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https://www.readbyqxmd.com/read/29678990/chemoattractant-receptor-homologous-molecule-expressed-on-th2-cells-crth2-antagonists-in-asthma-a-systematic-review-and-meta-analysis-protocol
#1
Wei Liu, Jie Min, Hongli Jiang, Bing Mao
INTRODUCTION: More than 20 orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists have moved forward to clinical development in recent years for the treatment of asthma. However, evidence from individual randomised controlled trials (RCTs) has demonstrated inconsistent results in their efficacy and safety. METHODS AND ANALYSIS: PubMed/Medline, Embase, Web of Science, Cochrane Database of Systematic Reviews, Global Index Medicus, Cochrane Central Register of Controlled Trials and Scopus will be searched from inception to 30 December 2017 for eligible RCTs, with additional studies being identified by manual searches...
April 20, 2018: BMJ Open
https://www.readbyqxmd.com/read/29454096/jak-stat-inhibitors-and-other-small-molecule-cytokine-antagonists-for-the-treatment-of-allergic-disease
#2
REVIEW
Michael D Howell, Carolyn Fitzsimons, Paul A Smith
OBJECTIVE: To provide an overview of janus kinase (JAK), chemoattractant receptor homologous molecule expressed on TH 2 cells (CRTH2), and phosphodiesterase 4 (PDE4) inhibitors in allergic disorders. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles included in this review discuss the emerging mechanism of action of small molecule inhibitors and their use in the treatment of atopic dermatitis (AD), asthma, and allergic rhinitis (AR)...
April 2018: Annals of Allergy, Asthma & Immunology
https://www.readbyqxmd.com/read/29427987/advances-and-evolving-concepts-in-allergic-asthma
#3
Hui-Ying Tung, Evan Li, Cameron Landers, An Nguyen, Farrah Kheradmand, J Morgan Knight, David B Corry
Allergic asthma is a heterogeneous disorder that defies a unanimously acceptable definition, but is generally recognized through its highly characteristic clinical expression of dyspnea and cough accompanied by clinical data that document reversible or exaggerated airway constriction and obstruction. The generally rising prevalence of asthma in highly industrialized societies despite significant therapeutic advances suggests that the fundamental cause(s) of asthma remain poorly understood. Detailed analyses of both the indoor (built) and outdoor environments continue to support the concept that not only inhaled particulates, especially carbon-based particulate pollution, pollens, and fungal elements, but also many noxious gases and chemicals, especially biologically derived byproducts such as proteinases, are essential to asthma pathogenesis...
February 2018: Seminars in Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29363343/fevipiprant-in-the-treatment-of-asthma
#4
REVIEW
Christobelle White, Adam Wright, Christopher Brightling
Asthma is common and in many, particularly those with more severe disease, there remains a substantial unmet need. Success with biologics targeting eosinophilic inflammation underscore the value of treating inflammation in asthma beyond corticosteroids. Fevipiprant (QAW039) is an oral treatment for asthma. It competitively and reversibly antagonises the prostaglandin D2 receptor 2 (DP2) expressed on inflammatory and structural cells. Areas covered: We reviewed fevipiprant's mode of action and efficacy against other current and emerging pharmacological interventions for moderate-to-severe asthma...
February 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29276415/crth2-antagonists-in-asthma-current-perspectives
#5
REVIEW
Dave Singh, Arjun Ravi, Thomas Southworth
Chemoattractant receptor-homologous molecule expressed on TH 2 cells (CRTH2) binds to prostaglandin D2 . CRTH2 is expressed on various cell types including eosinophils, mast cells, and basophils. CRTH2 and prostaglandin D2 are involved in allergic inflammation and eosinophil activation. Orally administered CRTH2 antagonists are in clinical development for the treatment of asthma. The biology and clinical trial data indicate that CRTH2 antagonists should be targeted toward eosinophilic asthma. This article reviews the clinical evidence for CRTH2 involvement in asthma pathophysiology and clinical trials of CRTH2 antagonists in asthma...
2017: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/28964637/neuroendocrine-cells-derived-chemokine-vasoactive-intestinal-polypeptide-vip-in-allergic-diseases
#6
REVIEW
Alok K Verma, Murli Manohar, Sathisha Upparahalli Venkateshaiah, Anil Mishra
Worldwide increase incidences of allergic diseases have heightened the interest of clinicians and researchers to understand the role of neuroendocrine cells in the recruitment and activation of inflammatory cells. Several pieces of evidence revealed the association of neuropeptides in the pathogenesis of allergic diseases. Importantly, one such peptide that is secreted by neuronal cells and immune cells exerts a wide spectrum of immunological functions as cytokine/chemokine is termed as Vasoactive Intestinal Peptide (VIP)...
December 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28888244/new-and-anticipated-therapies-for-severe-asthma
#7
Stephen P Peters, William W Busse
Asthma is frequently undertreated, resulting in a relatively high prevalence of patients with uncontrolled disease, characterized by the presence of symptoms and risk of adverse outcomes. Patients with uncontrolled asthma have a higher risk of morbidity and mortality, underscoring the importance of identifying uncontrolled disease and modifying management plans to improve control. Several assessment tools exist to evaluate control with various cutoff points and measures, but these tools do not reliably correlate with physiological measures and should be considered a supplement to physiological tests...
September 2017: Journal of Allergy and Clinical Immunology in Practice
https://www.readbyqxmd.com/read/28838980/fevipiprant-an-oral-prostaglandin-dp2-receptor-crth2-antagonist-in-allergic-asthma-uncontrolled-on-low-dose-inhaled-corticosteroids
#8
Eric D Bateman, Alfredo G Guerreros, Florian Brockhaus, Björn Holzhauer, Abhijit Pethe, Richard A Kay, Robert G Townley
Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d) or twice-daily (2, 25, 75 or 150 mg b.i.d) fevipiprant (n=782), montelukast 10 mg q.d (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.dFevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0...
August 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28822449/-cytokine-profiles-of-cd4-t-memory-cells-in-asthma-and-their-relationship-with-asthma-severity
#9
C L Du, K Xu, Z H Min, D D Li, H L Yuan, C Liu, Z H Chen
Objective: To study the phenotype of memory CD4(+) T cells in peripheral blood of asthmatics and its relationship with asthma severity. Methods: From Dec 2014 to Aug 2015, thirty-three asthmatics, twenty-six chronic obstructive pulmonary disease (COPD) patients and twenty-two healthy volunteers were enrolled in Respiratory Clinics of Zhongshan Hospital, Fudan University. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood. Cell surface markers (CD45RO, CRTH2, CD62L, and CCR7) and intracellular protein[interleukin (IL)-5, IL-17, interferon (IFN)-γ]staining was performed using flow-cytometric techniques...
August 8, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28818625/the-therapeutic-potential-of-crth2-dp2-beyond-allergy-and-asthma
#10
REVIEW
Katharina Jandl, Akos Heinemann
Prostaglandin (PG) D2 has been in the focus of research for quite a long time, but its biological effects and its roles in human disease are still not fully characterized. When in 2001 a second major PGD2 receptor termed chemoattractant receptor homologue expressed on Th2 cells (CRTH2; alternative name DP2) was discovered, diverse investigations started to shed more light on the complex and often controversial actions of the prostaglandin. With various immunomodulating effects, such as induction of migration, activation, and cytokine release of leukocytes observed both in vivo and in vitro, CRTH2 has emerged as a promising target for the treatment of allergic diseases...
November 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28669561/effects-of-icariin-on-asthma-mouse-model-are-associated-with-regulation-of-prostaglandin-d2-level
#11
J Qiao, S Sun, L Yuan, J Wang
BACKGROUND: We aimed to observe the effect of icariin on an asthma mouse model and explore the potential underlying mechanisms. METHODS: The asthma mouse model was established by ovalbumin (OVA) sensitisation and respiratory syncytial virus (RSV) infection and then treated with icariin. Airway resistance was assessed by whole body plethysmograph. In addition, pathological slides were stained with haematoxylin-eosin, and the peribronchial inflammation was observed microscopically...
June 29, 2017: Allergologia et Immunopathologia
https://www.readbyqxmd.com/read/28612233/targeting-the-pgd2-crth2-dp1-signaling-pathway-in-asthma-and-allergic-disease-current-status-and-future-perspectives
#12
Maciej Kupczyk, Piotr Kuna
Prostaglandin D2 (PGD2) released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of inflammation in allergies and asthma. The biological effects of PGD2 are mediated by D-prostanoid (DP1), CRTH2 (DP2), and thromboxane prostanoid (TP) receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 (Th2) lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th2-type cytokines (interleukin [IL]-4, 5, 13), whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils...
August 2017: Drugs
https://www.readbyqxmd.com/read/28609567/safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-the-novel-crth2-antagonist-bi-1021958-at-single-oral-doses-in-healthy-men-and-multiple-oral-doses-in-men-and-women-with-well-controlled-asthma
#13
Andy Fowler, Rüdiger Koenen, James Hilbert, Jon Blatchford, Dominik Kappeler, Ewald Benediktus, Chester Wood, Abhya Gupta
BI 1021958, a novel antagonist of the chemoattractant-receptor-homologous molecule (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin binding to CRTH2 receptors. Two phase 1 studies assessed BI 1021958 safety/tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) following single doses in healthy men and multiple doses in men/women with well-controlled asthma. Studies 1 had 2 parts: a placebo-controlled, fixed-sequence, single-blind, single-rising-dose part (n = 56) and a randomized, 2-way crossover, open-label, repeated-dose part studying the food effect on PK/PD (n = 12)...
November 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28442499/absorption-distribution-metabolism-and-excretion-of-the-oral-prostaglandin-d2-receptor-2-dp2-antagonist-fevipiprant-qaw039-in-healthy-volunteers-and-in-vitro
#14
David Pearson, H Markus Weiss, Yi Jin, Jan Jaap van Lier, Veit J Erpenbeck, Ulrike Glaenzel, Peter End, Ralph Woessner, Fabian Eggimann, Gian Camenisch
Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200 mg oral dose of [(14)C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding...
April 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28433687/steroid-resistance-of-airway-type-2-innate-lymphoid-cells-from-patients-with-severe-asthma-the-role-of-thymic-stromal-lymphopoietin
#15
Sucai Liu, Mukesh Verma, Lidia Michalec, Weimin Liu, Anand Sripada, Donald Rollins, James Good, Yoko Ito, HongWei Chu, Magdalena M Gorska, Richard J Martin, Rafeul Alam
BACKGROUND: Type 2 innate lymphoid cells (ILC2s) represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown. OBJECTIVE: We sought to assess steroid resistance of human blood and airway ILC2s from asthmatic patients and to examine its mechanism of induction. METHODS: We studied human blood and lung ILC2s from asthmatic patients and control subjects using flow cytometry and ELISA. RESULTS: Dexamethasone inhibited (P = ...
January 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28422515/allergen-induced-increases-in-sputum-levels-of-group-2-innate-lymphoid-cells-in-subjects-with-asthma
#16
Ruchong Chen, Steven G Smith, Brittany Salter, Amani El-Gammal, John Paul Oliveria, Caitlin Obminski, Rick Watson, Paul M O'Byrne, Gail M Gauvreau, Roma Sehmi
RATIONALE: Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines, initiate eosinophilic inflammatory responses in murine models of asthma. OBJECTIVES: To investigate the role of ILC2 in allergen-induced airway eosinophilic responses in subjects with atopy and asthma. METHODS: Using a diluent-controlled allergen challenge crossover study, where all subjects (n = 10) developed allergen-induced early and late responses, airway eosinophilia, and increased methacholine airway responsiveness, bone marrow, blood, and sputum samples were collected before and after inhalation challenge...
September 15, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28099820/new-and-developing-non-adrenoreceptor-small-molecule-drugs-for-the-treatment-of-asthma
#17
REVIEW
Neil C Thomson
Inhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta2-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic asthma. Additional drugs include leukotriene-receptor antagonists, slow-release theophylline and the long-acting muscarinic antagonist (LAMA) tiotropium (approved in 2015). There is a need for more effective therapies, as many patients continue to have poorly controlled asthma. Areas covered: New and developing long-acting non-adrenoreceptor synthetic drugs for the treatment of symptomatic chronic asthma despite treatment with an ICS alone or combined with a LABA...
February 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28035475/increased-baff-expression-in-nasal-polyps-is-associated-with-local-ige-production-th2-response-and-concomitant-asthma
#18
Dilidaer, Yan Zheng, Zhuofu Liu, Xianting Hu, Jia Zhang, Li Hu, Miaomiao Han, Dehui Wang, Huabin Li
B-cell activating factor of the TNF family is critical for the survival and maturation of B cells and play a role in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). In this study, nasal tissues were enrolled from 25 CRSwNP patients (asthmatic, 16; non-asthmatic, 9), 12 CRSsNP patients and ten control subjects, respectively. The immunoreactivity of BAFF, CD20 and CD138 were examined using immunohistochemistry staining. The mRNA expression of BAFF, CD20, εGLT, AID, GATA3 and CRTH2 were examined using real-time RT-PCR...
April 2017: European Archives of Oto-rhino-laryngology
https://www.readbyqxmd.com/read/27773851/intradermal-grass-pollen-immunotherapy-increases-t-h-2-and-ige-responses-and-worsens-respiratory-allergic-symptoms
#19
RANDOMIZED CONTROLLED TRIAL
Anna Slovick, Abdel Douiri, Rachel Muir, Andrea Guerra, Konstantinos Tsioulos, Evie Hay, Emily P S Lam, Joanna Kelly, Janet L Peacock, Sun Ying, Mohamed H Shamji, David J Cousins, Stephen R Durham, Stephen J Till
BACKGROUND: Repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy. OBJECTIVE: We sought to evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis. METHODS: We randomly assigned 93 adults with grass pollen-induced allergic rhinitis to receive 7 preseasonal intradermal allergen injections (containing 7 ng of Phl p 5 major allergen) or a histamine control...
June 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27699264/depletion-of-major-pathogenic-cells-in-asthma-by-targeting-crth2
#20
Tao Huang, Meredith Hazen, Yonglei Shang, Meijuan Zhou, Xiumin Wu, Donghong Yan, Zhonghua Lin, Margaret Solon, Elizabeth Luis, Hai Ngu, Yongchang Shi, Arna Katewa, David F Choy, Nandhini Ramamoorthi, Erick R Castellanos, Mercedesz Balazs, Min Xu, Wyne P Lee, Marissa L Matsumoto, Jian Payandeh, Joseph R Arron, Jo-Anne Hongo, Jianyong Wang, Isidro Hötzel, Cary D Austin, Karin Reif
Eosinophilic inflammation and Th2 cytokine production are central to the pathogenesis of asthma. Agents that target either eosinophils or single Th2 cytokines have shown benefits in subsets of biomarker-positive patients. More broadly effective treatment or disease-modifying effects may be achieved by eliminating more than one inflammatory stimulator. Here we present a strategy to concomitantly deplete Th2 T cells, eosinophils, basophils, and type-2 innate lymphoid cells (ILC2s) by generating monoclonal antibodies with enhanced effector function (19A2) that target CRTh2 present on all 4 cell types...
May 19, 2016: JCI Insight
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