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1.
Virology ; 554: 48-54, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33370597

RESUMO

The COVID-19 pandemic has urged for the repurposing of existing drugs for rapid management and treatment. Renin inhibitors down regulation of ACE2, which is an essential receptor for SARS-CoV-2 infection that is responsible for COVID-19, in addition to their ability to act as protease inhibitors were encouraging aspects for their investigation as possible inhibitors of main protease of SARS-CoV-2 via computational studies. A Pharmacophore model was generated using the newly released SARS-COV-2 main protease inhibitors. Virtual screening was performed on renin inhibitors, and Drug likeness filter identified remikiren and 0IU as hits. Molecular docking for both compounds showed that the orally active renin inhibitor remikiren (Ro 42-5892) of Hoffmann-La Roche exhibited good molecular interaction with Cys145 and His41 in the catalytic site of SARS-CoV-2 main protease. Molecular dynamics simulation suggested that the drug is stable in the active site of the enzyme.


Assuntos
/antagonistas & inibidores , Reposicionamento de Medicamentos , Inibidores de Proteases/farmacologia , Renina/antagonistas & inibidores , /efeitos dos fármacos , /tratamento farmacológico , Domínio Catalítico , /metabolismo , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacologia , Modelos Moleculares , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Ligação Proteica , /enzimologia
2.
Cochrane Database Syst Rev ; 10: CD012569, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33089502

RESUMO

BACKGROUND: Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown. OBJECTIVES: To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension. SEARCH METHODS: The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis. MAIN RESULTS: We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Renina/antagonistas & inibidores , Idoso , Amidas/efeitos adversos , Amidas/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Causas de Morte , Feminino , Fumaratos/efeitos adversos , Fumaratos/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Humanos , Irbesartana/uso terapêutico , Falência Renal Crônica/epidemiologia , Lisinopril/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Ramipril/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Lancet ; 395(10238): 1705-1714, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32416785

RESUMO

BACKGROUND: Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19. METHODS: In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437. FINDINGS: We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62-2·41) and risk factors (1·46, 1·23-1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77-1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64-1·00) or angiotensin-receptor blockers (1·10, 0·88-1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34-0·80). The adjusted ORs were similar across severity degrees of COVID-19. INTERPRETATION: RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19. FUNDING: Instituto de Salud Carlos III.


Assuntos
Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Infecções por Coronavirus/epidemiologia , Hospitalização/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Sistema Renina-Angiotensina , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Infecções por Coronavirus/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Pandemias , Pneumonia Viral/complicações , Renina/antagonistas & inibidores , Fatores de Risco , Espanha/epidemiologia
4.
BMC Cardiovasc Disord ; 20(1): 179, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32303191

RESUMO

BACKGROUND: Aliskiren is a newly developed drug. Its role in lowering BP has been recognized. However, the role of aliskiren in treating heart and renal diseases are still controversial. OBJECTIVE: To evaluate the existing evidence about clinical efficacy, safety and tolerability of aliskiren monotherapy (AM). METHODS: An umbrella review of systematic reviews of interventional studies. We searched Pubmed, Embase and Cochrane Library up to June 2019. Two reviewers applied inclusion criteria to the select potential articles independently. The extract and analyze of accessible data were did by two reviewers independently too. Discrepancies were resolved with discussion or the arbitration of the third author. RESULTS: Eventually, our review identified 14 eligible studies. Results showed that for essential hypertension patients, aliskiren showed a great superiority over placebo in BP reduction, BP response rate and BP control rate. Aliskiren and placebo, ARBs or ACEIs showed no difference in the number or extent of adverse events. For heart failure patients, AM did not reduce BNP levels (SMD -0.08, - 0.31 to 0.15) or mortality rate (RR 0.76, 0.32 to 1.80), but it decreased NT-proBNP (SMD -0.12, - 0.21 to - 0.03) and PRA levels (SMD 0.52, 0.30 to 0.75), increased PRC levels (SMD -0.66, - 0.8 to - 0.44). For patients who are suffered from hypertension and diabetes and/or nephropathy or albuminuria at the same time, aliskiren produced no significant effects (RR 0.97, 0.81 to 1.16). CONCLUSION: We found solid evidence to support the benefits of aliskiren in the treatment of essential hypertension, aliskiren can produce significant effects in lowering BP and reliable safety. However, the effects of aliskiren in cardiovascular and renal outcomes were insignificant. TRIAL REGISTRATION: Study has been registered in PROSPERO (CRD42019142141).


Assuntos
Albuminúria/tratamento farmacológico , Amidas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Hipertensão Essencial/tratamento farmacológico , Fumaratos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Renina/antagonistas & inibidores , Albuminúria/diagnóstico , Albuminúria/fisiopatologia , Amidas/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/fisiopatologia , Hipertensão Essencial/diagnóstico , Hipertensão Essencial/fisiopatologia , Fumaratos/efeitos adversos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Revisões Sistemáticas como Assunto , Resultado do Tratamento
5.
Clin Exp Hypertens ; 42(6): 545-552, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32037898

RESUMO

BACKGROUND: Renin is the starting point of the renin angiotensin (RA) system cycle. Aliskiren (AL), which is a direct renin inhibitor, suppressed the entire RA cycle. In the present study, the efficacy of add-on of AL treatment in patients with essential hypertension (HT) was investigated. METHODS: This study was a multi-center, open-label, prospective, observational study. Study subjects were patients with essential HT and poor blood pressure (BP) control, who had received calcium channel blocker monotherapy or angiotensin II receptor blocker monotherapy or had not received any BP lowering drugs. Following add-on of AL for 12 months, BP and additional laboratory findings were analyzed. RESULTS: A total of 150 subjects were enrolled. There were 50 dropout subjects including discontinuation. Dropouts were the highest in the ARB combination therapy group at 9 subjects due to adverse events, and 3 of them were due to hyperkalemia. A significantly higher number of patients with chronic kidney disease (CKD) dropped out compared to patients without CKD (φ = 0.166, p < .05). BP before add-on of AL was 155/88 mmHg. After add-on of AL, BP was significantly improved and this lowering was sustained for 3 months (136/78 mmHg, p < .001), 6 months (136/77 mmHg, p < .001) and 12 months (134/78 mmHg, p < .001). In contrast, add-on of AL increased the potassium level and decreased the estimated glomerular filtration rate. CONCLUSION: While add-on AL treatment achieved a favorable and sustained decrease of BP in this study, caution is necessary with regard to elevation of potassium levels and renal impairment.


Assuntos
Amidas , Fumaratos , Hiperpotassemia , Insuficiência Renal , Renina/antagonistas & inibidores , Idoso , Amidas/administração & dosagem , Amidas/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/classificação , Pressão Sanguínea/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Fumaratos/administração & dosagem , Fumaratos/efeitos adversos , Taxa de Filtração Glomerular , Humanos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/prevenção & controle , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/diagnóstico , Insuficiência Renal/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos
6.
Eur J Drug Metab Pharmacokinet ; 45(1): 15-26, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31494843

RESUMO

BACKGROUND: SPH3127 is a novel direct renin inhibitor designed as an oral drug for the regulation of blood pressure and body fluid homeostasis via the renin-angiotensin-aldosterone system (RAAS). This candidate is now being evaluated in a phase I clinical trial in China. OBJECTIVES: The purpose of this study is to investigate detailed nonclinical pharmacokinetic data, and to predict human pharmacokinetic parameters. METHODS: In vivo pharmacokinetic studies of SPH3127 were performed to investigate the exposure, absorption, clearance, distribution and metabolism after intravenous and oral administration in rats, beagle dogs and cynomolgus monkeys. The cynomolgus monkey pharmacokinetics/pharmacodynamics study was conducted to investigate the effect-concentration relationship of SPH3127. Its human pharmacokinetic properties were predicted employing an allometric scaling approach based on non-clinical species data. In vitro studies were also employed in a cytochrome P450 (CYP) enzyme phenotyping study, an inhibition and induction study, and a Caco-2 cell permeation and metabolites profile analysis. RESULTS: After a single intravenous administration of SPH3127 in rats and monkeys, high clearance and volume of distribution and a short terminal elimination half-life were seen for both species. The oral bioavailability of SPH3127 to rats and monkeys was about 11.5-24.5% and 3.3-11.3%, respectively, with the short peak time, Tmax, ranging from 0.25 to 1.3 h. SPH3127 shows low permeability across Caco-2 cell membranes, and as the substrate of p-gp with apparent efflux characteristics. SPH3127 is mainly distributed in the gastrointestine, liver, kidney, pancreas and lung after oral dose in rats, and which decreased quickly to a 1% peak concentration during 12 h. The plasma protein binding ratio of SPH3127 is low as 11.7-14.8% for all species. Excretion studies in rats suggested that fecal, urine and bile excretion represented about 15% of the intake dose, indicating that SPH3127 undergoes extensive metabolism after oral dosing. Phenotyping data revealed that CYP3A4 was the most active enzyme catalyzing the metabolism of SPH3127. The key metabolites were likely N-hydroxylation (M8-7), mono-oxidation-dehydrogenation (M7-4) and mono-oxidation (M8-1, M8-2), both for in vitro liver microsome incubation of all species and in vivo results in rats. The in vitro CYP inhibition study only found very weak action for CYP3A4 (midazolam 1'-hydroxylation) and CYP3A4 (midazolam 6ß-hydroxylation) with IC50 of 56.8 µM and 41.1 µM, respectively. Monkey pharmacokinetic/pharmacodynamic data showed favorable safety margins when compared with the exposure of the effect dose and that of the monkey NOAEL level. Simple four-species allometric scaling led to predicted human plasma clearance and volume of distribution, and then simulated the oral human plasma concentration-time profile, which are both in good consistency with phase I clinical trial pharmacokinetic data. CONCLUSIONS: SPH 3127 has appropriate pharmacokinetic properties for further clinical exploration.


Assuntos
Morfolinas/farmacocinética , Renina/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Absorção Intestinal , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Morfolinas/sangue , Morfolinas/química , Morfolinas/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
7.
Regul Toxicol Pharmacol ; 109: 104484, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31585137

RESUMO

SPH3127, a newly developed oral nonpeptide direct renin inhibitor with good tolerance and favorable ADME (absorption distribution metabolism excretion) properties in preclinical species, is now being evaluated in phase Ι clinical trial. In this work, the subchronic toxicity of SPH3127 in Sprague-Dawley rats and cynomolgus monkeys has been characterized. Rats and monkeys received SPH3127 orally (30, 300, 900 and 20, 100, 450 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days followed by a 28-days recovery period for one third of the animals. The adverse effects of SPH3127 on rats and monkeys mainly included kidney and cardiovascular toxicity, which were consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of renin signaling inhibitors. Moderate liver weight increases accompanied by CYP3A induction were seen in 300 and 900 mg/kg/day rats but not in monkeys or in vitro human hepatocytes. One 450 mg/kg/day monkey died early at day 23 with apparent myelosuppression characterized by atrophy of thymus and spleen, and the relevance to the action of SPH3127 remained unclear. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of SPH3127 was determined to be 30 mg/kg/day for Sprague-Dawley rats and 20 mg/kg/day for cynomolgus monkeys based on the kidney and cardiovascular changes found at mid- and high-dose animals.


Assuntos
Cardiotoxicidade/etiologia , Inibidores Enzimáticos/toxicidade , Rim/efeitos dos fármacos , Morfolinas/toxicidade , Renina/antagonistas & inibidores , Administração Oral , Animais , Células Cultivadas , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Feminino , Hepatócitos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macaca fascicularis , Masculino , Modelos Animais , Morfolinas/administração & dosagem , Nível de Efeito Adverso não Observado , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
9.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404946

RESUMO

Heart failure (HF) patients frequently have elevated plasma renin activity. We examined the significance of elevated plasma renin activity in a translationally-relevant model of dilated cardiomyopathy (DCM), which replicates the progressive stages (A-D) of human HF. Female mice with DCM and elevated plasma renin activity concentrations were treated with a direct renin inhibitor (aliskiren) in a randomized, blinded fashion beginning at Stage B HF. By comparison to controls, aliskiren treatment normalized pathologically elevated plasma renin activity (p < 0.001) and neprilysin levels (p < 0.001), but did not significantly alter pathological changes in plasma aldosterone, angiotensin II, atrial natriuretic peptide, or corin levels. Aliskiren improved cardiac systolic function (ejection fraction, p < 0.05; cardiac output, p < 0.01) and significantly reduced the longitudinal development of edema (extracellular water, p < 0.0001), retarding the transition from Stage B to Stage C HF. The normalization of elevated plasma renin activity reduced the loss of body fat and lean mass (cachexia/sarcopenia), p < 0.001) and prolonged survival (p < 0.05). In summary, the normalization of plasma renin activity retards the progression of experimental HF by improving cardiac systolic function, reducing the development of systemic edema, cachexia/sarcopenia, and mortality. These data suggest that targeting pathologically elevated plasma renin activity may be beneficial in appropriately selected HF patients.


Assuntos
Amidas/uso terapêutico , Cardiomiopatia Dilatada/tratamento farmacológico , Fumaratos/uso terapêutico , Renina/antagonistas & inibidores , Renina/sangue , Animais , Caquexia/sangue , Caquexia/complicações , Caquexia/tratamento farmacológico , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/complicações , Modelos Animais de Doenças , Edema/sangue , Edema/complicações , Edema/tratamento farmacológico , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Camundongos , Camundongos Endogâmicos C57BL
10.
J Food Biochem ; 43(1): e12648, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353494

RESUMO

Renin catalyzes the rate-determining step in the renin-angiotensin-aldosterone system that regulates mammalian blood pressure by converting angiotensinogen to angiotensin I (Ang I). Excessive plasma levels of Ang I is a causative factor in hypertension development. Therefore, inhibition of renin activity can lower blood pressure and provide relief from clinical symptoms associated with hypertension. Synthetic compounds are currently the most used group of renin inhibitors; however, only aliskiren is approved as a drug for hypertension treatment. But some negative side effects are associated with aliskiren therapy, which have necessitated the search for alternative natural compounds such as food protein-derived renin-inhibitory peptides with blood pressure-reducing effects. This paper is a concise review of the currently known sources and methods of production of renin-inhibitory peptides including their potential in vitro and in vivo extent of renin inhibition. PRACTICAL APPLICATIONS: Hypertension is a major human chronic disease that leads to severe cardiovascular impairment and ultimately death if not managed properly. Current therapeutic approach to hypertension management involves the use of drugs that inhibit excessive activities of renin and angiotensin converting enzyme (ACE), the two main enzymes that control mammalian blood pressure. Since renin catalyzes a single reaction that is the rate-determining step in the renin-angiotensin system, inhibition of this enzyme activity could be a highly effective strategy for controlling blood pressure without severe negative side effects. However, therapeutic control of renin activity remains difficult with only one approved drug. Some food protein-derived peptides have been found to inhibit renin activity inhibition, which could offer a drug-free treatment for hypertension. Therefore, this review provides a summary of recent developments in the advances and efficacy testing of renin-inhibitory peptides.


Assuntos
Proteínas na Dieta/química , Peptídeos/farmacologia , Renina/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Temperatura Alta , Humanos , Técnicas In Vitro , Microalgas/química , Peptídeos/química , Peptídeos/isolamento & purificação , Pressão , Sementes/química
11.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261774

RESUMO

Regardless of the cause, symptomatic heart failure (HF) with reduced ejection fraction (rEF) is characterized by pathological activation of the renin-angiotensin-aldosterone system (RAAS) with sodium retention and extracellular fluid expansion (edema). Here, we review the role of active renin, a crucial, upstream enzymatic regulator of the RAAS, as a prognostic and diagnostic plasma biomarker of heart failure with reduced ejection fraction (HFrEF) progression; we also discuss its potential as a pharmacological bio-target in HF therapy. Clinical and experimental studies indicate that plasma renin activity is elevated with symptomatic HFrEF with edema in patients, as well as in companion animals and experimental models of HF. Plasma renin activity levels are also reported to be elevated in patients and animals with rEF before the development of symptomatic HF. Modulation of renin activity in experimental HF significantly reduces edema formation and the progression of systolic dysfunction and improves survival. Thus, specific assessment and targeting of elevated renin activity may enhance diagnostic and therapeutic precision to improve outcomes in appropriate patients with HFrEF.


Assuntos
Insuficiência Cardíaca/sangue , Renina/sangue , Animais , Biomarcadores/sangue , Débito Cardíaco , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Renina/antagonistas & inibidores , Sístole
12.
Plant Foods Hum Nutr ; 74(3): 405-413, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273642

RESUMO

The aim of this work was to evaluate the ability of broken rice, an underutilized industrial by-product, as a potential functional and health promoting ingredient. With this purpose, the ability to inhibit the angiotensin converting enzyme and renin of a rice protein hydrolyzate (RPH) obtained from a high-protein variety of broken rice (var. Nutriar FCAyF) was analyzed (IC50 = 0.87 and 2.7 mg/mL, respectively). RPH was separated by gel permeation chromatography and in a second purification step by RP-HPLC. The sequence of antihypertensive peptides presented in two RP-HPLC fractions was analyzed. Peptides capable of interacting with the active sites of both enzymes were identified. In this study, we demonstrate that the hydrolysis treatment improves functional and biological properties of rice proteins. Protein preparations obtained from a by-product of rice industry, such as broken rice, are a promising ingredient with potentially good biological properties.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/isolamento & purificação , Oryza/química , Peptídeos/isolamento & purificação , Renina/antagonistas & inibidores , Anti-Hipertensivos/farmacologia , Cromatografia Líquida de Alta Pressão , Promoção da Saúde , Hidrólise , Simulação de Acoplamento Molecular , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/metabolismo , Renina/metabolismo
13.
Eur J Cardiothorac Surg ; 55(Suppl 1): i3-i10, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31106335

RESUMO

During the last 20 years, the prognosis for heart failure (HF) with reduced ejection fraction has steadily improved due to advances in drug treatment and the consistent implementation of guideline-recommended evidence-based drug therapy. Nevertheless, the morbidity and mortality rates of patients with HF can still be improved. The prevalence of HF is high and continues to increase steadily. Thus, timely and efficient drug treatment plays a central role in improving the quality of life and prognosis for patients with HF. Current therapeutic concepts combine inhibition of the renin-angiotensin-aldosterone system with blockage of the sympathetic system. New therapeutic approaches such as selective heart rate reduction, attenuation of the degradation of natriuretic peptides by neutral endopeptidase inhibition and treatment of comorbidities (e.g. iron deficiency, diabetes mellitus, hyperkalaemia) have led to a further improvement in the survival, time-out-of hospital and quality of life of affected patients. The goal of this article was to give an overview of the current standard drug therapy for HF and the value of new therapeutic approaches implemented in recent years.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Algoritmos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Glicosídeos Cardíacos/uso terapêutico , Cardiotônicos/uso terapêutico , Diuréticos/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Glucosídeos/uso terapêutico , Humanos , Hiperpotassemia/induzido quimicamente , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Ferro/uso terapêutico , Ivabradina/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Neprilisina/antagonistas & inibidores , Guias de Prática Clínica como Assunto , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Renina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Volume Sistólico , Ureia/análogos & derivados , Ureia/uso terapêutico
14.
BMC Pharmacol Toxicol ; 20(1): 23, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053170

RESUMO

BACKGROUND: The activation of neurohumoral compensatory mechanisms is a common physiological phenomenon in heart failure in order to make up for a failing heart, which will usually have a deteriorating effect on overall health condition. Many medications, such as neprilysin and angiotensin inhibitors, have recently been introduced to remediate neurohumoral changes. This study was conducted to evaluate the efficacy of the sacubitril-aliskiren combination versus the sacubitril-ramipril combination in the treatment of neurohumoral changes in rats with experimentally induced heart failure. METHOD: Thirty Wister rats were randomly assigned into five groups each of six rats, the first group was the control group. Intraperitoneal isoprenaline injections of 5 mg/kg/day for 1 week were used to induce experimental models of heart failure in rats of the rest of experimental groups. The second group served as a positive control. Rats in the third, fourth, and fifth groups received oral daily dose of sacubitril 30 mg/kg/day, sacubitril-aliskiren 30,10 mg/kg/day, and sacubitril-ramipril 30/10 mg/kg/day respectively, for 2 weeks. RESULTS: Induction of heart failure in rats has significantly increased circulating NT-proBNP (980 ± 116.71 pg/ml), MMP9 (15.85 ± 0.57 ng/ml), troponin-I (3.09 ± 0.147 ng/ml), CK-MB (31.55 ± 1.69 ng/ml), renin (736 ± 45.8 pg/ml), urea (52.1 ± 1.57 mg/dl), and creatinine (0.92 ± 0.04 mg/dl). Significant decreases in glomerular filtration rate (7.031 ± 1.6 ml/hr./kg), urine flow (0.2761 ± 0.06 ml/h/kg), total solute excretion (0.11 ± 0.03 meq/m), and mean blood pressure (83.5 ± 2.6 mm hg) were seen in rats with heart failure. Rats treated with sacubitril combined with aliskiren or ramipril showed a statistically significant reduction of NT-proBNP, MMP9, troponin serum urea, and serum creatinine. Sacubitril-aliskiren or sacubitril-ramipril administration produced a significant increase in renin plasma level, total solute excretion, urine flow, and glomerular filtration rate. CONCLUSION: Sacubitril in combination with aliskiren or with ramipril effectively reduced plasma cardiac biomarkers, such as CK-MB, MMP9, and NT-proBNP, in rats with heart failure. Both combinations showed significant remediation of renal function through increasing GFR, urine flow, and total solute excretion, as well as reducing plasma level of renin. Net results revealed that the sacubitril-aliskiren combination has similar remediating effects on neurohumoral changes compared to the sacubitril-ramipril combination.


Assuntos
Amidas/farmacologia , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Creatina Quinase Forma MB/sangue , Fumaratos/farmacologia , Insuficiência Cardíaca/sangue , Metaloproteinase 9 da Matriz/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Ramipril/farmacologia , Tetrazóis/farmacologia , Angiotensinas/antagonistas & inibidores , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiologia , Neprilisina/antagonistas & inibidores , Ratos Wistar , Renina/antagonistas & inibidores , Renina/sangue , Troponina I/sangue
15.
Heart ; 105(12): 904-910, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31118203

RESUMO

Inhibitors of the renin-angiotensin-aldosterone (RAAS) system are cornerstones of the management of patients with heart failure with reduced left ventricular ejection fraction (HFrEF). However, RAAS inhibitors may cause decline in renal function and/or hyperkalaemia, particularly during initiation and titration, intercurrent illness and during worsening of heart failure. There is very little evidence from clinical trials to guide the management of renal dysfunction. The Renal Association and British Society for Heart Failure have collaborated to describe the interactions between heart failure, RAAS inhibitors and renal dysfunction and give clear guidance on the use of RAAS inhibitors in patients with HFrEF. During initiation and titration of RAAS inhibitors, testing renal function is mandatory; a decline in renal function of 30% or more can be acceptable. During intercurrent illness, there is no evidence that stopping RAAS inhibitor is beneficial, but if potassium rises above 6.0 mmol/L, or creatinine rises more than 30%, RAAS inhibitors should be temporarily withheld. In patients with fluid retention, high doses of diuretic are needed and a decline in renal function is not an indication to reduce diuretic dose: if the patient remains congested, more diuretics are required. If a patient is hypovolaemic, diuretics should be stopped or withheld temporarily. Towards end of life, consider stopping RAAS inhibitors. RAAS inhibition has no known prognostic benefit in heart failure with preserved ejection fraction. Efforts should be made to initiate, titrate and maintain patients with HFrEF on RAAS inhibitor treatment, whether during intercurrent illness or worsening heart failure.


Assuntos
Angiotensinas/antagonistas & inibidores , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Rim/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Renina/antagonistas & inibidores , Árvores de Decisões , Humanos , Guias de Prática Clínica como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Volume Sistólico
16.
Mol Hum Reprod ; 25(4): 218-227, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30869150

RESUMO

In early gestation, the human placental renin-angiotensin system (RAS) is upregulated and plays a role in placental development. Among other functions, signalling through the angiotensin II type 1 receptor (AT1R) initiates proliferation. Many microRNAs (miRNAs) targeting placental RAS mRNAs are downregulated at this time. We propose that in early gestation miRNAs that target the placental RAS are downregulated, allowing for the increased RAS expression and proliferation required for adequate placentation. HTR-8/SVneo cells (an immortalized human trophoblast cell line) were used to assess the effect of nine miRNA mimics (at 0.08, 0.16, 0.32 and 0.64 ng/µL) on trophoblast cell proliferation and predicted RAS target mRNAs. The effect of the miRNA mimics on the rate of cell proliferation was assessed using the xCELLigence real-time cell analysis system over 48 h. Levels of miRNAs and predicted RAS target mRNAs were determined by RT-PCR (qPCR, n = 9/group). Statistically different levels of expression were determined (P < 0.05). All nine miRNA mimics significantly affected the proliferation rates of HTR-8/SVneo cells. Five of the miRNA mimics (miR-181a-5p (predicted to target: renin (REN), angiotensin converting enzyme (ACE)), miR-378 (REN, ACE), miR-663 (REN), miR-483-3p (ACE, ACE2, angiotensinogen (AGT), angiotensin II type 1 receptor (AGTR1)) and miR-514 (AGT)) were associated with a dose-dependent reduction in cell proliferation. Seven of the mimics significantly decreased expression of at least one of their predicted target RAS mRNAs. Our study shows that miRNAs targeting placental RAS mRNAs play a role in controlling trophoblast proliferation. As placentation is largely a process of proliferation, changes in expression of these miRNAs may be partly responsible for the expression of the placental RAS, proliferation and placentation.


Assuntos
Proliferação de Células/genética , MicroRNAs/genética , RNA Mensageiro/genética , Sistema Renina-Angiotensina/genética , Trofoblastos/metabolismo , Angiotensinogênio/antagonistas & inibidores , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Linhagem Celular Transformada , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Mimetismo Molecular , Anotação de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Placentação/genética , Gravidez , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/antagonistas & inibidores , Renina/genética , Renina/metabolismo , Transdução de Sinais , Trofoblastos/citologia
17.
Biomed Res Int ; 2019: 3027036, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809535

RESUMO

Aim: Vitamin D plays an important role in water and salt homeostasis. The aim of our study was to investigate the underlying relationship of Vitamin D and Aquaporins (AQP). Methods: The behaviors of 1α (OH)-ase knockout mice and wild type mice were observed before analysis. The ICR mice were treated with vehicle or paricalcitol, a vitamin D analogue, followed by animals receiving a standard diet and free access to drinking water either with aliskiren (renin blocker; 37.5 mg aliskiren in 100 ml water), or telmisartan (a angiotensin II type I receptor blocker; 40 mg telmisartan in 100 ml water) a week before study. The expressions of AQP-1, AQP-4, and renin in mice kidneys were detected by western bolting, immunohistochemistry, and immunofluorescence. Results: Diuresis and polydipsia were observed in 1α (OH)-ase knockout mice, and a decreased water intake and urine output in ICR mice was observed after paricalcitol treatment. Compared with wild type, the AQP-1 expressions were increased in renal papilla and AQP-4 expressions were decreased in renal proximal tubule of 1α(OH) ase knockout mice. In addition, AQP-1 was decreased in renal papilla and AQP-4 expressions were increased in proximal tubule by suppressing renin activity or supplement of Vitamin D analogue. After injecting renin into the lateral ventricle of the 1α(OH)ase knockout mice, the renin expression level was decreased in the kidney, followed by the decrease of AQP-1 in renal papilla and increase of AQP-4 in proximal tubule. Conclusions: Overall, Vitamin D and renin inhibitors have synergistic effects in regulating water channels in mice kidneys.


Assuntos
Aquaporina 1/genética , Aquaporina 4/genética , Renina/genética , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Amidas/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Fumaratos/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Camundongos , Camundongos Knockout , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Renina/administração & dosagem , Renina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , Telmisartan/administração & dosagem , Vitamina D/genética , Água/química
18.
Clin J Am Soc Nephrol ; 14(3): 354-363, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30755452

RESUMO

BACKGROUND AND OBJECTIVES: Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing. RESULTS: Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), -16% (imarikiren 5 mg), -27% (imarikiren 20 mg), -38% (imarikiren 40 mg), -39% (imarikiren 80 mg), and -31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo (P<0.001 each) as well as for candesartan cilexetil 8 mg versus placebo (P<0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated. CONCLUSIONS: Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.


Assuntos
Albuminúria/tratamento farmacológico , Benzimidazóis/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Morfolinas/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Renina/antagonistas & inibidores , Adulto , Idoso , Albuminúria/diagnóstico , Albuminúria/etiologia , Benzimidazóis/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Piperidinas/efeitos adversos , Inibidores de Proteases/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
Am J Cardiovasc Drugs ; 19(3): 259-286, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30737754

RESUMO

INTRODUCTION: Current guidelines recommend renin-angiotensin-aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events. OBJECTIVES: Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD. METHODS: This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors. RESULTS: Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria. CONCLUSION: Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Quimioterapia Combinada , Humanos , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Curr Diab Rep ; 19(1): 4, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30673886

RESUMO

PURPOSE OF REVIEW: Type 2 diabetes (T2D) is associated with an increased risk of diabetic kidney disease (DKD), cardiovascular disease, and heart failure, in part through activation of the renin-angiotensin-aldosterone system (RAAS). Although recent cardiovascular outcome trials have identified newer therapeutic agents such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists that reduce the risk of these complications, patients still exhibit residual cardiorenal morbidity and mortality. Accordingly, the identification of pharmacological agents that attenuate micro- and macrovascular complications related to T2D is a major priority. Our aim was to review evidence for the role of novel mineralocorticoid receptor antagonists (MRAs) that are being developed as adjunctive therapies to reduce the risk of DKD and cardiovascular disease in the setting of T2D. RECENT FINDINGS: Dual RAAS blockade with angiotensin-converting enzyme (ACE) inhibitor plus angiotensin receptor blockade (ARB) or ARB plus renin inhibition increases serious adverse events such as acute kidney injury and stroke. Due to the potential for these serious side effects, more recent interest has focused on newer, more selective non-steroidal MRAs such as finerenone as cardiorenal protective therapies. Finerenone reduces albuminuria in the setting of DKD in patients with T2D and has a lower risk of hyperkalemia compared to currently available MRAs. Novel MRAs such as finerenone have the potential to reduce the risk of DKD progression in patients with T2D. The impact of finerenone on hard, long-term cardiorenal endpoints is being examined in the FIGARO and FIDELIO trials in patients with DKD.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/uso terapêutico , Adulto , Albuminúria/tratamento farmacológico , Aldosterona/metabolismo , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Humanos , Hiperpotassemia/etiologia , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Naftiridinas/efeitos adversos , Renina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos
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