Efficacy of montelukast for adenoid hypertrophy in paediatrics: A systematic review and meta-analysis.

INTRODUCTION: Leukotrienes play a significant role in the pathogenesis of adenoid hypertrophy (A.H.). Therefore, we aimed to analyse the role of montelukast, a leukotriene receptor antagonist, alone or in combination with mometasone, a potent local intranasal steroid, for the treatment of A.H. METHODS: Participants were children with A.H. were treated with montelukast alone or montelukast and mometasone furoate. The main outcome measures were effect of montelukast on clinical symptoms of A.H. A literature review was conducted using online search engines, Cochrane Library, PubMed, Web of Science and Scopus, for randomized clinical trials assessing children with A.H. treated with montelukast alone or montelukast and mometasone furoate. Seven randomized clinical trials (RCTs) were included with 742 children. RESULTS: Our study reveals that montelukast alone or in combination with intranasal mometasone furoate significantly improves clinical symptoms of adenoid hypertrophy such as snoring, sleeping disturbance, mouth breathing and A/N ratio. Montelukast was superior to placebo in decreasing snoring (SMD = -1.00, 95% CI [-1.52, -0.49]), sleep discomfort (SMD = -1.26, 95% CI [-1.60, -0.93]), A/N ratio (MD = -0.11, 95% CI [-0.14, -0.09]) and mouth breathing (SMD = -1.36, 95% CI [-1.70, -1.02]). No difference was detected between montelukast and mometasone versus mometasone alone in snoring (SMD = -0.21, 95%CI [-0.69, 0.27]); however, the combination group was superior to the mometasone alone in mouth breathing (SMD = -0.46, 95% CI [-0.73, -0.19]). CONCLUSIONS: The limitation of studies included a small sample size, with an overall low to medium quality. Thus, further larger, higher-quality RCTs are recommended to provide more substantial evidence.

Comparative study evaluating antihistamine versus leukotriene receptor antagonist as adjuvant therapy for rheumatoid arthritis.

PURPOSE: Investigating the efficacy and safety of rupatadine (RUP) versus montelukast (MON) as adjuvant therapy for patients with rheumatoid arthritis (RA). METHODS: From December 2018 to December 2019, 75 patients with active RA were enrolled in this randomized double-blind placebo-controlled study. The patients were randomized into three groups (n = 25 in each group); methotrexate (MTX) group which received MTX 15-25 mg/week plus placebo tablet once daily; MTX/RUP group which received MTX plus RUP 10 mg once daily; and MTX/MON group which received MTX plus MON 10 mg once daily. The treatment duration was 3 months. At baseline and 3 months after treatment, blood samples were collected for the biochemical analysis of high-sensitivity C-reactive protein (hs-CRP), interleukins 8 and 17 (IL-8, IL-17), E-selectin, and clusterin (CLU) levels. Clinical and functional assessments using Disease Activity Score-CRP (DAS28-CRP) and Multidimensional Health Assessment Questionnaire (MDHAQ) were performed. RESULTS: Both RUP and MON produced clinical and functional improvements which were translated by significant improvements in DAS28-CRP score and MDHAQ. Rupatadine significantly reduced all measured parameters (P < 0.05) except for IL-17 and CLU. Montelukast significantly decreased all measured variables (P < 0.05) except for E-selectin. Interleukin-8 was positively correlated with IL-17 and CLU, while hs-CRP was positively correlated with E-selectin and body mass index (BMI). Both drugs were well tolerated; somnolence was the common side effect for RUP. No neuropsychiatric events were reported with MON. CONCLUSION: Rupatadine or montelukast may serve as a potential adjuvant therapy for patients with rheumatoid arthritis secondary to the preliminary evidence of efficacy and safety. ClinicalTrials.gov identifier NCT03770923, December 10, 2018.

Montelukast's ability to fight COVID-19 infection.

Montelukast can be effective in the treatment of SARS-CoV-2 infection.

Montelukast, a cysteinyl leukotriene receptor antagonist, exerts local antinociception in animal model of pain through the L-arginine/nitric oxide/cyclic GMP/KATP channel pathway and PPARγ receptors.

OBJECTIVE: The leukotrienes are inflammatory mediators. In the present study, the analgesic role of local montelukast, a cysteinyl leukotriene receptor antagonist, and the possible involvement of L-arginine/NO/cGMP/KATP channel pathway and PPARγ receptors was assessed in the formalin test in rats. METHODS AND RESULTS: The local administration of montelukast into the hind paw produced dose-related analgesia during both phases of the formalin test. Furthermore, pre-treatment with L-NAME, methylene blue, and glibenclamide prevented montelukast (10 µg/paw)-induced antinociception in both early and late phases of the test. Moreover, the local L-arginine and diazoxide before the sub-effective dose of montelukast (3 µg/paw) produced an analgesic effect. Also, local GW-9662 blocked antinociception induced by montelukast plus pioglitazone (10 µg/paw). CONCLUSION: In conclusion, montelukast produced peripheral analgesia through PPARγ receptors and activation of the L-arginine/NO/cGMP/KATP channel pathway, with potential for a new topical analgesic drug.

Combination of eudragit EPO with poloxamers for improved solubility and dissolution of Zafirlukast: An evaluation of solid dispersion formulations.

This study investigated the effect of solid dispersions (SD) on solubility and release of Zafirlukast (ZA) by physical mixture (PM), solvent evaporation (SE) and kneading method (KM) with Eudragit EPO (EPO) as binary component and Poloxamer 188 (P188) and Poloxamer 407 (P407) as ternary components. The binary and ternary systems caused an increase of 322 folds and 356 folds in aqueous solubility of ZA, respectively. Formulations were characterized for solubility, FTIR, PXRD, DSC, SEM and dissolution studies. P407 was found to be an excellent solubility booster in combination with EPO. It was concluded that solubility and dissolution rate of ZA increased significantly when SD of the ZA was prepared by solvent evaporation method (1:7 ratio) using 15% P407 as ternary component.

A comparison of tiotropium, long-acting ß2-agonists and leukotriene receptor antagonists on lung function and exacerbations in paediatric patients with asthma.

Diagnosing and treating asthma in paediatric patients remains challenging, with many children and adolescents remaining uncontrolled despite treatment. Selecting the most appropriate pharmacological treatment to add onto inhaled corticosteroids (ICS) in children and adolescents with asthma who remain symptomatic despite ICS can be difficult. This literature review compares the efficacy and safety of long-acting ß2-agonists (LABAs), leukotriene receptor antagonists (LTRAs) and long-acting muscarinic antagonists (LAMAs) as add-on treatment to ICS in children and adolescents aged 4-17 years.A literature search identified a total of 29 studies that met the inclusion criteria, including 21 randomised controlled trials (RCTs) of LABAs versus placebo, two RCTs of LAMAs (tiotropium) versus placebo, and four RCTs of LTRA (montelukast), all as add-on to ICS. In these studies, tiotropium and LABAs provided greater improvements in lung function than LTRAs, when compared with placebo as add-on to ICS. Although exacerbation data were difficult to interpret, tiotropium reduced the risk of exacerbations requiring oral corticosteroids when added to ICS, with or without additional controllers. LABAs and LTRAs had a comparable risk of asthma exacerbations with placebo when added to ICS. When adverse events (AEs) or serious AEs were analysed, LABAs, montelukast and tiotropium had a comparable safety profile with placebo.In conclusion, this literature review provides an up-to-date overview of the efficacy and safety of LABAs, LTRAs and LAMAs as add-on to ICS in children and adolescents with asthma. Overall, tiotropium and LABAs have similar efficacy, and provide greater improvements in lung function than montelukast as add-on to ICS. All three controller options have comparable safety profiles.

The efficacy of a leukotriene receptor antagonist in the treatment of human rectal aberrant crypt foci: a nonrandomized, open-label, controlled trial.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) are broadly used for the management of allergic asthma and have recently been indicated to inhibit carcinogenesis and cancer cell growth. In colorectal cancer (CRC) chemoprevention studies, the occurrence of adenoma or CRC itself is generally set as the trial endpoint. Although the occurrence rate of CRC is the most confident endpoint, it is inappropriate for chemoprevention studies because CRC incidence rate is low in the general population and needed for long-term monitoring. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and darker in methylene blue staining than normal crypts, are regarded to be a fine surrogate biomarker of CRC. Therefore, this prospective study was designed to explore the chemopreventive effect of LTRA on colonic ACF formation and the safety of the medicine in patients scheduled for a poly resection as a pilot trial leading the CRC chemoprevention trial. METHODS: This study is a nonrandomized, open-label, controlled trial in patients with colorectal ACF and polyps scheduled for a polypectomy. Participants meet the inclusion criteria will be recruited, and the number of ACF in the rectum will be counted at the baseline colonoscopic examination. Next, the participants will be assigned to the LTRA or no treatment group. Participants in the LTRA group will continue 10 mg of oral montelukast for 8 weeks, and those in the no treatment group will be observed without the administration of any additional drugs. At the end of the 8-week LTRA intervention period, a polypectomy will be conducted to evaluate the changes in the number of ACF, and cell proliferation in the normal colorectal epithelium will be analyzed. DISCUSSION: This will be the first study to investigate the effect of LTRAs on colorectal ACF formation in humans. TRIAL REGISTRATION: This trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029926 . Registered 10 November 2017.

Radioprotective effects of montelukast, a selective leukotriene CysLT1 receptor antagonist, against nephrotoxicity induced by gamma radiation in mice.

PURPOSE: In this study, we evaluated the renal protective effects of montelukast (MLK) against ionizing radiation (IR) induced nephrotoxicity in mice. MATERIALS AND METHODS: Radioprotective effects of MLK were assessed by biochemical analysis including measurements of kidney malondialdehyde (MDA), reduced glutathione (GSH), and serum creatinine and urea levels. Besides, for further evaluation of protective effects of MLK on renal system, 99m Tc-dimercaptosuccinic acid (DMSA) has been applied. The total antioxidant capacity of MLK was measured by using 1,1-diphenyl-2-picryl hydrazyl radical reagents and compared with butylated hydroxyl toluene standard antioxidant. RESULTS: The biochemical evaluation revealed that better results have been achieved for the groups administered with MLK than the only radiation group. Besides only IR-treated mice group, those treated with MLK demonstrated a significant decrease in urea and creatinine levels. Statistically, significant differences of MDA and SHG levels (P < .05) were found between the radiation group and MLK plus IR-treated group. Also, 99m Tc-DMSA kidney uptake value (%ID/g) was observed lower for MLK plus IR-treated mice group than only radiation-treated mice group. CONCLUSIONS: According to our findings, MLK has a potential role to be used as a renal protective agent against gamma radiation in radiotherapy.

Post hoc analysis of initial treatments and control status in the INITIAL study: an observational study of newly diagnosed patients with asthma.

BACKGROUND: The 12-week, multicentre, observational INITIAL study (NCT02143739) assessed asthma severity in newly diagnosed Chinese patients. METHODS: Post hoc analysis of medication combinations prescribed per routine clinical practice at baseline, and the impact on control levels evaluated using 2012 vs 2018 Global Initiative for Asthma (GINA) criteria. RESULTS: In total, 4491 patients were included in the analysis. At baseline, intermittent, mild, moderate and severe asthma was reported in 3.9, 12.0, 22.6 and 61.6% of patients, respectively. Most patients (90.2%) were prescribed inhaled corticosteroid/long-acting ß2 agonist (ICS/LABA). ICS/LABA plus ≥1 additional medication(s) was prescribed to 66.7% of patients, with leukotriene receptor antagonist (LTRA, 54.7%) being the most common additional medication. Distribution of ICS/LABA vs ICS/LABA+LTRA was comparable in patients with intermittent (3.2% vs 3.0%), mild (11.5% vs 9.7%), moderate (21.2% vs 19.9%) and severe asthma (64.1% vs 67.4%). Control levels among patients using ICS/LABA+LTRA vs ICS/LABA were comparable using GINA 2012 and lower using GINA 2018 criteria. The proportion of patients using ICS/LABA+LTRA vs ICS/LABA with intermittent, mild, moderate and severe asthma controlled at Week 12 (using GINA 2012) were 78.1% vs 80.0, 86.5% vs 85.8, 78.5% vs 71.3, and 59.6% vs 61.8%, respectively. Using GINA 2018 criteria proportions were 86.8% vs 95.9, 86.1% vs 93.2, 82.1% vs 85.3, and 71.9% vs 77.6%, respectively. CONCLUSIONS: Asthma control was not improved by adding LTRA to ICS/LABA and may have been unnecessary for some newly diagnosed patients. These findings were irrespective of the GINA criteria (2012 vs 2018) used and baseline severity.

Disagreement between guidelines regarding the third step of asthma drug therapy for school-age children.

With the help of a routine clinical case, we highlighted the difference between two of the best asthma guidelines available at the time regarding therapeutic suggestions for the so-called "third step" for school-age asthmatic children. We have analyzed the scientific evidence that each of the two guidelines brings to support their position. Finally, we have motivatedly solved the clinical scenario. However, the question of disagreement between two guidelines remains unresolved. This can lead to unjustified differences in the management of schoolchildren with persistent asthma.

Antagonism of cysteinyl leukot-riene receptor 1 (cysLT1R) by montelukast regulates differentiation of MC3T3-E1 cells under overloaded mechanical environment.

Long-term exposure to overloaded mechanical environment induces bone fatigue damage symptoms and osteoblast damages. Montelukast is a selective cysteinyl leukot-riene receptor 1 (cysLT1R) antagonist, which has been used for the treatment of bronchial asthma in clinics. In the current study, we have identified a novel pharmacological role of montelukast by finding that it has protective properties against overload damage in osteoblastic MC3T3-E1 cells. Firstly, our results show that CysLT1R is expressed in MC3T3-E1 cells. Mechanical tensile strain of 5000-7000 µÎµ resulted in a significant upregulation of CysLT1R in osteoblastic MC3T3-E1 cells in an intensity dependent manner. Secondly, MTT assay indicates that loading with 5000 µÎµ mechanical strain inhibited cell proliferation, which was suppressed by montelukast treatment. Furthermore, montelukast promotes cell differentiation by increasing the expression of ALP and RUNX2. Alizarin Red S staining assay showed that montelukast abolished the inhibitory effects of overload mechanics on osteoblast mineralization. Mechanistically, the effect of montelukast on osteoblastic differentiation acted by activating the extracellular regulated protein kinases (ERK) pathway. The obtained results suggested that montelukast promotes proliferation and differentiation in osteoblasts exposed to overload mechanics.

Leukotriene receptor antagonists for eczema.

BACKGROUND: Eczema is a common, chronic, inflammatory skin condition that is frequently associated with atopic conditions, including asthma. Leukotriene receptor antagonists (LTRAs) have a corticosteroid-sparing role in asthma, but their role in eczema remains controversial. Currently available topical therapies for eczema are often poorly tolerated, and use of systemic agents is restricted by their adverse effect profile. A review of alternative treatments was therefore warranted. OBJECTIVES: To assess the possible benefits and harms of leukotriene receptor antagonists for eczema. SEARCH METHODS: We searched the following databases to September 2017: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and the GREAT database. We also searched five trial registries, and handsearched the bibliographies of all extracted studies for further relevant trials. SELECTION CRITERIA: Randomised controlled trials of LTRAs alone or in combination with other (topical or systemic) treatments compared with other treatments alone such as topical corticosteroids or placebo for eczema in the acute or chronic (maintenance) phase of eczema in adults and children. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcome measures were change in disease severity, long-term symptom control, and adverse effects of treatment. Secondary outcomes were change in corticosteroid requirement, reduction of pruritis, quality of life, and emollient requirement. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: Only five studies (including a total of 202 participants) met the inclusion criteria, all of which assessed oral montelukast; hence, we found no studies assessing other LTRAs. Treatment ranged from four to eight weeks, and outcomes were assessed at the end of treatment; therefore, we could only report short-term measurements (defined as less than three months follow-up from baseline). Montelukast dosing was 10 mg for adults (age 14 years and above) and 5 mg for children (age 6 years to 14 years). One study included children (aged 6 years and above) among their participants, while the remaining studies only included adults (participant age ranged from 16 to 70 years). The participants were diagnosed with moderate-to-severe eczema in four studies and moderate eczema in one study. The study setting was unclear in two studies, multicentre in two studies, and single centre in one study; the studies were conducted in Europe and Bangladesh. Two studies were industry funded. The comparator was placebo in three studies and conventional treatment in two studies. The conventional treatment comparator was a combination of antihistamines and topical corticosteroids (plus oral antibiotics in one study).Four of the studies did not adequately describe their randomisation or allocation concealment method and were considered as at unclear risk of selection bias. Only one study was at low risk of performance and detection bias. However, we judged all studies to be at low risk of attrition and reporting bias.We found no evidence of a difference in disease severity of moderate-to-severe eczema after short-term use of montelukast (10 mg) when compared with placebo. The outcome was assessed using the modified EASI (Eczema Area and Severity Index) score and SASSAD (Six Area, Six Sign Atopic Dermatitis) severity score (standardised mean difference 0.29, with a positive score showing montelukast is favoured, 95% confidence interval (CI) -0.23 to 0.81; 3 studies; n = 131; low-quality evidence).When short-term montelukast (10 mg) treatment was compared with conventional treatment in one study, the mean improvement in severity of moderate-to-severe eczema was greater in the intervention group (measured using SCORAD (SCORing of Atopic Dermatitis) severity index) (mean difference 10.57, 95% CI 4.58 to 16.56; n = 31); however, another study of 32 participants found no significant difference between groups using the same measure (mean improvement was 25.2 points with montelukast versus 23.9 points with conventional treatment; no further numerical data provided). We judged the quality of the evidence as very low for this outcome, meaning the results are uncertain.All studies reported their adverse event rate during treatment. Four studies (136 participants) reported no adverse events. In one study of 58 participants with moderate eczema who received montelukast 10 mg (compared with placebo), there was one case of septicaemia and one case of dizziness reported in the intervention group, both resulting in study withdrawal, although whether these effects were related to the medication is unclear. Mild side effects (e.g. headache and mild gastrointestinal disturbances) were also noted, but these were fairly evenly distributed between the montelukast and placebo groups. The quality of evidence for this outcome was low.No studies specifically evaluated emollient requirement or quality of life. One study that administered treatment for eight weeks specifically evaluated pruritus improvement at the end treatment and topical corticosteroid use during treatment. We found no evidence of a difference between montelukast (10 mg) and placebo for both outcomes (low-quality evidence, n = 58). No other study assessed these outcomes. AUTHORS' CONCLUSIONS: The findings of this review are limited to montelukast. There was a lack of evidence addressing the review question, and the quality of the available evidence for most of the measured outcomes was low. Some primary and secondary outcomes were not addressed at all, including long-term control.We found no evidence of a difference between montelukast (10 mg) and placebo on disease severity, pruritus improvement, and topical corticosteroid use. Very low-quality evidence means we are uncertain of the effect of montelukast (10 mg) compared with conventional treatment on disease severity. Participants in only one study reported adverse events, which were mainly mild (low-quality evidence).There is no evidence that LTRA is an effective treatment for eczema. Serious limitations were that all studies focused on montelukast and only included people with moderate-to-severe eczema, who were mainly adults; and that each outcome was evaluated with a small sample size, if at all.Further large randomised controlled trials, with a longer treatment duration, of adults and children who have eczema of all severities may help to evaluate the effect of all types of LTRA, especially on eczema maintenance.

Comparison of the pharmacokinetics and tolerability of montelukast/levocetirizine administered as a fixed-dose combination and as separate tablets.

OBJECTIVE: A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. RESULTS: The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. CONCLUSION: The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option.
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Pharmacologic Treatment of Seasonal Allergic Rhinitis: Synopsis of Guidance From the 2017 Joint Task Force on Practice Parameters.

DESCRIPTION: The Joint Task Force on Practice Parameters, which comprises representatives of the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI), formed a workgroup to review evidence and provide guidance to health care providers on the initial pharmacologic treatment of seasonal allergic rhinitis in patients aged 12 years or older. METHODS: To update a prior systematic review, the workgroup searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 18 July 2012 to 29 July 2016 to identify studies that addressed efficacy and adverse effects of single or combination pharmacotherapy for seasonal allergic rhinitis. In conjunction with the Joint Task Force, the workgroup reviewed the evidence and developed recommendations about initial treatment approaches by using the Grading of Recommendations Assessment, Development and Evaluation approach. Members of the AAAAI, the ACAAI, and the general public provided feedback on the draft document, which the Joint Task Force reviewed before finalizing the guideline. RECOMMENDATION 1: For initial treatment of seasonal allergic rhinitis in persons aged 12 years or older, routinely prescribe monotherapy with an intranasal corticosteroid rather than an intranasal corticosteroid in combination with an oral antihistamine. (Strong recommendation). RECOMMENDATION 2: For initial treatment of seasonal allergic rhinitis in persons aged 15 years or older, recommend an intranasal corticosteroid over a leukotriene receptor antagonist. (Strong recommendation). RECOMMENDATION 3: For treatment of moderate to severe seasonal allergic rhinitis in persons aged 12 years or older, the clinician may recommend the combination of an intranasal corticosteroid and an intranasal antihistamine for initial treatment. (Weak recommendation).

Prescribing of asthma drugs for children 2004-2015. / Forskrivning av legemidler mot astma til barn i perioden 2004­15.

BAKGRUNN: Astma kan være vanskelig å diagnostisere hos barn. For barn under skolealder finnes det få tilgjengelige objektive diagnostiske undersøkelser, og retningslinjene for diagnose og behandling er basert på sykehistorie og klinisk undersøkelse. Dette kan gi rom for varierende behandlingspraksis. MATERIALE OG METODE: Data fra Reseptregisteret ble brukt til å studere forskrivning av legemidler mot astma til barn i aldersgruppene 0-4 år og 5-9 år fordelt på fylker fra 2004-15. RESULTATER: Det var stor variasjon mellom fylkene i andelen per 1 000 barn som fikk forskrevet legemidler mot astma i perioden 2012-14 (aldersgruppen 0-4 år: median: 104/1 000; ekstremverdier: 64-147, aldersgruppen 5-9 år: 68/1000; 46-86). Inhalasjonssteroider var hyppigst forskrevet, og det var her variasjonen mellom fylkene var størst i begge aldersgruppene (aldersgruppen 0-4 år: 85/1 000; 42-116, aldersgruppen 5-9 år: 51/1 000; 31-70). De fleste fikk kun en eller få forskrivninger med inhalasjonssteroider over en treårsperiode. Endring i forskrivningen av inhalasjonssteroider fra 2004 til 2015 varierte betydelig mellom fylkene, mest for aldersgruppen 0-4 år. FORTOLKNING: Stor forskjell i forskrivning av legemidler mot astma fylkene imellom, høy andel sporadisk bruk og endring over tid, særlig i den yngste aldersgruppen, kan tyde på en unaturlig variasjon i behandlingen som ikke kan forklares av forskjeller i astmaforekomst. Uklare retningslinjer som ikke er tilstrekkelig innarbeidet i klinisk praksis kan være én årsak.

The selective cysteinyl leukotriene receptor 1 (CysLT1R) antagonist montelukast regulates extracellular matrix remodeling.

Scar formation after filtration surgery of glaucoma is mainly caused by excessive synthesis of new extracellular matrix (ECM) and contraction of subconjunctival tissue mediated by human Tenon fibroblasts (HTFs) and the transforming growth factor (TGF-ß1). Montelukast, a potent and specific cysteinyl leukotriene receptor 1 (cysLT1R) antagonist, is a licensed drug clinically used for the treatment of bronchial asthma. In this study, we investigated the effects of montelukast on the contractility of HTFs cultured in a three-dimensional collagen gel. We found that cysLT1R was expressed in HTFs. Interestingly, the expression of cysLT1R was increased in response to TGF-ß1 in a dose dependent manner, suggesting its potential role in TGF-ß1 induced fibrosis. Importantly, we found that montelukast inhibited TGF-ß1-induced collagen gel contraction mediated by HTFs in a concentration- and time-dependent manner. In addition, TGF-ß1-induced expression of MMP-1 and MMP-3, generation of fibronectin and type I collagen production, focal adhesion kinase (FAK) and paxillin phosphorylation in HTFs were also ameliorated by montelukast in a dose dependent manner. These results suggested that montelukast might provide therapeutic possibilities for inhibition of scar formation after such surgery.

Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers: a systematic review.

BACKGROUND: Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remains limited. OBJECTIVE: To perform a systematic review of pharmacogenomics and pharmacogenetics of inhaled corticosteroids (ICS) and leukotriene modifiers (LTMs) in patients with asthma. METHODS: Articles published between 1999 and June 2015 were searched using PubMed and EMBASE. Pharmacogenomics/genetics studies of patients with asthma using ICS or LTMs were included if ≥1 of the following outcomes were studied: lung function, exacerbation rates or asthma symptoms. The studies of Single Nucleotide Polymorphisms (SNPs) that had been replicated at least once were assessed in more detail. RESULTS: In total, 59 publications were included in the systematic review: 26 addressed LTMs (including two genomewide Genome-Wide association studies [GWAS]) and 33 addressed ICS (including four GWAS). None of the GWAS reported similar results. Furthermore, none of the SNPs assessed in candidate gene studies were identified in a GWAS. No consistent reports were found for candidate gene studies of LTMs. In candidate gene studies of ICS, the most consistent results were found for rs28364072 in FCER2. This SNP was associated with all three outcomes of poor response, and the largest effect was reported with the risk of exacerbations (hazard ratio, 3.95; 95% CI, 1.64-9.51). CONCLUSION AND CLINICAL RELEVANCE: There is a lack of replication of genetic variants associated with poor ICS or LTM response. The most consistent results were found for the FCER2 gene [encoding for a low-affinity IgE receptor (CD23)] and poor ICS response. Larger studies with well-phenotyped patients are needed to assess the clinical applicability of ICS and LTM pharmacogenomics/genetics.

A randomized controlled phase II clinical trial comparing ONO-4053, a novel DP1 antagonist, with a leukotriene receptor antagonist pranlukast in patients with seasonal allergic rhinitis.

BACKGROUND: Prostaglandin D2 (PGD2 ) is primarily produced by mast cells and is contributing to the nasal symptoms including nasal obstruction and rhinorrhea. OBJECTIVE: This study aimed to evaluate the efficacy and safety of a novel PGD2 receptor 1 (DP1) antagonist, ONO-4053, in patients with seasonal allergic rhinitis (SAR). METHODS: This study was a multicenter, randomized, double-blind, parallel-group study of patients with SAR. Following a one-week period of placebo run-in, patients who met the study criteria were randomized to either the ONO-4053, leukotriene receptor antagonist pranlukast, or placebo group for a two-week treatment period. A total of 200 patients were planned to be randomly assigned to receive ONO-4053, pranlukast, or placebo in a 2:2:1 ratio. Nasal and eye symptoms were evaluated. RESULTS: Both ONO-4053 and pranlukast had higher efficacy than placebo on all nasal and eye symptoms. ONO-4053 outperformed pranlukast in a total of three nasal symptom scores (T3NSS) as well as in individual scores for sneezing, rhinorrhea, and nasal itching. For T3NSS, the Bayesian posterior probabilities that pranlukast was better than placebo and ONO-4053 was better than pranlukast were 70.0% and 81.6%, respectively, suggesting that ONO-4053 has a higher efficacy compared with pranlukast. There was no safety-related issue in this study. CONCLUSIONS: We demonstrated that the efficacy of ONO-4053 was greater than that of pranlukast with a similar safety profile. This study indicates the potential of ONO-4053 for use as a treatment for SAR (JapicCTI-142706).

General Management Principles of the Pregnant Woman.

Pregnancy is a dynamic process that consists of profound physiological changes mediated by hormonal, mechanical, and circulatory pathways. Understanding of changes in physiology is essential for distinguishing abnormal and normal signs and symptoms in a pregnant patient. These physiological changes also have important pharmacotherapeutic considerations for a pregnant patient. Although there are limited data to guide decisions regarding medications and diagnostic procedures in pregnancy, a careful review of risks should be balanced with review of risk of withholding a medication or procedure. Interventional pulmonary procedures can be safely performed in pregnant women while keeping in mind the maternal anatomic and physiologic changes. Furthermore, management of a maternal cardiopulmonary arrest requires important modifications in patient positioning and intravenous access to ensure adequate efficacy of chest compressions, circulation, and airway management. This review will provide an overview of maternal physiologic changes with a focus on cardiopulmonary physiology, pharmacotherapeutic considerations, diagnostic and interventional pulmonary procedures during pregnancy, and cardiopulmonary resuscitation in pregnancy.

Addition of anti-leukotriene agents to inhaled corticosteroids for adults and adolescents with persistent asthma.

BACKGROUND: Asthma management guidelines recommend low-dose inhaled corticosteroids (ICS) as first-line therapy for adults and adolescents with persistent asthma. The addition of anti-leukotriene agents to ICS offers a therapeutic option in cases of suboptimal control with daily ICS. OBJECTIVES: To assess the efficacy and safety of anti-leukotriene agents added to ICS compared with the same dose, an increased dose or a tapering dose of ICS (in both arms) for adults and adolescents 12 years of age and older with persistent asthma. Also, to determine whether any characteristics of participants or treatments might affect the magnitude of response. SEARCH METHODS: We identified relevant studies from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the trial registries clinicaltrials.gov and ICTRP from inception to August 2016. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of adults and adolescents 12 years of age and older on a maintenance dose of ICS for whom investigators added anti-leukotrienes to the ICS and compared treatment with the same dose, an increased dose or a tapering dose of ICS for at least four weeks. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. The primary outcome was the number of participants with exacerbations requiring oral corticosteroids (except when both groups tapered the dose of ICS, in which case the primary outcome was the % reduction in ICS dose from baseline with maintained asthma control). Secondary outcomes included markers of exacerbation, lung function, asthma control, quality of life, withdrawals and adverse events. MAIN RESULTS: We included in the review 37 studies representing 6128 adult and adolescent participants (most with mild to moderate asthma). Investigators in these studies used three leukotriene receptor antagonists (LTRAs): montelukast (n = 24), zafirlukast (n = 11) and pranlukast (n = 2); studies lasted from four weeks to five years. Anti-leukotrienes and ICS versus same dose of ICSOf 16 eligible studies, 10 studies, representing 2364 adults and adolescents, contributed data. Anti-leukotriene agents given as adjunct therapy to ICS reduced by half the number of participants with exacerbations requiring oral corticosteroids (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.86; 815 participants; four studies; moderate quality); this is equivalent to a number needed to treat for additional beneficial outcome (NNTB) over six to 16 weeks of 22 (95% CI 16 to 75). Only one trial including 368 participants reported mortality and serious adverse events, but events were too infrequent for researchers to draw a conclusion. Four trials reported all adverse events, and the pooled result suggested little difference between groups (RR 1.06, 95% CI 0.92 to 1.22; 1024 participants; three studies; moderate quality). Investigators noted between-group differences favouring the addition of anti-leukotrienes for morning peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1), asthma symptoms and night-time awakenings, but not for reduction in ß2-agonist use or evening PEFR. Anti-leukotrienes and ICS versus higher dose of ICSOf 15 eligible studies, eight studies, representing 2008 adults and adolescents, contributed data. Results showed no statistically significant difference in the number of participants with exacerbations requiring oral corticosteroids (RR 0.90, 95% CI 0.58 to 1.39; 1779 participants; four studies; moderate quality) nor in all adverse events between groups (RR 0.96, 95% CI 0.89 to 1.03; 1899 participants; six studies; low quality). Three trials reported no deaths among 834 participants. Results showed no statistically significant differences in lung function tests including morning PEFR and FEV1 nor in asthma control measures including use of rescue ß2-agonists or asthma symptom scores. Anti-leukotrienes and ICS versus tapering dose of ICSSeven studies, representing 1150 adults and adolescents, evaluated the combination of anti-leukotrienes and tapering-dose of ICS compared with tapering-dose of ICS alone and contributed data. Investigators observed no statistically significant difference in % change from baseline ICS dose (mean difference (MD) -3.05, 95% CI -8.13 to 2.03; 930 participants; four studies; moderate quality), number of participants with exacerbations requiring oral corticosteroids (RR 0.46, 95% CI 0.20 to 1.04; 542 participants; five studies; low quality) or all adverse events (RR 0.95, 95% CI 0.83 to 1.08; 1100 participants; six studies; moderate quality). Serious adverse events occurred more frequently among those taking anti-leukotrienes plus tapering ICS than in those taking tapering doses of ICS alone (RR 2.44, 95% CI 1.52 to 3.92; 621 participants; two studies; moderate quality), but deaths were too infrequent for researchers to draw any conclusions about mortality. Data showed no improvement in lung function nor in asthma control measures. AUTHORS' CONCLUSIONS: For adolescents and adults with persistent asthma, with suboptimal asthma control with daily use of ICS, the addition of anti-leukotrienes is beneficial for reducing moderate and severe asthma exacerbations and for improving lung function and asthma control compared with the same dose of ICS. We cannot be certain that the addition of anti-leukotrienes is superior, inferior or equivalent to a higher dose of ICS. Scarce available evidence does not support anti-leukotrienes as an ICS sparing agent, and use of LTRAs was not associated with increased risk of withdrawals or adverse effects, with the exception of an increase in serious adverse events when the ICS dose was tapered. Information was insufficient for assessment of mortality.