Concept: Leukotriene antagonist
Allergic rhinitis is the most common atopic disorder seen in ENT clinics. It is diagnosed by history, physical exam and objective testing. Patient education, environmental control measures, pharmacotherapy, and allergen-specific immunotherapy are the cornerstones of allergic rhinitis treatment and can significantly reduce the burden of disease. Current treatment guidelines include antihistamines, intranasal corticosteroids, oral and intranasal decongestants, intranasal anticholinergics, intranasal cromolyn, and leukotriene receptor antagonists. In the mechanism of allergic rhinitis, histamine is responsible for major allergic rhinitis symptoms such as rhinorrhea, nasal itching and sneezing. Its effect on nasal congestion is less evident. In contrast, leukotrienes result in increase in nasal airway resistance and vascular permeability. Antihistamines and leukotriene receptor antagonists are commonly used in the treatment of allergic rhinitis. The published literature about combined antihistamines and leukotriene antagonists in mono- or combination therapy is reviewed and presented.
Asthma is one of the most common conditions seen in clinical practice and carries both a significant disease burden in terms of patient morbidity and a high economic burden in both direct and indirect costs. Despite this, it remains a comparatively poorly understood disease, with only modest advances in treatment over the past decade. Corticosteroids remain the cornerstone of therapy. Both patient compliance with medications and physician adherence to evidence-based guidelines are often poor, and a high percentage of patients continue to have inadequately controlled disease even with optimal therapy. Following a contextual overview of the current treatment guidelines, this review focuses on novel asthma therapies, beginning with the introduction of the leukotriene receptor antagonist zafirlukast in the 1990s, continuing through advanced endoscopic therapy and into cytokine-directed biologic agents currently in development. Along with clinically relevant biochemistry and pharmacology, the evidence supporting the place of these therapies in current guidelines will be highlighted along with data comparing these agents with more conventional treatment. A brief discussion of other drugs, such as those developed for unrelated conditions and subsequently examined as potential asthma therapies, is included.
NSAIDs that inhibit cyclooxygenase-1 can provoke severe asthma and rhinosinusitis with nasal polyps and eosinophil infiltration. Cysteinyl leukotriene generation by the leukotriene C4 synthase pathway may cause the bronchoconstriction, vascular leak, and mucous secretion.
Airway remodeling is a detrimental and refractory process showing age-dependent clinical manifestations, which are mechanistically undefined. The leukotriene (LT) and wingless/ integrase (Wnt) pathways have been implicated in remodeling, but age-specific expression profiles and common regulators remained elusive.
Despite the availability of treatments such as glucocorticoids, leukotriene antagonists, long-acting bronchodilators, and a monoclonal antibody directed against IgE, a substantial proportion of patients with asthma continue to have uncontrolled disease.(1) Exacerbations requiring hospitalization and ongoing treatment with a regular maintenance dose of systemic glucocorticoids cause substantial morbidity and impair the quality of life of these patients. Recognition of the components of the airway disease that contribute to the severity (airway hyperresponsiveness and inflammation and airflow limitation) and the underlying mechanisms of those abnormalities is a logical starting point on the path toward the development of strategies to target and . . .
The cysteinyl leukotrienes (cys-LTs), leukotriene C4 (LTC4), a conjugation product of glutathione and eicosatetraenoic acid, and its metabolites LTD4 and LTE4, are lipid mediators of smooth muscle constriction and inflammation in asthma. LTD4 is the most potent ligand for the type 1 cys-LT receptor (CysLT1R) and LTC4 and LTD4 have similar lesser potency for CysLT2R, while LTE4 has little potency for either receptor. Cysltr1/Cysltr2(-/-) mice lacking the two defined receptors, exhibited a comparable dose-dependent vascular leak to intradermal injection of LTC4 or LTD4 and an augmented response to LTE4 compared to WT mice. As LTE4 retains a cysteine residue and might provide recognition via a dicarboxylic acid structure, we screened cDNAs within the P2Y nucleotide receptor family containing CysLTRs and dicarboxylic acid receptors with trans-activator reporter gene assays. GPR99 previously described as an oxoglutarate receptor (Oxgr1) showed both a functional and binding response to LTE4 in these transfectants. We generated Gpr99(-/-) and Gpr99/Cysltr1/Cysltr2(-/-) mice for comparison with WT and Cysltr1/Cysltr2(-/-) mice. Strikingly, GPR99 deficiency in the Cysltr1/Cysltr2(-/-) mice virtually eliminated the vascular leak in response to the cys-LT ligands, indicating GPR99 as a potential CysLT3R active in the Cysltr1/Cysltr2(-/-) mice. Importantly, the Gpr99(-/-) mice showed a dose-dependent loss of LTE4-mediated vascular permeability, but not to LTC4 or LTD4, revealing a preference of GPR99 for LTE4 even when CysLT1R is present. As LTE4 is the predominant cys-LT species in inflamed tissues, GPR99 may provide a new therapeutic target.
Omalizumab for the treatment of solar urticaria: case series and systematic review of the literature
- The journal of allergy and clinical immunology. In practice
- Published over 2 years ago
Solar urticaria (SU) is a rare photodermatosis causing a significant impact on patients' quality of life. Although the condition can be controlled with phototherapy and/or a combination therapy of antihistamines and leukotriene antagonist in most patients, a subset of patients require additional therapy with omalizumab; however, efficacy data is sparse.
Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLT2R), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease-like Ptges-/- mice. These responses were mitigated by deletions of either Cysltr2 or leukotriene C4 synthase (Ltc4s). Administrations of either LTC4 (the parent cysLT) or the selective CysLT2R agonist N-methyl LTC4 to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLT2R-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLT2R-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of Cysltr1 blunted LTC4-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLT2R prior to inhalation challenge of Ptges-/- mice with aspirin blocked IL-33-dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLT2R signaling, IL-33-dependent ILC2 expansion, and IL-33-driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLT2R-targeted drugs may interrupt these processes.
Diagnostic Accuracy of Urinary LTE4 Measurement to Predict Aspirin-Exacerbated Respiratory Disease in Patients with Asthma
- The journal of allergy and clinical immunology. In practice
- Published almost 3 years ago
Patients with aspirin-exacerbated respiratory disease (AERD) are distinguished from patients with aspirin-tolerant asthma (ATA) by significantly higher baseline concentrations of urinary leukotriene E4 (uLTE4). However, an overlap between the individual values of the groups exists.
Arachidonate-5-lipoxygenase (5-LO) activity and increased leukotriene B4 (LTB4) production have been implicated in various inflammatory conditions. Increased production of leukotrienes has been associated with periodontal diseases; however their relative contribution to the tissue destruction is unknown. We used an orally-active specific 5-LO inhibitor to assess its role in inflammation and bone resorption in a murine model of lipopolysaccharide (LPS)-induced periodontal disease.