Effect Of Leukotriene Receptor Antagonist Research Articles

Comparison of Leukotriene Receptor Antagonist and Theophylline in Addition to Inhaled Corticosteroid in Adult Asthma: A Meta-Analysis

This meta-analysis was performed to evaluate the difference of the therapeutic effi cacy and adverse effects of leukotriene receptor antagonist and theophylline added to inhaled corticosteroids in adult asthma. Databases were searched for studies published through Nov, 2010. Randomized-controlled trials containing inhaled corticosteroids plus leukotriene receptor antagonist and inhaled corticosteroids plus sustained-release theophylline for asthma therapy were selected. For each report, data were extracted to the outcomes analyzed: mean change in morning peak expiratory flow, mean change in evening peak expiratory flow, mean change in morning forced expiratory volume in 1 sec, mean change in daily short bete2-agonist use, asthma exacerbation and adverse effects. Four assessable trials including 182 asthmatic patients were identified. Inhaled corticosteroids plus leukotriene receptor antagonist was superior to inhaled corticosteroids plus theophylline therapy in improving morning peak expiratory flow in asthmatics (mean difference 19.08 [95% confidence interval 13.37-23.79] l/min, p<0.001) and morning forced expiratory volume in 1 sec in asthmatics (mean difference 0.09 [95% confidence interval 0.03-0.14] liter, p=0.001). In evening peak expiratory flow, daily short bete2-agonist use, asthma exacerbation and adverse effects, there was no significant difference between these two therapies (All p>0.05). Our meta-analysis showed that the combination of inhaled corticosteroids plus leukotriene receptor antagonist resulted in more improvement in both peak expiratory flow and forced expiratory volume in 1 sec in the morning than inhaled corticosteroids plus sustained-release theophylline in adult asthmatics. Further trials are necessary to evaluate the dominant effects of the former combination.

Leukotriene Antagonists in Asthma

Aim Cysteinyl leukotrienes are important pro-inflammatory mediators in the pathogenesis of asthma, while leukotriene C 4 synthase is a key enzyme in their biosynthesis. Our aim is to evaluate whether responsiveness to leukotriene receptor antagonists was determined by expression of the variant (C) or wild-type (A) polymorphism of this enzyme. Methods We carried out a retrospective analysis of 8 randomised, placebo-controlled trials performed in our department in mild-to-moderate asthmatics. In all trials, effect of leukotriene receptor antagonist was compared to placebo, where the primary outcome was bronchial hyperresponsiveness to adenosine monophosphate or methacholine. Secondary outcomes were forced expiratory volume in 1 second, exhaled nitric oxide and peripheral blood eosinophils . Results For the primary outcome of attenuation of bronchial hyperresponsiveness by leukotriene receptor antagonist vs placebo, there were significant effects within each genotype on adenosine monophosphate (AMP) ( n = 78): 2.21 and 2.07-fold improvements for AA and AC/CC, respectively; while for methacholine (n = 81) there were 1.39 and 1.36-fold improvements, respectively. There were no significant differences between genotypes (i.e. AA vs AC/CC): geometric mean fold-differences of 1.07 (95%CI 0.63–1.81) and 1.02 (95%CI 0.70–1.50) for AMP and methacholine, respectively. There were also no differences between genotypes for all secondary outcomes. Conclusion Polymorphisms of leukotriene C 4 synthase did not determine responsiveness, in terms of attenuation of bronchial hyperresponsiveness, to leukotriene receptor antagonists in mild-to-moderate asthmatics. Further prospective large pharmacogenetic studies are required in more severe patients, where there may be greater improvements in pharmacodynamic outcome measures such as bronchial hyperresponsiveness and exhaled nitric oxide.

Effect of leukotriene receptor antagonist on the airway inflammation in bronchiolitis after respiratory syncytial virus infection

Objective To explore the effect of leukotriene receptor antagonist on the airway inflammation in bronchiolitis after respiratory syncytial virus(RSV)infection and the prevention of post-bronchiolitis asthma by studying the changes of serum concentration of inflammatory cellular factors including ECP,IL-12,IL-13 and LTE4.Methods 156 children with mild and moderate RSV bronchiolitis were recruited in the study and they were randomly divided into three groups after alleviation of asthmatic symptoms:the intervention group with montelukast sodium tablets oral;hormone intervention group with Budesonide suspension spray;control group.Blood samples were collected on the first day on admission,before treatment,3 months after medication.Serum concentrations of ECP,IL-12,IL-13 and LTE4 were measured by ELISA.Clinical and telephone follow up was done for one year.Results Compared to control group,the ECP,IL-13 and LTE4 levels of 156 RSV bronchiolitis in acute phase and recovery phase were signifieantly increased,while the IL-12 level was significantly decreased.The ECP,IL-13levels of singulair intervention group and the hormone intervention group were decreased after intervention,and the IL-12 level rise to normal;the LTE4 level of singulair intervention group and the hormone intervention group decreased significantly than before intervention,singulair intervention group recovered to normal levels(t=1.0866,P＞0.05),but hormone treatment group did not recover to normal levels(t=3.4355,P＜0.01).Singulair intervention group had lower recurrence of asthma(χ2=7.8156,P＜0.01).Conclusion The leukotriene receptorantagonists could regulate the imbalance of Th1/Th2,reduce the release of LTE4 and the activation of eosinophils,alleviate airway inflammation and airway hyperreactivity,reduce wheezing,and it play a role in the prevention of asthma. Key words: Leukotriene receptor antagonist; Capillary bronchiolitis; Eosinophil cationic protein; Intefleukin-12; Interleukin-13; Leukotriene

Effects of montelukast on mRNA expression of MUC2 and MUC5B in human nasal epithelial cells

In this study, the effects of leukotriene receptor antagonist on mRNA expression of MUC2 and MUC5B in human nasal epithelial cells were investigated. Human nasal epithelial cells were randomly assigned into 4 groups: control group, IL-1β group, montelukast + IL-1β group and montelukast group. After 24 h of treatment, the mRNA expressions of MUC2 and MUC5B were determined by fluorescent quantitation PCR. The mRNA expression of MUC2 in the control group, IL-1β group, montelukast + IL-1β group and montelukast group was 2.93±1.57×106copies/μg, 6.63±1.73×106 copies/μg, 3.48±1.41)×106 copies/μg and 1.63±0.47×106 copies/μg, respectively(P<0.01). The MUC2 level in montelukast + IL-1β group was lower than in IL-1β group (P<0.01), but there was no marked difference between montelukast group and control group. The mRNA expression of MUC5B in control group, IL-1β group, montelukast + IL-1β group and montelukast group was 8.21±3.54×105 copies/μg, 3.40±2.79×107 copies/μg, 1.75±0.69×106copies/μg and 5.15±2.16×105 copies/μg, respectively, showing significant difference among these groups (P<0.01). In addition, the MUC5B level in montelukast + IL-1β group was lower than in IL-1β group (P<0.05), but there was no marked difference between the montelukast and the control group. Montelukast, a leukotriene receptor antagonist, can decrease the mRNA expressions of MUC2 and MUC5B in IL-1β treated nasal epithelial cells. Our results reveal montelukast may inhibit the inflammatory cytokine induced expression of mucins in nasal epithelial cells. Key words: Montelukast, leukotriene, MUC2, MUC5B, human nasal epithelial cells.

Effect of leukotriene receptor antagonists on lung fibrosis in rats

To compare the effects of montelukast, prednisone and the combination of both drugs in a rat model of bleomycin-induced lung fibrosis. Rats, injected intravenously with bleomycin daily for five consecutive days, were treated with either montelukast, prednisone or a combination of both drugs orally daily for 35 days starting 14 days after the commencement of the first dose of bleomycin. Montelukast-treated rats showed reduction in collagen deposition by 29% and significant reduction in lung hydroxyproline content by 32%. Prednisone produced nonsignificant difference in collagen deposition and in lung hydroxyproline content compared with the bleomycin group. There was also a significant reduction in collagen deposition and hydroxyproline content in montelukast and prednisone treated rats by 15 and 17%, respectively, compared with bleomycin group. A significant reduction occurred in the mean area percentage of myofibroblast α smooth muscle actin in montelukast and montelukast and prednisone-treated groups by 41 and 37%, respectively, with nonsignificant difference in prednisone-treated rats as compared with the bleomycin group. Montelukast may be therapeutically effective for inhibiting further progression of lung fibrosis through inhibition of α-SMA positive myofibroblasts.

Effects of Leukotriene Receptor Antagonists on Peripheral Eosinophil Counts and Serum IgE Levels in Children with Food Allergy

Background: Although the efficacy of leukotriene receptor antagonists (LTRAs) for bronchial asthma is already established, their effect on food allergy remains unclear. Objective: To investigate the efficacy of LTRAs in children with food allergy. Methods: This retrospective study examined 65 children with food allergy who were aged between 3 and 36 months (mean 14±9.6 months) from 2005 to 2008. Thirty-two children were treated as a dietary control group by avoiding any antigenic foods to which they had previously experienced adverse reactions. The remaining 33 children, designated the LTRA group, were treated with pranlukast (7mg/kg bodyweight/day) in addition to maintaining dietary control. Clinical symptoms and laboratory data before and after 1 year of treatment were compared between the groups. Results: Allergic symptoms improved in both the dietary controlled and LTRA groups, and there was no significant difference observed in the clinical parameters examined between the groups after the 1-year trial. Peripheral eosin-ophil count, serum IgE, interleukin (IL)-4, IL-5, IL-6, and eosinophil cationic protein (ECP) levels in children with food allergy were above standardized values in both groups. Although both the dietary controlled and LTRA groups showed a decreased eosinophil count (−273 ± 232 vs -595 ± 295/μL; p < 0.05 and p < 0.001, respectively), only children treated with LTRA showed a significant decrease in serum IgE (-73.5 ± 115 IU/mL; p < 0.01); conversely, the control group exhibited a significant increase in serum IgE (+159 ± 138 IU/mL; p < 0.01). Furthermore, the LTRA group also showed a significant decrease in serum IL-4 (54.5 ± 31.0 to 27.3 ± 10.1 pg/mL), IL-5 (6.7 ± 5.2 to 5.0 ± 0.4 pg/mL), and ECP (45.4 ± 15.0 to 15.0 ± 9.8 μg/L) levels (p < 0.05 for each). Conclusion: Early intervention with LTRAs may be effective in regulating eosinophil count and serum IgE, IL-4, IL-5, and ECP levels. These data support the potential effectiveness of LTRAs in young children with food allergy to prevent further allergic development.

Effects of Leukotriene Receptor Antagonists on Peripheral Eosinophil Counts and Serum IgE Levels in Children with Food Allergy

Background: Although the efficacy of leukotriene receptor antagonists (LTRAs) for bronchial asthma is already established, their effect on food allergy remains unclear.Objective: To investigate the efficacy of LTRAs in children with food allergy. Methods: This retrospective study examined 65 children with food allergy who were aged between 3 and 36 months (mean 14±9.6 months) from 2005 to 2008. Thirty-two children were treated as a dietary control group by avoiding any antigenic foods to which they had previously experienced adverse reactions. The remaining 33 children, designated the LTRA group, were treated with pranlukast (7mg/kg bodyweight/day) in addition to maintaining dietary control. Clinical symptoms and laboratory data before and after 1 year of treatment were compared between the groups.Results: Allergic symptoms improved in both the dietary controlled and LTRA groups, and there was no significant difference observed in the clinical parameters examined between the groups after the 1-year trial. Peripheral eosin-ophil count, serum IgE, interleukin (IL)-4, IL-5, IL-6, and eosinophil cationic protein (ECP) levels in children with food allergy were above standardized values in both groups. Although both the dietary controlled and LTRA groups showed a decreased eosinophil count (−273 ± 232 vs -595 ± 295/μL; p < 0.05 and p < 0.001, respectively), only children treated with LTRA showed a significant decrease in serum IgE (-73.5 ± 115 IU/mL; p < 0.01); conversely, the control group exhibited a significant increase in serum IgE (+159 ± 138 IU/mL; p < 0.01). Furthermore, the LTRA group also showed a significant decrease in serum IL-4 (54.5 ± 31.0 to 27.3 ± 10.1 pg/mL), IL-5 (6.7 ± 5.2 to 5.0 ± 0.4 pg/mL), and ECP (45.4 ± 15.0 to 15.0 ± 9.8 μg/L) levels (p < 0.05 for each).Conclusion: Early intervention with LTRAs may be effective in regulating eosinophil count and serum IgE, IL-4, IL-5, and ECP levels. These data support the potential effectiveness of LTRAs in young children with food allergy to prevent further allergic development.

Cost Effectiveness of Leukotriene Receptor Antagonists versus Long-Acting Beta-2 Agonists as Add-On Therapy to Inhaled Corticosteroids for Asthma

Information is lacking on the relative effectiveness and cost effectiveness--in a real-life primary-care setting--of leukotriene receptor antagonists (LTRAs) and long-acting beta2 adrenergic receptor agonists (beta2 agonists) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids (ICS). To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS. An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma insufficiently controlled with ICS (n = 361) were randomly assigned to add-on LTRAs (n = 176) or long-acting beta2 agonists (n = 185). The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), per point improvement in the Asthma Control Questionnaire (ACQ) and per QALY gained from perspectives of the UK NHS and society. Over 2 years, the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists, a (significant, adjusted) increase of pounds sterling 214 (95% CI 2, 411) [year 2005 values]. Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs (95% CI -0.077, 0.103). The incremental cost per QALY gained from the societal (NHS) perspective was pounds sterling 22,589 (pounds sterling 11,919). Uncertainty around this point estimate suggested that, given a maximum willingness to pay of pounds sterling 30,000 per QALY gained, the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52% from both societal and NHS perspectives. On balance, these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma. However, there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs. UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811.

Clinical Effects of Leukotriene Receptor Antagonists for the Treatment of Postnasal drip symptoms in Allergic Patients

Clinical Effects of Leukotriene Receptor Antagonists for the Treatment of Postnasal drip symptoms in Allergic Patients

Observational Study of the Additive Effects of Pranlukast on Inflammatory Markers of Clinically Stable Asthma with Inhaled Corticosteroids and Long-Acting Beta 2 Agonists

Background: Little is understood about the additive effects of leukotriene receptor antagonists (LTRA) on asthmatics currently medicated with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA). Objectives: The present study examines the anti-inflammatory effects of the LTRA pranlukast in addition to ICS and LABA, among asthmatic patients with normal pulmonary function and unremarkable clinical symptoms. Methods: Fifteen adult asthmatics participated in a 2-month, open-label, uncontrolled, prospective, multicenter, observational trial. Patients stabilized (predicted forced expiratory volume in 1 s >80%) by medication with ICS and LABA were also given pranlukast (450 mg daily). Asthma-related symptoms, pulmonary function, blood eosinophil counts and several inflammatory markers in sputum were monitored at week 0, as well as at 4 and 8 weeks after starting therapy with pranlukast. Results: Adding pranlukast did not further improve blood eosinophil counts, pulmonary function and symptoms, but significantly attenuated sputum cysteinyl leukotrienes, tumor necrosis factor-α and interleukin-5 concentrations. Conclusions: Although the clinical relevance remains obscure, adding an LTRA attenuates allergic airway inflammation in some asthmatics undergoing treatment with ICS and LABA.

Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

Relation of Adult-Onset Asthma to Coronary Heart Disease and Stroke

Asthma was associated with atherosclerotic disease in several studies, with evidence that this association may be limited to women. However, most previous studies failed to account for the heterogeneity of asthma subtypes. We previously reported increased carotid intima-medial thickness in women with adult-onset asthma. In this study, the association of adult- and child-onset asthma with incident coronary heart disease (CHD) and stroke were examined. Subjects were classified according to self-report of physician-diagnosed asthma and age of asthma onset. Cox proportional hazards models were used to test the association of adult- and child-onset asthma with incident CHD and stroke, testing for gender interaction. Subanalysis was also performed using only never smokers. Women with adult-onset asthma experienced a 2-fold increase in incident CHD and stroke that was independent of other risk factors, including smoking, body mass index, and physical activity, and persisted when analysis was restricted to never smokers. No significant association was found in women with child-onset asthma or in men. In conclusion, adult-onset asthma may be a significant risk factor for CHD and stroke in women, but not men.

Leukotriene Receptor Antagonists: A Good Choice in the Treatment of Premenstrual Asthma?

The aim of this study was to investigate the effects of leukotriene receptor antagonists (LTRAs) on the premenstrual exacerbation of asthma (PMA). Twenty-four female patients with mild asthma were enrolled in the study. Patients were followed for three menstrual cycles and separated into two groups based on whether they exibit premenstrual worsening of asthma symptoms (n = 11) or not (n = 13). During the first month all were treated with only inhaled steroids (IS) (run-in period); during the second month they received IS plus placebo; and during the third month they were given IS plus montelukast. Furthermore, they were advised to use beta 2 -agonists as needed. Peak expiratory flow rate (PEFR) and symptom scores were recorded during the 3 months. Pulmonary function tests (PFT) and the levels of oestrogen, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured a week before the begining of the menstrual period. At the end of the 3-month period, it was observed that following therapy with montelukast, the patients with PMA showed significant improvement in PEFR variability and symptom scores when compared with the placebo group. Baseline FSH levels were higher, but FSH and other hormone levels and PFTs did not change in these groups. However, in the group without PMA there was no difference between the montelukast or placebo groups in PEFR variability, symptom scores, PFTs, and hormone levels. Based on the data in hand, it could be stated that LTRAs have ensured the control of symptoms and improved PEFR variability in patients with PMA by supressing inflammation. We are of the view that LTRAs would be a right choice in the treatment of patients with PMA.

Effects of a leukotriene receptor antagonist on exhaled leukotriene E 4 and prostanoids in children with asthma

Leukotriene (LT) E(4) and 8-isoprostane concentrations are elevated in exhaled breath condensate in children with asthma. The effects of leukotriene receptor antagonists (LTRAs) on exhaled leukotriene and prostanoids in children with asthma are unknown. (1) To study the effect of montelukast, a LTRA, on exhaled LTE(4), 8-isoprostane, and prostaglandin E(2) in children with asthma and atopic children; (2) to measure exhaled nitric oxide. An open-label study with oral montelukast (5 mg once daily for 4 weeks) was undertaken in 17 atopic children with asthma and 16 atopic children without asthma. Pretreatment exhaled LTE(4) (P < .0001) and 8-isoprostane (P < .0001) values were higher in atopic children with asthma than in atopic children without asthma. In atopic children with asthma, montelukast reduced exhaled LTE(4) by 33% (P < .001), and this reduction was correlated with pretreatment LTE(4) values (r = -0.90; P = .0001). Posttreatment exhaled LTE(4) levels in children with asthma were higher than pretreatment LTE(4) values in atopic children without asthma (P < .004). Montelukast had no effect on exhaled LTE(4) in atopic children without asthma (P = .74), or on exhaled 8-isoprostane (atopic children with asthma, P = .94; atopic children without asthma, P = .55) and PGE(2) (atopic children with asthma, P = .56; atopic children without asthma, P = .93) in both groups. In atopic children with asthma, exhaled nitric oxide concentrations were reduced by 27% (P < .05) after montelukast. Leukotriene receptor antagonists decrease exhaled LTE(4) in atopic children with asthma. This reduction is dependent on baseline exhaled LTE(4) values. Measurement of exhaled LTE(4) might help identify children with asthma most likely to benefit from LTRAs.

Effects of leukotriene receptor antagonists on monocyte chemotaxis, p38 and cytoplasmic calcium

Montelukast and zafirlukast, two cysteinyl leukotriene receptor antagonists (LTRAs), have been shown to have a beneficial effect on the clinical symptoms of asthma. LTRAs can inhibit eosinophil recruitment; however, little is known about their role in monocyte migration. We investigated whether montelukast and zafirlukast could suppress chemokine-induced chemotaxis of monocytes and signaling. Chemotaxis of monocytes from peripheral blood mononuclear cells (PBMCs), cord blood mononuclear cells (CBMCs), and THP-1 cells was evaluated using a 24-well transwell microchamber. [Ca2+]i was measured with the fluorescence calcium indicator fura-2/AM photometry system. p38 MAPK expression was measured by Western blotting. Results showed that montelukast (1-100 microm) and zafirlukast (100 microm) significantly down-regulated monocyte chemoattractant protein-1(MCP-1)-induced chemotaxis of THP-1 cells and human primary monocytes from PBMCs and CBMCs (p<0.05, each comparison). Montelukast also abolished MCP-1-induced [Ca2+]i and pp38 MAPK expression in THP-1 cells in a dose-dependent manner. These data demonstrate that montelukast is effective in down-regulating human monocyte chemotaxis induced by MCP-1. This effect may involve the down-regulation of MCP-1-induced [Ca2+]i and p38 MAPK expression.

Leukotriene receptor antagonist for prolonged non-specific cough in children

Non-specific cough is defined as non-productive cough in the absence of identifiable respiratory disease or known aetiology. It is commonly seen in paediatric practice. These children are treated with a variety of therapies including a variety of asthma medications. The leukotriene pathway is reported to be involved in the sensory (neurogenic) pathway, which is a mechanism thought to be involved in the pathogenesis of chronic cough. To evaluate the effectiveness of leukotriene receptor antagonist (LTRA) in treating children with prolonged non-specific cough. The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register, MEDLINE and EMBASE databases were searched by the Cochrane Airways Group. The latest searches were carried out in September 2005. All randomised controlled trials comparing LTRA with a placebo medication in children with non-specific cough. Results of searches were reviewed against pre-determined criteria for inclusion. One eligible trial was identified but no data was available for analysis. It was not possible to separate results from children with non-specific cough from those without. There was no significant difference in all study endpoints between the montelukast and placebo groups (total N=256). With the lack of evidence, the routine use of LRTA in treating children with non-specific cough cannot be recommended.

The role of leukotrienes in allergic rhinitis

To review the role of cysteinyl leukotrienes (cysLTs) in allergic rhinitis and the scientific rationale for therapy with leukotriene receptor antagonists (LTRAs). Relevant basic science and clinical articles were identified by a search of the PubMed database for articles published from 1984 to 2004 using the following keywords: allergic rhinitis; nose; immune response; allergen challenge; leukotrienes C, D, and E; cysteinyl leukotriene; cysteinyl leukotriene receptor; cytokine; leukocyte; montelukast; zafirlukast; and pranlukast. The authors' expert opinion was used to select studies for inclusion in this review. CysLTs are synthesized via 5-lipoxygenase metabolism of arachidonic acid by mast cells and basophils during the early-phase response to antigen and by eosinophils and macrophages during the late phase. The cysLT levels in nasal secretions are elevated after short-term allergen instillation and in allergy season in patients with allergic rhinitis. These lipid mediators act locally and systemically by interacting with receptors, particularly the cysLT1 receptor, on target cells. Evidence derived from topical application of cysLTs in the nose and from the effects of LTRAs indicates that cysLTs contribute to nasal mucous secretion, congestion, and inflammation. CysLTs promote allergic inflammation by enhancing immune responses and the production, adhesion, migration, and survival of inflammatory cells such as eosinophils. They also increase the generation of an array of other proinflammatory mediators, such as cytokines, which in turn increase the production of and receptors for cysLTs. Clinical trials have demonstrated that LTRAs have significant but modest efficacy as single agents but additive efficacy when used with other classes of agents. CysLTs fulfill the criteria for relevant mediators of allergic rhinitis via their diverse effects on immune, inflammatory, and local structural components of disease. By blocking the cysLT1 receptor responsible for most of these effects, LTRAs represent a useful approach to treatment of this important and prevalent disorder.

Leukotriene Receptor Antagonists in Children with Cystic Fibrosis Lung Disease

Cystic fibrosis (CF) lung disease is characterized by chronic endobronchial infection resulting in progressive pulmonary destruction; this is a major cause of mortality and morbidity. Neutrophils are the primary effector cells responsible for the progressive deterioration of lung function. Peptido-leukotriene B4 antagonists, new anti-inflammatory agents that block the neutrophil-dominated inflammation, could have had the potential for long-term use. A trial on the pharmacokinetics of amelubant administered orally as a single dose of up to 75 mg in pediatric patients with CF and 300 mg in adults, and as a repeated dose of 75 mg and 150 mg, respectively, once daily for 15 days provided evidence that amelubant metabolism in adult and pediatric patients with CF is similar to that in healthy adults. In another study using the same dosage regimen, amelubant appeared to be safe and well tolerated. Safety measures included physical examination, vital signs, spirometry, oximetry, ECG, and clinical laboratory testing. However, a randomized, double-blind, placebo-controlled, multinational, phase II trial (Boehringer Ingelheim 543.45) was conducted to investigate the clinical efficacy of 24 weeks of treatment with amelubant in patients with CF with mild-to-moderate lung disease. Two doses of amelubant (75 and 150 mg) were tested in adult patients (> or = 18 years) and one dose of amelubant (75mg) was tested in pediatric (6-17 years) patients. The trial was terminated early due to a statistically significant increase in the risk of pulmonary-related, serious adverse events in adults receiving amelubant. Cysteinyl leukotrienes, eosinophilic inflammation, and viral infections also contribute to progressive pulmonary destruction in CF. Cysteinyl leukotrienes are potential targets for cysteinyl leukotriene receptor antagonist use. A study on the pharmacokinetics of montelukast in children with CF provided evidence that the dose of montelukast and the administration interval does not need to be modified if the goal is to mimic the serum concentrations used to treat asthma. In a randomized, double-blind, crossover, placebo-controlled study, 16 children with mild CF (median age 9.5 years; vital capacity [VC] >70%) were treated with montelukast (5 to < or =14 years; 5 mg; >14 years; 10 mg) or placebo as a once-daily tablet for 21 days. There was a significant (p < or = 0.02) reduction in serum eosinophil cationic protein levels and eosinophils (p < or = 0.027) with montelukast. However, neither lung function tests (VC, forced expiratory volume in 1 second [FEV1], maximum expiratory flow at 25% of forced VC), nor clinical symptom scores changed significantly. In another study, 26 patients aged 6-18 years with moderate CF (VC between 40% and 69% predicted) received montelukast or placebo for 8 weeks in a 20-week, randomized, double-blind, crossover, placebo-controlled trial. After treatment with montelukast there was a significant improvement in FEV1, peak expiratory flow, and forced expiratory flow between 25% and 75%, and a significant decrease in cough and wheezing scale scores (p < 0.001 for all). Montelukast treatment decreased serum and sputum levels of eosinophil cationic protein and interleukin-8 (IL-8), decreased sputum levels of myeloperoxidase, and increased serum and sputum levels of IL-10 (p < 0.001 for all) compared with placebo. To date, clinical experience and research data on the anti-inflammatory effects of leukotriene receptor antagonists in CF are limited. Multicenter trials with longer observation periods and greater patient numbers are needed to prove the hypothesis that leukotriene receptor antagonists have the potential to ameliorate CF lung disease with long term use.

Light and electron microscopic evaluation of antileukotriene therapy on human endometriosis

To evaluate the effect of leukotriene receptor antagonist (LTR-A) on human endometriosis, we examined morphological alterations under light and electron microscope, clinical symptoms, and formation of fibrous adhesion using the revised American Fertility Society classification (r-AFS score) in endometriosis cases with and without LTR-A treatment. Morphologically, the lesions of LTR-A-treated cases showed not only decrease of activated mast cells but also numerous apoptotic fibroblasts. Collagen fibers around these apoptotic fibroblasts were filamentous and thin compared with those of nontreated cases, partially condensed or disappeared completely. In LTR-A-treated cases, a significant decrease of r-AFS score was observed ( p<0.0001), and also a significant correlation between r-AFS score and LTR-A treatment period ( p<0.0001). The clinical symptoms were relieved; specifically, some patients became pregnant. Our findings revealed that LTR-A has significant therapeutic value for treatment of human endometriosis.

Pranlukast, a leukotriene receptor antagonist, prolongs the duration of the migrating motor complex in dogs.

Current information on the effects of leukotriene receptor antagonists on gastrointestinal motility and their mechanisms of gastrointestinal side effects are unknown. Our study aimed to answer the question whether the leukotriene inhibition induced by Pranlukast alters the normal gastrointestinal contraction patterns, and whether any motility abnormalities found explain the gastrointestinal side effects of these types of medications. Seven dogs were used after implanting force transducers in the body and antrum of the stomach, duodenum, and jejunum to monitor gastrointestinal motility. Pranlukast was given orally to each dog at the end of the migrating motor complex during fasting experiments and 30 min after a standard meal during the fed stage, with continuous monitoring. The migrating motor complex was significantly prolonged, especially during phase I of 208.5 +/- 15.4 min (P < 0.05) at 30 mg/kg and of 280.3 +/- 12.5 min (P < 0.05) at 60 mg/kg, compared with controls (93.5 +/- 5.5 min). A significant reduction in the postprandial motility index was also noticed at 60 mg/kg (445.20 +/- 31.30 g x min; P < 0.001) compared to controls (728.20 +/- 26.76 g x min). In conclusion, we are the first to demonstrate that Pranlukast produces a significant inhibitory effect on gastrointestinal motility, which could explain in part some of the side effects observed with these types of drugs.