Asthma Drugs Research Articles

Organization of biological therapy for patients with severe eosinophilic bronchial asthma in the Krasnoyarsk region

Patients with severe bronchial asthma, which remains uncontrolled despite the optimal basic therapy, carry a significant healthcare burden and require substantial financial investments. Severe asthma is a heterogeneous airway disease with complex pathophysiological mechanisms that can be broadly divided into inflammatory pathways with eosinophilic and non-eosinophilic inflammation.Aim. This study aimed to analyze the literature data on the use of targeted genetic engineering therapy in patients with severe bronchial asthma, as well as to analyze the organization of immunobiological therapy in the Krasnoyarsk Territory. The addition of targeted drugs for severe eosinophilic bronchial asthma based on phenotyping has proven to be effective and is recommended by all current guidelines. Today, several biologics targeting specific endotypes and phenotypes has been approved for the treatment of severe eosinophilic asthma worldwide. These are antibodies binding immunoglobulin E (omalizumab), antagonists of interleukin-5 (mepolizumab, reslizumab) and its receptor (benralizumab), as well as antibodies selectively binding to the IL-4 and IL-13 receptors (dupilumab). Eosinophilic inflammation therapy is a relatively new direction of asthma treatment, and understanding its long-term efficacy and safety is important.Conclusion. It is essential to differentiate patients with severe eosinophilic asthma from the general cohort of asthma patients, timely refer them to specialists who can prescribe this therapy and have experience with it, select the drug correctly, and monitor the patients during the treatment. This article describes organization of biological therapy for patients with severe eosinophilic bronchial asthma in the Krasnoyarsk Territory.

Mapping knowledge structure and research of the biologic treatment of asthma: A bibliometric study.

Bronchial asthma (asthma) is a chronic inflammatory disease of the airways, involving a variety of cells and cellular components, that manifests clinically as recurrent episodes of wheezing, shortness of breath, with or without chest tightness or cough, airway hyperresponsiveness, and variable airflow limitation. The number of people with asthma has reached 358 million worldwide and asthma causes huge economic loss. However, there is a subset of patients who are not sensitive to existing drugs and the existing drugs have many adverse effects. Therefore, it's important to find new drugs for asthma patients. Publications related to biologics in asthma published from 2000 to 2022 were retrieved from Web of Science Core Collection. The search strategies were as follows: topic: TS=(biologic* OR "biologic* product*" OR "biologic* therap*" OR biotherapy* OR "biologic* agent*" OR Benralizumab OR "MEDI-563" OR Fasenra OR "BIW-8405" OR Dupilumab OR SAR231893 OR "SAR-231893" OR Dupixent OR REGN668 OR "REGN-668" OR Mepolizumab OR Bosatria OR "SB-240563" OR SB240563 OR Nucala OR Omalizumab OR Xolair OR Reslizumab OR "SCH-55700" OR SCH55700 OR "CEP-38072" OR CEP38072 OR Cinqair OR "DCP-835" OR DCP835 OR Tezspire OR "tezepelumab-ekko" OR "AMG-157" OR tezspire OR "MEDI-9929" OR "MEDI-19929" OR MEDI9929 OR Itepekimab OR "REGN-3500"OR REGN3500 OR "SAR-440340"OR SAR440340 OR Tralokinumab OR "CAT-354" OR Anrukinzumab OR "IMA-638" OR Lebrikizumab OR "RO-5490255"OR "RG-3637"OR "TNX-650"OR "MILR1444A"OR "MILR-1444A"OR"PRO301444"OR "PRO-301444"OR Pitrakinra OR altrakincept OR "AMG-317"OR"AMG317" OR Etokimab OR Pascolizumab OR "IMA-026"OR Enokizumab OR "MEDI-528"OR "7F3COM-2H2" OR 7F3COM2H2 OR Brodalumab OR "KHK-4827" OR "KHK4827"OR "AMG-827"OR Siliq OR Ligelizumab OR "QGE-031" OR QGE031 OR Quilizumab OR Talizumab OR "TNX-901" OR TNX901 OR Infliximab OR Etanercept OR "PRS-060") AND TS=asthma*. The document type was set to articles and review articles and the language restriction was set to English. Three different analysis tools including one online platform, VOS viewer1.6.18, and CiteSpace V 6.1.R1 software were used to conduct this bibliometric study. This bibliometric study included 1,267 English papers published in 244 journals from 2,012 institutions in 69 countries/regions. Omalizumab, benralizumab, mepolizumab, and tezepelumab in relation to asthma were the research hotspots in the field. This study systematically uncovers a holistic picture of existing literature related to the biologic treatment of asthma over the past 20 years. We consulted scholars in order to understand key information in this field from the perspective of bibliometrics, which we believe may greatly facilitate future research in this field.

Proof of lung muscarinic receptor occupancy by tiotropium: Translational Positron Emission Tomography studies in non-human primates and humans.

Molecular imaging has not been used to support the development of drugs for the treatment of pulmonary disorders. The aim of the present translational study was to advance quantitative pulmonary PET imaging by demonstrating occupancy of the reference asthma drug tiotropium at muscarinic acetylcholine receptors (mAChR). PET imaging was performed using the muscarinic radioligand [11C]VC-002. The key methodological step involved estimating muscarinic receptor binding while disentangling it from the background of non-specific binding. The relationship between tiotropium exposure and receptor occupancy (RO) was assessed in non-human primates (NHPs) after intravenous injection of tiotropium doses at a broad dose interval (0.03-1 µg/kg). The feasibility of measuring RO in the human lung was then confirmed in seven healthy human subjects after inhalation of a single therapeutic dose of tiotropium (18 µg). There was an evident effect of tiotropium on [11C]VC-002 binding to mAChRs in lungs in both NHPs and humans. In NHPs, RO was 11 to 78% and increased in a dose dependent manner. Non-displaceable binding in NHPs was about 10% of total binding. In humans, RO was 6%-65%, and non-displaceable binding was about 20% of total binding at baseline. The results demonstrate that [11C]VC-002 binds specifically to mAChRs in the lungs enabling the assessment of RO following administration of muscarinic antagonist drugs. Furthermore, the methodology has potential not only for dose finding and comparison of drug formulations in future applied studies, but also for evaluating changes in lung receptor distribution during disease or in response to therapy. ClinicalTrials.gov, identifier: NCT03097380.

A Retrospective Claims Database Study to Clarify Disease Burden of Severe Asthma Patients with Type 2 High or Low Inflammation

The disease burden of severe asthma patients stratified by type 2 (T2) biomarkers is not well studied in large patient samples, especially for T2-low severe asthma patients. Using a Japanese medical record database, we investigated disease and economic burdens in T2-high and T2-low severe asthma patients. Data of severe asthma patients (receiving high-dose inhaled corticosteroids and additional asthma-related controller medications or oral corticosteroids [OCS] prescription [≥183 days] during the 1-year baseline period) were analyzed in the Real World Data database, comprising electronic medical records from Japanese medical institutions. Severe asthma patients were stratified into a T2-high population with higher eosinophils (≥150 cells/μL) and/or higher total immunoglobulin E (IgE, ≥75 IU/mL) or a T2-low population with lower eosinophils (<150 cells/μL) and lower total IgE (<75 IU/mL). The incidence of asthma exacerbation events and drug costs were analyzed for each population. Different T2 thresholds were explored, including eosinophil count 300 cells/μL and/or IgE 150 IU/mL. Of the 732 severe asthma patients, 599 (81.8%) patients had T2-high type, and 133 (18.2%) had T2-low type. Proportions of the T2-high patients (30.6%) with asthma exacerbations, defined as a composite outcome, including OCS burst, injectable steroid use, and hospitalization, were similar to those of T2-low type (34.6%). The annual drug cost was similar between T2-high (175,487 JPY) and T2-low (165,322 JPY) populations. In this large-scale study, both T2-high and T2-low severe asthma patients in Japan were shown to have a high disease burden and high economic burden, suggesting an unmet treatment need.

Shegan Mahuang Decoction May Reduce Airway Inflammation in Neutrophilic Asthmatic Mice by Improving the Mitochondrial Function of Bronchoalveolar Lavage Fluid Exosomes.

Asthma is a common pulmonary disease mainly caused by the infiltration of neutrophils. There is a limit to the therapeutic effects of the available asthma drugs on neutrophilic asthma. Shegan Mahuang Decoction (SMD) is one of the representative traditional Chinese medicine (TCM) prescriptions for asthma, and it can effectively relieve the clinical symptoms of patients. However, the effect of SMD on the treatment of neutrophilic asthma remains unknown. In this study, a mouse model of neutrophilic asthma induced by lipopolysaccharide (LPS)/ovalbumin (OVA) was established, and the effect of a modified SMD prescription on the model was evaluated. After treatment, SMD was demonstrated to be therapeutically effective on asthmatic mice via airway resistance detection and lung pathology and was able to affect cytokine levels in vivo. Further experiments verified that SMD regulated the expression of mitochondrial function proteins in bronchoalveolar lavage fluid (BALF) exosomes. The results demonstrate that SMD confers a therapeutic effect on a neutrophilic asthma mouse model, and it may reduce neutrophil airway inflammation by regulating myeloid-derived regulatory cell (MDRC) function and airway exosome mitochondrial function.

Investigation on the molecular, electronic and spectroscopic properties of rosmarinic acid: an intuition from an experimental and computational perspective

Various drugs such as corticosteroids, salbutamol, and β2 agonist are available for the treatment of asthma an inflammatory disease and its symptoms, although the ingredient and the mode of action of these drugs are not clearly elucidated. Hence this research aimed at carrying out improved scientific research with respect to the use of natural product rosmarinic acid which poses minima, side effects. Herein, we first carried out extraction, isolation, and spectroscopic (FT-IR, 1H-NMR and 13C-NMR) investigation, followed by molecular modeling analysis on the naturally occurring rosmarinic acid extracted from Rosmarinus officinalis. A detailed comparison of the experimental and theoretical vibrational analysis has been carried out using five DFT functionals: BHANDH, HSEH1PBE, M06-2X, MPW3PBE and THCTHHYB with the basis set 6-311++G (d, p) to investigate into the structural, reactivity, and stability of the isolated compound. Frontier molecular orbital analysis and appropriate quantum descriptors were calculated. Results showed that the compound was more stable at M06-2X and more reactive at HSEH1PBE with an energy gap of 6.43441 eV and 3.8047 eV, respectively, which was later affirmed by the global quantum reactivity parameters. From natural bond orbital analysis, π* π* is the major contributor to electron transition with the summation perturbation energy of 889.57 kcal/mol, while π π* had the perturbation energy totaling of 145.3 kcal/mol. Geometry analysis shows BHANDH to have lower bond length values and lesser deviation from 120° in carbon–carbon angle. The potency of the title molecule as an asthma drug was tested via a molecular docking approach and the binding score of −8.2 kcal/mol was observed against −7.0 of salbutamol standard drug, suggesting romarinic acid as a potential natural organic treatment for asthma. Communicated by Ramaswamy H. Sarma

β-sitosterol targets glucocorticoid receptor to reduce airway inflammation and remodeling in allergic asthma

IntroductionIn most asthma patients, symptoms are controlled by treatment with glucocorticoid, but long-term or high-dose use can produce adverse effects. Therefore, it is crucial to find new therapeutic strategies. β-sitosterol could suppress type Ⅱ inflammation in ovalbumin (OVA)-induced mice, but its mechanisms have remained unclear. MethodsA binding activity of β-sitosterol with glucocorticoid receptor (GR) was analyzed by molecular docking. Human bronchial epithelial cells (BEAS-2B) and human bronchial smooth muscle cells (HBSMC) were treated with different concentrations (0, 1, 5, 10, 20, and 50 μg/mL) of β-sitosterol for suitable concentration selection. In transforming growth factor (TGF)-β1 treated BEAS-2B and HBSMC, cells were treated with 20 μg/mL β-sitosterol or dexamethasone (Dex) to analyze its possible mechanism. In OVA-induced mice, 2.5 mg/kg β-sitosterol or Dex administration was performed to analyze the therapeutic mechanism of β-sitosterol. A GR antagonist RU486 was used to confirm the mechanism of β-sitosterol in the treatment of asthma. ResultsA good binding of β-sitosterol to GR (score = −8.2 kcal/mol) was found, and the GR expression was upregulated with β-sitosterol dose increase in BEAS-2B and HBSMC. Interleukin (IL)-25 and IL-33 secretion was significantly decreased by β-sitosterol in the TGF-β1-induced BEAS-2B, and the levels of collagen 1A and α-smooth muscle actin (SMA) were reduced in the TGF-β1-induced HBSMC. In the OVA-challenged mice, β-sitosterol treatment improved airway inflammation and remodeling through suppressing type Ⅱ immune response and collagen deposition. The therapeutic effects of β-sitosterol were similar to Dex treatment in vitro and in vivo. RU486 treatment clearly hampered the therapeutic effects of β-sitosterol in the TGF-β1-induced cells and OVA-induced mice. ConclusionThis study identified that β-sitosterol binds GR to perform its functions in asthma treatment. β-sitosterol represent a potential therapeutic drug for allergic asthma.

LBMON186 Beta-agonist Profiling Reveals Novel Biased Signaling Phenotypes For The Beta 2-adrenergic Receptor With Implications In The Treatment Of Asthma

Abstract Asthma involves chronic airway inflammation and airway smooth muscle (ASM) cell contraction. Treatment include agonists of the beta 2-AR, a GPCR that induces the Gs/cAMP pathway leading to ASM relaxation. These agonists can also promote severe side effects which have been correlated with beta-arrestins (barr) activation. Therefore, biased ligands selective for the Gs/cAMP pathway over the barr-induced side effects should be beneficial. To test this, we have used high-throughput screening to identify Gs-biased agonists. The initial lead candidates were further analyzed for their ability to modulate Gs and Gi interaction, cAMP production, and barr interaction. We identified three compounds which showed minimal barr recruitment as well as decreased barr-mediated outputs including receptor internalization and ERK activation. They also showed reduced GRK-mediated phosphorylation of the receptor as well as decreased agonist-promoted receptor desensitization in human ASM cells. These Gs-biased agonists may contribute to develop more effective drugs for asthma and may help to determine the structure determinants of receptor mediated biased signaling. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Effects of Different Intervention Factors on Vascular Endothelial Growth Factor-Induced Human Airway Smooth Muscle Cell Migration.

Background Asthma airway remodeling is closely related to the abnormal migration of human airway smooth muscle cells (ASMCs), and vascular endothelial growth factor (VEGF) is involved in the pathophysiological process of asthma. This study aimed to investigate the effect of VEGF on ASMC migration through in vitro cell experiments and to intervene in ASMC migration with different asthma drugs and signaling pathway inhibitors to provide a basis for screening effective drugs for airway remodeling. Methods The effect of VEGF on the proliferation of ASMCs was detected by the CCK-8 method, and the effect of VEGF on the migration of ASMCs was proven by scratch and transwell assays. Different asthma drugs and signaling pathway inhibitors were used to interfere with the migration of ASMCs. The number of migrating cells was compared between the intervention and nonintervention groups. Results Our results showed that VEGF induction enhanced ASMC migration; pretreatment with the commonly used asthma drugs (salbutamol, budesonide, and ipratropium bromide) significantly attenuated VEGF-induced ASMC migration; and inhibitors SB203580, LY294002, and Y27632 blocked the VEGF-induced activation of p38 MAPK, PI3K, and ROCK signaling pathway targets in ASMCs and inhibited migration. Conclusion This study shows that the current commonly used asthma drugs salbutamol, budesonide, and ipratropium have potential value in the treatment of airway remodeling, and the p38 MAPK, PI3K, and ROCK signaling pathway targets are involved in the VEGF-induced ASMC migration process. Signaling pathway inhibitor drugs may be a new way to treat asthma-induced airway remodeling in asthma patients in the future. However, the related mechanism and safety profile still need further research.

A bibliometric and scientific knowledge map study of the drug therapies for asthma-related study from 1982 to 2021

Objective: Asthma drug research has been increasing yearly, and its clinical application value has increasingly attracted attention. This study aimed to analyze the development status, research hotspots, research frontiers, and future development trends of the research works on drugs for patients with asthma, especially severe asthma. Methods: Asthma drug-related articles published between 1982 and 2021 were retrieved from the Web of Science Core Collection (WOSCC) database, and only articles published in English were included. CiteSpace and VOSviewer software were utilized to conduct collaborative network analysis of countries/regions, institutions, keywords, and co-citation analysis of references. Results: A total of 3,234 asthma drug-related eligible articles were included. The United States was in a leading position, and Karolinska Institute (Sweden) was the most active institution. The most prolific journal in this field was Journal of Asthma, and the most cited journal was Journal of Allergy and Clinical Immunology. Keyword co-occurrence studies suggested that the current hotspots and frontiers were as follows: ① asthma: fully revealing the potential of existing conventional asthma drugs, determining the best drug delivery system, and indicating the best combination. To continue to explore potential targets for severe asthma or other phenotypes. Inhaled glucocorticoids and budesonide are still one of the important aspects of current asthma drug research and ② severe asthma: the research and development of new drugs, especially monoclonal antibodies including omalizumab, mepolizumab, and benralizumab to improve asthma control and drug safety, have become a research hotspot in recent years, highlighting the importance of “target” selection. Conclusion: This study demonstrates the global research hotspots and trends of the research works on drugs for patients with asthma/severe asthma. It can help scholars quickly understand the current status and hotspots of research in this field.

Identification of Drugs Associated with Lower Risk of Parkinson's Disease Using a Systematic Screening Approach in a Nationwide Nested Case-Control Study.

Drugs for other indications may be repurposable as disease-modifying drugs for Parkinson's disease (PD). A systematic hypothesis-free approach can enable identification of candidates for repurposing. We applied a hypothesis-free systematic approach to identify drugs associated with lower risk of PD to discover candidates with potential for repurposing as disease-modifying drugs for PD and to illustrate challenges in observational studies that simultaneously investigate multiple repurposing candidates. The Finnish Parkinson's disease study (FINPARK), a nationwide nested case-control study, was randomized to screening (10,183 cases, 67,849 controls) and replication (10,184 cases, 67,754 controls) samples, including cases diagnosed in 1998-2015. After screening all univariable associations of register-derived exposure to individual-drug, group- and subgroup level since 1995 (exposure ≥3 years before outcome, threshold P = 0.1), different exposure periods were used in confounder-adjusted replication analyses. In screening stage, the group-level (antipsoriatics and antigout preparations) and subgroup-level (cicatrizants, topical antipsoriatics, antigout preparations and mydriatics and cycloplegics) associations were mainly due to individual drugs. Seven other drugs (eg methotrexate, drugs for chronic obstructive pulmonary disease, COPD and/or asthma) were associated with lower risk. Associations of antigout preparations and antipsoriatics were replicated. COPD/asthma drugs, methotrexate and diabetes drugs were studied in separate, indication-restricted designs. The results reflect the known risk factors and the implied role of the immune system in PD pathogenesis and spurious associations. They underline the importance of controlling for confounding by indication, which is challenging to apply to systematic screening.

The Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO): Comparisons between Quebec, Manitoba, Saskatchewan, and Alberta.

BackgroundGiven that pregnant women taking medications are excluded from clinical trials, real-world evidence is essential. We aimed to build a Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO) and compare frequency of prematurity, low-birth-weight (LBW), major malformations, multiplicity, and gestational medication use across four provinces.MethodsCAMCCO is a collaborative research infrastructure that uses real-world data from large provincial health care databases in Canada; developed with standardized methods to similarly construct population-based pregnancy/child cohorts with longitudinal follow-up by linking administrative/hospital/birth databases. CAMCCO also includes a common repository to i) share algorithms and case definitions based on diagnostic and procedural codes for research/training purpose, and ii) download aggregate data relevant to primary care providers, researchers, and decision makers. For this study, data from Quebec (1998–2015), Manitoba (1995–2019), Saskatchewan (1996–2020), and Alberta (2005–2018) are compared (Chi-square tests, p-values), and trends are calculated using Cochran-Armitage trend tests.ResultsAlmost two-thirds (61%) of women took medications during pregnancy, mostly antibiotics (26%), asthma drugs (8%), and antidepressants (4%). Differences in the prevalence of prematurity (5.9–6.8%), LBW (4.0–5.2%), and multiplicity (1.0–2.5%) were statistically significant between provinces (p<0.001). Frequency of major malformations increased over time in Quebec (7–11%; p<0.001), Saskatchewan (5–11%; p<0.001), and Alberta (from 7–8%; p<0.001), and decreased in Manitoba (5–3%; p<0.001). Cardiovascular and musculoskeletal malformations were the most prevalent.InterpretationMedications are often used among Canadian pregnancies but adverse pregnancy outcomes vary across provinces. Digitized health data may help researchers and care providers understand the risk-benefit ratios related to gestational medication use, as well as province-specific trends.

Chemokines in allergic asthma inflammation

Asthma is the most frequent noncommunicable disease and one of the leading causes of years lived with disability. Asthma has a severe impact on a patient's life, being able to disturb the activities of both children and adults. The morbidity and mortality of asthma may depend on the severity and progressiveness of the symptoms experienced by the patient. Different and complex pathomechanisms underline the pathology of asthma, in which the regulation of innate and adaptive immune responses plays a role. There is a complex interaction between immune cells including chemokines involved in the pathogenesis of asthma. Immune cell trafficking is orchestrated by a family of small proteins called chemokines. Leukocytes express cell-surface receptors that bind to chemokines and trigger transendothelial migration. This review article outlines the main role of chemokines in inflammatory reactions that occur in allergic asthma, based on the latest literature studies that have been published previously. The allergic reaction in asthma expresses various chemokines and their receptors. Chemokines including eotaxins (CCL11, CCL24, and CCL26), CCL2, CCL5, CCL17, and CCL22 regulate immune cells that under pathological conditions travel to the inflammatory site, mainly in the lung, to protect the body from pathogen invasion. Chemokines are released by a number of immune cells such as monocytes, dendritic cells, mast cells, and epithelial cells in the airway. The biological effects of chemokine production are enhanced by secreted cytokines when an allergic reaction occurs in asthma, such as IL-4, IL-5, and IL-13. Chemokines cause an accumulation of different inflammatory cells at the site of inflammation, which ultimately results in tissue damage to the airway. The inhibition of the reactions evoked by the interaction between chemokines and their receptors is considered a candidate for the development of potent therapeutic drugs for asthma in the future.

A Comparative Study of Montelukast and Salbutamol in Bronchial Asthma

Current asthma drug therapy is highly effective, having evolved from naturally occurring substances via logical pharmaceutical developments. Pharmacology has played an important role in the development of asthma drugs, and several key experimental findings have been published in this journal. Understanding the pharmacology of effective drug therapies has also taught us a lot about the mechanisms underlying asthma. 2-Adrenoceptor agonists, which evolved from catecholamines in the adrenal medulla, are the most effective bronchodilators, whereas corticosteroids, which evolved from catecholamines in the adrenal cortex, are by far the most effective controllers of the underlying inflammatory process in the airways. A combination inhaler containing a long-acting 2-agonist and a corticosteroid - an improved form of adrenal gland extract - is the current "gold standard" of asthma therapy. Theophylline, a dietary methyl xanthine, and chromoglycate, a plant-derived substance, have both been widely utilized in the treatment of asthma, but their molecular mechanisms are still unknown. Pharmacology has been crucial in enhancing natural products to create effective, long-lasting, and secure asthma medications, but it has faced difficulties in developing new classes of anti-asthma treatments. Leukotriene antagonists, the only brand-new type of anti-asthma therapy established in the previous 30 years, are less efficient than currently available medications. Corticosteroids are less successful than new, more focused medicines that target particular cytokines, but more focused medications run the risk of having side effects that may not be tolerable. Pharmacology, not molecular genetics, appears to be the most likely direction for future advancements in asthma treatment.

Frequent occurrence of mutations in nsp3 and nsp4 of SARS-CoV-2, presumably caused by the inhaled asthma drug ciclesonide.

Mutations in nonstructural protein 3 (nsp3) and nsp4 of SARS-CoV-2, presumably induced by the asthma drug ciclesonide (which also has anti-SARS-CoV-2 activity), were counted 5,851 cases in the GISAID EpiCoV genome database. Sporadic occurrence of mutants not linked to each other in the phylogenetic tree were identified at least 88 times; of which, 58 had one or more descendants in the same branch. Five of these had spread to more than 100 cases, and one had expanded to 4,748 cases, suggesting the mutations are frequent, selected in individual patients, and transmitted to form clusters of cases. Clinical trials of ciclesonide as a treatment for COVID-19 are the presumed cause of the frequent occurrence of mutations between 2020 June and 2021 November. In addition, because ciclesonide is a common treatment for asthma, it can drive mutations in asthmatics suffering from COVID-19. Ciclesonide-resistant mutations, which have unpredictable effects in humans, are likely to continue to emerge because SARS-CoV-2 remains prevalent globally.

Exploring the deactivation mechanism of human β 2 adrenergic receptor by accelerated molecular dynamic simulations.

The β 2 adrenergic receptor (β2AR), one of important members of the G protein coupled receptors (GPCRs), has been suggested as an important target for cardiac and asthma drugs. Two replicas of Gaussian accelerated molecular dynamics (GaMD) simulations are performed to explore the deactivation mechanism of the active β2AR bound by three different substrates, including the agonist (P0G), antagonist (JTZ) and inverse agonist (JRZ). The simulation results indicate that the Gs protein is needed to stabilize the active state of the β2AR. Without the Gs protein, the receptor could transit from the active state toward the inactive state. During the transition process, helix TM6 moves toward TM3 and TM5 in geometric space and TM5 shrinks upwards. The intermediate state is captured during the transition process of the active β2AR toward the inactive one, moreover the changes in hydrophobic interaction networks between helixes TM3, TM5, and TM6 and the formation of a salt bridge between residues Arg3.50 and Glu6.30 drive the transition process. We expect that this finding can provide energetic basis and molecular mechanism for further understanding the function and target roles of the β2AR.

Variations in the respiratory microbiota amongst asthmatic and non-asthmatic subjects in Jordan

In this work, variation in microbiota in the lower respiratory tract (LRT) among asthmatic and non-asthmatic subjects is identified. All participants (27 asthmatic patients and 27 non-asthmatic subjects) were asked to expectorate a sputum sample in special sterile tubes after rinsing the mouth with a sterilizing solution. The expectorated sputum specimen was immediately homogenized and stored in the deep freezer for DNA extraction for microbial gene sequencing and sequence analyses. For sequencing the V4 region of the 16S rRNA gene was sequenced using Illumina MiSeq, followed by an analysis of alpha and beta diversity. It was found that asthmatic patients had greater bacterial diversity than non-asthmatic subjects. Bacteria associated to the phyla (Bacteroidetes, Proteobacteria, and Firmicutes) accounted for 90 % of all sequences. The relative abundance of Proteobacteria in the asthmatic patients was higher than that of non-asthmatic (30 % vs 17 %; P-value = 0.044), along with a high abundance of the pathogen Haemophilus influenza. In contrast, Firmicutes (41 %) and Bacteroidetes (31 %) showed higher relative abundances in the non-asthmatic subjects. No significant link was found between the type of asthma drug or the method of drug usage (orally or via inhalation) and the respiratory microbiota. Therefore, the variations in LRS microbiota are not caused by the drugs taken by the asthmatic patients, rather they might be connected to the etiology of asthma. Since the asthmatic patients had higher proportions of Haemophilus influenzae, these organisms could be a causative factor in the pathophysiology of asthma.

S-nitrosylation is required for β2AR desensitization and experimental asthma

The β2-adrenergic receptor (β2AR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of β-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation, the β2AR is modified by S-nitrosylation, which is essential for both classic desensitization by PKA as well as desensitization of NO-based signaling that mediates bronchorelaxation. Strikingly, S-nitrosylation alone can drive β2AR internalization in the absence of traditional agonist. Mutant β2AR refractory to S-nitrosylation (Cys265Ser) exhibits reduced desensitization and internalization, thereby amplifying NO-based signaling, and mice with Cys265Ser mutation are resistant to bronchoconstriction, inflammation, and the development of asthma. S-nitrosylation is thus a central mechanism in β2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain.

Determination of albuterol and montelukast post-expiry drug strength by HPLC

BackgroundKnowing the level of active ingredients in an expired drug is a matter of concern irrespective of its final disposition. This is also a matter of national security and defense as it has important implications on the nation’s stockpile of prescription medications. Current literature has limited information about the strength of expired medications and any relevant trends. ObjectiveTo utilize high performance liquid chromatography (HPLC) to determine the strength of selected drugs for asthma and chronic obstructive pulmonary disease (COPD) as a class of therapeutic agents commonly used in free clinics. MethodsSamples from expired lots of montelukast and albuterol pharmaceutical products were analyzed for their levels of their respective active ingredients. Two HPLC methods were developed, validated, and applied to achieve this goal. Quantitative analysis of each drug was performed using two different reversed phase C18 columns with a linear gradient of acetonitrile in 0.1% aqueous formic acid at a flow rate of 1 mL/min for both methods. Detection wavelength for montelukast and albuterol was 280 and 277 nm, respectively. ResultsExpiry dates of analyzed batches ranged from 2003 to 2019. Despite the extended time range beyond expiry dates, levels of both drugs were relatively consistent and exceeded 90% of the listed strength in most analyzed lots. ConclusionsOur results introduce a new perspective towards reducing the financial burden resulting from disposal of expired medications with retained strength. They also offer supporting evidence to extend the use of out-of-date montelukast and albuterol preparations at home and in free clinics.

Effects of NP-1815-PX, a P2X4 Receptor Antagonist, on Contractions in Guinea Pig Tracheal and Bronchial Smooth Muscles.

Administration of a P2X4 receptor antagonist to asthma model mice improved asthma symptoms, suggesting that P2X4 receptor antagonists may be new therapeutics for asthma. However, the effects of these antagonists on tracheal/bronchial smooth muscle (TSM and BSM) have not been investigated. This study examined the effects of NP-1815-PX, a selective P2X4 receptor antagonist, on guinea pig TSM and BSM contractions. In epithelium-intact TSM, NP-1815-PX (10-5 M) strongly suppressed ATP-induced contractions. ATP-induced contractions were strongly suppressed by indomethacin (3 × 10-6 M) and ONO-8130 (a prostanoid EP1 receptor antagonist, 10-7 M). ATP-induced contractions were partially suppressed by SQ 29,548 (a prostanoid TP receptor antagonist, 3 × 10-7 M), although the difference was not significant. In contrast, ATP-induced contractions were not affected by AL 8810 (a prostanoid FP receptor antagonist, 10-5 M) or L-798,106 (a prostanoid EP3 receptor antagonist, 10-8 M). NP-1815-PX (10-5-10-4 M) strongly suppressed U46619 (a TP receptor agonist)- and prostaglandin F2α (PGF2α)-induced epithelium-denuded TSM and BSM contractions, which were largely inhibited by SQ 29,548. Additionally, NP-1815-PX (10-5-10-4 M) strongly suppressed the U46619-induced increase in intracellular Ca2+ concentrations in human TP receptor-expressing cells. However, NP-1815-PX (10-4 M) did not substantially inhibit the TSM/BSM contractions induced by carbachol, histamine, neurokinin A, or 50 mM KCl. These findings indicate that NP-1815-PX inhibits guinea pig TSM and BSM contractions mediated through the TP receptor, in addition to the P2X4 receptor, whose stimulation mainly induces EP1 receptor-related mechanisms. Thus, these findings support the usefulness of NP-1815-PX as a therapeutic drug for asthma.