Chest
Laboratory and Animal InvestigationsA Randomized, Placebo-Controlled Trial of a Leukotriene Synthesis Inhibitor in Patients With COPD
Section snippets
Variability Study
Six patients with COPD and chronic bronchitis12 but without A1AT deficiency each provided three spontaneous sputum samples over a 4-month period of clinical stability, in order to assess the normal variability in LTB4 and myeloperoxidase concentrations. The sputum samples were collected and assayed as described below.
Study Subjects
We studied 17 other patients with stable COPD (FEV1 < 65% of predicted for age and sex) and a history of chronic bronchitis,12 aged between 40 and 75 years, with a stable smoking
Variability Study
The six patients (four men; three current smokers and three ex-smokers; mean age ± SD, 68.8 ± 5.4 years) had moderate-to-severe airflow obstruction (FEV1 31.6 ± 22.2% of predicted; FEV1/VC, 29.5 ± 13.9%), significant gas trapping (RV/TLC, 148.6 ± 30.0% of predicted), and a reduced transfer coefficient (Dlco/Va, 60.7 ± 24.0% of predicted). The median (IQR) concentrations of LTB4 and myeloperoxidase for each of the three sets of sputum samples are indicated in Table 1. There were no significant
Discussion
The results indicate that the FLAP antagonist, BAYx1005, produced a modest but significant reduction in sputum LTB4 concentrations in the patients studied in this trial. This agent has been shown to inhibit the formation of 5-LO products in vitro in a dose-related manner.20 Although the preclinical studies20 showed an almost complete inhibition of leukotriene synthesis, it is clear that the dose studied here was insufficient to completely suppress LTB4 production. However, the reductions in LTB4
Conclusion
The results from this small, preliminary study have established that a leukotriene synthesis inhibitor may affect neutrophilic bronchial inflammation in patients with stable COPD and chronic bronchitis, and that this class of drug merits further studies in a larger number of patients.
References (28)
- et al.
Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis and chronic obstructive pulmonary disease
J Allergy Clin Immunol
(1993) - et al.
Stimulation of human leukocyte degranulation by leukotriene B4 and its ω-oxidised metabolites
FEBS Lett
(1981) - et al.
Molecules in focus: leukotriene B4
Int J Biochem Cell Biol
(1998) - et al.
A 48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration
J Immunol Methods
(1980) - et al.
Mode of action of the new selective leukotriene synthesis inhibitor BAYx1005 {(R)-2-[4-(quinolin-2-YL-methoxy)phenyl]-2-cyclopentyl acetic acid} and structurally related compounds
Biochem Pharmacol
(1993) - et al.
Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis
Am Rev Respir Dis
(1993) - et al.
Inflammation: role of the neutrophil and the eosinophil
Semin Respir Infect
(2000) - et al.
Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect
Thorax
(1984) - et al.
Subcellular localization and dynamics of Mac-1 (αmβm) in human neutrophils
J Clin Invest
(1993) - et al.
Leukotriene B, a potent chemotactic and aggregating substance released from polymorphonuclear leukocytes
Nature
(1980)
Leukotriene B4 production by the human alveolar macrophage: a potential mechanism for amplifying inflammation in the lung
Am Rev Respir Dis
Effects of leukotriene B4 in the human lung: recruitment of neutrophils into the alveolar space without a change in protein permeability
J Clin Invest
Changes in bronchial inflammation during acute exacerbations of chronic bronchitis
Eur Respir J
Definition and classification of chronic bronchitis for clinical and epidemiological purposes
Lancet
Cited by (90)
Piperine attenuates production of inflammatory biomarkers, oxidative stress and neutrophils in lungs of cigarette smoke-exposed experimental mice
2022, Food BioscienceCitation Excerpt :Targeting the chemoattractants responsible for neutrophil recruitment into the lung and drugs targeting these mediators are under experimental trials in inflammatory diseases of airways. A leukotriene synthesis inhibitor, reducing LTB-4 production, has exhibited benefits on bronchial inflammation in patients with stable COPD in small phase II trial (Gompertz & Stockley, 2002; Zhang et al., 2019). Oxidative stress is another essential element related to chronic inflammation of airways in COPD.
Other Drugs for Asthma and COPD
2021, Encyclopedia of Respiratory Medicine, Second EditionEffects of a FLAP inhibitor, GSK2190915, in asthmatics with high sputum neutrophils
2014, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :Studies investigating the effects of FLAP or leukotriene inhibitors on sputum neutrophils in COPD have shown inconclusive results. A two week study investigating the effects of the FLAP inhibitor BAYx1005 in 17 COPD patients, showed modest decreases in LTB4 measured in spontaneous sputum samples, but no effects on MPO as a marker of neutrophil activation, compared with placebo [27]. Treatment with the LT antagonist, LTB019, for four weeks in moderate COPD also showed no treatment effects on sputum neutrophils, related cytokine levels, or on lung function endpoints [28].
Aberrant neutrophil functions in stable chronic obstructive pulmonary disease: The neutrophil as an immunotherapeutic target
2013, International ImmunopharmacologyCitation Excerpt :There was great interest in identifying COPD-specific inflammatory biomarkers that could be targeted in disease. However, studies of COPD have failed to identify a single target consistently [37] because most inflammatory proteins that have been identified are raised in COPD and interventional studies focusing on a single inflammatory protein (such as leukotriene B4 or Tumour necrosis factor alpha) have not been proved beneficial [38,39]. In light of this, there has been increasing interest in targeting cells directly, especially since there is emerging evidence suggesting that aberrant neutrophil function may contribute to COPD pathology/progression.
Azabenzthiazole inhibitors of leukotriene A<inf>4</inf> hydrolase
2012, Bioorganic and Medicinal Chemistry LettersThe role of sex hormones in asthma therapy
2023, Advances in Health and Disease
Financial support was provided by a noncommercial scientific grant from Bayer.