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Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial.
Mathur, VS, Wesson, DE, Tangri, N, Li, E, Bushinsky, DA
BMC nephrology. 2022;(1):82
Abstract
BACKGROUND Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. METHODS This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial. RESULTS At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002). CONCLUSIONS Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.
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Pharmacomagnetography to evaluate the performance of magnetic enteric-coated tablets in the human gastrointestinal tract.
Pinto, LA, Corá, LA, Rodrigues, GS, Prospero, AG, Soares, GA, de Andreis, U, de Arruda Miranda, JR
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2021;:50-55
Abstract
A magnetic enteric-coated tablet containing diclofenac sodium was produced, and its performance under physiological and disturbed gastrointestinal motility was assessed through pharmacomagnetography analysis. In vitro studies were performed using conventional methods and in vivo studies were conducted on healthy volunteers before (control) and after domperidone administration. The magnetic tablet's gastrointestinal (GI) transit and disintegration process were monitored using the Alternating Current Biosusceptometry sensors combined with drug plasmatic concentration. The Gastric Residence Time, Colon Arrival Time, Small Bowel Transit Time, Disintegration Time and the pharmacokinetics parameters were calculated. The pH-dependent polymers used to coat the magnetic tablets were able to avoid the premature drug release on gastric or small intestine simulated medium. Gastric Residence Time was accelerated compared with the control group (p < 0.01). No significant differences were found regarding small bowel transit, colon arrival, disintegration process, or pharmacokinetics parameters. A strong correlation between magnetic monitoring and pharmacokinetics parameters analysis was determinant to evaluate the efficiency in the drug delivery at a specific site in the human gastrointestinal tract. In addition, a tablet with a damaged coating was used as a proof of concept to show the suitability of our methodology to evaluate the tablet. Our study showed that pharmacomagnetography is a multi-instrumental approach towards assessing drug delivery and bioavailability.
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Clinical hemocompatibility of double-filtration lipoprotein apheresis comparing polyethersulfone and ethylene-vinyl alcohol copolymer membranes.
Krieter, DH, Jeyaseelan, J, Rüth, M, Lemke, HD, Wanner, C, Drechsler, C
Artificial organs. 2021;(9):1104-1113
Abstract
Activation of the complement system and leukocytes by blood-membrane interactions may further promote arteriosclerosis typically present in patients on lipoprotein apheresis. As clinical data on the hemocompatibility of lipoprotein apheresis are scarce, a controlled clinical study comparing two different types of plasma separation and fractionation membranes used in double-filtration lipoprotein apheresis was urgently needed, as its outcome may influence clinical decision-making. In a prospective, randomized, crossover controlled trial, eight patients on double-filtration lipoprotein apheresis were subjected to one treatment with recent polyethersulfone (PES) plasma separation and fractionation membranes and one control treatment using a set of ethylene-vinyl alcohol copolymer (EVAL) membranes. White blood cell (WBC) and platelet (PC) counts, complement factor C5a and thrombin-antithrombin III (TAT) concentrations were determined in samples drawn at defined times from different sites of the extracorporeal blood and plasma circuit. With a nadir at 25 minutes, WBCs in EVAL decreased to 33.5 ± 10.7% of baseline compared with 63.8 ± 22.0% at 20 minutes in PES (P < .001). The maximum C5a levels in venous blood reentering the patients were measured at 30 minutes, being 30.0 ± 11.2 µg/L with EVAL and 12.3 ± 9.0 µg/L with PES (P < .05). The highest C5a concentrations were found in plasma after the plasma filters (EVAL 56.1 ± 22.0 µg/L at 15 minutes vs PES 23.3 ± 15.2 µg/L at 10 minutes; P < .001). PC did not significantly decrease over time with both membrane types, whereas TAT levels did not rise until the end of the treatment without differences between membranes. Regarding lipoprotein(a) and low-density lipoprotein (LDL) cholesterol removal, both membrane sets performed equally. Compared with EVAL, PES membranes cause less leukocyte and complement system activation, the classical parameters of hemocompatibility of extracorporeal treatment procedures, at identical treatment efficacy. Better hemocompatibility may avoid inflammation-promoting effects through blood-material interactions in patients requiring double-filtration lipoprotein apheresis.
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Patiromer for Treatment of Hyperkalemia in the Emergency Department: A Pilot Study.
Rafique, Z, Liu, M, Staggers, KA, Minard, CG, Peacock, WF
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2020;(1):54-60
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Abstract
BACKGROUND Hyperkalemia is common and potentially life threatening. Patiromer is a Food and Drug Administration (FDA)-cleared oral potassium binder effective in the chronic treatment of hyperkalemia. OBJECTIVE The objective was to investigate the potential efficacy and safety of oral patiromer in treating acute hyperkalemia in the emergency department (ED). METHODS This is a single-center, randomized, open-label convenience sample pilot study in an inner-city ED. Adult patients with end-stage renal disease and a serum potassium level of ≥ 6.0 mEq/L were randomized to standard of care (SOC) or one dose of 25.2 g oral patiromer plus SOC (PAT). Blood samples and electrocardiograms were collected at enrollment and at 1, 2, 4, and 6 hours thereafter. The primary outcome was the difference in potassium between groups at 6 hours. Secondary outcomes were the amount and number of times insulin and albuterol were given. RESULTS Thirty patients were included in the final analysis, 15 in each group. There were no differences in age, sex, or baseline serum potassium. There was no difference in mean serum potassium between SOC and PAT groups at 6 hours (6.32 mEq/L, confidence interval [CI] = 6.0 to 6.63 mEq/L vs. 5.81 mEq/L, CI = 5.48 to 6.14 mEq/L). However, 2 hours posttreatment the serum potassium of the PAT group was lower than SOC group (5.90 mEq/L, CI = 5.63 to 6.17 mEq/L vs. 6.51 mEq/L, CI = 6.25 to 6.78 mEq/L) and also 0.61 mEq/L lower than baseline. There were no differences in the amount or number of administrations of insulin or albuterol between groups, although the amount of albuterol used in the PAT group at 6 hours was lower but not significant (median, 0 mg vs. 12.5 mg; p = 0.097). There were no differences in adverse events between groups. CONCLUSION In this open-label pilot study of severe hyperkalemia, a single dose of 25.2 g of oral patiromer reduced serum potassium within 2 hours but did not show a difference at 6 hours. This is the first study showing that patiromer may have a role in the acute management of hyperkalemia; however, more rigorous studies are needed.
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Thin, Very Thin, or Ultrathin Strut Biodegradable or Durable Polymer-Coated Drug-Eluting Stents: 3-Year Outcomes of BIO-RESORT.
Buiten, RA, Ploumen, EH, Zocca, P, Doggen, CJM, Danse, PW, Schotborgh, CE, Scholte, M, van Houwelingen, KG, Stoel, MG, Hartmann, M, et al
JACC. Cardiovascular interventions. 2019;(17):1650-1660
Abstract
OBJECTIVES The aim of this study was to assess the 3-year safety and efficacy of treating all-comer patients with 3 contemporary drug-eluting stents (DES). BACKGROUND The BIO-RESORT (Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population) (TWENTE III) randomized trial (NCT01674803) found similar 1-year safety and efficacy for the 2 biodegradable-polymer DES (i.e., ultrathin-strut cobalt-chromium Orsiro sirolimus-eluting stent [SES] and very-thin-strut platinum-chromium Synergy everolimus-eluting stent) compared with the durable-polymer thin-strut cobalt-chromium Resolute Integrity zotarolimus-eluting stent (ZES). Two-year follow-up suggested that the SES might reduce repeat revascularizations beyond 1 year compared with the ZES. METHODS A total of 3,514 all-comer patients were treated at 4 centers for coronary intervention. The main clinical endpoint, target vessel failure, was a composite of safety (cardiac death or target vessel-related myocardial infarction) and efficacy (target vessel revascularization). Secondary endpoints included the individual components of target vessel failure and stent thrombosis. RESULTS Three-year follow-up data were available for 3,393 of 3,514 patients (96.6%). Target vessel failure occurred in 8.5% with SES and 10.0% with ZES (plog rank = 0.22) and in 8.8% with everolimus-eluting stents (vs. ZES, plog rank = 0.32). Rates of cardiac death, target vessel myocardial infarction, and target vessel revascularization were similar between stent groups. Landmark analyses found no statistically significant between-stent difference in repeat revascularization between 1 and 3 years. Definite or probable stent thrombosis rates were low (SES, 1.1%; everolimus-eluting stent, 1.1%; ZES, 0.9%) and similar with all 3 DES. CONCLUSIONS Despite substantial differences in stent backbone and polymer coating, all 3 DES showed favorable 3-year safety and efficacy in all comers, without significant between-stent differences. Further follow-up is required to definitely answer the question of whether one stent might improve clinical outcomes at a later stage.
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Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
Agarwal, R, Rossignol, P, Romero, A, Garza, D, Mayo, MR, Warren, S, Ma, J, White, WB, Williams, B
Lancet (London, England). 2019;(10208):1540-1550
Abstract
BACKGROUND Spironolactone is effective at reducing blood pressure in patients with uncontrolled resistant hypertension. However, the use of spironolactone in patients with chronic kidney disease can be restricted by hyperkalaemia. We evaluated use of the potassium binder patiromer to allow more persistent use of spironolactone in patients with chronic kidney disease and resistant hypertension. METHODS In this phase 2 multicentre, randomised, double-blind, placebo-controlled study, we enrolled participants aged 18 years and older with chronic kidney disease (estimated glomerular filtration rate 25 to ≤45 mL/min per 1·73 m2) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries (Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the UK, and the USA). Patients meeting all eligibility criteria at the final screening visit were stratified by local serum potassium measurement (4·3 to <4·7 mmol/L vs 4·7 to 5·1 mmol/L) and history of diabetes. Participants were randomly assigned (1:1) with an interactive web response system to receive either placebo or patiromer (8·4 g once daily), in addition to open-label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Participants, the study team that administered treatments and measured blood pressure, and the investigators were masked to assigned treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks (spironolactone). The primary endpoint was the between-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomised patients (intention to treat). The study was registered with Clinicaltrials.gov, NCT03071263. FINDINGS Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574 patients met all inclusion criteria and were randomly assigned to spironolactone in addition to double-blind treatment with either placebo (n=148) or patiromer (n=147). At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0-29·0; p<0·0001). Adverse events were mostly mild or moderate in severity and occurred in 79 (53%) of 148 patients in the placebo group and 82 (56%) of 147 patients in the patiromer group. INTERPRETATION In patients with resistant hypertension and chronic kidney disease, patiromer enabled more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent spironolactone enablement in this population of patients has clinical relevance for the treatment of resistant hypertension. FUNDING Relypsa, a Vifor Pharma Group Company.