Exploiting the potential of dupilumab in the treatment of eosinophilic COPD.

Chronic obstructive pulmonary disease (COPD) often involves type 1 (T1) inflammation, but 40% of patients have T2 inflammation, which worsens outcomes. Dupilumab, targeting interleukin (IL)-4 and IL-13, shows promise in phase 3 trials. The new NOTUS trial1 showed effectiveness in reducing exacerbations and improving lung function. However, its predominantly white population limits generalizability. Future research should include diverse populations and assess different therapies combined with dupilumab to improve outcomes.

Drug-drug interactions and synergy: from pharmacological models to clinical application.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts such as concentration-response curves, additive effects, and predictive models are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. While various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected at bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care. Significance Statement Combining drugs with different mechanisms of action for synergistic interactions optimizes treatment efficacy and safety. Accurate interpretation of synergy requires the identification of the expected additive effect. Despite innovative models to predict the additive effect, consensus in drug interaction research is lacking, hindering the bench-to-bedside development of combination therapies. Collaboration among science, industry, and regulation is crucial for advancing combination therapy development, ensuring rigorous application of predictive models in clinical settings.

The Role of Short-Chain Fatty Acids, Particularly Butyrate, in Oncological Immunotherapy with Checkpoint Inhibitors: The Effectiveness of Complementary Treatment with Clostridium butyricum 588.

The discovery of immune checkpoints (CTLA-4, PD-1, and PD-L1) and their impact on the prognosis of oncological diseases have paved the way for the development of revolutionary oncological treatments. These treatments do not combat tumors with drugs "against" cancer cells but rather support and enhance the ability of the immune system to respond directly to tumor growth by attacking the cancer cells with lymphocytes. It has now been widely demonstrated that the presence of an adequate immune response, essentially represented by the number of TILs (tumor-infiltrating lymphocytes) present in the tumor mass decisively influences the response to treatments and the prognosis of the disease. Therefore, immunotherapy is based on and cannot be carried out without the ability to increase the presence of lymphocytic cells at the tumor site, thereby limiting and nullifying certain tumor evasion mechanisms, particularly those expressed by the activity (under positive physiological conditions) of checkpoints that restrain the response against transformed cells. Immunotherapy has been in the experimental phase for decades, and its excellent results have made it a cornerstone of treatments for many oncological pathologies, especially when combined with chemotherapy and radiotherapy. Despite these successes, a significant number of patients (approximately 50%) do not respond to treatment or develop resistance early on. The microbiota, its composition, and our ability to modulate it can have a positive impact on oncological treatments, reducing side effects and increasing sensitivity and effectiveness. Numerous studies published in high-ranking journals confirm that a certain microbial balance, particularly the presence of bacteria capable of producing short-chain fatty acids (SCFAs), especially butyrate, is essential not only for reducing the side effects of chemoradiotherapy treatments but also for a better response to immune treatments and, therefore, a better prognosis. This opens up the possibility that favorable modulation of the microbiota could become an essential complementary treatment to standard oncological therapies. This brief review aims to highlight the key aspects of using precision probiotics, such as Clostridium butyricum, that produce butyrate to improve the response to immune checkpoint treatments and, thus, the prognosis of oncological diseases.

Can glucagon-like peptide-1 receptor agonists induce asthma? An analysis of the FAERS database.

OBJECTIVE: Glucagon-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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

An overview of the efficacy and safety of ß2-adrenoceptor antagonists for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: The safety of ß2-AR antagonists in the treatment of patients with COPD continues to be a topic of research and discussion within the medical community. Emerging evidence suggests potentially benefits in the management of this complex respiratory condition. However, antagonists that display a preference for ß2-AR over ß1-AR present a complex therapeutic challenge in COPD management, necessitating an understanding of differences in their pharmacological profiles and clinical implications. AREAS COVERED: An overview of the mechanisms of action of ß2-AR antagonists and their potential impact on respiratory function, their pharmacological interactions, clinical implications, and future perspectives in COPD. EXPERT OPINION: ß-Blockers have the potential to become a versatile class of therapeutic agents with benefits beyond their original cardiovascular use. However, the one-size-fits-all approach of prescribing ß-blockers regardless of their receptor selectivity to COPD patients with concomitant heart disease may not be appropriate. Instead, it is advisable to develop an individualized treatment strategy based on a thorough assessment of the patient's overall health. The use of non selective ß2-AR antagonists, functioning as inverse agonists at ß2-ARs, has garnered interest and debate, but further research efforts should focus on elucidating the optimal use of ß-AR antagonists in COPD, balancing cardiovascular benefits with potential respiratory risks to enhance outcomes and quality of life for individuals living with this debilitating respiratory condition.

Sirtuins and Cellular Senescence in Patients with Idiopathic Pulmonary Fibrosis and Systemic Autoimmune Disorders.

The sirtuin family is a heterogeneous group of proteins that play a critical role in many cellular activities. Several degenerative diseases have recently been linked to aberrant sirtuin expression and activity because of the involvement of sirtuins in maintaining cell longevity and their putative antiaging function. Idiopathic pulmonary fibrosis and progressive pulmonary fibrosis associated with systemic autoimmune disorders are severe diseases characterized by premature and accelerated exhaustion and failure of alveolar type II cells combined with aberrant activation of fibroblast proliferative pathways leading to dramatic destruction of lung architecture. The mechanisms underlying alveolar type II cell exhaustion in these disorders are not fully understood. In this review, we have focused on the role of sirtuins in the pathogenesis of idiopathic and secondary pulmonary fibrosis and their potential as biomarkers in the diagnosis and management of fibrotic interstitial lung diseases.

Sports-Related Gastrointestinal Disorders: From the Microbiota to the Possible Role of Nutraceuticals, a Narrative Analysis.

Intense physical exercise can be related to a significant incidence of gastrointestinal symptoms, with a prevalence documented in the literature above 80%, especially for more intense forms such as running. This is in an initial phase due to the distancing of the flow of blood from the digestive system to the skeletal muscle and thermoregulatory systems, and secondarily to sympathetic nervous activation and hormonal response with alteration of intestinal motility, transit, and nutrient absorption capacity. The sum of these effects results in a localized inflammatory process with disruption of the intestinal microbiota and, in the long term, systemic inflammation. The most frequent early symptoms include abdominal cramps, flatulence, the urge to defecate, rectal bleeding, diarrhea, nausea, vomiting, regurgitation, chest pain, heartburn, and belching. Promoting the stability of the microbiota can contribute to the maintenance of correct intestinal permeability and functionality, with better control of these symptoms. The literature documents various acute and chronic alterations of the microbiota following the practice of different types of activities. Several nutraceuticals can have functional effects on the control of inflammatory dynamics and the stability of the microbiota, exerting both nutraceutical and prebiotic effects. In particular, curcumin, green tea catechins, boswellia, berberine, and cranberry PACs can show functional characteristics in the management of these situations. This narrative review will describe its application potential.

Impact of biologics on lung hyperinflation in patients with severe asthma.

BACKGROUND: In asthma, inflammation affects both the proximal and distal airways and can cause significant hyperinflation, which is thought to be a major cause of dyspnea. METHODS: This is a retrospective observational study evaluating the effect of three months of treatment with different biologic drugs (benralizumab, dupilumab and omalizumab) on pulmonary hyperinflation in a cohort of patients with severe asthma already receiving regular triple inhaled therapy. Changes in RV, RV/TLC ratio, FRC and FRC/TLC ratio were the primary efficacy measures. Secondary outcomes included FEV1, FVC, FEV1/FVC ratio, IC, IC/TLC ratio, asthma control test, the percentage of eosinophils in the blood and fractional FENO. RESULTS: Benralizumab led to significant changes (p < 0.001) in RV, RV/TLC, FRC, and FRC/TLC. Dupilumab demonstrated a notable reduction in RV (p = 0.017) and RV/TLC (p = 0.002), but the decreases in FRC and FRC/TLC were merely numerical and not as pronounced as those induced by benralizumab. Omalizumab's positive impact on RV (p = 0.057) and RV/TLC (p = 0.085), as well as FRC (p = 0.202) and FRC/TLC (p = 0.096), was also predominantly numerical, with a tendency towards efficacy, albeit excluding the effect on FRC. Treatment with biologics resulted in improvements in all other lung function parameters assessed and a decrease in FENO levels. CONCLUSION: This study, although limited by small sample size, lack of a placebo control, and unbalanced group sizes, suggests that biological agents are effective in reducing lung hyperinflation even after a relatively short treatment.

The pharmacological management of asthma in adults: 2023 update.

INTRODUCTION: The pharmacotherapy of asthma is a dynamic process that changes as our knowledge of the underlying pathophysiology and treatment of this disease continues to evolve. This implies the need for continuous revision of the recommendations of asthma guidelines and strategies. AREAS COVERED: This review summarizes the latest key practical information on the pharmacological management of asthma in adults. We provide the background to the 2023 update of the GINA strategy report, focusing on changes and discussing areas of uncertainty. We review current and emerging pharmacotherapy for uncontrolled asthma, including synthetic agents and new biologics, and provide expert perspectives and opinions on the treatment of uncontrolled asthma. EXPERT OPINION: The current pharmacological treatment of asthma, based on a step-by-step, control-based approach, with ICSs, LABAs and LAMAs being the mainstay generally provides good symptom control. Biologic therapies are often effective in treating T2high severe asthma. However, there is still room for improvement, such as the discovery of new molecules that specifically target chronic inflammation and, most importantly, the ability to provide solutions to the various areas of uncertainty that still exist. Also finding solutions to improve the accessibility and affordability of rescue ICS in resource-constrained settings is critical.

The effect of combining an inhaled corticosteroid and a long-acting muscarinic antagonist on human airway epithelial cells in vitro.

BACKGROUND: Airway epithelial cells (AECs) are a major component of local airway immune responses. Direct effects of type 2 cytokines on AECs are implicated in type 2 asthma, which is driven by epithelial-derived cytokines and leads to airway obstruction. However, evidence suggests that restoring epithelial health may attenuate asthmatic features. METHODS: We investigated the effects of passive sensitisation on IL-5, NF-κB, HDAC-2, ACh, and ChAT in human bronchial epithelial cells (HBEpCs) and the effects of fluticasone furoate (FF) and umeclidinium (UME) alone and in combination on these responses. RESULTS: IL-5 and NF-κB levels were increased, and that of HDAC-2 reduced in sensitised HEBpCs. Pretreatment with FF reversed the effects of passive sensitisation by concentration-dependent reduction of IL-5, resulting in decreased NF-κB levels and restored HDAC-2 activity. Addition of UME enhanced these effects. Sensitized HEBpCs also exhibited higher ACh and ChAT levels. Pretreatment with UME significantly reduced ACh levels, and addition of FF caused a further small reduction. CONCLUSION: This study confirmed that passive sensitisation of AECs results in an inflammatory response with increased levels of IL-5 and NF-κB, reduced levels of HDAC-2, and higher levels of ACh and ChAT compared to normal cells. Combining FF and UME was found to be more effective in reducing IL-5, NF-κB, and ACh and restoring HDAC-2 compared to the individual components. This finding supports adding a LAMA to established ICS/LABA treatment in asthma and suggests the possibility of using an ICS/LAMA combination when needed.

Cardiovascular Events with the Use of Long-Acting Muscarinic Receptor Antagonists: An Analysis of the FAERS Database 2020-2023.

PURPOSE: This study aimed to examine reports of cardiovascular adverse events (CV AEs) observed in the real-world during treatment with aclidinium, tiotropium, glycopyrronium, and umeclidinium alone or in combination with a LABA and, in the context of triple therapy, with the addition of an ICS, and submitted to the food and drug administration adverse event reporting system (FAERS). METHODS: A retrospective disproportionality analysis was conducted utilizing CV AE reports submitted to the FAERS from January 2020 to 30 September 2023. Disproportionality was measured by calculating the reporting odds ratio. RESULTS: Compared with ipratropium, tiotropium was associated with fewer reports of CV AEs. Compared with tiotropium, other LAMAs were more likely to be associated with reports of CV AEs. Combinations of glycopyrronium with indacaterol or formoterol and umeclidinium with vilanterol significantly reduced reports of CV AEs compared with the respective LAMA. The addition of an ICS to these combinations further reduced the risk of CV AE reports. CONCLUSION: Our study suggests that inhaled LAMAs are not free from cardiac AE risks. This risk may be more evident when the newer LAMAs are used, but it is generally significantly reduced when COPD patients are treated with dual bronchodilators or triple therapy. However, these results do not prove that LAMAs cause CV AEs, as FAERS data alone are not indicative of a drug's safety profile. Given the frequency with which COPD and cardiovascular disease co-exist, a large study in the general population could shed light on this very important issue.

Biologics for asthma and risk of pneumonia.

OBJECTIVE: Modification of the immune system with biologics raises theoretical concerns about the risk of infections but it is still unclear whether currently routinely used biologics in severe asthma may facilitate the development of pneumonia. Therefore, we aimed to determine whether omalizumab, mepolizumab, benralizumab, and dupilumab are associated with pneumonia in a real-world setting. METHODS: A retrospective disproportionality analysis was performed using adverse event (AE) reports submitted to FAERS from January 2020 to September 30, 2023. MedDRA was used to identify infections and infestations and then pneumonia cases. ROR and PRR were used to measure disproportionality. RESULTS: The percentage of reported cases of pneumonia compared to infections and infestations was highest for mepolizumab (36.8%), followed by omalizumab (32.6%), benralizumab (19.2%) and dupilumab (5.7%). We found a moderate or strong signal for increased risk of pneumonia with mepolizumab (ROR = 3.74, 95%CI 3.50-4.00), omalizumab (ROR = 3.26, 95%CI 3.06-3.49) and benralizumab (ROR = 2.65, 95%CI 2.49-2.83). CONCLUSIONS: Mepolizumab, omalizumab and benralizumab, but not dupilumab, were associated with high odds of reporting pneumonia. Our results represent only potential associations between these biologics and pneumonia but not causality. The nature of the FAERS database is such that the cause of the reported events is uncertain. Therefore, we can only roughly estimate the incidence of AEs by the signal strength (ROR value). Nevertheless, although causality could not be assessed, the signal from our study is interesting. We believe it deserves to be further substantiated by real-world studies with robust designs.

Use of human airway smooth muscle in vitro and ex vivo to investigate drugs for the treatment of chronic obstructive respiratory disorders.

Isolated airway smooth muscle has been extensively investigated since 1840 to understand the pharmacology of airway diseases. There has often been poor predictability from murine experiments to drugs evaluated in patients with asthma or chronic obstructive pulmonary disease (COPD). However, the use of isolated human airways represents a sensible strategy to optimise the development of innovative molecules for the treatment of respiratory diseases. This review aims to provide updated evidence on the current uses of isolated human airways in validated in vitro methods to investigate drugs in development for the treatment of chronic obstructive respiratory disorders. This review also provides historical notes on the pioneering pharmacological research on isolated human airway tissues, the key differences between human and animal airways, as well as the pivotal differences between human medium bronchi and small airways. Experiments carried out with isolated human bronchial tissues in vitro and ex vivo replicate many of the main anatomical, pathophysiological, mechanical and immunological characteristics of patients with asthma or COPD. In vitro models of asthma and COPD using isolated human airways can provide information that is directly translatable into humans with obstructive lung diseases. Regardless of the technique used to investigate drugs for the treatment of chronic obstructive respiratory disorders (i.e., isolated organ bath systems, videomicroscopy and wire myography), the most limiting factors to produce high-quality and repeatable data remain closely tied to the manual skills of the researcher conducting experiments and the availability of suitable tissue.

Hyperglycaemia and Chronic Obstructive Pulmonary Disease.

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.

Advances in adrenergic receptors for the treatment of chronic obstructive pulmonary disease: 2023 update.

INTRODUCTION: Strong scientific evidence and large experience support the use of ß2-agonists for the symptomatic alleviation of COPD. Therefore, there is considerable effort in discovering highly potent and selective ß2-agonists. AREAS COVERED: Recent research on novel ß2-agonists for the treatment of COPD. A detailed literature search was performed in two major databases (PubMed/MEDLINE and Scopus) up to September 2023." EXPERT OPINION: Compounds that preferentially activate a Gs- or ß-arrestin-mediated signaling pathway via ß- adrenoceptors (ARs) are more innovative. Pepducins, which target the intracellular region of ß2-AR to modulate receptor signaling output, have the most interesting profile from a pharmacological point of view. They stabilize the conformation of the ß2-AR and influence its signaling by interacting with the intracellular receptor-G protein interface. New bifunctional drugs called muscarinic antagonist-ß2 agonist (MABA), which have both muscarinic receptor (mAChR) antagonism and ß2-agonist activity in the same molecule, are a new opportunity. However, all tested compounds have been shown to act predominantly as mAChR antagonists or ß2-agonists. An intriguing idea is to utilize allosteric modulators that bind to ß2-ARs at sites different than those bound by orthosteric ligands to augment or reduce the signaling transduced by the orthosteric ligand.

Is it preferable to administer a bronchodilator once- or twice-daily when treating COPD?

Nocturnal and early morning symptoms are common and uncomfortable in many patients with COPD, and are likely to affect their long-term outcomes. However, it is still debated whether it is better to give long-acting bronchodilators once- or twice-daily to symptomatic COPD patients. The functional link between circadian rhythms of autonomic tone and airway calibre explains why the timing of administration of bronchodilators in chronic airway diseases can induce different effects when taken at different biological (circadian) times. However, the timing also depends on the pharmacological characteristics of the bronchodilator to be used. Because the profile of bronchodilation produced by once-daily vs. twice-daily long-acting bronchodilators differs throughout 24 h, selecting long-acting bronchodilators may be customized to specific patient preferences based on the need for further bronchodilation in the evening. This is especially helpful for people who experience respiratory symptoms at night or early morning. Compared to placebo, evening bronchodilator administration is consistently linked with persistent overnight improvements in dynamic respiratory mechanics and inspiratory neural drive. The current evidence indicates that nocturnal and early morning symptoms control is best handled by a LAMA taken in the evening. In contrast, it seems preferable to use a LABA for daytime symptoms. Therefore, it can be speculated that combining a LAMA with a LABA can improve bronchodilation and control symptoms better. Both LAMA and LABA must be rapid in their onset of action. Aclidinium/formoterol, a twice-daily combination, is the most studies of the available LAMA/LABA combinations in terms of impact on daytime and nocturnal symptoms.

What role will ensifentrine play in the future treatment of chronic obstructive pulmonary disease patients? Implications from recent clinical trials.

Data from the phase III ENHANCE clinical trials provide compelling evidence that ensifentrine, an inhaled 'bifunctional' dual phosphodiesterase 3/4 inhibitor, can provide additional benefit to existing treatments in patients with chronic obstructive pulmonary disease and represents a 'first-in-class' drug having bifunctional bronchodilator and anti-inflammatory activity in a single molecule. Ensifentrine, generally well tolerated, can provide additional bronchodilation when added to muscarinic receptor antagonists or ß2-agonists and reduce the exacerbation risk. This information allows us to consider better the possible inclusion of ensifentrine in the future treatment of chronic obstructive pulmonary disease. However, there is less information on whether it provides additional benefit when added to inhaled corticosteroid or 'triple therapy' and, therefore, when this drug is best utilized in clinical practice.

Chronic obstructive pulmonary disease (COPD) is the name for a group of lung conditions that cause breathing difficulties/airflow limitations. The airflow limitation is not completely reversible and is associated with a state of chronic inflammation of lung tissue. Treatment of the disease is still heavily dependent on the use of medications called bronchodilators and corticosteroids. However, corticosteroids have little-to-no impact on the underlying inflammation in most COPD patients. Therefore, innovative anti-inflammatory approaches are required. In this context, single molecules that are capable of simultaneously inducing bronchodilation, relaxing the muscles in the lungs and widening the airways (bronchi), and anti-inflammatory activity are a highly intriguing possibility for treating COPD. One approach is to develop drugs that can simultaneously inhibit enzymes called phosphodiesterase (PDE)3 and PDE4. Enzymes are proteins that help speed up metabolism, or the chemical reactions in our bodies. PDE4 inhibitors are intracellular enzymes (work inside the cell) expressed in most inflammatory cells, even in neutrophils (a type of white blood cells), which are involved in the pathogenesis of COPD, where an infection turns into a disease. However, its inhibition does not produce severe bronchodilator effects, which is instead obtained by inhibiting PDE3, the PDE isoenzyme (a different form of the same enzyme) that is predominantly expressed in airway smooth muscle cells. A treatment called ensifentrine is a dual PDE3/4 inhibitor (inhibits both PDE3 and PDE4). Two recent phase III studies (ENHANCE-1 and ENHANCE-2) have shown that it induces significant bronchodilation and reduces the risk of COPD worsening, exerting an anti-inflammatory effect. Data from the ENHANCE studies also showed the benefit of adding ensifentrine to treatment with bronchodilators. Certainly, the drug represents a useful therapeutic option, but further clinical studies are needed to be able to correctly position ensifentrine in the context of regular COPD treatment.

Strategies for overcoming the biological barriers associated with the administration of inhaled monoclonal antibodies for lung diseases.

INTRODUCTION: Monoclonal antibodies (mAbs) should be administered by inhalation rather than parenterally to improve their efficiency in lung diseases. However, the pulmonary administration of mAbs in terms of aerosol technology and the formulation for inhalation is difficult. AREAS COVERED: The feasible or suitable strategies for overcoming the barriers associated with administering mAbs are described. EXPERT OPINION: Providing mAbs via inhalation to individuals with lung disorders is still difficult. However, inhalation is a desirable method for mAb delivery. Inhaled mAb production needs to be well thought out. The illness, the patient group(s), the therapeutic molecule selected, its interaction with the biological barriers in the lungs, the formulation, excipients, and administration systems must all be thoroughly investigated. Therefore, to create inhaled mAbs that are stable and efficacious, it will be essential to thoroughly examine the problems linked to instability and protein aggregation. More excipients will also need to be manufactured, expanding the range of formulation design choices. Another crucial requirement is for novel carriers for topical delivery to the lungs since carriers might significantly enhance proteins' stability and pharmacokinetic profile.

A comprehensive overview of investigational elastase inhibitors for the treatment of acute respiratory distress syndrome.

INTRODUCTION: Excessive activity of neutrophil elastase (NE), the main enzyme present in azurophil granules in the neutrophil cytoplasm, may cause tissue injury and remodeling in various lung diseases, including acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), in which it is crucial to the immune response and inflammatory process. Consequently, NE is a possible target for therapeutic intervention in ALI/ARDS. AREAS COVERED: The protective effects of several NE inhibitors in attenuating ALI/ARDS in several models of lung injury are described. Some of these NE inhibitors are currently in clinical development, but only sivelestat has been evaluated as a treatment for ALI/ARDS. EXPERT OPINION: Preclinical research has produced encouraging information about using NE inhibitors. Nevertheless, only sivelestat has been approved for this clinical indication, and only in Japan and South Korea because of the conflicting results of clinical trials and likely also because of the potential adverse events. Identifying subsets of patients with ARDS most likely to benefit from NE inhibitor treatment, such as the hyperinflammatory phenotype, and using a more advanced generation of NE inhibitors than sivelestat could enable better clinical results than those obtained with elastase inhibitors.