Asthma management with triple ICS/LABA/LAMA combination to reduce the risk of exacerbation: an umbrella review compliant with the PRIOR statement.

INTRODUCTION: According to Global Initiative for Asthma (GINA) guidelines, long-acting muscarinic antagonists (LAMAs) should be considered as add-on therapy in patients with asthma that remains uncontrolled, despite treatment with medium-dose (MD) or high-dose (HD) inhaled corticosteroids (ICS)/long-acting ß2-agonist (LABA) combinations. In patients ≥ 18 years, LAMA may be added in triple combination with an ICS and a LABA. To date, the precise efficacy of triple ICS/LABA/LAMA combination remains uncertain concerning the impact on exacerbation risk in patients with uncontrolled asthma. Therefore, an umbrella review was performed to systematically summarize available data on the effect of triple ICS/LABA/LAMA combination on the risk of asthma exacerbation. METHODS: An umbrella review has been performed according to the PRIOR statement. RESULTS: The overall results obtained from 5 systematic reviews and meta-analyses suggest that triple ICS/LABA/LAMA combination reduces the risk of asthma exacerbation. HD-ICS showed a greater effect particularly in reducing severe asthma exacerbation, especially in patients with evidence of type 2 inflammation biomarkers. CONCLUSIONS: The findings of this umbrella review suggest an optimization of ICS dose in triple ICS/LABA/LAMA combination, based on the severity of exacerbation and type 2 biomarkers expression.

Assessing the relationship between cardiovascular and small airway disease and acute events in COPD: The ARCADIA study protocol.

The initial alterations of chronic obstructive pulmonary disease (COPD) involve the small airways. Small airway disease (SAD) is related to lung hyperinflation and air trapping. Several lung function tests may detect the presence of SAD, namely forced mid-expiratory flows, residual volume (RV), RV/total lung capacity (TLC) ratio, functional residual capacity, airway resistances obtained with body-plethysmography and oscillometry, and the single-breath nitrogen washout test. Additionally, high-resolution computed tomography can detect SAD. In addition to SAD, COPD is related to cardiovascular disease (CVD) such as heart failure, peripheral vascular disease, and ischemic heart disease. No studies have assessed the relationship between CVD, COPD, and SAD. Therefore, the main objective of the Assessing the Relationship between Cardiovascular and small Airway Disease and Acute events in COPD (ARCADIA) study is to assess the risk of CVD in COPD patients according to SAD in a real-life setting. The correlation between CVD, mortality, and acute exacerbation of COPD (AECOPD) is also evaluated. ARCADIA is a 52-week prospective, multicentre, pilot, observational, cohort study conducted in ≥22 pulmonary centres in Italy and that enrols ≥500 COPD patients, regardless of disease severity (protocol registration: ISRCTN49392136). SAD is evaluated at baseline, after that CVD, mortality, and AECOPD are recorded at 6 and 12 months. Bayesian inference is used to quantify the risk and correlation of the investigated outcomes in COPD patients according to SAD. The ARCADIA study provides relevant findings in the daily clinical management of COPD patients.

Experimental drugs in clinical trials for COPD: artificial intelligence via machine learning approach to predict the successful advance from early-stage development to approval.

INTRODUCTION: Therapeutic advances in drug therapy of chronic obstructive pulmonary disease (COPD) really effective in suppressing the pathological processes underlying the disease deterioration are still needed. Artificial Intelligence (AI) via Machine Learning (ML) may represent an effective tool to predict clinical development of investigational agents. AREAL COVERED: Experimental drugs in Phase I and II development for COPD from early 2014 to late 2022 were identified in the ClinicalTrials.gov database. Different ML models, trained from prior knowledge on clinical trial success, were used to predict the probability that experimental drugs will successfully advance toward approval in COPD, according to Bayesian inference as follows: ≤25% low probability, >25% and ≤50% moderate probability, >50% and ≤75% high probability, and >75% very high probability. EXPERT OPINION: The Artificial Neural Network and Random Forest ML models indicated that, among the current experimental drugs in clinical trials for COPD, only the bifunctional muscarinic antagonist - ß2-adrenoceptor agonists (MABA) navafenterol and batefenterol, the inhaled corticosteroid (ICS)/MABA fluticasone furoate/batefenterol, and the bifunctional phosphodiesterase (PDE) 3/4 inhibitor ensifentrine resulted to have a moderate to very high probability of being approved in the next future, however not before 2025.

The Impact of Corticosteroids on Human Airway Smooth Muscle Contractility and Airway Hyperresponsiveness: A Systematic Review.

Classically, the effects elicited by corticosteroids (CS) are mediated by the binding and activation of cytosolic glucocorticoid receptors (GR). However, several of the non-genomic effects of CS seem to be mediated by putative non-classic membrane receptors characterized by pharmacological properties that are different from those of classic cytosolic GR. Since pre-clinical findings suggest that inhaled CS (ICS) may also regulate the bronchial contractile tone via putative CS membrane-associate receptors, the aim of this review was to systematically report and discuss the impact of CS on human airway smooth muscle (ASM) contractility and airway hyperresponsiveness (AHR). Current evidence indicates that CS have significant genomic/non-genomic beneficial effects on human ASM contractility and AHR, regardless of their anti-inflammatory effects. CS are effective in reducing either the expression, synthesis or activity of α-actin, CD38, inositol phosphate, myosin light chain kinase, and ras homolog family member A in response to several pro-contractile stimuli; overall these effects are mediated by the genomic action of CS. Moreover, CS elicited a strong bronchorelaxant effect via the rapid activation of the Gsα-cyclic-adenosine-monophosphate-protein-kinase-A pathway in hyperresponsive airways. The possibility of modulating the dose of the ICS in a triple ICS/long-acting ß2-adrenoceptor agonist/long-acting muscarinic antagonist fixed-dose combination supports the use of a Triple MAintenance and Reliever Therapy (TriMART) in those asthmatic patients at Step 3-5 who may benefit from a sustained bronchodilation and have been suffering from an increased parasympathetic tone.

Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma.

Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really change the natural course of asthma, including disease remission. Considering the highly heterogeneous nature of asthma, there is a strong need for innovative medications that selectively target components of the inflammatory cascade. The aim of this review was to systematically assess current investigational agents in Phase I and II randomised controlled trials (RCTs) over the last five years. Sixteen classes of novel therapeutic options were identified from 19 RCTs. Drugs belonging to different classes, such as the anti-interleukin (IL)-4Rα inhibitors, anti-IL-5 monoclonal antibodies (mAbs), anti-IL-17A mAbs, anti-thymic stromal lymphopoietin (TSLP) mAbs, epithelial sodium channel (ENaC) inhibitors, bifunctional M3 receptor muscarinic antagonists/ß2-adrenoceptor agonists (MABAs), and anti-Fel d 1 mAbs, were found to be effective in the treatment of asthma, with lung function being the main assessed outcome across the RCTs. Several novel investigational molecules, particularly biologics, seem promising as future disease-modifying agents; nevertheless, further larger studies are required to confirm positive results from Phase I and II RCTs.

Impact of Sex on Proper Use of Inhaler Devices in Asthma and COPD: A Systematic Review and Meta-Analysis.

Despite females being more often affected by asthma than males and the prevalence of COPD rising in females, conflicting evidence exists as to whether sex may modulate the correct inhaler technique. The aim of this study was to assess the impact of sex on the proper use of inhaler devices in asthma and COPD. A pairwise meta-analysis was performed on studies enrolling adult males and females with asthma or COPD and reporting data of patients making at least one error by inhaler device type (DPI, MDI, and SMI). The data of 6,571 patients with asthma or COPD were extracted from 12 studies. A moderate quality of evidence (GRADE +++) indicated that sex may influence the correct use of inhaler device in both asthma and COPD. The critical error rate was higher in females with asthma (OR 1.31, 95%CI 1.14−1.50) and COPD (OR 1.80, 95%CI 1.22−2.67) using DPI vs. males (p < 0.01). In addition, the use of SMI in COPD was associated with a greater rate of critical errors in females vs. males (OR 5.36, 95%CI 1.48−19.32; p < 0.05). No significant difference resulted for MDI. In conclusion, choosing the right inhaler device in agreement with sex may optimize the pharmacological treatment of asthma and COPD.

Muscarinic receptor antagonists and airway inflammation: A systematic review on pharmacological models.

Airway inflammation is crucial in the pathogenesis of many respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. Current evidence supports the beneficial impact of muscarinic receptor antagonists against airway inflammation from bench-to-bedside. Considering the numerous sampling approaches and the ethical implications required to study inflammation in vivo in patients, the use of pre-clinical models is inevitable. Starting from our recently published systematic review concerning the impact of muscarinic antagonists, we have systematically assessed the current pharmacological models of airway inflammation and provided an overview on the advances in in vitro and ex vivo approaches. The purpose of in vitro models is to recapitulate selected pathophysiological parameters or processes that are crucial to the development of new drugs within a controlled environment. Nevertheless, immortalized cell lines or primary airway cells present major limitations, including the inability to fully replicate the conditions of the corresponding cell types within a whole organism. Induced animal models are extensively used in research in the attempt to replicate a respiratory condition reflective of a human pathological state, although considering animal models with spontaneously occurring respiratory diseases may be more appropriate since most of the clinical features are accompanied by lung pathology resembling that of the human condition. In recent years, three-dimensional organoids have become an alternative to animal experiments, also because animal models are unable to fully mimic the complexity of human pulmonary diseases. Ex vivo studies performed on human isolated airways have a superior translational value compared to in vitro and animal models, as they retain the morphology and the microenvironment of the lung in vivo. In the foreseeable future, greater effort should be undertaken to rely on more physiologically relevant models, that provide translational value into clinic and have a direct impact on patient outcomes.

Inflammatory and contractile profile in LPS-challenged equine isolated bronchi: Evidence for IL-6 as a potential target against AHR in equine asthma.

BACKGROUND: Airway inflammation and airway hyperresponsiveness (AHR) are pivotal characteristics of equine asthma. Lipopolysaccharide (LPS) may have a central role in modulating airway inflammation and dysfunction. Therefore, the aim of this study was to match the inflammatory and contractile profile in LPS-challenged equine isolated bronchi to identify molecular targets potentially suitable to counteract AHR in asthmatic horses. METHODS: Equine isolated bronchi were incubated overnight with LPS (0.1-100 ng/ml). The contractile response to electrical field stimulation (EFS) and the levels of cytokines, chemokines, and neurokinin A (NKA) were quantified. The role of capsaicin sensitive-sensory nerves, neurokinin-2 (NK2) receptor, transient receptor potential vanilloid type 1 receptors (TRPV1), and epithelium were also investigated. RESULTS: LPS 1 ng/ml elicited AHR to EFS (+238.17 ± 25.20% P < 0.001 vs. control). LPS significantly (P < 0.05 vs. control) increased the levels of IL-4 (+36.08 ± 1.62%), IL-5 (+38.60 ± 3.58%), IL-6 (+33.79 ± 2.59%), IL-13 (+40.91 ± 1.93%), IL-1ß (+1650.16 ± 71.16%), IL-33 (+88.14 ± 8.93%), TGF-ß (22.29 ± 1.03%), TNF-α (+56.13 ± 4.61%), CXCL-8 (+98.49 ± 17.70%), EOTAXIN (+32.26 ± 2.27%), MCP-1 (+49.63 ± 4.59%), RANTES (+36.38 ± 2.24%), and NKA (+112.81 ± 6.42%). Capsaicin sensitive-sensory nerves, NK2 receptor, and TRPV1 were generally involved in the LPS-mediated inflammation. Epithelium removal modulated the release of IL-1ß, IL-33, and TGF-ß. Only the levels of IL-6 fitted with AHR to a wide range of EFS frequencies, an effect significantly (P < 0.05) inhibited by anti-IL-6 antibody; exogenous IL-6 induced significant (P < 0.05) AHR to EFS similar to that elicited by LPS. CONCLUSION: Targeting IL-6 with specific antibody may represent an effective strategy to treat equine asthma, especially in those animals suffering from severe forms of this disease.

Immunoprophylaxis pharmacotherapy against canine leishmaniosis: A systematic review and meta-analysis on the efficacy of vaccines approved in European Union.

Leishmania (L.) infantum is a vector-borne parasite currently endemic in several Southern countries of European Union (EU), and dogs represent the main reservoir and hosts. Data from clinical trials are inconsistent with respect to the efficacy of vaccination against L. infantum infection. Therefore, a quantitative synthesis via pairwise meta-analysis was performed in agreement with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) to increase the strength of evidence and assess the real efficacy profile of vaccines against L. infantum currently approved in EU. Data obtained from 1,394 dogs were extracted from 10 studies. The overall analysis indicated that vaccination is significantly effective in protecting against L. infantum infection (RR 0.40, 95%CI 0.23-0.72; I2 70%; P < 0.01 vs. negative controls). The subset analysis performed by excluding the effect modifiers and by considering only the studies that assessed the efficacy of vaccines currently available in EU, indicated that CaniLeish® (RR 0.38, 95%CI 0.20-0.72; I2 0%), but not Letifend® (RR 0.43, 95%CI 0.15-1.22; I2 37%), significantly protected against L. infantum infection when compared to negative controls (P < 0.05). The number needed to treat analysis showed that 3.77 (95%CI 2.59-6.94) and 10.99 (95%CI 8.28-16.34) dogs had to be treated with CaniLeish® and Letifend®, respectively, to prevent one case of infection compared to negative controls. Vaccination is effective in protecting against the risk L. infantum infection, but further studies are needed to assess whether CaniLeish® and Letifend® are characterized by similar efficacy profile.

Anthelminthic medicinal plants in veterinary ethnopharmacology: A network meta-analysis following the PRISMA-P and PROSPERO recommendations.

Medicinal plants may be effective against helminthic infestation in animals, but to date few studies have investigated the real impact of anthelminthic medicinal plants in veterinary ethnopharmacology. The aim of this study was to assess the geographical use of anthelminthic medicinal plants in livestock in European Union (EU), and to quantify the anthelminthic efficacy of medicinal plants in comparison with anthelminthic drugs. Surveys on the use of anthelminthic traditional medicinal plants in livestock in the EU were included in the qualitative synthesis. Studies that investigated the efficacy of anthelminthic traditional medicinal plants in animals, compared with negative control and/or anthelminthic drugs, were included in the quantitative synthesis (network meta-analysis). Twelve surveys (9 in Italy, 2 in Spain, 1 in Austria) reported the use of anthelminthic medicinal plants in livestock living in EU Countries. Data obtained from 256 animals and extracted from 6 studies were included in the network meta-analysis. Medicinal plants and drugs were more effective than negative control (standardized mean difference [SMD]: -0.60 95%CrI -0.88 to -0.31, -0.73 95%CrI -1.08 to -0.38, respectively, P < 0.001). Overall, no difference was detected between anthelminthic medicinal plants and anthelminthic drugs, namely albendazole, ivermectin, fenbendazole, and doramectin (SMD: 0.26 95%CrI -0.02 to 0.55, P > 0.05). The most effective anthelminthic medicinal plants were Artemisia absintihium, Allium sativum, and Duranta erecta. There is the strong medical need of performing adequately powered randomized controlled trials in different livestock species aimed to improve the quality of the current evidence concerning the anthelminthic efficacy of medicinal plants compared to that of the currently available antiparasitic drugs.

Isolated airways in equine respiratory pharmacology: They never lie.

Pre-clinical studies on human isolated bronchi have relevant translational value in human in vivo, conversely no investigation has been performed to assess whether data resulting from equine isolated airways can have any translational application in asthmatic horses. Thus, a meta-regression analysis via random-effect method was carried out to correlate the pharmacological characteristics of bronchodilators resulting from experiments performed in equine isolated bronchi with their impact on the lung function outcomes in asthmatic horses. Data on the potency of different bronchodilators were extracted from four ex vivo studies involving 68 horses, and related with the maximum change in transpulmonary pressure (ΔPplmax), pulmonary resistance (RL), and dynamic lung compliance (Cdyn) resulting from the meta-analysis of clinical trials aimed to assess the effect of different bronchodilator classes, namely antimuscarinic agents and ß2-adrenoreceptor (ß2-AR) agonists, on lung function of asthmatic horses. The potency (pEC50) detected in equine isolated bronchi for each specific bronchodilator did not significantly (P > 0.05) influence the bronchorelaxant effect resulting from clinical trials. RL was characterized by a flatter meta-regression line (slope 0.01, 95%CI -0.25 - 0.28) with respect to ΔPplmax (slope 0.90, 95%CI -4.06 - 2.26) and Cdyn (slope 0.09, 95%CI -0.21 - 0.04). The quality of evidence was moderate for RL and ΔPplmax and low for Cdyn. This quantitative synthesis provides the indirect evidence that pre-clinical investigations performed by using equine isolated airways may produce useful data to predict the impact of bronchodilators on the RL of asthmatic horses. Further translational studies are needed to directly confirm the results of this research.

Effect of lipopolysaccharide on the responsiveness of equine bronchial tissue.

Recurrent airway obstruction (RAO) is a main characteristic of horses with severe equine asthma syndrome. The presence of bacterial lipopolysaccharide (LPS) in the airways of horses is thought to play a crucial role in the clinical expression of this disorder. This study pharmacologically characterized the effect of LPS on the responsiveness of equine bronchial tissue. Equine isolated bronchi were incubated overnight with LPS (0.1-100 ng/ml) and then stimulated by electrical field stimulation (EFS). The role of capsaicin sensitive-sensory nerves (capsaicin desensitization treatment), neurokinin-2 (NK2) receptors (blocked by GR159897), transient receptor potential vanilloid type 1 receptors (TRPV1; blocked by SB366791), and neurokinin A (NKA) were investigated. Untreated bronchi were used as control tissues. LPS (1 ng/ml) significantly increased the EFS-evoked contractility of equine bronchi compared with control tissues (+742 ± 123 mg; P < 0.001). At higher concentrations LPS induced desensitization to airways hyperresponsiveness (AHR; EC50: 5.9 ±â€¯2.6 ng/ml). Capsaicin desensitization and GR159897 significantly prevented AHR induced by LPS at EFS1-50Hz (-197 ±â€¯25%; P < 0.01). SB366791 inhibited AHR at very low EFS frequency (EFS1Hz -193 ±â€¯29%; P < 0.01 vs. LPS-treated bronchi). LPS (1 ng/ml) significantly (P < 0.01) increased 3.7 ±â€¯0.7 fold the release of NKA compared with control bronchi. LPS induces biphasic dysfunctional bronchial contractility due to the stimulation of capsaicin sensitive-sensory nerves, increased release of NKA, and activation of NK2 receptors, whereas TRPV1 receptors appear to play a marginal role in this response. The overnight challenge with low concentrations of LPS represents a suitable model to investigate pharmacological options that may be of value in the treatment of equine RAO.

Pharmacological characterization of the interaction between tiotropium and olodaterol administered at 5:5 concentration-ratio in equine bronchi.

Equine airways represent a suitable ex vivo model to study the functional impact of pharmacological treatments on human chronic obstructive pulmonary disorders, such as asthma and chronic obstructive pulmonary disease (COPD). We aimed to characterize the pharmacological interaction between the long-acting muscarinic antagonist (LAMA) tiotropium and the long-acting ß2-agonist (LABA) olodaterol in equine airways. The effect of tiotropium and olodaterol, administered alone and in combination at the ratio of concentrations reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (FDC) (5:5), was investigated on the cholinergic contractile tone induced by the parasympathetic activation of equine isolated airways. The drug interaction was analysed by using the Bliss Independence and Unified Theory models. Both tiotropium and olodaterol induced a sub-maximal concentration-dependent inhibition of bronchial contractility (Emax: tiotropium 83.6 ± 14.8%, olodaterol 76.9 ± 17.9%; pEC50: tiotropium 8.2 ± 0.5; olodaterol 8.3 ± 0.6). When administered at 5:5 concentration-ratio, tiotropium plus olodaterol completely inhibited the bronchial contractility (Emax 102.7 ± 8.4%; pEC50 9.0 ± 0.7). Strong synergistic interaction was detected for tiotropium/olodaterol combination (combination index 0.011). When administered at low concentrations, the drug mixture elicited up to 94.6 ± 9.5% effect that was 36.0 ± 8.1% greater than the expected additive effect. The results of this study demonstrate that the co-administration of tiotropium plus olodaterol at 5:5 concentration-ratio leads to synergistic inhibition of equine bronchial contractility when compared with either drug administered alone. These findings suggest that the currently available LABA/LABA FDC may be effective in delivering tiotropium/olodaterol combination at equipotency concentrations of each monocomponent into the lung and, thus, inducing synergistic effect in the airways.

Propofol protects against opioid-induced hyperresponsiveness of airway smooth muscle in a horse model of target-controlled infusion anaesthesia.

General anaesthesia in horses is associated with elevated mortality rate in subjects suffering of heaves. Target-controlled infusion (TCI) of sedative-hypnotic medications and opioids represents a total intravenous anaesthesia (TIVA) method validated in veterinary medicine. Since there are no data concerning the impact of these classes of drugs in inducing bronchial hyperresponsiveness (BHR) in horses, the aim of this study was to investigate the effect propofol and remifentanil on the contractile response of equine airway smooth muscle. The influence of propofol and remifentanil on the contractile response of equine isolated bronchi to electrical field stimulation (EFS) was assessed. The role of capsaicin-sensitive sensory nerves, inducible nitric oxide synthase (iNOS) and neurokinin 2 (NK2) receptor was also assessed. The interaction analysis was performed by Bliss Independence theory. Experiments were repeated in desensitized and passively sensitized airways. Remifentanil induced BHR in both non-sensitized and passively sensitized bronchi, (+56.33±8.01% and +99.10±14.52%, respectively; P<0.01 vs. control) and propofol significantly prevented this effect (P>0.05 vs. remifentanil). The inactivation of capsaicin-sensitive sensory nerves via desensitization and blocking NK2 receptor inhibited the BHR remifentanil-induced (P>0.05 vs. controls). The inhibition of iNOS reverted the protective effect of propofol on the BHR induced by remifentanil (non-sensitized: +47.11±7.70%; passively sensitized: +70.51±11.39%; P<0.05 vs. control). Propofol synergistically interacted (overall ≈40%) in preventing the remifentanil-induced BHR. Remifentanil induces BHR via stimulating capsaicin-sensitive sensory nerves that facilitate the cholinergic neurotransmission through the activation of NK2 receptor. The propofol/remifentanil combination may be safely administered in course of TCI-TIVA procedures also in heaves affected horses.

Novel and effective balanced intravenous-inhalant anaesthetic protocol in swine by using unrestricted drugs.

Nowadays, because of increasing employment of swine for experimental studies and medical training, it is hopeful to investigate novel and effective anaesthetic protocols for preserving the animal welfare in medical investigation and concurrently improving the quality of research. Therefore, the aim of this study was to investigate a novel and effective anaesthetic protocol in swine undergoing major surgery, by translating know-how of combined anaesthesia from human protocols. Seven landrace swine were anaesthetized for three hours by a combined trial anaesthetic protocol (sedation: medetomidine, acepromazine, atropine and tramadol; induction: propofol, medetomidine and acepromazine; anaesthesia: isofluorane, propofol, medetomidine and acepromazine) and both clinical and haemodynamic parameters were compared with those of five swine anaesthetized with a control protocol (sedation: diazepam, ketamine and atropina; induction: diazepam and ketamine; anaesthesia: isofluorane). Both cardiac frequency (CF) and mean blood pressure (MBP) were significantly (P<0.05) more stable in trial protocol (CF: 78.3 ± 4.6-81.1 ± 5, MBP: 63.9 ± 10.7-96.4 ± 13.0) compared to control protocol (CF: 93.7 ± 5.5-102.5 ± 8.5, MBP: 71.0 ± 6.6-108.7 ± 7.2). The body temperature remained stable in trial protocol (°C: 36.9 ± 0.7-37.2 ± 0.3) compared to control anaesthesia (°C: 36.4 ± 0.3-37.3 ± 0.2, P<0.05). Haematosis improved undergoing combined anaesthesia (+2%, P<0.05) whereas did not change in control animals. There were no differences in respiratory rate between trial and control protocols. This study demonstrates that the proposed balanced intravenous-inhalant protocol permits to carry out a very effective, stable and safe anaesthesia in swine undergoing deep anaesthesia.