RESUMEN
Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for type 2 diabetes (T2D) treatment, have demonstrated significant cardiovascular and renal benefits in heart failure (HF) and chronic kidney disease (CKD), irrespective of T2D. This review provides an analysis of the multifaceted mechanisms underlying the cardiorenal benefits of SGLT2i in HF and CKD outside of the T2D context. Eight major aspects of the protective effects of SGLT2i beyond glycemic control are explored: 1) the impact on renal hemodynamics and tubuloglomerular feedback; 2) the natriuretic effects via proximal tubule Na+/H+ exchanger NHE3 inhibition; 3) the modulation of neurohumoral pathways with evidence of attenuated sympathetic activity; 4) the impact on erythropoiesis, not only in the context of local hypoxia but also systemic inflammation and iron regulation; 5) the uricosuria and mitigation of the hyperuricemic environment in cardiorenal syndromes; 6) the multiorgan metabolic reprogramming including the potential induction of a fasting-like state, improvement in glucose and insulin tolerance, and stimulation of lipolysis and ketogenesis; 7) the vascular endothelial growth factor A (VEGF-A) upregulation and angiogenesis, and 8) the direct cardiac effects. The intricate interplay between renal, neurohumoral, metabolic, and cardiac effects underscores the complexity of SGLT2i actions and provides valuable insights into their therapeutic implications for HF and CKD. Furthermore, this review sets the stage for future research to evaluate the individual contributions of these mechanisms in diverse clinical settings.
Asunto(s)
Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Animales , Riñón/efectos de los fármacos , Riñón/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidoresRESUMEN
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in patients with hypertension, yet the precise molecular mechanisms remain elusive. SGLT2i inhibits proximal tubule (PT) NHE3-mediated sodium reabsorption in normotensive rodents, yet no hypotensive effect is observed under this scenario. This study examined the effect of empagliflozin (EMPA) on renal tubular sodium transport in normotensive and spontaneously hypertensive rats (SHRs). It also tested the hypothesis that EMPA-mediated PT NHE3 inhibition in normotensive rats is associated with upregulation of distal nephron apical sodium transporters. EMPA administration for 14 days reduced BP in 12-wk-old SHRs but not in age-matched Wistar rats. PT NHE3 activity was inhibited by EMPA treatment in both Wistar and SHRs. In Wistar rats, EMPA increased NCC activity, mRNA expression, protein abundance, and phosphorylation levels, but not in SHRs. SHRs showed higher NKCC2 activity and an abundance of cleaved ENaC α and γ subunits compared with Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), and EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP reduction was observed only with combined EMPA and HCTZ treatment, not with either drug alone. These findings suggest that NCC upregulation counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, maintaining their baseline BP. Moreover, the reduction of NHE3 activity without further upregulation of major apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension.NEW & NOTEWORTHY This study suggests that reduced NHE3-mediated sodium reabsorption in the renal proximal tubule may account, at least in part, for the BP-lowering effect of SGLT2 inhibitors in the setting of hypertension. It also demonstrates that chronic treatment with SGLT2 inhibitors upregulates NCC activity, phosphorylation, and expression in the distal tubule of normotensive but not hypertensive rats. SGLT2 inhibitor-mediated upregulation of NCC seems crucial to counteract proximal tubule natriuresis in subjects with normal BP.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Hipertensión , Ratas Endogámicas SHR , Ratas Wistar , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Intercambiador 3 de Sodio-Hidrógeno , Regulación hacia Arriba , Animales , Masculino , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/genética , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Glucósidos/farmacología , Compuestos de Bencidrilo/farmacología , Regulación hacia Arriba/efectos de los fármacos , Ratas , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Presión Sanguínea/efectos de los fármacos , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Riñón/metabolismo , Riñón/efectos de los fármacosRESUMEN
BACKGROUND: Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations >5.5 mg/dL, despite treatment. SUMMARY: This review pre-sents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65-80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC9A3 gene, and blocks paracellular phosphate absorption. Key Messages: Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.
Asunto(s)
Hiperfosfatemia/tratamiento farmacológico , Absorción Intestinal , Intestino Delgado/fisiopatología , Isoquinolinas/uso terapéutico , Fosfatos/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Sulfonamidas/uso terapéutico , Animales , Transporte Biológico , Humanos , Hiperfosfatemia/etiología , Hiperfosfatemia/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidoresRESUMEN
BACKGROUND: Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action-tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders-is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis. METHODS: This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4. RESULTS: Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl, P<0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively. CONCLUSIONS: A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: AMPLIFY, NCT03824587.
Asunto(s)
Quelantes/uso terapéutico , Hiperfosfatemia/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Diálisis Renal , Sulfonamidas/uso terapéutico , Adulto , Anciano , Quelantes/efectos adversos , Diarrea/inducido químicamente , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Hiperfosfatemia/sangre , Isoquinolinas/efectos adversos , Masculino , Persona de Mediana Edad , Fósforo/sangre , Insuficiencia Renal Crónica/terapia , Sevelamer/uso terapéutico , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Sulfonamidas/efectos adversosRESUMEN
Freshwater fishes maintain an internal osmolality of ~300 mOsm, while living in dilute environments ranging from 0 to 50 mOsm. This osmotic challenge is met at least partially, by Na+/H+ exchangers (NHE) of fish gill and kidney. In this study, we cloned, expressed, and pharmacologically characterized fish-specific Nhes of the commercially important species Oncorhynchus mykiss. Trout (t) Nhe3a and Nhe3b isoforms from gill and kidney were expressed and characterized in an NHE-deficient cell line. Western blotting and immunocytochemistry confirmed stable expression of the tagged trout tNhe proteins. To measure NHE activity, a transient acid load was induced in trout tNhe expressing cells and intracellular pH was measured. Both isoforms demonstrated significant activity and recovered from an acute acid load. The effect of the NHE transport inhibitors amiloride, EIPA (5-(N-ethyl-N-isopropyl)-amiloride), phenamil, and DAPI was examined. tNhe3a was inhibited in a dose-dependent manner by amiloride and EIPA and tNhe3a was more sensitive to amiloride than EIPA, unlike mammalian NHE1. tNhe3b was inhibited by high concentrations of amiloride, while even in the presence of high concentrations of EIPA (500 µM), some activity of tNhe3b remained. Phenamil and DAPI were ineffective at inhibiting tNhe activity of either isoform. The current study aids in understanding the pharmacology of fish ion transporters. Both isoforms display inhibitory profiles uniquely different from mammalian NHEs and show resistance to inhibition. Our study allows for more direct interpretation of past, present, and future fish-specific sodium transport studies, with less reliance on mammalian NHE data for interpretation.
Asunto(s)
Proteínas de Peces/metabolismo , Oncorhynchus mykiss , Bloqueadores de los Canales de Sodio/farmacología , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Amilorida/análogos & derivados , Amilorida/farmacología , Animales , Células CHO , Clonación Molecular , Cricetulus , Proteínas de Peces/antagonistas & inhibidores , Proteínas de Peces/genética , Expresión Génica , Branquias/fisiología , Indoles/farmacología , Mamíferos , Especificidad de Órganos , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 3 de Sodio-Hidrógeno/genética , TransfecciónRESUMEN
Mercury is an environmental pollutant and a threat to human health. Mercuric chloride (HgCl2)-induced acute renal failure has been described by several reports, but the mechanisms of renal dysfunction remain elusive. This study tested the hypothesis that HgCl2 directly impairs renal vascular reactivity. Additionally, due to the mercury toxicity on the proximal tubule, we investigated whether the HgCl2-induced natriuresis is accompanied by inhibition of Na+/H+ exchanger isoform-3 (NHE3). We found that 90-min HgCl2 infusion (6.5 µg/kg i.v.) remarkably increased urinary output, reduced GFR and renal blood flow, and increased vascular resistance in rats. "In vitro" experiments of HgCl2 infusion in isolated renal vascular bed demonstrated an elevation of perfusion pressure in a concentration- and time-dependent manner, associated with changes on the endothelium-dependent vasodilatation and the flow-pressure relationship. Moreover, by employing "in vivo" stationary microperfusion of the proximal tubule, we found that HgCl2 inhibits NHE3 activity and increases the phosphorylation of NHE3 at serine 552 in the renal cortex, in line with the HgCl2-induced diuresis. Changes in renal proximal tubular function induced by HgCl2 were parallel to increased urinary markers of proximal tubular injury. Besides, atomic spectrometry showed that mercury accumulated in the renal cortex. We conclude that acute HgCl2 exposure causes renal vasoconstriction that is associated with reduced endothelial vasodilator agonist- and flow-mediated responses and inhibition of NHE3-mediated sodium reabsorption. Thus, our data suggest that HgCl2-induced acute renal failure may be attributable at least in part by its direct effects on renal hemodynamics and NHE3 activity.
Asunto(s)
Endotelio Vascular/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Riñón/irrigación sanguínea , Cloruro de Mercurio/toxicidad , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Animales , Contaminantes Ambientales/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Riñón/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Resistencia Vascular/efectos de los fármacosRESUMEN
The majority of patients with chronic kidney disease (CKD) receiving dialysis do not achieve target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a nonbinder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This preclinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-h urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer [0-3% (wt/wt)]. We also evaluated the effect of the addition of tenapanor or vehicle on 24-h urinary phosphorus excretion to rats on a stable dose of sevelamer [1.5% (wt/wt)]. When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose [1.5% (wt/wt)] reduced mean ± SE urinary phosphorus excretion by 42 ± 3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37 ± 6% (P < 0.05). Although both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.
Asunto(s)
Quelantes/farmacología , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Isoquinolinas/farmacología , Riñón/efectos de los fármacos , Fósforo/orina , Eliminación Renal/efectos de los fármacos , Sevelamer/farmacología , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Sinergismo Farmacológico , Humanos , Mucosa Intestinal/metabolismo , Riñón/metabolismo , Masculino , Ratas Sprague-Dawley , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Factores de TiempoRESUMEN
The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the "cancer problem"? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article's goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.
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Concentración de Iones de Hidrógeno , Neoplasias/metabolismo , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Espacio Extracelular/metabolismo , Humanos , Espacio Intracelular/metabolismo , Terapia Molecular Dirigida , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Pronóstico , Intercambiador 1 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Bloqueadores del Canal de Sodio Activado por Voltaje , Canales de Sodio Activados por Voltaje/metabolismoRESUMEN
INTRODUCTION: Irritable bowel syndrome with constipation is associated with higher rates of functional impairment, as compared to other subtypes of the syndrome. Conventional laxative-based pharmacologic therapy of IBS-C, which is mostly symptom-based, is often unsatisfactory. Tenapanor represents a first-in-class orally available inhibitor of NHE3, which is minimally absorbed in the GI tract, what constitutes a significant therapeutic benefit, as it may act on the drug target. AREAS COVERED: Aim of this article is to sum up the evidences about pharmacodynamics and pharmacokinetics of tenapanor, focusing on animal models and in vitro studies, but also discuss clinical trials on tenapanor's safety and efficacy in view of its important potential role in IBS-C treatment. EXPERT OPINION: In the challenging setting of irritable bowel syndrome with constipation, tenapanor represents a novel strategy in the pipeline of the therapies of IBS-C. Its pharmacokinetic and pharmacodynamic profile provides that it is minimally absorbed from the intestinal lumen and that its action is local, but not systemic action, therefore guaranteeing the reduction of drug-drug interactions, toxicity and severe adverse effects. Phase 2b and 3 trials showed an optimal satisfaction of primary and secondary endpoints.
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Fármacos Gastrointestinales/uso terapéutico , Síndrome del Colon Irritable/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Animales , Estreñimiento/tratamiento farmacológico , Estreñimiento/etiología , Interacciones Farmacológicas , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/farmacología , Humanos , Síndrome del Colon Irritable/fisiopatología , Isoquinolinas/efectos adversos , Isoquinolinas/farmacología , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Sulfonamidas/efectos adversos , Sulfonamidas/farmacologíaRESUMEN
Irritable bowel syndrome (IBS) is among the most common gastrointestinal disorders encountered in primary and secondary care and is associated with impaired quality of life, increased healthcare utilization, and significant costs to patients and society. There are three primary phenotypes of IBS, categorized according to stool pattern: IBS with diarrhea (IBS-D), IBS with constipation (IBS-C) and IBS with a mixed bowel pattern (IBS-M). The treatment approach to all forms of IBS is typically hierarchal, with initial therapies consisting of dietary and lifestyle modifications. When these interventions are impractical or ineffective, pharmacotherapy with over-the-counter and prescription therapies is often employed. Tenapanor is a locally acting, minimally absorbed, selective small-molecule inhibitor of the intestinal sodium/hydrogen exchanger 3 (NHE3) that was approved in September 2019 by the U.S. Food and Drug Administration (FDA) for IBS-C. This agent works by increasing the sodium level in the intestinal lumen and promoting the efflux of fluid into the gut lumen to maintain osmotic balance in addition to having an antinociceptive effect. Tenapanor has been shown to improve bowel movement frequency/form and abdominal pain in patients with IBS-C. This article will elaborate on the clinical development program for tenapanor for this indication.
Asunto(s)
Estreñimiento/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Síndrome del Colon Irritable/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Estreñimiento/complicaciones , Humanos , Síndrome del Colon Irritable/complicaciones , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidoresRESUMEN
OBJECTIVES: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C). METHODS: In this phase 3, double-blind study (ClinicalTrials.gov identifier NCT02621892), patients with IBS-C were randomized to tenapanor 50 mg b.i.d. or placebo b.i.d. for 12 weeks followed by a 4-week randomized withdrawal period. The primary efficacy variable was the proportion of patients who reported a reduction in average weekly worst abdominal pain of ≥30.0% and an increase of ≥1 complete spontaneous bowel movement from baseline, both in the same week, for ≥6 weeks of the 12-week treatment period. RESULTS: Of the 629 randomized patients with IBS-C, 606 (96.3%) were included in the intention-to-treat analysis set (tenapanor: n = 307; placebo: n = 299) and 533 (84.7%) completed the 12-week treatment period. In the intention-to-treat analysis set (mean age 45 years, 81.4% women), a significantly greater proportion of patients treated with tenapanor met the primary endpoint than patients treated with placebo (27.0% vs 18.7%, P = 0.020). Abdominal symptoms and global symptoms of IBS also improved with tenapanor (P < 0.05 vs placebo). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in 6.5% and 0.7% of patients receiving tenapanor and placebo, respectively, during the 12-week treatment period. DISCUSSION: Tenapanor 50 mg b.i.d. improved IBS-C symptoms and was generally well tolerated, offering a potential new treatment option for patients with IBS-C.
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Estreñimiento/tratamiento farmacológico , Síndrome del Colon Irritable/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Dolor Abdominal/etiología , Dolor Abdominal/fisiopatología , Adulto , Estreñimiento/etiología , Estreñimiento/fisiopatología , Deprescripciones , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Humanos , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/fisiopatología , Masculino , Persona de Mediana Edad , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
The selective sodium hydrogen exchanger 3 (NHE3) inhibitor tenapanor is being developed by Ardelyx Inc. for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) [under the tradename IBSRELA®] and for hyperphosphataemia in patients with chronic kidney disease (CKD) on dialysis or with end stage renal disease (ESRD). Based on positive results from the phase III T3MPO trial program, tenapanor was recently approved in the USA for the treatment of IBS-C in adults. This article summarises the milestones in the development of tenapanor leading to this first approval.
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Aprobación de Drogas , Hiperfosfatemia/tratamiento farmacológico , Síndrome del Colon Irritable/tratamiento farmacológico , Isoquinolinas/farmacología , Fallo Renal Crónico/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Sulfonamidas/farmacología , Adulto , Ensayos Clínicos Fase III como Asunto , Humanos , Conformación MolecularRESUMEN
BACKGROUND: Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. METHODS: In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. RESULTS: Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action. CONCLUSIONS: Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.
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Hiperfosfatemia/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Fallo Renal Crónico/terapia , Fosfatos/sangre , Sulfonamidas/uso terapéutico , Adulto , Anciano , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Humanos , Hiperfosfatemia/sangre , Isoquinolinas/efectos adversos , Masculino , Persona de Mediana Edad , Diálisis Renal , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Sulfonamidas/efectos adversosRESUMEN
IMPACT STATEMENT: This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a "Western" diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.
Asunto(s)
Absorción Intestinal/fisiología , Fosfatos/farmacocinética , Fósforo Dietético/farmacocinética , Animales , Ensayos Clínicos como Asunto , Dieta Occidental , Electroquímica , Enterocitos/efectos de los fármacos , Enterocitos/metabolismo , Humanos , Hiperfosfatemia/etiología , Hiperfosfatemia/fisiopatología , Hiperfosfatemia/terapia , Absorción Intestinal/efectos de los fármacos , Isoquinolinas/uso terapéutico , Ratones , Ratones Noqueados , Niacinamida/uso terapéutico , Compuestos Orgánicos/química , Fosfatos/orina , Conejos , Ratas , Proteínas Recombinantes/metabolismo , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Sodio/fisiología , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 3 de Sodio-Hidrógeno/deficiencia , Intercambiador 3 de Sodio-Hidrógeno/fisiología , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/antagonistas & inhibidores , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/deficiencia , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/fisiología , Sulfonamidas/uso terapéuticoRESUMEN
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are well-established glucose-lowering drugs for type 2 diabetes mellitus (T2DM) management. Acute GLP-1RA administration increases urinary excretion of sodium and other electrolytes. However, the renal tubular effects of prolonged GLP-1RA treatment are largely unknown. In this secondary analysis of a randomized trial, we determined the renal tubular effects of 8-wk treatment with 20 µg lixisenatide, a short-acting (prandial) GLP-1RA, versus titrated once-daily insulin glulisine in 35 overweight T2DM-patients on stable insulin glargine background therapy (age: 62 ± 7 yr, glycated hemoglobin: 8.0 ± 0.9%, estimated glomerular filtration rate: >60 ml·min-1·1.73 m-2). After a standardized breakfast, lixisenatide increased absolute and fractional excretions of sodium, chloride, and potassium and increased urinary pH. In contrast, lixisenatide reduced absolute and fractional excretions of magnesium, calcium, and phosphate. At week 8, patients treated with lixisenatide had significantly more phosphorylated sodium-hydrogen exchanger isoform 3 (NHE3) in urinary extracellular vesicles than those on insulin glulisine treatment, which suggested decreased NHE3 activity in the proximal tubule. A rise in postprandial blood pressure with lixisenatide partly explained the changes in the urinary excretion of sodium, potassium, magnesium, and phosphate and the changes in urinary pH. In conclusion, lixisenatide affects postprandial urinary excretion of several electrolytes and increases urinary pH compared with insulin glulisine in T2DM patients after 8 wk of treatment. This is most likely explained by a drug-induced rise in blood pressure or direct inhibitory effects on NHE3 in the proximal tubule.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/efectos adversos , Túbulos Renales Proximales/efectos de los fármacos , Péptidos/efectos adversos , Adulto , Anciano , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/orina , Esquema de Medicación , Femenino , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/fisiopatología , Masculino , Persona de Mediana Edad , Péptidos/administración & dosificación , Fosforilación , Eliminación Renal/efectos de los fármacos , Sodio/orina , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 3 de Sodio-Hidrógeno/orina , Factores de Tiempo , Resultado del TratamientoRESUMEN
Intestinal cell line studies indicated luminal Na+ homeostasis is essential for proton-coupled peptide absorption, because the driving force of PepT1 activity is supported by the apical Na+/H+ exchanger NHE3. However, there is no direct evidence demonstrating the importance of in vivo luminal Na+ for peptide absorption in animal experiments. To investigate the relationship between luminal Na+ homeostasis and peptide absorption, we took advantage of claudin 15-deficient (cldn15-/-) mice, whereby Na+ homeostasis is disrupted. We quantitatively assessed the intestinal segment responsible for peptide absorption using radiolabeled nonhydrolyzable dipeptide (glycylsarcosine, Gly-Sar) and nonabsorbable fluid phase marker polyethylene glycol (PEG) 4000 in vivo. In wild-type (WT) mice, the concentration ratio of Gly-Sar to PEG 4000 decreased in the upper jejunum, suggesting the upper jejunum is responsible for peptide absorption. Gly-Sar absorption was decreased in the jejunum of cldn15-/- mice. To elucidate the mechanism underlining these impairments, a Gly-Sar-induced short-circuit ( Isc) current was measured. In WT mice, increments of Gly-Sar-induced Isc were inhibited by the luminal application of a NHE3-specific inhibitor S3226 in a dose-dependent fashion. In contrast to in vivo experiments, robust Gly-Sar-induced Isc increments were observed in the jejunal mucosa of cldn15-/- mice. Gly-Sar-induced Isc was inhibited by S3226 or a reduction of luminal Na+ concentration, which mimics low luminal Na+ concentrations in vivo . Our study demonstrates that luminal Na+ homeostasis is important for peptide absorption in native epithelia and that there is a cooperative functional relationship between PepT1 and NHE3. NEW & NOTEWORTHY Our study is the first to demonstrate that luminal Na+ homeostasis is important for proton-coupled peptide absorption in in vivo animal experiments.
Asunto(s)
Dipéptidos/farmacocinética , Homeostasis , Absorción Intestinal , Yeyuno/metabolismo , Sodio/metabolismo , Animales , Claudinas/deficiencia , Claudinas/genética , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 3 de Sodio-Hidrógeno/metabolismoRESUMEN
Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia. We investigated the mechanism by which tenapanor reduces gastrointestinal phosphate uptake, using in vivo studies in rodents and translational experiments on human small intestinal stem cell-derived enteroid monolayers to model ion transport physiology. We found that tenapanor produces its effect by modulating tight junctions, which increases transepithelial electrical resistance (TEER) and reduces permeability to phosphate, reducing paracellular phosphate absorption. NHE3-deficient monolayers mimicked the phosphate phenotype of tenapanor treatment, and tenapanor did not affect TEER or phosphate flux in the absence of NHE3. Tenapanor also prevents active transcellular phosphate absorption compensation by decreasing the expression of NaPi2b, the major active intestinal phosphate transporter. In healthy human volunteers, tenapanor (15 mg, given twice daily for 4 days) increased stool phosphorus and decreased urinary phosphorus excretion. We determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition.
Asunto(s)
Permeabilidad de la Membrana Celular/efectos de los fármacos , Tracto Gastrointestinal/metabolismo , Isoquinolinas/farmacología , Fosfatos/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Sulfonamidas/farmacología , Adulto , Anciano , Animales , Secuencia de Bases , Células Cultivadas , Impedancia Eléctrica , Epitelio/metabolismo , Femenino , Voluntarios Sanos , Humanos , Concentración de Iones de Hidrógeno , Absorción Intestinal/efectos de los fármacos , Iones/orina , Masculino , Ratones , Persona de Mediana Edad , Potasio/metabolismo , Protones , Ratas , Sodio/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Proteínas de Uniones Estrechas/metabolismo , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to summarize the most recent data available on advances in development of novel medical treatments for hypertension and related comorbidities. RECENT FINDINGS: Approximately half of all hypertensive patients have not achieved goal blood pressure with current available antihypertensive medications. Recent landmark studies and new hypertension guidelines have called for stricter blood pressure control, creating a need for better strategies for lowering blood pressure. This has led to a shift in focus, in recent years, to the development of combination pills as a means of achieving improved blood pressure control by increasing adherence to prescribed medications along with further research and development of promising novel drugs based on discovery of new molecular targets such as the counter-regulatory renin-angiotensin system. Fixed-dose combination pills and novel treatments based on recently discovered pathogenic mechanisms of hypertension that have demonstrated promising results as treatments for hypertension and related comorbidities will be discussed in this review.
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Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Aminopeptidasas/antagonistas & inhibidores , Bloqueadores de los Canales de Calcio/farmacología , Combinación de Medicamentos , Antagonistas de los Receptores de Endotelina/farmacología , Humanos , Antagonistas de Receptores de Mineralocorticoides/farmacología , Ouabaína/antagonistas & inhibidores , Receptores de Péptido Intestinal Vasoactivo/agonistas , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Vacunas/farmacología , Proteínas ras/antagonistas & inhibidoresRESUMEN
KEY POINTS: Dietary Na restriction, through the mineralocorticoid aldosterone, acts on epithelial Na channels via both fast (24 h) and slow (5-7 days) mechanisms in the kidney. The fast effect entails increased proteolytic processing and trafficking of channel protein to the apical membrane. It is rapidly reversible by the mineralocorticoid receptor antagonist eplerenone and is largely lost when tubules are studied ex vivo. The slow effect does not require increased processing or surface expression, is refractory to acute eplerenone treatment, and is preserved ex vivo. Both slow and fast effects contribute to Na retention in vivo. Increased Na+ reabsorption in the proximal tubule also promotes Na conservation under conditions of chronic dietary Na restriction, reducing Na+ delivery to the distal nephron. ABSTRACT: Changes in the activity of the epithelial Na channel (ENaC) help to conserve extracellular fluid volume. In rats fed a low-salt diet, proteolytic processing of ENaC increased within 1 day, and was almost maximal after 3 days. The rapid increase in the abundance of cleaved αENaC and γENaC correlated with decreased urinary Na+ excretion and with increased ENaC surface expression. By contrast, ENaC activity, measured ex vivo in isolated cortical collecting ducts, increased modestly after 3 days and required 5 days to reach maximal levels. The mineralocorticoid receptor antagonist eplerenone reversed the increase in cleaved γENaC and induced natriuresis after 1 or 3 days but failed to alter either ENaC currents or Na+ excretion after 7 days of Na restriction. We conclude that Na depletion, through aldosterone, stimulates ENaC via independent fast and slow mechanisms. In vivo, amiloride-induced natriuresis increased after 1 day of Na depletion. By contrast, hydrochlorothiazide (HCTZ)-induced natriuresis decreased gradually over 7 days, consistent with increased ability of ENaC activity to compensate for decreased Na+ reabsorption in the distal convoluted tubule. Administration of amiloride and HCTZ together increased Na+ excretion less in Na-depleted compared to control animals, indicating decreased delivery of Na+ to the distal nephron when dietary Na is restricted. Measurements of creatinine and Li+ clearances indicated that increased Na reabsorption by the proximal tubules is responsible for the decreased delivery. Thus, Na conservation during chronic dietary salt restriction entails enhanced transport by both proximal and distal nephron segments.
Asunto(s)
Restricción Calórica , Diuréticos/farmacología , Canales Epiteliales de Sodio/metabolismo , Túbulos Renales Distales/metabolismo , Natriuresis , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Sodio/deficiencia , Aldosterona/farmacología , Amilorida/farmacología , Animales , Canales Epiteliales de Sodio/química , Hidroclorotiazida/farmacología , Túbulos Renales Distales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidoresRESUMEN
BACKGROUND: Eosinophilic esophagitis (EoE) is characterized by histopathologic modifications of esophageal tissue, including eosinophil-rich inflammation, basal zone hyperplasia, and dilated intercellular spaces (DIS). The underlying molecular processes that drive the histopathologic features of EoE remain largely unexplored. OBJECTIVE: We sought to investigate the involvement of solute carrier family 9, subfamily A, member 3 (SLC9A3) in esophageal epithelial intracellular pH (pHi) and DIS formation and the histopathologic features of EoE. METHODS: We examined expression of esophageal epithelial gene networks associated with regulation of pHi in the EoE transcriptome of primary esophageal epithelial cells and an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI). Molecular and cellular analyses and ion transport assays were used to evaluate the expression and function of SLC9A3. RESULTS: We identified altered expression of gene networks associated with regulation of pHi and acid-protective mechanisms in esophageal biopsy specimens from pediatric patients with EoE (healthy subjects, n = 6; patients with EoE, n = 10). The most dysregulated gene central to regulating pHi was SLC9A3. SLC9A3 expression was increased within the basal layer of esophageal biopsy specimens from patients with EoE, and expression positively correlated with disease severity (eosinophils/high-power field) and DIS (healthy subjects, n = 10; patients with EoE, n = 10). Analyses of esophageal epithelial cells revealed IL-13-induced, signal transducer and activator of transcription 6-dependent SLC9A3 expression and Na+-dependent proton secretion and that SLC9A3 activity correlated positively with DIS formation. Finally, we showed that IL-13-mediated, Na+-dependent proton secretion was the primary intracellular acid-protective mechanism within the esophageal epithelium and that blockade of SLC9A3 transport abrogated IL-13-induced DIS formation. CONCLUSIONS: SLC9A3 plays a functional role in DIS formation, and pharmacologic interventions targeting SLC9A3 function may suppress the histopathologic manifestations in patients with EoE.