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It is unclear which factor Xa (FXa) inhibitors are associated with higher bleeding risk in patients with respiratory diseases, and there are no studies on the association between prothrombin time-international normalized ratio (PT-INR) and bleeding risk. We conducted a retrospective cohort study comparing 1-year-outcomes and PT-INR between patients with respiratory diseases treated with rivaroxaban (R group, n = 82) or edoxaban (E group, n = 138) for atrial fibrillation or venous thromboembolism from 2013 to 2021. The most frequent event of all bleeding discontinuations was respiratory bleeding in both groups (7.3 and 4.3%, respectively). The cumulative incidence of bleeding discontinuation was significantly higher in the R group (25.6%) than in the E group (14.4%) (hazard ratio [HR], 2.29; 95% confidence interval [CI] 1.13-4.64; P = 0.023). PT-INR after initiation of therapy significantly increased and was higher in the R group than in the E group (median value, 1.4 and 1.2, respectively; P < 0.001). Multivariate analysis using Cox proportional hazards and Fine-Gray models revealed that PT-INR after initiation of therapy was an independent risk factor of bleeding discontinuation events (HR = 4.37, 95% CI 2.57-7.41: P < 0.001). Respiratory bleeding occasionally occurs in patients receiving FXa inhibitors, and monitoring the PT-INR may need to ensure safety., (© 2024. The Author(s).)

The significance of Vitamin D has been appreciated beyond bone health and calcium metabolism. The importance of Vitamin D in respiratory health has been recognized due to its immunomodulatory and anti-microbial properties. The hypothesis is that Vitamin D could have a significant role in the pathogenesis of respiratory diseases and may represent a novel preventive and therapeutic strategy. Furthermore, enumerable observational studies established the association of Vitamin D deficiency with respiratory diseases such as asthma, bronchiolitis, pneumonia, tuberculosis, etc. However, experimental studies have not shown the encouraging results. This brief review will summarize and discuss the synthesis and metabolism of Vitamin D, the prevalence of Vitamin D deficiency in children, its role in the pathogenesis of various childhood respiratory diseases, and an overview of the therapeutic trials assessing the role of Vitamin D supplementation in childhood respiratory diseases., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Nonsteroidal anti‑inflammatory drug-exacerbated respiratory disease (N‑ERD) is a unique and often clinically severe disease affecting a subgroup of adults with asthma, chronic rhinosinusitis with nasal polyposis, and respiratory reactions with exposure to all cyclooxygenase 1-inhibiting nonsteroidal anti‑inflammatory drugs. N‑ERD has a high disease burden and is estimated to affect 7% of adults with asthma and 30% of patients who have both asthma and nasal polyps. The disease is underdiagnosed and underrecognized by physicians on a routine basis, which leads to a delay in appropriate management. The goal of this review is to focus on the disease recognition, diagnosis, and different modes of up‑to‑date therapies, including medical management, surgical intervention, aspirin desensitization, and biologic therapy.

Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, APR was widely used as an antithrombotic and anti-inflammatory drug in cardiac and noncardiac surgeries for reduction of bleeding and thus limiting the need for blood transfusion. The ability of APR to inhibit proteolytic activation of some viruses leads to its use as an antiviral drug for the prevention and treatment of acute respiratory virus infections. However, due to incompetent interpretation of several clinical trials followed by incredible controversy in the literature, the usage of APR was nearly stopped for a decade worldwide. In 2015-2020, after re-analysis of these clinical trials' data the restrictions in APR usage were lifted worldwide. This review discusses antiviral mechanisms of APR action and summarizes current knowledge and prospective regarding the use of APR treatment for diseases caused by RNA-containing viruses, including influenza and SARS-CoV-2 viruses, or as a part of combination antiviral treatment.

Introduction: Current treatments for allergic fungal airway disease are not specific for asthma and are associated with limited efficacy or safety concerns. This Phase IIa randomized, multicenter, double-blind, sponsor-open, comparative trial assessed the efficacy and safety of GSK3772847, an anti-interleukin-33 receptor monoclonal antibody, in moderate-to-severe asthma patients with allergic fungal airway disease (ClinicalTrials.gov: NCT03393806)., Methods: Key inclusion criteria required participants of ≥18 years of age with a documented diagnosis of moderate-to-severe asthma (≥12 months) treated with inhaled corticosteroid and long-acting β2-agonist (≥4 months); evidence of allergic fungal airway disease (fungal sensitization to Aspergillus fumigatus [>0.35 KU/L] or Penicillium chrysogenum [>0.35 KU/L] and no history of concurrent respiratory disease/recurrent or ongoing non-pulmonary infections. Participants were randomized (1:1) to GSK3772847 (10 mg/kg) or matching placebo intravenously administered at Weeks 0, 4, and 8, in addition to standard of care. Randomization was based on systemic anti-fungal treatment status at screening. Primary endpoints were change from baseline (Week 0) to Week 12 in blood eosinophils and fractional exhaled nitric oxide., Results: Participants (n = 17) were randomized to GSK3772847 (n = 8) or placebo (n = 9) for 12 weeks and included in efficacy and safety analyses. This study was terminated early due to the high rate of screen failure, low enrollment, and unlikely feasibility of timely study completion. There were no differences observed in blood eosinophils or fractional exhaled nitric oxide between treatment arms. Target engagement was demonstrated by reductions in free soluble suppressor of tumorigenicity 2 levels in the GSK3772847 arm throughout the treatment period. No deaths occurred and no new safety signals were identified., Conclusions: Lack of clinical benefits with GSK3772847 was likely due to the small sample size, highlighting the need for larger prospective studies., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CA, AN and DF are employees of and hold stocks/shares in GSK. CC is a former employee of GSK and holds stock/shares in GSK. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Akinseye et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: While the safety and efficacy of inhaled budesonide-formoterol, used as-needed for symptoms, has been established for patients with asthma, it has not been trialed in undifferentiated patients with chronic respiratory diseases. We aimed to assess the feasibility of a pragmatic intervention that entails a stepped algorithm using inhaled budesonide-formoterol (dry powder inhaler, 160μg/4.5μg per dose) for patients presenting with chronic respiratory diseases to three rural district hospitals in Hanoi, Vietnam., Methods: We recruited patients with evidence of airflow obstruction on spirometry and/or symptoms consistent with asthma. The algorithm consisted of three steps: 1. as-needed inhaled budesonide-formoterol for symptoms, 2. maintenance plus as-needed inhaled budesonide-formoterol, and 3. referral to a higher-level healthcare facility. All participants started at step 1, with escalation to the next step at review visits if there had been exacerbation(s) or inadequate symptom control. Patients were followed for 12 months., Results: Among 313 participants who started the treatment algorithm, 47.2% had ≥ 1 episode of acute respiratory symptoms requiring a visit to hospital or clinic and 35.4% were diagnosed with an exacerbation. Twelve months after enrolment, 50.7% still adhered to inhaled budesonide-formoterol at the recommended treatment step. The mean and median number of doses per day was 1.5 (standard deviation 1.2) doses and 1.3 (interquartile range 0.7-2.3) doses, respectively. The proportion of patients taking more than 800μg budesonide per day was 3.8%., Conclusion: This novel therapeutic algorithm is feasible for patients with chronic respiratory diseases in a rural setting in Vietnam. Further studies are required to establish the effectiveness, safety and cost-effectiveness of similar approaches in different settings., Trial Registration: ACTRN12619000554167., Competing Interests: The authors have declared that no competing interests exist.

Subcutaneous immunotherapy is recognized as a cornerstone in the management of allergic respiratory disease in patients who are properly characterized with allergy and with allergic rhinoconjunctivis and/or well-controlled asthma, and who are willing to adhere to the rigorous treatment program. A key tenet is that it affords the opportunity to effect long-term clinical remission through its disease-modifying properties. Furthermore, it has the potential to prevent the progression of allergic rhinitis to asthma, prevent new allergen sensitivities, and improve a patient's quality of life.

Respiratory mycosis is a major health concern, due to the expanding population of immunosuppressed and immunocompromised patients and the increasing resistance to conventional antifungals and their undesired side-effects, thus justifying the development of new therapeutic strategies. Plant metabolites, namely essential oils, represent promising preventive/therapeutic strategies due to their widely reported antifungal potential. However, regarding fungal infections of the respiratory tract, information is disperse and no updated compilation on current knowledge is available. Therefore, the present review aims to gather and systematize relevant information on the antifungal effects of several essential oils and volatile compounds against the main type of respiratory mycosis that impact health care systems. Particular attention is paid to Aspergillus fumigatus , the main pathogen involved in aspergillosis, Candida auris , currently emerging as a major pathogen in certain parts of the world, and Cryptococcus neoformans , one of the main pathogens involved in pulmonary cryptococcosis. Furthermore, the main mechanisms of action underlying essential oils' antifungal effects and current limitations in clinical translation are presented. Overall, essential oils rich in phenolic compounds seem to be very effective but clinical translation requires more comprehensive in vivo studies and human trials to assess the efficacy and tolerability of these compounds in respiratory mycosis.

To analyze the effectiveness of dexamethasone in preventing upper airway obstruction (UAO) symptoms after extubation and the need of reintubation in critically ill children. Multicenter, prospective, double-blind, randomized, phase IV clinical trial involving five pediatric intensive care units. Children between 1 month and 16 years-of-age intubated for more than 48 h were included. Patients were randomized to receive placebo or dexamethasone 0.25 mg/kg every 6 h, 6-to-12 h prior to extubation (four doses). 48 h follow-up was carried out after extubation. Severity of UAO symptoms (Taussig score, stridor) and reintubation requirement were compared. 147 patients were randomized (10 were excluded), 70 patients received dexamethasone and 67 placebo. No global differences were found in the presence of stridor or moderate-to-severe UAO symptoms (Taussig ≥ 5), but Taussig ≥ 5 was less frequent in patients less than 2 years-of-age treated with steroids (p = 0.014). Median Taussig score was lower in the dexamethasone group 1 h after extubation, p < 0.001. 27 patients required reintubation, 9 due to UAO: 3 (4.3%) in the dexamethasone group and 6 (8.9%) in the placebo group, p = 0.319. In those intubated > 5 days, reintubation due to UAO was higher in the placebo group (2.4% vs. 14.3, p = 0.052). Nebulized epinephrine and budesonide were required more frequently in the placebo group in the first 2 h (p = 0.041) and 1 h (p = 0.02) after extubation, respectively. No relevant side effects were observed. Dexamethasone prior to extubation did not significantly reduce moderate-severe UAO symptoms, except for patients under 2-years of age. Dexamethasone could decrease Taussig score and the need of rescue therapies, as well as reintubation rates in those intubated for more than 5 days., (© 2022. The Author(s).)

Background: Aspirin-exacerbated respiratory disease (AERD) is a syndrome characterised by chronic rhinosinusitis, nasal polyps, asthma and aspirin intolerance. An imbalance of eicosanoid metabolism with anover-production of cysteinyl leukotrienes (CysLTs) has been associated with AERD. However, the precise mechanisms underlying AERD are unknown., Objective: To establish the transcriptome of the nasal polyp airway epithelial cells derived from AERD patients to discover gene expression patterns in this disease., Methods: Nasal airway epithelial cells were isolated from 12 AERD polyps and 8 AERD non-polyp nasal mucosa samples as controls from the same subjects. Utilising the Illumina HiSeq 2500 platform, RNA samples were sequenced. Potential gene candidate DMRT3 was selected from the differentially-expressed genes for validation., Results: Comparative transcriptome profiling of nasal epithelial cells was accomplished in AERD. A total of 20 genes had twofold mean regulation expression differences or greater. In addition, 8 genes were upregulated, including doublesex and mab-3 related transcription factor 3 (DMRT3), and 12 genes were downregulated. Differentially regulated genes comprised roles in inflammation, defence and immunity. Metabolic process and embryonic development pathways were significantly enriched. Enzyme-linked immune sorbent assay (ELISA) results of DMRT3 in AERD patients were significantly upregulated compared to controls ( p = 0.03). Immunohistochemistry (IHC) of AERD nasal polyps localised DMRT3 and was predominantly released in the airway epithelia., Conclusion: Findings suggest that DMRT3 could be potentially involved in nasal polyp development in AERD patients. Furthermore, several genes are downregulated, hinting at the dedifferentiation phenomenon in AERD polyps. However, further studies are imperative to confirm the exact mechanism of polyp formation in AERD patients.

Background: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis., Methods and results: Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI., Conclusions: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

Objectives: Surgery for acute type A aortic dissection is associated with several perioperative complications, such as acute respiratory dysfunction (ARD). The aim of this study was to investigate perioperative risk factors involved in the development of ARD and whether antibiotic treatment has an impact., Methods: 243 patients underwent surgery for acute type A aortic dissection between 2008 and 2017. The patients were retrospectively divided into the ARD and NON-ARD group. ARD was defined as PaO2/FiO2 ≤ 200 mmHg (PF ratio) within 48 hours after surgery. All patients received either narrow- or broad-spectrum antibiotics., Results: After the exclusion of 42 patients, 201 patients were analyzed. The PF ratio of the ARD group was significantly lower than of the NON-ARD group within the first 7 days. ARD patients (n = 111) were significantly older (p = .031) and had a higher body mass index (BMI) (p = .017). ARD patients required longer postoperative ventilation (2493 vs. 4695 [min], p = .006) and spent more days in the intensive care unit (7.0 vs. 8.9 [days], p = .043) compared to NON-ARD. The mortality was significantly lower for ARD than for NON-ARD patients (p = .030). The incidence of pneumonia was independent of the antibiotic treatment regime (p = .391). Renal and neurological complication rate was higher in patients treated with broad-spectrum antibiotic., Conclusion: ARD is the main complication (55%) that occurs approximately 24 hours after surgery for acute type A aortic dissection. The preoperative risk factors for ARD were higher age and increased BMI. Patients on broad-spectrum antibiotics did not show an improved postoperative outcome compared to patients with narrow-spectrum antibiotics., Competing Interests: The authors have declared that no competing interests exist.

The quest to find novel strategies to tackle respiratory illnesses has led to the exploration of the potential therapeutic effects of carbon monoxide (CO) as an endogenous signaling molecule and a cytoprotective agent. Further, several studies have demonstrated the pharmacological efficacy of CO in animal models of respiratory disorders, such as acute lung injury and pulmonary hypertension. Because of the gaseous nature of CO and its affinity for multiple targets, its controlled delivery has been a challenge. Past studies have employed different delivery modalities, including CO gas, HO-1 inducers, and CO donors, sometimes leading to substantive variations in the resulting pharmacological effects for various reasons. Herein, this review summarizes and analyzes the differences among the profiles of various CO-delivery modalities in terms of their efficacy, dosing regimen, and pharmacokinetics in airways models. We believe that analysis of these issues will help in understanding the fundamental roles of CO in airways, and eventually, contribute to its development as a medicine for respiratory diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Isoquinoline analogs are an important, structurally diverse class of compounds that are extensively used as pharmaceuticals. Derivatives containing the isoquinoline scaffold have become a focus of therapeutic research because of their wide range of biological characteristics. Examples of these drugs, many of which are in clinical application or at the pre-clinical stage, are used to treat a broad swathe of ailments, such as tumors, respiratory diseases, infections, nervous system diseases, cardiovascular and cerebrovascular diseases, endocrine and metabolic diseases., Methods: Data were collected from PubMed, Web of Science, and SciFinder, through searches of drug names., Results: At least 38 isoquinoline-based therapeutic drugs are in clinical application or clinical trials, and their chemical structure and pharmacokinetics are described in detail., Conclusion: The isoquinoline ring is a privileged scaffold which is often preferred as a structural basis for drug design, and plays an important role in drug discovery. This review provides a guide for pharmacologists to find effective preclinical/clinical drugs and examines recent progress in the application of the isoquinoline scaffold., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Monoclonal antibodies, biologics, are a relatively new treatment option for severe chronic airway diseases, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS). In this review, we focus on the physiological and pathomechanisms of monoclonal antibodies, and we present recent study results regarding their use as a therapeutic option against severe airway diseases. Airway mucosa acts as a relative barrier, modulating antigenic stimulation and responding to environmental pathogen exposure with a specific, self-limited response. In severe asthma and/or CRS, genome-environmental interactions lead to dysbiosis, aggravated inflammation, and disease. In healthy conditions, single or combined type 1, 2, and 3 immunological response pathways are invoked, generating cytokine, chemokine, innate cellular and T helper (Th) responses to eliminate viruses, helminths, and extracellular bacteria/fungi, correspondingly. Although the pathomechanisms are not fully known, the majority of severe airway diseases are related to type 2 high inflammation. Type 2 cytokines interleukins (IL) 4, 5, and 13, are orchestrated by innate lymphoid cell (ILC) and Th subsets leading to eosinophilia, immunoglobulin E (IgE) responses, and permanently impaired airway damage. Monoclonal antibodies can bind or block key parts of these inflammatory pathways, resulting in less inflammation and improved disease control.

Respiratory dysfunction is one of the most devastating and life-threatening deficits that occurs following cervical spinal cord injury (SCI). Assisted breathing with mechanical ventilators is a necessary part of care for many cervical injured individuals, but it is also associated with increased risk of secondary complications such as infection, muscle atrophy and maladaptive plasticity. Pre-clinical studies with epidural stimulation (EDS) have identified it as an alternative/additional method to support adequate lung ventilation without mechanical assistance. The full potential of EDS, however, may be limited by spinal inhibitory mechanisms within the injured spinal cord. The goal of the present work is to assess the potential improvement for EDS in combination with pharmacological disinhibition of spinal circuits following complete high cervical SCI. All experiments were performed in decerebrate, unanesthetized, non-paralyzed (n = 13) and paralyzed (n = 8) adult Sprague-Dawley rats 6 h following a complete C1 transection. The combination of high-frequency EDS (HF-EDS) at the C4 spinal segment with intrathecal delivery of GABA and glycine receptors antagonists (GABAzine and strychnine, respectively) resulted in significantly increased phrenic motor output, tidal volume and amplitude of diaphragm electrical activity compared to HF-EDS alone. Thus, it appears that spinal fast inhibitory mechanisms limit phrenic motor output and present a new neuropharmacological target to improve paced breathing in individuals with cervical SCI., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Although ample evidence indicates that child health is compromised by early adversity (e.g., abuse and poverty), less is known about the contribution of parenting in low-stress contexts to child health, especially in infancy. This longitudinal study extends previous research on early adversity to ask the question: Does quality of parental care predict infant health in a low-risk community sample?, Method: Participants were 187 healthy mothers and their full-term infants (86 girls) from the Netherlands, followed from birth to age 1. Home observations of mothers' behavior were conducted during a naturalistic task (bathing session) when infants were 5 weeks old. Trained researchers interviewed mothers about the infants' health and prescribed antibiotic use every month for 12 months. Infant health problems were categorized into 4 domains according to the International Classification of Primary Care to capture a range of outcomes: respiratory, digestive, skin, and general illnesses and symptoms., Results: Controlling for health-related covariates (e.g., maternal smoking and breastfeeding), maternal sensitivity predicted reduced rates of infant respiratory symptoms and skin conditions and marginally lower prescribed antibiotic use over the first year. Maternal behavior was unrelated to infant digestive and general illnesses., Conclusion: Even in the absence of adversity, quality of maternal care may have implications for the development of physical health, beginning as early as the first year of life. That such findings emerge in a low-risk sample helps rule out potential confounders and underscores the importance of parenting for physical and psychological health outcomes.

Oseltamivir, a pro-drug, is the best option for treatment and chemoprophylaxis for influenza outbreaks. However, many patients treated with oseltamivir developed adverse reactions, including hypersensitivity, gastritis, and neurological symptoms. The aim of this study was to determine the adverse drug reactions (ADRs) in Mexican patients treated with oseltamivir and whether these ADRs are associated with SNPs of the genes involved in the metabolism, transport, and interactions of oseltamivir. This study recruited 310 Mexican patients with acute respiratory diseases and treated them with oseltamivir (75 mg/day for 5 days) because they were suspected to have influenza A/H1N1 virus infection. Clinical data were obtained from medical records and interviews. Genotyping was performed using real-time polymerase chain reaction and TaqMan probes. The association was assessed under genetic models with contingency tables and logistic regression analysis. Out of 310 patients, only 38 (12.25%) presented ADRs to oseltamivir: hypersensitivity (1.9%), gastritis (10%), and depression and anxiety (0.9%). The polymorphism ABCB1-rs1045642 was associated with adverse drug reactions under the recessive model (P = 0.017); allele C was associated with no adverse drug reactions, while allele T was associated with adverse drug reactions. The polymorphisms SLC15A1-rs2297322, ABCB1-rs2032582, and CES1-rs2307243 were not consistent with Hardy-Weinberg equilibrium, and no other associations were found for the remaining polymorphisms. In conclusion, the polymorphism rs1045642 in the transporter encoded by the ABCB1 gene is a potential predictive biomarker of ADRs in oseltamivir treatment.

Objectives: Chronic respiratory diseases (CRD) put patients at increased risk of respiratory infection and antimicrobial use, but surveillance results on community antimicrobial use are generally not adjusted for this risk factor. The objective of this study was to demonstrate the importance of accounting for CRD when interpreting indicators of community antimicrobial use in people over 65 years old, in Québec, Canada., Methods: Retrospective cohort study of antimicrobial use according to CRD status in individuals over 65 years old covered by Québec's public drug insurance plan between 2010 and 2015. Defined daily doses per 1000 person-days (DID) were computed per antimicrobial class and were further stratified according to chronic disease group, fiscal year, gender and age group., Results: Antimicrobial use was 2.3 times higher in the CRD group (29.7 DID) compared with the other chronic disease group (13.1 DID) and 3.1 times higher than in the no chronic disease group (9.6 DID). The same gradient was reflected as well in use per antimicrobial class, per age group, per gender, and in time. Antimicrobial use increased throughout the study period and was higher in older age groups and in women., Conclusions: Interpretation of results of antimicrobial use surveillance should consider the prevalence of CRD in populations. In order to identify opportunities for adapted interventions targeting inappropriate use, finer analyses are necessary.

Background . Intermittent hypoxia can induce respiratory neuroplasticity to enhance respiratory motor outputs following hypoxic treatment. This type of respiratory neuroplasticity is primarily mediated by the activation of Gq-protein-coupled 5-HT2 receptors and constrained by Gs-protein-coupled 5-HT7 receptors. Objective . The present study hypothesized that the blockade of 5-HT7 receptors can potentiate the effect of intermittent hypercapnic-hypoxia on respiratory function after cervical spinal cord contusion injury. Methods . The ventilatory behaviors of unanesthetized rats with midcervical spinal cord contusions were measured before, during, and after daily acute intermittent hypercapnic-hypoxia (10 episodes of 5 minutes of hypoxia [10% O 2 , 4% CO 2 , 86% N 2 ] with 5 minutes of normoxia intervals for 5 days) at 8 weeks postinjury. On a daily basis, 5 minutes before intermittent hypercapnic-hypoxia, rats received either a 5-HT7 receptor antagonist (SB269970, 4 mg/kg, intraperitoneal) or a vehicle (dimethyl sulfoxide). Results . Treatment with intermittent hypercapnic-hypoxia induced a similar increase in tidal volume between rats that received SB269970 and those that received dimethyl sulfoxide within 60 minutes post-hypoxia on the first day. However, after 2 to 3 days of daily acute intermittent hypercapnic-hypoxia, the baseline tidal volumes of rats treated with SB269970 increased significantly. Conclusions . These results suggest that inhibiting the 5-HT7 receptor can transiently improve daily intermittent hypercapnic-hypoxia-induced tidal volume increase in midcervical spinal contused animals. Therefore, combining pharmacological treatment with rehabilitative intermittent hypercapnic-hypoxia training may be an effective strategy for synergistically enhancing respiratory neuroplasticity to improve respiratory function following chronic cervical spinal cord injury.

A constant improvement in understanding of mitochondrial biology has provided new insights into mitochondrial dysfunction in human disease pathogenesis. Impaired mitochondrial dynamics caused by various stressors are characterized by structural abnormalities and leakage, compromised turnover, and reactive oxygen species overproduction in mitochondria as well as increased mitochondrial DNA mutation frequency, which leads to modified energy production and mitochondria-derived cell signaling. The mitochondrial dysfunction in airway epithelial, smooth muscle, and endothelial cells has been implicated in diseases including chronic obstructive lung diseases and acute lung injury. Increasing evidence indicates that the NRF2-antioxidant response element (ARE) pathway not only enhances redox defense but also facilitates mitochondrial homeostasis and bioenergetics. Identification of functional or potential AREs further supports the role for Nrf2 in mitochondrial dysfunction-associated airway disorders. While clinical reports indicate mixed efficacy, NRF2 agonists acting on respiratory mitochondrial dynamics are potentially beneficial. In lung cancer, growth advantage provided by sustained NRF2 activation is suggested to be through increased cellular antioxidant defense as well as mitochondria reinforcement and metabolic reprogramming to the preferred pathways to meet the increased energy demands of uncontrolled cell proliferation. Further studies are warranted to better understand NRF2 regulation of mitochondrial functions as therapeutic targets in airway disorders.

Background: Atopic dermatitis (AD, atopic eczema) is a pruritic, inflammatory, chronic skin disease. Since there is limitation of conventional treatment of AD, traditional herbal medicine can be an attractive therapeutic option in patients having AD for a long time. So-Cheong-Ryong-Tang (SCRT) has been found to inhibit histamine release and degranulation of mast cells, differentiation of basophils, and proliferation of eosinophils. We designed this clinical trial to evaluate the efficacy and safety of SCRT as compared to placebo in patients with AD and respiratory disorders., Methods/design: This study is a single-center, randomized, double-blind, placebo-controlled, and investigator-initiated clinical trial. A total of 60 patients between 7 and 65 years of age with AD and respiratory disorders who received a diagnosis of AD by Hanifin and Rajka criteria who scored 15 to 50 in a scoring atopic dermatitis (SCORAD) will be enrolled. Participants will be randomly assigned to the SCRT or placebo group in a ratio of 1:1 and they will have a visit schedule comprising 4 visits including a screening visit during 8 to 10 weeks. The participants will be administered SCRT or placebo 3 times a day for 4 weeks. The primary outcome will be measured by a change of the SCORAD index. The secondary outcomes will be measured by changes in the dose and frequency of usage of the AD ointment, dermatology life quality index scores, pruritus and sleep disorder in visual analog scale, skin moisture content, skin surface temperature, Hamilton anxiety rating scale scores, depression rating scale scores, stress/autonomic nervous function test, and attention deficit hyperactivity disorder survey scores at week 4 as compared to those at the baseline., Discussion: To the best of our knowledge, SCRT has rarely been reported for dermatologic diseases. This will be the first clinical trial to assess the efficacy and safety of SCRT in patients with AD and respiratory disorders. We hope that the results of this trial will provide evidence for the use of SCRT as a new treatment for AD with respiratory disorders., Trial Registration: Korean National Clinical Trial Registry, Clinical Research Information Service. (KCT0004148) (https://cris.nih.go.kr/cris/search/search&#95;result&#95;st01&#95;en.jsp?seq=14981&ltype=&rtype=).

Decline in respiratory function in patients with DMD starts during early teenage years and leads to early morbidity and mortality. Published evidence of efficacy for idebenone on respiratory function outcomes is currently limited to 12 months of follow-up time. Here we report data collected as retrospective cohort study (SYROS) from 18 DMD patients not using glucocorticoids who were treated with idebenone (900 mg/day) under Expanded Access Programs (EAPs). The objective was to assess the long-term respiratory function evolution for periods On-Idebenone compared to periods Off-Idebenone in the same patients. The mean idebenone exposure in the EAPs was 4.2 (range 2.4-6.1) years. The primary endpoint was the annual change in forced vital capacity percent of predicted (FVC%p) compared between Off-Idebenone and On-Idebenone periods. The annual rate of decline in FVC%p was reduced by approximately 50% from -7.4% (95% CI: -9.1, -5.8) for the Off-Idebenone periods to -3.8% (95% CI: -4.8, -2.8) for the On-Idebenone periods (N = 11). Similarly, annual change in peak expiratory flow percent of predicted (PEF%p) was -5.9% (95% CI: -8.0, -3.9) for the Off-Idebenone periods (N = 9) and reduced to -1.9% (95% CI: -3.2, -0.7) for the On-Idebenone periods during the EAPs. The reduced rates of decline in FVC%p and PEF%p were maintained for several years with possible beneficial effects on the rate of bronchopulmonary adverse events, time to 10% decline in FVC%p and risk of hospitalization due to respiratory cause. These long-term data provide Class IV evidence to further support the disease modifying treatment effect of idebenone previously observed in randomized, controlled trials., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Flavonoids are an important class of phytopharmaceuticals in plants. Naringin (naringenin- 7-O-rhamnoglucoside) is a flavanone glycoside isolated from folk herbal medicine Exocarpium Citri grandis (called Huajuhong in Chinese). Massive experimental works have been performed on naringin describing its phytochemical, pharmacokinetic, and bioactive properties. Naringin was found to possess multiple pharmacological activities in relieving inflammation, diabetes, neurodegeneration, cardiovascular disorders, and metabolic syndrome. Recently, it has been approved as a potential antitussive and expectorant for clinical trials. However, the pharmacokinetic aspects of naringin and its therapeutic potentials in respiratory diseases have not been comprehensively reviewed. The present review provides highlights of naringin with respect to its absorption, distribution, metabolism, excretion and its therapeutic effects on cough, phlegm, and pulmonary inflammation. This review would be helpful for the interpretation of pharmacokinetics and pharmacodynamics of naringin in clinical trials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Mechanically ventilated patients with respiratory disorders may require sedatives, such as opioids., Objectives: To define methodological trends, gaps, and the reporting quality of the comparative clinical and economic evaluations of fentanyl and morphine in ventilated patients in the intensive care unit., Methods: We conducted a literature review of the MEDLINE, Embase, OVID, ScienceDirect, Springer Link, and EconLit databases, comparing studies in the management of ventilated patients with respiratory disorders in the intensive care unit using either fentanyl or morphine, or both. We assessed the methodological aspects of the literature characteristics and trends of, for example, modeling, data sources, cost calculation, and data analysis, appraising the quality of reporting via the CONsolidated Standards Of Reporting Trials, STrengthening the Reporting of OBservational studies in Epidemiology, and the Consolidated Health Economic Evaluation Reporting Standards checklists., Results: Among 1327 articles, 33 (comprising 22 in adults, 8 in neonates, and 3 in pediatrics) met the inclusion criteria. No head-to-head morphine versus fentanyl evaluations explicitly confined to subjects with respiratory conditions were undertaken. Studies relied on various scales to measure the sedation level as a primary study outcome, limiting the comparability of study conclusions. Seven articles of adults were identified to be economic studies from the hospital perspective. On the basis of different endpoints, the same sedation regimen performed differently in various studies. None of the randomized controlled trials, observational cohorts, or pharmacoeconomics studies met most of the assessed reporting quality criteria., Conclusions: Our review identified poor reporting quality and high heterogeneity of methods used, potentially limiting the degree to which studies could be interpreted, decisions could be influenced, and findings could be generalized., (Copyright © 2018 ISPOR–The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

Pneumonia is one of the most economically important respiratory diseases of calves and knowledge of the impact of clinical disease on pharmacokinetics (PK) in young calves is limited. This study was undertaken to investigate the efficacy and PK of two antibiotics, tulathromycin and danofloxacin, in two age groups of calves experimentally infected with Pasteurella multocida. Both danofloxacin, a fluoroquinolone antibiotic, and tulathromycin, a macrolide antibiotic is approved for the treatment of bovine respiratory disease (BRD). To evaluate potential influences of age and disease on drug distribution and elimination in calves, plasma, interstitial fluid (ISF), and pulmonary epithelial lining fluid (PELF) were analyzed for drug concentrations. Concentrations for both drugs in the PELF were estimated by a urea dilution assay of the collected bronchoalveolar lavage fluids. Age was determined to be a significant covariate for calves administered danofloxacin and tulathromycin for plasma PK parameters. For calves administered danofloxacin, the area under the curve (AUC) in the plasma was lower in 6-month old calves (18.9 ± 12.6 hr* μg/mL) vs. 3-week old calves (32.0 ± 8.2 hr* μg/mL). Clearance (CL/F) of danofloxacin was higher in 6-month old calves. In contrast, tulathromycin plasma concentrations were higher in 6 month old calves and CL/F was higher in 3-week old calves. Age did not significantly influence the ISF concentrations of danofloxacin or tulathromycin in calves with respiratory disease, unlike previous studies which reported higher ISF concentrations of danofloxacin and tulathromycin in 6-month old calves when compared to younger calves. PELF concentrations were higher than plasma and ISF for both danofloxacin and tulathromycin, but did not differ between age groups. Potential reasons for age-related differences on plasma concentration-time profiles and the impact of disease on the partitioning of the drug from the blood to the lungs and ISF as a function of age are explored., Competing Interests: The authors have declared that no competing interests exist.

Background: Originally, studies on exhaled droplets explored properties of airborne transmission of infectious diseases. More recently, the interest focuses on properties of exhaled droplets as biomarkers, enabled by the development of technical equipment and methods for chemical analysis. Because exhaled droplets contain nonvolatile substances, particles is the physical designation. This review aims to outline the development in the area of exhaled particles, particularly regarding biomarkers and the connection with small airways, i e airways with an internal diameter < 2 mm., Main Body: Generation mechanisms, sites of origin, number concentrations of exhaled particles and the content of nonvolatile substances are studied. Exhaled particles range in diameter from 0.01 and 1000 μm depending on generation mechanism and site of origin. Airway reopening is one scientifically substantiated particle generation mechanism. During deep expirations, small airways close and the reopening process produces minute particles. When exhaled, these particles have a diameter of < 4 μm. A size discriminating sampling of particles < 4 μm and determination of the size distribution, allows exhaled particle mass to be estimated. The median mass is represented by particles in the size range of 0.7 to 1.0 μm. Half an hour of repeated deep expirations result in samples in the order of nanogram to microgram. The source of these samples is the respiratory tract ling fluid of small airways and consists of lipids and proteins, similarly to surfactant. Early clinical studies of e g chronic obstructive pulmonary disease and asthma, reported altered particle formation and particle composition., Conclusion: The physical properties and content of exhaled particles generated by the airway reopening mechanism offers an exciting noninvasive way to obtain samples from the respiratory tract lining fluid of small airways. The biomarker potential is only at the beginning to be explored.

Objectives: The aim of our study is to evaluate whether the use of heliox (79:21) delivered through a low flow nasal cannula would improve respiratory distress in infants with acute bronchiolitis caused by respiratory syncytial virus., Methods: We have conducted a prospective randomized controlled study. All patients fulfilled inclusion criteria were randomized to either heliox (79:21) or air via NC at 2 L/min for a continuous 24hours. Measurements were taken at baseline, after 2hours and at the end of the 24hours., Results: We have included 104 patients into our study. The MCA-S did not show any significant difference between the two groups after 2hours 4.3 vs. 4.1 (P =.78), or at 24hours after 4.2 vs. 4.3 (P =.89). No difference was found in the proportion of participants progressed to MV, n-CPAP or oxygen via nasal cannula (RR 1.0, 0.86 and 0.89) (P= 1.0, .77 and .73). There was no notable reduction in length of treatment in Heliox group 2.42 days vs. 2.79 days in air group P =.65. The in oxygen saturation, PaO 2 , and PaCO 2 did not to have any statistical difference between the two studied groups after 2hours and 24hours of treatment., Conclusion: Our data showed absence of any beneficial effect of heliox in a concentration (79:21) delivered through low flow nasal cannula in terms of respiratory distress improvement in infants with RSV acute bronchiolitis., (Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Mounting evidence indicates that out-of-pocket costs for prescription medications, particularly among low- and middle-income patients with chronic diseases, are imposing financial burden, reducing medication adherence, and worsening health outcomes. This problem is exacerbated by a paucity of generic alternatives for prevalent lung diseases, such as asthma and chronic obstructive pulmonary disease, as well as high-cost medicines for rare diseases, such as cystic fibrosis. Affordability and access challenges are especially salient in the United States, as citizens of many other countries pay lower prices for and have greater access to prescription medications., Methods: The American Thoracic Society convened a multidisciplinary committee comprising experts in health policy pharmacoeconomics, behavioral sciences, and clinical care, along with individuals providing industry and patient perspectives. The report and its recommendation were iteratively developed over a year of in-person, telephonic, and electronic deliberation., Results: The committee unanimously recommended the establishment of a publicly funded, politically independent, impartial entity to systematically draft evidence-based pharmaceutical policy recommendations. The goal of this entity would be to generate evidence and action steps to ensure people have equitable and affordable access to prescription medications, to maximize the value of public and private pharmaceutical expenditures on health, to support novel drug development within a market-based economy, and to preserve clinician and patient choice regarding personalized treatment. An immediate priority is to examine the evidence and make recommendations regarding the need to have essential medicines with established clinical benefit from each drug class in all Tier 1 formularies and propose recommendations to reduce barriers to timely generic drug availability., Conclusions: By making explicit, evidence-based recommendations, the entity can support the establishment of coherent national policies that expand access to affordable medications, improve the health of patients with chronic disease, and optimize the use of public and private resources.

Hypoxia elicits complex cell signaling mechanisms in the respiratory control system that can produce long-lasting changes in respiratory motor output. In this article, we review experimental approaches used to elucidate signaling pathways associated with hypoxia, and summarize current hypotheses regarding the intracellular signaling pathways evoked by intermittent exposure to hypoxia. We review data showing that pharmacological treatments can enhance neuroplastic responses to hypoxia. Original data are included to show that pharmacological modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function can reveal a respiratory neuroplastic response to a single, brief hypoxic exposure in anesthetized mice. Coupling pharmacologic treatments with therapeutic hypoxia paradigms may have rehabilitative value following neurologic injury or during neuromuscular disease. Depending on prevailing conditions, pharmacologic treatments can enable hypoxia-induced expression of neuroplasticity and increased respiratory motor output, or potentially could synergistically interact with hypoxia to more robustly increase motor output., (Copyright © 2017. Published by Elsevier B.V.)

IntroductionPallid breath-holding spells are common and dramatic forms of recurrent syncope in infancy. They are very stressful despite their harmless nature and sometimes require treatment., Objective: The objective of this study was to evaluate the efficacy of belladonna in severe breath-holding spells., Methods: This is a multicentric, retrospective series involving 84 children with severe pallid breath-holding spells. Inclusion criteria were >1 pallid breath-holding spell with loss of consciousness, paediatric cardiology evaluation, and follow-up >6 months. In total, 45 patients received belladonna and 39 patients did not receive treatment, according to physician preference., Results: Mean age was 11 months, ranging from 4 to 18 months, with 54% of males. Mean spell duration was 30 seconds (interquartile range 15, 60), and the frequency was four episodes per month (interquartile range 0.5, 6.5). Comparison of baseline characteristics between groups showed similar demographics, with the single difference in the severity of the spells, being more severe in the treated group. When comparing the treated and non-treated groups at 3 months, only two (5%) patients had a complete remission in the first group, whereas 20 (44%) had remission in the belladonna group (p<0.01). When considering the characteristics of the spells before and after the initiation of treatment with belladonna, 75% of the patients presented a positive response, with 44% of the patients presenting with complete resolution of the spells (p<0.01). No major adverse reaction was reported, with only 5% minor adverse events., Conclusions: Belladonna is highly effective to alleviate severe breath-holding spells in young children, without any major adverse effects.

We studied the dynamics of respiratory function in rats during intratracheal poisoning with diisopropyl fluorophosphate and pentylenetetrazole in doses corresponding to the LD50 in humans. The maximum of external respiration impairment was recorded in 30 min after poisoning. Administration of diazepam and atropine both separately and in combination during the development of the first signs of poisoning did not significantly affect the respiration parameters, but reduced the incidence of seizures and contributed to a decrease in the rate of animal death. Intratracheal administration of cholinolytic, β 2 -adrenomimetic, or glutamate receptors antagonist promoted correction of the respiratory function. It was found that the maximum therapeutic effect in case of diisopropyl fluorophosphates poisoning was achieved after intratracheal administration of ipratropium bromide (0.086 mg/kg), salbutamol (0.086 mg/kg), and MK-801 (0.1 mg/kg), while in case of pentylenetetrazole poisoning, intratracheal administration of ipratropium bromide (0.086 mg/kg) was most effective.

More than 1 billion people suffer from chronic respiratory diseases worldwide, accounting for more than 4 million deaths annually. Inhaled corticosteroid is a popular medication for treating chronic respiratory diseases. Its side effects include decreased bone mineral density and osteoporosis. The aims of this study are to investigate the association of inhaled corticosteroids and fracture and to design a clinical support system for fracture prediction. The data of patients aged 20 years and older, who had visited healthcare centers and been prescribed with inhaled corticosteroids within 2002-2010, were retrieved from the National Health Insurance Research Database (NHIRD). After excluding patients diagnosed with hip fracture or vertebrate fractures before using inhaled corticosteroid, a total of 11645 patients receiving inhaled corticosteroid therapy were included for this study. Among them, 1134 (9.7%) were diagnosed with hip fracture or vertebrate fracture. The statistical results showed that demographic information, chronic respiratory diseases and comorbidities, and corticosteroid-related variables (cumulative dose, mean exposed daily dose, follow-up duration, and exposed duration) were significantly different between fracture and nonfracture patients. The clinical decision support systems (CDSSs) were designed with integrated genetic algorithm (GA) and support vector machine (SVM) by training and validating the models with balanced training sets obtained by random and cluster-based undersampling methods and testing with the imbalanced NHIRD dataset. Two different objective functions were adopted for obtaining optimal models with best predictive performance. The predictive performance of the CDSSs exhibits a sensitivity of 69.84-77.00% and an AUC of 0.7495-0.7590. It was concluded that long-term use of inhaled corticosteroids may induce osteoporosis and exhibit higher incidence of hip or vertebrate fractures. The accumulated dose of ICS and OCS therapies should be continuously monitored, especially for patients with older age and women after menopause, to prevent from exceeding the maximum dosage.

Background: Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms., Methods: In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 μg, two puffs twice per day, equivalent to 800 μg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279., Findings: Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95% CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%])., Interpretation: FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease., Funding: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We investigated the association between the use of inhaled bronchodilators and the risk of AMI. A nested case-control study using the nationwide insurance claims database was conducted. Overall, 11,054 AMI cases and 47,815 matched (up to 1:5) controls were identified from 1,036,119 subjects without acute major cardiovascular events in the past year. Long-acting and short-acting β-agonists (LABAs and SABAs) were associated with increase in the risk of AMI, although an inhaled corticosteroid combined with a long-acting β-agonist was not. Long-acting muscarinic antagonists (LAMAs) in a dry powder inhaler (DPI) were significantly associated with reduced risk of AMI, while LAMAs in a soft mist inhaler (SMI) didn't decrease the risk of it. In hypertensive or diabetic patients, LAMAs in a DPI were associated with reduced risk of AMI, but LABAs were associated with increased risk. Among the β-blocker users, the reduction of AMI risk by LAMAs was the most significant. In conclusions, inhaled β-agonists were associated with increase in the risk of AMI, while LABAs accompanied by ICSs were not associated with increase in the risk of AMI. LAMAs in a DPI use were associated with lower risk of AMI.

Respiratory system diseases are common and major ailments that seriously endanger human health. Resveratrol, a polyphenolic phytoalexin, is considered an anti-inflammatory, antioxidant, and anticancer agent. Thanks to its wide range of biological activities, resveratrol has become a hotspot in many fields, including respiratory system diseases. Indeed, research has demonstrated that resveratrol is helpful to relieve pulmonary function in the general population. Meanwhile, growing evidence indicates that resveratrol plays a protective role in respiratory system diseases. This review aimed to summarize the main protective effects of resveratrol in respiratory system diseases, including its anti-inflammatory, antiapoptotic, antioxidant, antifibrotic, antihypertensive, and anticancer activities. We found that resveratrol plays a protective role in the respiratory system through a variety of mechanisms, and so it may become a new drug for the treatment of respiratory system diseases., Competing Interests: Disclosure The authors report no conflict of interest in this work.

Pulmonary diseases are one of the most important causes of morbidity and mortality. Although vitamin D is best known for its role in calcium, phosphorus, and bone homeostasis, it has gained attention in the recent years because of a wide range of extraskeletal effects, including its immunomodulatory and antibacterial potential. Vitamin D deficiency is highly prevalent in chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, tuberculosis, and asthma, and several clinical studies have been conducted investigating the effect of vitamin D supplementation on disease outcomes. In this review, we searched for positive evidence on vitamin D supplementation from randomized controlled trials and elaborated on the optimal serum vitamin D levels and dosing regimens for an effective intervention. While vitamin D supplementation seems to be beneficial as an add‑on treatment for adult patients with asthma and a potent intervention to reduce exacerbations in patients with COPD, there is little evidence for its therapeutic use in cystic fibrosis, pneumonia, and tuberculosis.

The current work was conducted to verify the contribution of neuromuscular transmission defects at the neuromuscular junction to Duchenne Muscular Dystrophy disease progression and respiratory dysfunction. We tested pyridostigmine and pyridostigmine encapsulated in liposomes (liposomal PYR), an acetylcholinesterase inhibitor to improve muscular contraction on respiratory muscle function in mdx mice at different ages. We evaluated in vivo with the whole-body plethysmography, the ventilatory response to hypercapnia, and measured in vitro diaphragm strength in each group. Compared to C57BL10 mice, only 17 and 22 month-old mdx presented blunted ventilatory response, under normocapnia and hypercapnia. Free pyridostigmine (1mg/kg) was toxic to mdx mice, unlike liposomal PYR, which did not show any side effect, confirming that the encapsulation in liposomes is effective in reducing the toxic effects of this drug. Treatment with liposomal PYR, either acute or chronic, did not show any beneficial effect on respiratory function of this DMD experimental model. The encapsulation in liposomes is effective to abolish toxic effects of drugs., (Copyright © 2017. Published by Elsevier B.V.)

Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is a protein with anti-inflammatory properties and the archetypal member of the dual-specificity phosphatases (DUSPs) family that have emerged over the past decade as playing an instrumental role in the regulation of airway inflammation. Not only does MKP-1 serve a critical role as a negative feedback effector, controlling the extent and duration of pro-inflammatory MAPK signalling in airway cells, upregulation of this endogenous phosphatase has also emerged as being one of the key cellular mechanism responsible for the beneficial actions of clinically-used respiratory medicines, including β 2 -agonists, phosphodiesterase inhibitors and corticosteroids. Herein, we review the role and regulation of MKP-1 in the context of airway inflammation. We initially outline the structure and biochemistry of MKP-1 and summarise the multi-layered molecular mechanisms responsible for MKP-1 production more generally. We then focus in on some of the key in vitro studies in cell types relevant to airway disease that explain how MKP-1 can be regulated in airway inflammation at the transcriptional, post-translation and post-translational level. And finally, we address some of the potential challenges with MKP-1 upregulation that need to be explored further to fully exploit the potential of MKP-1 to repress airway inflammation in chronic respiratory disease.

Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication, and no effective preventive strategies are currently available for this fatal disorder. Clinical and animal studies of SUDEP demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures in many cases. Enhancing brain levels of serotonin reduces S-IRA in animal models relevant to SUDEP, including the DBA/1 mouse. Given that serotonin in the brain plays an important role in modulating respiration and arousal, these findings suggest that deficits in respiration and/or arousal may contribute to S-IRA. It is well known that norepinephrine is an important neurotransmitter that modulates respiration and arousal in the brain as well. Therefore, we hypothesized that enhancing noradrenergic neurotransmission suppresses S-IRA. To test this hypothesis, we examined the effect of atomoxetine, a norepinephrine reuptake inhibitor (NRI), on S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice. We report the original observation that atomoxetine specifically suppresses S-IRA without altering the susceptibility to seizures evoked by acoustic stimulation, and atomoxetine also reduces S-IRA evoked by pentylenetetrazole in DBA/1 mice. Our data suggest that the noradrenergic signaling is importantly involved in S-IRA, and that atomoxetine, a medication widely used to treat attention deficit hyperactivity disorder (ADHD), is potentially useful to prevent SUDEP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aspirin hypersensitivity associated with chronic rhinosinusitis-with or without nasal polyposis-and asthma resistant to conventional therapy defines the aspirin-exacerbated respiratory disease (AERD). We describe the case of a 15-year-old female patient with adverse reaction to aspirin, chronic rhinosinusitis, and severe asthma. She also experienced chronic idiopathic urticaria worsened by non-steroidal anti-inflammatory drug administration. AERD was diagnosed based on clinical history and symptoms. Given the poor responsiveness to standard therapy for respiratory and cutaneous symptoms, omalizumab was administered for 24 weeks with control of respiratory symptoms and short term improvement of cutaneous symptoms. Pediatr Pulmonol. 2017;52:E26-E28. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Clinical trials play a key role in advancing medical knowledge, improving patient care and promoting economic growth in Europe. We have assessed the clinical trial activity in any respiratory diseases in Europe, with a specific focus on Italy., Methods: Information from public sources (EFPIA, clinicaltrials.gov, clinicaltrialsregister. eu, AIFA) was used to describe clinical trial activity of in respiratory diseases in Europe and by country., Results: In 2015, 3908 clinical trials were reported in Europe, 386 in respiratory diseases (9.9%). Germany was the first country both as absolute number (76 trials) and as percentage within country trials (14%), followed by Poland. Spain, Italy and France were the countries with the lowest number and percentage of trials in respiratory diseases. In 2013, the Italian Drug Agency reported 9 trials with respiratory compounds in Italy (2.1% of overall trials, 12ˆ position in the therapeutic area rank), 33% in phase 2 and 66% in phase 3. No phase 1 or phase 4 trials were reported for respiratory trials. Prevalence of respiratory trials by non-profit sponsors (28.3%) was below the average for the country (38.3%)., Conclusions: Europe has a greater potential for clinical research on drugs for respiratory diseases, particularly in countries with less activity, such as Spain, France and Italy, that should identify and implement actions to increase attractiveness for clinical trials of drugs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Individuals with bipolar disorder (BD) have high rates of nonadherence, medical illness, and premature mortality. This analysis reexamined correlates of poor adherence to nonpsychiatric medication in 73 patients with BD and medical comorbidities. The majority was female (74%) and African American (77%) with mean age of 48.08 (SD, 8.04) years, mean BD duration of 28.67 (SD, 10.24) years, mean years of education of 12.01 (SD, 1.87), and mean proportion of days with missed doses in past week of 43.25 (SD, 31.14). Sex, age, education, race, and living alone did not correlate with adherence. More BD medications and more severe psychiatric symptoms correlated with worse adherence. Specifically, poor adherence correlated with the retardation and vegetative factors of Montgomery-Åsberg Depression Rating Scale and affect factor of the Brief Psychiatric Rating Scale. Among poorly adherent patients with BD and medical comorbidities, the number of BD medications, tension/anxiety, and somatic symptoms of depression related to worse nonpsychiatric medication adherence.

Aim: The purpose of this study was to determine the incidence of reintubation due to upper airway obstruction in a homogeneous group of ventilated infants with Respiratory Syncytial Virus bronchiolitis. Our secondary objective was to determine whether prophylactic administration of dexamethasone prior to extubation was associated with decreased risk of reintubation., Methods: This retrospective observational study in two Pediatric Intensive Care Units in 2 university hospitals in The Netherlands included two hundred patients younger than 13 months admitted with respiratory insufficiency caused by Respiratory Syncytial Virus bronchiolitis, requiring invasive mechanical ventilation. A logistic regression analysis with propensity score method was used to adjust for possible confounding., Results: Reintubation due to post-extubation stridor occurred in 17 (8.5%) of 200 patients. After propensity score matching, administration of dexamethasone prior to extubation was associated with a significantly (p = 0.0011) decreased risk of reintubation due to post-extubation stridor compared to patients not receiving prophylactic dexamethasone (absolute risk reduction 13%, 95% CI 5.3-21%)., Conclusion: Reintubation due to post-extubation stridor is an important complication of ventilation for Respiratory Syncytial Virus bronchiolitis. Dexamethasone administered prior to extubation probably reduces the risk of post-extubation stridor necessitating reintubation in these infants. The results of this study support initiation of a placebo-controlled trial to confirm the beneficial effect of prophylactic dexamethasone.

Background: The continuous bilateral infusion of a local anaesthetic solution around the sternotomy wound (bilateral sternal) is an innovative technique for reducing pain after sternotomy., Objective: To assess the effects of the technique on the need for intensive care in cardiac patients at increased risk of respiratory complications., Design: Randomised, observer-blind controlled trial., Setting: Single centre, French University Hospital., Patients: In total, 120 adults scheduled for open-heart surgery, with one of the following conditions: age more than 75 years, BMI >30 kg m, chronic obstructive pulmonary disease, active smoking habit., Intervention: Either a bilateral sternal infusion of 0.2% ropivacaine (3 ml h through each catheter; 'intervention' group), or standardised care only ('control' group). Analgesia was provided with paracetamol and self-administered intravenous morphine., Main Outcome Measures: The length of time to readiness for discharge from ICU, blindly assessed by a committee of experts., Results: No effect was found between groups for the primary outcome (P = 0.680, intention to treat); the median values were 42.4 and 37.7 h, respectively for the control and intervention groups (P = 0.873). Similar nonsignificant trends were noted for other postoperative delays. Significant effects favouring the intervention were noted for dynamic pain, patient satisfaction, occurrence of nausea and vomiting, occurrence of delirium or mental confusion and occurrence of pulmonary complications. In 12 patients, although no symptoms actually occurred, the total ropivacaine plasma level exceeded the lowest value for which neurological symptoms have been observed in healthy volunteers., Conclusion: Because of a small size effect, and despite significant analgesic effects, this strategy failed to reduce the time spent in ICU., Trial Registration: EudraCT (N°: 2012-005225-69); ClinicalTrials.gov (NCT01828788).

Rhodiola as one of traditional medicines has been used for clinical treatments due to its strong antioxidant properties. Phytochemical analysis revealed the presence of flavonoids, phenylpropanoids, phenylethanol/benzyl alcohol derivatives, cyanogenic glycosides and terpenoids. The bioactive compounds had been demonstrated to be effective at scavenging reactive oxygen species (ROS). The structures contain phenolic hydroxyl groups and unsaturated bonds. This article reviews antioxidant capacities of the extracts and bioactive components derived from Rhodiola plants. As the major pharmacological ingredient, salidroside is rigorously investigated and used in scientific researches and clinical practices. Accumulated evidences indicated that extracts of Rhodiola plants or salidroside could be able to reverse DNA damage and alter expression of cytokines and antioxidative enzymes induced by ROS. The underlying mechanisms for the antioxidative effects of the herb have been investigated in the last two decades. We summarize the possible effects and acting pathways for the herb involved in several chronic diseases in cardiovascular, respiratory, and nervous systems, as well as potential epigenetic influences. The information generated from experimental and clinical studies offered valuable insights for further investigations of medical potentials of Rhodiola plants., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis, are among the most common chronic diseases and their prevalence is increasing. Each of these diseases is characterized by the secretion of cytokines and pro-inflammatory molecules which are thought to play a critical role in their pathogenesis. Moreover, immune cells, particularly neutrophils, macrophages and dendritic cells as well structural cells such as epithelial and airway smooth muscle cells are also involved in the pathogenic cycle of these diseases. There is a pressing need for the development of new therapies for these pulmonary diseases, particularly as no existing treatment has been shown to reduce disease progression. HMGB1 (high-mobility group box 1), originally identified as a nuclear non histone protein with DNA-binding domains can be secreted by living and dying cells and it is now regarded as an important endogenous danger signaling molecule. Besides as a signal of tissue injury, HMGB1 is considered a powerful mediator of inflammation and high levels of HMGB1 are found in chronic lung diseases. The role of HMGB1 in respiratory diseases is still elusive nevertheless these studies suggest an involvement of this cytokine in their pathogenesis. Nucleic acid-based drugs (NABDs) are a novel class of pharmaceuticals including antisense oligonucleotides, DNA-zymes, and RNA interference as mediated by small interfering RNA (siRNA), which are used to dampen the expression of disease-causing genes having therapeutic potential for controlling chronic airway diseases. Due to their inherent difficulties, such as for example sensitivity to endonucleases, their delivery in vivo should be assured by vectors. Non-viral lipid- and polymer-based nanosystems have acquired much importance in this context. In this review, we will discuss these emerging tools in gene therapy of chronic lung diseases, particularly the use of siRNA in the down-regulation of critical molecules in the pathogenesis of chronic lung diseases, with particular emphasis on HMGB1 as therapeutic target., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Vesicular systems like nanotechnology and liposomes are gaining tremendous attention lately in the field of respiratory diseases. These formulations enhance bioavailability of the drug candidate, which could be achieved through a novel drug delivery mechanism. Moreover, the therapeutic potential achieved through these systems is highly controllable over long durations of time providing better efficacy and patient compliance., Objective: The objective of this paper is to review the recent literature on vesicular drug delivery systems containing curcumin., Methods: We have collated and summarized various recent attempts made to develop different controlled release drug delivery systems containing curcumin which would be of great interest for herbal, formulation and biological scientists. There are several vesicular nanotechnological techniques involving curcumin which have been studied recently, targeting pulmonary diseases., Results: Different vesicular systems containing curcumin are being studied for their therapeutic potential in different respiratory diseases. There has been a renewed interest in formulations containing curcumin recently, primarily owing to the broad spectrum therapeutic potential of this miracle substance. Various types of formulations, containing curcumin, targeting different bodily systems have recently emerged and, nevertheless, the search for newer frontiers with this drug goes on., Conclusion: This mini review, in this direction, tries to highlight the key research interventions employing vesicular systems of drug delivery with curcumin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: The respiratory tract as a non-invasive route of drug administration is gaining increasing attention in the present time on achieving both local and the systemic therapeutic effects. Success in achieving pulmonary delivery, requires overcoming barriers including mucociliary clearance and uptake by macrophages. An effective drug delivery system delivers the therapeutically active moieties at the right time and rate to target sites. A major limitation associated with most of the currently available conventional and controlled release drug delivery devices is that not all the drug candidates are well absorbed uniformly locally or systemically., Methods: We searched and reviewed the literature focusing on chitosan and chitosan derivative based nanocarrier systems used in pulmonary drug delivery. We focused on the applications of chitosan in the development of nanoparticles for this purpose., Results: Chitosan, a natural linear bio-polyaminosaccharide is central in the development of novel drug delivery systems (NDDS) including nanoparticles for use in the treatment of various respiratory diseases. It achieves this through its unique properties of biodegradability, biocompatibility, mucoadhesivity and its ability to enhance macromolecule permeation across membranes. It also achieves sustained and targeted effects, primary requirements for an effective pulmonary drug delivery system. This review highlights the applications and importance of chitosan with special emphasis on nanotechnology, employed in the management of respiratory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), lung cancer and pulmonary fibrosis., Conclusion: This review will be of interest to both the biological and formulation scientists as it provides a summary on the utility of chitosan in pulmonary drug delivery systems. At present, there are no patented chitosan based controlled release products available for pulmonary drug delivery and so this area has enormous potential in the field of respiratory science., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)