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1.
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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2.
Divergent behavior of hydrogen sulfide pools and of the sulfur metabolite lanthionine, a novel uremic toxin, in dialysis patients.
Perna, AF, Di Nunzio, A, Amoresano, A, Pane, F, Fontanarosa, C, Pucci, P, Vigorito, C, Cirillo, G, Zacchia, M, Trepiccione, F, et al
Biochimie. 2016;:97-107
Abstract
Dialysis patients display a high cardiovascular mortality, the causes of which are still not completely explained, but are related to uremic toxicity. Among uremic toxins, homocysteine and cysteine are both substrates of cystathionine β-synthase and cystathionine γ-lyase in hydrogen sulfide biosynthesis, leading to the formation of two sulfur metabolites, lanthionine and homolanthionine, considered stable indirect biomarkers of its production. Hydrogen sulfide is involved in the modulation of multiple pathophysiological responses. In uremia, we have demonstrated low plasma total hydrogen sulfide levels, due to reduced cystathionine γ-lyase expression. Plasma hydrogen sulfide levels were measured in hemodialysis patients and healthy controls with three different techniques in comparison, allowing to discern the different pools of this gas. The protein-bound (the one thought to be the most active) and acid-labile forms are significantly decreased, while homolanthionine, but especially lanthionine, accumulate in the blood of uremic patients. The hemodialysis regimen plays a role in determining sulfur compounds levels, and lanthionine is partially removed by a single dialysis session. Lanthionine inhibits hydrogen sulfide production in cell cultures under conditions comparable to in vivo ones. We therefore propose that lanthionine is a novel uremic toxin. The possible role of high lanthionine as a contributor to the genesis of hyperhomocysteinemia in uremia is discussed.
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3.
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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4.
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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5.
PET imaging of serotonin transporters with [11C]DASB: test-retest reproducibility using a multilinear reference tissue parametric imaging method.
Kim, JS, Ichise, M, Sangare, J, Innis, RB
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2006;(2):208-14
Abstract
UNLABELLED Parametric imaging of serotonin transporters (SERT) with 11C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([11C]DASB) PET is a useful data analysis tool. The purpose of this study was to evaluate the reproducibility of measurements of SERT binding potential (BP) and relative blood flow (R1) by a 2-parameter multilinear reference tissue parametric imaging method (MRTM2) for human [11C]DASB studies. METHODS Eight healthy subjects (3 men, 5 women; age, 26 +/- 9 y) underwent 2 [11C]DASB PET scans separated by 1 h on the same day (dose, 703 +/- 111 MBq). Parametric images of BP and R1 were generated by MRTM2 using the cerebellum as a reference region. The k'2 (clearance rate constant from the reference region) required by MRTM2 was estimated by the 3-parameter MRTM. Reproducibility of BP and R1 measurements was evaluated by calculating bias (100 x (retest - test/test), variability (SD of the bias), and reliability (intraclass correlation coefficient = rho) for several representative regions of interest (ROIs). BP and R1 were estimated for ROI time-activity curves fitted by MRTM2 and were compared with those based on the parametric images. RESULTS The test-retest (0.066 +/- 0.013/0.06 +/- 0.011 min(-1)) MRTM k'2 reproducibility was excellent with small bias (3%) and variability (6%) and high reliability (0.95). Retest BP values were consistently lower than those of test BP values in all regions (a mean negative bias of approximately 6%; P < 0.001). The test-retest BP variability was relatively small, ranging from 4% to 13%, with rho ranging from 0.44 to 0.85. In contrast to BP, test-retest R1 values were similar with negligible bias of < or =0.1%. The test-retest R1 variability was excellent and smaller than that of BP ranging from 3% to 6%, with rho ranging from 0.58 to 0.95. BP and R1 values estimated by the ROI time-activity curve-fitting method were slightly lower ( approximately 3% and approximately 1%, respectively) than those by the parametric imaging method (P < 0.001). However, the test-retest bias and variability of BP and R1 were very similar for both ROI and parametric methods. CONCLUSION Our results suggest that [11C]DASB parametric imaging of BP and R1 with the noninvasive MRTM2 method is reproducible and reliable for PET studies of SERT.
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6.
An intervention study to prevent gastric cancer by micro-selenium and large dose of allitridum.
Li, H, Li, HQ, Wang, Y, Xu, HX, Fan, WT, Wang, ML, Sun, PH, Xie, XY
Chinese medical journal. 2004;(8):1155-60
Abstract
BACKGROUND People have more and more concerned about allitridum as studies have shown that taking more raw garlic associated with a lower risk for cancers of the alimentary system. In the present study, we tried to examine whether a large dose of allitridum and a microdose of selenium prevent gastric cancer. METHODS A double-blind intervention study was performed on the participants aged (35 - 74) years, who had matched at least one of the following criteria: (1) a medical history of stomach disorder, (2) a family history of tumour, or (3) smoking and/or alcohol consumption. A total of 2,526 and 2,507 persons were randomly enrolled into intervention group and control group respectively from 288 natural villages of seven communities in Qixia County, Shandong Province, China. Each person of the intervention group orally took 200 mg synthetic allitridum every day and 100 microg selenium every other day for one month of each year during November 1989 to December 1991. At the same time, people in control group were given 2 placebo capsules containing corn oid with the identical appearance to that in the intervention group. RESULTS For all subjects the large dose of allitridum was accepted and no harmful side effects were found during the study. In the first follow-up five years (1992 - 1997) after stopping the intervention, the morbidity rates of malignant tumours in the intervention group declined by 22%, in contrast to the control group, declined by 47.3%. After adjusting for age, gender, and other potential confounders, relative risks (RRs) for all tumours and gastric cancer of the whole population were 0.67 (95% CL: 0.43 - 1.03) and 0.48 (95% CL: 0.21 - 1.06), respectively, and for male group they were 0.51 (95% CL: 0.30 - 0.85) and 0.36 (95% CL: 0.14 - 0.92), respectively. No signigicantly protective effect was found for the female subgroup. CONCLUSION The present study proves that large doses of allitridum and microdorse of selenium may effectively prevent gastric cancer, especially in men.
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7.
Relationship between periodontal pocket sulfide levels and subgingival species.
Torresyap, G, Haffajee, AD, Uzel, NG, Socransky, SS
Journal of clinical periodontology. 2003;(11):1003-10
Abstract
BACKGROUND Many species implicated in the pathogenesis of periodontal disease produce volatile sulfur compounds (VSC). This investigation examined the relationship between levels of sulfide and subgingival bacterial species in the same periodontal pockets. MATERIAL AND METHODS Twenty chronic periodontitis subjects were measured clinically at six sites per tooth for plaque, gingivitis, bleeding on probing, suppuration, pocket depth and attachment level. Subgingival plaque samples, taken from the mesial aspect of each tooth, were individually analyzed for their content of 40 bacterial species using checkerboard DNA-DNA hybridization. Sulfide levels were measured at the same sites using a Diamond Probe/Perio 2000 system. Clinical and microbiological data were averaged for sulfide-positive and -negative sites separately in each subject and then averaged across subjects. Significance differences in clinical and microbial parameters between sulfide-positive and -negative sites were sought using the Wilcoxon signed ranks test. RESULTS Mean total DNA probe counts (x10(5), +/-SEM) at sulfide-negative and -positive sites were 44.0 +/- 9.9 and 65.0 +/- 13.3, respectively (p < 0.01). Seventeen species were found at significantly higher levels in sulfide-positive than -negative sites. These included abundant producers of VSC such as members of the genera Fusobacterium, Campylobacter, Prevotella, Treponema and Eubacterium, and Bacteriodes forsythus, Selenomonas noxia and Propionibacterium acnes. Prevotella intermedia, Bacteriodes forsythus, Prevotella nigrescens, Fusobacterium nucleatum ss vincentii and Treponema denticola exhibited the greatest difference in mean counts between sulfide-negative and -positive sites. Orange and red complex species were at higher counts at shallow (< 4 mm) sulfide-positive than shallow sulfide-negative sites. Although not statistically significant, mean clinical parameters were somewhat higher at sulfide-positive than sulfide-negative sites. CONCLUSIONS Intra-pocket sulfide levels reflect the levels of sulfide-producing species and may provide useful diagnostic information.
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8.
Effect of topical PPARbeta/delta and PPARgamma agonists on plaque psoriasis. A pilot study.
Kuenzli, S, Saurat, JH
Dermatology (Basel, Switzerland). 2003;(3):252-6
Abstract
BACKGROUND Ligands of nuclear hormone receptors such as glucocorticoid, retinoid and vitamin D are useful antipsoriatic drugs. Peroxisome proliferator-activated receptors (PPARs), which also belong to the nuclear hormone receptor superfamily, are pleiotropic regulators of growth and differentiation in many cell types, including the keratinocytes. Recent reports have dealt with the involvement of PPARalpha in epidermal processes such as barrier development, proliferation and differentiation. In a pilot study of topical clofibrate, a PPARalpha ligand, we did not find any antipsoriatic activity. No study on the effect of topical application of other PPAR subtype ligands (PPARbeta/delta and gamma) has been published. OBJECTIVES The purpose of this pilot study is to explore the clinical efficacy of the topical application of potent PPARbeta/delta and gamma agonists on plaque psoriasis, tetradecylthioacetic acid (TTA) and rosiglitazone, respectively. METHODS In a pilot study on psoriatic patients, 8 individuals (5 male/3 female) were treated twice daily for 30 days with vehicle (n = 14 plaques), rosiglitazone 0.5% (n = 18) and TTA 0.5% (n = 18). Assessments of the PASI plaque score were carried out on days 0, 4, 7, 11, 14 and 30. RESULTS No statistically significant difference was found at any of the examination times, between vehicle, rosiglitazone and TTA in terms of reduction of the PASI plaque score for total, scale and infiltration scores. Treatments were well tolerated, and skin irritation, adverse drug-related symptoms and dropouts did not occur. CONCLUSIONS With the reservations due to the limited nature of this pilot trial, it seems that these topical PPARbeta/delta and gamma agonists do not exert a strong antipsoriatic effect when used alone at 0.5%.
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9.
Effect of periodontal therapy on sulcular sulphide level a longitudinal study.
Gleissner, C, Springborn, I, Willershausen, B
European journal of medical research. 2003;(1):33-46
Abstract
PURPOSE The identification of active disease sites is a leading goal in basic periodontal research. Of toxic bacterial metabolites detectable in gingival crevicular fluid, volatile sulphur compounds (VSC) have been implicated in periodontal tissue destruction. Several bacteria associated with active destructive disease are capable of producing VSC, this fact supporting the idea of sulcular VSC being a possible marker of disease activity. A new portable sulphide monitor providing chairside information on sulcular sulphide level (SU) has been developed. The aim of this study was 1) to monitor the effect of mechanical therapy on SU and clinical parameters and 2) to clarify whether SU-measurements might have the potential to detect disease activity. METHODS 34 patients (22 M, 12 F) with generalized or localized chronic periodontitis received periodontal treatment in a private practice consisting of an oral hygiene phase (HP) lasting several weeks, scaling and root planing (SRP), and flap surgery at sites >5 mm or with furcation involvement. Subjects were examined three times (1 week after the diagnosis was made, at the end of HP and at the 1st maintenance session 3 months after SRP) recording clinical parameters (clinical attachment loss CAL, probing depth PD, bleeding on probing intensity BI, plaque index PI) and sulcular sulphide level (SU) measured by the portable monitor as as digital score ranging from 0.0 (<10 superset 6 M of S superset 2-) to 5.0 (10 superset 2 M of S superset 2-) in increments of 0.5. RESULTS 23 patients (15 M, 8 F, 47.5 +/- 9 years) were included in the data analysis. Periodontal therapy resulted in a significant reduction of mean BI by 0.69 +/- 0.45, of mean PD by 1.39 +/- 0.33 mm and in a mean gain of attachment of 1.07 +/- 0.38 mm (p = 0.0001). The clinical improvement was accompanied by a reduction of mean SU by 0.20 +/- 0.13 and of the mean percentage of SU-positive sites per patient (SUp) by 20.09 +/- 13. SU-positive sites were located at all types of teeth. 67.9 % of SU-positive sites and 83.8 % of sites with a SU > 1 were found at the molars. 16.1 % of initially 579 SU-positive sites remained SU-positive. For these sites, BI reduction by treatment was significantly lower compared with SU-negative sites (p < 0.01). SU was significantly correlated with PD, CAL, BI and PI (p = 0.0001). Sensitivity and specificity of SU related to BOP (BI > 0) was 29.3 % and 96.8 %, respectively. CONCLUSIONS Sulcular VSC as measured by the portable sulphide monitor may be an indicator of therapeutical success and periodontal stability. The sensor system offers chairside information on sulcular sulphide production at specific sites and is a valuable supplementation of traditional clinical methods in periodontal examination. More controlled longitudinal studies are needed to clarify the role of sulcular VSC at sites undergoing periodontal destruction.