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Urinary Leukotriene E4 as a Biomarker in NSAID-Exacerbated Respiratory Disease (N-ERD): a Systematic Review and Meta-analysis. Curr Allergy Asthma Rep 2022; 22:209-229. [PMID: 36374376 PMCID: PMC9732072 DOI: 10.1007/s11882-022-01049-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE OF REVIEW Non-steroidal exacerbated respiratory disease (N-ERD) currently requires aspirin challenge testing for diagnosis. Urinary leukotriene E4 (uLTE4) has been extensively investigated as potential biomarker in N-ERD. We aimed to assess the usefulness of uLTE4 as a biomarker in the diagnosis of N-ERD. RECENT FINDINGS N-ERD, formerly known as aspirin-intolerant asthma (AIA), is characterised by increased leukotriene production. uLTE4 indicates cysteinyl leukotriene production, and a potential biomarker in N-ERD. Although several studies and have examined the relationship between uLTE4 and N-ERD, the usefulness of uLTE4 as a biomarker in a clinical setting remains unclear. FINDINGS Our literature search identified 38 unique eligible studies, 35 were included in the meta-analysis. Meta-analysis was performed (i.e. pooled standardised mean difference (SMD) with 95% confidence intervals (95% CI)) and risk of bias assessed (implementing Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (Cochrane DTA)). Data from 3376 subjects was analysed (1354 N-ERD, 1420 ATA, and 602 HC). uLTE4 was higher in N-ERD vs ATA (n = 35, SMD 0.80; 95% CI 0.72-0.89). uLTE4 increased following aspirin challenge in N-ERD (n = 12, SMD 0.56; 95% CI 0.26-0.85) but not ATA (n = 8, SMD 0.12; CI - 0.08-0.33). This systematic review and meta-analysis showed that uLTE4 is higher in N-ERD than ATA or HC. Likewise, people with N-ERD have greater increases in uLTE4 following aspirin challenge. However, due to the varied uLTE4 measurement and result reporting practice, clinical utility of these findings is limited. Future studies should be standardised to increase clinical significance and interpretability of the results.
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Miyata J, Fukunaga K, Kawashima Y, Ohara O, Kawana A, Asano K, Arita M. Dysregulated metabolism of polyunsaturated fatty acids in eosinophilic allergic diseases. Prostaglandins Other Lipid Mediat 2020; 150:106477. [PMID: 32711128 DOI: 10.1016/j.prostaglandins.2020.106477] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 01/06/2023]
Abstract
Polyunsaturated fatty acids (PUFAs), represented by the omega-6 fatty acid arachidonic acid (AA) and omega-3 fatty acid docosahexaenoic acid (DHA), are essential components of the human body. PUFAs are converted enzymatically into bioactive lipid mediators, including AA-derived cysteinyl leukotrienes (cys-LTs) and lipoxins and DHA-derived protectins, which orchestrate a wide range of immunological responses. For instance, eosinophils possess the biosynthetic capacity of various lipid mediators through multiple enzymes, including 5-lipoxygenase and 15-lipoxygenase, and play central roles in the regulation of allergic diseases. Dysregulated metabolism of PUFAs is reported, especially in severe asthma, aspirin-exacerbated respiratory disease, and eosinophilic chronic rhinosinusitis (ECRS), which is characterized by the overproduction of cys-LTs and impaired synthesis of pro-resolving mediators. Recently, by performing a multi-omics analysis (lipidomics, proteomics, and transcriptomics), we demonstrated the metabolic derangement of eosinophils in inflamed tissues of patients with ECRS. This abnormality occurred subsequent to altered enzyme expression of gamma-glutamyl transferase-5. In this review, we summarize the previous findings of dysregulated PUFA metabolism in allergic diseases, and discuss future prospective therapeutic strategies for correcting this imbalance.
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Affiliation(s)
- Jun Miyata
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan; Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
| | - Koichi Fukunaga
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
| | - Yusuke Kawashima
- Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan; Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
| | - Osamu Ohara
- Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan; Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
| | - Akihiko Kawana
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
| | - Koichiro Asano
- Division of Pulmonary Medicine, Department of Medicine, Tokai University, School of Medicine, Kanagawa, Japan.
| | - Makoto Arita
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan; Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
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Abstract
Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein-coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting β 2-agonists are widely used bronchodilators that signal through the activation of the β 2-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D2 receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A2B receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment. SIGNIFICANCE STATEMENT: Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein-coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.
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Affiliation(s)
- Stacy Gelhaus Wendell
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
| | - Hao Fan
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
| | - Cheng Zhang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
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Current state and future prospect of the therapeutic strategy targeting cysteinyl leukotriene metabolism in asthma. Respir Investig 2019; 57:534-543. [PMID: 31591069 DOI: 10.1016/j.resinv.2019.08.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/12/2019] [Accepted: 08/29/2019] [Indexed: 12/18/2022]
Abstract
Asthma is an allergic disorder with dominant type 2 airway inflammation, and its prevalence is increasing worldwide. Inhalation of corticosteroids is the primary treatment for asthma along with add-on drugs, including long-acting β2 agonists and/or cysteinyl leukotriene (cys-LT) receptor antagonists, in patients with poorly controlled asthma. Cys-LTs are composed of leukotriene C4 (LTC4), LTD4, and LTE4, which are enzymatically metabolized from arachidonic acid. These molecules act as inflammatory mediators through different types of high-affinity receptors, namely, CysLT1, CysLT2, and CysLT3 (also named as GPR99). CysLT1 antagonists possessing anti-inflammatory and bronchodilatory effects can be orally administered to patients with asthma. Recently, molecular biology-based studies have revealed the mechanism of inflammatory responses via other receptors, such as CysLT2 and CysLT3, as well as the importance of upstream inflammatory regulators, including type 2 cytokines (e.g., interleukins 4 and 5), in controlling cys-LT metabolism. These findings indicate the therapeutic potential of pharmacological agents targeting cys-LT metabolism-related receptors and enzymes, and antibody drugs neutralizing or antagonizing type 2 cytokines. This review focuses on the current state and future prospect of the therapeutic strategy targeting cys-LT metabolism.
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Blanca-Lopez N, Soriano V, Garcia-Martin E, Canto G, Blanca M. NSAID-induced reactions: classification, prevalence, impact, and management strategies. J Asthma Allergy 2019; 12:217-233. [PMID: 31496752 PMCID: PMC6690438 DOI: 10.2147/jaa.s164806] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 02/03/2019] [Indexed: 12/20/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading cause of hypersensitivity drug reactions. The different chemical structures, cyclooxygenase 1 (COX-1) and/or COX-2 inhibitors, are taken at all ages and some can be easily obtained over the counter. Vasoactive inflammatory mediators like histamine and leukotriene metabolites can produce local/systemic effects. Responders can be selective (SR), IgE or T-cell mediated, or cross-intolerant (CI). Inhibition of the COX pathway is the common mechanism in CI, with the skin being the most frequent organ involved, followed by the lung and/or the nose. An important number of cases have skin and respiratory involvement, with systemic manifestations ranging from mild to severe anaphylaxis. Among SR, this is the most frequent entity, often being severe. Recent years have seen an increase in reactions involving the skin, with many cases having urticaria and/or angioedema in the absence of chronic urticaria. Aspirin, the classical drug involved, has now been replaced by other NSAIDs, with ibuprofen being the universal culprit. For CI, no in vivo/in vitro diagnostic methods exist and controlled administration is the only option unless the cases evaluated report repetitive and consistent episodes with different NSAIDs. In SR, skin testing (patch and intradermal) with 24-48 reading can be useful, mainly for delayed T-cell responses. Acetyl salicylic acid (ASA) is the test drug to establish the diagnosis and confirm/exclude CI by controlled administration. Desensitization to ASA has been extensively used in respiratory cases though it can also be applied in those cases where it is required.
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Affiliation(s)
| | - Victor Soriano
- General University Hospital of Alicante-ISABIAL
, Alicante, Madrid, Spain
| | - Elena Garcia-Martin
- Medical and Surgery Therapy Department, University of Extremadura, Caceres, Spain
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Kowalski ML, Agache I, Bavbek S, Bakirtas A, Blanca M, Bochenek G, Bonini M, Heffler E, Klimek L, Laidlaw TM, Mullol J, Niżankowska‐Mogilnicka E, Park H, Sanak M, Sanchez‐Borges M, Sanchez‐Garcia S, Scadding G, Taniguchi M, Torres MJ, White AA, Wardzyńska A. Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper. Allergy 2019; 74:28-39. [PMID: 30216468 DOI: 10.1111/all.13599] [Citation(s) in RCA: 237] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 09/02/2018] [Indexed: 01/04/2023]
Abstract
NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.
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Affiliation(s)
| | - Ioana Agache
- Medical School Brasov Transylvania University Brasov Romania
| | - Sevim Bavbek
- Division of Allergy and Clinical Immunology Department of Chest Diseases School of Medicine Ankara University Ankara Turkey
| | - Arzu Bakirtas
- Department Pediatric Allergy and Asthma Faculty of Medicine Gazi University Ankara Turkey
| | - Miguel Blanca
- Allergy Service Hospital Infanta Leonor Madrid Spain
| | - Grażyna Bochenek
- Department of Internal Medicine Jagiellonian University Medical College Krakow Poland
| | - Matteo Bonini
- National Heart and Lung Institute Royal Brompton Hospital & Imperial College London London UK
| | - Enrico Heffler
- Department of Biomedical Sciences, Personalized Medicine Asthma and Allergy Clinic Humanitas University Milano Italy
| | - Ludger Klimek
- Center for Rhinology and Allergology Wiesbaden Germany
| | - Tanya M. Laidlaw
- Division of Rheumatology, Allergy, and Immunology Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts
| | - Joaquim Mullol
- Rhinology Unit & Smell Clinic ENT Department Hospital Clínic, Clinical & Experimental Respiratory Immunoallergy IDIBAPS, and CIBERES Barcelona Spain
| | | | - Hae‐Sim Park
- Department of Allergy and Clinical Immunology Ajou University School of Medicine Suwon Korea
| | - Marek Sanak
- Division of Molecular Biology and Clinical Genetics Department of Internal Medicine Jagiellonian University Medical College Kraków Poland
| | - Mario Sanchez‐Borges
- Allergy and Clinical Immunology Department Centro Medico‐Docente La Trinidad Caracas Venezuela
| | | | - Glenis Scadding
- Department of Allergy & Rhinology Royal National TNE Hospital London UK
| | - Masami Taniguchi
- Clinical Research Center for Allergy and Rheumatology Sagamihara National Hospital Sagamihara Japan
| | - Maria J. Torres
- Allergy Unit Malaga Regional University Hospital‐IBIMA ARADyAL Málaga Spain
| | - Andrew A. White
- Department of Allergy, Asthma and Immunology Scripps Clinic San Diego California
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Kim CK, Callaway Z, Park JS, Nishimori H, Ogino T, Nagao M, Fujisawa T. Montelukast Reduces Serum Levels of Eosinophil-Derived Neurotoxin in Preschool Asthma. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2018; 10:686-697. [PMID: 30306750 PMCID: PMC6182197 DOI: 10.4168/aair.2018.10.6.686] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 08/06/2018] [Accepted: 08/07/2018] [Indexed: 11/26/2022]
Abstract
PURPOSE Several markers for eosinophilic inflammation have been proposed to predict response to asthma treatment. However, definitive criteria for treatment decisions have not yet been established. We investigate a potentially useful relatively non-invasive biomarker, eosinophil-derived neurotoxin (EDN), to predict favorable responses to budesonide or montelukast, common treatment for children with asthma. METHODS Young children (1 to 6 years old) were enrolled in this randomized, parallel, 2-group, open-label trial. Criteria for eligibility included: 1) being symptomatic during the run-in period; and 2) having a serum EDN (sEDN) level ≥ 53 ng/mL, with positive specific immunoglobulin E to house dust mite. Eligible patients were randomly placed into 2 groups: the BIS group received budesonide inhalation suspension (BIS) 0.5 mg once daily; the MONT group received montelukast 4 mg once daily. Ineligible patients were invited to receive montelukast 4 mg once daily (OBS group). Treatment period was 12 weeks. RESULTS Asthma control days increased significantly in the BIS and MONT groups (P < 0.000) over the 12-week study period. There was no significant change in sEDN in the BIS group but there was a significant decrease in the MONT group (P < 0.000). Patients in the OBS group with high EDN levels (< 53 ng/mL) showed a significant decrease due to MONT treatment (P = 0.023). Rescue medication usage significantly decreased in the BIS and MONT groups (P < 0.000). CONCLUSIONS EDN is a useful relatively non-invasive biomarker for predicting responses to montelukast and budesonide treatment of preschool children with beta2-agonist responsive recurrent wheeze and multiple-trigger wheeze (Trial registry at UMIN Clinical Trials Registry, UMIN000008335).
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Affiliation(s)
- Chang Keun Kim
- Asthma & Allergy Center, Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Zak Callaway
- Asthma & Allergy Center, Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea
- School of Biological Sciences, University of Ulsan, Ulsan, Korea
| | - Jin Sung Park
- Asthma & Allergy Center, Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Hisashi Nishimori
- Department of Pediatrics, Mie Prefectural General Medical Center, Tsu, Japan
| | | | - Mizuho Nagao
- Institute for Clinical Research, Mie National Hospital, Tsu, Japan
| | - Takao Fujisawa
- Institute for Clinical Research, Mie National Hospital, Tsu, Japan.
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Nakagome K, Nagata M. Involvement and Possible Role of Eosinophils in Asthma Exacerbation. Front Immunol 2018; 9:2220. [PMID: 30323811 PMCID: PMC6172316 DOI: 10.3389/fimmu.2018.02220] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 09/07/2018] [Indexed: 01/21/2023] Open
Abstract
Eosinophils are involved in the development of asthma exacerbation. Recent studies have suggested that sputum and blood eosinophil counts are important factors for predicting asthma exacerbation. In severe eosinophilic asthma, anti-interleukin (IL)-5 monoclonal antibody decreases blood eosinophil count and asthma exacerbation frequency. However, even in the absence of IL-5, eosinophilic airway inflammation can be sufficiently maintained by the T helper (Th) 2 network, which comprises a cascade of vascular cell adhesion molecule-1/CC chemokines/eosinophil growth factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF). Periostin, an extracellular matrix protein and a biomarker of the Th2 immune response in asthma, directly activates eosinophils in vitro. A major cause of asthma exacerbation is viral infection, especially rhinovirus (RV) infection. The expression of intercellular adhesion molecule (ICAM)-1, a cellular receptor for the majority of RVs, on epithelial cells is increased after RV infection, and adhesion of eosinophils to ICAM-1 can upregulate the functions of eosinophils. The expressions of cysteinyl leukotrienes (cysLTs) and CXCL10 are upregulated in virus-induced asthma. CysLTs can directly provoke eosinophilic infiltration in vivo and activate eosinophils in vitro. Furthermore, eosinophils express the CXC chemokine receptor 3, and CXCL10 activates eosinophils in vitro. Both eosinophils and neutrophils contribute to the development of severe asthma or asthma exacerbation. IL-8, which is an important chemoattractant for neutrophils, is upregulated in some cases of severe asthma. Lipopolysaccharide (LPS), which induces IL-8 from epithelial cells, is also increased in the lower airways of corticosteroid-resistant asthma. IL-8 or LPS-stimulated neutrophils increase the transbasement membrane migration of eosinophils, even in the absence of chemoattractants for eosinophils. Therefore, eosinophils are likely to contribute to the development of asthma exacerbation through several mechanisms, including activation by Th2 cytokines, such as IL-5 or GM-CSF or by virus infection-related proteins, such as CXCL10, and interaction with other cells, such as neutrophils.
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Affiliation(s)
- Kazuyuki Nakagome
- Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.,Allergy Center, Saitama Medical University, Saitama, Japan
| | - Makoto Nagata
- Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.,Allergy Center, Saitama Medical University, Saitama, Japan
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House Dust Mite Respiratory Allergy: An Overview of Current Therapeutic Strategies. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2015; 3:843-55. [PMID: 26342746 DOI: 10.1016/j.jaip.2015.06.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 05/15/2015] [Accepted: 06/01/2015] [Indexed: 01/24/2023]
Abstract
Although house dust mite (HDM) allergy is a major cause of respiratory allergic disease, specific diagnosis and effective treatment both present unresolved challenges. Guidelines for the treatment of allergic rhinitis and asthma are well supported in the literature, but specific evidence on the efficacy of pharmacotherapy treatment for known HDM-allergic patients is weaker. The standard diagnostic techniques--skin prick test and specific IgE testing--can be confounded by cross-reactivity. However, component-resolved diagnosis using purified and recombinant allergens can improve the accuracy of specific IgE testing, but availability is limited. Treatment options for HDM allergy are limited and include HDM avoidance, which is widely recommended as a strategy, although evidence for its efficacy is variable. Clinical efficacy of pharmacotherapy is well documented; however, symptom relief does not extend beyond the end of treatment. Finally, allergen immunotherapy has a poor but improving evidence base (notably on sublingual tablets) and its benefits last after treatment ends. This review identifies needs for deeper physician knowledge on the extent and impact of HDM allergy in respiratory disease, as well as further development and improved access to molecular allergy diagnosis. Furthermore, there is a need for the development of better-designed clinical trials to explore the utility of allergen-specific approaches, and uptake of data into guidance for physicians on more effective diagnosis and therapy of HDM respiratory allergy in practice.
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Enhanced cysteinyl-leukotriene type 1 receptor expression in T cells from house dust mite-allergic individuals following stimulation with Der p. J Immunol Res 2015; 2015:384780. [PMID: 25918735 PMCID: PMC4396553 DOI: 10.1155/2015/384780] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 02/20/2015] [Accepted: 03/04/2015] [Indexed: 01/01/2023] Open
Abstract
In order to determine the potential for allergen to modulate T cell expression of the CysLT1 receptor and responsiveness to leukotrienes, peripheral blood mononuclear cells from house dust mite-allergic or nonallergic individuals were incubated with D. pteronyssinus allergen (Der p). Baseline CysLT1 expression was similar in both groups of donors, but Der p significantly enhanced CysLT1 expression in CD4+ and CD8+ T cells of only allergic individuals and induced enhanced responsiveness of CD4+ T cells to LTD4 in terms of calcium mobilisation. This effect was prevented by the CysLT1 antagonist MK571. Der p also induced IL-4 and IL-10 production, and neutralizing antibody to IL-4 prevented both the enhanced CysLT1 expression and the enhanced responsiveness of T cells to LTD4 induced by Der p. In allergic individuals, Der p also induced T cell proliferation and a Th2-biased phenotype. Our data suggest that, in allergen-sensitized individuals, exposure to allergen can enhance T cell expression of CysLT1 receptors through a mechanism involving IL-4 production. This, in turn, would induce CD4+ T cell responsiveness to cysteinyl-leukotrienes and Th2 cell activation.
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Mastalerz L, Celejewska-Wójcik N, Wójcik K, Gielicz A, Januszek R, Cholewa A, Stręk P, Sanak M. Induced sputum eicosanoids during aspirin bronchial challenge of asthmatic patients with aspirin hypersensitivity. Allergy 2014; 69:1550-9. [PMID: 25123806 DOI: 10.1111/all.12512] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2014] [Indexed: 01/06/2023]
Abstract
BACKGROUND Altered metabolism of eicosanoids is a characteristic finding in aspirin-exacerbated respiratory disease (AERD). Bronchial challenge with lysyl-aspirin can be used as a confirmatory diagnostic test for this clinical condition. Induced sputum allows to measure mediators of asthmatic inflammation in bronchial secretions. OBJECTIVES To investigate the influence of inhaled lysyl-aspirin on sputum supernatant concentration of eicosanoids during the bronchial challenge test. Subjects with asthma hypersensitive to nonsteroidal anti-inflammatory drugs were compared with aspirin-tolerant asthmatic controls. METHODS Induced sputum was collected before and following bronchial challenge with lysyl-aspirin. Sputum differential cell count and sputum supernatant concentrations of selected lipoxygenases products: 5-,12-,15-hydroxyeicosatetraenoic acid, cysteinyl leukotrienes, leukotriene B4 , 11-dehydro-thromboxane B2 , and prostaglandins E2 , D2 , and F2α and their metabolites, were measured using validated methods of chromatography-mass spectrometry. RESULTS Aspirin precipitated bronchoconstriction in all AERD subjects, but in none of the aspirin-tolerant asthmatics. Phenotypes of asthma based on the sputum cytology did not differ between the groups. Baseline sputum eosinophilia correlated with a higher leukotriene D4 (LTD4 ) and leukotriene E4 (LTE4 ) concentrations. LTC4 , PGE2 , and 11-dehydro-TXB2 did not differ between the groups, but levels of LTD4 , LTE4 , and PGD2 were significantly higher in AERD group. Following the challenge, LTD4 and LTE4 increased, while PGE2 and LTB4 decreased in AERD subjects only. CONCLUSIONS During the bronchial challenge, decrease in PGE2 and its metabolite is accompanied by a surge in bronchoconstrictory cysteinyl leukotrienes produced at the expense of LTB4 in AERD subjects. Bronchial PGE2 inhibition in AERD seems specific and sensitive to a low dose of aspirin.
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Affiliation(s)
- L. Mastalerz
- Department of Medicine; School of Medicine; Jagiellonian University; Cracow Poland
| | - N. Celejewska-Wójcik
- Department of Medicine; School of Medicine; Jagiellonian University; Cracow Poland
| | - K. Wójcik
- Department of Medicine; School of Medicine; Jagiellonian University; Cracow Poland
| | - A. Gielicz
- Department of Medicine; School of Medicine; Jagiellonian University; Cracow Poland
| | - R. Januszek
- Department of Medicine; School of Medicine; Jagiellonian University; Cracow Poland
| | - A. Cholewa
- Department of Medicine; School of Medicine; Jagiellonian University; Cracow Poland
| | - P. Stręk
- Department of Medicine; School of Medicine; Jagiellonian University; Cracow Poland
| | - M. Sanak
- Department of Medicine; School of Medicine; Jagiellonian University; Cracow Poland
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Matsuse H, Tsuchida T, Fukahori S, Kawano T, Tomari S, Matsuo N, Nishino T, Fukushima C, Kohno S. Retrospective cohort study of leukotriene receptor antagonist therapy for preventing upper respiratory infection-induced acute asthma exacerbations. ALLERGY & RHINOLOGY 2014; 4:e127-31. [PMID: 24498517 PMCID: PMC3911801 DOI: 10.2500/ar.2013.4.0062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Upper respiratory tract infections (URIs) represent the most frequent cause of acute asthma exacerbations. It has yet to be determined whether leukotriene receptor antagonist (LTRA) treatment prevents URI-induced acute asthma exacerbations in adults. The objective of the present study was to evaluate the preventive effects of LTRA treatment on URI-induced acute asthma exacerbations. The incidences of URI alone, acute asthma exacerbation without URI, and URI-induced acute asthma exacerbation were determined retrospectively by analyzing diary and medical records of 321 adult asthmatic patients (mean age, 56.3 ± 17.2 years; male/female ratio, 117:204) over 1 year. Results were compared between patients who had been taking an LTRA (n = 137) and those who had never taken any LTRA (n = 184) during the study periods. Significantly fewer URIs alone and acute asthma exacerbations without URI occurred in patients with than in those without prophylactic daily use of LTRA. LTRA treatment significantly reduced the durations of URIs alone and of total acute asthma exacerbations, as well as the incidence of mild exacerbations of asthma. In contrast, in patients with URI-induced acute asthma exacerbations, LTRA treatment failed to significantly reduce the interval between URI onset and acute asthma exacerbation, as well as the duration and severity of both URIs and acute asthma exacerbations. Use of an LTRA for adult asthmatic patients appears to reduce the incidences of URIs alone and acute asthma exacerbations without URI, but it failed to prevent URI-induced acute asthma exacerbations once a URI occurred.
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Affiliation(s)
- Hiroto Matsuse
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Tomoko Tsuchida
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Susumu Fukahori
- Department of Internal Medicine, Sasebo City General Hospital, Sasebo, Japan
| | - Tetsuya Kawano
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Shinya Tomari
- Department of Internal Medicine, Isahaya Health Insurance General Hospital, Nagasaki, Japan, and
| | - Nobuko Matsuo
- Department of Internal Medicine, Nagasaki Municipal Hospital, Nagasaki, Japan
| | - Tomoya Nishino
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Chizu Fukushima
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Shigeru Kohno
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
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Matsuse H, Kohno S. Leukotriene receptor antagonists pranlukast and montelukast for treating asthma. Expert Opin Pharmacother 2013; 15:353-63. [PMID: 24350802 DOI: 10.1517/14656566.2014.872241] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION The prevalence of bronchial asthma, which is a chronic inflammatory disorder of the airway, is increasing worldwide. Although inhaled corticosteroids (ICS) play a central role in the treatment of asthma, they cannot achieve good control for all asthmatics, and medications such as leukotriene receptor antagonists (LTRAs) with bronchodilatory and anti-inflammatory effects often serve as alternatives or add-on drugs. AREAS COVERED Clinical trials as well as basic studies of montelukast and pranlukast in animal models are ongoing. This review report clarifies the current status of these two LTRAs in the treatment of asthma and their future direction. EXPERT OPINION LTRAs could replace ICS as first-line medications for asthmatics who are refractory to ICS or cannot use inhalant devices. Further, LTRAs are recommended for asthmatics under specific circumstances that are closely associated with cysteinyl leukotrienes (cysLTs). Considering the low incidence of both severe adverse effects and the induction of tachyphylaxis, oral LTRAs should be more carefully considered for treating asthma in the clinical environment. Several issues such as predicted responses, effects of peripheral airway and airway remodeling and alternative administration routes remain to be clarified before LTRAs could serve a more effective role in the treatment of asthma.
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Affiliation(s)
- Hiroto Matsuse
- Nagasaki University School of Medicine, Second Department of Internal Medicine , 1-7-1 Sakamoto, Nagasaki 852-8501 , Japan +81 95 819 7273 ; +81 95 849 7285 ;
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Jian W, Edom RW, Xue X, Huang MQ, Fourie A, Weng N. Quantitation of leukotriene B(4) in human sputum as a biomarker using UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 932:59-65. [PMID: 23831697 DOI: 10.1016/j.jchromb.2013.06.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 06/03/2013] [Accepted: 06/07/2013] [Indexed: 11/17/2022]
Abstract
Leukotriene B4 (LTB4) is a potent mediator of inflammation and has been recognized as an important target for therapeutic intervention for treatment of diseases such as asthma. In the current work, a highly selective and sensitive UPLC-MS/MS assay was developed for quantitation of LTB4 in human sputum as a biomarker for LTB4 biosynthesis inhibition. A fit-for-purpose strategy for method development, assay qualification, and study support was adopted for this biomarker project. A surrogate matrix (protein buffer) was used for preparation of calibration samples and certain levels of quality control (QC) samples to avoid interference from endogenous analyte, while the low QC was prepared in authentic matrix, human sputum. The analytical methodology utilized a liquid-liquid extraction procedure in 96-well plate format. Chromatographic separation was achieved with a reversed-phase ultra high pressure liquid chromatography (UPLC) column using gradient elution, and the run time was 4.5min per sample. The lower limit of quantitation (LLOQ) was 0.2ng/mL, and the calibration curve range was 0.2-20ng/mL. Acceptable accuracy, precision, linearity, specificity, recovery, and matrix effect was obtained. Bench-top stability (6h), freeze-thaw stability (3 cycles at -20°C), and autosampler stability (97h at ambient temperature) all met acceptance criteria. Frozen long-term stability for 166 days at -20°C in sputum did not meet acceptance criteria by showing only ≥75% of nominal concentration and the information was taken into consideration for study support. Two important observations in the current work were: (1) LTB4 was unstable in sputum in the presence of liquification reagent dithiothreitol (DTT). Therefore, a non-DTT treatment method for sputum processing was developed and applied to the bioanalytical assay and clinical study support; and (2) chromatographic separation of LTB4 from its three non-enzymatically derived isomers, i.e. 6-trans-LTB4, 12-epi-LTB4, and 6-trans-12-epi-LTB4, was achieved. This assay was successfully applied to a Phase II clinical study for proof-of-concept of a LTA4 hydrolase inhibitor for treatment of asthma.
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Affiliation(s)
- Wenying Jian
- Drug Safety Sciences, Janssen Research & Development, Johnson & Johnson, Raritan, NJ 08869, USA.
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15
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Aspirin sensitivity and chronic rhinosinusitis with polyps: a fatal combination. J Allergy (Cairo) 2012; 2012:817910. [PMID: 22927869 PMCID: PMC3425836 DOI: 10.1155/2012/817910] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Revised: 05/16/2012] [Accepted: 06/13/2012] [Indexed: 12/17/2022] Open
Abstract
Aspirin-exacerbated respiratory disease (AERD) refers to aspirin sensitivity, chronic rhinosinusitis (CRS), nasal polyposis, asthma, eosinophil inflammation in the upper and lower airways, urticaria, angioedema, and anaphylaxis following the ingestion of NSAIDs. Epidemiologic and pathophysiological links between these diseases are established. The precise pathogenesis remains less defined, even though there is some progress in the understanding of several molecular mechanisms. Nevertheless, these combinations of diseases in patients classified by AERD constitute a fatal combination and may be difficult to treat with standard medical and surgical interventions. This paper reviews in brief the epidemiology, clinical features, diagnosis, molecular pathogenesis, and specific therapies of patients classified by AERD and postulates future attempts to gain new insights into this disease.
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Bäck M, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE. International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions. Pharmacol Rev 2011; 63:539-84. [PMID: 21771892 DOI: 10.1124/pr.110.004184] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
The seven-transmembrane G protein-coupled receptors activated by leukotrienes are divided into two subclasses based on their ligand specificity for either leukotriene B(4) or the cysteinyl leukotrienes (LTC(4), LTD(4), and LTE(4)). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT(1) and BLT(2) receptors and CysLT(1) and CysLT(2) receptors has been established. However, recent findings have also indicated the existence of putative additional leukotriene receptor subtypes. Furthermore, other ligands interact with the leukotriene receptors. Finally, leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the leukotriene receptors as well as the therapeutic developments in this area of research.
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Affiliation(s)
- Magnus Bäck
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
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Oh SH, Kim YH, Park SM, Cho SH, Park JS, Jang AS, Park SW, Uh ST, Lee YM, Kim MK, Choi IS, Cho SH, Hong CS, Lee YW, Lee JY, Choi BW, Park BL, Shin HD, Park CS. Association analysis of thromboxane A synthase 1 gene polymorphisms with aspirin intolerance in asthmatic patients. Pharmacogenomics 2011; 12:351-63. [PMID: 21449675 DOI: 10.2217/pgs.10.181] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
AIM Thromboxane A synthase (TBXAS1) converts prostaglandin H to thromboxane A, a potent constrictor of smooth respiratory muscle. Thus, functional alterations of the TBXAS1 gene may contribute to aspirin-intolerant asthma (AIA). MATERIALS & METHODS We investigated the relationship between SNPs in the TBXAS1 gene and AIA. Asthmatics (n = 470) were categorized into AIA (20% or greater decreases in forced expiratory volume in 1 s [FEV(1)], or 15% to 19% decreases in FEV(1) with naso-ocular or cutaneous reactions) and aspirin-tolerant asthma (ATA). A total of 101 SNPs were genotyped. mRNA expression of the TBXAS1 gene by peripheral blood mononuclear cells and plasma thromboxane B2 (TXB2) concentrations were measured by reverse transcriptase (RT)-PCR and ELISA. RESULTS Logistic regression analysis showed that the rare allele frequency of rs6962291 in intron 9 was significantly lower in the AIA group (n = 115) than in the ATA group (n = 270) (p(corr) = 0.04). The linear regression analysis revealed a strong association of rs6962291 with the aspirin challenge-induced FEV(1) fall (p = 0.003). RT-PCR revealed an exon-12-deleted splice variant. We measured TBXAS1 mRNA levels in peripheral blood mononuclear cells. The mRNA levels of the full-length wild-type and splice variant were significantly higher in the TT homozygotes than in the AA homozygotes of rs6962291 (1.00 ± 0.18 vs 0.57 ± 0.03 and 1.00 ± 0.18 vs 0.21 ± 0.05, p = 0.047 and 0.001, respectively). The plasma TXB2 level was significantly lower in rs6962291 AA carriers than in rs6962291 TT (p = 0.016) carriers. CONCLUSION The rare allele of rs6962291 may play a protective role against aspirin hypersensitivity via a lower catalytic activity of the TBXAS1 gene, attributed to the increase of a nonfunctioning isoform of TBXAS1.
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Affiliation(s)
- Sun-Hee Oh
- Genome Research Center for Allergy & Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do, 420-767, Republic of Korea
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Ono E, Taniguchi M, Higashi N, Mita H, Yamaguchi H, Tatsuno S, Fukutomi Y, Tanimoto H, Sekiya K, Oshikata C, Tsuburai T, Tsurikisawa N, Otomo M, Maeda Y, Hasegawa M, Miyazaki E, Kumamoto T, Akiyama K. Increase in salivary cysteinyl-leukotriene concentration in patients with aspirin-intolerant asthma. Allergol Int 2011; 60:37-43. [PMID: 21099251 DOI: 10.2332/allergolint.09-oa-0166] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Accepted: 07/08/2010] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Cysteinyl-leukotrienes (CysLTs; LTC4, LTD4, and LTE4) play a considerable role in the pathophysiology of aspirin-intolerant asthma (AIA). Saliva has recently been validated as novel, simple, and noninvasive method for investigating inflammation in patients with asthma. The aim of this study is to clarify the molecular species of CysLT in saliva and to evaluate the CysLT and LTB4 concentrations in saliva in AIA patients. We also examined how the CysLT concentration in saliva reflects that of their corresponding urinary metabolite. METHODS We preformed an analytical cross-sectional study. CysLT and LTB4 concentrations in saliva were quantified by enzyme immunoassay (EIA) following purification by high-performance liquid chromatography (HPLC). RESULTS 1. When analyzed by EIA in combination with HPLC, saliva was found to consist of LTC4, LTD4 and LTE4 in similar amounts. 2. In saliva analysis among the three groups (AIA patients, aspirin-tolerant asthma [ATA] patients, and healthy subjects), both the concentrations of CysLTs and LTB4 were significantly higher in AIA patients than in ATA patients and healthy subjects. 3. We found significant correlations between CysLT concentration and LTB4 concentration in saliva in each group. 4. No significant correlation was found between the concentration of LTE4 in urine and that of CysLTs in saliva. CONCLUSIONS In this study, we found higher concentrations of CysLTs and LTB4 in saliva from AIA patients than in saliva from ATA patients, suggesting that the quantification of CysLT and LTB4 concentrations in saliva may be another diagnostic strategy for AIA.
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Affiliation(s)
- Emiko Ono
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan. onoemii@oita−u.ac.jp
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Kim JH, Cha JY, Cheong HS, Park JS, Jang AS, Uh ST, Kim MK, Choi IS, Cho SH, Park BL, Bae JS, Park CS, Shin HD. KIF3A, a cilia structural gene on chromosome 5q31, and its polymorphisms show an association with aspirin hypersensitivity in asthma. J Clin Immunol 2010; 31:112-21. [PMID: 20922562 DOI: 10.1007/s10875-010-9462-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Accepted: 09/07/2010] [Indexed: 11/28/2022]
Abstract
INTRODUCTION The kinesin family number 3A (KIF3A) gene on the human chromosomal 5q31-33 region, which is known as a susceptibility locus for immune diseases including asthma, plays a crucial role in generation of cilia. RESULTS A treatment with aspirin in the human bronchial epithelial cells increased the mRNA expression level of KIF3A compared to that of the untreated control (P ≤ 0.01), and nasal polyp epithelia from aspirin-intolerant asthma (AIA) patients also showed a higher expression of KIF3A protein than aspirin-tolerant asthma controls. Further logistic analyses revealed that most polymorphisms of KIF3A were significantly associated with AIA (P = 0.0004-0.02; P(corr) = 0.004-0.04) and the decline of forced expiratory volume at 1 s (FEV(1))% by aspirin provocation (P = 0.004-0.04; P(corr) = 0.03). DISCUSSION Our findings suggest that the KIF3A gene and/or its polymorphisms might have a susceptibility effect on AIA, providing a new step toward controlling aspirin intolerance in asthmatics.
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Affiliation(s)
- Jeong-Hyun Kim
- Department of Life Science, Sogang University, Seoul 121-742, Republic of Korea
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Kim CK, Choi J, Kim HB, Callaway Z, Shin BM, Kim JT, Fujisawa T, Koh YY. A randomized intervention of montelukast for post-bronchiolitis: effect on eosinophil degranulation. J Pediatr 2010; 156:749-54. [PMID: 20171653 DOI: 10.1016/j.jpeds.2009.12.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2009] [Revised: 10/08/2009] [Accepted: 12/01/2009] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To investigate the effect of montelukast on eosinophil degranulation and recurrent wheezing episodes in post-respiratory syncytial virus (RSV) bronchiolitis. STUDY DESIGN Two hundred infants (age, 6-24 months) who were hospitalized with their first episode of acute RSV bronchiolitis were randomized in a double-blind, placebo-controlled, parallel comparison of 4-mg montelukast granules (RSV-MONT group) or matching placebo (RSV-PLC group) administered for 3 months. Serum eosinophil-derived neurotoxin (EDN) levels were measured (primary outcome), and recurrent wheezing was documented (secondary outcome) for 12 months. Comparisons were made with control subjects (control group, n = 50). RESULTS At the end of the 3-month treatment period, the RSV-PLC group (n = 71) exhibited significantly elevated EDN levels (P < .0001), and the RSV-MONT group (n = 79) showed significantly decreased EDN levels (P < .01) when compared with the initial levels. As a result, EDN levels in the 2 RSV groups significantly differed at this point (P < .0001) and remained different for the entire 12-month follow-up period. Cumulative recurrent wheezing episodes at 12 months were significantly lower in the RSV-MONT group (P = .039). CONCLUSION Montelukast treatment reduces eosinophil degranulation and is associated with a decrease in recurrent wheezing episodes in post-RSV bronchiolitis.
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Affiliation(s)
- Chang-Keun Kim
- Department of Pediatrics and Asthma and Allergy Center, Inje University Sanggye Paik Hospital, Seoul, Korea
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Palikhe NS, Kim JH, Park HS. Update on recent advances in the management of aspirin exacerbated respiratory disease. Yonsei Med J 2009; 50:744-50. [PMID: 20046412 PMCID: PMC2796398 DOI: 10.3349/ymj.2009.50.6.744] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2009] [Indexed: 02/02/2023] Open
Abstract
Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1*301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.
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Affiliation(s)
- Nami Shrestha Palikhe
- Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea
| | - Joo-Hee Kim
- Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea
| | - Hae-Sim Park
- Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea
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Kim SH, Ye YM, Hur GY, Lee SK, Sampson AP, Lee HY, Park HS. CysLTR1 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients. Pharmacogenomics 2008; 8:1143-50. [PMID: 17924829 DOI: 10.2217/14622416.8.9.1143] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVES Leukotriene receptor antagonists (LTRA), such as montelukast, have been used as a first-line treatment for patients with aspirin-intolerant asthma (AIA). This study evaluated associations between the clinical requirement for LTRA and genetic polymorphisms of the ALOX5, LTC4S, COX-2, CysLTR1 and TBXA2R genes in the arachidonic acid cascade in the long-term management of 89 AIA patients from a Korean population. METHODS Asthma control status was monitored for 1 year with maintenance medications of inhaled corticosteroid and oral LTRA, and AIA patients were classified into three groups according to the mean montelukast dose required per month to maintain asthma control for 1 year: group I (> or = 200 mg montelukast/month; n = 37), group II (5-150 mg/month; n = 25) and group III (< 5 mg/month; n = 27). Genetic polymorphisms in the arachidonic acid cascade were determined using a single-base extension method. RESULTS We found that there was a significant difference in the genotype frequency of the CysLTR1 promoter polymorphism -634C > T among the three groups (p = 0.007 for group I vs group II, p = 0.017 for group I vs group III), while there were no significant associations between LTRA requirements and polymorphisms of the other genes. The patients with the variant genotype (CT or TT) of the -634C = T CysLTR1 promoter polymorphism showed a higher expression level than those with the common genotype (CC). CONCLUSION These findings indicate that the CysLTR1 promoter polymorphism is a useful genetic marker for predicting LTRA requirements in the long-term management of AIA patients.
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Affiliation(s)
- Seung-Hyun Kim
- Ajou University School of Medicine, Department of Allergy and Rheumatology, Yeongtonggu Wonchondong San-5, Suwon 443-721, Korea
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Kim SH, Hur GY, Choi JH, Park HS. Pharmacogenetics of aspirin-intolerant asthma. Pharmacogenomics 2008; 9:85-91. [PMID: 18154450 DOI: 10.2217/14622416.9.1.85] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Leukotriene overproduction is the major characteristic of aspirin-intolerant asthma (AIA). Most studies examining the molecular genetic mechanisms of AIA have focused on leukotriene-related genes, including ALOX5, LTC4S, TXA2R and prostanoid-receptor genes. One study suggested that the human leukocyte antigen (HLA) allele DPB1*0301 may be a genetic marker for the AIA phenotype in European and Asian populations, and HLA-DPB1*0301 has been suggested as a useful genetic marker for predicting more favorable responders to leukotriene-receptor antagonists for long-term management of AIA. Although several reports have indicated possible associations between genetic polymorphisms and variable responses to leukotriene modifiers in nonaspirin sensitive asthmatic patients, few have suggested relationships between such genetic polymorphisms and variable responses to asthma drugs in AIA patients.
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Affiliation(s)
- Seung-Hyun Kim
- Ajou University School of Medicine, Department of Allergy & Rheumatology, San-5, WonchonDong, YoungtongGu, Suwon, Korea
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Carpagnano GE, Resta O, Gelardi M, Spanevello A, Di Gioia G, Giliberti T, Depalo A, Foschino Barbaro MP. Exhaled inflammatory markers in aspirin-induced asthma syndrome. ACTA ACUST UNITED AC 2008; 21:542-7. [PMID: 17999786 DOI: 10.2500/ajr.2007.21.3066] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Interleukin (IL)-4 and IL-6, respectively, markers of neutrophilic and eosinophilic inflammation, were analyzed in nasal and oral exhaled breath condensate to understand the inflammation of upper and lower airways in subjects with aspirin-induced asthma (AIA) syndrome, evaluating possible differences between AIA and the single pathological conditions included in AIA syndrome. METHODS Twelve patients with AIA, 17 patients with mild asthma (MA), 12 patients with nasal polyposis (NP), 11 patients with mild asthma + nasal polyposis (MA + NP), and 10 healthy subjects (HSs) were enrolled. Nasal and oral exhaled IL-4 and IL-6 were measured by enzyme immunoassay kit. RESULTS Higher levels of nasal and oral exhaled IL-4 and IL-6 were observed in AIA compared with MA, NP, MA + NP, and HSs. Moreover, a positive correlation was identified between nasal exhaled IL-4 and IL-6 and, respectively, the number of neutrophils and eosinophils and in nasal scraping. CONCLUSION The concentration of eosinophilic and neutrophilic markers in upper and lower airways of subjects with AIA syndrome is higher compared with HS and subjects with MA, NP, and MA + NP.
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Affiliation(s)
- Giovanna E Carpagnano
- Institute of Respiratory Disease, Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy.
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Capra V, Thompson MD, Sala A, Cole DE, Folco G, Rovati GE. Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: critical update and emerging trends. Med Res Rev 2007; 27:469-527. [PMID: 16894531 DOI: 10.1002/med.20071] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cysteinyl-leukotrienes (cysteinyl-LTs), that is, LTC4, LTD4, and LTE4, trigger contractile and inflammatory responses through the specific interaction with G protein-coupled receptors (GPCRs) belonging to the purine receptor cluster of the rhodopsin family, and identified as CysLT receptors (CysLTRs). Cysteinyl-LTs have a clear role in pathophysiological conditions such as asthma and allergic rhinitis (AR), and have been implicated in other inflammatory conditions including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. Molecular cloning of human CysLT1R and CysLT2R subtypes has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Interestingly, recent data provide evidence for the immunomodulation of CysLTR expression, the existence of additional receptor subtypes, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Furthermore, genetic variants have been identified for the CysLTRs that may interact to confer risk for atopy. Finally, a crosstalk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize and attempt to integrate recent data derived from studies on the molecular pharmacology and pharmacogenetics of CysLTRs, and will consider the therapeutic opportunities arising from the new roles suggested for cysteinyl-LTs and their receptors.
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MESH Headings
- Adult
- Animals
- Asthma/drug therapy
- Asthma/physiopathology
- Cardiovascular Diseases/physiopathology
- Child
- Child, Preschool
- Dermatitis, Atopic/drug therapy
- Dermatitis, Atopic/etiology
- Female
- Humans
- Hydroxyurea/adverse effects
- Hydroxyurea/analogs & derivatives
- Leukotriene Antagonists/adverse effects
- Leukotriene Antagonists/therapeutic use
- Leukotriene C4/physiology
- Leukotriene D4/physiology
- Leukotriene E4/physiology
- Membrane Proteins/drug effects
- Membrane Proteins/genetics
- Membrane Proteins/physiology
- Pharmacogenetics
- Receptors, Leukotriene/drug effects
- Receptors, Leukotriene/genetics
- Receptors, Leukotriene/physiology
- Receptors, Purinergic/physiology
- Recombinant Proteins/pharmacology
- Rhinitis, Allergic, Seasonal/drug therapy
- Rhinitis, Allergic, Seasonal/physiopathology
- SRS-A/biosynthesis
- Tissue Distribution
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Affiliation(s)
- Valérie Capra
- Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
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26
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Suzuki K, Hasegawa T, Sakagami T, Koya T, Toyabe S, Akazawa K, Arakawa M, Gejyo F, Suzuki E. Analysis of perimenstrual asthma based on questionnaire surveys in Japan. Allergol Int 2007; 56:249-55. [PMID: 17519579 DOI: 10.2332/allergolint.o-06-475] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2006] [Accepted: 12/25/2006] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Perimenstrual asthma (PMA) has been documented in 30% to 40% of asthmatic women; the characteristics of PMA have also been well described. However, there have been few epidemiological investigations of PMA in practice. In this study, we analyzed PMA based on a questionnaire survey carried out in Japan and compared the results with those of studies reported previously. METHODS For 8 weeks from September through October 2004, a questionnaire survey was administered to patients with bronchial asthma and their attending physicians. The questionnaire surveyed asthma control, asthma-related emergencies and satisfaction in daily life. The attending physicians were questioned about patient profiles and medications. All female patients who were menstruating during the survey period and who were known to have asthma exacerbation related to menstruation were allocated to the PMA group; those who were not were allocated to the non-PMA group. RESULTS The rate of PMA in female patients who were menstruating during the survey period was 11.3% in this study. Characteristic features of the PMA group (n = 54) included more severe disease, worsened disease control and more aggressive patient management, including increased oral corticosteroid use compared with the non-PMA group. The rates of emergency episodes in the PMA group were higher than in the non-PMA group. There was a significant increase in aspirin intolerant asthma (AIA, 25.5%) in the PMA group compared with the non-PMA group (8.4%). CONCLUSIONS Attention should be paid to the lack of knowledge regarding PMA in patients with asthma in actual clinical settings. The low rate of PMA reported in this study may be due to the study method using self-reports of PMA by patients without sufficient knowledge, and may not be an accurate representation of the actual incidence of the disease. The clinical similarity of PMA to AIA in this study may also provide a new insight into the mechanism of PMA.
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Affiliation(s)
- Kazuo Suzuki
- Division of Respiratory Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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27
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Kim SH, Yang EM, Park HJ, Ye YM, Lee HY, Park HS. Differential contribution of the CysLTR1 gene in patients with aspirin hypersensitivity. J Clin Immunol 2007; 27:613-9. [PMID: 17641958 DOI: 10.1007/s10875-007-9115-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2007] [Accepted: 06/14/2007] [Indexed: 11/26/2022]
Abstract
In this study, we compared the roles of CysLT receptor type 1 (CysLTR1) and leukotriene C4 synthase (LTC4S) gene polymorphisms in two major aspirin-related allergic diseases, aspirin-intolerant asthma (AIA) and aspirin-induced chronic urticaria/angioedema (AICU). CysLTR1-634C>T and LTC4S-444A>C polymorphisms were genotyped and its functional effect on the promoter activity was compared. As in vivo functional study, changes of peripheral mRNA level of CysLTR1 were measured by real-time PCR before and after aspirin challenge. A significant association was found for the CysLTR1 promoter polymorphism and the AIA phenotype compared to AICU (P = 0.015). In U937 cells, the variant genotype reporter construct showed significantly higher promoter activity than the common genotype (P < 0.05). The CysLTR1 mRNA levels increased significantly after aspirin challenge in AIA patients (P = 0.013). In conclusion, the CysLTR1 polymorphism may contribute to develop to the AIA phenotype and be used as a genetic marker for differentiating two major aspirin hypersensitivity phenotypes.
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Affiliation(s)
- Seung-Hyun Kim
- Department of Allergy and Rheumatology, Ajou University School of Medicine, San-5, Woncheondong, Youngtonggu, Suwon, Republic of Korea
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28
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Menzies D, Nair A, Lipworth BJ. Non-invasive measurement of airway inflammation in asthma. J Asthma 2006; 43:407-15. [PMID: 16952856 DOI: 10.1080/02770900600758218] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Assessing the severity and control of a patient's asthma is of great importance to ensure that pharmacotherapy is optimized. Measures such as lung function, symptoms, and reliever use have traditionally been used as objective means of undertaking this assessment, but until now the level of airway inflammation has not been quantified. As asthma is primarily an inflammatory disorder, it would be desirable to include a measure of this process when evaluating disease control. The following article outlines methods of non-invasively measuring asthmatic airway inflammation and highlights their potential role in clinical practice.
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Affiliation(s)
- Daniel Menzies
- Department of Medicine and Therapeutics, Asthma & Allergy Research Group, Ninewells Hospital and Perth Royal Infirmary, University of Dundee, Scotland, UK.
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29
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Abstract
Aspirin-induced asthma (AIA) and aspirin-induced urticaria/ angioedema (AIU) are two major aspirin-related allergies. We summarize recent findings related to their molecular genetic mechanisms in order to identify genetic susceptibility markers for differentiating AIU and AIA. The overproduction of cysteinyl leukotriene has been suggested as a mechanism in both AIU and AIA. Increased expression of CYSLTR1 with CYLSTR1 and CYSLTR2 polymorphisms are new findings in AIA, while the ALOX5 promoter polymorphism has been noted in AIU. An HLA study suggested that DPB1*0301 is a strong genetic marker for AIA, and that HLA DRB1*1302 and DQB1*0609 are markers for AIU susceptibility. Several single nucleotide polymorphisms (SNPs) in the promoters of EP2, TBX21, COX-2, Fc epsilon RIbeta, and TBXA2R were associated with AIA, while an Fc epsilon RIalpha promoter polymorphism was associated with AIU. The functional studies of the key genes involved in AIA and AIU are summarized. The identification and functional study of genetic markers for AIA and AIU susceptibility would further elucidate the pathogenic mechanisms and facilitate the development of early diagnostic markers to establish therapeutic targets.
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Affiliation(s)
- Seung-Hyun Kim
- Department of Allergy & Rheumatology, Ajou University School of Medicine, Suwon, Korea
| | - Hae-Sim Park
- Department of Allergy & Rheumatology, Ajou University School of Medicine, Suwon, Korea
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30
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Yoshimine F, Hasegawa T, Suzuki E, Terada M, Koya T, Kondoh A, Arakawa M, Yoshizawa H, Gejyo F. Contribution of aspirin-intolerant asthma to near fatal asthma based on a questionnaire survey in Niigata Prefecture, Japan. Respirology 2006; 10:477-84. [PMID: 16135171 DOI: 10.1111/j.1440-1843.2005.00740.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Prevention of deaths due to asthma is one of the most important issues in asthma management. However, there are few epidemiological studies of asthma deaths in Japan. METHODOLOGY Over an 8-week period in Niigata Prefecture, Japan, a questionnaire on asthma control and emergency episodes was administered to adult asthmatic patients. A questionnaire was also given to the patients' physicians to obtain further clinical information. Patients who became unconscious during episodes of asthma, or who required intubation and ventilation, were allocated to a near-fatal asthma group (NFA). Patients who did not fulfill these criteria were allocated to the non-NFA group. The NFA group was divided into two subgroups, based on the date of their last NFA episode (old NFA>or= 5 years and recent NFA<4 years). RESULTS Characteristic features of the NFA group included severe disease (23.1%vs 7.6%) with more aggressive patient management, including inhaled corticosteroid use (84.3%vs 72.0%). Multiple regression analysis confirmed that aspirin-intolerant asthma (AIA) was strongly associated with NFA. There was no difference in the incidence of AIA between the recent and old NFA patients. This suggests the incidence of AIA in NFA did not improve over time. CONCLUSIONS A history of AIA may be a useful indicator of potential NFA and allow preventative methods to be introduced. It is therefore important to obtain a history of AIA and to be aware of the risk of NSAID administration to these patients.
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Affiliation(s)
- Fumitoshi Yoshimine
- Niigata Asthma Treatment Study Group, Niigata University Hospital, Niigata, Japan
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31
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Szczeklik A, Sanak M. The broken balance in aspirin hypersensitivity. Eur J Pharmacol 2006; 533:145-55. [PMID: 16457808 DOI: 10.1016/j.ejphar.2005.12.053] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2005] [Indexed: 10/25/2022]
Abstract
Aspirin was introduced into medicine over a century ago and has become the most popular drug in the world. Although the first hypersensitivity reaction was described soon after aspirin had been marketed, only recently a phenomenon of cysteinyl leukotriene overproduction brought new insights on a balance between pro- and anti-inflammatory mediators derived from arachidonic acid. We describe the most common clinical presentations of aspirin hypersensitivity, i.e. aspirin-induced asthma, rhinosinusitis and aspirin-induced urticaria. We also present their biochemical background. Despite relatively high incidence of these reactions, aspirin hypersensitivity remains underdiagnosed worldwide. Acute reactions of aspirin hypersensitivity are elicited via cyclooxygenase inhibition by non-steroid anti-inflammatory drugs. Coxibs, selective inhibitors of cyclooxygenase-2 isoenzyme, do not precipitate symptoms in susceptible patients. Though hypersensitivity correlates with cyclooxygenase-1 inhibition, diminished tissue expression was described only for cyclooxygenase-2. Aspirin-induced asthma and aspirin-induced urticaria, in a substantial part of the patients, are driven by a release of mediators from activated mast cells. These cells in physiological conditions are under inhibitory control of prostaglandin E2. The origin of aspirin hypersensitivity remains unknown, but accumulating data from genetic studies strongly suggest that environmental factor, possibly a common viral infection, can trigger the disease in susceptible subjects.
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Affiliation(s)
- Andrzej Szczeklik
- Department of Medicine, Jagiellonian University School of Medicine, Skawinska 8, 31-066 Krakow, Poland.
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32
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Obase Y, Matsuse H, Shimoda T, Haahtela T, Kohno S. Pathogenesis and management of aspirin-intolerant asthma. ACTA ACUST UNITED AC 2005; 4:325-36. [PMID: 16137190 DOI: 10.2165/00151829-200504050-00004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
In 2-23% of adults with asthma, and rarely in children with asthma, aspirin (acetylsalicylic acid) and non-steroidal anti-inflammatory drugs (NSAIDs) cause asthma exacerbations. Within 3 hours of ingestion of aspirin/NSAIDs, individuals with aspirin-intolerant asthma (AIA) develop bronchoconstriction, often accompanied by rhinorrhea, conjunctival irritation, and scarlet flush. In severe cases, a single therapeutic dose of aspirin/NSAIDs can provoke violent bronchospasm, loss of consciousness, and respiratory arrest. In order to diagnose AIA, oral, inhaled, nasal or intravenous aspirin challenge tests are performed in facilities where experienced physicians are present and emergency treatment is available. The exact differences in the pathogenesis of AIA and other types of asthma are not fully understood. The interference of aspirin/NSAIDs with arachidonic acid metabolism in the lungs plays an important role in the mechanism of AIA; inhibition of cyclo-oxygenase is accompanied by overproduction of cysteinyl leukotrienes (cys-LTs). It has been proposed that overproduction of cys-LTs, together with removal by aspirin/NSAIDs of the 'brake' imposed by the bronchodilator prostaglandin E2, may cause an asthma attack in patients with AIA. Development of a suitable animal model to investigate the pathogenesis of AIA would help to clarify this question. Although it is still controversial whether leukotriene modifiers are more effective in patients with AIA compared with other types of asthma, because LT plays an important role in the pathogenesis of AIA, leukotriene modifiers are the preferred medication for the long-term control of AIA. Add-on efficacy of leukotriene modifiers has been confirmed in patients with AIA already treated with inhaled corticosteroids. However, this does not mean that aspirin/NSAIDs can be safely taken by aspirin-sensitive patients treated with leukotriene modifiers. To prevent attacks of AIA, sensitive patients should avoid the use of aspirin/NSAIDs or use selective cyclo-oxygenase 2 inhibitors when required. When patients with AIA need aspirin for specific situations they should receive aspirin desensitization therapy or treatment with selective cyclo-oxygenase 2 inhibitors.
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Affiliation(s)
- Yasushi Obase
- Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, Finland.
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33
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Hamad AM, Sutcliffe AM, Knox AJ. Aspirin-induced asthma: clinical aspects, pathogenesis and management. Drugs 2005; 64:2417-32. [PMID: 15482000 DOI: 10.2165/00003495-200464210-00004] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Aspirin (acetylsalicylic acid)-induced asthma (AIA) consists of the clinical triad of asthma, chronic rhinosinusitis with nasal polyps, and precipitation of asthma and rhinitis attacks in response to aspirin and other NSAIDs. The prevalence of the syndrome in the adult asthmatic populations is approximately 4-10%. Respiratory disease in these patients may be aggressive and refractory to treatment. The aetiology of AIA is complex and not fully understood, but most evidence points towards an abnormality of arachidonic acid (AA) metabolism. Cyclo-oxygenase (COX), the rate-limiting enzyme in AA metabolism, exists as two main isoforms. COX-1 is the constitutive enzyme responsible for synthesis of protective prostanoids, whereas COX-2 is induced under inflammatory conditions. A number of theories regarding its pathogenesis have been proposed. The shunting hypothesis proposes that inhibition of COX-1 shunts AA metabolism away from production of protective prostanoids and towards cysteinyl leukotriene (cys-LT) biosynthesis, resulting in bronchoconstriction and increased mucus production. The COX-2 hypothesis proposes that aspirin causes a structural change in COX-2 that results in the generation of products of the lipoxygenase pathway. It is speculated that this may result in the formation of mediators that cause respiratory reactions in AIA. Related studies provide evidence for abnormal regulation of the lipoxygenase pathway, demonstrating elevated levels of cys-LTs in urine, sputum and peripheral blood, before and following aspirin challenge in AIA patients. These studies suggest that cys-LTs are continually and aggressively synthesised before exposure to aspirin and, during aspirin-induced reactions, acceleration of synthesis occurs. A genetic polymorphism of the LTC4S gene has been identified consisting of an A to C transversion 444 nucleotides upstream of the first codon, conferring a relative risk of AIA of 3.89. Furthermore, carriers of the C444 allele demonstrate a dramatic rise in urinary LTE(4) following aspirin provocation, and respond better to the cys-LT antagonist pranlukast than A444 homozygotes.AIA patients have an aggressive form of disease, and treatment should include combination therapy with inhaled corticosteroids, beta(2)-adrenoceptor agonists and LT modifiers. Furthermore, recently developed inhibitors of COX-2 may be safer in patients with AIA.
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Affiliation(s)
- Ahmed M Hamad
- Department of Respiratory Medicine, Al-Mansourah University, Al-Dakahlia, Egypt
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34
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Kawano T, Matsuse H, Kondo Y, Machida I, Saeki S, Tomari S, Mitsuta K, Fukushima C, Obase Y, Shimoda T, Kohno S. Tacrolimus reduces urinary excretion of leukotriene E(4) and inhibits aspirin-induced asthma to threshold dose of aspirin. J Allergy Clin Immunol 2005; 114:1278-81. [PMID: 15577823 DOI: 10.1016/j.jaci.2004.09.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND The exact mechanism of aspirin-induced asthma is not clear. It has been postulated that precipitation of asthma attacks by aspirin is linked to inhibition of COX activity and massive release of cysteinyl leukotriene into the airway. Tacrolimus, a macrolide-derived immunosuppressant, is used for immunosuppression in organ transplantation and also for allergic diseases such as atopic dermatitis. OBJECTIVE We evaluated the effects of tacrolimus in aspirin-induced asthma by using a double-blind, crossover study design. METHODS Twelve patients with aspirin-induced asthma (male:female, 3:9; mean age +/- SD, 36.7 +/- 7.2 years) received either tacrolimus (0.1 mg/kg) or placebo 2 hours before the threshold dose of oral aspirin. RESULTS In the placebo arm, oral aspirin significantly decreased FEV 1 concomitant with significant increases in sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. Tacrolimus significantly inhibited bronchoconstriction and abrogated aspirin-induced increase in both sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. CONCLUSION The current study suggested that tacrolimus inhibited bronchoconstriction to a threshold dose of aspirin by inhibition of cysteinyl leukotriene excretion.
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Affiliation(s)
- Tetsuya Kawano
- Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
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35
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Dahlen SE, Sundstrom E, Gulliksson M, Gyllfors P, Kumlin M, Dahlen B. Leukotrienes and other mast cell mediators cause asthmatic airway obstruction. ACTA ACUST UNITED AC 2004. [DOI: 10.1111/j.1472-9725.2004.00057.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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36
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Parameswaran K, Liang H, Fanat A, Watson R, Snider DP, O'Byrne PM. Role for cysteinyl leukotrienes in allergen-induced change in circulating dendritic cell number in asthma. J Allergy Clin Immunol 2004; 114:73-9. [PMID: 15241347 DOI: 10.1016/j.jaci.2004.03.054] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Dendritic cells are important antigen-presenting cells. After an allergen inhalation, their numbers rapidly decrease in circulation and increase in the airway mucosa. OBJECTIVE To investigate whether allergen-induced changes in the number of circulating dendritic cells are mediated by cysteinyl leukotrienes. METHODS In a randomized, double-blind, crossover study, we examined the effects of 2 weeks of treatment with pranlukast (a cysteinyl leukotriene 1 [CysLT1] receptor antagonist) 300 mg twice daily and placebo on allergen-induced changes in airway responses and circulating dendritic cells in 15 subjects with mild asthma. We examined by flow cytometry, before and at 3 hours and 24 hours after allergen inhalation, the proportion of myeloid (CD33+) and plasmacytoid (CD123+) dendritic cells (HLA-DR+, CD14-, CD16-) among all peripheral blood mononuclear cells. The fraction of dendritic cells expressing CysLT1 receptor was also determined. RESULTS Compared with placebo, pranlukast significantly attenuated both the maximum early (by 55%) and the late (by 39%) asthma responses, the allergen-induced methacholine airway hyperresponsiveness, and the increase in macrophage inflammatory protein 1alpha and 3alpha in induced sputum. A significantly greater proportion of CD33+ cells (55%) expressed CysLT1 receptor compared with CD123+ cells (11%). Consistent with this, pranlukast prevented the allergen-induced decrease in CD33+ dendritic cells at 3 hours postallergen (mean Delta from baseline, +4.4%) compared with placebo (mean Delta, -8.4; P <.05), but not CD123+ cells. CONCLUSION Pretreatment with pranlukast attenuated allergen-induced airway responses and the decrease in circulating myeloid dendritic cells, demonstrating a novel role of cysteinyl leukotrienes in dendritic cell trafficking.
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Affiliation(s)
- Krishnan Parameswaran
- Firestone Institute for Respiratory Health, St. Joseph's Healthcare, Department of Medicine, McMaster University, Hamilton, Canada
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37
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Machida I, Matsuse H, Kondo Y, Kawano T, Saeki S, Tomari S, Obase Y, Fukushima C, Kohno S. Cysteinyl leukotrienes regulate dendritic cell functions in a murine model of asthma. THE JOURNAL OF IMMUNOLOGY 2004; 172:1833-8. [PMID: 14734767 DOI: 10.4049/jimmunol.172.3.1833] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Dendritic cells (DCs) act as APCs in the airway and play a critical role in allergy. Cysteinyl leukotrienes (cysLTs) synthesized from arachidonic acid are primary mediators of immediate asthmatic reaction. The aim of this study was to investigate the effects of cysLTs on Dermatophagoides farinae (Der f)-pulsed mouse myeloid DCs in inducing allergic airway inflammation in vitro and in vivo. Control DC (medium-pulsed), Der f-pulsed DC, cysLT-pulsed DC, Der f- and cysLT-pulsed DC, and Der f-pulsed and cysLT receptor antagonist (LTRA)-treated DC were prepared from murine bone marrow, and the production of cytokines ws compared. Subsequently, these DCs were intranasally instilled into another group of naive mice, followed by intranasal Der f challenge to induce allergic airway inflammation in vivo. Der f-pulsed DC produced significantly higher amounts of IL-10 and IL-12 compared with control DC. Der f- and cysLT-pulsed DC further increased IL-10 production compared with Der f-pulsed DC. In contrast, treatment of Der f-pulsed DC with LTRA increased IL-12 and decreased IL-10. Intranasal instillation of Der f-pulsed DC resulted in airway eosinophilia associated with a significant rise in IL-5 levels in the airway compared with control DC. Pulmonary eosinophilia and excess IL-5 were further enhanced in Der f- and cysLT-pulsed DC-harboring mice. In contrast, Der f-pulsed and LTRA-treated DC significantly inhibited airway eosinophilia, reduced IL-5, and increased IFN-gamma in the airway. Our results suggest that cysLTs play an important role in the development of allergic airway inflammation by regulating the immunomodulatory functions of DCs.
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Affiliation(s)
- Ikuko Machida
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
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38
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Parameswaran K, Watson R, Gauvreau GM, Sehmi R, O'Byrne PM. The effect of pranlukast on allergen-induced bone marrow eosinophilopoiesis in subjects with asthma. Am J Respir Crit Care Med 2004; 169:915-20. [PMID: 14742305 DOI: 10.1164/rccm.200312-1645oc] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
We investigated the mechanisms by which leukotriene receptor antagonists decrease airway eosinophil number. In a randomized, double-blind crossover study, we examined the effects of 2 weeks of treatment with pranlukast 300 mg twice a day or placebo on allergen-induced changes in airway eosinophil number and bone marrow eosinophil progenitors in 15 subjects with mild asthma. Pranlukast treatment for 2 weeks decreased mean sputum eosinophil count from 0.15 x 10(6)/g (5.3% of cells) before treatment to 0.02 x 10(6)/g (0.7% of cells) after treatment (p < 0.05), whereas placebo did not. Pranlukast also decreased the eosinophil count (5.6% at 7 hours and 7.5% at 24 hours) (p < 0.05) after allergen inhalation compared with placebo (13.8% at 7 hours and 15.3% at 24 hours). There was a similar trend for sputum cells immunostaining for EG2, eotaxin, interleukin-5, and regulated upon activation, normal T cell expressed and secreted. Pranlukast also significantly attenuated the allergen-induced increase in the number of bone marrow eosinophil/basophil cfu (mean 0.3) at 24 hours compared with placebo (mean 6.2). The proportion of CD34(+) cells expressing the eotaxin receptor CC chemokine receptor 3, 24 hours after allergen inhalation, was also reduced by pranlukast. We conclude that, the cysteinyl leukotriene receptor antagonist, pranlukast, attenuates allergen-induced increase in airway eosinophils by decreasing bone marrow eosinophilopoiesis and airway chemotactic and eosinophilopoietic cytokines.
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Affiliation(s)
- Krishnan Parameswaran
- Firestone Institute for Respiratory Health, St. Joseph's Healthcare, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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39
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Abstract
The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term treatment. Although inhaled glucocorticoids are highly effective in controlling airway inflammation in asthma, they are ineffective in the small group of patients with glucocorticoid-dependent and -resistant asthma. With very few exceptions, COPD is caused by tobacco smoking, and smoking cessation is the only truly effective treatment of COPD available. Current pharmacological treatment of COPD is unsatisfactory, as it does not significantly influence the severity of the disease or its natural course. Glucocorticoids are scarcely effective in COPD patients without concomitant asthma. Bronchodilators improves symptoms and quality of life, in COPD patients, but, with the exception of tiotropium, they do not significantly influence the natural course of the disease. Theophylline is the only drug which has been demonstrated to have a significant effect on airway inflammation in patients with COPD. Here we review the pharmacology of currently used antiinflammatory therapies for asthma and COPD and their proposed mechanisms of action. Recent understanding of disease mechanisms in severe steroid-dependent and -resistant asthma and in COPD, has lead to the development of novel compounds, which are in various stages of clinical development. We review the current status of some of these new potential drugs.
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Affiliation(s)
- Gaetano Caramori
- Department of Thoracic Medicine, National Heart and Lung Institute at Imperial College School of Science, Technology and Medicine, Dovehouse Street, SW3 6LY, London, UK
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40
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Abstract
UNLABELLED Pranlukast (Onon, Azlaire), is an orally administered, selective, competitive antagonist of the cysteinyl leukotrienes (LT) C(4), LTD(4) and LTE(4). It is indicated for the prophylactic treatment of chronic bronchial asthma in paediatric and adult patients. The efficacy of pranlukast 225mg twice daily in adults with mild to moderate asthma was demonstrated in double-blind, placebo- or azelastine-controlled studies of 4 or 8 weeks' duration. The drug at this dosage was superior to both comparators in improving mean attack scores and morning and/or evening peak expiratory flow rates, and decreasing the use of rescue bronchodilators (p < 0.05). In limited clinical studies, pranlukast 225mg twice daily appeared to be as effective as montelukast 10mg once daily and zafirlukast 40mg twice daily in adults with mild to moderate asthma. Tachyphylaxis was absent when the drug was administered for up to 4 years. In patients requiring high-dose inhaled corticosteroid therapy, pranlukast 225 mg twice daily plus a halved dosage of inhaled corticosteroid was as effective as the original dosage of inhaled corticosteroid. Pranlukast was also effective in patients with mild to severe asthma in a clinical practice setting. In a double-blind trial, greater improvements in most outcome measures were observed with pranlukast than with oxatomide in children and adolescents with asthma. In clinical trials, pranlukast was well tolerated in adult and paediatric patients with asthma, with an adverse event profile similar to that of placebo. Gastrointestinal events and hepatic function abnormalities were the most commonly reported adverse events. No clinically significant differences in adverse event profiles between pranlukast, zafirlukast or montelukast were shown in limited comparisons. Although Churg-Strauss syndrome has been noted in pranlukast recipients, a direct causal relationship is unlikely. CONCLUSIONS Pranlukast is a well tolerated and effective preventative treatment in adult and paediatric patients with persistent asthma of all severities. In some patients, pranlukast may be beneficial when added to low-dose inhaled corticosteroids; it may also be a viable alternative to increasing inhaled corticosteroid dosages. The efficacy of pranlukast relative to placebo has been confirmed; its efficacy relative to other therapy awaits further investigation. Nonetheless, pranlukast is a useful therapeutic option (with as-required short-acting beta(2)-agonists), either as preventative monotherapy for the treatment of mild persistent asthma or in conjunction with inhaled corticosteroids in the management of moderate or severe persistent asthma.
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Affiliation(s)
- Susan J Keam
- Adis International Limited, Auckland, New Zealand.
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Abstract
AIM: To explore the characteristics of diarrhea caused by acaroid mites.
METHODS: Acaroid mites in fresh stools of 241 patients with diarrhea were separated by flotation in saturated saline. Meanwhile, skin prick test, total IgE and mite-specific IgE were detected in all patients.
RESULTS: The total positive rate of mites in stool samples of the patients was 17.01% (41/241), the positive rates of mites in male and female patients were 15.86% (23/145) and 18.75% (18/96), respectively, without significant difference (P > 0.05). The percentage of skin prick test as" +++", "++", "+", and "-" was 9.13% (22/241), 7.47% (18/241), 5.81% (14/241), 4.98% (12/241) and 72.61% (175/241), respectively. The serum levels of total IgE, mite-specific IgE in patients with and without mites in stool samples were (165.72 ± 78.55) IU/ml, (132.44 ± 26.80) IU/mL and (145.22 ± 82.47) IU/ml, (67.35 ± 45.28) IU/ml, respectively, with significant difference (P < 0.01). The positive rate of mites in stool samples in staffs working in traditional Chinese medicine storehouses or rice storehouses (experimental group) was 26.74% (23/86), which was significantly higher than that (11.61%, 18/155) in people engaged in other professions (χ2 = 8.97, P < 0.01).
CONCLUSION: Acaroid mites cause diarrhea and increase serum levels of total IgE and mite-specific IgE of patients, and the prevalence of diarrhea caused by acaroid mites is associated with occupations rather than the gender of patients.
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Affiliation(s)
- Chao-Pin Li
- Department of Etiology and Immunology, School of Medicine, Anhui University of Science Technology, Huainan 232001, Anhui Province, China.
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Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003; 111:913-21; quiz 922. [PMID: 12743549 DOI: 10.1067/mai.2003.1487] [Citation(s) in RCA: 309] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
In some asthmatic individuals, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygen-ase 1 (COX-1) exacerbate the condition. This distinct clinical syndrome, called aspirin-induced asthma (AIA), is characterized by an eosinophilic rhinosinusitis, nasal polyposis, aspirin sensitivity, and asthma. There is no in vitro test for the disorder, and diagnosis can be established only by provocation challenges with aspirin or NSAIDs. Recent major advances in the molecular biology of eicosanoids, exemplified by the cloning of 2 cysteinyl leukotriene receptors and the discovery of a whole family of cyclooxygenase enzymes, offer new insights into mechanisms operating in AIA. The disease runs a protracted course even if COX-1 inhibitors are avoided, and the course is often severe, many patients requiring systemic corticosteroids to control their sinusitis and asthma. Aspirin and NSAIDs should be avoided, but highly specific COX-2 inhibitors, known as coxibs, are well tolerated and can be safely used. Aspirin desensitization, followed by daily aspirin treatment, is a valuable therapeutic option in most patients with AIA, particularly those with recurrent nasal polyposis or overdependence on systemic corticosteroids.
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Affiliation(s)
- Andrew Szczeklik
- Department of Medicine, Jagellonian University School of Medicine, Krakow, Poland
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Abstract
AIM: To investigate epidemiology and pathogenic mite species of intestinal and urinary acariasis in individuals with different occupations.
METHODS: A total of 1994 individuals were tested in this study. History collection, skin prick test and pathogen identification were conducted. The mites were isolated from stool and urine samples by saturated saline flotation methods and sieving following centrifugation, respectively.
RESULTS: Among the 1994 individuals examined, responses to the skin prick test of “+++”, “++”, “+”, “±” and “-” were observed at frequencies of 3.96% (79), 3.21% (64), 2.31% (46), 1.25% (25) and 89.27% (1780), respectively. A total number of 161 (8.07%) individuals were shown to carry mites, with 92 (4.61%) positive only for stool samples, 37 (1.86%) positive only for urine samples and 32 (1.60%) for both. The positive rate of mites in stool samples was 6.22% (124/1994), being 6.84% (78/1140) for males and 5.39% (46/854) for females. No gender difference was observed in this study (χ2 = 1.77, P > 0.05). The mites from stool samples included Acarus siro, TyroPhagus putrescentiae, Dermatophagoides farinae, D. pteronyssinus, Glycyphagus domesticus, G.ornatus, Carpoglyphus lactis and Tarsonemus granaries. The positive rate of mites in urine samples was 3.46% (69/1994). The positive rates for male and female subjects were found to be 3.95% (45/1140) and 2.81% (24/854) respectively, with no gender difference observed (χ2 = 1.89, P > 0.05). Mites species in urine samples included Acarus siro, Tyrophagus putrescentiae, T. longior, Aleuroglyphus ovatus, Caloglyphus berlesei, C. mycophagus, Suidasia nesbitti, Lardoglyphus konoi, Glycyphagus domesticus, Carpoglyphus lactis, Lepidoglyphus destructor, Dermatophagoides farinae, D. pteronyssinus, Euroglyphus magnei, Caloglyphus hughesi, Tarsonemus granarus and T. hominis. The species of mites in stool and urine samples were consistent with those separated from working environment. A significant difference was found among the frequencies of mite infection in individuals with different occupations (χ2 = 82.55, P < 0.001), with its frequencies in those working in medicinal herb storehouses, those in rice storehouse or mills, miners, railway workers, pupils and teachers being 15.89% (68/428), 12.96% (53/409), 3.28% (18/549), 2.54% (6/236), 5.10% (13/255) and 2.56% (3/117), respectively.
CONCLUSION: The prevalence of human intestinal and urinary acariasis was not associated with gender, and these diseases are more frequently found in individuals working in medicinal herb, rice storehouses or mills and other sites with high density of mites. More attention should be paid to the mite prevention and labor protection for these high-risk groups.
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Affiliation(s)
- Chao-Pin Li
- Department of Etiology and Immunology, School of Medicine, Anhui University of Science and Technology, Huainan 232001, Anhui Province, China.
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Lipworth BJ, Jackson CM. Second-line controller therapy for persistent asthma uncontrolled on inhaled corticosteroids: the step 3 dilemma. Drugs 2003; 62:2315-32. [PMID: 12396225 DOI: 10.2165/00003495-200262160-00001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The asthma syndrome is characterised by airway inflammation with associated bronchial hyperresponsiveness (BHR) and reversible airflow obstruction. Therapy has benefited from an enhanced understanding of the pathophysiology of asthma and the resulting guidelines that emphasise the pivotal role of anti-inflammatory inhaled corticosteroids (ICS) as first-line therapy. Most patients with mild-to-moderate asthma can be adequately controlled on low-to-medium dosages of ICS alone. For patients with moderate-to-severe asthma who are not adequately controlled by ICS, it is unclear which medication should be added on. The two principal drugs under consideration are long-acting beta(2)-agonists (LABAs) and leukotriene antagonists (LTAs). Although both LABAs and LTAs are both effective at improving lung function, reducing symptoms and decreasing exacerbations, important differences exist that may determine the selection of one over the other in particular circumstances. LABAs and LTAs are equally effective at reducing exacerbations and improving symptoms and quality of life when used as add-on therapy. LABAs tend to be more effective bronchodilators than LTAs. Although LABAs stabilise the airway smooth muscle, they do not affect the underlying inflammatory process. Their long-term use also leads to subsensitivity of response to both LABAs and short-acting beta(2)-agonists (SABAs). The subsensitivity of response to SABAs is more pronounced in the presence of acute bronchoconstriction, which could be relevant during an acute attack. When combined with an ICS, LTAs provide additive non-steroidal anti-inflammatory properties and alleviate associated BHR, but do not induce subsensitivity of response. Not only is the efficacy of LTAs maintained over time, but also they do not affect the response to SABAs as reliever therapy. LTAs also have beneficial effects in patients who have concomitant allergic rhinitis, thus treating the unified airway. The choice between LABA and LTA as add-on therapy will therefore be determined by the needs of the individual patient in terms of providing anti-inflammatory versus bronchodilatory control. For patients with poor lung function where bronchodilatation is required, then an LABA would seem to be a logical choice. For the patient whose lung function is less impaired, with evidence of ongoing BHR where bronchoprotection is needed (e.g. exercise, allergen, cold air), or when there is concomitant allergic rhinitis, then an LTA would be more suitable.
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Affiliation(s)
- Brian J Lipworth
- Department of Clinical Pharmacology and Therapeutics, Asthma and Allergy Research Group, Ninewells University Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
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