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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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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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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.
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Anti-inflammatory and hypolipidemic effects of the modified fatty acid tetradecylthioacetic acid in psoriasis--a pilot study.
Morken, T, Bohov, P, Skorve, J, Ulvik, R, Aukrust, P, Berge, RK, Livden, JK
Scandinavian journal of clinical and laboratory investigation. 2011;(4):269-73
Abstract
Tetradecylthioacetic acid (TTA) is a bioactive 3-thia fatty acid, giving hypolipidemic response, inhibiting the proliferation and increasing the differentiation of normal adult epidermal keratinocytes and showing anti-oxidant and anti-inflammatory effects. Psoriasis is an inflammatory disease associated with abnormalities in lipid profile, lipid peroxidation, antioxidant capacity, eicosanoid metabolism and increased frequency of cardiovascular events. On this background we have conducted a pilot study to explore the hypothesis that this modified fatty acid could improve dyslipidemia and reduce inflammation in psoriatic patients. In this double-blinded, placebo-controlled study, we assessed the metabolic effects of systemic TTA in a limited number of patients with mild to moderate psoriasis, 1000 mg TTA daily for 28 days. The most important findings were: (i) TTA reduced plasma total cholesterol, non HDL-cholesterol, LDL/HDL cholesterol ratio, triglycerides and total fatty acids; (ii) TTA decreased plasma TNF-α, IL-8 and VCAM-1; and (iii) plasma fatty acid composition changed with an increased level of monounsaturated fatty acids and decreased n-3 polyunsaturated fatty acids. In conclusion TTA exerts both hypolipidemic and anti-inflammatory effects in psoriasis patients. The results further indicate that TTA can be of therapeutic benefit for a subgroup of psoriatic patients.
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5.
Pharmacokinetics and tolerability of rabeprazole in children 1 to 11 years old with gastroesophageal reflux disease.
Zannikos, PN, Doose, DR, Leitz, GJ, Rusch, S, Gonzalez, MD, Solanki, B, Haddad, I, Mulberg, AE
Journal of pediatric gastroenterology and nutrition. 2011;(6):691-701
Abstract
BACKGROUND The pharmacokinetics of rabeprazole after a single oral dose and once-daily administration for 5 consecutive days was characterized in children 1 to 11 years old with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS The initial 8 patients received rabeprazole sodium (hereafter referred to as rabeprazole) 0.14 mg/kg (part 1); the next 20 patients were randomized to receive 0.5 or 1 mg/kg (part 2) to target concentrations in plasma expected to be safe and effective. Pharmacokinetic parameters of rabeprazole and the thioether metabolite were calculated using noncompartmental methods. Subjective evaluations of GERD severity, rabeprazole short-term effectiveness, palatability, and safety were also characterized. RESULTS Rabeprazole concentrations increased in a dose-dependent manner. Little or no accumulation was observed after repeated administration. The results suggest that formation of the thioether is an important metabolic pathway in young patients, which is consistent with adults. Plasma area under the concentration-time curve values of rabeprazole and the metabolite were poorly correlated with individual age and body weight. Furthermore, oral rabeprazole clearance values (not adjusted for weight) were similar to historical adult data. However, weight-adjusted values were higher for the pediatric patients, and approximately 2 to 3 times the milligram per kilogram dose of rabeprazole in these children was necessary to achieve comparable concentrations in adults. Subjective evaluations demonstrated an improvement of GERD symptoms in most patients after rabeprazole treatment. CONCLUSIONS Palatability of the formulation was reported to be good or excellent. Rabeprazole was well tolerated, with no notable differences in safety among the dose groups.