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AIMS: Finerenone has been approved for treating diabetic kidney disease (DKD) with reducing cardiorenal risk. Real-world data on finerenone treatment for the management of DKD are presently lacking. This study aimed to investigate the effect of finerenone on the renal parameters of the Chinese DKD population in the real-world medical setting for the first time, especially in combination with renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). METHODS: Forty-two DKD patients were selected and completed a 6-month finerenone treatment. Renal parameters and adverse effects were collected at every visit. RESULTS: The median urine albumin-to-creatinine ratio (UACR) was 1426.11 (755.42, 3638.23) mg/g. Among them, the proportion of patients with a UACR of 300-5000 mg/g was 76.2%, and the proportion of patients with a UACR of >5000 mg/g was 14.3%. The median estimated glomerular filtration rate (eGFR) was 54.50 (34.16, 81.73) mL/min/1.73 m2. Finerenone decreased the UACR significantly throughout the study period (p < .05). The maximal decline of UACR at month 6 was 73%. Moreover, the proportion of patients with a 30% or greater reduction in UACR was 68.42% in month 6. There was a smaller decline (9-11%) in the eGFR after initiating finerenone (p > .05). One patient each discontinued finerenone due to hyperkalemia (2.4%) and acute kidney injury (2.4%). No patient reported hypotension, breast pain, and gynecomastia. CONCLUSIONS: This study from China first demonstrated finerenone decreased UACR with manageable safety in real-world DKD treatment. A triple regimen of RASi, SGLT2i, and finerenone may be a promising treatment strategy for lowering albuminuria and reducing hyperkalemia risk in advanced DKD patients.
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Nefropatías Diabéticas , Tasa de Filtración Glomerular , Naftiridinas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Masculino , Femenino , Nefropatías Diabéticas/tratamiento farmacológico , China , Persona de Mediana Edad , Anciano , Naftiridinas/uso terapéutico , Naftiridinas/efectos adversos , Tasa de Filtración Glomerular/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Albuminuria/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Creatinina/sangre , Creatinina/orina , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Resultado del TratamientoRESUMEN
The emergence and spread of chloroquine-resistant Plasmodium vivax have necessitated the assessment of alternative blood schizonticidal drugs. In Vietnam, chloroquine-resistant P. vivax malaria has been reported. In an open-label, single-arm trial, the safety, tolerability, and efficacy of pyronaridine-artesunate (Pyramax, PA) was evaluated in Dak Nong province, Vietnam. A 3-day course of PA was administered to adults and children (≥20 kg) infected with P. vivax. Patients also received primaquine (0.25 mg/kg daily for 14 days). PA was well tolerated with transient asymptomatic increases in liver transaminases. The per-protocol proportion of patients with day 42 PCR-unadjusted adequate clinical and parasitological response was 96.0% (95% CI, 84.9%-99.0%, n = 48/50). The median parasite clearance time was 12 h (range, 12-36 h), with a median fever clearance time of 24 h (range, 12-60 h). Single nucleotide polymorphisms (SNPs) as potential genetic markers of reduced drug susceptibility were analyzed in three putative drug resistance markers, Pvcrt-o, Pvmdr1, and PvK12. Insertion at position K10 of the Pvcrt-o gene was found in 74.6% (44/59) of isolates. Pvmdr1 SNPs at Y976F and F1076L were present in 61% (36/59) and 78% (46/59), respectively. Amplification of Pvmdr1 gene (two copies) was found in 5.1% (3/59) of parasite samples. Only 5.1% (3/59) of isolates had mutation 552I of the PvK12 gene. Overall, PA rapidly cleared P. vivax blood asexual stages and was highly efficacious in treating vivax malaria, with no evidence of artemisinin resistance found. PA provides an alternative to chloroquine treatment for vivax malaria in Vietnam. CLINICAL TRIALS: This study is registered with the Australian New Zealand Clinical Trials Registry as ACTRN12618001429246.
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Antimaláricos , Artemisininas , Artesunato , Malaria Vivax , Naftiridinas , Plasmodium vivax , Humanos , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/parasitología , Naftiridinas/uso terapéutico , Antimaláricos/uso terapéutico , Artesunato/uso terapéutico , Vietnam , Adulto , Plasmodium vivax/efectos de los fármacos , Plasmodium vivax/genética , Masculino , Artemisininas/uso terapéutico , Adolescente , Niño , Femenino , Persona de Mediana Edad , Adulto Joven , Primaquina/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Preescolar , Proteínas Protozoarias/genética , Resistencia a Medicamentos/genética , Proteínas de Transporte de MembranaRESUMEN
BACKGROUND: The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. METHODS AND RESULTS: We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. CONCLUSIONS: We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.
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Modelos Animales de Enfermedad , Fibrosis , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Óxido Nítrico Sintasa de Tipo III , Insuficiencia Renal Crónica , Disfunción Ventricular Izquierda , Animales , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/metabolismo , Naftiridinas/farmacología , Naftiridinas/uso terapéutico , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Tasa de Filtración Glomerular/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Diástole/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Riñón/metabolismo , Fosforilación , Miocardio/metabolismo , Miocardio/patología , Ratas Sprague-Dawley , Ratas , NefrectomíaRESUMEN
Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase ß (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.
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1-Fosfatidilinositol 4-Quinasa , Antimaláricos , Hemoproteínas , Naftiridinas , Plasmodium falciparum , Pez Cebra , Plasmodium falciparum/efectos de los fármacos , Animales , Naftiridinas/farmacología , Naftiridinas/química , Naftiridinas/síntesis química , Naftiridinas/uso terapéutico , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , 1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Humanos , Relación Estructura-Actividad , Hemoproteínas/antagonistas & inhibidores , Hemoproteínas/metabolismo , Ratones , Ratas , Malaria Falciparum/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis químicaRESUMEN
INTRODUCTION: Adding finerenone to current standard of care (SoC), as recommended by Chinese guidelines, has shown substantial benefit in delaying chronic kidney disease (CKD) progression and reducing cardiovascular risk in patients with CKD and type 2 diabetes (T2D) in the landmark FIDELIO-DKD trial. This study aimed to evaluate the cost-effectiveness of finerenone + SoC versus SoC alone among Chinese patients with T2D and CKD from a healthcare system perspective. METHODS: A cost-effectiveness model (FINE-CKD) has been developed and published, with health states defined for CKD stages (CKD 1/2, CKD 3, CKD 4, and CKD 5 without renal replacement therapy (RRT), dialysis, or transplant) and cardiovascular event history. Additionally, the model also considered adverse events. Transition probabilities and event risks were derived using patient-level data from Asian population analysis of FIDELIO-DKD. Since the price of finerenone after the national reimbursement drug list (NRDL) inclusion was confidential, the cost of finerenone in the model was assumed to be the same as that of SoC. Other health resource costs were gathered from literature and supplemented by physician interviews. Measured by the EQ-5D-5L questionnaire, quality of life was translated into utilities based on the Chinese EQ-5D-5L value set. RESULTS: Discounted at 5.0% annually, over a lifetime horizon, finerenone + SoC resulted in a quality-adjusted life years (QALYs) gain of 0.321 versus SoC alone (8.660 vs. 8.338 QALYs), due to a reduction in the incidence of cardiovascular events and dialysis. Total costs per patient were lower under finerenone + SoC than SoC alone (381,130 CNY vs. 392,390 CNY). As a result, finerenone + SoC was a dominant treatment strategy compared with SoC alone. Sensitivity analysis has confirmed the robustness of this study. CONCLUSION: Adding finerenone to SoC was likely to be either a dominant or cost-effective treatment option compared with SoC alone in Chinese patients with CKD and T2D.
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Análisis Costo-Beneficio , Diabetes Mellitus Tipo 2 , Naftiridinas , Insuficiencia Renal Crónica , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , China , Insuficiencia Renal Crónica/terapia , Masculino , Naftiridinas/uso terapéutico , Naftiridinas/economía , Femenino , Años de Vida Ajustados por Calidad de Vida , Nivel de Atención , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/economía , AncianoRESUMEN
AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.
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Insuficiencia Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Volumen Sistólico/fisiología , Femenino , Masculino , Anciano , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Naftiridinas/uso terapéutico , Método Doble Ciego , Función Ventricular Izquierda/fisiología , Función Ventricular Izquierda/efectos de los fármacos , Persona de Mediana Edad , Resultado del Tratamiento , Tasa de Filtración Glomerular/fisiología , Péptido Natriurético Encefálico/sangreRESUMEN
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Naftiridinas , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Animales , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Ratones , Naftiridinas/farmacología , Naftiridinas/síntesis química , Naftiridinas/química , Naftiridinas/uso terapéutico , Línea Celular Tumoral , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Ratones Desnudos , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1-2 h, the elimination half-life was 8-9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC90: 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.
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Antimaláricos , Voluntarios Sanos , Malaria Falciparum , Naftiridinas , Parasitemia , Plasmodium falciparum , Humanos , Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Antimaláricos/farmacología , Antimaláricos/administración & dosificación , Naftiridinas/farmacocinética , Naftiridinas/uso terapéutico , Naftiridinas/farmacología , Naftiridinas/administración & dosificación , Plasmodium falciparum/efectos de los fármacos , Adulto , Masculino , Adulto Joven , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Femenino , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Administración Oral , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
AIM: Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non-steroidal MRA finerenone. The FINEARTS-HF trial is designed to evaluate the long-term efficacy and safety of the selective non-steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. METHODS: FINEARTS-HF is a global, multicentre, event-driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II-IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml (or B-type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT-proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate <25 ml/min/1.73 m2 or serum potassium >5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. CONCLUSIONS: The FINEARTS-HF trial will determine the efficacy and safety of the non-steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04435626 and EudraCT 2020-000306-29.
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Insuficiencia Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/fisiología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Naftiridinas/uso terapéutico , Masculino , Femenino , Método Doble Ciego , Persona de Mediana Edad , Resultado del Tratamiento , Anciano , Función Ventricular Izquierda/fisiología , Función Ventricular Izquierda/efectos de los fármacosAsunto(s)
Albuminuria , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Naftiridinas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Masculino , Nefropatías Diabéticas/complicaciones , Persona de Mediana Edad , Naftiridinas/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Anciano , FemeninoAsunto(s)
Diabetes Mellitus Tipo 2 , Naftiridinas , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Naftiridinas/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/terapiaRESUMEN
Azacitidine/venetoclax is an active regimen in patients with newly diagnosed acute myeloid leukemia (AML). However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/ venetoclax in relapsed/refractory AML, we conducted a phase I, multicenter, open-label study in 16 adults with relapsed/ refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at doses of 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission in five of seven (71.4%) patients who had not previously been treated with the hypomethylating agent/venetoclax. No measurable residual disease was detected in 80.0% of the patients who achieved complete remission. The median time to best response was 50 (range, 23-77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).
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Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Pirimidinas , Sulfonamidas , Humanos , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Azacitidina/administración & dosificación , Azacitidina/uso terapéutico , Azacitidina/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Naftiridinas/uso terapéutico , Naftiridinas/administración & dosificación , Recurrencia , Resultado del Tratamiento , Resistencia a Antineoplásicos , Anciano de 80 o más Años , CiclopentanosRESUMEN
OBJECTIVES: This study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or sex. DESIGN: FIDELITY post hoc analysis; median follow-up of 3 years. SETTING: FIDELITY: a prespecified analysis of the FIDELIO-DKD and FIGARO-DKD trials. PARTICIPANTS: Adults with type 2 diabetes and chronic kidney disease receiving optimised renin-angiotensin system inhibitors (N=13 026). INTERVENTIONS: Randomised 1:1; finerenone or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: Cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure (HHF)) and kidney (kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline or renal death) composite outcomes. RESULTS: Mean age was 64.8 years; 45.2%, 40.1% and 14.7% were aged <65, 65-74 and ≥75 years, respectively; 69.8% were male. Cardiovascular benefits of finerenone versus placebo were consistent across age (HR 0.94 (95% CI 0.81 to 1.10) (<65 years), HR 0.84 (95% CI 0.73 to 0.98) (65-74 years), HR 0.80 (95% CI 0.65 to 0.99) (≥75 years); Pinteraction=0.42) and sex categories (HR 0.86 (95% CI 0.77 to 0.96) (male), HR 0.89 (95% CI 0.35 to 2.27) (premenopausal female), HR 0.87 (95% CI 0.73 to 1.05) (postmenopausal female); Pinteraction=0.99). Effects on HHF reduction were not modified by age (Pinteraction=0.70) but appeared more pronounced in males (Pinteraction=0.02). Kidney events were reduced with finerenone versus placebo in age groups <65 and 65-74 but not ≥75; no heterogeneity in treatment effect was observed (Pinteraction=0.51). In sex subgroups, finerenone consistently reduced kidney events (Pinteraction=0.85). Finerenone reduced albuminuria and eGFR decline regardless of age and sex. Hyperkalaemia increased with finerenone, but discontinuation rates were <3% across subgroups. Gynaecomastia in males was uncommon across age subgroups and identical between treatment groups. CONCLUSIONS: Finerenone improved cardiovascular and kidney composite outcomes with no significant heterogeneity between age and sex subgroups; however, the effect on HHF appeared more pronounced in males. Finerenone demonstrated a similar safety profile across age and sex subgroups. TRIAL REGISTRATION NUMBERS: NCT02540993, NCT02545049.
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Insuficiencia Cardíaca/complicaciones , Riñón , Naftiridinas/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicacionesRESUMEN
BACKGROUND: The mineralocorticoid receptor plays an important pathophysiological role in cardiorenal diseases by causing inflammation and fibrosis. Mineralocorticoid receptor antagonists (MRAs) are well known in treating cardiovascular disease and diverse nephropathies. However, the first-generation MRA (spironolactone) and the second-generation MRA (eplerenone) remain underutilized because of the risk of inducing severe adverse events. As a selective nonsteroidal MRA, finerenone is safer and more effective and improves cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). However, the effect of finerenone on cardiorenal outcomes in patients of different races and kidney function (estimated glomerular filtration rate) is unclear. SUMMARY: In this review, we summarized the impact of finerenone on patients with CKD and T2DM from randomized controlled trials. The synthesis of published data aims to address the questions pertaining to the cardiorenal benefits of finerenone among various racial groups and different levels of kidney function. KEY MESSAGE: Finerenone presents racial differences and effects associated with kidney function in CKD and T2DM patients. Due to the limited data for subgroups, it is prudent to approach the conclusion with caution.
Asunto(s)
Tasa de Filtración Glomerular , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Insuficiencia Renal Crónica , Humanos , Naftiridinas/uso terapéutico , Naftiridinas/farmacología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Riñón/fisiopatología , Riñón/efectos de los fármacos , Grupos RacialesRESUMEN
Chronic kidney disease (CKD) is a prevalent complication of Type II diabetes (T2D). The coexistence of CKD with T2D is comparable to cardiovascular disease (CVD) when the estimated glomerular filtration rate declines below 60 ml/min/1.73 m2. Screening and early detection of people with high risk for CKD would be beneficial in managing CKD progress and the associated complications such as CV complications. Renin-angiotensin-aldosterone system inhibitors (RAASi) have demonstrated beneficial effects in delaying CKD progression, but they carry the risk of hyperkalemia. Nonsteroidal mineralocorticoid antagonists (nsMRA), such as finerenone, exhibit considerable efficacy in their anti-inflammatory, antifibrotic, and renal protective effects with demonstrable reductions in CV complications. In addition, nsMRAs do not cause significant changes in serum potassium levels compared to traditional steroidal MRA. Ongoing research explores the capacity of the sodium-glucose transport protein 2 inhibitors (SGLT-2i), combined with nsMRA, to produce synergistic renal protective effects and reduce the risk of hyperkalemia. Also, a dedicated renal outcomes study (FLOW study) involving a once-weekly injectable Glucagon-like peptide-1 receptor agonist, semaglutide, was halted early by the data monitoring committee due to having achieved the predefined efficacy endpoint and considerations related to renal disease. In CKD patients with T2D on nsMRA, hyperkalemia management requires a comprehensive approach involving lifestyle adjustments, dietary modifications, regular serum potassium level monitoring, and potassium binders, if necessary. Withholding or down-titration of nsMRAs with close monitoring of serum potassium levels may be required in patients with concerning potassium levels. In light of the current state of knowledge, this review article explores the perspectives and approaches that HCPs may consider when monitoring and managing hyperkalemia in CKD patients with T2D.
Chronic Kidney Disease (CKD) is a common and serious problem among people with Type II Diabetes (T2D). People who have CKD with T2D are at a higher risk for heart disease after normal kidney function declines below certain levels. Renin-angiotensin-aldosterone system inhibitors are a group of medications that can help delay CKD progression but may cause a rise in circulating potassium levels. Nonsteroidal mineralocorticoid antagonist (nsMRA), such as finerenone, can reduce kidney inflammation and damage, with noted cardiovascular benefits, and with less effect on serum potassium levels as compared to their steroid-based counterparts. Researchers are studying whether combining blood sugar medications such as sodium-glucose transport protein-2 inhibitors (SGLT-2i) and finerenone can help protect the kidneys and heart. They also want to see if this combination can prevent high potassium levels. This article talks about ways to check and monitor potassium levels in CKD patients with T2D who may be taking nsMRA. To manage high potassium levels in people with CKD and T2D, doctors may suggest lifestyle changes, dietary adjustments, potassium-lowering medication, or adjustment of other medications with close monitoring of potassium levels.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hiperpotasemia , Antagonistas de Receptores de Mineralocorticoides , Insuficiencia Renal Crónica , Humanos , Hiperpotasemia/etiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Naftiridinas/uso terapéutico , Naftiridinas/administración & dosificaciónRESUMEN
Approved therapies for hepatitis B virus (HBV) treatment include nucleos(t)ides and interferon alpha (IFN-α) which effectively suppress viral replication, but they rarely lead to cure. Expression of viral proteins, especially surface antigen of the hepatitis B virus (HBsAg) from covalently closed circular DNA (cccDNA) and the integrated genome, is believed to contribute to the persistence of HBV. This work focuses on therapies that target the expression of HBV proteins, in particular HBsAg, which differs from current treatments. Here we describe the identification of AB-452, a dihydroquinolizinone (DHQ) analogue. AB-452 is a potent HBV RNA destabilizer by inhibiting PAPD5/7 proteins in vitro with good in vivo efficacy in a chronic HBV mouse model. AB-452 showed acceptable tolerability in 28-day rat and dog toxicity studies, and a high degree of oral exposure in multiple species. Based on its in vitro and in vivo profiles, AB-452 was identified as a clinical development candidate.
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Virus de la Hepatitis B , Hepatitis B Crónica , Ratones , Ratas , Animales , Perros , Virus de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B , Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , ARN Viral/genética , Relación Estructura-Actividad , Naftiridinas/farmacología , Naftiridinas/uso terapéutico , ADN Viral/genética , Replicación ViralRESUMEN
BACKGROUND: The most common cause of chronic kidney disease (CKD) is diabetic nephropathy (DN). Primarilymineralocorticoid receptor antagonists (MRAs) (spironolactone and eplerenone), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used for the treatment of CKD, but due to the high risk of hyperkalaemia, the combination was infrequently used. Currently after approval by FDA in 2021, finerenone was found to be effective in the treatment of CKD. Finerenone slowdowns the progression of diabetic nephropathy and lessens the cardiovascular morbidity in DN patients. OBJECTIVE: The main objective of this review article is to provide a comprehensive and insightful overview of the role of finerenone by mainly focusing on its pharmacological properties, toxicity, uses, bioanalytical technique used for determination, and treatment options. MATERIALS AND METHOD: Finerenone works by inhibiting the action of the mineralocorticoid receptor. Finerenone is quickly absorbed from the digestive tract after oral treatment and achieves peak plasma concentrations in 1-2 hours. RESULT: Finerenone is actively metabolized through oxidation, epoxidation substitution, and direct hydroxylation. Elimination of finerenone is done through urine and feces. Determination of finerenone can be done through HPLC-MS and LSC. CONCLUSION: The present review covers the complete picture of ADME properties, bioanalytical techniques, clinical trials, toxicity, and possible avenues in this arena. Finerenone is effective compared to other mineralocorticoid receptor-like spironolactone and eplerenone, for the treatment of chronic kidney disease.
Asunto(s)
Descubrimiento de Drogas , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Insuficiencia Renal Crónica , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Naftiridinas/uso terapéutico , Naftiridinas/farmacología , Naftiridinas/farmacocinética , Descubrimiento de Drogas/métodos , Animales , Nefropatías Diabéticas/tratamiento farmacológicoRESUMEN
Kidney disease frequently coexists with cardiovascular (CV) diseases, and this dual presence significantly amplifies the risk of adverse clinical outcomes. Shared pathophysiological mechanisms and common CV risk factors contribute to the increased expression of mineralocorticoid receptors, which in turn can drive the progression of chronic CV-kidney disorders. The steroidal mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have demonstrated efficacy in improving patient outcomes in cases of heart failure with reduced ejection fraction or after a myocardial infarction, but have limited value in patients with chronic kidney disease. The non-steroidal MRA finerenone has now established itself as a foundational guideline-recommended therapy in patients with diabetic kidney disease. To date, these pharmacological agents have been developed in distinct patient populations. The consequences of their distinct pharmacological profiles necessitate further consideration. They have not undergone testing across the entire spectrum of cardiorenal scenarios, and the evidence base is currently being complemented with ongoing trials. In this review, we aim to synthesize the existing body of evidence and chart the future trajectory for the use of spironolactone, eplerenone and finerenone in improving clinical outcomes across the diverse spectrum of cardiorenal diseases. By consolidating the current state of knowledge, we seek to provide valuable insights for informed decision making in the management of patients with these complex and interconnected conditions.
Asunto(s)
Eplerenona , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Espironolactona , Humanos , Espironolactona/uso terapéutico , Espironolactona/análogos & derivados , Eplerenona/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Naftiridinas/uso terapéutico , Síndrome Cardiorrenal/tratamiento farmacológicoRESUMEN
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.