized airways, this effect seemed to be dependent by the activation of a Gsα – cyclic adenosine monophosphate (cAMP) – protein kinase A cascade. While no synergistic interaction was detected in non-sensitized bronchi, the beclomethasone/glycopyrronium combination synergistically enhanced the relaxation of passively sensitized medium and small bronchi. The synergistic interaction between beclomethasone and glycopyrronium was associated with an increase of cAMP concentrations. Conclusions Our study provides for the first time the pharmacological rationale for combining low doses of an ICS plus a LAMA. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) guidelines and strategies suggest escalating treatment, mainly depending on the severity of airflow obstruction. However, some de-escalation of therapy in COPD would be appropriate, although we still do not know when we should switch, step-up or step-down treatments in our patients. Unfortunately, trials comparing different strategies of step-up and step-down treatment (e.g. treatment initiation with one single agent and then further step-up if symptoms are not controlled versus initial use of double or triple therapy, possibly with lower doses of the individual components, or the role of N-acetylcysteine in combination therapy for a step-down approach) are still lacking. In general, there is a large and often inappropriate use of the inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) combination. However, the withdrawal of the ICS in COPD patients at low risk of exacerbation can be safe, provided that patients are under regular treatment with long-acting bronchodilators. Maximising the treatment in patients with a degree of clinical instability by including an ICS in the therapeutic regimen is useful to control the disease, but may not be needed during periods of clinical stability. In patients with severe but stable COPD, the withdrawal of the ICS from triple therapy [LABA + long-acting muscarinic antagonist (LAMA) + ICS] is possible, but not when the patient has been hospitalised for an acute exacerbation of COPD. We must still establish how long we should wait before withdrawing the ICS. It is still unclear whether the same is true when only the LABA or the LAMA is withdrawn while continuing treatment with the other bronchodilator and the ICS. In any case, we strongly believe that it is always better to avoid a therapeutic step-up progression when it is not needed rather than being forced subsequently into a step-down approach in which the outcome is always unpredictable. [ABSTRACT FROM AUTHOR]

Background The dual PDE3/4 inhibitor RPL 554 causes bronchodilation in patients with asthma or COPD and synergistically interacts with muscarinic receptor antagonists in relaxing human isolated bronchi in acute experimental settings. In the present study we investigated the long-lasting interaction between RPL554 and glycopyrronium by testing these drugs for their ability to relax both medium and small human isolated bronchi. Methods The relaxant effect and duration of action of RPL554 and glycopyrronium, alone, or in combination, were studied on the contractile tone induced by electrical field stimulation (EFS) or carbachol in medium and small human isolated bronchi. Relaxation was expressed as percentage of maximal response and synergy analyzed by Bliss Independence theory. Results Low concentrations of RPL554 and glycopyrronium induced maximal relaxation of medium bronchi at 160 ± 20 min and 50 ± 10 min, respectively, an effect detectable for at least 4 h. Maximal synergy was observed at ≃2 hrs (−71.4 ± 5.1%), and the combination extended the relaxation to at least 6 hrs, when the contractile tone was −41.2 ± 8.5% of the control responses. The combination induced the greatest effectiveness for EFS at 3 Hz and low-to-middle concentrations also produced significant synergism on small airways (21.1 ± 4.0%,P < 0.05), compared with the additive response. The combination induced lumen area enhancement of 69.1 ± 2.4% (P < 0.05), compared with the additive response (51.0 ± 5.4%). Conclusions RPL554 and glycopyrronium demonstrated a synergistic interaction in relaxing both human medium and small isolated bronchi, in terms of peak relaxation and an extended duration of action, suggesting that this combination may have a beneficial role in the treatment of asthma or COPD. [ABSTRACT FROM AUTHOR]

We aimed to explore whether the acute bronchodilation induced by indacaterol 150 μg and glycopyrronium bromide 50 μg is additive or synergistic with respect to monocomponents by testing the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. Both indacaterol and glycopyrronium caused a concentration-dependent relaxation of human isolated bronchial tissues sub-maximally pre-contracted with acetylcholine; glycopyrronium was significantly more potent than indacaterol. The analysis of data using the Bliss Independence (BI) criterion indicated that glycopyrronium plus indacaterol produced an additive interaction at the isoeffective concentrations inducing EC20 and a significant synergistic relaxant effect at isoeffective concentrations inducing EC30. In COPD patients, the inhalation of indacaterol and glycopyrronium in combination significantly anticipated at 15 min post-administration the mean peak of bronchodilatory effect compared to the two drugs administered alone. The study of interaction between indacaterol and glycopyrronium by BI analysis evidenced an additive effect for FEV1 between 5 min and 180 min post-inhalation, with synergistic interaction at 15 min post-administration, compared to the bronchodilation induced by these drugs administered alone. This study suggests that the combination ensures a broncholytic effect that is greater than that induced by the single monocomponents. [ABSTRACT FROM AUTHOR]

The long-acting inhaled bronchodilators available for use in chronic obstructive pulmonary disease (COPD) vary in their pharmacological class (β 2 -adrenergic agonist or antimuscarinic/anticholinergic, alone or combined), durations of action and speed of onset of bronchodilator effect. In the early stages of development of a maintenance bronchodilator, the goals are to identify a molecule with the theoretically ‘ideal’ profile of fast onset and prolonged duration of action in comparison with existing agents, while minimizing non-specific activity at organs outside the lungs. The move towards increasing duration of bronchodilator action is generally paralleled by improved effects on clinical outcomes, and the advent of more potent agents seems likely to provide an opportunity to reduce overreliance on the use of inhaled corticosteroids in treating COPD. In terms of onset of action, an immediately perceived benefit in reducing dyspnea, although not definitively demonstrated, might prove useful in increasing adherence, which is very poor among patients with COPD. Once-daily administration may also be helpful in this respect. Shared decision-making between patient and physician in the choice of treatment is important in optimizing adherence and, thus, treatment effectiveness. [ABSTRACT FROM AUTHOR]

Long-acting muscarinic receptor antagonists (LAMAs) and long-acting β 2 -adrenoceptor agonists (LABAs) cause airway smooth muscle (ASM) relaxation via different signal transduction pathways, but there are limited data concerning the interaction between these two drug classes on human bronchi. The aim of this study was to investigate the potential synergistic interaction between aclidinium bromide and formoterol fumarate on the relaxation of human ASM. We evaluated the influence of aclidinium bromide and formoterol fumarate on the contractile response induced by acetylcholine or electrical field stimulation (EFS) on human isolated airways (segmental bronchi and bronchioles). We analyzed the potential synergistic interaction between the compounds when administered in combination by using Bliss independence (BI) theory. Both aclidinium bromide and formoterol fumarate completely relaxed segmental bronchi pre-contracted with acetylcholine ( E max : 97.5±2.6% and 96.4±1.1%; pEC 50 8.5±0.1 and 8.8±0.1; respectively). Formoterol fumarate, but not aclidinium bromide, abolished the contraction induced by acetylcholine in bronchioles ( E max : 68.1±4.5% and 99.0±5.6%; pEC 50 7.9±0.3 and 8.4±0.3; respectively). The BI analysis indicated synergistic interaction at low concentrations in segmental bronchi (+18.4±2.7%; P <0.05 versus expected effect) and from low to high concentrations in bronchioles (+19.7±0.9%; P <0.05 versus expected effect). Low concentrations of both drugs produced a synergistic relaxant interaction on isolated bronchi stimulated with EFS that was sustained for 6 h post-treatment (+55.1±9.4%; P <0.05 versus expected effect). These results suggest that combining aclidinium bromide plus formoterol fumarate provides synergistic benefit on ASM relaxation of both medium and small human airways, which may have major implications for the use of this combination in the clinic. [ABSTRACT FROM AUTHOR]

Ensifentrine is an inhaled 'bifunctional' dual phosphodiesterase 3/4 inhibitor that exhibits both bronchodilator and anti-inflammatory activities. Preclinical research has shown that ensifentrine can induce significant relaxation of human bronchi in vitro and suggested the possibility of a synergistic interaction between ensifentrine and ß2-adrenoceptor agonists and, mainly, muscarinic receptor antagonists. Ensifentrine is the only dual phosphodiesterase 3/4 inhibitor under clinical development for the treatment of chronic obstructive pulmonary disease (COPD). It has been shown to induce bronchodilation, with a peak bronchodilator effect in patients with COPD similar to that seen after salbutamol administration, and anti-inflammatory activity in healthy individuals. Combined with standard bronchodilators (salbutamol, ipratropium or tiotropium), ensifentrine causes additional bronchodilation and, importantly, a significant reduction in hyperinflation in patients with stable moderate to severe COPD. A recent statement on the top-line phase III ENHANCE-2 study reported that ensifentrine induced significant bronchodilation and reduced the risk of moderate-to-severe COPD exacerbations in study participants. Ensifentrine continues to show promise as a novel drug for treating patients with COPD. Nevertheless, it is necessary to understand whether ensifentrine will be able to replace or reduce the use of currently available classes of bronchodilators, and/or whether it will be a valuable add-on therapy to the current standard of care to further optimize bronchodilation. Furthermore, it will be critical to clarify the anti-inflammatory profile of ensifentrine. [ABSTRACT FROM AUTHOR]

Our understanding of the genetic basis of myeloproliferative neoplasms began in 2005, when the J4K2 (V617F) mutation was identified In polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2 exon 12 and MPL exon 10 mutations were then detected in subsets of patients, and subclonal driver mutations in other genes were found to be associated with disease progression. Recently, somatic mutations in the gene CALR, encoding calreticulin, have been found in most patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 and MPL. The JAK-STAT pathway appears to be activated in ail myeloproliferative neoplasms, regardless of founding driver mutations. These latter, however, have different effects on clinical course and outcomes. Thus, evaluation of JAK2, MPL, and CALR mutation status is important not only for diagnosis but also for prognostication. These genetic data should now also be considered in designing clinical trials. [ABSTRACT FROM AUTHOR]

Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ⩾1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in 1⩾0% MDS patients, whereas a long tail of ∼50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient's genome are now needed. [ABSTRACT FROM AUTHOR]

Abstract: The use of muscarinic receptor antagonists in the treatment of chronic obstructive pulmonary disease (COPD) is well established. More recently, the potential for long-acting muscarinic receptor antagonists (LAMAs) in the treatment of asthma has also been investigated. While LAMAs offer advantages over short-acting muscarinic receptor antagonists, in terms of a reduced dosing frequency, there remains a need for therapies that improve symptom control throughout both the day and night, provide better management of exacerbations and deliver improved health-related quality of life. Furthermore, the potential for unwanted anticholinergic side effects, particularly cardiovascular effects, remains a concern for this class of compounds. Novel LAMAs in clinical development for the treatment of respiratory disease include: aclidinium bromide, NVA237 (glycopyrronium bromide), GP-MDI, EP-101, CHF-5259, umeclidinium bromide, CHF-5407, TD-4208, AZD8683 and V-0162. These compounds offer potential advantages in terms of onset of action, symptom control and safety. In addition, a number of LAMAs are also being developed as combination treatments with long-acting β2-agonists (LABAs) or inhaled glucocorticosteroids, potentially important treatment options for patients who require combination therapy to achieve an optimal therapeutic response as their disease progresses. More recently, compounds such as GSK961081 and THRX-198321 have been identified that combine LAMA and LABA activity in the same molecule, and have the potential to offer the benefits of combination therapy in a single compound. Here, we review novel LAMAs and dual action compounds in clinical development, with a particular focus on how they may address the current unmet clinical needs in the treatment of respiratory disease, particularly COPD. [Copyright &y& Elsevier]