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Analysis from the EMPA-REG OUTCOME® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics.
Mayer, GJ, Wanner, C, Weir, MR, Inzucchi, SE, Koitka-Weber, A, Hantel, S, von Eynatten, M, Zinman, B, Cherney, DZI
Kidney international. 2019;(2):489-504
Abstract
In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events.
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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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Rationale and Design of a Randomized Placebo-Controlled Clinical Trial Assessing the Renoprotective Effects of Potassium Supplementation in Chronic Kidney Disease.
Gritter, M, Vogt, L, Yeung, SMH, Wouda, RD, Ramakers, CRB, de Borst, MH, Rotmans, JI, Hoorn, EJ
Nephron. 2018;(1):48-57
Abstract
BACKGROUND/AIMS: Dietary potassium (K+) has beneficial effects on blood pressure and cardiovascular (CV) outcomes. Recently, several epidemiological studies have revealed an association between urinary K+ excretion (as proxy for dietary intake) and better renal outcomes in subjects with chronic kidney disease (CKD). To address causality, we designed the "K+ in CKD" study. METHODS The K+ in CKD study is a multicenter, randomized, double blind, placebo-controlled clinical trial aiming to include 399 patients with hypertension, CKD stage 3b or 4 (estimated glomerular filtration rate [eGFR] 15-44 mL/min/1.73 m2), and an average eGFR decline > 2 mL/min/1.73 m2/year. As safety measure, all included subjects will start with a 2-week open-label phase of 40 mmol potassium chloride daily. Patients who do not subsequently develop hyperkalemia (defined as serum K+ >5.5 mmol/L) will be randomized to receive potassium chloride, potassium citrate (both K+ 40 mmol/day), or placebo for 2 years. The primary end point is the difference in eGFR after 2 years of treatment. Secondary end points include other renal outcomes (> 30% decrease in eGFR, doubling of serum creatinine, end-stage renal disease, albuminuria), ambulatory blood pressure, CV events, all-cause mortality, and incidence of hyperkalemia. Several measurements will be performed to analyze the effects of potassium supplementation, including body composition monitoring, pulse wave velocity, plasma renin and aldosterone concentrations, urinary ammonium, and intracellular K+ concentrations. CONCLUSION The K+ in CKD study will demonstrate if K+ sup-plementation has a renoprotective effect in progressive CKD, and whether alkali therapy has additional beneficial effects.
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Comparative studies on the hypolipidemic, antioxidant and hepatoprotective activities of catechin-enriched green and oolong tea in a double-blind clinical trial.
Venkatakrishnan, K, Chiu, HF, Cheng, JC, Chang, YH, Lu, YY, Han, YC, Shen, YC, Tsai, KS, Wang, CK
Food & function. 2018;(2):1205-1213
Abstract
This study aimed to compare the beneficial effect of catechin-enriched green tea and oolong tea on mildly hypercholesterolemic subjects. Sixty mildly hypercholesterolemic subjects (180-220 mg dL-1) were enrolled and divided into three groups as catechin-enriched green tea (CEGT), catechin-enriched oolong tea (CEOT) or placebo. The subjects were instructed to drink 2 × 300 mL of CEGT (780.6 mg of catechin), CEOT (640.4 mg of catechin) or placebo beverage for 12 weeks. Drinking CEGT and CEOT significantly decreased (p < 0.05) the body weight, fat, and BMI, lipid peroxidation as well as lipid profile (TC, LDL-c, HDL-c, and TG). Also, intervention with CEGT and CEOT significantly improved (p < 0.05) the oxidative indices (TEAC and GSH) and antioxidant enzymes (SOD, CAT, GPx, and GR). Moreover, ultrasound examination endorsed the hepatoprotective activity of CEGT and CEOT by reverting mild fatty liver to the normal hepatic condition because of antioxidant and hypolipidemic activities. To summarize, both CEGT and CEOT showed similar antioxidant and hepatoprotective activities. However, CEOT displayed superior lipid-lowering activity compared to CEGT or placebo, and hence it could be used to amend the wellness condition of mildly hypercholesterolemic subjects.
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Protective effect of nicorandil on myocardial injury following percutaneous coronary intervention in older patients with stable coronary artery disease: Secondary analysis of a randomized, controlled trial (RINC).
Kawakita, N, Ejiri, K, Miyoshi, T, Kohno, K, Nakahama, M, Doi, M, Munemasa, M, Murakami, M, Nakamura, K, Ito, H, et al
PloS one. 2018;(4):e0194623
Abstract
BACKGROUND Our previous study examined an effect of remote ischemic preconditioning (RIPC) or intravenous nicorandil on reduction of periprocedural myocardial injury (pMI) following percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD). We further investigated the effect of RIPC or nicorandil on pMI in older patients. METHODS Patients with stable CAD who planned to undergo PCI were assigned to a 1:1:1 ratio to control, intravenous nicorandil, or upper-limb RIPC groups. This substudy analyzed patients aged >65 years (n = 282) from the principal cohort. The primary outcome was the incidence of pMI following PCI. We defined pMI as an elevated level of high-sensitive cardiac troponin T or creatine kinase myocardial band 12 or 24 hours after PCI. RESULTS We found that pMI following PCI was significantly reduced in the nicorandil group compared with the control group (37.2% vs. 53.7%, multiplicity-adjusted p = 0.046), but not in the RIPC group compared with the control group (43.0% vs. 53.7%, multiplicity-adjusted p = 0.245). The adjusted odds ratios (95% confidence interval) for pMI in the RIPC and nicorandil groups versus the control group were 0.63 (0.34 to 1.16) and 0.51 (0.27 to 0.96), respectively. CONCLUSION Intravenous nicorandil significantly reduces pMI following PCI in a subgroup of older patients with stable CAD. Phase 3 trials are required to validate our results. TRIAL REGISTRATION UMIN Clinical Trials Registry UMIN000005607.
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A Chilean Berry Concentrate Protects against Postprandial Oxidative Stress and Increases Plasma Antioxidant Activity in Healthy Humans.
Urquiaga, I, Ávila, F, Echeverria, G, Perez, D, Trejo, S, Leighton, F
Oxidative medicine and cellular longevity. 2017;:8361493
Abstract
This study formulated and characterized an antioxidant-rich concentrate of berries (BPC-350) produced in Chile, which was used to perform a crossover study aimed at determining the effect of the berries on the modulation of plasma postprandial oxidative stress and antioxidant status. Healthy male volunteers (N = 11) were randomly assigned to three experimental meals: (1) 250 g of ground turkey burger (GTB) + 500 mL of water; (2) 250 g of GTB + 500 mL of 5% BPC-350; (3) 250 g of GTB prepared with 6% BPC-350 + 500 mL of 5% BPC-350. Venous blood samples were collected prior to meal intake and every hour for six hours after intake. Malondialdehyde (MDA), carbonyls in proteins, and DPPH (2,2-diphenyl-1-picrylhydrazyl) antioxidant capacity were quantified in plasma. Significant differences indicated that BPC-350 decreases MDA plasma concentration and protein carbonyls (p < 0.05). Additionally, a significant increase in the DPPH antioxidant capacity was observed in Meals 2 and 3 when compared to Meal 1 (p < 0.05). The results are discussed in terms of oxidative reactions that occur during digestion at the stomach level and the important effect of oxidative reactions that occur during the thermal processing of red meat.
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Comparison of the myocardial protective effect of sevoflurane versus propofol in patients undergoing heart valve replacement surgery with cardiopulmonary bypass.
Yang, XL, Wang, D, Zhang, GY, Guo, XL
BMC anesthesiology. 2017;(1):37
Abstract
BACKGROUND This study aimed to compare myocardial protective effects of anaesthesia with intravenous infusion of propofol versus inhalation of sevoflurane in patients undergoing heart valve replacement surgery with cardiopulmonary bypass. METHODS Seventy-six patients undergoing valve replacement with cardiopulmonary bypass were randomly assigned to propofol or sevoflurane anesthesia during the surgery, respectively. For assessing myocardial injury, cardiac troponin I (cTnI) and creatine kinase isozyme (CK-MB) were determined before induction (T0), 0.5 h (T1) and 3 h (T2) after aortic unclamping, and 24 h (T3) and 48 h (T4) after surgery. The concentrations of interleukin (IL)-6 and IL-10 as the systemic inflammatory and anti-inflammatory markers were also measured at above time points. RESULTS In the sevoflurane group, the plasma concentrations of cTnI and CK-MB from Tl to T4 and the levels of IL-6 and IL-10 from T1 to T2 were lower than those in the propofol group. Moreover, a higher ratio of automatic heart beat recovery and a shorter length of intensive care unit or hospital stay were found in the sevoflurane group comparing with the propofol group. CONCLUSION Sevoflurane anaesthesia produced more prominent myocardial protection and attenuated inflammatory response than propofol anaesthesia in patients with valve replacement surgery under cardiopulmonary bypass, resulting in shorter ICU and in-hospital stay. RETROSPECTIVE CLINICAL TRIAL REGISTRATION Identified as ChiCTR-IOR-16009979 at http://www.chictr.org.cn/ .
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Melatonin and hydroxytyrosol protect against oxidative stress related to the central nervous system after the ingestion of three types of wine by healthy volunteers.
Marhuenda, J, Medina, S, Martínez-Hernández, P, Arina, S, Zafrilla, P, Mulero, J, Oger, C, Galano, JM, Durand, T, Ferreres, F, et al
Food & function. 2017;(1):64-74
Abstract
Adrenic acid (AdA) and docosahexaenoic acid (DHA) peroxidation produces F2-dihomo-IsoPs and neuroprostanes, which have been related to oxidative damage in the central nervous system. Besides polyphenols, melatonin (MEL) and hydroxytyrosol (OHTyr) could be partly responsible for the antioxidant benefits of red wine (excluding colon derivatives). In order to elucidate whether these compounds are responsible for the protective antioxidant effects of red wine, a double-blind, crossover, placebo-controlled in vivo study - involving the intake of red wines and their native musts by healthy volunteers - was performed. The urinary metabolites decreased after the administration of red wines, to a greater extent than after the intake of their corresponding musts or ethanol. Melatonin is the most effective compound that protects adrenic acid from oxidative attack, judged by the reduction in the formation of F2-dihomo-isoprostanes. Similarly, hydroxytyrosol, being the most effective bioactive compound in reducing the formation of F3-neuroprostanes n-6 DPA and F4-neuroprostanes, protected docosahexaenoic and eicosapentaenoic acids from oxidative attack.
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The Oral β-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies.
Kokai-Kun, JF, Roberts, T, Coughlin, O, Sicard, E, Rufiange, M, Fedorak, R, Carter, C, Adams, MH, Longstreth, J, Whalen, H, et al
Antimicrobial agents and chemotherapy. 2017;(3)
Abstract
SYN-004 (ribaxamase) is a β-lactamase designed to be orally administered concurrently with intravenous β-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess β-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated, and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine (registered at ClinicalTrials.gov under NCT02419001 and NCT02473640).
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Randomized Controlled Trial of Talactoferrin Oral Solution in Preterm Infants.
Sherman, MP, Adamkin, DH, Niklas, V, Radmacher, P, Sherman, J, Wertheimer, F, Petrak, K
The Journal of pediatrics. 2016;:68-73.e3
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Abstract
OBJECTIVE To evaluate the safety and explore the efficacy of recombinant human lactoferrin (talactoferrin [TLf]) to reduce infection. STUDY DESIGN We conducted a randomized, double blind, placebo-controlled trial in infants with birth weight of 750-1500 g. Infants received enteral TLf (n = 60) or placebo (n = 60) on days 1 through 28 of life; the TLf dose was 150 mg/kg every 12 hours. Primary outcomes were bacteremia, pneumonia, urinary tract infection, meningitis, and necrotizing enterocolitis (NEC). Secondary outcomes were sepsis syndrome and suspected NEC. We recorded clinical, laboratory, and radiologic findings, along with diseases and adverse events, in a database used for statistical analyses. RESULTS Demographic data were similar in the 2 groups of infants. We attributed no enteral or organ-specific adverse events to TLf. There were 2 deaths in the TLf group (1 each due to posterior fossa hemorrhage and postdischarge sudden infant death), and 1 death in the placebo group, due to NEC. The rate of hospital-acquired infections was 50% lower in the TLf group compared with the placebo group (P < .04), including fewer blood or line infections, urinary tract infections, and pneumonia. Fourteen infants in the TLf group weighing <1 kg at birth had no gram-negative infections, compared with only 3 of 14 such infants in the placebo group. Noninfectious outcomes were not statistically significantly different between the 2 groups, and there were no between-group differences in growth or neurodevelopment over a 1-year posthospitalization period. CONCLUSION We found no clinical or laboratory toxicity and a trend toward less infectious morbidity in the infants treated with TLf. TRIAL REGISTRATION ClinicalTrials.gov: NCT00854633.