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

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

Pharmacology and Therapeutics of Bronchodilators Revisited.

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

The anti-proliferative effects of adiponectin on human lung adenocarcinoma A549 cells and oxidative stress involvement.

Adiponectin (Acrp30) plays an important role in energy metabolism and inflammation. Recently, in vivo serum Acrp30 levels have been reported to be correlated to risk of developing several types of cancers such as lung cancer, and in vitro studies have demonstrated a role for Acrp30 in the control of cell proliferation and survival. However, the molecular effects of Acrp30 on lung cancer have not yet been clearly defined. In the present study, we investigated the effects of different concentrations of Acrp30 on the A549 human alveolar epithelial cell line, an in vitro model of lung adenocarcinoma. A549 cells were exposed to various concentrations of Acrp30 and successively, proliferation, apoptosis and oxidative stress were evaluated by MTT test, caspase activity assay, flow-cytometry and western blotting analysis. Our results demonstrated that Acrp30 causes, in a time- and dose-dependent manner, a reduction of cell viability and duplication together with an increase in cell apoptosis rate. In addition, we found that Acrp30 induces an increase of lipid peroxidation evaluated by TBARS assay and a concomitant reduction of nitric oxide release, both markers of cellular oxidative stress. Taken together, our data on A549 cells provides new insight into potential involvement of Acrp30 on physio-pathologic mechanisms of lung diseases through interference with proliferation, apoptosis and oxidative status.

Combining long-acting bronchodilators with different mechanisms of action: A pharmacological approach to optimize bronchodilation of equine airways.

The ultra long-acting ß2 -adrenoceptor agonist olodaterol plus the ultra long-acting muscarinic antagonist tiotropium bromide are known to relax equine airways. In human bronchi combining these drugs elicits a positive interaction, thus we aimed to characterize this information further in equine isolated airways stimulated by electrical field stimulation (EFS) and using the Concentration-Reduction Index (CRI) and Combination Index (CI) equations. The drugs were administered alone and together by reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (1:1). The single agents elicited a significant (p < .05) concentration-dependent reduction in the EFS-induced contractility, that was synergistically improved (CI 0.18) when administered in combination (0.9 logarithms more potent, 24% more effective than the monocomponents). The drugs mixture allowed a reduction in the concentration of olodaterol from ≃1 to ≃2.3 logarithms. A favorable CRI was detected also for tiotropium bromide, whose concentration can be reduced ≃1 logarithm at medium effect levels, remaining positive up to submaximal relaxant effect in the presence of olodaterol. The combination of tiotropium bromide/olodaterol allows the reduction in the concentration of the monocomponents to achieve airway smooth muscle relaxation, thus potentially decreases the risk of adverse events when these drugs are used to treat severe asthmatic horses.

Clinical effect of corticosteroids in asthma-affected horses: A quantitative synthesis.

BACKGROUND: There are limited findings from low-powered studies based on few number of subjects with equine asthma. Furthermore, no studies have been performed to assess a meaningful clinically detectable impact of corticosteroids in equine asthma. OBJECTIVES: To assess and compare the clinical effect of inhaled and systemic corticosteroids in equine asthma and identify a quantitative clinical score suitable to assess the Minimal Important Difference (MID), expressed as the Minimally Clinically Detectable Difference (MCDD). STUDY DESIGN: Pair-wise and network meta-analysis. METHODS: Literature searches for studies on corticosteroid therapy in equine asthma were performed. The risk of publication bias was assessed by Funnel plots and Egger's test. The effect on changes in clinical scores vs. control was analysed via random-effects models and Bayesian networks. RESULTS: Corticosteroids significantly improved the clinical condition (Standardised Mean Difference: -1.52, 95% CrI -2.07 to -0.98; P<0.001 vs. control). No difference was detected between inhaled and systemic corticosteroids with regard to the changes in clinical scores (Relative Effect: 0.08, 95% CrI -1.45 to 1.32; P = 0.8). An Improved clinically Detectable Equine Asthma Scoring System (IDEASS) indicated that corticosteroids improved the clinical condition of asthmatic horses by 30% compared with controls (IDEASS value: -2.36, 95% CI -3.39 to -1.33; P<0.001). A one-point change in IDEASS represented the MCDD in equine asthma. MAIN LIMITATIONS: Moderate quality of evidence for systemic corticosteroids. CONCLUSIONS: Inhaled corticosteroids are effective in improving the clinical condition of horses with equine asthma and prevent exacerbations. Systemic corticosteroids should be used only in selected cases with symptomatic airway hyperresponsiveness during exacerbation. IDEASS requires further validation but may represent a suitable approach to rank the level of asthma severity and assess the clinical effect of pharmacotherapy in horses with equine asthma.

Pharmacological treatments in asthma-affected horses: A pair-wise and network meta-analysis.

BACKGROUND: Equine asthma is a disease characterised by reversible airflow obstruction, bronchial hyper-responsiveness and airway inflammation following exposure of susceptible horses to specific airborne agents. Although clinical remission can be achieved in a low-airborne dust environment, repeated exacerbations may lead to irreversible airway remodelling. The available data on the pharmacotherapy of equine asthma result from several small studies, and no head-to-head clinical trials have been conducted among the available medications. OBJECTIVES: To assess the impact of the pharmacological interventions in equine asthma and compare the effect of different classes of drugs on lung function. STUDY DESIGN: Pair-wise and network meta-analysis. METHODS: Literature searches for clinical trials on the pharmacotherapy of equine asthma were performed. The risk of publication bias was assessed by funnel plots and Egger's test. Changes in maximum transpulmonary or pleural pressure, pulmonary resistance and dynamic lung compliance vs. control were analysed via random-effects models and Bayesian networks. RESULTS: The results obtained from 319 equine asthma-affected horses were extracted from 32 studies. Bronchodilators, corticosteroids and chromones improved maximum transpulmonary or pleural pressure (range: -8.0 to -21.4 cmH2 O; P<0.001). Bronchodilators, corticosteroids and furosemide reduced pulmonary resistance (range: -1.2 to -1.9 cmH2 O/L/s; P<0.001), and weakly increased dynamic lung compliance. Inhaled ß2 -adrenoreceptor (ß2 -AR) agonists and inhaled corticosteroids had the highest probability of being the best therapies. Long-term treatments were more effective than short-term treatments. MAIN LIMITATIONS: Weak publication bias was detected. CONCLUSIONS: This study demonstrates that long-term treatments with inhaled corticosteroids and long-acting ß2 -AR agonists may represent the first choice for treating equine asthma. Further high quality clinical trials are needed to clarify whether inhaled bronchodilators should be preferred to inhaled corticosteroids or vice versa, and to investigate the potential superiority of combination therapy in equine asthma.

Benralizumab for the treatment of asthma.

Benralizumab is a humanized monoclonal antibody directed at the a subunit of the interleukin-5 receptor (IL-5R) that is under clinical development. The binding of benralizumab with the alpha chain of IL-5R results in inhibition of hetero-oligomerization of alpha and beta subunits and thus no signal transduction occurs. Consequently, this inhibition prevents proliferation of eosinophils and basophils and the cascade of events following it. Several pivotal trials have documented that benralizumab reduces asthma exacerbation rates with a significant increase in time to the next exacerbation, statistically improves prebronchodilator forced expiratory volume in 1 second (FEV1) and disease-specific health-related quality of life, and is well tolerated in patients with severe asthma and blood eosinophil counts greater than or equal to 150 cells/mcL.

Fluticasone furoate/vilanterol combination for the treatment of COPD and asthma.

The critical role of the combination therapy of an inhaled corticosteroid (ICS) and a long-acting ß-adrenoceptor agonist (LABA) in the treatment of patients suffering from asthma and also severe chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations explains why there is a strong interest within the pharmaceutical industry in developing a once-daily ICS/LABA fixed-dose combination (FDC), in an attempt to simplify the treatment and, consequently, increase adherence to the prescribed therapy, and also to overcome the loss of patent protection. GlaxoSmithKline and Theravance have developed an inhaled FDC of the ICS fluticasone furoate (FF) and the LABA vilanterol (VI) as a once-daily treatment for asthma and COPD. FF/VI, by simplifying the dosing schedule, allows, for the first time, a shift from twice-daily to once-daily treatment, with an acceptable safety and tolerability profile that is consistent with the ICS/LABA class. The decision to prescribe FF/VI rather than another ICS/LABA FDC is likely to be based on the patient's preference for the inhaler device, their ability to use the device correctly and the convenience of once-daily dosing frequency as well as comparative costs with other combination products. However, further studies are required to specifically assess these possibilities.

Aclidinium/formoterol fixed-dose combination for the treatment of chronic obstructive pulmonary disease.

This review will be focused on the development of aclidinium bromide/formoterol fumarate (ACLI/FORM) fixed-dose combinations (FDC) that have been granted marketing authorization by the European Commission to be used as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). ACLI/FORM FDC has been studied in 2 pivotal trials involving over 3,400 patients with COPD, in which it was compared with ACLI alone, FORM alone and placebo. The addition of FORM to ACLI resulted in greater bronchodilation than FORM or ACLI alone. ACLI/FORM FDC was also shown to increase the percentage of patients who had an improvement in symptoms and health-related quality of life compared with monotherapies. The frequency of side effects reported with ACLI/FORM FDC was low and their nature did not raise any major safety concern.

Effects of chronic administration of ß-blockers on airway responsiveness in a murine model of heart failure.

Lung function abnormalities, both at rest and during exercise, are frequently observed in patients with chronic heart failure (HF), also in absence of respiratory disease. It has been documented that, in HF, chronic adrenergic stimulation down-regulates ß-adrenoceptors (ß-ARs) and modifies airway relaxant responses. This study was designed to investigate in an animal model of HF whether a treatment with a ß-AR blocker, metoprolol, could modify the altered airway hyperresponsiveness. In rats, randomly assigned to 3 experimental groups sham-operated rats (SH), rats with HF induced by left anterior descending coronaric occlusion (HF n = 10), and rats treated with metoprolol 100 mg/kg/die (MET = 10), HF was evaluated after 10 weeks and resulted in increases in plasma norepinephrine and epinephrine and left ventricular end diastolic pressure. ß2-ARs and G-protein-ßAR2-kinase (GRK2) mRNA levels were determined by real time reverse transcriptase PCR. Carbachol-precontracted isolated tracheal rings were used to functionally assess airway smooth muscle relaxation. In pulmonary tissues, ß2-AR mRNA level was significantly decreased in HF groups (-48.73 ± 5.18%, P < 0.01); in the same groups the GRK2 mRNA-levels were significantly enhanced (+222.50 ± 6.13%, P < 0.001); in lung deriving from MET groups the levels of mRNA were significantly increased (+339.86 ± 11.26%, P < 0.001), while the GRK2 mRNA-levels unchanged (-59.02 ± 3.97%, P < 0.001), when compared to SH groups. Relaxation of tracheal strips in response to salbutamol was significantly reduced in HF groups; in tracheal rings, deriving from MET groups, the relaxant effects of salbutamol were significantly enhanced (SH, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; HF, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; MET, Emax: 85.43 ± 6.80%, pD2: 6.95 ± 0.59, P < 0.001). In HF, the down-regulation of pulmonary ß-ARs results in a significant attenuation of airway relaxation. These effects have been reversed by a treatment with metoprolol, suggesting a potential role of ß-AR blockers in the treatment of patients suffering from HF and chronic obstructive airway diseases.

LABAs in asthmatic children: highlights and new inside.

International asthma guidelines recommend increasing the dose of ICS or adding leukotriene modifiers or the use of long-acting inhaled beta2-agonists (LABAs) in combination with inhaled corticosteroids (ICS) when uncontrolled asthma occurs in adult and children in treatment with low-dose inhaled corticosteroids. However, in children, the effects of this last treatment option are unclear because there are few studies on the efficacy and safety of these drugs in pediatric age. Furthermore, salmeterol is licensed for use in children over 4 years and formoterol in children of more than 6 years. Finally, recent data provides evidence that repeated bronchoconstriction induces epithelial cell stress that may lead to remodeling and these findings may have potential implications for asthma management, particularly for LABAs treatment in the future.

ß2-agonist therapy in lung disease.

ß2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of ß2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between ß2-agonists. Traditional inhaled short-acting ß2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily ß2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer ß2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, ß2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting ß2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of ß2-adrenoceptors that occurs during the first few days of regular use of ß2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of ß2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily ß2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent.

Pharmacology and therapeutics of bronchodilators.

Bronchodilators are central in the treatment of of airways disorders. They are the mainstay of the current management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma, although controversies around the use of these drugs remain. Bronchodilators work through their direct relaxation effect on airway smooth muscle cells. at present, three major classes of bronchodilators, ß(2)-adrenoceptor (AR) agonists, muscarinic receptor antagonists, and xanthines are available and can be used individually or in combination. The use of the inhaled route is currently preferred to minimize systemic effects. Fast- and short-acting agents are best used for rescue of symptoms, whereas long-acting agents are best used for maintenance therapy. It has proven difficult to discover novel classes of bronchodilator drugs, although potential new targets are emerging. Consequently, the logical approach has been to improve the existing bronchodilators, although several novel broncholytic classes are under development. An important step in simplifying asthma and COPD management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence. Several once-daily ß(2)-AR agonists or ultra-long-acting ß(2)-AR-agonists (LABAs), such as indacaterol, olodaterol, and vilanterol, are already in the market or under development for the treatment of COPD and asthma, but current recommendations suggest the use of LABAs only in combination with an inhaled corticosteroid. In addition, some new potentially long-acting antimuscarinic agents, such as glycopyrronium bromide (NVA-237), aclidinium bromide, and umeclidinium bromide (GSK573719), are under development, as well as combinations of several classes of long-acting bronchodilator drugs, in an attempt to simplify treatment regimens as much as possible. This review will describe the pharmacology and therapeutics of old, new, and emerging classes of bronchodilator.

Treatment of COPD: moving beyond the lungs.

We still do not know whether the successful treatment of the comorbid diseases associated with COPD, mainly cardiovascular disease, also positively influences the course of the lung disease because so far there are few definite data documenting that treatment of COPD comorbidities will reduce morbidity and mortality rates in these patients. Observational studies suggest that COPD patients treated with statins, angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, and ß-adrenoceptor blockers may have improved survival and reduced hospitalisation from exacerbations. Progress in basic and translational research has led to a better understanding of pharmacological mechanisms that may explain the effects of these drugs on COPD and some small clinical trial activity is beginning to generate promising results.

Emerging anti-inflammatory strategies for COPD.

The hallmark of chronic obstructive pulmonary disease (COPD) is an enhanced or abnormal inflammatory immune response of the lungs to inhaled particles and gases, usually from cigarette smoke, characterised by increased numbers of neutrophils, activated macrophages and activated T-lymphocytes (Tc1 and Th1 cells). Therefore, suppression of the inflammatory response is a logical approach to the treatment of COPD. Despite the inflammatory nature of COPD, currently available anti-inflammatory therapies provide little or no benefit in COPD patients and may have detrimental effects. For this reason, there is an urgent need to discover effective and safe anti-inflammatory treatments that might prevent the relentless progression of the disease. In recent years, attention has largely been focused on inhibition of recruitment and activation of inflammatory cells, and on antagonism of their products. In this review, we put together a summary of the state-of-the-art development of clearly and/or potentially useful anti-inflammatory strategies in COPD.

Bacterial lysates as a potentially effective approach in preventing acute exacerbation of COPD.

The use of bacterial lysates to reduce acute exacerbations of COPD (AECOPDs) is an intriguing concept. Bacterial lysates are powerful inducers of a specific immune response against bacterial infections, but their mechanism of action is not fully understood. Apparently, they lower bacterial carriage levels in the respiratory tract, decrease the incidence and severity of exacerbations, decrease hospitalizations owing to exacerbations, and reduce the need for antibiotics. Unfortunately, almost all trials conducted to date are small and methodologically flawed. Further studies are needed to produce a greater level of evidence that can support the recommendation for a more widely use of bacterial lysates as a prophylactic treatment of AECOPDs.

Dual bronchodilatory and pulmonary anti-inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors.

BACKGROUND AND PURPOSE: Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC(1) and VPAC(2). RO5024118 is a selective VPAC(2) receptor agonist derived via chemical modification of an earlier VPAC(2) agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118. EXPERIMENTAL APPROACH: Stability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model. KEY RESULTS: RO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting ß-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting ß-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8(+) cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases. LINKED ARTICLES: This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.

Indacaterol for chronic obstructive pulmonary disease (COPD).

Indacaterol (Onbrez), previously known as QAB-149-AFA, is a novel ultra-long-acting beta2-adrenoceptor agonist that was recently approved by the European Commission as a new once-daily maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD). COPD is a major cause of chronic morbidity worldwide. According to World Health Organisation, it was the fifth cause of death in 2002 and it is projected to be the fourth cause of mortality by 2030. The rapid onset of action of indacaterol, duration of bronchodilation for at least 24 hours, and an optimal safety profile make this drug an interesting and attractive weapon for its use in fight against the COPD.