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Rodríguez‐Ruiz L, Lozano‐Gil JM, Ocaña‐Esparza M, Conesa‐Hernández AM, Pérez‐Oliva AB, Fuster JL, Jérez A, Murillo‐Sanjuán L, Díaz‐de‐Heredia C, López‐de‐Hontanar G, Sevilla J, García‐Moreno D, Cayuela ML, Martínez‐López A, Tyrkalska SD, Mulero V. Spironolactone inhibits the NLRP1 inflammasome and alleviates defective erythropoiesis in Diamond-Blackfan anemia. Hemasphere 2025; 9:e70131. [PMID: 40248129 PMCID: PMC12005213 DOI: 10.1002/hem3.70131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 02/18/2025] [Accepted: 03/25/2025] [Indexed: 04/19/2025] Open
Affiliation(s)
- Lola Rodríguez‐Ruiz
- Departmento de Biología Celular e HistologíaFacultad de Biología, Universidad de MurciaMurciaSpain
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
| | - Juan M. Lozano‐Gil
- Departmento de Biología Celular e HistologíaFacultad de Biología, Universidad de MurciaMurciaSpain
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
| | - María Ocaña‐Esparza
- Departmento de Biología Celular e HistologíaFacultad de Biología, Universidad de MurciaMurciaSpain
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
| | - Ana M. Conesa‐Hernández
- Departmento de Biología Celular e HistologíaFacultad de Biología, Universidad de MurciaMurciaSpain
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
| | - Ana B. Pérez‐Oliva
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
| | - José L. Fuster
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Sección de Oncohematología Pediátrica, Servicio de PediatríaHospital Clínico Universitario Virgen de la ArrixacaMurciaSpain
| | - Andrés Jérez
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
- Departamento de Hematología y Oncología ClínicaCentro Regional de Hemodonación, Hospital General Universitario Morales MeseguerMurciaSpain
| | - Laura Murillo‐Sanjuán
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
- Servicio de Oncología y Hematología Pediátricas. Hospital Universitario Vall d'HebronBarcelonaSpain
| | - Cristina Díaz‐de‐Heredia
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
- Servicio de Oncología y Hematología Pediátricas. Hospital Universitario Vall d'HebronBarcelonaSpain
| | - Guzmán López‐de‐Hontanar
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
- Departamento de Hematología y Oncología PediátricaHospital Infantil Universitario Niño JesúsMadridSpain
| | - Julián Sevilla
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
- Departamento de Hematología y Oncología PediátricaHospital Infantil Universitario Niño JesúsMadridSpain
| | - Diana García‐Moreno
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
| | - María L. Cayuela
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
- Sección de Cirugía General, Hospital Clínico Universitario Virgen de la ArrixacaMurciaSpain
| | - Alicia Martínez‐López
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
| | - Sylwia D. Tyrkalska
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
| | - Victoriano Mulero
- Departmento de Biología Celular e HistologíaFacultad de Biología, Universidad de MurciaMurciaSpain
- Instituto Murciano de Investigación Biosanitaria (IMIB)‐Pascual ParrillaMurciaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos IIIMadridSpain
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Sosnowska A, Chojnacki J, Samaszko-Fiertek J, Madaj J, Dmochowska B. Crystal Structures of d-Lyxono-1,4-lactone and Its O-Tosyl Derivative. Molecules 2025; 30:287. [PMID: 39860157 PMCID: PMC11767691 DOI: 10.3390/molecules30020287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/10/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
γ- and δ-lactones were formed by bromine oxidation of commercially available D-lyxose, as confirmed by IR analysis. The former was isolated, and its structure was confirmed by NMR spectra and X-ray analysis. In this structure, the presence of both intermolecular and intramolecular hydrogen bonds was found. Intermolecular interactions in the crystal were illustrated using the Hirshfeld surfaces. Due to steric reasons, 3,5-O-isopropylidene-d-lyxono-1,4-lactone was formed, which in a further step led to the formation of a 2-O-tosyl derivative. Its structure was confirmed by X-ray diffraction analysis. The additional ring of the O-isopropylidene derivative caused the lactone ring to change conformation to 3E. In the crystal structure of this compound, only C-H⸱⸱⸱O intermolecular interactions were present, as confirmed by the Hirshfeld surface analysis.
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Affiliation(s)
- Anna Sosnowska
- Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (A.S.); (J.S.-F.)
| | - Jarosław Chojnacki
- Department of Inorganic Chemistry, GdańskTech, G. Narutowicza 11/12, 80-233 Gdansk, Poland;
| | - Justyna Samaszko-Fiertek
- Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (A.S.); (J.S.-F.)
| | - Janusz Madaj
- Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (A.S.); (J.S.-F.)
| | - Barbara Dmochowska
- Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (A.S.); (J.S.-F.)
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Pradhan A, Tripathi UC. Finerenone: a breakthrough mineralocorticoid receptor antagonist for heart failure, diabetes and chronic kidney disease. Egypt Heart J 2024; 76:159. [PMID: 39680348 PMCID: PMC11649598 DOI: 10.1186/s43044-024-00586-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 11/13/2024] [Indexed: 12/17/2024] Open
Abstract
Background Aldosterone is categorized as a mineralocorticoid hormone produced in the zona glomerulosa of the adrenal cortex. Aldosterone has considerable action in sodium and water retention along with cardiac remodeling, promoting fibrosis and these detrimental effects have been counteracted by mineralocorticoid receptors antagonists over time. Spironolactone, a non-selective steroidal MRA used extensively is potent but has serious adverse effects like gynecomastia and hyperkalemia. Eplerenone another second generation MRA, though non-steroidal and selective causes hyperkalemia and adversely effecting renal functions. Main body Recently Finerenone- a novel MRA has been introduced which is as potent like spironolactone with less adverse effects and improved cardiovascular outcomes particularly in chronic kidney failure with diabetes. The article reviews the physical and chemical properties of Finerenone and compares it with MRAs already in use, and then about the patient specific uses of Finerenone and future avenues of it. Finerenone is non-steroidal selective MRA, with promising results in improving the deterioration of renal functions in CKD with DM, reducing albuminuria with less hyperkalemia along with improvement in cardiovascular outcomes by reducing heart failure events. Conclusion Mineralocorticoid receptor antagonists have a proven role in preventing the adverse effects of RAAS pathway on heart, kidneys and blood vessels. Non-selective steroidal MRAs have potent action but by virtue of their non-selectivity associated with adverse effects like gynecomastia, hirsutism along with hyperkalemia Finerenone is novel non-steroidal & highly selective MRA, with promising results in halting the deterioration of renal functions in CKD with DM, reducing albuminuria, improvement in cardiovascular outcomes by reducing heart failure events albeit with less hyperkalemia. More randomized studies in dedicated HF patients are ongoing with Finerenone to prove it is worth in this sector with huge unmet need despite GDMT. Finerenone alleviates the risk of adverse renal and cardiac outcomes in patients with diabetes and CKD despite baseline medical therapy.
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Affiliation(s)
- Akshyaya Pradhan
- Department of Cardiology, King George’s Medical University, Lucknow, Uttar Pradesh 226003 India
| | - Umesh Chandra Tripathi
- Department of Cardiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014 India
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Ferreira JP, Pitt B, Zannad F. Mineralocorticoid Receptor Antagonists in Heart Failure: An Update. Circ Heart Fail 2024; 17:e011629. [PMID: 39584253 DOI: 10.1161/circheartfailure.124.011629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 10/11/2024] [Indexed: 11/26/2024]
Abstract
Spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA), has been used to treat patients with heart failure (HF) for more than half a century. Spironolactone improved outcomes in patients with severely symptomatic HF with reduced ejection fraction, and later, eplerenone expanded the benefits to patients with mildly symptomatic HF with reduced ejection fraction and myocardial infarction complicated by HF. Spironolactone reduced HF events in some patients with HF with preserved ejection fraction, but the results were not generalizable to all patients with HF with preserved ejection fraction. More recently, the nonsteroidal MRA finerenone improved the HF outcomes of patients with HF with preserved ejection fraction, expanding the benefits previously seen among patients with diabetes and albuminuric chronic kidney disease. The use of MRAs has been limited due to excessive concern about hyperkalemia. Education about the limited true risk associated with hyperkalemia, and about how to predict, prevent, and manage hyperkalemia, may lead to wider acceptability and use of these agents. Several ongoing trials are testing steroidal and nonsteroidal MRAs in HF populations. In this review, we perform a critical appraisal of MRA use in HF populations and point toward future directions.
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Affiliation(s)
- João Pedro Ferreira
- Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Centre - UnIC@RISE, Faculty of Medicine of the University of Porto, Portugal (J.P.F.)
- Heart Failure Clinic, Internal Medicine Department, Unidade Local de Saude de Gaia/Espinho, Gaia, Portugal (J.P.F.)
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, Nancy, France (J.P.F., F.Z.)
| | - Bertram Pitt
- University of Michigan School of Medicine, Ann Arbor (B.P.)
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, Nancy, France (J.P.F., F.Z.)
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de la Puente-Aldea J, Lopez-Llanos O, Horrillo D, Marcos-Sanchez H, Sanz-Ballesteros S, Franco R, Jaisser F, Senovilla L, Palacios-Ramirez R. Mineralocorticoid Receptor and Sleep Quality in Chronic Kidney Disease. Int J Mol Sci 2024; 25:12320. [PMID: 39596384 PMCID: PMC11594958 DOI: 10.3390/ijms252212320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
The classical function of the mineralocorticoid receptor (MR) is to maintain electrolytic homeostasis and control extracellular volume and blood pressure. The MR is expressed in the central nervous system (CNS) and is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as sleep physiology, playing a role in the non-rapid eye movement (NREM) phase of sleep. Some patients with psychiatric disorders have very poor sleep quality, and a relationship between MR dysregulation and this disorder has been found in them. In addition, the MR is involved in the regulation of the renal peripheral clock. One of the most common comorbidities observed in patients with chronic kidney disease (CKD) is poor sleep quality. Patients with CKD experience sleep disturbances, including reduced sleep duration, sleep fragmentation, and insomnia. To date, no studies have specifically investigated the relationship between MR activation and CKD-associated sleep disturbances. However, in this review, we analyzed the environment that occurs in CKD and proposed two MR-related mechanisms that may be responsible for these sleep disturbances: the circadian clock disruption and the high levels of MR agonist observed in CKD.
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Affiliation(s)
- Juan de la Puente-Aldea
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
| | - Oscar Lopez-Llanos
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
| | - Daniel Horrillo
- Facultad de ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Spain; (D.H.); (R.F.)
| | | | | | - Raquel Franco
- Facultad de ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Spain; (D.H.); (R.F.)
| | - Frederic Jaisser
- INSERM U1166, Team Diabetes, Metabolic Diseases and Comorbidities, Sorbonne Université, 75013 Paris, France;
- INSERM UMR 1116, Centre d’Investigations Cliniques-Plurithématique 1433, Université de Lorraine, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, 54500 Nancy, France
| | - Laura Senovilla
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
- INSERM U1138, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Sorbonne Université, Institut Universitaire de France, 75006 Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Roberto Palacios-Ramirez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
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Wei FF, Pellicori P, Ferreira JP, González A, Mariottoni B, An DW, Verdonschot JAJ, Liu C, Ahmed FZ, Petutschnigg J, Rossignol P, Heymans S, Cuthbert J, Girerd N, Clark AL, Li Y, Nawrot TS, Díez J, Zannad F, Cleland JGF, Staessen JA. Effects of spironolactone on exercise blood pressure in patients at increased risk of developing heart failure: report from the HOMAGE trial. Hypertens Res 2024; 47:3225-3236. [PMID: 39242826 PMCID: PMC11534698 DOI: 10.1038/s41440-024-01843-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/13/2024] [Accepted: 07/23/2024] [Indexed: 09/09/2024]
Abstract
None of the spironolactone trials in heart failure (HF) assessed the blood pressure (BP) responses to exercise, while conflicting results were reported for exercise capacity. In the HOMAGE trial, 527 patients at increased HF risk were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current substudy included 113 controls and 114 patients assigned spironolactone, who all completed the incremental shuttle walk test at baseline and months 1 and 9. Quality of life (QoL) was assessed by EQ5D questionnaire. Between-group differences (spironolactone minus control [Δs]) were analyzed by repeated measures ANOVA with adjustment for baseline and, if appropriate, additionally for sex, age and body mass index. Δs in the pre-exercise systolic/diastolic BP were -8.00 mm Hg (95% CI, -11.6 to -4.43)/-0.85 mm Hg (-2.96 to 1.26) at month 1 and -9.58 mm Hg (-14.0 to -5.19)/-3.84 mm Hg (-6.22 to -1.47) at month 9. Δs in the post-exercise systolic/diastolic BP were -8.08 mm Hg (-14.2 to -2.01)/-2.07 mm Hg (-5.79 to 1.65) and -13.3 mm Hg (-19.9 to -6.75)/-4.62 mm Hg (-8.07 to -1.17), respectively. For completed shuttles, Δs at months 1 and 9 were 2.15 (-0.10 to 4.40) and 2.49 (-0.79 to 5.67), respectively. Δs in QoL were not significant. The correlations between the exercise-induced BP increases and the number of completed shuttles were similar in both groups. In conclusion, in patients at increased risk of developing HF, spironolactone reduced the pre- and post-exercise BP, but did not improve exercise capacity or QoL.
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Affiliation(s)
- Fang-Fei Wei
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium
| | - Pierpaolo Pellicori
- Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK
| | - João Pedro Ferreira
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto Portugal, Porto, Portugal
- Portugal Heart Failure Clinics, Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
| | - Arantxa González
- Program of Cardiovascular Diseases, CIMA. Universidad de Navarra and IdiSNA, Pamplona, Spain CIBERCV, Carlos III Institute of Health, Madrid, Spain
| | | | - De-Wei An
- Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium
- Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Job A J Verdonschot
- Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Chen Liu
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Fozia Z Ahmed
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Johannes Petutschnigg
- Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité University Medicine Berlin, Berlin Institute of Health and German Center for Cardiovascular Research, Partner Site Berlin, Berlin, Germany
| | - Patrick Rossignol
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Stephane Heymans
- Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Joe Cuthbert
- Department of Cardiology, University of Hull, Castle Hill Hospital, Cottingham, East Riding of Yorkshire, Hull, UK
| | - Nicolas Girerd
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Andrew L Clark
- Department of Cardiology, University of Hull, Castle Hill Hospital, Cottingham, East Riding of Yorkshire, Hull, UK
| | - Yan Li
- Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Tim S Nawrot
- Research Unit Environment and Health, KU Leuven Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium
- Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Javier Díez
- Program of Cardiovascular Diseases, CIMA. Universidad de Navarra and IdiSNA, Pamplona, Spain CIBERCV, Carlos III Institute of Health, Madrid, Spain
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France
| | - John G F Cleland
- Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK
| | - Jan A Staessen
- Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium.
- Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Biomedical Science Group, University of Leuven, Leuven, Belgium.
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Sabina M, Trube J, Shah S, Lurie A, Grimm M, Bizanti A. Finerenone: A Third-Generation MRA and Its Impact on Cardiovascular Health-Insights from Randomized Controlled Trials. J Clin Med 2024; 13:6398. [PMID: 39518537 PMCID: PMC11547165 DOI: 10.3390/jcm13216398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/17/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction: Finerenone, a third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), offers a targeted approach to managing cardiovascular outcomes, particularly in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). Unlike traditional MRAs such as spironolactone and eplerenone, which can cause off-target hormonal side effects and hyperkalemia, Finerenone selectively binds to mineralocorticoid receptors, reducing these risks. Recent randomized controlled trials have demonstrated Finerenone's potential to improve cardiovascular outcomes, making it a promising alternative in the management of heart failure and other cardiovascular conditions associated with CKD and T2D. Methods: We conducted a scoping review using PRISMA guidelines. A search for "Finerenone" in the PubMed, Embase, and Cochrane Library databases included randomized controlled trials (RCTs), post hoc analyses, and relevant meta-analyses on cardiovascular outcomes. Data were synthesized narratively, assessing study quality through strengths and limitations. Discussion: Finerenone has shown significant benefits and a superior safety profile compared with traditional MRAs like spironolactone and eplerenone in managing CKD, T2D, and heart failure. It effectively reduces cardiovascular and renal events while minimizing risks such as hyperkalemia and hormonal side effects associated with steroidal MRAs. Future studies, including the REDEFINE-HF, FINALITY-HF, and CONFIRMATION-HF trials, will further explore Finerenone's potential across diverse heart failure phenotypes, including its role in heart failure with mildly reduced and preserved ejection fractions, potentially establishing it as a cornerstone therapy in heart failure management. Conclusions: Finerenone represents a significant advancement in MRA therapy, offering enhanced safety and efficacy in managing cardiovascular outcomes in CKD and T2D patients. The current evidence supports its use as a promising alternative to traditional MRAs, particularly in patients intolerant to steroidal MRAs. Further trials are needed to fully establish its potential across diverse patient populations, including those with varying heart failure phenotypes.
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Affiliation(s)
- Michael Sabina
- Lakeland Regional Health Medical Center, Lakeland, FL 33805, USA; (J.T.); (S.S.); (A.L.); (M.G.); (A.B.)
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Hu JR, Schwann AN, Tan JW, Nuqali A, Riello RJ, Beasley MH. Sequencing Quadruple Therapy for Heart Failure with Reduced Ejection Fraction: Does It Really Matter? Heart Fail Clin 2024; 20:373-386. [PMID: 39216923 DOI: 10.1016/j.hfc.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
The conventional sequence of guideline-directed medical therapy (GDMT) initiation in heart failure with reduced ejection fraction (HFrEF) assumes that the effectiveness and tolerability of GDMT agents mirror their order of discovery, which is not true. In this review, the authors discuss flexible GDMT sequencing that should be permitted in special populations, such as patients with bradycardia, chronic kidney disease, or atrial fibrillation. Moreover, the initiation of certain GDMT medications may enable tolerance of other GDMT medications. Most importantly, the achievement of partial doses of all four pillars of GDMT is better than achievement of target dosing of only a couple.
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Affiliation(s)
- Jiun-Ruey Hu
- Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, CT 06520, USA. https://twitter.com/ruey_hu
| | - Alexandra N Schwann
- Department of Internal Medicine, Yale New Haven Hospital, P.O. Box 208030, New Haven, CT, 06520-8030, USA. https://twitter.com/aschwann212
| | - Jia Wei Tan
- Division of Nephrology, Stanford University School of Medicine, 780 Welch Road, Palo Alto, CA 94304, USA. https://twitter.com/jiiiiawei
| | - Abdulelah Nuqali
- Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, CT 06520, USA. https://twitter.com/AbdulelahNuqali
| | - Ralph J Riello
- Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, CT 06520, USA. https://twitter.com/ralphadelta
| | - Michael H Beasley
- Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, CT 06520, USA.
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Upadhyay A, Haider L. Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease: Clinical Evidence and Potential Adverse Events. Clin Diabetes 2024; 43:43-52. [PMID: 39829701 PMCID: PMC11739366 DOI: 10.2337/cd24-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) globally and is associated with an increased risk of developing cardiovascular disease (CVD). DKD management requires a multipronged approach to decrease the progression of CKD and CVD. Mineralocorticoid receptor antagonists (MRAs) added to renin-angiotensin-aldosterone system blockade and sodium-glucose cotransporter 2 inhibitor therapy reduce the incidence of cardiovascular outcomes and progression of CKD. This review examines the cardiorenal benefits of MRAs and summarizes evidence on potential risks for acute kidney injury, hyperkalemia, and sexual dysfunction for steroidal and nonsteroidal MRAs.
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Affiliation(s)
- Ashish Upadhyay
- Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA
| | - Lalarukh Haider
- UConn Health, University of Connecticut School of Medicine, Farmington, CT
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10
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Elshahat A, Mansour A, Ellabban M, Diaa A, Hassan A, Fawzy A, Saad OA, Abouelmagd M, Eid M, Elaraby A, Elkasaby MH, Abdelaziz A. Comparative effectiveness and safety of eplerenone and spironolactone in patients with heart failure: a systematic review and meta-analysis. BMC Cardiovasc Disord 2024; 24:489. [PMID: 39271992 PMCID: PMC11395778 DOI: 10.1186/s12872-024-04103-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/07/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND Eplerenone and spironolactone, recognized as mineralocorticoid receptor antagonists (MRAs), have been reported to improve clinical prognosis among individuals diagnosed with heart failure (HF). However, the difference in the clinical effects between eplerenone and spironolactone in individuals with HF remains uncertain. We aimed to assess the impact of eplerenone compared to spironolactone on clinical outcomes within the HF population. METHODS An extensive search was executed in several databases (PubMed, Web of Science, Scopus, Cochrane Library). All relevant studies evaluating eplerenone compared to spironolactone in patients with HF were included. Dichotomous data were pooled as Hazard ratio (HR) or Risk ratio (RR) with a 95% confidence interval (CI). Our main outcome was all-cause mortality. Secondary outcomes included death from cardiovascular causes, treatment withdrawal, and gynecomastia. RESULTS Ten studies, comprising 21,930 HF individuals, were included in our investigation. Eplerenone showed a lower risk of all-cause mortality (HR = 0.78, 95%CI [0.64 to 0.94], P = 0.009) and cardiovascular mortality (HR = 0.54, 95%CI [0.39, 0.74], P = 0.0001) compared to spironolactone. Furthermore, eplerenone exhibited a reduced risk of treatment withdrawal (RR = 0.69, 95% CI [0.62, 0.78], P = 0.0001) and gynecomastia (RR = 0.07, 95% CI [0.02 to 0.31], P = 0.0001) than spironolactone. CONCLUSION Eplerenone revealed lower all-cause and cardiovascular mortality events in comparison to spironolactone. Moreover, eplerenone was associated with lower gynecomastia and treatment withdrawal events compared to spironolactone. Further well-designed randomized controlled trials are still warranted better to identify the clinical differences between eplerenone and spironolactone. TRIAL REGISTRATION Protocol registration: https://doi.org/10.17605/OSF.IO/VNMGK.
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Affiliation(s)
- Ahmed Elshahat
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA.
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
| | - Ahmed Mansour
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohamed Ellabban
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed Diaa
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Atef Hassan
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed Fawzy
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Omar Abdulrahman Saad
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Moaz Abouelmagd
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mahmoud Eid
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed Elaraby
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohamed Hamouda Elkasaby
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed Abdelaziz
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
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11
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Deng N, Zhong J, Deng Z, Chen M, Yan L, Li H, Han J, Tao E. Case report: A pregnant woman accidental treated with spironolactone in mid-gestation. Front Pharmacol 2024; 15:1404251. [PMID: 39119600 PMCID: PMC11306061 DOI: 10.3389/fphar.2024.1404251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
Spironolactone, a potassium-sparing diuretic, is used to treat hypertension, heart failure, and certain hyperandrogenic disorders. Its use during pregnancy is not recommended due to the risk of feminizing male fetuses, primarily because of its antiandrogenic activity. However, human data remain scarce and largely inconclusive. Here, we present the first case of a 25-year-old pregnant woman, at 16 weeks of gestation, who was inadvertently exposed to spironolactone (240 mg/day) for 1 week due to a pharmacy dispensing error. The patient subsequently delivered a healthy male infant with normal genitalia at 38 weeks of gestation following vaginal delivery. Current follow-up shows that the infant is healthy and developing normally. This article summarizes the potential causes of spironolactone-induced anomalous genital development and explores the safety of new-generation mineralocorticoid receptor antagonists (MRAs) during pregnancy. The mechanisms behind spironolactone-induced anomalous genital development in male fetuses have not been fully elucidated. Spironolactone competes with dihydrotestosterone for binding to androgen receptors and inhibits enzymes involved in androgen biosynthesis, which may partly explain its antiandrogenic effects. Recent advancements in MRAs have led to the development of compounds with higher selectivity for the mineralocorticoid receptor, thereby reducing the incidence of antiandrogen side effects. These new-generation MRAs may be effective alternatives during pregnancy, but more data are needed to establish their safety in pregnant women. This case contributes to the limited but growing body of literature on the safety profile of spironolactone in pregnancy, providing insights into its effects during a critical period of fetal development.
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Affiliation(s)
- Nianying Deng
- Department of Pharmacy, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
| | - Jiayi Zhong
- Department of Pharmacy, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
| | - Zhengjun Deng
- Department of Pharmacy, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
| | - Minling Chen
- Department of Maternity, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
| | - Liangqi Yan
- Department of Ultrasound, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
| | - Haiting Li
- Department of Neonatology and NICU, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
| | - Jiawei Han
- Department of Pharmacy, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
| | - Enfu Tao
- Department of Neonatology and NICU, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
- Department of Science and Education, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
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12
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Guan X, Yang Y, Li X, Feng Y, Li J, Li X. Analysis of eplerenone in the FDA adverse event reporting system (FAERS) database: a focus on overall patient population and gender-specific subgroups. Front Pharmacol 2024; 15:1417951. [PMID: 39086389 PMCID: PMC11288857 DOI: 10.3389/fphar.2024.1417951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/28/2024] [Indexed: 08/02/2024] Open
Abstract
Introduction: Eplerenone is approved for the treatment of hypertension as well as symptomatic heart failure with reduced ejection fraction (HFrEF) following an acute myocardial infarction. However, the adverse events (AEs) have not been systematically analyzed. The aim of this study was to identify adverse drug reactions (ADRs) related to eplerenone using the FDA Adverse Event Reporting System (FAERS) database. By identifying previously unreported AEs, the study could potentially contribute to updating the drug's label. Methods: In order to find significant AEs, four algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN) and Empirical Bayesian Geometric Mean (EBGM), were used to analyze the signal strength of the ADRs connected to eplerenone that were gathered from the FAERS database over the previous 20 years. Results: From 2004Q1 to 2023Q4, a total of 20, 629, 811 reported cases were gathered from the FAERS database for this study. After processing the data and filtering, 1,874 case reports were analyzed. Of these cases, 1,070 AEs were identified, 128 of which were eplerenone-related ADRs. We investigated the occurrence of ADRs induced by eplerenone in 27 organ systems. Our study showed that the AEs listed in the medication's package insert correspond with those listed in the literature, including hyperkalemia and increased creatinine. Additionally, the prescription label for eplerenone does not include all system organ class (SOC) terms, like Vascular disorders, hepatobiliary Disorders, etc. Discussion: The study used multiple algorithms to quantify the signal strength and then identified any previously unrecognized ADRs, further studies are needed to confirm the association of ADRs with eplerenone. The findings of this study may provide important insights into the safety profile of eplerenone, ensure that healthcare providers have up-to-date information about their potential risks and help guide them in the correct use of the drug.
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Affiliation(s)
- Xin Guan
- Department of Cardiology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Yusi Yang
- Department of Cardiology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Xinru Li
- Department of Cardiology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Yue Feng
- Department of Cardiology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Jizhen Li
- Second School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Xuewen Li
- Department of Cardiology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
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13
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Finsen SH, Hansen MR, Hansen PBL, Mortensen SP. Eight weeks of treatment with mineralocorticoid receptor blockade does not alter vascular function in individuals with and without type 2 diabetes. Physiol Rep 2024; 12:e16010. [PMID: 38610066 PMCID: PMC11014871 DOI: 10.14814/phy2.16010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 03/27/2024] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
Aldosterone has been suggested to be involved in the microvascular complications observed in type 2 diabetes. We aimed to investigate the effect of mineralocorticoid receptor (MR) blockade on endothelial function in individuals with type 2 diabetes compared to healthy controls. We included 12 participants with type 2 diabetes and 14 controls. We measured leg hemodynamics at baseline and during femoral arterial infusion of acetylcholine and sodium nitroprusside before and 8 weeks into treatment with MR blockade (eplerenone). Acetylcholine infusion was repeated with concomitant n-acetylcysteine (antioxidant) infusion. No difference in leg blood flow or vascular conductance was detected before or after the treatment with MR blockade in both groups and there was no difference between groups. Infusion of n-acetylcysteine increased baseline blood flow and vascular conductance, but did not change the vascular response to acetylcholine before or after treatment with MR blockade. Skeletal muscle eNOS content was unaltered by MR blockade and no difference between groups was detected. In conclusion, we found no effect of MR blockade endothelial function in individuals with and without type 2 diabetes. As the individuals with type 2 diabetes did not have vascular dysfunction, these results might not apply to individuals with vascular dysfunction.
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Affiliation(s)
- Stine H. Finsen
- Department of Cardiovascular and Renal Research, Institute of Molecular MedicineUniversity of Southern DenmarkOdenseDenmark
- Department of NephrologyOdense University HospitalOdenseDenmark
| | - Mie R. Hansen
- Department of Cardiovascular and Renal Research, Institute of Molecular MedicineUniversity of Southern DenmarkOdenseDenmark
| | - Pernille B. L. Hansen
- Department of Cardiovascular and Renal Research, Institute of Molecular MedicineUniversity of Southern DenmarkOdenseDenmark
| | - Stefan P. Mortensen
- Department of Cardiovascular and Renal Research, Institute of Molecular MedicineUniversity of Southern DenmarkOdenseDenmark
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14
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Zhou S, Liu Y, Huang X, Wu C, Pórszász R. Omecamtiv Mecarbil in the treatment of heart failure: the past, the present, and the future. Front Cardiovasc Med 2024; 11:1337154. [PMID: 38566963 PMCID: PMC10985333 DOI: 10.3389/fcvm.2024.1337154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 03/07/2024] [Indexed: 04/04/2024] Open
Abstract
Heart failure, a prevailing global health issue, imposes a substantial burden on both healthcare systems and patients worldwide. With an escalating prevalence of heart failure, prolonged survival rates, and an aging demographic, an increasing number of individuals are progressing to more advanced phases of this incapacitating ailment. Against this backdrop, the quest for pharmacological agents capable of addressing the diverse subtypes of heart failure becomes a paramount pursuit. From this viewpoint, the present article focuses on Omecamtiv Mecarbil (OM), an emerging chemical compound said to exert inotropic effects without altering calcium homeostasis. For the first time, as a review, the present article uniquely started from the very basic pathophysiology of heart failure, its classification, and the strategies underpinning drug design, to on-going debates of OM's underlying mechanism of action and the latest large-scale clinical trials. Furthermore, we not only saw the advantages of OM, but also exhaustively summarized the concerns in sense of its effects. These of no doubt make the present article the most systemic and informative one among the existing literature. Overall, by offering new mechanistic insights and therapeutic possibilities, OM has carved a significant niche in the treatment of heart failure, making it a compelling subject of study.
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Affiliation(s)
- Shujing Zhou
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ying Liu
- Department of Cardiology, Sixth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xufeng Huang
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Faculty of Dentistry, University of Debrecen, Debrecen, Hungary
| | - Chuhan Wu
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Róbert Pórszász
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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15
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Matta A, Ohlmann P, Nader V, Levai L, Kang R, Carrié D, Roncalli J. A review of the conservative versus invasive management of ischemic heart failure with reduced ejection fraction. Curr Probl Cardiol 2024; 49:102347. [PMID: 38103822 DOI: 10.1016/j.cpcardiol.2023.102347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 12/13/2023] [Indexed: 12/19/2023]
Abstract
Heart failure is increasing in terms of prevalence, morbidity, and mortality rates. Clinical trials and studies are focusing on heart failure as it is the destiny end-stage for several cardiovascular disorders. Recently, medical therapy has dramatically progressed with novel classes of medicines providing better quality of life and survival outcomes. However, heart failure remains a heavy impactful factor on societies and populations. Current guidelines from the American and European cardiac societies are not uniform with respect to the class and level of treatment recommendations for coronary artery disease patients with heart failure and reduced ejection fraction. The discrepancy among international recommendations, stemming from the lack of evidence from adequately powered randomized trials, challenges physicians in choosing the optimal strategy. Hybrid therapy including optimal medical therapy with revascularization strategies are commonly used for the management of ischemic heart failure. Coronary artery bypass graft (CABG) has proved its efficacy on improving long term outcome and prognosis while no large randomized clinical trials for percutaneous coronary intervention (PCI) are still available. Regardless of the lack of data and recommendations, the trends of performing PCI in ischemic heart failure prevailed over CABG whereas lesion complexity, chronic total occlusion and complete revascularization achievement are limiting factors. Lastly, regenerative medicine seems a promising approach for advanced heart failure enhancing cardiomyocytes proliferation, reverse remodeling, scar size reduction and cardiac function restoration.
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Affiliation(s)
- Anthony Matta
- Department of Cardiology, Civilian Hospital of Colmar, Colmar, France.
| | - Patrick Ohlmann
- Department of Cardiology, University Hospital of Strasbourg, Strasbourg, France
| | - Vanessa Nader
- Department of Cardiology, Civilian Hospital of Colmar, Colmar, France
| | - Laszlo Levai
- Department of Cardiology, Civilian Hospital of Colmar, Colmar, France
| | - Ryeonshi Kang
- Department of Cardiology, University Hospital of Toulouse, Toulouse, France
| | - Didier Carrié
- Department of Cardiology, University Hospital of Toulouse, Toulouse, France
| | - Jerome Roncalli
- Department of Cardiology, University Hospital of Toulouse, Toulouse, France
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16
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Ekman N, Grossman AB, Dworakowska D. What We Know about and What Is New in Primary Aldosteronism. Int J Mol Sci 2024; 25:900. [PMID: 38255973 PMCID: PMC10815558 DOI: 10.3390/ijms25020900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Primary aldosteronism (PA), a significant and curable cause of secondary hypertension, is seen in 5-10% of hypertensive patients, with its prevalence contingent upon the severity of the hypertension. The principal aetiologies of PA include bilateral idiopathic hypertrophy (BIH) and aldosterone-producing adenomas (APAs), while the less frequent causes include unilateral hyperplasia, familial hyperaldosteronism (FH) types I-IV, aldosterone-producing carcinoma, and ectopic aldosterone synthesis. This condition, characterised by excessive aldosterone secretion, leads to augmented sodium and water reabsorption alongside potassium loss, culminating in distinct clinical hallmarks: elevated aldosterone levels, suppressed renin levels, and hypertension. Notably, hypokalaemia is present in only 28% of patients with PA and is not a primary indicator. The association of PA with an escalated cardiovascular risk profile, independent of blood pressure levels, is notable. Patients with PA exhibit a heightened incidence of cardiovascular events compared to counterparts with essential hypertension, matched for age, sex, and blood pressure levels. Despite its prevalence, PA remains frequently undiagnosed, underscoring the imperative for enhanced screening protocols. The diagnostic process for PA entails a tripartite assessment: the aldosterone/renin ratio (ARR) as the initial screening tool, followed by confirmatory and subtyping tests. A positive ARR necessitates confirmatory testing to rule out false positives. Subtyping, achieved through computed tomography and adrenal vein sampling, aims to distinguish between unilateral and bilateral PA forms, guiding targeted therapeutic strategies. New radionuclide imaging may facilitate and accelerate such subtyping and localisation. For unilateral adrenal adenoma or hyperplasia, surgical intervention is optimal, whereas bilateral idiopathic hyperplasia warrants treatment with mineralocorticoid antagonists (MRAs). This review amalgamates established and emerging insights into the management of primary aldosteronism.
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Affiliation(s)
- Natalia Ekman
- Department of Hypertension & Diabetology, Medical University of Gdańsk, 80-214 Gdańsk, Poland;
| | - Ashley B. Grossman
- Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK;
| | - Dorota Dworakowska
- Department of Hypertension & Diabetology, Medical University of Gdańsk, 80-214 Gdańsk, Poland;
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Viggiano P, Boscia G, Borrelli E, Toto L, Grassi MO, Evangelista F, Giancipoli E, Alessio G, Boscia F. Choriocapillaris Reperfusion in Resolved Chronic Central Serous Chorioretinopathy Treated with Eplerenone: Long-Term Effects on the Fellow Eye. Ophthalmol Ther 2023; 12:3199-3210. [PMID: 37747638 PMCID: PMC10640459 DOI: 10.1007/s40123-023-00816-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 09/06/2023] [Indexed: 09/26/2023] Open
Abstract
INTRODUCTION The aim of this work is to utilize swept-source optical coherence tomography angiography (SS-OCTA) to assess the long-term changes in the choroidal and choriocapillaris (CC) layers of the fellow unaffected eye of patients with unilateral resolved chronic central serous chorioretinopathy (cCSC) following treatment with continuous oral eplerenone (EPL). METHODS The study included 35 patients with cCSC and subretinal fluid (SRF) in one eye. SS-OCTA imaging was performed on the fellow cCSC eyes at baseline, 6 months, and 12 months during eplerenone therapy. CC OCT angiography was analyzed to determine the percentage of choriocapillaris flow deficits (FD%), the number of flow deficits (FDn), and the average area of flow deficits (FDa). RESULTS The results demonstrated significant changes in CC flow deficits from baseline to follow-up visits. Specifically, there was a significant decrease in FD% from 28.9 ± 2.2% at baseline to 26.4 ± 1.9% at 6 months (p = 0.023), and further to 24.9 ± 1.7% at 12 months (p = 0.001). Additionally, the FD area gradually contracted over the follow-up period (p < 0.05). Conversely, there was a significant increase in the number of flow deficits compared to baseline (p < 0.05). No statistically significant changes were observed in best-corrected visual acuity (BCVA) at the follow-up visits (p > 0.05). CONCLUSIONS The findings of this study demonstrated long-term reperfusion of the choriocapillaris in unaffected fellow cCSC eyes during continuous oral eplerenone therapy. The beneficial effects of eplerenone therapy were observed after 6 months and maintained at 1 year. These results suggest that specific mineralocorticoid receptor (MR) antagonists may be effective in promoting choriocapillaris recovery in the unaffected eyes of patients with cCSC.
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Affiliation(s)
- Pasquale Viggiano
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Piazza Giulio Cesare, 11, Bari, Italy.
| | - Giacomo Boscia
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Piazza Giulio Cesare, 11, Bari, Italy
| | - Enrico Borrelli
- Ophthalmology Department, San Raffaele University Hospital, Milan, Italy
| | - Lisa Toto
- Department of Medicine and Science of Ageing, Ophthalmology Clinic, University G. D'Annunzio Chieti-Pescara, Chieti, Italy
| | - Maria Oliva Grassi
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Piazza Giulio Cesare, 11, Bari, Italy
| | - Federica Evangelista
- Department of Ophthalmology, Ente Ecclesiastico Ospedale Generale Regionale "F. Miulli", Acquaviva Delle Fonti, Bari, Italy
| | | | - Giovanni Alessio
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Piazza Giulio Cesare, 11, Bari, Italy
| | - Francesco Boscia
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Piazza Giulio Cesare, 11, Bari, Italy
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18
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Pince CL, Whiting KE, Wang T, Lékó AH, Farinelli LA, Cooper D, Farokhnia M, Vendruscolo LF, Leggio L. Role of aldosterone and mineralocorticoid receptor (MR) in addiction: A scoping review. Neurosci Biobehav Rev 2023; 154:105427. [PMID: 37858908 PMCID: PMC10865927 DOI: 10.1016/j.neubiorev.2023.105427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/24/2023] [Accepted: 10/13/2023] [Indexed: 10/21/2023]
Abstract
Preclinical and human studies suggest a role of aldosterone and mineralocorticoid receptor (MR) in addiction. This scoping review aimed to summarize (1) the relationship between alcohol and other substance use disorders (ASUDs) and dysfunctions of the aldosterone and MR, and (2) how pharmacological manipulations of MR may affect ASUD-related outcomes. Our search in four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) indicated that most studies focused on the relationship between aldosterone, MR, and alcohol (n = 30), with the rest focused on opioids (n = 5), nicotine (n = 9), and other addictive substances (n = 9). Despite some inconsistencies, the overall results suggest peripheral and central dysregulations of aldosterone and MR in several species and that these dysregulations depended on the pattern of drug exposure and genetic factors. We conclude that MR antagonism may be a promising target in ASUD, yet future studies are warranted.
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Affiliation(s)
- Claire L Pince
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA; Stress & Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA
| | - Kimberly E Whiting
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA
| | - Tammy Wang
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA
| | - András H Lékó
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA; Center on Compulsive Behaviors, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lisa A Farinelli
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA
| | - Diane Cooper
- Office of Research Services, Division of Library Services, National Institutes of Health, Building 10, Bethesda, MD 20892, USA
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA
| | - Leandro F Vendruscolo
- Stress & Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA.
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, USA.
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19
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Charbonnel C, Jagu A, Vannier C, De Cordoue M, Aroulanda MJ, Lozinguez O, Komajda M, Garcon P, Antakly-Hanon Y, Moeuf Y, Lesage JB, Mantes L, Midey C, Izabel M, Boukefoussa W, Manne J, Standish B, Duc P, Iliou MC, Cador R. [Introduction of treatments for heart failure and reduced ejection fraction under 50 % : In-hospital optimization using an algorithmic approach]. Ann Cardiol Angeiol (Paris) 2023; 72:101640. [PMID: 37677914 DOI: 10.1016/j.ancard.2023.101640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 09/09/2023]
Abstract
Recent international guidelines recommend rapid initiation and titration of basic treatments of heart failure but do not explain how to achieve this goal. Despite these recommendations, implementation of treatment in daily practice is poor. This may be partly explained by the profile of the patients (frailty, comorbidities), safety considerations and tolerability issues related to kydney function, low blood pressure or heart rate and hyperkalaemia. In this special article, we intended to help the physician, through an algorithmic approach, to quickly and safely introduce guideline-directed medical therapy in the field of heart failure with ejection fraction under 50%.
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Affiliation(s)
- Clément Charbonnel
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France.
| | - Annabelle Jagu
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Claire Vannier
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Maylis De Cordoue
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | | | - Olivier Lozinguez
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Michel Komajda
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Philippe Garcon
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Yara Antakly-Hanon
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Yoann Moeuf
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | | | - Lucie Mantes
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Charlotte Midey
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Mathilde Izabel
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Wahiba Boukefoussa
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Julien Manne
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Brigitte Standish
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Philippe Duc
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | | | - Romain Cador
- Service de Cardiologie, Groupe Hospitalier Paris Saint Joseph, Paris, France
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20
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Hu JR, Schwann AN, Tan JW, Nuqali A, Riello RJ, Beasley MH. Sequencing Quadruple Therapy for Heart Failure with Reduced Ejection Fraction: Does It Really Matter? Cardiol Clin 2023; 41:511-524. [PMID: 37743074 PMCID: PMC12070421 DOI: 10.1016/j.ccl.2023.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
The conventional sequence of guideline-directed medical therapy (GDMT) initiation in heart failure with reduced ejection fraction (HFrEF) assumes that the effectiveness and tolerability of GDMT agents mirror their order of discovery, which is not true. In this review, the authors discuss flexible GDMT sequencing that should be permitted in special populations, such as patients with bradycardia, chronic kidney disease, or atrial fibrillation. Moreover, the initiation of certain GDMT medications may enable tolerance of other GDMT medications. Most importantly, the achievement of partial doses of all four pillars of GDMT is better than achievement of target dosing of only a couple.
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Affiliation(s)
- Jiun-Ruey Hu
- Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, CT 06520, USA. https://twitter.com/ruey_hu
| | - Alexandra N Schwann
- Department of Internal Medicine, Yale New Haven Hospital, P.O. Box 208030, New Haven, CT, 06520-8030, USA. https://twitter.com/aschwann212
| | - Jia Wei Tan
- Division of Nephrology, Stanford University School of Medicine, 780 Welch Road, Palo Alto, CA 94304, USA. https://twitter.com/jiiiiawei
| | - Abdulelah Nuqali
- Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, CT 06520, USA. https://twitter.com/AbdulelahNuqali
| | - Ralph J Riello
- Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, CT 06520, USA. https://twitter.com/ralphadelta
| | - Michael H Beasley
- Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, CT 06520, USA.
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21
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Razavi SMS, Daneshvar R. Possible dose-dependent effect of eplerenone on intraocular pressure. Indian J Ophthalmol 2023; 71:3357-3360. [PMID: 37787235 PMCID: PMC10683679 DOI: 10.4103/ijo.ijo_175_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 05/20/2023] [Accepted: 06/08/2023] [Indexed: 10/04/2023] Open
Abstract
Purpose Intraocular pressure (IOP) is the main modifiable risk factor for glaucoma. Current therapies target the anterior outflow of aqueous humor or its production. This study aims to demonstrate eplerenone could reduce IOP through a possible posterior outflow path via retinal pigment epithelium (RPE). Methods In this retrospective study, IOP changes in patients undergoing eplerenone treatment were investigated. Inclusion criteria were IOP data immediately before and during treatment. Exclusion criteria included ophthalmic procedures, changes in topical glaucoma treatment, or taking systemic medications affecting IOP. After reviewing 162 charts, 41 subjects were eligible. Pearson correlation test was used to investigate the correlation between continuous IOP and eplerenone dosage. Results The mean ± SD IOP before eplerenone treatment was 14.31 ± 3.73 mmHg and decreased to 13.50 ± 4.04 mmHg; however, this was not statistically significant (P = 0.39). In subset of patients with eplerenone dose of more than 25 mg/day and baseline IOP equal to or less than 15 mmHg, the mean IOP before eplerenone treatment was 12.33 ± 2.59 mmHg and decreased to 10.33 ± 2.99, which is a trend toward IOP reduction with a 16% reduction in IOP (P = 0.055). Conclusion A possible dose-dependent decrease in IOP with eplerenone provides indirect evidence for the posterior flow model and suggests the mineralocorticoid receptors (MRs) in RPE play a role in the posterior flow of aqueous humor. It can be deduced that the RPE pumps responsible for the posterior flow of aqueous humor are MR-regulated and their function can be enhanced with MR antagonists.
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Affiliation(s)
| | - Ramin Daneshvar
- Department of Ophthalmology, University of Florida College of Medicine, Florida, USA
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22
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Shah M, Awad AS, Abdel-Rahman EM. Nonsteroidal Mineralocorticoid Receptor Antagonist (Finerenone) in Cardiorenal Disease. J Clin Med 2023; 12:6285. [PMID: 37834929 PMCID: PMC10573495 DOI: 10.3390/jcm12196285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/23/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Nonsteroidal mineralocorticoid receptor antagonists (MRAs) present a promising therapeutic option in cardiorenal diseases, mitigating the limitations of steroidal MRAs. Finerenone, a third-generation nonsteroidal MRA, has demonstrated beneficial effects in heart failure (HF) and chronic kidney disease (CKD). Clinical trials, including FIDELIO-DKD and FIGARO-DKD, revealed finerenone's efficacy in improving kidney and cardiovascular (CV) outcomes. Patients with CKD and type 2 diabetes (T2DM) on finerenone experienced reduced rates of cardiovascular events, including hospitalization for HF. However, these trials excluded symptomatic HF patients, focusing on asymptomatic or early-stage HF. The ongoing FINEARTS-HF trial evaluates finerenone in HF with preserved ejection fraction (HFpEF). Additionally, studies exploring finerenone and sodium-glucose cotransporter 2 (SGLT2) inhibitors' (Empagliflozin) combination effects in CKD and T2DM (CONFIDENCE) and the selective MR modulator AZD9977 with another SGLT2 inhibitor (dapagliflozin) in HF and CKD (MIRACLE) aim to expand treatment options. While SGLT-2 inhibitors were shown to reduce hyperkalemia risk in FIDELIO-DKD and potentially lower new-onset HF incidence in FIGARO-DKD, further research is essential. So far, the evidence for the beneficial effect of finerenone in the spectrum of cardiorenal diseases is based only on the results of studies conducted in patients with T2DM, and clinical trials of finerenone in patients with nondiabetic kidney disease are ongoing. Nonsteroidal MRAs hold significant potential as pivotal treatment targets across the cardiorenal disease spectrum. This review will focus on the effects of finerenone on cardiorenal disease.
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Affiliation(s)
- Monarch Shah
- Division of Nephrology, University of Virginia, Charlottesville, VA 22902, USA;
| | - Alaa S. Awad
- Division of Nephrology, University of Florida, Jacksonville, FL 32209, USA;
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23
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Larsson JE, Denholt CS, Thune JJ, Raja AA, Fosbøl E, Schou M, Køber L, Nielsen OW, Gustafsson F, Kristensen SL. Initiation of eplerenone or spironolactone, treatment adherence, and associated outcomes in patients with new-onset heart failure with reduced ejection fraction: a nationwide cohort study. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2023; 9:546-552. [PMID: 37355774 DOI: 10.1093/ehjcvp/pvad045] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 04/19/2023] [Accepted: 06/22/2023] [Indexed: 06/26/2023]
Abstract
BACKGROUND The mineralocorticoid receptor antagonists (MRAs) eplerenone and spironolactone are beneficial in heart failure with reduced ejection fraction (HFrEF), but have not been prospectively compared. We compared clinical outcomes, daily dosages, and discontinuation rates for the two drugs in a nationwide cohort. METHODS We identified all patients with HFrEF in the period 2016-2020, who were alive and had initiated MRA treatment at study start, 180 days after HF diagnosis. We estimated the 2-year risk of a composite of death and HF hospitalization, as well as each component separately, using Kaplan-Meier, cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, and comorbidities. Secondly, we assessed treatment withdrawal, cross-over, and daily drug dosage. RESULTS We included 7479 patients; 653 (9%) on eplerenone and 6840 (91%) on spironolactone. Patients in the eplerenone group were younger (median age 65 vs. 69 years), and more often men (91% vs. 68%), both P < 0.001. In adjusted analyses, with spironolactone as reference, there were no differences in the risk of the composite of all-cause death and HF hospitalization (HR 1.02, 95% CI 0.82-1.27), all-cause death (HR 0.93, 95% CI 0.67-1.30), or HF hospitalization (HR 1.10, 95% CI 0.84-1.42). Treatment withdrawal occurred in 34% in the eplerenone group and 53% in the spironolactone group (P < 0.001), treatment cross-over in 3%, and 10%, respectively. Daily dose >25 mg at 12 months, was observed in 230 patients (37%) in the eplerenone group and 771 patients (12%) in the spironolactone (P < 0.001). CONCLUSIONS In a contemporary nationwide cohort of patients with new-onset HFrEF who initiated MRA, we found no differences in clinical outcomes associated with initiation of eplerenone vs. spironolactone. Treatment was more frequently withdrawn, and daily drug dosage was lower among patients treated with spironolactone.
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Affiliation(s)
- Johan E Larsson
- Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Cæcilie Stilling Denholt
- Department of Cardiology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark
| | - Jens Jakob Thune
- Department of Cardiology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Anna Axelsson Raja
- Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Emil Fosbøl
- Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Morten Schou
- Department of Cardiology, Copenhagen University Hospital-Herlev and Gentofte, Borgmester Ib Juuls Vej 11, 2730 Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Lars Køber
- Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Olav Wendelboe Nielsen
- Department of Cardiology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Finn Gustafsson
- Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Søren L Kristensen
- Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
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24
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Ren Z, Zhang Z, Ling L, Liu X, Wang X. Drugs for treating myocardial fibrosis. Front Pharmacol 2023; 14:1221881. [PMID: 37771726 PMCID: PMC10523299 DOI: 10.3389/fphar.2023.1221881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 08/29/2023] [Indexed: 09/30/2023] Open
Abstract
Myocardial fibrosis, which is a common pathological manifestation of many cardiovascular diseases, is characterized by excessive proliferation, collagen deposition and abnormal distribution of extracellular matrix fibroblasts. In clinical practice, modern medicines, such as diuretic and β receptor blockers, and traditional Chinese medicines, such as salvia miltiorrhiza and safflower extract, have certain therapeutic effects on myocardial fibrosis. We reviewed some representative modern medicines and traditional Chinese medicines (TCMs) and their related molecular mechanisms for the treatment of myocardial fibrosis. These drugs alleviate myocardial fibrosis by affecting related signaling pathways and inhibiting myocardial fibrosis-related protein synthesis. This review will provide more references and help for the research and treatment of myocardial fibrosis.
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Affiliation(s)
- Zhanhong Ren
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Zixuan Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Li Ling
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Xiufen Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Xin Wang
- School of Mathematics and Statistics, Hubei University of Science and Technology, Xianning, China
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25
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Jadhav U, Nair T, Mohanan P, Chopra V, Kerkar P, Das Biswas A, Hazra PK, Zalte N, Sugumaran A, Mohanasundaram S. Impact of Mineralocorticoid Receptor Antagonists in the Treatment of Heart Failure: Targeting the Heart Failure Cascade. Cureus 2023; 15:e45241. [PMID: 37849613 PMCID: PMC10578196 DOI: 10.7759/cureus.45241] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/14/2023] [Indexed: 10/19/2023] Open
Abstract
Epidemiological data from the Indian subcontinent on the burden of Heart failure (HF) is scarce. Mineralocorticoid receptor antagonists (MRAs) are usually used in the management of HF and hypertension. A consortium of experts reviewed and opined on the pathophysiological role of aldosterone in HF and its cascading effects on the heart in terms of cardiac fibrosis, cardiac hypertrophy, and remodeling, increased propensity to cause arrhythmias in addition to its effect on sodium and water retention. This expert opinion document highlights the various mechanisms of action of MRAs. It provides clinical experience and practice-based expert opinion on the use of spironolactone and eplerenone in patients with HF. The role of MRAs in diabetic patients with HF has also been profiled.
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Affiliation(s)
- Uday Jadhav
- Department of Cardiology, Mahatma Gandhi Mission (MGM) New Bombay Hospital, Navi Mumbai, IND
| | - Tiny Nair
- Department of Cardiology, PRS Hospital, Trivandrum, IND
| | | | - Vijay Chopra
- Department of Cardiology, Max Super Speciality Hospital, New Delhi, IND
| | - Prafulla Kerkar
- Department of Cardiology, Asian Heart Institute, Mumbai, IND
| | - Arup Das Biswas
- Department of Cardiology, Institute of Post-graduate Medical Education and Research and Seth Sukhlal Karnani Memorial (IPGMER-SSKM) Hospital, Kolkata, IND
| | - Prakash K Hazra
- Department of Cardiology, AMRI Hospitals Limited, Kolkata, IND
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26
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Rivera A, Vega C, Ramos-Rivera A, Maldonado ER, Prado GN, Karnes HE, Fesko YA, Snyder LM, Alper SL, Romero JR. Blockade of the mineralocorticoid receptor improves markers of human endothelial cell dysfunction and hematological indices in a mouse model of sickle cell disease. FASEB J 2023; 37:e23092. [PMID: 37482902 PMCID: PMC10372847 DOI: 10.1096/fj.202300671r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 06/24/2023] [Accepted: 07/03/2023] [Indexed: 07/25/2023]
Abstract
Increased endothelin-1 (ET-1) levels in patients with sickle cell disease (SCD) and transgenic mouse models of SCD contribute to disordered hematological, vascular, and inflammatory responses. Mineralocorticoid receptor (MR) activation by aldosterone, a critical component of the Renin-Angiotensin-Aldosterone-System, modulates inflammation and vascular reactivity, partly through increased ET-1 expression. However, the role of MR in SCD remains unclear. We hypothesized that MR blockade in transgenic SCD mice would reduce ET-1 levels, improve hematological parameters, and reduce inflammation. Berkeley SCD (BERK) mice, a model of severe SCD, were randomized to either sickle standard chow or chow containing the MR antagonist (MRA), eplerenone (156 mg/Kg), for 14 days. We found that MRA treatment reduced ET-1 plasma levels (p = .04), improved red cell density gradient profile (D50 ; p < .002), and increased mean corpuscular volume in both erythrocytes (p < .02) and reticulocytes (p < .024). MRA treatment also reduced the activity of the erythroid intermediate-conductance Ca2+ -activated K+ channel - KCa 3.1 (Gardos channel, KCNN4), reduced cardiac levels of mRNAs encoding ET-1, Tumor Necrosis Factor Receptor-1, and protein disulfide isomerase (PDI) (p < .01), and decreased plasma PDI and myeloperoxidase activity. Aldosterone (10-8 M for 24 h in vitro) also increased PDI mRNA levels (p < .01) and activity (p < .003) in EA.hy926 human endothelial cells, in a manner blocked by pre-incubation with the MRA canrenoic acid (1 μM; p < .001). Our results suggest a novel role for MR activation in SCD that may exacerbate SCD pathophysiology and clinical complications.
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Affiliation(s)
- Alicia Rivera
- Division of Nephrology, Vascular Biology Research Center, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts, USA
- Departments of Laboratory Medicine and Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - Christopher Vega
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Arelys Ramos-Rivera
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Enrique R. Maldonado
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Gregory N. Prado
- Departments of Laboratory Medicine and Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | | | | | | | - Seth L. Alper
- Division of Nephrology, Vascular Biology Research Center, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts, USA
| | - Jose R. Romero
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
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27
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Boscia G, Viggiano P, Marzulli F, Grassi MO, Puzo P, Dore S, Pinna A, Alessio G, Boscia F. Continuous Eplerenone Treatment in Chronic Central Serous Chorioretinopathy: Long-Term Results from a Pilot Study. Clin Ophthalmol 2023; 17:2003-2012. [PMID: 37483844 PMCID: PMC10361091 DOI: 10.2147/opth.s411094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/01/2023] [Indexed: 07/25/2023] Open
Abstract
Purpose To assess the long-term morpho-functional retinal and choroidal changes in chronic central serous chorioretinopathy (cCSC) pachychoroid eyes in response to continuous oral eplerenone (EPL) treatment. Methods This pilot study was conducted on patients with unilateral exudative cCSC. We enrolled a total of 17 exudative cCSC and 17 non-exudative fellow eyes of 17 patients. Baseline best-corrected visual acuity (BCVA) and anatomical (structural optical coherence tomography [OCT] and OCT angiography) parameters in both eyes were collected at baseline. Follow-up data were collected at 6, 12, and 48 months after initiation of EPL treatment. Results (i) Exudative cCSC eyes: Compared with baseline (0.34±0.13 LogMAR), BCVA significantly improved at follow-up examinations (6 months: 0.28±0.13 LogMAR, p=0.039; 12 months: 0.22±0.11 LogMAR, p=0.025; 48 months: 0.21±0.08 LogMAR, p=0.028). Furthermore, there was a significant reduction from baseline in all structural OCT parameters (subretinal fluid and subfoveal choroidal thickness [SFCT]; p<0.05). (ii) Non-exudative fellow eyes: There was no significant change in BCVA. There was a significant reduction from baseline in SFCT and choriocapillaris flow deficit percentage (p<0.05). Conclusion In this pilot study, continuous oral EPL therapy in cCSC pachychoroid eyes resulted in long-term morpho-functional improvement. The beneficial effect of EPL occurred within the first year and was maintained after four years. Based on these preliminary observations, EPL may be effective in the exudative forms of CSC.
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Affiliation(s)
- Giacomo Boscia
- Department of Translational Biomedicine Neuroscience, University of Bari “Aldo Moro”, Bari, Italy
| | - Pasquale Viggiano
- Department of Translational Biomedicine Neuroscience, University of Bari “Aldo Moro”, Bari, Italy
| | - Federica Marzulli
- Department of Translational Biomedicine Neuroscience, University of Bari “Aldo Moro”, Bari, Italy
| | - Maria Oliva Grassi
- Department of Translational Biomedicine Neuroscience, University of Bari “Aldo Moro”, Bari, Italy
| | - Pasquale Puzo
- Department of Translational Biomedicine Neuroscience, University of Bari “Aldo Moro”, Bari, Italy
| | - Stefano Dore
- Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy
| | - Antonio Pinna
- Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy
| | - Giovanni Alessio
- Department of Translational Biomedicine Neuroscience, University of Bari “Aldo Moro”, Bari, Italy
| | - Francesco Boscia
- Department of Translational Biomedicine Neuroscience, University of Bari “Aldo Moro”, Bari, Italy
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28
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Piccirillo F, Liporace P, Nusca A, Nafisio V, Corlianò A, Magarò F, Antonelli Incalzi R, Ussia GP, Grigioni F. Effects of Finerenone on Cardiovascular and Chronic Kidney Diseases: A New Weapon against Cardiorenal Morbidity and Mortality-A Comprehensive Review. J Cardiovasc Dev Dis 2023; 10:236. [PMID: 37367401 PMCID: PMC10299623 DOI: 10.3390/jcdd10060236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/19/2023] [Accepted: 05/24/2023] [Indexed: 06/28/2023] Open
Abstract
Patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) show high rates of cardiorenal outcomes. In addition, the progression towards renal failure and cardiovascular events rises as CKD worsens. Several studies suggest that the activation of the mineralocorticoid receptor (MR) induces cardiac and renal injury, including inflammation and fibrosis. Finerenone is a novel, nonsteroidal, selective MR antagonist (MRA) which has demonstrated anti-inflammatory and anti-fibrotic effects in pre-clinical studies. Moreover, two large trials (FIDELIO-DKD and FIGARO-DKD) investigated the renal and cardiovascular outcomes in patients with mild to severe CKD in type 2 diabetes which received finerenone. On these bases, this comprehensive review aims to summarize the current knowledge regarding finerenone and its effects on CKD and the cardiovascular system, emphasizing its role in modifying cardiorenal outcomes.
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Affiliation(s)
- Francesco Piccirillo
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Paola Liporace
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Annunziata Nusca
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Vincenzo Nafisio
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Andrea Corlianò
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Francesca Magarò
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Raffaele Antonelli Incalzi
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Geriatrics, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Gian Paolo Ussia
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Francesco Grigioni
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (P.L.); (V.N.); (A.C.); (F.M.); (R.A.I.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
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Abstract
Primary aldosteronism (PA) is the most common form of secondary hypertension. Although hypertensive disorders seem to affect around 5-10% of pregnancies worldwide, literature counts less than 80 cases of PA diagnosed during the peri-partum period. In this review we discuss about current knowledge on pathophysiology, natural history, diagnosis and treatment of PA in pregnancy. Because of the physiologic changes in the renin-angiotensin-aldosterone system (RAAS) and the contraindication to both confirmatory test and subtype differentiation, diagnosis of PA during pregnancy is challenging and relies mostly on detection of low/suppressed renin and high aldosterone levels. The course of pregnancy in patients with PA is highly variable, ranging from progesterone-induced amelioration of blood pressure (BP) control to severe and resistant hypertension with potential maternal and fetal complications. Mineralcorticoid receptor antagonists (MRA) are the recommended and most effective drugs for treatment of PA. As the anti-androgenic effect of spironolactone can potentially interfere with sexual development, their prescription is not recommended during pregnancy. On the other side, eplerenone, has proven to be safe and effective in 6 pregnant women and may be added to conventional first line drug regimen in presence of resistant hypertension or persistent hypokalemia. Ideally, patients with unilateral forms of PA should undergo adrenalectomy prior to conception, however, when PA is diagnosed during pregnancy and medical therapy fails to adequately control hypertension or its complications, adrenalectomy can be considered during the second trimester in case of unilateral adrenal mass at MRI-scan.
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Affiliation(s)
- Vittorio Forestiero
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Via Genova 3, 10126, Torino, Italy
| | - Elisa Sconfienza
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Via Genova 3, 10126, Torino, Italy
| | - Paolo Mulatero
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Via Genova 3, 10126, Torino, Italy.
| | - Silvia Monticone
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Via Genova 3, 10126, Torino, Italy
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30
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Mori T, Abe K, Shirakawa S. Asymmetric Synthesis of α-Spiro-γ-lactones and α-Substituted γ-Lactones via Chiral Bifunctional Sulfide-Catalyzed Bromolactonizations. J Org Chem 2023. [PMID: 36697373 DOI: 10.1021/acs.joc.2c02283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
An efficient enantioselective synthesis of γ-chiral α-spiro-γ-lactones, which are important building blocks for pharmaceuticals, was achieved via BINOL-derived chiral bifunctional sulfide-catalyzed bromolactonizations of α-allyl carboxylic acids containing either hetero- or carbocyclic structures. Transformations of the resultant α-spiro-type bromolactonization product were examined to obtain optically active γ-functionalized α-spiro-γ-lactones. The utility of this catalytic system was also demonstrated in the asymmetric synthesis of α,α-diaryl- and dialkyl-substituted γ-lactones.
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Affiliation(s)
- Taiki Mori
- Department of Environmental Science, Graduate School of Fisheries and Environmental Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan
| | - Koki Abe
- Department of Environmental Science, Graduate School of Fisheries and Environmental Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan
| | - Seiji Shirakawa
- Department of Environmental Science, Graduate School of Fisheries and Environmental Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan
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31
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Gomes TF, Soares RO. Pediatric androgenetic alopecia: an updated review. J Dtsch Dermatol Ges 2023; 21:19-25. [PMID: 36688435 DOI: 10.1111/ddg.14940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 09/23/2022] [Indexed: 01/24/2023]
Abstract
Pediatric androgenetic alopecia is an underrecognized disorder. A clinical evaluation with trichoscopy should be made in children and adolescents with hair loss and/or reduced hair density. Diagnosis is usually clinical, by observation of the hair loss pattern and performance of trichoscopy. In some cases, hyperandrogenism should be excluded. Although there is no approved therapy for androgenetic alopecia in pediatric age, topical minoxidil, oral minoxidil and topical finasteride may be very useful. Hair transplant may be an option for girls in selected cases. This article is a review of the current state of evidence concerning pediatric androgenetic alopecia.
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32
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Gomes TF, Soares RO. Aktuelle Übersicht zur androgenetischen Alopezie bei Kindern und Jugendlichen. J Dtsch Dermatol Ges 2023; 21:19-26. [PMID: 36721944 DOI: 10.1111/ddg.14940_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 09/23/2022] [Indexed: 02/02/2023]
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Beavers CJ. The Role of the Non-Steroidal Mineralocorticoid Antagonist Finerenone in Cardiorenal Management. Curr Cardiol Rep 2022; 24:1785-1790. [PMID: 36272052 DOI: 10.1007/s11886-022-01795-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/05/2022] [Indexed: 01/11/2023]
Abstract
PURPOSE OF REVIEW Finerenone is a novel, non-steroidal mineralocorticoid receptor antagonist (MRAs) that has been investigated for the management of cardiorenal conditions. This article provides an overview of recent evidence of benefits on cardiovascular (CV) outcomes. RECENT FINDINGS The recently published phase III FIDELIO-DKD and FIGARO-DKD, alone and pooled, in patients with CKD and diabetes demonstrate that finerenone reduces the composite of CV death, non-fatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure (HF) with hospitalization for HF being the primary driver of this composite. Finerenone is indicated to reduce renal and CV outcomes in patients with CKD and diabetes. Future investigations of this agent include patients with non-diabetic CKD, HF with preserved ejection fraction, and with the use of sodium-glucose transporter type 2 inhibitors.
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Affiliation(s)
- Craig J Beavers
- Department of Practice and Science, University of Kentucky College of Pharmacy, 789 South Limestone, Lexington, KY, 40508, USA.
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34
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Parfianowicz D, Shah S, Nguyen C, Maitz TN, Hajra A, Goel A, Sreenivasan J, Aronow WS, Vyas A, Gupta R. Finerenone: A New Era for Mineralocorticoid Receptor Antagonism and Cardiorenal Protection. Curr Probl Cardiol 2022; 47:101386. [PMID: 36057315 DOI: 10.1016/j.cpcardiol.2022.101386] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/03/2022]
Abstract
The renin-angiotensin-aldosterone system is a neurohormonal system responsible for maintaining homeostasis of fluid regulation, sodium balance, and blood pressure. The complexity of this pathway enables it to be a common target for blood pressure and volume-regulating medications. The mineralocorticoid receptor is one of these targets, and is found not only in the kidney, but also tissues making up the heart, blood vessels, and adipose. Mineralocorticoid receptor antagonists have been shown to slow progression of chronic kidney disease, treat refractory hypertension and primary aldosteronism, and improve morbidity and mortality in management of heart failure with reduced ejection fraction. The more well-studied medications were derived from steroid-based compounds, and thus come with a distinct side-effect profile. To avoid these adverse effects, developing a mineralocorticoid receptor antagonist (MRA) from a non-steroidal base compound has gained much interest. This review will focus on the novel non-steroidal MRA, Finerenone, to describe its unique mechanism of action while summarizing the available clinical trials supporting its use in patients with various etiologies of cardiorenal disease.
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Affiliation(s)
| | - Swara Shah
- Department of Medicine, Lehigh Valley Health Network, Allentown, PA
| | - Catherine Nguyen
- Department of Medicine, Lehigh Valley Health Network, Allentown, PA
| | - Theresa N Maitz
- Department of Medicine, Lehigh Valley Health Network, Allentown, PA
| | - Adrija Hajra
- Department of Medicine, Jacobi Medical Center, Bronx, NY
| | - Akshay Goel
- Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - Jayakumar Sreenivasan
- Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT
| | - Wilbert S Aronow
- Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - Apurva Vyas
- Department of Cardiology, Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, PA
| | - Rahul Gupta
- Department of Cardiology, Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, PA.
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35
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Missner AA, Johns JD, Gu S, Hoa M. Repurposable Drugs That Interact with Steroid Responsive Gene Targets for Inner Ear Disease. Biomolecules 2022; 12:1641. [PMID: 36358991 PMCID: PMC9687275 DOI: 10.3390/biom12111641] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/25/2022] [Accepted: 11/02/2022] [Indexed: 10/28/2023] Open
Abstract
Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere's disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate of complete recovery remains low, and results across the literature demonstrates significant heterogeneity with respect to the effect of corticosteroids, suggesting a need to identify more efficacious treatment options. Previously, our group has cross-referenced steroid-responsive genes in the cochlea with published single-cell and single-nucleus transcriptome datasets to demonstrate that steroid-responsive differentially regulated genes are expressed in spiral ganglion neurons (SGN) and stria vascularis (SV) cell types. These differentially regulated genes represent potential druggable gene targets. We utilized multiple gene target databases (DrugBank, Pharos, and LINCS) to identify orally administered, FDA approved medications that potentially target these genes. We identified 42 candidate drugs that have been shown to interact with these genes, with an emphasis on safety profile, and tolerability. This study utilizes multiple databases to identify drugs that can target a number of druggable genes in otologic disorders that are commonly treated with steroids, providing a basis for establishing novel repurposing treatment trials.
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Affiliation(s)
| | - James Dixon Johns
- Department of Otolaryngology-Head and Neck Surgery, Georgetown University Medical Center, Washington, DC 20007, USA
| | - Shoujun Gu
- Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael Hoa
- Department of Otolaryngology-Head and Neck Surgery, Georgetown University Medical Center, Washington, DC 20007, USA
- Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
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36
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Kumar R, Maurya SK. Synthesis of
γ
‐Butyrolactone Derivatives from Dihydrotagetone and Evaluation of Their Antidiabetic Activity. ChemistrySelect 2022. [DOI: 10.1002/slct.202203064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Rahul Kumar
- Chemical Technology Division CSIR-Institute of Himalayan Bioresource Technology Palampur Himachal Pradesh 176061 India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad 201002 India
| | - Sushil K. Maurya
- Chemical Technology Division CSIR-Institute of Himalayan Bioresource Technology Palampur Himachal Pradesh 176061 India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad 201002 India
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Mineralocorticoid Receptor Pathway Is a Key Mediator of Carfilzomib-induced Nephrotoxicity: Preventive Role of Eplerenone. Hemasphere 2022; 6:e791. [PMID: 36285072 PMCID: PMC9584194 DOI: 10.1097/hs9.0000000000000791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 09/20/2022] [Indexed: 11/06/2022] Open
Abstract
Carfilzomib is an irreversible proteasome inhibitor indicated for relapsed/refractory multiple myeloma. Carfilzomib toxicity includes renal adverse effects (RAEs) of obscure pathobiology. Therefore, we investigated the mechanisms of nephrotoxicity developed by Carfilzomib. In a first experimental series, we used our previously established in vivo mouse models of Carfilzomib cardiotoxicity, that incorporated 2 and 4 doses of Carfilzomib, to identify whether Carfilzomib affects renal pathways. Hematology and biochemical analyses were performed, while kidneys underwent histological and molecular analyses. In a second and third experimental series, the 4 doses protocol was repeated for 24 hours urine collection and proteomic/metabolomic analyses. To test an experimental intervention, primary murine collecting duct tubular epithelial cells were treated with Carfilzomib and/or Eplerenone and Metformin. Finally, Eplerenone was orally co-administered with Carfilzomib daily (165 mg/kg) in the 4 doses protocol. We additionally used material from 7 patients to validate our findings and patients underwent biochemical analysis and assessment of renal mineralocorticoid receptor (MR) axis activation. In vivo screening showed that Carfilzomib-induced renal histological deficits and increased serum creatinine, urea, NGAL levels, and proteinuria only in the 4 doses protocol. Carfilzomib decreased diuresis, altered renal metabolism, and activated MR axis. This was consistent with the cytotoxicity found in primary murine collecting duct tubular epithelial cells, whereas Carfilzomib + Eplerenone co-administration abrogated Carfilzomib-related nephrotoxic effects in vitro and in vivo. Renal SGK-1, a marker of MR activation, increased in patients with Carfilzomib-related RAEs. Conclusively, Carfilzomib-induced renal MR/SGK-1 activation orchestrates RAEs and water retention both in vivo and in the clinical setting. MR blockade emerges as a potential therapeutic approach against Carfilzomib-related nephrotoxicity.
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Bild W, Vasincu A, Rusu RN, Ababei DC, Stana AB, Stanciu GD, Savu B, Bild V. Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases. Biomolecules 2022; 12:1429. [PMID: 36291638 PMCID: PMC9599929 DOI: 10.3390/biom12101429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/28/2022] [Accepted: 10/03/2022] [Indexed: 11/17/2022] Open
Abstract
Brain neurodegenerative diseases (BND) are debilitating conditions that are especially characteristic of a certain period of life and considered major threats to human health. Current treatments are limited, meaning that there is a challenge in developing new options that can efficiently tackle the different components and pathophysiological processes of these conditions. The renin-angiotensin-aldosterone system (RAS) is an endocrine axis with important peripheral physiological functions such as blood pressure and cardiovascular homeostasis, as well as water and sodium balance and systemic vascular resistance-functions which are well-documented. However, recent work has highlighted the paracrine and autocrine functions of RAS in different tissues, including the central nervous system (CNS). It is known that RAS hyperactivation has pro-inflammatory and pro-oxidant effects, thus suggesting that its pharmacological modulation could be used in the management of these conditions. The present paper underlines the involvement of RAS and its components in the pathophysiology of BNDs such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), motor neuron disease (MND), and prion disease (PRD), as well as the identification of drugs and pharmacologically active substances that act upon RAS, which could alleviate their symptomatology or evolution, and thus, contribute to novel therapeutic approaches.
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Affiliation(s)
- Walther Bild
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Center of Biomedical Research of the Romanian Academy, 700506 Iasi, Romania
| | - Alexandru Vasincu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Răzvan-Nicolae Rusu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Daniela-Carmen Ababei
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Aurelian Bogdan Stana
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Gabriela Dumitrița Stanciu
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Bogdan Savu
- Department of Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Veronica Bild
- Center of Biomedical Research of the Romanian Academy, 700506 Iasi, Romania
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
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Iovanovici DC, Bungau SG, Vesa CM, Moisi M, Babes EE, Tit DM, Horvath T, Behl T, Rus M. Reviewing the Modern Therapeutical Options and the Outcomes of Sacubitril/Valsartan in Heart Failure. Int J Mol Sci 2022; 23:11336. [PMID: 36232632 PMCID: PMC9570001 DOI: 10.3390/ijms231911336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/22/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Sacubitril/valsartan (S/V) is a pharmaceutical strategy that increases natriuretic peptide levels by inhibiting neprilysin and regulating the renin-angiotensin-aldosterone pathway, blocking AT1 receptors. The data for this innovative medication are mainly based on the PARADIGM-HF study, which included heart failure with reduced ejection fraction (HFrEF)-diagnosed patients and indicated a major improvement in morbidity and mortality when S/V is administrated compared to enalapril. A large part of the observed favorable results is related to significant reverse cardiac remodeling confirmed in two prospective trials, PROVE-HF and EVALUATE-HF. Furthermore, according to a subgroup analysis from the PARAGON-HF research, S/V shows benefits in HFrEF and in many subjects having preserved ejection fraction (HFpEF), which indicated a decrease in HF hospitalizations among those with a left ventricular ejection fraction (LVEF) < 57%. This review examines the proven benefits of S/V and highlights continuing research in treating individuals with varied HF characteristics. The article analyses published data regarding both the safeness and efficacy of S/V in patients with HF, including decreases in mortality and hospitalization, increased quality of life, and reversible heart remodeling. These benefits led to the HF guidelines recommendations updating and inclusion of S/V combinations a key component of HFrEF treatment.
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Affiliation(s)
- Diana-Carina Iovanovici
- Doctoral School of Biomedical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Simona Gabriela Bungau
- Doctoral School of Biomedical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Cosmin Mihai Vesa
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Madalina Moisi
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Elena Emilia Babes
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Delia Mirela Tit
- Doctoral School of Biomedical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Tunde Horvath
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Bidholi, Dehradun 248007, India
| | - Marius Rus
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
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40
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Sanjay S, Acharya I, Kawali A, Shetty R, Mahendradas P. Unilateral recurrent central serous chorioretinopathy (CSCR) following COVID-19 vaccination- A multimodal imaging study. Am J Ophthalmol Case Rep 2022; 27:101644. [PMID: 35818570 PMCID: PMC9258414 DOI: 10.1016/j.ajoc.2022.101644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/25/2022] [Accepted: 06/28/2022] [Indexed: 11/17/2022] Open
Abstract
Corona virus disease-19 (COVID-19) vaccines have been approved for emergency use. Ocular adverse effects following the vaccines have been reported. Purpose To report an unique case of recurrent central serous chorioretinopathy following both doses of COVID-19 vaccine. Observations A 40-year-old male presented with blurring of vision in the left eye during 2 days following COVISHIELD™ (Serum Institute of India). He had a previous history of central serous chorioretinopathy in the right eye 2 years back and was treated with micropulse laser. Ocular examination showed a best corrected visual acuity of 20/20 right eye and 20/60 left eye. Fundus evaluation of left eye showed central serous chorioretinopathy. Spectral domain optical coherence tomography of the left eye revealed neurosensory detachment. Fundus fluorescein angiography of the left eye showed multiple window defects and ink-blot appearance in the macula. Oral eplerenone 50mg once a day for a month showed significant reduction in the subretinal fluid. Patient developed central serous chorioretinopathy in the left eye 3 days after 2nd dose of COVISHIELD™. Conclusion and Importance CSCR following vaccination may be a temporal event. In our patient it occurred following the vaccination. This is the first case of a recurrent CSCR after either dose of COVID-19 vaccination. Ocular symptoms after vaccination warrant a thorough eye evaluation.
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Affiliation(s)
- Srinivasan Sanjay
- Department of Uveitis and Ocular Immunology, Narayana Nethralaya, Bangalore, India
| | - Isha Acharya
- Department of Uveitis and Ocular Immunology, Narayana Nethralaya, Bangalore, India
| | - Ankush Kawali
- Department of Uveitis and Ocular Immunology, Narayana Nethralaya, Bangalore, India
| | - Rohit Shetty
- Departments of Cornea, Refractive Surgery and Neuro-Ophthalmology Narayana Nethralaya, Bangalore, India
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Pandey AK, Bhatt DL, Cosentino F, Marx N, Rotstein O, Pitt B, Pandey A, Butler J, Verma S. Non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Eur Heart J 2022; 43:2931-2945. [PMID: 35713973 DOI: 10.1093/eurheartj/ehac299] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 05/11/2022] [Accepted: 05/24/2022] [Indexed: 12/25/2022] Open
Abstract
Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin-angiotensin-aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium-glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.
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Affiliation(s)
- Arjun K Pandey
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - Deepak L Bhatt
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, USA
| | - Francesco Cosentino
- Cardiology Unit, Department of Medicine Solna, Karolinska Institute & Karolinska University Hospital, Stockholm, Sweden
| | - Nikolaus Marx
- Department of Internal Medicine I, Cardiology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Ori Rotstein
- Department of Surgery, St Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Bertram Pitt
- Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Ambirash Pandey
- Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Javed Butler
- Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA
| | - Subodh Verma
- Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, ON, Canada
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42
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Iijima T, Katoh M, Takedomi K, Yamamoto Y, Akatsuka H, Shirata N, Nishi A, Takakuwa M, Watanabe Y, Munakata H, Koyama N, Ikeda T, Iguchi T, Kato H, Kikkawa K, Kawaguchi T. Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist. J Med Chem 2022; 65:8127-8143. [PMID: 35652647 DOI: 10.1021/acs.jmedchem.2c00402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, kidney disease, and heart failure. Thus, MR antagonists (MRAs) are expected to be beneficial to patients with these diseases. In order to identify novel nonsteroidal MRAs that overcome the issues of already marketed steroidal MRAs, we searched for new compounds guided by our hypothesis that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR. We discovered that the novel 1,4-benzoxazin-3-one derivative 19 (apararenone: MT-3995) acted as a highly selective and potent nonsteroidal MRA. Apararenone exhibited a more potent antihypertensive and organ-protective activity than steroidal MRA eplerenone in a primary aldosteronism rat model obtained by infusing aldosterone in uninephrectomized rats.
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Affiliation(s)
- Toru Iijima
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.,Lead Exploration Unit, Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Makoto Katoh
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Kei Takedomi
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Yasuo Yamamoto
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Hidenori Akatsuka
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Naritoshi Shirata
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Akito Nishi
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Misae Takakuwa
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Yoshinori Watanabe
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Hitomi Munakata
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Naomi Koyama
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Tomoko Ikeda
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Taku Iguchi
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Harutoshi Kato
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Kohei Kikkawa
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Takayuki Kawaguchi
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
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Morales M, Martín-Vasallo P, Ávila J. Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment. Biomedicines 2022; 10:biomedicines10061271. [PMID: 35740293 PMCID: PMC9220762 DOI: 10.3390/biomedicines10061271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/25/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
Enzalutamide is a nonsteroidal inhibitor of the androgen receptor (AR) signaling pathway and is used to treat patients with metastatic castration-resistant prostate cancer. However, the risk of cardiovascular-related hospitalization in patients with no contraindications for the use of enzalutamide is about 1–2%. To date, the underlying molecular basis of this has not been established. The androgen receptor, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are nuclear receptors that share structural similarities and have closely related DNA-binding sites and coregulators. In non-epithelial cells, a fine balance of the activities of these receptors is essential to ensure correct cellular function. In this study, we present a molecular characterization of these nuclear receptors in a prostate cancer patient who developed congestive heart failure after enzalutamide treatment. White cell RNAseq revealed a homozygous rs5522 MR polymorphism and both the rs143711342 and rs56149945 GR polymorphisms, carried in different alleles. No different specific splice isoforms were detected. Recent research suggests that AR inhibition by enzalutamide makes available a coregulator that specifically interacts with the rs5522-mutated MR, increasing its activity and producing adverse effects on cardiovascular health. We suggest an evaluation of the MR rs5522 polymorphism before starting therapy with AR inhibitors.
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Affiliation(s)
- Manuel Morales
- Service of Medical Oncology, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
| | - Pablo Martín-Vasallo
- Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular and Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, 38200 La Laguna, Spain;
| | - Julio Ávila
- Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular and Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, 38200 La Laguna, Spain;
- Correspondence:
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Advances in the Treatment Strategies in Hypertension: Present and Future. J Cardiovasc Dev Dis 2022; 9:jcdd9030072. [PMID: 35323620 PMCID: PMC8949859 DOI: 10.3390/jcdd9030072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 12/11/2022] Open
Abstract
Hypertension is the most frequent chronic and non-communicable disease all over the world, with about 1.5 billion affected individuals worldwide. Its impact is currently growing, particularly in low-income countries. Even in high-income countries, hypertension remains largely underdiagnosed and undertreated, with consequent low rates of blood pressure (BP) control. Notwithstanding the large number of clinical observational studies and randomized trials over the past four decades, it is sad to note that in the last few years there has been an impressive paucity of innovative studies. Research focused on BP mechanisms and novel antihypertensive drugs is slowing dramatically. The present review discusses some advances in the management of hypertensive patients, and could play a clinical role in the years to come. First, digital/health technology is expected to be increasingly used, although some crucial points remain (development of non-intrusive and clinically validated devices for ambulatory BP measurement, robust storing systems enabling rapid analysis of accrued data, physician-patient interactions, etc.). Second, several areas should be better outlined with regard to BP diagnosis and treatment targets. Third, from a therapeutic standpoint, existing antihypertensive drugs, which are generally effective and well tolerated, should be better used by exploiting available and novel free and fixed combinations. In particular, spironolactone and other mineral-corticoid receptor antagonists should be used more frequently to improve BP control. In particular, some drugs initially developed for conditions different from hypertension including heart failure and diabetes have demonstrated to lower BP significantly and should therefore be considered. Finally, renal artery denervation is another procedure that has proven effective in the management of hypertension.
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45
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Pardo-Martínez P, Barge-Caballero E, Bouzas-Mosquera A, Barge-Caballero G, Couto-Mallón D, Paniagua-Martín MJ, Sagastagoitia-Fornie M, Prada-Delgado Ó, Muñiz J, Almenar-Bonet L, Vázquez-Rodríguez JM, Crespo-Leiro MG. Real world comparison of spironolactone and eplerenone in patients with heart failure. Eur J Intern Med 2022; 97:86-94. [PMID: 35000806 DOI: 10.1016/j.ejim.2021.12.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/19/2021] [Accepted: 12/28/2021] [Indexed: 11/03/2022]
Abstract
AIMS In the absence of previous direct comparative studies, we aimed to evaluate the effectiveness of spironolactone and eplerenone in patients with heart failure and reduced ejection fraction (HFrEF) in a real-world clinical setting. METHODS Using Fine-Gray´s competing risk regression, we compared the clinical outcomes of 293 patients with chronic HF and left ventricular ejection fraction <40% treated with eplerenone and 293 propensity-score matched individuals treated with spironolactone. Study subjects were selected from a prospective cohort of 1404 ambulatory patients with HFrEF seen since 2010 to 2019 in a single specialized HF clinic, among which 992 received a mineralocorticoid receptor antagonist at baseline. Median follow-up was 3.95 years. RESULTS No statistically significant differences between patients treated with eplerenone versus spironolactone were observed with regard to the risk of the primary composite end-point cardiovascular death or HF hospitalization (HR 0.95; 95% CI 0.73-1.23; p= 0.677). However, eplerenone use was associated to lower cardiovascular mortality (HR 0.55; 95% CI 0.35-0.85; p= 0.008) and lower all-cause mortality (HR 0.67; 95% CI 0.47-0.95; p= 0.027). The incidence of drug suspension due to side effects (HR 0.58, 95% CI 0.40-0.85; p= 0.005) and drug suspension due to any reason (HR 0.70, 95% CI 0.51-0.97; p= 0.033) were lower among patients treated with eplerenone. CONCLUSIONS In this observational, real-world, propensity-score matched study of patients with HFrEF, eplerenone was associated to lower cardiovascular mortality and lower all-cause mortality than spironolactone.
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Affiliation(s)
- Patricia Pardo-Martínez
- Servicio de Cardiología, Hospital Universitario Arquitecto Marcide, Ferrol (A Coruña), Spain
| | - Eduardo Barge-Caballero
- Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Grupo de Investigación Cardiovascular (GRINCAR), Universidad de A Coruña (UDC), A Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain.
| | - Alberto Bouzas-Mosquera
- Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - Gonzalo Barge-Caballero
- Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Grupo de Investigación Cardiovascular (GRINCAR), Universidad de A Coruña (UDC), A Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - David Couto-Mallón
- Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - María J Paniagua-Martín
- Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Grupo de Investigación Cardiovascular (GRINCAR), Universidad de A Coruña (UDC), A Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Sagastagoitia-Fornie
- Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Grupo de Investigación Cardiovascular (GRINCAR), Universidad de A Coruña (UDC), A Coruña, Spain
| | - Óscar Prada-Delgado
- Servicio de Cardiología, Hospital Universitario Arquitecto Marcide, Ferrol (A Coruña), Spain
| | - Javier Muñiz
- Grupo de Investigación Cardiovascular (GRINCAR), Universidad de A Coruña (UDC), A Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - Luis Almenar-Bonet
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain; Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - José M Vázquez-Rodríguez
- Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - María G Crespo-Leiro
- Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Grupo de Investigación Cardiovascular (GRINCAR), Universidad de A Coruña (UDC), A Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
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Defeudis G, Mazzilli R, Tenuta M, Rossini G, Zamponi V, Olana S, Faggiano A, Pozzilli P, Isidori AM, Gianfrilli D. Erectile dysfunction and diabetes: A melting pot of circumstances and treatments. Diabetes Metab Res Rev 2022; 38:e3494. [PMID: 34514697 PMCID: PMC9286480 DOI: 10.1002/dmrr.3494] [Citation(s) in RCA: 122] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus (DM), a chronic metabolic disease characterised by elevated levels of blood glucose, is among the most common chronic diseases. The incidence and prevalence of DM have been increasing over the years. The complications of DM represent a serious health problem. The long-term complications include macroangiopathy, microangiopathy and neuropathy as well as sexual dysfunction (SD) in both men and women. Erectile dysfunction (ED) has been considered the most important SD in men with DM. The prevalence of ED is approximately 3.5-fold higher in men with DM than in those without DM. Common risk factors for the development of DM and its complications include sedentary lifestyle, overweight/obesity and increased caloric consumption. Although lifestyle changes may help improve sexual function, specific treatments are often needed. This study aims to review the definition and prevalence of ED in DM, the impact of DM complications and DM treatment on ED and, finally, the current and emerging therapies for ED in patients with DM.
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Affiliation(s)
- Giuseppe Defeudis
- Unit of Endocrinology and DiabetesDepartment of MedicineUniversity Campus Bio‐Medico di RomaRomeItaly
| | - Rossella Mazzilli
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | - Marta Tenuta
- Department of Experimental MedicineSapienza University of RomeRomeItaly
| | - Giovanni Rossini
- Unit of Endocrinology and DiabetesDepartment of MedicineUniversity Campus Bio‐Medico di RomaRomeItaly
| | - Virginia Zamponi
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | - Soraya Olana
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | - Antongiulio Faggiano
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | - Paolo Pozzilli
- Unit of Endocrinology and DiabetesDepartment of MedicineUniversity Campus Bio‐Medico di RomaRomeItaly
| | - Andrea M. Isidori
- Department of Experimental MedicineSapienza University of RomeRomeItaly
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Wang R, Chai L, Guo X. Diuretics in Cirrhotic Patients with Ascites. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:167-178. [DOI: 10.1007/978-981-19-2615-0_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Barrera-Chimal J, Kolkhof P, Lima-Posada I, Joachim A, Rossignol P, Jaisser F. Differentiation between emerging non-steroidal and established steroidal mineralocorticoid receptor antagonists: head-to-head comparisons of pharmacological and clinical characteristics. Expert Opin Investig Drugs 2021; 30:1141-1157. [PMID: 34758679 DOI: 10.1080/13543784.2021.2002844] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Mineralocorticoid receptor (MR) antagonists (MRAs) provide cardiorenal protection. However steroidal MRAs might induce hyperkalemia and sex hormone-related adverse effects. Several novel non-steroidal MRAs are being developed that are highly selective for the MR and may have an improved safety profile. AREAS COVERED This narrative review summarizes data from head-to-head comparisons of emerging non-steroidal MRAs with older steroidal MRAs, including pharmacological characteristics, pharmacokinetic properties, clinical outcomes, and safety, and highlights similarities and differences between emerging agents and established steroidal MRAs. EXPERT OPINION Head-to-head comparisons in phase 2 trials suggest that the new non-steroidal MRAs exhibit at least equivalent efficacy to steroidal MRAs but may have a better safety profile in patients with heart failure and/or kidney disease. When also taking into account data from recent phase 3 placebo-controlled trials, these novel non-steroidal MRAs have the potential to provide a cardiorenal benefit above that of current optimized standard-of-care treatment in a high-risk population with reduced renal function, and with a lower risk of hyperkalemia. To optimize therapy, further research is needed to clarify the molecular differences in the mode of action of non-steroidal MRAs versus steroidal MRAs, and biomarkers that are predictive of MRA response need to be identified and validated.
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Affiliation(s)
- Jonatan Barrera-Chimal
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.,Unidad de Investigación UNAM-INC, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Peter Kolkhof
- Heart and Vascular Diseases, R&D Preclinical Research, Bayer AG, Germany
| | - Ixchel Lima-Posada
- Centre de Recherche Des Cordeliers, Sorbonne Université, Université de Paris, Paris, France
| | - Alexandre Joachim
- Normandy University, University of Caen Normandy, Centre Hospitalier Universitaire (CHU) de Caen Normandie, Department of Pharmacology, Ea 4650, Signalisation, Électrophysiologie Et Imagerie Des Lésions d'Ischémie-Reperfusion Myocardique, Caen, France
| | - Patrick Rossignol
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique - 1433, and Inserm U1116; Chru Nancy; F-crin Ini-crct, Nancy, France
| | - Frederic Jaisser
- Centre de Recherche Des Cordeliers, Sorbonne Université, Université de Paris, Paris, France.,Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique - 1433, and Inserm U1116; Chru Nancy; F-crin Ini-crct, Nancy, France
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Asghar A, Tan YC, Shahid M, Yow YY, Lahiri C. Metabolite Profiling of Malaysian Gracilaria edulis Reveals Eplerenone as Novel Antibacterial Compound for Drug Repurposing Against MDR Bacteria. Front Microbiol 2021; 12:653562. [PMID: 34276590 PMCID: PMC8279767 DOI: 10.3389/fmicb.2021.653562] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/06/2021] [Indexed: 11/13/2022] Open
Abstract
With a continuous threat of antimicrobial resistance on human health worldwide, efforts for new alternatives are ongoing for the management of bacterial infectious diseases. Natural products of land and sea, being conceived to be having fewer side effects, pose themselves as a welcome relief. In this respect, we have taken a scaffolded approach to unearthing the almost unexplored chemical constituents of Malaysian red seaweed, Gracilaria edulis. Essentially, a preliminary evaluation of the ethyl acetate and acetone solvent extracts, among a series of six such, revealed potential antibacterial activity against six MDR species namely, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enterica, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes, and Bacillus subtilis. Detailed analyses of the inlying chemical constituents, through LC-MS and GC-MS chromatographic separation, revealed a library of metabolic compounds. These were led for further virtual screening against selected key role playing proteins in the virulence of the aforesaid bacteria. To this end, detailed predictive pharmacological analyses added up to reinforce Eplerenone as a natural alternative from the plethora of plausible bioactives. Our work adds the ongoing effort to re-discover and repurpose biochemical compounds to combat the antimicrobial resistance offered by the Gram-positive and the -negative bacterial species.
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Affiliation(s)
- Ali Asghar
- Department of Biological Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Yong-Chiang Tan
- Department of Biological Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Muhammad Shahid
- Department of Food Sciences, Universiti Kebangsaan, Bangi, Malaysia
| | - Yoon-Yen Yow
- Department of Biological Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Chandrajit Lahiri
- Department of Biological Sciences, Sunway University, Petaling Jaya, Malaysia
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Böhm R, Westermann P, Gleim M, Cascorbi I, Gruenewald M, Herdegen T, Ohnesorge H. High-dose spironolactone lacks effectiveness in treatment of fibromyalgia (RCT). Eur J Pain 2021; 25:1739-1750. [PMID: 33909330 DOI: 10.1002/ejp.1784] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Spironolactone (SPL) is a reversible mineralocorticoid receptor (MR) and androgen receptor (AR) antagonist which attracts pharmacotherapeutic interest not only because of its beneficial effects in heart failure but also because of the pathogenetic roles of MR and AR activities in neuropsychiatric diseases. Recently, beneficial and rapid-onset effects of SPL have been documented in a case series of women with fibromyalgia syndrome (FMS). To reaffirm this observation, we performed a double-blind placebo-controlled randomized clinical trial (RCT). METHODS A total of 69 patients were screened, 56 patients were eligible and randomized to SPL or placebo (each n = 28). Forty-three patients completed the clinical trial to the last visit (n = 21 and n = 22). After a run-in phase of 50 and 100 mg/day, 200 mg/day SPL or placebo were applied between days 7 and 28. Primary outcome was the change in the FIQ-G score (Fibromyalgia Impact Questionnaire, German version). Secondary outcome parameters were the changes in pain (numeric rating scale, NRS), mood (ADS), quality of life (SF-36) and change in FIQ scores 14 days after the end of the medication. RESULTS SPL of 200 mg/day did not change significantly either the primary or the secondary end points. SPL evoked a transient rise in serum potassium and a transient fall in GFR maximal after 2 weeks, but without clinical relevance. CONCLUSIONS SPL at 200 mg/day does not improve symptoms in women with FMS, but was considered not to cause harm. SIGNIFICANCE The mineralocorticoid receptor and androgen receptor antagonist spironolactone is repeatedly tested for its therapeutic effectivity against neuropsychiatric disorders. The present RCT demonstrated that 200 mg spironolactone does not change the symptoms of the fibromyalgia syndrome (FMS) in adult women. Between 2 and 4 weeks, spironolactone evokes a transient decrease in GFR and increase in serum potassium. Spironolactone cannot be recommended for the treatment of FMS.
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Affiliation(s)
- Ruwen Böhm
- Institute for Experimental and Clinical Pharmacology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Paul Westermann
- Clinic for Anesthesiology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Martin Gleim
- Clinic for Anesthesiology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Ingolf Cascorbi
- Institute for Experimental and Clinical Pharmacology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Matthias Gruenewald
- Institute for Experimental and Clinical Pharmacology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Thomas Herdegen
- Institute for Experimental and Clinical Pharmacology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Henning Ohnesorge
- Clinic for Anesthesiology, University Medical Center Schleswig-Holstein, Kiel, Germany
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