Lung function improvement in asthma with a cysteinylleukotriene receptor antagonist

doi:10.1016/0140-6736(91)91709-4

The Lancet

Volume 337, Issue 8749, 4 May 1991, Pages 1062-1063

https://doi.org/10.1016/0140-6736(91)91709-4 Get rights and content

Abstract

In a double-blind study ten asthmatic patients with impaired lung function received the cysteinylleukotriene receptor antagonist ICI 204,219 (40 mg by mouth) and placebo in random order on 2 days at least 1 week apart. The increase in forced expiratory volume in 1 s (FEV₁) above baseline was significantly greater after ICI 204,219 than after placebo. This effect persisted after nebulised salbutamol. These findings suggest that cysteinylleukotrienes are one of the causes of persistent bronchoconstriction in chronic asthma.

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Cited by (200)

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2023, Journal of Allergy and Clinical Immunology: In Practice
Leukotriene receptor antagonists (LTRAs) are commonly prescribed to patients with allergic diseases. Several case reports and pharmacovigilance studies have indicated that LTRAs might increase the risk of neuropsychiatric (NP) entities. However, the results are mixed in observational studies. Thus, the association between LTRAs and NP entities remains controversial.
To quantitatively evaluate the NP risk with LTRAs based on current observational studies to provide a reference for clinical practice.
We systematically reviewed the literature in Medline, Embase, Web of Science, Cochrane Library, Scopus, and PsycINFO. A meta-analysis of observational studies that investigated the association between LTRA use and the risk of NP entities was performed. Odds ratios (OR) with 95% confidence intervals (CI) were used to measure the effect; heterogeneity was evaluated using I-squared (I²) statistics. Subgroup and sensitivity analyses were conducted to assess bias.
Eleven articles were included in the primary analysis. No significant association was found between LTRA use and NP entities (OR: 1.08, 95% CI: 0.93-1.24, I² = 93.7%). In patients with allergic rhinitis (AR), a mildly increased NP risk was found (OR: 1.099, 95% CI: 1.004-1.202). The association between LTRA use and NP entities was not significant in patients with asthma (OR: 1.06, 95% CI: 0.90-1.26). LTRAs increased the risk of NP entities in a single study using data from an asthma clinic (OR: 9.00, 95% CI: 1.20-69.50), but not in studies from databases (OR: 1.07, 95% CI: 0.93-1.23).
At the population level, LTRAs and NP entities were unrelated. However, the association may exist in particular groups (eg, patients with AR or NP history). Subject-specific studies are required to further examine the relationship between LTRAs and NP entities and identify the underlying mechanisms.
Current state and future prospect of the therapeutic strategy targeting cysteinyl leukotriene metabolism in asthma
2019, Respiratory Investigation
Citation Excerpt :
Table 2 enumerates the therapeutic effects of LTRAs on long-term asthma management. The therapeutic effects of LTRAs on improving the respiratory function and quality of life in patients with mild asthma are similar to those of ICSs [55–58]. These agents also possess anti-inflammatory properties and reduce the number of eosinophils, lymphocytes, and mast cells in sputum and bronchial biopsy tissue [59], while also decreasing the levels of fractional exhaled nitric oxide (FeNO), which is a biomarker that reflects airway eosinophilic inflammation [60,61].
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.
Patient stratification and the unmet need in asthma
2017, Pharmacology and Therapeutics
Asthma is often described as an inflammatory disease of the lungs and in most patients symptomatic treatment with bronchodilators or inhaled corticosteroids is sufficient to control disease. Unfortunately there are a proportion of patients who fail to achieve control despite treatment with the best current treatment. These severe asthma patients have been considered a homogeneous group of patients that represent the unmet therapeutic need in asthma. Many novel therapies have been tested in unselected asthma patients and the effects have often been disappointing, particularly for the highly specific monoclonal antibody-based drugs such as anti-IL-13 and anti-IL-5. More recently, it has become clear that asthma is a syndrome with many different disease drivers. Clinical trials of anti-IL-13 and anti-IL-5 have focused on biomarker-defined patient groups and these trials have driven the clinical progression of these drugs. Work on asthma phenotyping indicates that there is a group of asthma patients where T helper cell type 2 (Th2) cytokines and inflammation predominate and these type 2 high (T2-high) patients can be defined by biomarkers and response to therapies targeting this type of immunity, including anti-IL-5 and anti-IL-13. However, there is still a subset of T2-low patients that do not respond to these new therapies. This T2-low group will represent the new unmet medical need now that the T2-high-targeting therapies have made it to the market. This review will examine the current thinking on patient stratification in asthma and the identification of the T2-high subset. It will also look at the T2-low patients and examine what may be the drivers of disease in these patients.
Inundation of asthma target research: Untangling asthma riddles
2016, Pulmonary Pharmacology and Therapeutics
Asthma is an inveterate inflammatory disorder, delineated by the airway inflammation, bronchial hyperresponsiveness (BHR) and airway wall remodeling. Although, asthma is a vague term, and is recognized as heterogenous entity encompassing different phenotypes. Targeting single mediator or receptor did not prove much clinical significant, as asthma is complex disease involving myriad inflammatory mediators. Asthma may probably involve a large number of different types of molecular and cellular components interacting through complex pathophysiological pathways. This review covers the past, present, and future therapeutic approaches and pathophysiological mechanisms of asthma. Furthermore, review describe importance of targeting several mediators/modulators and receptor antagonists involved in the physiopathology of asthma. Novel targets for asthma research include Galectins, Immunological targets, K ⁺ Channels, Kinases and Transcription Factors, Toll-like receptors, Selectins and Transient receptor potential channels. But recent developments in asthma research are very promising, these include Bitter taste receptors (TAS2R) abated airway obstruction in mouse model of asthma and Calcium-sensing receptor obliterate inflammation and in bronchial hyperresponsiveness allergic asthma. All these progresses in asthma targets, and asthma phenotypes exploration are auspicious in untangling of asthma riddles.
Evaluating the role of leukotriene-modifying drugs in asthma management: Are their benefits ‘losing in translation’?
2016, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Since, 5-LO inhibitors block the synthesis of LTs, it is assumed that such agents might deliver better efficacy than the cys-LT1 receptor antagonists. Zileuton evolved as the first evidence of 5-LO inhibitor that could suppress allergen-induced eosinophilia in the lungs and administer both acute and chronic improvement of lung function in asthma [41]. The acute improvement in FEV1 is fairly comparable in magnitude to that observed with the cys-LT1 receptor antagonists and is observed within hours of the first oral dose [42].
Leukotrienes (LTs) initiate a cascade of reactions that cause bronchoconstriction and inflammation in asthma. LT-modifying drugs have been proved very effective to reduce inflammation and associated exacerbation however despite some illustrious clinical trials the usage of these drugs remains overlooked because the evidence to support their utility in asthma management has been mixed and varied between studies. Although, there are plenty of evidences which suggest that the leukotriene-modifying drugs provide consistent improvement even after just the first oral dose and reduce asthma exacerbations, the beneficial effect of these drugs has remained sparse and widely debated. And these beneficial effects are often overlooked because most of the clinical studies include a mixed population of asthmatics who do not respond to LT-modifiers equally. Therefore, in the present era of personalized medicine, it is important to properly stratify the patients and non-invasive measurements of biomarkers may warrant the possibility to characterize biological/pathological pathway to direct treatment to those who will benefit from it. Endotyping based on individual's leukotriene levels should probably ascertain a subgroup of patients that would clearly benefit from the treatment even though the trial fails to show overall significance. In this article, we have methodically evaluated contemporary literature describing the efficacy of LT-modifying drugs in the management of asthma and highlighted the importance of phenotyping the asthmatics for better treatment outcomes.
Pulmonary Mast Cells
2015, Comparative Biology of the Normal Lung: Second Edition
Mast cells are well known as key effector cells of allergic disease, act as sentinels of innate immunity, and are regulators of adaptive immune responses. Phenotypic plasticity, characteristics and key locations of resident mast cells in a variety of host tissues contribute to the versatility of the mast cell response. While classically identified with IgE dependent allergy and innate immunity, mast cells are also known to play an indispensible role in modulating other effector cells, and delineating subsequent adverse pulmonary outcomes. The activation and function of mast cells is integral to the etiology of numerous lung pathophysiologies, exacerbation of pre-existing pulmonary conditions and detrimental toxicant exposures. Several therapeutics targeting mast cell activation and downstream effects of mediators have been developed to neutralize allergy and hypersensitivity. Advancements in mast cell biology have renewed focus on the importance of mast cells in pulmonary physiology and disease pathology.

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SHORT REPORTSLung function improvement in asthma with a cysteinylleukotriene receptor antagonist

Abstract

J Allergy Clin Immunol

J Clin Allergy Immunol

Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation

Science

Comparative effects of inhaled leukotriene C4, leukotriene D4 and histamine in normal human subjects

Thorax

Standardised lung function testing

Bull Eur Physiopathol Respir

SHORT REPORTS
Lung function improvement in asthma with a cysteinylleukotriene receptor antagonist

Comparative effects of inhaled leukotriene C₄, leukotriene D₄ and histamine in normal human subjects