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1.
The Montelukast Therapy in Asthmatic Children with and without Food Allergy: Does It Make Any Difference?
Sahiner, UM, Arik Yilmaz, E, Fontanella, S, Haider, S, Soyer, O, Custovic, A, Kalayci, O, Sackesen, C
International archives of allergy and immunology. 2021;(12):1212-1221
Abstract
INTRODUCTION Children with food allergy are at increased risk for asthma and asthma morbidity. Since leukotrienes are implicated in the pathogenesis of both asthma and probably in food allergies, we hypothesized that asthmatic children with concomitant food allergy may have a favorable response to antileukotriene treatment. METHODS Asthmatic children aged 6-18 years with and without food allergy were treated with montelukast and placebo in a double-blind, placebo-controlled cross-over parallel-group study. The primary outcome of the study was improvement in FEV1%. Asthma control tests, spirometry and methacholine challenges were performed as well as Fractional Exhaled Nitric Oxide (FeNO) levels. PGD2, CystLT, and lipoxin levels were measured in exhaled breath condensate (EBC). RESULTS A total of 113 children were enrolled and 87 completed the study in accordance with the protocol. At baseline, children with food allergy and asthma (FAA) had higher levels of PGD2 and CysLT levels in the EBC than children with asthma alone (AA) (p < 0.001 for each). In the montelukast arm, although FEV1% was significantly higher in the FAA group compared to AA (p = 0.005), this effect was linked to the baseline difference of FEV1% between both arms. Montelukast treatment failed to improve FEV1% in both groups compared to the placebo. No effect of montelukast was observed in the remaining study parameters. CONCLUSION Although children with FAA do not show a more favorable response to montelukast treatment compared to AA, a significant difference between baseline PGD2 and CystLT levels between FAA and AA groups may point to a different endotype of childhood asthma.
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2.
The leukotriene receptor antagonist montelukast in the treatment of non-alcoholic steatohepatitis: A proof-of-concept, randomized, double-blind, placebo-controlled trial.
Abdallah, MS, Eldeen, AH, Tantawy, SS, Mostafa, TM
European journal of pharmacology. 2021;:174295
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with fat accumulation in the liver which can progress into non-alcoholic steatohepatitis (NASH). There is no specific treatment strategy for NASH. In this context, this study aimed at evaluating the efficacy and safety of montelukast in the treatment of patients with NASH. In this randomized double-blind placebo-controlled study, 52 overweight/obese patients with NASH were randomized into group 1 (n = 26) which received montelukast 10 mg tablets once daily and group 2 (n = 26) which received placebo tablets once daily for 12 weeks. The fibro-scan was used to assess liver stiffness as a primary outcome at baseline and 12 weeks post-treatment. Furthermore, patients were assessed for biochemical analysis of liver aminotransferases, metabolic parameters, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), liver fibrosis biomarkers including hyaluronic acid (HA) and transforming growth factor beta-1 (TGF-β1). Beck depression inventory questionnaire was used to report depressive symptoms. Data were statistically analyzed by paired and unpaired student's t-test, and Chi-square test. A total number of 44 patients completed the study. The two groups were statistically similar at baseline. After treatment and as compared to baseline data and placebo, montelukast showed a statistically significant improvement in liver stiffness, liver enzymes, metabolic parameters (except LDL-C), TNF-α, 8-OHdG, and liver fibrosis biomarkers (HA and TGF-β1). Furthermore, montelukast was well tolerated and didn't provoke depression. In this proof-of-concept study, treatment with montelukast may represent a promising therapeutic strategy for patients with non-alcoholic steatohepatitis secondary to its efficacy and safety. Clinicaltrial.gov ID: NCT04080947.
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3.
Efficacy of Chinese Medicine Acupoint Application Combined with Montelukast on Children with Perennial Allergic Rhinitis: A Randomized Controlled Trial.
Li, YJ, Zong, M, Ding, LF, Rui, XQ, Ma, BY, Qin, LP
Chinese journal of integrative medicine. 2020;(11):845-852
Abstract
OBJECTIVE To evaluate the efficacy of Chinese medicine acupoint application (CMAA) combined with Western medicine for perennial allergic rhinitis (PAR) in children. METHODS In this prospective, parallel, randomized, placebo-controlled and single-blind trial from August to September, 2017, 180 children with PAR were randomly assigned to an integrative group (CMAA and Montelukast), CMAA group (CMAA and placebo tablet), or Montelukast group (placebo CMAA and Montelukast). Participants were applied with CMAA for 6 sessions over 2 weeks, and/or Montelukast Chewable Tablet orally once daily for 12 weeks. The changes in severity of symptoms were measured by Visual Analog Scale (VAS) and rhinitis control assessment test (RCAT) at 0, 2, 4 and 12 weeks of treatment. Blood samples were collected for serum interleukin-4, interferon gamma γ and T helper type 1 (Th1)/Th2 flow cytometric analysis at the time points of 0, 4 and 12 weeks. RESULTS Eight cases dropped out from the trial, 3 in the integrative group, 2 in the CMAA group and 3 in the Montelukast group. The VAS scores decreased significantly while the RCAT scores increased significantly in all three groups at 4 and 12 weeks compared with baseline (P<0.01 or P<0.05). The VAS scores were significantly lower while the RCAT scores were significantly higher in the integrative and CMAA groups than the Montelukast group at 2 and 4 weeks (P<0.01 or P<0.05). At 2, 4 and 12 weeks, the scores of nasal congestion, sneezing, sleep problem, and rhinitis symptom control in the integrative and CMAA groups increased significantly compared with baseline (P<0.01 or P<0.05). The least percentages of Th2 and the most alleviated Th2 shift (highest Th1/Th2) were observed in the integrative group at 12 weeks compared with the other two groups (P<0.05). CONCLUSION The combination of CMAA with Montelukast might be more effective and appropriate than either option alone for children with PAR. (Registered at Chinese Clinical Trial Register, registration No. ChiCTR-IOR-17012434).
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4.
Airway mechanics after withdrawal of a leukotriene receptor antagonist in children with mild persistent asthma: Double-blind, randomized, cross-over study.
Kim, JH, Lee, S, Shin, YH, Ha, EK, Lee, SW, Kim, MA, Yoon, JW, Baek, HS, Choi, SH, Han, MY
Pediatric pulmonology. 2020;(12):3279-3286
Abstract
BACKGROUND To determine the response of airway mechanics and the changes in asthma symptoms to stepping down of leukotriene receptor antagonist (LTRA) therapy. METHODS Thirty children (mean age: 7.1 years) with mild, well-controlled, and persistent asthma who took LTRA as maintenance treatment were randomized into a double-blind, placebo-controlled, cross-over study. Each group received an LTRA (montelukast) or placebo daily for 2 weeks, followed by a 1-week washout period, and then the alternate treatment for 2 weeks. Spirometry and impulse oscillation system (IOS) measurements before and after four puffs of salbutamol inhalation, fractional exhaled nitric oxide (FeNO), and the childhood asthma control test (C-ACT) were evaluated at baseline, the end of placebo treatment, and the end of LTRA treatment. RESULTS Changes of FEV1 /FVC (p = .113) and FEV1 (p = .109) from baseline to posttreatment did not differ significantly between the placebo and montelukast groups. In the placebo group, prebronchodilator (pre-) FEV1 /FVC was decreased (83% vs. 86%) and bronchodilator response (BDR) in FEV1 was diminished (10.7% vs. 6.4%) at posttreatment compared with baseline. However, the montelukast group had no significant changes in pre-FEV1 /FVC (p = .865) and BDR in FEV1 (p = .461). In addition, compared with the montelukast group, the placebo group showed no significant changes in Rrs5 (total airway resistance), Rrs5-20 (peripheral airway resistance), FeNO, and symptoms by the C-ACT. CONCLUSION In children with well-controlled mild persistent asthma, changes in spirometry, IOS, FeNO, and C-ACT results did not differ between the placebo and montelukast groups within 2 weeks.
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5.
The effects of vortioxetine on cognitive dysfunction in patients with inadequate response to current antidepressants in major depressive disorder: A short-term, randomized, double-blind, exploratory study versus escitalopram.
Vieta, E, Sluth, LB, Olsen, CK
Journal of affective disorders. 2018;:803-809
Abstract
BACKGROUND Major Depressive Disorder (MDD) is a heterogeneous disease characterized by emotional, physical and cognitive symptoms. This study explored the effects of vortioxetine versus escitalopram on outcomes of cognition, functioning and mood symptoms in depressed patients with inadequate response to current antidepressant treatment. METHODS In this parallel-group, active-comparator study, adult patients (18-65 years, N = 101) with MDD, with inadequate response to current antidepressant monotherapy, were randomized 1:1 to 8 weeks' double-blind treatment with flexible doses (10-20mg/day) of either vortioxetine or escitalopram. Primary and key secondary efficacy measures were the Digit Symbol Substitution Test (DSST), analyzed using a mixed model for repeated measurements, and the University of San Diego Performance-based Skills Assessment - Brief (UPSA-B), analyzed using analysis of covariance (last observation carried forward method). RESULTS At week 8, DSST and UPSA-B performance had improved in both treatment groups, with no statistically significant treatment differences. Numerical improvements across measures of cognition, functioning and mood symptoms generally favored vortioxetine. Most adverse events were mild or moderate, with nausea being the most common adverse event. LIMITATIONS This was an exploratory study with small sample sizes implying limited statistical power. CONCLUSION Although this explorative study did not meet primary endpoints, the results confirm vortioxetine in doses of 10-20mg/day as an efficacious and well-tolerated antidepressant switch treatment. The overall direction of numerical effect sizes across cognition endpoints support previous findings that vortioxetine specifically benefits cognitive function in MDD.
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6.
The effect of vortioxetine on health-related quality of life in patients with major depressive disorder.
Florea, I, Danchenko, N, Brignone, M, Loft, H, Rive, B, Abetz-Webb, L
Clinical therapeutics. 2015;(10):2309-2323.e6
Abstract
PURPOSE Major depressive disorder (MDD) has detrimental effects on health-related quality of life (HRQoL). We describe the effect of vortioxetine on HRQoL in MDD patients by using patient-reported outcome instruments. METHODS HRQoL was evaluated in 5 short-term (6-8 weeks), randomized studies of vortioxetine (5-20 mg/d; n = 2155) versus placebo (n = 1316) in adults with MDD by using the 36-item Short-Form Health Survey (SF-36), the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form, the EuroQol 5-Dimension Questionnaire (EQ-5D), and the 12-item Health Status Questionnaire in 1 study in elderly patients. Only patients receiving the approved doses of vortioxetine 5, 10, 15, or 20 mg/d were included in the analysis. A random effects meta-analysis was performed on the 4 adult MDD studies that used the SF-36. A within-studies mixed model for repeated measures analysis based on the full analysis set (FAS) was used unless otherwise specified. Standardized effect size (SES) was calculated to reflect clinical relevance, based on a Cohen's d of 0.2. FINDINGS Vortioxetine produced significantly better results compared with placebo in the SF-36 mental component summary score (5 mg: 2.6, P = 0.001, SES of 0.22, n = 604; 10 mg: 4.8, P < 0.001, SES of 0.42, n = 328) and 4 domain scores (vitality, social functioning, role emotional, and mental health). Vortioxetine was also significantly better in the EuroQoL-5 Dimension Questionnaire Health State score (10 mg: 7.5, P < 0.05, SES of 0.33, n = 86) and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form total score (15 mg: 3.3, P < 0.01, SES of 0.38, n = 127; 20 mg: 4.5, P < 0.0001, SES of 0.52, n = 134) (FAS, last-observation-carried-forward). In the study of elderly patients, vortioxetine 5 mg (n = 136) improved 12-item Health Status Questionnaire scores significantly more than placebo (n = 148) for the domains of health perception (10.4, P < 0.0001, SES of 0.54), mental health (7.9, P < 0.001, SES of 0.44), and energy (6.4, P < 0.05, SES of 0.28) (FAS, mixed model for repeated measures). IMPLICATIONS Vortioxetine yielded significant, meaningful HRQoL improvements in 6 MDD studies of 6 to 8 weeks' duration.
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7.
A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults.
McIntyre, RS, Lophaven, S, Olsen, CK
The international journal of neuropsychopharmacology. 2014;(10):1557-67
Abstract
The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18-65 yr, N = 602) were randomized (1:1:1) to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10 mg, p < 0.0001) and 0.33 (vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were -4.7 (10 mg: p < 0.0001) and -6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.
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8.
[Effects of allitridi capsules on endothelial function and clinical prognosis after percutaneous coronary intervention in coronary artery disease patients with diabetes mellitus].
Nie, XM, Zhao, YX, Shi, DM, Liu, YY, Zhou, ZM, Su, LX, Zhou, YJ
Zhonghua yi xue za zhi. 2013;(26):2052-5
Abstract
OBJECTIVE To explore the effects of allitridi capsules on endothelial function and clinical prognosis after percutaneous coronary intervention (PCI) in coronary artery disease (CAD) patients with diabetes mellitus (DM). METHODS A total of 120 CAD patients with DM undergoing PCI were randomly assigned to receive conventional (control, n = 60) and additional allitridi treatment (120 mg/day, n = 60) for 3 months.Serum nitric oxide (NO) and intercellular adhesion molecule 1 (ICAM-1) levels were determined by enzyme-linked immunosorbent assay (ELISA) immediately and at 3 months post-PCI. Endothelial function was assessed by endothelium dependent flow-mediated dilation (FMD). Duration of follow-up was 1 year after PCI. RESULTS The clinical characteristics, serum NO and ICAM-1 levels and FMD at baseline were not different between two groups. At Month 3 post-PCI, serum NO level was markedly higher ((147 ± 32) vs (112 ± 24) µmol/L, P = 0.009) and serum ICAM-1 level was significantly lower ((182 ± 21) vs (232 ± 29) µmol/L, P = 0.021) in the allitridi group than in the control group.Furthermore, treatment of allitridi resulted in a significant improvement of FMD (8.2% ± 2.4% vs 6.4% ± 2.3%, P = 0.013). At Year 1 post-PCI, the incidence of major adverse cardiovascular event (MACE) was lower in the allitridi group than that in the control group (10.5% vs 17.2%, P = 0.022). CONCLUSIONS Allitridi capsules significantly improve the clinical prognosis after PCI in CAD patients with DM. Its mechanism may lies in improved endothelial function and vascular inflammatory state.
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9.
Randomized, open-label, single-dose, crossover, relative bioavailability study in healthy adults, comparing the pharmacokinetics of rabeprazole granules administered using soft food or infant formula as dosing vehicle versus suspension.
Thyssen, A, Solanki, B, Treem, W
Clinical therapeutics. 2012;(7):1636-45
Abstract
BACKGROUND A sprinkle capsule formulation containing enteric-coated, delayed-release rabeprazole granules is being developed for the treatment of children with gastrointestinal reflux disease. The granules are designed to be mixed with vehicles that facilitate delivery to children, who may be unable to swallow solid formulations. OBJECTIVE The primary objective of this study-conducted on the sponsor's initiative-was to compare the bioavailability of rabeprazole granules when mixed with various dosing vehicles (small amount of soft food or infant formula) with that of a rabeprazole suspension with inactive vehicle granules (reference), to determine which dosing vehicle can be used to deliver rabeprazole in children. Tolerability was also assessed. METHODS This single-center, single-dose, randomized, open-label, 5-period crossover study was conducted in 35 healthy adult subjects. In a randomized sequence, fasting subjects received a single dose of 10-mg rabeprazole granules per treatment period, mixed with small amounts of 1 of 5 dosing vehicles (a strawberry-flavored suspension of rabeprazole granules with inactive vehicle granules reconstituted with water, yogurt [1 tablespoon], applesauce [1 tablespoon], or infant formula [5 mL], or a suspension of rabeprazole granules with inactive vehicle tablet reconstituted with water). Full plasma pharmacokinetic (PK) profiles of rabeprazole and its thioether metabolite were collected; concentrations were estimated via LC-MS/MS. PK properties were estimated using noncompartmental methods; 90% CIs around least squares mean test-to-reference ratios were calculated for C(max) and AUC values. All treatment-emergent adverse events (TEAEs) were recorded and assessed for severity (mild, moderate, or severe) and relationship to study drug. RESULTS A total of 35 subjects were enrolled (mean age, 38 years; 54.3% female; 100% white; mean weight, 71.4 kg). Thirty-four subjects completed the study. Rabeprazole and rabeprazole thioether plasma PK properties were comparable between all of the dosing vehicles tested. Median T(max) was 2.5 to 3.0 hours, and mean elimination half-life was 1.27 to 1.43 hours. The 90%CIs for the least squares mean ratios for rabeprazole and rabeprazole thioether exposure were within the 80% to 125% bioequivalence limits for all relevant comparisons. All TEAEs were of mild or moderate intensity, with headache being the most commonly reported; 21 subjects (60%) experienced TEAEs during the study. No deaths or serious AEs were reported during the study; 1 subject experienced a TEAE (urinary tract infection) that led to the discontinuation of treatment. CONCLUSION In these healthy adult subjects, the bioavailability of rabeprazole granules was comparable between all of the dosing vehicles tested, and rabeprazole was well tolerated. Soft food suitable for young children or infant formula may be appropriate for use as dosing vehicles for rabeprazole granules.
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10.
Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis.
Seymour, M, Pétavy, F, Chiesa, F, Perry, H, Lukey, PT, Binks, M, Donatien, PD, Freidin, AJ, Eckersley, RJ, McClinton, C, et al
Clinical and experimental rheumatology. 2012;(2):254-61
Abstract
OBJECTIVES To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). METHODS A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. RESULTS At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). CONCLUSIONS This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.