Potential For Treatment Of Asthma Research Articles

Allergo-immunopathology mechanism of thymol-inhibiting airway remodeling in asthmatic mice by regulating TGF-β/Smad3 pathway.

Allergic asthma is an important public health problem and is a complicated respiratory sickness that is characterized by bronchial inflammation, bronchoconstriction, and breathlessness. Asthma is orchestrated by type 2 immune response and remodeling is one of the important outputted problem in chronic asthma. Thymol is a naturally occurring monocyclic phenolic, it has a series of biological properties, and its immunomodulatory and anti-remodeling effects on allergic asthma were evaluated. The OVA-LPS-induced asthmatic mice were treated with thymol. Methacholine challenge test, eosinophil count, and levels of IL-4, IL-5, IL-13, and IL-33 in bronchoalveolar lavage fluid, total and OVA-specific IgE levels in serum, remodeling factors, gene expression of TGF-β, Smad2, Smad3, and lung histopathology were done. Treatment with thymol could control AHR, eosinophil percentage levels of Th2 cytokines and Igs, remodeling factors, expression of TGF-β, Smad2 and Smad3 genes, inflammation, goblet cell hyperplasia, and mucus production in asthmatic mice. Thymol can control asthma pathogens and related remodeling and fibrosis bio-factors and can be a potential treatment of asthma.

Quantitative Determination of AZD3264, a Selective Ikb-Kinase IKK2 Inhibitor, in Dog Plasma by Solvent-Induced Phase Transition Extraction Coupled with HPLC-MS/MS and its Application to Pharmacokinetic Study in Dogs.

AZD3264 is a small molecule inhibitor of selective IkB-kinase IKK2 currently in preclinical development for the potential treatment of asthma and chronic pulmonary obstructive disorder. A method for the quantitative analysis of AZD3264 was established and optimized by using HPLC tandem mass spectrometry in dog plasma. Plasma samples were pretreated using a solvent-induced phase transition extraction method with a methanol solution of omeprazole as the internal standard. Chromatographic separation was performed using a Thermo Hypersil GOLD-C18 (50 mm × 4.6 mm, 3 μm) column with the temperature maintained at 25°C. Mobile phase consisted of 0.1% formic acid in water and acetonitrile in a gradient mode at a flow rate of 0.6 mL/min. Mass spectrometric detection was carried out in selected reaction monitoring mode with positive electrospray ionization, and the mass transitions of AZD3264 and omeprazole were m/z 442.1 → 425.0 and m/z 346.0 → 198.0, respectively. The intra-batch accuracy was within 95.11-105.06% and the precision was within 6.50-9.98%. The inter-batch accuracy was within 96.83-102.80% with a precision of 7.62-9.50%. The selectivity, sensitivity, linearity, dilution linearity, extraction recovery and matrix effect, stability, and carry-over met all requirements of the guidelines for bioanalytical method validation. AZD3264 showed linear pharmacokinetic characteristics following intravenous administration to dogs at 0.3-2.7 mg/kg. The developed and validated method was successfully employed in pharmacokinetic studies in dogs following intravenous administration at the doses of 0.3, 0.9, and 2.7 mg/kg. This was the first investigation of the in vivo pharmacokinetic characteristics of AZD3264 in dogs by LC-MS/MS with SIPTE method for plasma sample preparation.

Inhaled Janus Kinase (JAK) inhibitors for the treatment of asthma.

Multiple asthma-relevant cytokines including IL-4, IL-5, IL-13, and TSLP depend upon JAKs for signaling. JAK inhibition may, therefore, offer a novel intervention strategy for patients with disease refractory to current standards of care. Multiple systemically delivered JAK inhibitors have been approved for human use or are under clinical evaluation in autoimmune diseases such as rheumatoid arthritis. However, the on-target side effect profiles of these agents are likely not tolerable for many asthmatic patients. Limiting JAK inhibition to the lung is expected to improve therapeutic index relative to systemic inhibition. Thus, inhaled JAK inhibitors with lung-restricted exposure are of high interest as potential treatments for asthma.

Equine lung decellularization: a potential approach for in vitro modeling the role of the extracellular matrix in asthma

Contrary to conventional research animals, horses naturally develop asthma, a disease in which the extracellular matrix of the lung plays a significant role. Hence, the horse lung extracellular matrix appears to be an ideal candidate model for in vitro studying the mechanisms and potential treatments for asthma. However, so far, such model to study cell–extracellular matrix interactions in asthma has not been developed. The aim of this study was to establish a protocol for equine lung decellularization that maintains the architecture of the extracellular matrix and could be used in the future as an in vitro model for therapeutic treatment in asthma. For this the equine lungs were decellularized by sodium dodecyl sulfate detergent perfusion at constant gravitational pressure of 30 cmH2O. Lung scaffolds were assessed by immunohistochemistry (collagen I, III, IV, laminin, and fibronectin), scanning electron microscopy, and DNA quantification. Their mechanical property was assessed by measuring lung compliance using the super-syringe technique. The optimized protocol of lung equine decellularization was effective to remove cells (19.8 ng/mg) and to preserve collagen I, III, IV, laminin, and fibronectin. Moreover, scanning electron microscopy analysis demonstrated maintained microscopic lung structures. The decellularized lungs presented lower compliance compared to native lung. In conclusion we described a reproducible decellularization protocol that can produce an acellular equine lung feasible for the future development of novel treatment strategies in asthma.

Benralizumab as a potential treatment of asthma

ABSTRACTIntroduction: Current anti-inflammatory asthma therapies including inhaled corticosteroids and leukotriene modifiers, are not always able to appropriately control the disease and other approaches are needed. These therapies specific target IgE (omalizumab) or IL-5 (mepolizumab). However, there is research underway investigating interleukin-based monoclonal antibodies such as benralizumab, an anti-IL-5R monoclonal antibody which is currently in phase III clinical development.Areas covered: This review summarizes the existing preclinical and clinical data of benralizumab. Data reviewed includes benralizumab’s efficacy and safety data. The author also provides their expert opinion on this potential therapeutic and provide their perspectives for its future development.Expert opinion: Benralizumab was able to interfere significantly with disease-related morbidity and in particular with hospitalizations due to asthma exacerbation rates in a subset of patients with higher systemic eosinophil burden and higher doses of inhaled corticosteroids. The sustained inhibitory effect on eosinophilic inflammation might be an advantage which can be translated in less frequent dosing. Further attempts should be made to better define the asthma endotype in which such an antibody would be the most efficacious.

NF-kappaB Signaling in Chronic Inflammatory Airway Disease.

Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments. In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression. The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology. The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription. Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression). However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling. Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD. Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression. This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD.

Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function.

Mesenchymal stem cells (MSCs) have been investigated in the treatment of numerous autoimmune diseases. However, the immune properties of MSCs on the development of asthma have remained to be fully elucidated. Airway dendritic cells (DCs) have an important role in the pathogenesis of allergic asthma, and disrupting their function may be a novel therapeutic approach. The present study used a mouse model of asthma to demonstrate that transplantation of MSCs suppressed features of asthma by targeting the function of lung myeloid DCs. MSCs suppressed the maturation and migration of lung DCs to the mediastinal lymph nodes, and thereby reducing the allergen-specific T helper type 2 (Th2) response in the nodes. In addition, MSC-treated DCs were less potent in activating naive and effector Th2 cells and the capacity of producing chemokine (C-C motif) ligand 17 (CCL17) and CCL22, which are chemokines attracting Th2 cells, to the airways was reduced. These results supported that MSCs may be used as a potential treatment for asthma.

Improvement of Pulmonary Function by Oral Treatment with a VLA-4 Antagonist in a Mouse Asthmatic Model

We investigated in vivo efficacies of the newly synthesized VLA-4 antagonist Compound A {trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid} on Ascaris antigen–induced airway inflammation and hyperresponsiveness in a murine asthmatic model. Oral administration of Compound A significantly inhibited eosinophil infiltration into BALF and airway hyperresponsiveness 48 h after the antigen challenge. Histologic analysis of the lung sections confirmed the BALF result and revealed suppression of edema and mucus hyperplasia at 8 and 48 h after the challenge, respectively. These findings clearly show that orally active Compound A has therapeutic potential for treatment of asthma.

Prostaglandin I2 Analogs Suppress Tumor Necrosis Factor α Production and the Maturation of Human Monocyte-Derived Dendritic Cells

BackgroundDendritic cells (DCs) are professional antigen-presenting cells and have critical roles in regulating immune responses. Prostaglandin I2 (PGI2) analogs are considered to be potential treatments for asthma. However, the effect...

Prostaglandin I2 Analogues Enhance Growth-Related Oncogene-α Expression in Human Monocyte-Derived Dendritic Cells

Chemokines for neutrophils such as growth-related oncogene-alpha (GRO-alpha) are important in patients with refractory or severe asthma. Prostaglandin I(2) (PGI(2)) analogues were regarded as potential treatments for asthma. Dendritic cells (DCs) are the professional antigen-presenting cells and play a critical role in regulating immune response. However, it is unknown whether PGI(2) analogues have regulatory effects on GRO-alpha expression in human monocyte-derived DCs (MDDCs). The human MDDCs were pretreated with iloprost and treprostinil (two PGI(2) analogues) or forskolin, a cyclic adenosine monophosphate (cAMP) activator, before stimulation with lipopolysaccharide (LPS). In some cases, I prostanoid (IP) receptor and E prostanoid (EP) antagonists were pretreated before PGI(2) analogue treatment. To investigate the intracellular signaling, nuclear factor (NF)-kappaB inhibitor and the mitogen-activated protein kinase (MAPK) inhibitors were pretreated before PGI(2) analogue treatment. GRO-alpha was measured by enzyme-linked immunosorbent assay. Intracellular signaling was also investigated by Western blot. Iloprost and treprostinil enhanced LPS-induced GRO-alpha expression in MDDCs. This effect could be reversed by an I prostanoid receptor antagonist, CAY10449, but not EP receptor antagonists. Forskolin conferred a similar modulating effect as that noted in iloprost- and treprostinil-treated MDDCs. PGI(2) analogue-enhanced LPS-induced GRO-alpha expression was reduced by MAPK-p38 inhibitor, SB203580. PGI(2) analogues enhanced LPS-induced phospho-p38 expression. PGI(2) analogues enhanced LPS-induced GRO-alpha expression via the IP receptor-cAMP and p38-MAPK pathways in human MDDCs, which may further recruit neutrophil accumulation and adversely affect patients with refractory or severe asthma because of airway neutrophilia. These effects should be considered for PGI(2) analogues as candidates for the treatment of asthma.

Bioactivation of a Novel 2-Methylindole-Containing Dual Chemoattractant Receptor-Homologous Molecule Expressed on T-Helper Type-2 Cells/d-Prostanoid Receptor Antagonist Leads to Mechanism-Based CYP3A Inactivation: Glutathione Adduct Characterization and Prediction of In Vivo Drug-Drug Interaction

The 2-methyl substituted indole, 2MI [2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid] is a potent dual inhibitor of 1) chemoattractant receptor-homologous molecule expressed on T-helper type-2 cells and 2) d-prostanoid receptor. During evaluation as a potential treatment for asthma and allergic rhinitis, 2MI was identified as a mechanism-based inactivator of CYP3A4 in vitro. The inactivation was shown to be irreversible by dialysis and accompanied by an NADPH-dependent increase in 2MI covalent binding to a 55- to 60-kDa microsomal protein, consistent with irreversible binding to CYP3A4. Two glutathione (GSH) adducts, G1 and G2, were identified in vitro, and the more abundant adduct (G1) was unambiguously determined via NMR to be GSH adducted to the 3-position of the 2-methylindole moiety. The potential for a clinical drug-drug interaction arising from mechanism-based inactivation of CYP3A4 by 2MI was predicted using a steady-state model, and a 4.3- to 7.5-fold increase in the exposure of midazolam was predicted at anticipated therapeutic concentrations. To better assess the potential for in vivo drug-drug interactions, the Sprague-Dawley rat was used as an in vivo model. An excellent in vitro-in vivo correlation was observed for the reduction in enzyme steady-state concentration (E'(ss/Ess)) as well as the change in the exposure of a prototypical CYP3A substrate, indinavir (area under the curve (AUC) for indinavir/AUC). In summary, 2MI was identified as a potent mechanism-based inactivator of CYP3A and was predicted to elicit a clinically relevant drug-drug interaction in humans at an anticipated therapeutic concentration.

Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma

A number of compounds bearing a quaternary ammonium moiety were found to be antagonists with nanomolar binding affinity for the chemokine receptor-2. The structure–activity relationships in the series are described herein along with some detailed characterization of the interesting compounds.

Synthesis of a CCR3 Antagonist

The CCR3 antagonist M is a potential treatment for asthma and allergic rhinitis. The synthesis depicted provided 20 kg of the target. Key steps include the asymmetric hydrogenation of B to C and the quinidine-mediated desymmetrization of the meso-anhydride E.

Discovery of potent CRTh2 (DP 2) receptor antagonists

Starting with the weak agonist indomethacin, a series of potent, selective CRTh2 (DP 2) antagonists have been discovered as potential treatments for asthma, allergic rhinitis and other inflammatory diseases.

CD28/CTLA‐4–CD80/CD86 and ICOS–B7RP‐1 costimulatory pathway in bronchial asthma

Costimulatory molecules are cell surface glycoproteins that can direct, modulate and fine-tune T-cell receptor signals. The B7-1/B7-2--CD28/CTLA-4 and ICOS-B7RP-1 pathway provides key second signals that can regulate the activation, inhibition and fine-tuning of T-lymphocyte responses. The expression of B7-1/B7-2--CD28/CTLA-4 molecules on clinical samples from patients with asthma have been well studied, and the results indicate that different extents of these molecules are expressed on the surface of various cells, and that the concentrations of soluble form of these molecules are elevated in the sera of patients with asthma. There is a burst of papers describing an important role for B7-1/B7-2--CD28/CTLA-4 pathway in the Th1/Th2 balance. Similarly, ICOS stimulates both Th1 and Th2 cytokine production but may have a preferential role in Th2 cell development. Moreover, The B7-1/B7-2-CD28/CTLA-4 and ICOS-B7RP-1 pathway has been suggested of being involved in the development of airway inflammation and airway hyperresponsiveness. Further study of the functions of the pathways within the CD28/CTLA-4--CD80/CD86 and ICOS--B7RP-1 superfamily individually and their interplay should provide insights into the pathogenesis of asthma, and has great therapeutic potential for treatment of asthma.

A Prospective Feasibility Study of Bronchial Thermoplasty in the Human Airway

Bronchial thermoplasty is a novel procedure being developed as a potential treatment for asthma. Experience with animal studies has enabled development of appropriate reliable equipment, definition of therapeutic parameters, and descriptions of tissue effects of treatment. This study was undertaken to assess the feasibility and general safety of the application of bronchial thermoplasty in the human airway, and to determine if the reduction in airway smooth muscle seen in animal studies could be replicated. A prospective study. Academic thoracic surgery center. Nine patients scheduled to undergo lung resection for suspected or proven lung cancer. Bronchial thermoplasty was performed during routine preoperative bronchoscopy up to 3 weeks prior to prescheduled lung resection. Treatment was limited to areas of the segmental bronchi within the lobe that was to be removed. Treated airways were inspected via bronchoscopy at the time of thoracotomy, and were examined histologically following surgical resection. There were no adverse clinical effects of the procedure, including no new symptoms and no unscheduled visits for medical care. Treated sites exhibited slight redness and edema of the mucosa within 2 weeks of treatment, and appeared normal at later time points. There was narrowing (visually estimated at 25 to 50%) in four airways in two subjects examined at 5 days and 13 days after treatment, with excess mucus in two of these airways. There was no bronchoscopic evidence of scarring in any of the airways examined. Histologic examination showed a reduction in airway smooth muscle, and the extent of the treatment effect was confined to the airway wall and the immediate peribronchial region. Application of bronchial thermoplasty to the human airway appears to be well tolerated. Treatment resulted in significant reduction of smooth muscle mass in the airways. Bronchial thermoplasty may provide therapeutic benefit in disease states such as asthma.

8‐Methoxyquinoline‐5‐carboxamides as PDE4 Inhibitors: A Potential Treatment for Asthma.

AbstractFor Abstract see ChemInform Abstract in Full Text.

8-Methoxyquinoline-5-carboxamides as PDE4 inhibitors: a potential treatment for asthma

A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4).

7-Methoxyfuro[2,3- c]pyridine-4-carboxamides as PDE4 Inhibitors: A Potential Treatment for Asthma

The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3- c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4). Initial

ChemInform Abstract: 7-Methoxybenzofuran-4-carboxamides as PDE 4 Inhibitors: A Potential Treatment for Asthma.

ChemInform Abstract: 7-Methoxybenzofuran-4-carboxamides as PDE 4 Inhibitors: A Potential Treatment for Asthma.