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1.
Biomed Pharmacother ; 153: 113466, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076576

RESUMO

Novel oral therapeutic agents based on inhibition or binding activity without adverse events in CKD patients are urgently needed. Here, 5/6 nephrectomy (NX) rats were used to construct a CKD model. Aminated cellulose (AC711), which is metal-free, non-absorbable, and low-volume expansive, was used as a novel oral therapeutic agent for hyperphosphataemia treatment in rats. The efficacy of AC711 on serum and urinary phosphate levels, the expression of type II sodium-dependent phosphate cotransporter (NPT2b), and type III Na-dependent phosphate cotransporter (PiT-1/2) was examined. Serum fibroblast growth factor-23 (FGF-23) levels, parathyroid hormone (PTH) levels, and the phenotypic transformation of vascular smooth muscle cell markers (smooth muscle 22 (SM22) and Runx2) are considered an adaptive response to elevated serum phosphate levels. A similar efficacy of AC711 was observed on serum and urinary phosphate levels when the same dose of AC711 and sevelamer was administered to 5/6 NX rats. The decreasing expression of NPT2b, PiT-1, and PiT-2 was examined in the AC711 groups in a dose-dependent manner. The sevelamer and AC711-MD groups for FGF-23 and PTH indicated no significant difference. The down-regulation of Runx2 expression and up-regulation of SM22 expression were seen in the AC711 groups in a dose-dependent manner. Two suppression mechanisms (binding and inhibiting activities) were observed in the gastrointestinal (GI) tract in the AC711 groups. A novel oral phosphate binder, AC711, showed both binding and inhibition characteristics. The low-volume expansion of AC711 following exposure to simulated intestinal fluid provides the potential therapeutic benefits with the advantage of moderate GI side effects.


Assuntos
Hiperfosfatemia , Insuficiência Renal Crônica , Animais , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hiperfosfatemia/tratamento farmacológico , Hormônio Paratireóideo , Fosfatos/metabolismo , Ratos , Insuficiência Renal Crônica/tratamento farmacológico , Sevelamer
2.
Iran J Kidney Dis ; 16(4): 215-227, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35962636

RESUMO

Chronic kidney disease is a public health problem. The purpose of this study was to compare the effects of sevelamer and calciumbased binders on mortality of hemodialysis patients. PubMed, EMBASE and Web of Science were searched for related articles published before May 14, 2020. We included six studies with 43330 participants, of which 21147 and 22183 received calciumbased phosphate binders and sevelamer, respectively. In the analysis of unadjusted data, sevelamer could lower cardiovascular mortality. When adjusted HRs was pooled, the cardiovascular mortality did not differ significantly in the sevelamer and calcium-based phosphate binders groups. Additionally, the all-cause mortality rate in sevelamer group was different from that in calcium-based phosphate binders group. However, sevelamer could not lower all-cause mortality in terms of the adjusted data. No significant difference was found in calcium and phosphorus between calcium-based phosphate binders and sevalmer. Sensitivity analysis showed that partial results of the study were inconsistent. There was no difference in the effect of sevelamer and calciumbased phosphate binders on the risk of all-cause mortality in patients with hemodialysis, after adjusting confounders. However, given the instability of the results, the results need to be further confirmed by a large sample and high quality RCTs.  DOI: 10.52547/ijkd.6814.


Assuntos
Cálcio , Doenças Cardiovasculares , Cálcio na Dieta , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Quelantes/efeitos adversos , Humanos , Fosfatos , Diálise Renal/efeitos adversos , Sevelamer/uso terapêutico
3.
Int J Pharm ; 621: 121806, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35526696

RESUMO

Sevelamer hydrochloride (SH) or Renagel® is an effective phosphate binder prescribed to prevent the absorption of phosphate in end stage renal disease (ESRD) patients. The relationship between SH structure and binding capacity and affinity is very important and can be used in characterising the sensitivity of the hydrogel to binding conditions. Thus, a series of hydrogels were prepared by varying the amount of crosslinker, whilst the other hydrogel components were kept constant. Variation of this parameter influenced the hydrogel structure as shown by swelling data, differential scanning calorimetry and solid state nuclear magnetic resonance spectroscopy. The hydrogels' physical characteristics were found to correlate with the number of phosphate binding sites and affinity obtained from the Langmuir-Freundlich Isotherm (L-FI) and affinity distribution spectra (AD). The hydrogels formed using lower amounts of crosslinker showed a slight increase in binding capacity but with lower affinity. However, the influence of the pH of the binding media on the binding parameters of sevelamer hydrochloride was significant. This is the first report on the use of AD spectra generated from L-FI binding parameters in hydrogels, which demonstrates the sensitivity of the affinity and binding site numbers to changes in hydrogel physical properties and the pH of the binding media.


Assuntos
Hidrogéis , Poliaminas , Humanos , Fosfatos/metabolismo , Poliaminas/química , Sevelamer
4.
Nanotechnology ; 33(35)2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35616242

RESUMO

Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives,in situgelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackablein vivo. In this paper, we proposed a concept of 'responsive embolization'. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from 'bench to bedside' as a new type of vascular embolic.


Assuntos
Embolização Terapêutica , Nanopartículas , Animais , Microesferas , Fosfatos , Polímeros , Coelhos , Sevelamer
5.
Drug Deliv ; 29(1): 1447-1456, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35532152

RESUMO

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.


Assuntos
Antineoplásicos , Arsenicais , Arsenitos , Nanopartículas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Arsenicais/farmacologia , Arsenitos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/farmacologia , Sinergismo Farmacológico , Óxidos , Sevelamer/farmacologia
8.
Brasília; CONITEC; fev. 2022.
Não convencional em Português | BRISA/RedTESA, BRISA/RedTESA | ID: biblio-1368891

RESUMO

CONTEXTO: A doença renal crônica (DRC) é um problema de saúde pública crescente em todo o mundo, acompanhada de comorbidades muitas vezes mais graves do que a própria perda da função renal. Dentre elas, destacam-se os distúrbios do metabolismo ósseo e mineral (DMO), que levam à doença óssea e cardiovascular. Dessa forma, o DMO-DRC, além de poder resultar em fraturas, dor, deformidades ósseas e menor velocidade de crescimento nas crianças, também é fator de risco para calcificação vascular e associa-se a miocardiopatia e hipertrofia do ventrículo esquerdo, com consequente aumento do risco para doença cardíaca isquêmica, insuficiência cardíaca e morte de causa cardiovascular. Os mecanismos comuns entre a doença óssea e cardiovascular se apoiam nas crescentes evidências de que alterações na remodelação óssea favorecem o desenvolvimento de calcificações extra ósseas, principalmente vasculares. As alterações no metabolismo mineral e ósseo são frequentes na DRC, observadas já nos estágios iniciais da DRC, quando a taxa de filtração glomerular está em


Assuntos
Humanos , Insuficiência Renal Crônica/fisiopatologia , Hiperfosfatemia/tratamento farmacológico , Sevelamer/uso terapêutico , Sistema Único de Saúde , Brasil , Análise Custo-Benefício
9.
Pharmacol Res Perspect ; 10(2): e00938, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35194979

RESUMO

An excess phosphate burden in renal disease has pathological consequences for bone, kidney, and heart. Therapies to decrease intestinal phosphate absorption have been used to address the problem, but with limited success. Here, we describe the in vivo effects of a novel potent inhibitor of the intestinal sodium-dependent phosphate cotransporter NPT2b, LY3358966. Following treatment with LY3358966, phosphate uptake into plasma 15 min following an oral dose of radiolabeled phosphate was decreased 74% and 22% in mice and rats, respectively, indicating NPT2b plays a much more dominant role in mice than rats. Following the treatment with LY3358966 and radiolabeled phosphate, mouse feces were collected for 48 h to determine the ability of LY3358966 to inhibit phosphate absorption. Compared to vehicle-treated animals, there was a significant increase in radiolabeled phosphate recovered in feces (8.6% of the dose, p < .0001). Similar studies performed in rats also increased phosphate recovered in feces (5.3% of the dose, p < .05). When used in combination with the phosphate binder sevelamer in rats, there was a further small, but not significant, increase in fecal phosphate. In conclusion, LY3358966 revealed a more prominent role for NPT2b on acute intestinal phosphate uptake into plasma in mice than rats. However, the modest effects on total intestinal phosphate absorption observed in mice and rats with LY3359866 when used alone or in combination with sevelamer highlights the challenge to identify new more effective therapeutic targets and/or drug combinations to treat the phosphate burden in patients with renal disease.


Assuntos
Absorção Intestinal , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/antagonistas & inibidores , Animais , Células CHO , Quelantes/administração & dosagem , Quelantes/farmacologia , Cricetulus , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Sevelamer/administração & dosagem , Sevelamer/farmacologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Especificidade da Espécie
10.
Expert Opin Drug Saf ; 21(7): 947-955, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35180026

RESUMO

INTRODUCTION: Hyperphosphatemia is an inevitable complication for patients undergoing dialysis, as is the resulting need for treatment with phosphate binders. Currently, various phosphate binders are clinically available. In addition to their phosphate-lowering activity, individual phosphate binders have differing safety profiles and off-target actions. AREAS COVERED: This paper reviews the safety of phosphate binders and issues to be resolved. EXPERT OPINION: Calcium-based phosphate binders are well tolerated but may increase calcium overload risk. Sevelamer reduces serum cholesterol levels and exerts anti-inflammatory effects. Compared to sevelamer, bixalomer is associated with fewer gastrointestinal symptoms. Aluminum-containing binders, lanthanum carbonate, and sucroferric oxyhydroxide exhibit strong phosphate-lowering activity. Although ferric citrate reduces erythropoiesis-stimulating agents and intravenous iron doses, its use requires monitoring of iron metabolic markers to avoid overload. Occasionally, combined use of multiple phosphate binders can offer the advantages of each phosphate binder while minimizing their drawbacks; thus, this may be desirable according to individual patients' conditions and comorbidities. However, increased pill burden and nonadherence to phosphate binders emerge as new problems. We expect that novel therapeutic strategies will be developed to resolve these issues.


Assuntos
Hiperfosfatemia , Insuficiência Renal Crônica , Cálcio , Humanos , Hiperfosfatemia/tratamento farmacológico , Hiperfosfatemia/etiologia , Ferro/uso terapêutico , Fosfatos/metabolismo , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/terapia , Sevelamer/efeitos adversos
11.
Nephrology (Carlton) ; 27(4): 337-354, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34882904

RESUMO

Sevelamer, has been shown to have many pleiotropic actions on lipid panel, various inflammatory markers, and blood glucose levels in chronic kidney disease patients. We conducted a systematic review and meta-analysis to compare these pleiotropic effects of sevelamer to other phosphate binders used in chronic kidney disease patients. The relevant randomized controlled trials published from 1 January 2001 to 31 November 2019 on the following databases: Cochrane Central Register of Controlled Trials published in The Cochrane Library, PubMed, Scopus and Google Scholar were identified. All the included studies were independently assessed for eligibility and risk of bias. The modified data extraction form of Cochrane was used. This review included 44 studies for qualitative analysis and 28 reports for quantitative analysis. A meta-analysis of three studies (n = 180) showed that glycated haemoglobin had significantly decreased in sevelamer-treated patients (MD: 0.5%; p = <.001). Compared with calcium-based phosphate binders, sevelamer showed a significant reduction in low-density lipoprotein (MD: -19.43 mg/dL; p = <.001) and total cholesterol (MD: -19.98 mg/dL; p < .001). A significant increase in high-density lipoprotein (MD: 1.29 mg/dL; p = .05) was also prominent in sevelamer treated patients. However, we were not able to observe a significant change in other biochemical parameters such as TG, CRP, hs-CRP, FGF-23, IL-6 and albumin as, no statistically significant difference was observed.


Assuntos
Fosfatos , Insuficiência Renal Crônica , Cálcio , Quelantes/efeitos adversos , Humanos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Sevelamer/efeitos adversos
12.
J Am Soc Nephrol ; 33(1): 59-76, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34645696

RESUMO

BACKGROUND: Benefits of phosphate-lowering interventions on clinical outcomes in patients with CKD are unclear; systematic reviews have predominantly involved patients on dialysis. This study aimed to summarize evidence from randomized controlled trials (RCTs) concerning benefits and risks of noncalcium-based phosphate-lowering treatment in nondialysis CKD. METHODS: We conducted a systematic review and meta-analyses of RCTs involving noncalcium-based phosphate-lowering therapy compared with placebo, calcium-based binders, or no study medication, in adults with CKD not on dialysis or post-transplant. RCTs had ≥3 months follow-up and outcomes included biomarkers of mineral metabolism, cardiovascular parameters, and adverse events. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Unstandardized mean differences were used as effect sizes for continuous outcomes with common measurement units and Hedge's g standardized mean differences (SMD) otherwise. Odds ratios were used for binary outcomes. Cochrane risk of bias and GRADE assessment determined the certainty of evidence. RESULTS: In total, 20 trials involving 2498 participants (median sample size 120, median follow-up 9 months) were eligible for inclusion. Overall, risk of bias was low. Compared with placebo, noncalcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.37; 95% CI, -0.58 to -0.15 mg/dl, low certainty evidence) and urinary phosphate excretion (eight trials, SMD -0.61; 95% CI, -0.90 to -0.31, low certainty evidence), but resulted in increased constipation (nine trials, log odds ratio [OR] 0.93; 95% CI, 0.02 to 1.83, low certainty evidence) and greater vascular calcification score (three trials, SMD, 0.47; 95% CI, 0.17 to 0.77, very low certainty evidence). Data for effects of phosphate-lowering therapy on cardiovascular events (log OR, 0.51; 95% CI, -0.51 to 1.17) and death were scant. CONCLUSIONS: Noncalcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but there was an unclear effect on clinical outcomes and intermediate cardiovascular end points. Adequately powered RCTs are required to evaluate benefits and risks of phosphate-lowering therapy on patient-centered outcomes.


Assuntos
Hiperfosfatemia/prevenção & controle , Fosfatos/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Quelantes/uso terapêutico , Compostos Férricos/uso terapêutico , Humanos , Hiperfosfatemia/etiologia , Lantânio/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Sevelamer/uso terapêutico
13.
Int J Clin Pharm ; 44(2): 389-398, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34850339

RESUMO

Background Sevelamer and polystyrene sulfonate are used for treating hyperphosphatemia and hyperkalaemia in chronic kidney disease patients. Because of their binding properties, these resins potentially bind other drugs in the gastrointestinal tract, thereby decreasing their bioavailability and clinical effectiveness. Aim The aim of this study was to explore co-dispensed drug use in patients on sevelamer or polystyrene sulfonate to identify potential novel binding interactions. Method In this in silico study, the 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate in the period 2000-2018 were extracted from the University Groningen IADB.nl database. Drugs dispensed to < 5% of patients, drugs not orally administered, drugs administered once daily before bedtime and drugs for which information on binding interactions with sevelamer or polystyrene was already available were excluded. The likelihood of an interaction (yes or no) of the included drugs was assessed based on pKa- and Log P values. For sevelamer, drugs with a pKa (acid) between 1.5 and 7.4 and or a Log P value > 2.0 were identified as potential interacting drug. For polystyrene sulfonate, drugs with a pKa (base) > 1.5 were identified as potential interacting drug. Results Of the top 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate, 22 and 27 potentially clinically relevant new interacting drugs were identified for sevelamer and polystyrene sulfonate respectively. Conclusion Several potentially relevant novel binding interactions for sevelamer and polystyrene sulfonate were identified based on dispensing data and assessment of chemical properties for which further interaction research is warranted.


Assuntos
Hiperpotassemia , Poliestirenos , Estudos Transversais , Feminino , Humanos , Hiperpotassemia/induzido quimicamente , Masculino , Poliestirenos/efeitos adversos , Sevelamer/uso terapêutico
14.
J Nephrol ; 35(2): 473-491, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34061337

RESUMO

BACKGROUND: Besides reducing hyperphosphatemia in chronic kidney disease (CKD) patients, phosphate lowering agents might provide beneficial effects on clinical and laboratory parameters. This meta-analysis was conducted to comprehensively examine the impact of all phosphate lowering agents on various aspects of clinical and laboratory outcomes in CKD patients. METHOD: A systematic literature search was performed in MEDLINE, Scopus, and the Cochrane Register of Controlled Trials until July 2020 to identify randomized controlled trials (RCTs) which compared the effects of each phosphate lowering agent with controls, comprising placebo and all other phosphate lowering agents. Various clinical and laboratory outcomes were analyzed. Random effects model was used to compute the standardized mean difference for continuous variables and the risk ratio (RR) for binary variables. RESULTS: This meta-analysis included 127 RCTs with 20,215 patients. Sevelamer and lanthanum significantly reduced all-cause mortality (RR 0.610, 95% CI 0.401-0.929 and 0.467, 95% CI 0.337-0.647, respectively) but not cardiovascular (CV) mortality or CV events. Hospitalization rates were significantly diminished by sevelamer (RR 0.527; 95% CI 0.308-0.902). Certain phosphate lowering agents improved biochemical parameters including serum phosphate, calcium, coronary artery calcium scores, fibroblast growth factor-23, bone biomarkers, and lipid profiles. Intact parathyroid hormone and bone mineral density were not significantly changed. CONCLUSIONS: In addition to decreasing serum phosphate levels, various beneficial effects on clinical and laboratory parameters of phosphate lowering agents might play potential roles in diminishing morbidity and mortality in CKD patients.


Assuntos
Hiperfosfatemia , Insuficiência Renal Crônica , Humanos , Hiperfosfatemia/tratamento farmacológico , Hiperfosfatemia/etiologia , Fosfatos , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Sevelamer/uso terapêutico
16.
Clin Transl Sci ; 15(2): 353-360, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34599865

RESUMO

Hyperphosphatemia is present in most patients with end-stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium-based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL-cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF-23 levels and there was no change with CA treatment. The inflammatory markers IL-8, IFN-γ, and TNFα decreased with response to both treatments. The levels of IL-6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti-inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.


Assuntos
Insuficiência Renal Crônica , Calcificação Vascular , Acetatos , Cálcio , Compostos de Cálcio , Quelantes/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Poliaminas/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Sevelamer/uso terapêutico , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/etiologia
17.
Blood Purif ; 51(8): 639-648, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34375976

RESUMO

INTRODUCTION: Constipation is prevalent in patients with kidney failure partly due to the use of medication, such as phosphate binders. We hypothesized that serum levels of gut microbiome-derived uremic toxins (UTOX) may be affected by the choice of phosphate binder putatively through its impact on colonic transit time. We investigated two commonly prescribed phosphate binders, sevelamer carbonate (SEV) and sucroferric oxyhydroxide (SFO), and their association with gut microbiome-derived UTOX levels in hemodialysis (HD) patients. METHODS: Weekly blood samples were collected from 16 anuric HD participants during the 5-week observational period. All participants were on active phosphate binder monotherapy with either SFO or SEV for at least 4 weeks prior to enrollment. Eight UTOX (7 gut microbiome-derived) and tryptophan were quantified using liquid chromatography-mass spectrometry. Serum phosphorus, nutritional, and liver function markers were also measured. For each substance, weekly individual levels, the median concentration per participant, and differences between SFO and SEV groups were reported. Patient-reported bowel movements, by the Bristol Stool Scale (BSS), and pill usage were assessed weekly. RESULTS: The SEV group reported a 3.3-fold higher frequency of BSS stool types 1 and 2 (more likely constipated, p < 0.05), whereas the SFO group reported a 1.5-fold higher frequency of BSS stool types 5-7 (more likely loose stool and diarrhea, not significant). Participants in the SFO group showed a trend toward better adherence to phosphate binder therapy (SFO: 87.6% vs. SEV: 66.6%, not significant). UTOX, serum phosphorus, nutritional and liver function markers, and tryptophan were not different between the two groups. CONCLUSION: There was no difference in the gut microbiome-derived UTOX levels between phosphate binders (SFO vs. SEV), despite SFO therapy resulting in fewer constipated participants. This pilot study may inform study design of future clinical trials and highlights the importance of including factors beyond bowel habits and their association with UTOX levels.


Assuntos
Microbioma Gastrointestinal , Hiperfosfatemia , Toxinas Biológicas , Quelantes/uso terapêutico , Humanos , Hiperfosfatemia/tratamento farmacológico , Hiperfosfatemia/etiologia , Fosfatos , Fósforo , Projetos Piloto , Diálise Renal/efeitos adversos , Sevelamer/uso terapêutico , Triptofano/uso terapêutico , Toxinas Urêmicas
18.
Ren Fail ; 43(1): 1378-1393, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34602015

RESUMO

OBJECTIVE: The aim of this study was to determine the efficacy and safety of lanthanum carbonate (LC) versus calcium salts, non-LC phosphate binders (PBs), sevelamer, or placebo in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: A literature search on PubMed, Embase, and Cochrane Library databases was conducted up to 18 June 2021. Data acquisition and quality assessment were performed by two reviewers. Meta-analysis was performed to evaluate the serum biochemical parameters, adverse events, and patient-level outcomes of LC, non-LC PBs, and sevelamer for hyperphosphatemia in patients with CKD. Heterogeneity across studies was assessed utilizing the I2 statistic and Q-test, and a random effect model was selected to calculate the pooled effect size. RESULTS: A total of 26 randomized, controlled trials and 3 observational studies were included. Compared to the other groups, better control effect of serum phosphorus (RR = 2.68, p < 0.001), reduction in serum phosphorus (95%CI = -1.93, -0.99; p < 0.001), Ca × P (95%CI = -13.89, -2.99; p = 0.002), serum intact parathyroid hormone levels (95%CI = -181.17, -3.96, p = 0.041) were found in LC group. Besides, reduced risk of various adverse effects, such as hypotension, abdominal pain, diarrhea, dyspepsia, and a score of coronary artery calcification were identified with LC in comparison to calcium salt, non-LC PBs, or placebo group. Significantly lower risk in mortality with LC treatment vs. non-LC PBs was observed, while no significant difference was identified between LC and calcium salt groups. CONCLUSION: LC might be an alternative treatment for hyperphosphatemia in patients with CKD considering its comprehensive curative effect.


Assuntos
Hiperfosfatemia/tratamento farmacológico , Lantânio/uso terapêutico , Fosfatos/sangue , Insuficiência Renal Crônica/complicações , Sevelamer/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Humanos , Hiperfosfatemia/etiologia , Lantânio/efeitos adversos , Estudos Observacionais como Assunto , Hormônio Paratireóideo/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
19.
Toxins (Basel) ; 13(10)2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34678981

RESUMO

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.


Assuntos
Quelantes/administração & dosagem , Cresóis/sangue , Hiperfosfatemia/tratamento farmacológico , Indicã/sangue , Sevelamer/administração & dosagem , Ésteres do Ácido Sulfúrico/sangue , Carbonato de Cálcio/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/tratamento farmacológico , /sangue
20.
Pharmacol Res Perspect ; 9(4): e00834, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34302439

RESUMO

This study explored the binding of 28 drugs, which were selected based on frequency of concomitant use and chemical properties, to sevelamer and polystyrene sulfonate in vitro. The relative binding was determined by dissolving the investigated drugs alone (=control), together with 800 mg of sevelamer and 15 g of polystyrene sulfonate at different pH levels (1.5, 5.5, and 7.4), respectively. After incubation at 37℃ and shaking for 60 min, the solutions were diluted and centrifuged, and the drug concentrations were quantified with validated analytical assays. The binding assays were performed in threefold. The mean relative binding (MRB) at each pH level was calculated, with a MRB >20% for at least one pH level to be considered as relevant binding. Fourteen and 23 potentially new binding interactions were identified with sevelamer and polystyrene sulfonate, respectively. These potentially new binding interactions have to be studied in vivo to assess their clinical relevance.


Assuntos
Preparações Farmacêuticas/química , Poliestirenos/química , Sevelamer/química , Concentração de Íons de Hidrogênio
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