Ensifentrine Plus a Long-Acting Muscarinic Antagonist in COPD: A Trifunctional Dual Bronchodilation Perspective.

Chronic obstructive pulmonary disease (COPD) management has evolved with the emergence of advanced pharmacological strategies, notably dual bronchodilation and bifunctional agents. Among these innovations, the selective inhaled phosphodiesterase (PDE)3/4 inhibitor ensifentrine represents a novel therapeutic class that combines bronchodilatory and anti-inflammatory properties within a single molecular entity. Dual bronchodilation, traditionally achieved through the combination of long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists, has demonstrated superior efficacy compared with monotherapies, including enhanced pulmonary function, reduced symptom burden, and decreased exacerbation frequency.

The interplay between asthma and type 2 diabetes mellitus: mutual interactions and therapeutic implications.

Introduction: Asthma and type 2 diabetes mellitus (T2DM) are chronic diseases with a significant global health burden. Recent studies have highlighted the complex relationship between these two diseases, particularly regarding their pharmacological management.

Areas Covered: This review discusses the mechanisms linking asthma and T2DM and the interactions between asthma and T2DM therapies, highlighting the potential clinical implications.

Interaction of Erdosteine with TrkA Signaling Pathways: Implications for Analgesia.

Thiol-containing drugs may interact with a region of tropomyosin receptor kinase A (TrkA), potentially inhibiting its activation by nerve growth factor (NGF). This action has been linked to potential analgesic activities. Here, we describe the ability of erdosteine, a thiolic compound classified as a mucolytic agent, to bind to the TrkA receptor sequence in silico and its in vitro effects on TrkA activation induced by NGF in cultured human neuroblastoma cells.

Kappa and Mu Opioid Receptors in Chronic Cough: Current Evidence and Future Treatment.

Chronic cough is a significant burden on patient quality of life and is associated with poor health outcomes. Chronic cough may be a result of neural hypersensitivity due to changes in both the peripheral and the central nervous systems, although the exact mechanisms underlying its pathogenesis are not completely understood. Opioid receptors, specifically kappa and mu, are potential therapeutic targets in the management of chronic cough because they play a pivotal role in both the peripheral and the central neural pathways implicated in the act of coughing.

P2Y receptor activation of platelets induces Ca mobilization and Rho-GTPase-dependent motility that requires an interaction with P2Y receptors.

Background And Purpose: Platelet function during inflammation is dependent on activation by endogenous nucleotides acting on purinergic receptors. The P2Y receptor has been reported to be expressed on platelets and is involved in leukocyte recruitment during inflammation. However, a role for P2Y receptors in platelet function has not yet been determined.

Animal models of chronic obstructive pulmonary disease and their role in drug discovery and development: a critical review.

Introduction: The use of laboratory animals is essential to understand the mechanisms underlying COPD and to discover and evaluate new drugs. However, the complex changes associated with the disease in humans are difficult to fully replicate in animal models.

Areas Covered: This review examines the most recent literature on animal models of COPD and their implications for drug discovery and development.

Asthma and Cardiovascular Diseases: Navigating Mutual Pharmacological Interferences.

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.

The discovery and development of gefapixant as a novel antitussive therapy.

Introduction: Gefapixant, a P2X 3 receptor antagonist, shows considerable potential in managing refractory or unexplained chronic cough. Clinical trials have consistently demonstrated its efficacy in significantly reducing cough frequency and alleviating associated symptoms. However, its adverse effect profile, particularly taste disturbances such as dysgeusia and hypogeusia, the incidence of which is dose-dependent, poses a significant challenge to patient compliance and overall treatment satisfaction.

Prospects for macrolide therapy of asthma and COPD.

Macrolide compounds, many of which are derived from natural sources, all share a lactone ring structure, but of varying sizes. Their biological activities differ with structure and size but tend to overlap. Marketed macrolide drugs include immunosuppressives and antibiotics.

Use of thiols and implications for the use of inhaled corticosteroids in the presence of oxidative stress in COPD.

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.

Revisiting asthma pharmacotherapy: where do we stand and where do we want to go?

Several current guidelines/strategies outline a treatment approach to asthma, which primarily consider the goals of improving lung function and quality of life and reducing symptoms and exacerbations. They suggest a strategy of stepping up or down treatment, depending on the patient's overall current asthma symptom control and future risk of exacerbation. While this stepwise approach is undeniably practical for daily practice, it does not always address the underlying mechanisms of this heterogeneous disease.

Novel Anti-Inflammatory Approaches to COPD.

Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4 and CD8 T lymphocytes are key players in this process, although the extent of their participation varies according to the patient's endotype. Anti-inflammatory medications may modify the natural history and progression of COPD.

INVESTIGATION INTO P2Y RECEPTOR FUNCTION IN PLATELETS FROM PATIENTS WITH SEPSIS.

Key underlying pathological mechanisms contributing to sepsis are hemostatic dysfunction and overwhelming inflammation. Platelet aggregation is required for hemostasis, and platelets are also separately involved in inflammatory responses that require different functional attributes. Nevertheless, P2Y receptor activation of platelets is required for this dichotomy of function.

An Update on Outcomes for COPD Pharmacological Trials: A COPD Investigators Report - Reassessment of the 2008 American Thoracic Society/European Respiratory Society Statement on Outcomes for COPD Pharmacological Trials.

In 2008, a dedicated American Thoracic Society/European Respiratory Society task force published a paper on the possible use and limitations of clinical outcomes and biomarkers to evaluate the impact of pharmacological therapy in patients with chronic obstructive pulmonary disease. Since then, our scientific understanding of chronic obstructive pulmonary disease has increased considerably; there has been a progressive shift from a one-size-fits-all diagnostic and therapeutic approach to a personalized approach; and many new treatments currently in development will require new endpoints to evaluate their efficacy adequately. The emergence of several new relevant outcome measures motivated the authors to review advances in the field and highlight the need to update the content of the original report.

Pharmacology of Heparin and Related Drugs: An Update.

Heparin has been used extensively as an antithrombotic and anticoagulant for close to 100 years. This anticoagulant activity is attributed mainly to the pentasaccharide sequence, which potentiates the inhibitory action of antithrombin, a major inhibitor of the coagulation cascade. More recently it has been elucidated that heparin exhibits anti-inflammatory effect via interference of the formation of neutrophil extracellular traps and this may also contribute to heparin's antithrombotic activity.

Stimulation of platelet P2Y receptors by different endogenous nucleotides leads to functional selectivity via biased signalling.

Background And Purpose: Platelet function during inflammation is dependent on activation by endogenous nucleotides. Non-canonical signalling via the P2Y receptor is important for these non-thrombotic functions of platelets. However, apart from ADP, the role of other endogenous nucleotides acting as agonists at P2Y receptors is unknown.

Single and Multiplex Immunohistochemistry to Detect Platelets and Neutrophils in Rat and Porcine Tissues.

Platelet-neutrophil complexes (PNCs) occur during the inflammatory response to trauma and infections, and their interactions enable cell activation that can lead to tissue destruction. The ability to identify the accumulation and tissue localisation of PNCs is necessary to further understand their role in the organs associated with blast-induced shock wave trauma. Relevant experimental lung injury models often utilise pigs and rats, species for which immunohistochemistry protocols to detect platelets and neutrophils have yet to be established.

Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development.

Macrolides are among the most widely prescribed broad spectrum antibacterials, particularly for respiratory infections. It is now recognized that these drugs, in particular azithromycin, also exert time-dependent immunomodulatory actions that contribute to their therapeutic benefit in both infectious and other chronic inflammatory diseases. Their increased chronic use in airway inflammation and, more recently, of azithromycin in COVID-19, however, has led to a rise in bacterial resistance.

A peptide derived from chaperonin 60.1, IRL201104, inhibits LPS-induced acute lung inflammation.

Chaperonin 60.1 (Cpn60.1) is a protein derived from that has been shown, along with its peptide fragment IRL201104, to have beneficial effects in models of allergic inflammation.

Novel pharmacological therapies for the treatment of bronchial asthma.

Asthma has long been recognized as a chronic inflammatory disease of the airways, often in response to inhaled allergens prompting inappropriate activation of the immune response involving a range of cells including mast cells, Th2 lymphocytes and eosinophils alongside a wide range of inflammatory mediators. First-line therapy for treatment of persistent asthma involves the use of inhaled corticosteroids (ICS) in combination with inhaled β2-agonists enabling both the control of the underlying airways inflammation and a reduction of airway hyperresponsiveness. However, many patients remain symptomatic despite high-dose therapy.

Platelets Independently Recruit into Asthmatic Lungs and Models of Allergic Inflammation via CCR3.

Platelet activation and pulmonary recruitment occur in patients with asthma and in animal models of allergic asthma, in which leukocyte infiltration, airway remodeling, and hyperresponsiveness are suppressed by experimental platelet depletion. These observations suggest the importance of platelets to various characteristics of allergic disease, but the mechanisms of platelet migration and location are not understood. The aim of this study was to assess the mechanism of platelet recruitment to extravascular compartments of lungs from patients with asthma and after allergen challenge in mice sensitized to house dust mite (HDM) extract (contains the DerP1 [ extract peptidase 1] allergen); in addition, we assessed the role of chemokines in this process.

Red Blood Cells Elicit Platelet-Dependent Neutrophil Recruitment Into Lung Airspaces.

Hemolysis that occurs in intravascular hemolytic disorders, such as sickle cell disease and malaria, is associated with inflammation and platelet activation. Alveolar hemorrhage, for example following primary blast lung injury or acute respiratory distress syndrome, results in the escape of erythrocytes (RBCs) into alveolar spaces, where they subsequently lyse and release their intracellular contents. However, the inflammatory effects of RBCs in the airways are not fully understood.

A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.

Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection.