• Clinical and Experimental Pediatrics
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• v.52 no.6
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• pp.680-688
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• 2009

Purpose : Cysteinyl leukotrienes are important proinflammatory mediators in asthma. Recently, it was suggested that a promoter polymorphism in the genes encoding for leukotriene C4 synthase (LTC4S), a key enzyme in the leukotriene synthetic pathway, and cysteinyl leukotriene receptor 1 (CysLTR1) might be associated with aspirin-intolerant asthma. We investigated whether polymorphisms in LTC4S and CysLTR1 genes or their interactions were associated with the asthma phenotype, lung function, or bronchial hyperreactivity (BHR) in Korean children. Methods : A total of 856 asthmatic children and 254 non-asthmatic controls were enrolled; a skin prick test, lung function test and bronchial provocation test were performed. Of those enrolled, 395 children underwent exercise challenge tests. The LTC4S A(-444)C and CysLTR1 T(＋927)C were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. Results : Of those enrolled, 699 children were classified as having atopic asthma and 277 children, as having exercise-induced asthma (EIA). LTC4S and CysLTR1 polymorphisms were not associated with atopic asthma, EIA, or asthma per se. Lung function and BHR were not significantly different between the wild type (AA or TT) and the variant (AC＋CC or TC＋CC) genotypes in asthmatics, atopic asthmatics, and EIA (＋) asthmatics, while total eosinophil counts were higher in the variant type of LTC4S than in the wild type in atopic asthmatics. There were no associations between the gene-gene interactions of LTC4S and CysLTR1 genotypes and the asthma phenotypes. Conclusion : LTC4S A(-444)C and CysLTR1 T(＋927)C polymorphisms and their gene-gene interactions are not associated with asthma phenotype, lung function, or BHR in Korean children.

• Journal of Integrative Natural Science
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• v.8 no.1
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• pp.13-18
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• 2015

Cysteinyl leukotrienes are inflammatory mediators having important role in pathophysiological conditions such as asthma, allergic rhinitis and have been implicated in a number of inflammatory conditions including cardiovascular and gastrointestinal diseases. Most of the disease regulatory actions of the CysLTs are mediated through CysLT1 receptor. Hence in the present study, homology modeling of CysLT1 was performed because the availability of 3D structure would enhance the development of new drugs for inflammatory diseases. However the templates identified have low sequence identity which increases the complexity of modeling. Hence, homology modeling was performed using single template, multiple templates and also using threading I-TASSER server. The best model was selected based on the validation of the generated models using Ramachandran and ERRAT plot. The model developed could be useful for identifying crucial residues and docking study.

• Journal of Integrative Natural Science
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• v.9 no.4
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• pp.228-233
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• 2016

Cysteinyl leukotrienes are inflammatory mediators having important role in pathophysiological conditions such as asthma and allergic rhinitis. CysLT1 receptor mediates most of the disease regulatory actions of the CysLTs and it is been implicated in a number of inflammatory conditions including gastrointestinal and cardiovascular diseases. Hence in the present study, molecular docking of CysLT1 was performed with its potent and orally efficacious antagonist CP-199330 and CP-199331. The aim of this study was to compare the interaction of CP-199330 and CP-199331 with known drugs such as Zafirlukast, Pranlukast and Montelukast which had already showed clinical efficacy in the treatment of asthma. The residues such as TYR83, GLN274, LYS311 and SER313 were found to interact with both the antagonist and the known drugs. Also, we noticed the docking scores and interaction of the antagonists were comparable with the known drugs. Hence these antagonists could serve as better drugs for the treatment of allergy.

• Mass Spectrometry Letters
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• v.11 no.4
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• pp.71-76
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• 2020

While montelukast (ML), a cysteinyl-leukotriene type 1 receptor (CysLT1) antagonist is widely used to treat symptoms of rhinitis or asthma, its formulations are mainly limited to solid preparation due to its instability. Recently, there have been attempts to develop various ML dosage forms, and this situation increases the demand of sensitive and creditable methods to determine ML in various samples such as plasma. Thus, here, a simple and efficient method to determine ML in rat plasma using liquid-liquid extraction (LLE) and multiple reaction monitoring was presented. The mixture of DCM:EtOAc (25:75, v/v), the optimized extract solvent for LLE was found to be effective to extract ML without hydrophilic salts and proteins from the sample with limited volume. Also, the use of zafirlukast, instead of expensive ML-d6, as the internal standard makes the present method economical. The developed method was successfully validated in terms of selectivity, matrix effects (-14.8--6.9%), linearity (r230.998 within 0.5-500 ng/mL), sensitivity (the limit of detection and the lower limit of quantitation, ≤0.5 ng/mL), accuracy (88.4-100.6%), precision (3.0-13.3%), and recovery (80.8-86.3%) by following the FDA guidelines. Finally, the applicability of the validated method to pharmacokinetics (PK) studies was confirmed by the successful determination of PK parameters through it following oral administration of Singulair® granule in rats. Therefore, the present method can contribute to the development of new ML formulations through its performance to determine ML in rat plasma efficiently and sensitively.

• Clinical and Experimental Pediatrics
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• v.52 no.2
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• pp.181-186
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• 2009

Purpose : Inflammation plays a potential role in the pathogenesis of bronchopulmonary dysplasia (BPD). Strategies for preventing BPD include respiratory management, antioxidants, nutritional treatment, and others such as anti-inflammatory agents. We aimed to assess the safety, tolerability, and efficacy of montelukast (MK), a cysteinyl leukotriene 1 receptor antagonist, as an add-on therapy in BPD. Methods : In addition to currently available standard measures such as oxygen supplementation, bronchodilators, nutritional support, and/or diuretics, montelukast was administered to 15 preterm infants with BPD. MK was given orally (1 mg/kg/d) for a mean period of 12 weeks. We compared safety and efficacy parameters with historical controls. Results : All 15 patients survived, and no differences were found in the incidence of adverse reactions between the 2 groups. The ventilation index was significantly improved after 2 weeks in MK group compared with historical controls. There were no significant differences in other respiratory parameters (MAP, oxygen dependency, and ventilator dependency) between the groups, but the MK group showed trends of greater improvement. Conclusion : Administration of MK 1 mg/kg/d was well tolerated in preterm BPD patients as an add-on therapy. We demonstrated that after 2 weeks of MK administration of 1 mg/kg/d, MK had beneficial therapeutic effects on BPD patients as an add-on to the standard therapy. Further multicenter randomized controlled clinical trials are needed to confirm the efficacy and safety of MK as a useful supplement to standard therapy for BPD patients.

• Tuberculosis and Respiratory Diseases
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• v.63 no.4
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• pp.337-345
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• 2007

Backgrounds: Although glucocorticoids are one of the most potent anti-inflammatory agents, they have limited effect on cysteinyl leukotriene biosynthesis. In addition, the response to inhaled corticosteroids (ICS) and inhaled long-acting ${\beta}_2-agonists$ (LABA) combination therapy in moderate to severe persistent asthmatics varies. Additional therapy with leukotriene receptor antagonists (LTRA) in patients with moderate to severe asthma suboptimally controlled with ICS and LABA combination therapy would be complementary to asthma control. Methods: One hundred and ninety eight asthmatics entered a 2 month, open-label descriptive study. Patients suffering from persistent asthma and suboptimally controlled on a combination therapy of fluticasone/salmeterol or budesonide/formoterol were given montelukast 10 mg daily as an add-on therapy. The level of asthma control was assessed using the Asthma Control Questionnaire (ACQ) including $FEV_1%$ predicted at the baseline and after a 2-month treatment with montelukast. A global evaluation of the treatment was also made by the patients and physicians. Results: The mean ACQ score decreased significantly on montelukast ($11.5{\pm}5.4$ at baseline vs. $6.7{\pm}5.0$), with a significant improvement in all individual symptom scores (p<0.01). The $FEV_1%$ predicted values did not show any significant change. 59.9% of patients and 59.4% of physicians reported global improvement in their asthma (${\kappa}=0.85$). Conclusion: These results suggest that the addition of montelukast in patients with persistent asthma that is suboptimally contolled by combination therapy of ICS and LABA might confer complementary effects on asthma control.

• Tuberculosis and Respiratory Diseases
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• v.46 no.5
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• pp.697-708
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• 1999

Background : Leukotriene (LT) $C_4$, $D_4$, and $E_4$, the main components of slow-reacting substance of anaphylaxis (SRS-A), have been suggested to play an important role in bronchial asthma such as antigen-induced bronchoconstriction, airway hyperreactivity, and pulmonary eosinophil accumulation. The purpose of this study was to evaluate the effects of treatment with the cysteinyl-LTs (cys-LTs) antagonist, pranlukast on allergen-induced guinea pig asthma model. Methods : Guinea pigs of treatment and placebo groups were sensitized by subcutaneous injection of ovalbumin(OVA) and challenged by inhalation of aerosolized OVA (1% weight/volume OVA). Normal control group did not sensitize with OVA. Oral ingestion of pranlukast and normal saline to the treatment and placebo groups was performed. In the treatment and placebo groups, airway resistance was measured before and after oral ingestion. Serum $LTC_4$ and eosinophilic infiltration of the bronchiolar and peribronchiolar tissues were measured after ingestion in the treatment and placebo groups. Results : Allergen-induced airway constriction developed in 20 (8 in treatment group, 12 in placebo group) among 35 guinea pigs. Airway resistance was significantly decreased at 3 and 6 minutes after OVA challenge in the pranlukast treatment group. In the placebo group, there was no difference of airway resistance between before and after saline ingestion. Serum $LTC_4$ levels showed 348.4 pg/ml in the treatment group, 373.9 pg/ml in the placebo group, and 364.4 pg/ml in the control group. There were no statistically significant difference between treatment and placebo group (p=0.232), and treatment and control group (p=0.501). Eosinophilic infiltrations in the peribronchiolar region per one-microscopic field ($\times$400 high power fields) demonstrated 7.06 in the treatment group, 19.2 in the placebo group, and 4.50 in the control group. There was significant decrement of eosinophilic infiltration in the treatment group which was compared with placebo group (p=0.001). Conclusion : These results demonstrate that pranlukast, a cys-LTs receptor antagonist, can attenuate allergen induced early-phase bronchoconstriction and eosinophilic infiltration in the bronchiolar tissues.