Benefits from Adding the 5-Lipoxygenase Inhibitor Zileuton to Conventional Therapy in Aspirin-intolerant Asthmatics

Dahlén, Barbro; Nizankowska, E; Szczeklik, A; Zetterström, Olle; Bochenek, Grażyna; Kumlin, Maria; Mastalerz, Lucyna; Pinis, Grazyna; Swanson, Linda J.; Boodhoo, Terry; Wright, Stephen; Dubé, Louise M.; Dahlén, Sven‐Erik

doi:10.1164/ajrccm.157.4.9707089

Cited by 369 publications

(209 citation statements)

References 32 publications

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“…Addition of a leukotriene receptor antagonist or synthesis inhibitor has shown some efficacy on lung function when added to ICS in three studies of adults with moderate-to-severe asthma who were not taking LABAs. Two of these studies were performed in aspirin-sensitive asthma in which systemic corticosteroids were used in 35% [215][216][217]. In contrast, in a study of 72 non-phenotyped severe adult asthmatics receiving LABA and ICS, some of whom are also on OCS, the addition of montelukast did not improve clinical outcomes over 14 days [218].…”

Section: Leukotriene Pathway Modifiersmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations.When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

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Section: Leukotriene Pathway Modifiersmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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“…Eosinophils in turn seem to be the main source of cysteinyl-LTs in the nasal tissue. The effectiveness of anti-LT drugs in attenuation of nasal symptoms in AIA patients also points to cysteinyl-LTs as the important local mediators [33]. A smaller rise in urinary LTE 4 occurred during the challenges with typical bronchial adverse reactions (with at least a 20% decrease in FEV1).…”

Section: Discussionmentioning

confidence: 95%

Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma

Nizankowska¹,

Bestynska-Krypel²,

Ćmiel³

et al. 2000

Eur Respir J

158

129

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In 35 asthmatic patients with acetylsalicylic acid (aspirin; ASA) intolerance (AIA) and 15 asthmatics tolerating ASA well, the authors compared the diagnostic value of the placebo-controlled oral ASA versus inhaled L-lysine (L) ASA challenges.All AIA subjects gave a history of asthmatic attacks following ingestion of ASA and in all of them the intolerance was confirmed by oral challenge test over the past 10 yrs. Doses of ASA increasing in geometric progression were used in oral tests 10±312 mg (cumulative dose 500 mg); in bronchial tests 0.18±115 mg (cumulative dose 182 mg). Either challenge was considered as positive, if forced expiratory volume in one second (FEV1) dropped at least 20% from the baseline value and/or strong extrabronchial symptoms of intolerance occurred. Urinary leukotriene E 4 excretion was determined at baseline and following the challenges.In 24 out of 35 patients the oral test was positive, based on a 20% decrease in FEV1. When including extrabronchial symptoms this was positive in 31 cases. Bronchial L-ASA challenge led to $20% fall FEV1 in 21 out of 35 cases, and in 27 cases when including extrabronchial symptoms. No correlation was observed between ASA provocative dose causing a 20% fall in FEV1, determined by the oral route compared to the inhalation route. Urinary LTE 4 increased after both challenges the rise being higher following oral as compared to inhalation provocation (p=0.0001).It is concluded that both tests had similar specificity whilst the oral test showed a tendency to higher sensitivity for the clinical diagnosis of acetylsalicylic acid intolerance. The inclusion of extrabronchial symptoms into the criteria of test positivity enhanced the diagnostic value of both procedures. In both tests the highest leukotriene E 4 increases were found in the presence of extrabronchial symptoms, suggesting the participation of tissues other than the lung in aspirin induced leukotriene E 4 release to urine. Eur Respir J 2000; 15: 863±869.

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“…It involves severe eosinophilic respiratory tract inflammation and is defined by bronchoconstriction following the ingestion of nonselective COX inhibitors (6). Cysteinyl leukotrienes (cysLTs) (LTC 4 , LTD 4 , and LTE 4 ) drive these reactions, as well as some of the chronic features of AERD (7,8). CysLTs derive from arachidonic acid metabolized by 5-lipoxygenase (5-LO) to LTA 4 , conjugated to reduced glutathione by leukotriene C 4 synthase (LTC 4 S) to LTC 4 in mast cells (MCs), eosinophils, basophils, macrophages, and granulocyte-platelet complexes (9).…”

mentioning

confidence: 99%

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Liu

Laidlaw

Katz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

105

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Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, tissue eosinophilia, overproduction of cysteinyl leukotrienes (cysLTs), and respiratory reactions to nonselective cyclooxygenase (COX) inhibitors. Ex vivo studies suggest that functional abnormalities of the COX-2/microsomal prostaglandin (PG)E 2 synthase-1 system may underlie AERD. We demonstrate that microsomal PGE 2 synthase-1 null mice develop a remarkably AERD-like phenotype in a model of eosinophilic pulmonary inflammation. Lysine aspirin (Lys-ASA)-challenged PGE 2 synthase-1 null mice exhibit sustained increases in airway resistance, along with lung mast cell (MC) activation and cysLT overproduction. A stable PGE 2 analog and a selective E prostanoid (EP) 2 receptor agonist blocked the responses to Lys-ASA by ∼90%; EP 3 and EP 4 agonists were also active. The increases in airway resistance and MC products were blocked by antagonists of the type 1 cysLT receptor or 5-lipoxygenase, implying that bronchoconstriction and MC activation were both cysLT dependent. Lys-ASA-induced cysLT generation and MC activation depended on platelet-adherent granulocytes and T-prostanoid (TP) receptors. Thus, lesions that impair the inducible generation of PGE 2 remove control of platelet/granulocyte interactions and TP-receptor-dependent cysLT production, permitting MC activation in response to COX-1 inhibition. The findings suggest applications of antiplatelet drugs or TP receptor antagonists for the treatment of AERD.A spirin-exacerbated respiratory disease (AERD) affects 5-10% of all adults with asthma (1-3), ∼30% with severe asthma (4), and ∼40% with refractory chronic hyperplastic sinusitis (5). It involves severe eosinophilic respiratory tract inflammation and is defined by bronchoconstriction following the ingestion of nonselective COX inhibitors (6). Cysteinyl leukotrienes (cysLTs) (LTC 4 , LTD 4 , and LTE 4 ) drive these reactions, as well as some of the chronic features of AERD (7,8). CysLTs derive from arachidonic acid metabolized by 5-lipoxygenase (5-LO) to LTA 4 , conjugated to reduced glutathione by leukotriene C 4 synthase (LTC 4 S) to LTC 4 in mast cells (MCs), eosinophils, basophils, macrophages, and granulocyte-platelet complexes (9). After export, LTC 4 is converted sequentially to LTD 4 and LTE 4 . CysLTs induce bronchoconstriction (10, 11), tissue eosinophilia (12), and remodeling (13) through G-protein-coupled receptors (GPCRs) expressed by structural and hematopoietic cells (14-16). Individuals with AERD display higher urinary levels of LTE 4 than do aspirin-tolerant asthmatic (ATA) control subjects (17). Reactions to aspirin or other nonselective COX inhibitors are accompanied by marked further increases in urinary levels of LTE 4 and can be blocked by pretreatment with the 5-LO inhibitor zileuton or with antagonists of the type 1 receptor for cysLTs (CysLT 1 R) (18,19). The dependency on COX products to maintain homeostasis over 5-LO activity is a unique feature of AERD. Remarkably, subjects with AERD can tolerate selective ant...

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Benefits from Adding the 5-Lipoxygenase Inhibitor Zileuton to Conventional Therapy in Aspirin-intolerant Asthmatics

Cited by 369 publications

References 32 publications

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

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Benefits from Adding the 5-Lipoxygenase Inhibitor Zileuton to Conventional Therapy in Aspirin-intolerant Asthmatics

Cited by 369 publications

References 32 publications

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

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Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes