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Predictive Factors for Efficacy of AST-120 Treatment in Diabetic Nephropathy: a Prospective Single-Arm, Open-Label, Multi-Center Study.
Hwang, YC, Kim, SW, Hur, KY, Cha, BS, Kim, IJ, Park, TS, Baik, SH, Yoon, KH, Lee, KW, Lee, IK, et al
Journal of Korean medical science. 2019;(15):e117
Abstract
BACKGROUND Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. METHODS A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. RESULTS Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 μol/L to 1.91 ± 0.72 μol/L; P = 0.002) but not in the non-responder group. CONCLUSION The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.
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Adequate nephroprotection reduces renal complications after hyperthermic intrathoracic chemotherapy.
Markowiak, T, Kerner, N, Neu, R, Potzger, T, Großer, C, Zeman, F, Hofmann, HS, Ried, M
Journal of surgical oncology. 2019;(7):1220-1226
Abstract
BACKGROUND AND OBJECTIVES Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern. METHODS This single-center study was performed retrospectively in patients who underwent pleural tumor resection and HITOC between September 2008 and December 2018. RESULTS A total of 84 patients (female n = 33; 39.3%) with malignant pleural tumors underwent surgical cytoreduction with subsequent HITOC (60 minutes; 42°C). During the study period, we gradually increased the dosage of cisplatin (100-150 mg/m2 BSA n = 36; 175 mg/m2 BSA n = 2) and finally added doxorubicin (cisplatin 175 mg/m2 BSA/doxorubicin 65 mg; n = 46). All patients had perioperative fluid balancing. The last 54 (64.3%) patients also received perioperative cytoprotection. Overall 29 patients (34.5%) experienced renal insufficiency. Despite higher cisplatin concentrations, patients with cytoprotection showed significantly lower postoperative serum creatinine levels after 1 week (P = .006) and at discharge (P = .020). Also, they showed less intermediate and severe renal insufficiencies (5.6% vs 13.3%). CONCLUSIONS Adequate perioperative fluid management and cytoprotection seem to be effective in protecting renal function. This allows the administration of higher intracavitary cisplatin doses without raising the rate of renal insufficiencies.
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Meta-analysis on allopurinol preventive intervention on contrast-induced acute kidney injury with random controlled trials: PRISMA.
Ma, G, Wang, G, Xiao, D, Teng, W, Hui, X, Ma, G
Medicine. 2019;(25):e15962
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Abstract
OBJECTIVES The objective of this meta-analysis on randomized controlled trials is to evaluate whether the administration of allopurinol with or without hydration will reduce contrast-induced acute kidney injury (CI-AKI) in patients undergoing contrast exposure. BACKGROUND The efficacy of allopurinol in the prevention of CI-AKI after cardiac catheterization and percutaneous coronary intervention (PCI) is significantly related to the heterogeneous results. METHODS Two investigators independently searched MEDLINE, EMBASE, the Cochrane Controlled Trials Registry, the China Wanfang Data, the China Biological Medicine Database and the China National Knowledge Infrastructure (CNKI) databases for randomized controlled trials (RCTs) comparing allopurinol with placebo or no allopurinol for the prevention of CI-AKI in patients from their inception to July 31, 2018. The primary outcome was the incidence of CI-AKI, and the secondary outcomes were the differences of serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), and estimated glomerular filtration rate (eGFR) levels between groups after contrast media exposure. We used fixed-effects or random-effects models according to I statistics. The meta-analytic procedures were completed by Review Manager, version 5.3. ACHIEVEMENTS Eight random controlled trials with 1141 patients were included for this analysis. Compared with the control, allopurinol was associated with a reduced risk of CI-AKI (Relatives Risk (RR) 0.39, 95% confidence interval [CI] 0.20,0.74, P = .004) and only a intend for decrease a post-procedure uric acid levels compared with the controlled ones at 48 hours (standardized mean difference (SMD) -0.72, 95% CI -1.44, 0.01, P = .05). But the difference of post-procedure uric acid levels was not statistically significant in allopurinol groups compared with controlled groups. There were lower post-procedure Scr and BUN levels in allopurinol groups than those in controlled groups (SMD -0.50, 95% CI -0.79,-0.21, P = .0009; SMD -0.40, 95% CI -0.60,-0.20, P < .0001;respectively). There were higher post-procedure eGFR levels in allopurinol groups than those in controlled groups (SMD 0.65, 95% CI 0.48, 0.83, P < .0001). CONCLUSION The main findings of this meta-analysis are focus on allopurinol may cause reduces in the incidence of CI-AKI in patients undergoing interventional coronary procedures. Further researches are still required for confirmation.
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Cinnamomum zeylanicum (Darchini): A Boon to Medical Science and a Possible Therapy for Stress-Induced Ailments.
Hussain, Z, Khan, JA, Rashid, H
Critical reviews in eukaryotic gene expression. 2019;(3):263-276
Abstract
Plants have been an imperative source of medicine and drugs for therapy of different ailments in humans from the early history until today. Many phytochemicals present in plants act as antioxidants and are utilized as health-protecting agents. Cinnamon, a widely used spice and folk medicine obtained from Cinnamomum zeylanicum, is an effective therapy for various diseases because of its antioxidant and protective efficacy. In the present review, we investigate the beneficial effects of cinnamon on stress-induced ailments. The data regarding therapeutic effects of cinnamon on stress-induced conditions were systematically collected from PubMed, ScienceDirect, Google Scholar, and the Web of Science databases published in the English language from 2000 until July 2018 with the following terms: cinnamon, antioxidant properties, anti-inflammatory, and multifaceted plant. The articles reviewed demonstrated that free radicals play a significant role in the pathophysiology of oxidative stress-associated diseases; therefore cinnamon, with its free radical scavenging activity, represents a promising therapeutic option for ameliorating these debilitating conditions. In this context, the use of cinnamon and its derivatives might be a beneficial way to reduce oxidative stress-induced complications. However, more studies are needed at the molecular level to understand the pathophysiology of the clinical conditions observed as a result of oxidative stress.
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Inhibition of copper-induced aggregation of human γD-crystallin by rutin and studies on its role in molecular level for enhancing the chaperone activity of human αA-crystallin by using multi-spectroscopic techniques.
Chauhan, P, Ghosh, KS
Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy. 2019;:229-236
Abstract
Oxidative aggregation of γ-crystallins induced by copper in aged lens increases the lens opacity and causes cataract formation. Therefore, chelation of free Cu2+ by small molecules can inhibit metal-mediated aggregation of γ-crystallin. In this work, the inhibition potency of several naturally occurring flavonoid compounds was studied against aggregation of human γD-crystallin (HGD) mediated by copper ions. Among them, rutin demonstrated ~20% inhibition of HGD aggregation induced by Cu2+ through its metal chelation ability. Not only that, the chaperone activity of lens chaperone, human αA-crystallin (HAA) was found to be enhanced in the presence of rutin. Subsequently, the molecular interactions between HAA and rutin were investigated using fluorescence and CD spectroscopy to understand the molecular basis of the chaperone activity enhancement by rutin. Quenching of HAA fluorescence by rutin with a quenching constant in the order of ~105 M-1 depicts a complexation between them. Entropy driven process of complexation between HAA and rutin suggests significant involvement of hydrophobic interactions. Fluorescence resonance energy transfer between protein and ligand can occur at a distance of 2.73 nm. Synchronous fluorescence and circular dichroism spectroscopy revealed that protein-ligand interaction does not cause any notable conformational changes in HAA. Experimental observations have been well substantiated by docking.
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The Protective Role of Adiponectin for Lipoproteins in End-Stage Renal Disease Patients: Relationship with Diabetes and Body Mass Index.
Coimbra, S, Reis, F, Nunes, S, Viana, S, Valente, MJ, Rocha, S, Catarino, C, Rocha-Pereira, P, Bronze-da-Rocha, E, Sameiro-Faria, M, et al
Oxidative medicine and cellular longevity. 2019;:3021785
Abstract
Cardiovascular disease (CVD) events are the main causes of death in end-stage renal disease (ESRD) patients on dialysis. The number and severity of CVD events remain inappropriate and difficult to explain by considering only the classic CVD risk factors. Our aim was to clarify the changes and the relationship of lipoprotein subfractions with other CVD risk factors, namely, body mass index (BMI) and adipokines, inflammation and low-density lipoprotein (LDL) oxidation, and the burden of the most prevalent comorbidities, diabetes mellitus (DM) and hypertension (HT). We studied 194 ESRD patients on dialysis and 22 controls; lipid profile, including lipoprotein subpopulations and oxidized LDL (oxLDL), C-reactive protein (CRP), adiponectin, leptin, and paraoxonase 1 activity were evaluated. Compared to controls, patients presented significantly lower levels of cholesterol, high-density lipoprotein cholesterol (HDLc), LDLc, oxLDL, and intermediate and small HDL and higher triglycerides, CRP, adiponectin, large HDL, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein- (IDL) B. Adiponectin levels correlated positively with large HDL and negatively with intermediate and small HDL, oxLDL/LDLc, and BMI; patients with DM (n = 17) and with DM+HT (n = 70), as compared to patients without DM or HT (n = 69) or only with HT (n = 38), presented significantly higher oxLDL, oxLDL/LDLc, and leptin and lower adiponectin. Obese patients (n = 45), as compared to normoponderal patients (n = 81), showed lower HDLc, adiponectin, and large HDL and significantly higher leptin, VLDL, and intermediate and small HDL. In ESRD, the higher adiponectin seems to favor atheroprotective HDL modifications and protect LDL particles from oxidative atherogenic changes. However, in diabetic and obese patients, adiponectin presents the lowest values, oxLDL/LDLc present the highest ones, and the HDL profile is the more atherogenic. Our data suggest that the coexistence of DM and adiposity in ESRD patients on dialysis contributes to a higher CVD risk, as showed by their lipid and adipokine profiles.
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Effect of rutin on cisplatin-induced damage in human mesangial cells via apoptotic pathway.
Zhang, Y, Wang, Q, Wang, YD, Sun, B, Leng, XW, Li, Q, Ren, LQ
Human & experimental toxicology. 2019;(1):118-128
Abstract
Cisplatin (CP) is one of the most effective and widely used compounds in the treatment of disease, including cancer, but is known to induce toxicity in patients. Rutin (RUT) is a flavonoid glycoside from Sophora japonica L. that has been shown to possess antioxidative, anti-inflammatory, and antiviral properties. RUT is also known to attenuate cardiotoxicity, isoproterenol-induced cardiac fibrosis, and ischemia/reperfusion-associated hemodynamic alteration, and prevents high glucose-induced renal glomerular endothelial hyperpermeability. In this study, we investigated the effect of RUT on CP-induced nephrotoxicity. CP was used to induce toxicity in human mesangial cells (HMCs), HMCs were pretreated with different concentrations of RUT before being exposed to 10 μg/mL of CP. A positive group was pretreated with antioxidant agent N-acetylcysteine prior to CP administration. At doses between 12.5 and 25 μM, RUT prevented CP-induced reduction in cell viability. Treatment with RUT suppressed intracellular reactive oxygen species and malonic dialdehyde levels and inhibited cell apoptosis. RUT reversed the CP-induced upregulation of p53, cleaved-caspase-3, and increased pro-caspase-3 and pro-caspase-9 levels. In conclusion, the RUT can relieve CP-induced nephrotoxicity by inhibiting the p53/caspase signaling pathway.
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Protective Effect of Dinitrosyl Iron Complexes with Glutathione in Red Blood Cell Lysis Induced by Hypochlorous Acid.
Shumaev, KB, Gorudko, IV, Kosmachevskaya, OV, Grigorieva, DV, Panasenko, ОM, Vanin, AF, Topunov, AF, Terekhova, MS, Sokolov, AV, Cherenkevich, SN, et al
Oxidative medicine and cellular longevity. 2019;:2798154
Abstract
Hypochlorous acid (HOCl), one of the major precursors of free radicals in body cells and tissues, is endowed with strong prooxidant activity. In living systems, dinitrosyl iron complexes (DNIC) with glutathione ligands play the role of nitric oxide donors and possess a broad range of biological activities. At micromolar concentrations, DNIC effectively inhibit HOCl-induced lysis of red blood cells (RBCs) and manifest an ability to scavenge alkoxyl and alkylperoxyl radicals generated in the reaction of HOCl with tert-butyl hydroperoxide. DNIC proved to be more effective cytoprotective agents and organic free radical scavengers in comparison with reduced glutathione (GSH). At the same time, the kinetics of HOCl-induced oxidation of glutathione ligands in DNIC is slower than in the case of GSH. HOCl-induced oxidative conversions of thiolate ligands cause modification of DNIC, which manifests itself in inclusion of other ligands. It is suggested that the strong inhibiting effect of DNIC with glutathione on HOCl-induced lysis of RBCs is determined by their antioxidant and regulatory properties.
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Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12 h regimen of N-acetylcysteine for paracetamol overdose (POP trial).
Morrison, EE, Oatey, K, Gallagher, B, Grahamslaw, J, O'Brien, R, Black, P, Oosthuyzen, W, Lee, RJ, Weir, CJ, Henriksen, D, et al
EBioMedicine. 2019;:423-430
Abstract
BACKGROUND The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose. METHODS Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24 h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n = 6) or NAC alone (n = 2). Calmangafodipir doses were 2, 5, or 10 μmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395). FINDINGS All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC + calmangafodipir (2 μmol/kg), 4/6; NAC + calmangafodipir (5 μmol/kg), 2/6; NAC + calmangafodipir (10 μmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT > 100 U/L; with NAC + calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20 h fold change, NAC + calmangafodipir (5 μmol/kg) compared to NAC alone: 0.48 (95%CI 0.28-0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. INTERPRETATION Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.
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Do we have enough evidence to support the use of SGLT2 inhibitors for MACE reduction in patients with advance kidney disease?
Doshi, R, Meghji, Z, Kumar, A, Shariff, M, Adalja, D
European journal of internal medicine. 2019;:e25-e26