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1.
Role of Tris-CaEDTA as an adjuvant with nebulised tobramycin in cystic fibrosis patients with Pseudomonas aeruginosa lung infections: A randomised controlled trial.
Puvvadi, R, Mikkelsen, H, McCahon, L, Grogan, S, Ditcham, W, Reid, DW, Lamont, I, Stick, SM, Clements, B
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2021;(2):316-323
Abstract
BACKGROUND We tested if disrupting iron utilisation by P. aeruginosa by adding the Tris-buffered chelating agent CaEDTA to nebulised tobramycin would enhance bacterial clearance and improve lung function in CF patients. METHODS In this double-blind, randomised controlled trial, 26 episodes (25 patients) with P. aeruginosa infection admitted to two CF centres for treatment of an acute pulmonary exacerbation were randomly assigned to receive either 75 mg CaEDTA in Tris-buffered saline or placebo (Tris-buffered saline) nebulised in combination with 250 mg tobramycin twice daily for six weeks followed with four week safety follow-up. Primary endpoints were safety, tolerability, and bacterial density of P. aeruginosa. A secondary endpoint was lung function. RESULTS The study drug was well tolerated with adverse events comparable in both groups. The mean (SD) reduction in sputum P. aeruginosa count (log10 CFU/g) in the CaEDTA vs placebo group was 2·05 (2·57) vs 0·82 (2·71) at two weeks relative to admission (p = 0·39). The mean improvement in ppFEV1 was 16 vs 5 (p = 0·16); 11 vs 2 (p = 0·28); and 6 vs 2 percentage points (p = 0·47) at two, six, and ten weeks in CaEDTA and placebo groups, respectively. CONCLUSIONS In this pilot study in CF patients, an increase in the reduction of sputum density of P. aeruginosa and an increase in ppFEV1 was observed in the group of patients who received Tris-CaEDTA added to inhaled tobramycin compared to the group who received inhaled tobramycin alone, although these differences were not statistically significant. The treatment was also shown to be safe.
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2.
Association of fibroblast growth factor 23 and α-klotho in hemodialysis patients during administration of ferric citrate hydrate: post hoc analysis of ASTRIO study.
Ito, K, Yokoyama, K, Nakayama, M, Fukagawa, M, Hirakata, H
BMC nephrology. 2021;(1):374
Abstract
BACKGROUND Fibroblast growth factor-23 (FGF23) and α-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and α-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and α-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients. METHODS The ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-klotho were conducted. RESULTS Patients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p < 0.001). The mean change from baseline to EOT in c-FGF23 was significantly different between the FC and control groups (mean ± standard deviation (SD): - 0.2 ± 0.8 loge pg/mL vs. 0.2 ± 0.8 loge pg/mL, respectively; p = 0.04). The mean change from baseline to EOT in i-FGF23 and α-klotho were not significantly different between the FC and control groups (mean ± SD: - 0.1 ± 0.8 loge pg/mL vs. 0.1 ± 0.9 loge pg/mL; p = 0.33, and 2.0 ± 91.5 pg/mL vs. - 8.9 ± 145.3; p = 0.58, respectively). However, both forms of FGF23 and α-klotho were not significantly associated with each other in both groups. CONCLUSIONS Iron absorbed via FC administration in HD patients did not influence the correlation relationship between plasma levels of FGF23 and α-klotho under the condition of serum P and Hb were maintained. TRIAL REGISTRATION ASTRIO study ( UMIN000019176 , registered at UMIN Clinical Trials Registry on October 1, 2015).
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3.
Protein-Bound Uremic Toxins Lowering Effect of Sevelamer in Pre-Dialysis Chronic Kidney Disease Patients with Hyperphosphatemia: A Randomized Controlled Trial.
Takkavatakarn, K, Puapatanakul, P, Phannajit, J, Sukkumme, W, Chariyavilaskul, P, Sitticharoenchai, P, Leelahavanichkul, A, Katavetin, P, Praditpornsilpa, K, Eiam-Ong, S, et al
Toxins. 2021;(10)
Abstract
P-cresyl sulfate and indoxyl sulfate are strongly associated with cardiovascular events and all-cause mortality in chronic kidney disease (CKD). This randomized controlled trial was conducted to compare the effects between sevelamer and calcium carbonate on protein-bound uremic toxins in pre-dialysis CKD patients with hyperphosphatemia. Forty pre-dialysis CKD patients with persistent hyperphosphatemia were randomly assigned to receive either 2400 mg of sevelamer daily or 1500 mg of calcium carbonate daily for 24 weeks. A significant decrease of total serum p-cresyl sulfate was observed in sevelamer therapy compared to calcium carbonate therapy (mean difference between two groups -5.61 mg/L; 95% CI -11.01 to -0.27 mg/L; p = 0.04). There was no significant difference in serum indoxyl sulfate levels (p = 0.36). Sevelamer had effects in terms of lowering fibroblast growth factor 23 (p = 0.01) and low-density lipoprotein cholesterol levels (p = 0.04). Sevelamer showed benefits in terms of retarding CKD progression. Changes in vascular stiffness were not found in this study.
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4.
A study of susceptibility-weighted imaging in patients with Wilson disease during the treatment of metal chelator.
Zhou, X, Xiao, X, Li, XH, Qin, HL, Pu, XY, Chen, DB, Wu, C, Feng, L, Liang, XL
Journal of neurology. 2020;(6):1643-1650
Abstract
OBJECTIVE A randomized-controlled trial comparing study of the changes in brain sensitive-weighted imaging (SWI) of Wilson disease (WD) patients during the treatment with metal chelator was done. METHODS 100 untreated WD patients (80 cases of cerebral type, 20 cases of hepatic type, age 20.13 ± 9.12 years old) and 20 normal controls were selected. Neurological symptoms were scored using the modified Young scale. Liver function tests and copper indices were collected. All study objects received SWI test of the brain. The values of corrected phase (CP) were calculated on SWI. Cerebral-type WD patients were treated with D-penicillamine (DPA) (group 1) or Dimercaptopropane Sulfonate (DMPS) + Dimercaptosuccinic Acid (DMSA) (group 2). Hepatic-type WD patients were treated with DPA (group 3). All patients received annual neurological symptom score, liver function, copper indices, and SWI examination. RESULTS At the first year of treatment, score of the modified Young scale in group 2 was lower than that in group 1 (P = 0.023) and lower than that before treatment (P = 0.040). After 2 years of treatment, the score of the modified Young scale in group 1 was lower than that before treatment (P = 0.012). At the second year after treatment, the urinary copper in group 2 was higher than that in group 1 (P = 0.014). Urinary copper was maintained at 200 µg/day in group 1 and 300 µg/day in group 2 after 3 years of treatment. At the first year of treatment, serum copper in group 1 was lower than that in group 2 (P = 0.032). At the first year of treatment, CP values of the pallidum and substantia nigra in group 2 were higher than those in group 1 (P = 0.026, 0.040). At the second year of treatment, CP value of substantia nigra in group 2 was higher than that in group 1 (P = 0.037). After 3 years of treatment, there was no difference in CP values between WD patients and normal controls. CONCLUSIONS Therapy with DMPS and DMSA improves neurological symptoms of WD patients more quickly and leads to less aggravation, compared with therapy with DPA. The metal content in the brain of WD patients was at a low level after 3 years of treatment. DMPS and DMSA can remove metal from brain tissue faster than DPA.
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5.
The Effects of Long-Term Magnesium Creatine Chelate Supplementation on Repeated Sprint Ability (RAST) in Elite Soccer Players.
Zajac, A, Golas, A, Chycki, J, Halz, M, Michalczyk, MM
Nutrients. 2020;(10)
Abstract
AIM: The aim of the study was to evaluate the effects of 16 weeks of a low dose of magnesium creatine chelate supplementation on repeated sprint ability test (RAST) results in elite soccer players. MATERIALS Twenty well-trained soccer players participated in the study. The players were divided randomly into two groups: the supplemented group (SG = 10) and placebo group (PG = 10). Out of the 20 subjects selected for the study, 16 (SG = 8, PG = 8) completed the entire experiment. The SG ingested a single dose of 5500 mg of magnesium creatine chelate (MgCr-C), in 4 capsules per day, which was 0.07 g/kg/d. The PG received an identical 4 capsules containing corn starch. Before and after the study, the RAST was performed. In the RAST, total time (TT), first and sixth 35 m sprint length (s), average power (AP) and max power (MP) were measured. Additionally, before and after the test, lactate LA (mmol/L) and acid-base equilibrium pH (-log(H+)), bicarbonates HCO3- (mmol/L) were evaluated. Also, in serum at rest, creatinine (mg/dL) concentration was measured. RESULTS After the study, significantly better results in TT, AP and MP were observed in the SG. No significant changes in the RAST results were observed in the PG. After the study, significant changes in the first 35 m sprint, as well as the sixth 35 m sprint results were registered in the SG, while insignificant changes occurred in the PG. A significantly higher creatinine concentration was observed. Also, a higher post-RAST concentration of LA, HCO3- and lower values of pH were observed in April, May and June compared with baseline values. CONCLUSIONS The long timeframe, i.e., 16 weeks, of the low dose of magnesium creatine chelate supplementation improved the RAST results in the SG. Despite the long period of MgCr-C supplementation, in the end of the study, the creatinine level in the SG reached higher but still reference values.
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6.
Randomized Crossover Trial of Phosphate-binding Medication on Serum Phosphate Levels in Patients With Aortic Stenosis.
Wald, DS, Chambers, J, Bestwick, JP, Wald, NJ
Clinical therapeutics. 2019;(10):2066-2072.e2
Abstract
PURPOSE Aortic stenosis is a common cause of valvular heart disease with no means of prevention. The recognized association between aortic stenosis and serum phosphate raises the possibility of preventing progression of the disorder by using phosphate-binding drugs, but there is uncertainty whether such treatment lowers serum phosphate levels in patients without diagnosed renal failure. This pilot study was conducted to answer this question in patients with aortic stenosis. METHODS A randomized, double-blind, crossover trial of the phosphate-binding drug sevelamer was conducted in 72 patients. Patients were prescribed sevelamer 0.8 g (low-dose), sevelamer 2.4 g (high-dose), and matching placebo, 3 times daily with food; each regimen lasted 6 weeks and was allocated at random. Serum phosphate levels were measured at the end of each treatment period, and within-person levels were compared. FINDINGS Sixty-one patients completed the 3 treatment periods. There was no significant difference in the mean end-treatment phosphate levels across all patients (3.38, 3.36, and 3.31 mg/dL with placebo, low-dose sevelamer, and high-dose sevelamer, respectively). Post hoc analysis showed a reduction in phosphate levels with increasing sevelamer dose in the highest baseline phosphate quartile group; a 0.3 mg/dL reduction (mean, 4.09 mg/dL with placebo, 3.95 mg/dL with low-dose sevelamer, and 3.79 mg/dL with high-dose sevelamer; Ptrend = 0.027). IMPLICATIONS Sevelamer had no overall statistically significant effect in lowering serum phosphate levels, but a reduction was observed in patients with phosphate levels in the highest quartile group of the population distribution. This hypothesis-generating result requires confirmation in an independent study. If confirmed, a trial of sevelamer in preventing the progression of aortic stenosis may be justified in patients with high phosphate levels. ISRCTN Registry identifier: ISRCTN17365679.
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7.
Efficacy and safety of sevelamer carbonate in hyperphosphatemic pediatric patients with chronic kidney disease.
Fathallah-Shaykh, S, Drozdz, D, Flynn, J, Jenkins, R, Wesseling-Perry, K, Swartz, SJ, Wong, C, Accomando, B, Cox, GF, Warady, BA
Pediatric nephrology (Berlin, Germany). 2018;(2):325-333
Abstract
BACKGROUND Treatment for hyperphosphatemia in chronic kidney disease (CKD) involves dietary control of phosphorus intake, dialysis, and treatment with oral phosphate binders, none of which were approved by the Federal Food and Drug Administration in pediatric patients at the time of this study. METHODS This was a phase 2, multicenter study (NCT01574326) with a 2-week, randomized, placebo-controlled, fixed-dose period (FDP) followed by a 6-month, single-arm, open-label, dose-titration period (DTP), with the aim to evaluate the safety and efficacy of sevelamer carbonate (SC) in hyperphosphatemic pediatric patients with CKD. Following a 2-4 week screening phase, pediatric patients with a serum phosphorus level higher than age-appropriate levels were randomized to receive either SC or placebo as powder/tablets in 0.4-1.6 g doses, based on body surface area. The primary efficacy outcome was the change in serum phosphorus from baseline to end of the FDP in the SC versus placebo arms (analysis of covariance). The secondary outcome was mean change in serum phosphorus from baseline to end of DTP by treatment group and overall. Treatment-emergent/serious adverse events (AEs) were recorded. RESULTS Of 101 enrolled patients (29 centers), 66 completed the study. The majority of patients were adolescents (74%; mean age 14.1 years) and on dialysis (77%). Renal transplant was the main reason for discontinuation. SC significantly reduced serum phosphorus from baseline levels (7.16 mg/dL) during the FDP compared to placebo (least square mean difference - 0.90 mg/dL, p = 0.001) and during the DTP (- 1.18 mg/dL, p < 0.0001). The safety and tolerability of SC and placebo were similar during the FDP, with patients in both groups reporting mild/moderate gastrointestinal AEs during the DTP. CONCLUSIONS Sevelamer carbonate significantly lowered serum phosphorus levels in hyperphosphatemic children with CKD, with no serious safety concerns identified.
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8.
Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer.
Brønden, A, Mikkelsen, K, Sonne, DP, Hansen, M, Våben, C, Gabe, MN, Rosenkilde, M, Tremaroli, V, Wu, H, Bäckhed, F, et al
Diabetes, obesity & metabolism. 2018;(7):1623-1631
Abstract
AIMS: Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes. MATERIALS AND METHODS In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed. RESULTS Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed. CONCLUSIONS Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.
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9.
Calcium-Polystyrene Sulfonate Decreases Inter-Dialytic Hyperkalemia in Patients Undergoing Maintenance Hemodialysis: A Prospective, Randomized, Crossover Study.
Wang, J, Lv, MM, Zach, O, Wang, LY, Zhou, MY, Song, GR, Zhang, X, Lin, HL
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2018;(6):609-616
Abstract
Hyperkalemia is a life-threatening emergency in maintenance hemodialysis (MHD) patients. This clinical trial investigated the efficacy and safety of calcium-polystyrene sulfonate (Ca-PS) in MHD patients with interdialytic hyperkalemia. A total of 58 hemodialysis patients with hyperkalemia (≥5.5 mol/L) were selected and administered either a 3-week Ca-PS (3 × 5 g/day) or a blank control following the model of a prospective, randomized, crossover clinical trial with a 1-week washout period. All patients were followed up for another 3 weeks for safety evaluations. The primary outcome was the magnitude of the change in serum potassium levels. The secondary outcomes were electrocardiography (ECG) changes and treatment safety (volume overload, electrolyte imbalance). Compared with the control group, Ca-PS treatment significantly reduced serum potassium levels (P <0.01). More patients in the Ca-PS group had lower serum potassium levels than the safety level of <5.5 mmol/L (32% for control vs. 61% for Ca-PS, P <0.01). Peaked T-wave occurred less frequently in patients in the Ca-PS group (13.8% for Ca-PS vs. 31.03% for control, P <0.01). In addition, Ca-PS reduced serum phosphorus levels with no effects on serum levels of calcium and sodium, fluid volume, blood pressure, or interdialytic weight gain. Ca-PS treatment decreases serum levels of potassium and phosphorus in MHD patients with interdialytic hyperkalemia. Ca-PS does not induce volume overload or disrupt electrolyte balance.
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10.
Factors associated with serum fetuin-A concentrations after long-term use of different phosphate binders in hemodialysis patients.
Lin, HH, Liou, HH, Wu, MS, Huang, CC
BMC nephrology. 2016;:33
Abstract
BACKGROUND Fetuin-A is known as a circulating inhibitor of vascular calcification. Factors associated with serum fetuin-A concentrations after long-term use of different phosphate binders in hemodialysis patients is still uncertain. METHODS In the post-hoc study, we analyzed serum fetuin-A and biochemical factors (Ca, P, i-PTH, hsCRP, TG, LDL-C) in 50 hemodialysis patients, who completed a 48-week, open-Label, controlled randomized parallel-group study. 23 patients received sevelamer and 27 patients received calcium carbonate. RESULTS After the 48-week treatment, the sevelamer group had less serum calcium increment, less iPTH decrement, more ALK-P increment, more hsCRP decrement and more LDL-C decrement. There was no significant difference in the serum fetuin-A decrement between two groups. Decreased serum fetuin-A levels were found after 48-week treatment in both groups: from 210.61 (104.73) to 153.85 (38.64) ug/dl, P = 0.003 in sevelamer group, from 203.95 (107.87) to 170.90 (58.02) ug/mL, P =0.002 in calcium group. The decrement in serum fetuin-A (Δfetuin-A) levels was associated with ΔCa (ρ = - 0.230, P = 0.040), ΔiPTH (ρ = 0.306, P = 0.031) and Δalbumin (ρ = 0.408, P = 0.003), not associated with sevelamer use, ΔP and ΔhsCRP. CONCLUSION After long-term sevelamer or calcium carbonate treatment, both groups of maintenance HD patients had lower serum fetuin-A levels. Serum levels of increased calcium, decreased iPTH and decreased albumin were associated with the serum fetuin-A decrement.