Therapeutic efficacy of candidate antischistosomal drugs in a murine model of schistosomiasis mansoni.

Schistosomiasis is a neglected tropical disease associated with considerable morbidity. Praziquantel (PZQ) is effective against adult schistosomes, yet, it has little effect on juvenile stages, and PZQ resistance is emerging. Adopting the drug repurposing strategy as well as assuming enhancing the efficacy and lessening the doses and side effects, the present study aimed to investigate the in vivo therapeutic efficacy of the widely used antiarrhythmic, amiodarone, and diuretic, spironolactone, and combinations of them compared to PZQ. Mice were infected by Schistosoma mansoni "S. mansoni" cercariae (Egyptian strain), then they were divided into two major groups: Early- [3 weeks post-infection (wpi)] and late- [6 wpi] treated. Each group was subdivided into seven subgroups: positive control, PZQ, amiodarone, spironolactone, PZQ combined with amiodarone, PZQ combined with spironolactone, and amiodarone combined with spironolactone-treated groups. Among the early-treated groups, spironolactone had the best therapeutic impact indicated by a 69.4% reduction of total worm burden (TWB), 38.6% and 48.4% reduction of liver and intestine egg load, and a significant reduction of liver granuloma number by 49%. Whereas, among the late-treated groups, amiodarone combined with PZQ was superior to PZQ alone evidenced by 96.1% reduction of TWB with the total disappearance of female and copula in the liver and intestine, 53.1% and 84.9% reduction of liver and intestine egg load, and a significant reduction of liver granuloma number by 67.6%. Comparatively, spironolactone was superior to PZQ and amiodarone in the early treatment phase targeting immature stages, while amiodarone had a more potent effect when combined with PZQ in the late treatment phase targeting mature schistosomes.

Combination of spironolactone and DPP-4 inhibitors for treatment of SARS-CoV-2 infection: a literature review.

Coronavirus disease 2019 (COVID-19) is still causing hospitalization and death, and vaccination appears to become less effective with each emerging variant. Spike, non-spike, and other possible unrecognized mutations have reduced the efficacy of recommended therapeutic approaches, including monoclonal antibodies, plasma transfusion, and antivirals. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) and probably dipeptidyl peptidase 4 (DPP-4) to initiate the process of endocytosis by employing host proteases such as transmembrane serine protease-2 (TMPRSS-2) and ADAM metallopeptidase domain 17 (ADAM17). Spironolactone reduces the amount of soluble ACE2 and antagonizes TMPRSS-2 and ADAM17. DPP-4 inhibitors play immunomodulatory roles and may block viral entry. The efficacy of treatment with a combination of spironolactone and DPP-4 inhibitors does not appear to be affected by viral mutations. Therefore, the combination of spironolactone and DPP-4 inhibitors might improve the clinical outcome for COVID-19 patients by decreasing the efficiency of SARS-CoV-2 entry into cells and providing better anti-inflammatory, antiproliferative, and antifibrotic effects than those achieved using current therapeutic approaches such as antivirals and monoclonal antibodies.

Beta blockers are associated with lower all-cause mortality among HFpEF patients.

BACKGROUND: The evidence regarding beta blocker (BB) benefit in heart failure with preserved ejection fraction (HFpEF) remains inconclusive, leading to consideration of BB withdrawal in this population. OBJECTIVES: In this study, we retrospectively analyzed the association of BB on all-cause mortality in HFpEF patients. METHODS: This is a single-center retrospective cohort study of 20,206 patients with left ventricular ejection fraction (EF) ≥ 50% who were hospitalized with decompensated HF between January 2011 and March 2020. Survival is reported at 30 days, 1 year, and 3 years. A secondary analysis comparing mortality for patients on BB with additional indications including hypertension (HTN), coronary artery disease (CAD), and atrial fibrillation (AF) was completed. Mortality was compared between patients on BB and additional therapies of spironolactone or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs). RESULTS: BB showed lower all-cause mortality at 30 days, 1 year, and 3 years (p < 0.0001). This association with lower all-cause mortality was validated by a supplementary propensity score-matched analysis. At 3 years, there was significant mortality reduction with addition of BB to either spironolactone (p = 0.0359) or ACEi/ARBs (p < 0.0001). CONCLUSION: In a large single-center retrospective registry, BB use was associated with lower mortality in HFpEF patients with a recent decompensated HF hospitalization. The mortality benefit persisted in those treated with spironolactone or ACEi/ARBs, and in those with AF. This provocative data further highlights the uncertainty of the benefit of BB use in this cohort and calls for re-consideration of BB withdrawal, especially in those tolerating it well, without conclusive, large, and randomized trials showing lack of benefit or harm.

Blood Pressure Lowering in Patients With Central Hypertension: A Randomized Clinical Trial.

BACKGROUND: Cuff blood pressure (BP) is recommended for guiding hypertension management. However, central BP has been proposed as a superior clinical measurement. This study aimed to determine whether controlling hypertension as measured by central BP was beneficial in reducing left ventricular mass index beyond control of standard cuff hypertension. METHODS: This multicenter, open-label, blinded-end point trial was conducted in individuals treated for uncomplicated hypertension with controlled cuff BP (<140/90 mm Hg) but elevated central BP (≥0.5 SD above age- and sex-specific normal values). Participants were randomized to 24-months intervention with spironolactone 25 mg/day (n=148) or usual care control (n=153). The primary outcome was change in left ventricular mass index measured by cardiac MRI. Cuff and central BPs were measured by clinic, 7-day home and 24-hour ambulatory BPs. RESULTS: At 24-months, there was a greater reduction in left ventricular mass index (-3.2 [95% CI, -5.0 to -1.3] g/m2; P=0.001) with intervention compared with control. Cuff and central BPs were lowered by a similar magnitude across all BP measurement modes (eg, clinic cuff systolic BP, -6.16 [-9.60 to -2.72] mm Hg and clinic central systolic BP, -4.96 [-8.06 to -1.86] mm Hg; P≥0.48 all). Secondary analyses found that changes in left ventricular mass index correlated to changes in BP, with the magnitude of effect nearly identical for BP measured by cuff (eg, 24-hour systolic BP, ß, 0.17 [0.02-0.31] g/m2) or centrally (24-hour systolic BP, ß, 0.16 [0.01-0.32] g/m2). CONCLUSIONS: Among individuals with central hypertension, spironolactone had beneficial effects in reducing LV mass. Secondary analyses showed that changes in LV mass were equally well associated with lower measured standard cuff BP and central BP. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12613000053729.

Effect of spironolactone on survival in patients undergoing maintenance hemodialysis.

BACKGROUND: Previous studies have reported inconsistent results regarding the advantages or disadvantages of spironolactone use in patients undergoing hemodialysis (HD). This study aimed to evaluate survival according to the use of spironolactone in a large sample of patients undergoing maintenance HD. METHODS: This retrospective study used laboratory and clinical data from the national HD Quality Assessment Program and claims data. The participants of the quality assessment program were patients who had been undergoing maintenance HD for ≥ 3 months, patients undergoing HD at least twice a week. Patients with no spironolactone prescription during the assessment periods were designated as the control group. Patients with one or more prescriptions of spironolactone during the assessment periods were assigned to the SPR group. RESULTS: The number of patients in the control and SPR groups were 54,588 and 315, respectively. The 5-year survival rates were 69.1% and 59.1% in the control and SPR groups, respectively (P < 0.001). Cox regression analyses showed that the hazard ratio in the SPR group was 1.34 (P < 0.001) in univariate analysis and 1.13 (P = 0.249) in multivariable analysis. Univariate Cox-regression analysis showed a better patient survival rate in the control group than in the SPR group; however, multivariable analyses showed similar patient survival rates between the two groups. CONCLUSION: This study showed no difference in survival between patients undergoing HD with and without spironolactone use.

Therapeutic potential of ramipril, losartan, and spironolactone against sepsis-associated liver tissue injury induced by cecal ligation and puncture in rats.

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.

Subthreshold laser compared to oral spironolactone for the treatment of chronic central serous chorioretinopathy: a retrospective study.

PURPOSE: To compare functional and morphological outcomes of Subthreshold Laser (STL) and Oral Spironolactone (SPR) in treating chronic central serous chorioretinopathy (CSCR). METHODS: This is a retrospective observational study. Treatment-naïve patients with chronic CSCR treated with STL or SPR were included, and data was reviewed at baseline, 1, 3, 6 and 12-month follow-up. Main outcome measures were changes in Central Macular Thickness (CMT) and Subretinal Fluid (SRF) height, and complete resolutions of SRF. Sub-analysis based on retinal pigmented epithelium (RPE) status at baseline was performed. RESULTS: 47 and 47 patients received STL and SPR, respectively. At all timepoints, both treatments significantly improved CMT and SRF (p < 0.05). No significant changes in best corrected visual acuity (BCVA) were recorded and no significant differences between treatment groups were present at each corresponding follow-up. Complete resolution of SRF was achieved in 29% and 36% of patients treated with STL or SPR, respectively, at 12-months follow up. Eyes treated with STL and intact RPE showed significant SRF decrease at 6 months and significantly better BCVA at 1, 3 and 6 months compared to eyes with disrupted RPE layer (p < 0.05). In both treatment groups, intact RPE was associated with a higher rate of complete SRF resolutions, with 43% vs 13% in the STL group and 50% vs 26% in the SPR group. CONCLUSION: STL and SPR are effective treatments for chronic CSCR. Greater resolution of subretinal fluid was observed in eyes with intact RPE, hence both treatments should be initiated in the earlier stages of the disease.

Previous heart failure hospitalization, spironolactone, and outcomes in heart failure with preserved ejection fraction - a secondary analysis of TOPCAT.

BACKGROUND: Hospitalization for heart failure (HHF) is associated with poor postdischarge outcomes but the role of time since most recent HHF and potential treatment interactions are unknown. We aimed to assess history of and time since previous HHF, associations with composite of cardiovascular (CV) death and total HHF, first HHF and interactions with randomization to spironolactone, in heart failure with preserved ejection fraction. METHODS AND RESULTS: We assessed these objectives using uni- and multivariable regressions and spline analyses in TOPCAT-Americas. Among 1,765 patients, 66% had a previous HHF. Over a median of 2.9 years, 1,064 composite events of CV death or total HHFs occurred. Previous HHF was associated with more severe HF, and was independently associated with the composite outcome (HR 1.26, 95%CI 1.05-1.52, P = .014), and all secondary outcomes. A shorter time since most recent HHF appeared to be associated with subsequent first HHF, but not the composite of CV death or total HHF. Spironolactone had a significant interaction with previous HHF (interaction-P .046). Patients without a previous HHF had a larger effect of spironolactone on the composite outcome (HR 0.63, 95%CI 0.46-0.87, P = .005) than patients with a previous HHF (HR 0.91, 95%CI 0.78-1.06, P = .224). CONCLUSION: In TOPCAT-Americas, previous HHF was associated with CV death and first and total HHF. Duration since most recent HHF seemed to be associated with time to first HHF only. Spironolactone was associated with better outcomes in patients without a previous HHF. This interaction is hypothesis-generating and requires validation in future trials.

Volume overload is a major characteristic in primary aldosteronism: a 3-year follow-up study.

OBJECTIVES: We examined haemodynamics, focusing on volume balance and forward and backward wave amplitudes, before and after 2.8 years of targeted treatment of primary aldosteronism. Patients with essential hypertension and normotensive individuals were examined for comparison ( n  = 40 in each group). METHODS: Recordings were performed using radial artery pulse wave analysis and whole-body impedance cardiography. Unilateral aldosteronism was treated with adrenalectomy ( n  = 20), bilateral aldosteronism with spironolactone-based medication ( n  = 20), and essential hypertension with standard antihypertensive agents. RESULTS: Aortic SBP and DBP, forward and backward wave amplitudes, and systemic vascular resistance were equally elevated in primary aldosteronism and essential hypertension. All these haemodynamic variables were similarly reduced by the treatments. Primary aldosteronism presented with 1 litre (∼10%) extracellular water excess ( P  < 0.001) versus the other groups, and this excess was normalized by treatment. Initial pulse wave velocity (PWV) was similarly increased in primary aldosteronism and essential hypertension, but final values remained higher in primary aldosteronism ( P  < 0.001). In regression analyses, significant explanatory factors for treatment-induced forward wave amplitude reduction were decreased systemic vascular resistance ( ß â€Š= 0.380) and reduced extracellular water volume ( ß â€Š= 0.183). Explanatory factors for backward wave amplitude reduction were changes in forward wave amplitude ( ß â€Š= 0.599), heart rate ( ß â€Š= -0.427), and PWV ( ß â€Š= 0.252). CONCLUSION: Compared with essential hypertension, the principal haemodynamic difference in primary aldosteronism was higher volume load. Volume excess elevated forward wave amplitude, which was subsequently reduced by targeted treatment of primary aldosteronism, along with normalization of volume load. We propose that incorporating extracellular water evaluation alongside routine diagnostics could enhance the identification and diagnosis of primary aldosteronism.

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

Comprehensive characterization of the effect of mineralocorticoid receptor antagonism with spironolactone on the renin-angiotensin-aldosterone system in healthy dogs.

OBJECTIVE: To characterize the dose-exposure-response effect of spironolactone on biomarkers of the classical and alternative arms of the renin-angiotensin-aldosterone system (RAAS) in healthy dogs. ANIMALS: Ten healthy purpose-bred Beagle dogs. PROCEDURES: Study dogs were randomly allocated to 2 spironolactone dosing groups (2 mg/kg PO q24hr, 4 mg/kg PO q24hr). The dogs received 7-day courses of spironolactone followed by a 14-day washout period in a crossover (AB/BA) design. Angiotensin peptides and aldosterone were measured in serum using equilibrium analysis, and plasma canrenone and 7-α-thiomethyl spironolactone (TMS) were quantified via liquid chromatography-mass spectrometry/mass spectroscopy (LC-MS/MS). Study results were compared before and after dosing and between groups. RESULTS: Following spironolactone treatment, dogs had a significant increase in serum aldosterone concentration (P = 0.07), with no statistical differences between dosing groups. Significant increases in angiotensin II (P = 0.09), angiotensin I (P = 0.08), angiotensin 1-5 (P = 0.08), and a surrogate marker for plasma renin activity (P = 0.06) were detected compared to baseline following spironolactone treatment during the second treatment period only. Overall, changes from baseline did not significantly differ between spironolactone dosages. RAAS analytes were weakly correlated (R < 0.4) with spironolactone dosage and plasma canrenone or plasma TMS. There were no adverse clinical or biochemical effects seen at any spironolactone dosage during treatment. CONCLUSIONS: Treatment with spironolactone increased serum aldosterone concentration in healthy dogs and impacted other biomarkers of the classical and alternative arms of the RAAS. There was no difference in effect on the RAAS between 2 and 4 mg/kg/day dosing. Dosage of 4 mg/kg/day was safe and well-tolerated in healthy dogs.

Pharmacological Treatment of Heart Failure: Recent Advances.

BACKGROUND: Heart failure is a clinical condition with high mortality and morbidity that occurs when the heart is unable to pump enough blood to meet the metabolic demands of the body. The pharmacological management of heart failure has been revolutionized over the past decade with novel treatments. OBJECTIVE: The aim of the review is to highlight the recent pharmacological advances in the management of heart failure. RESULTS: Sodium-glucose cotransporter-2 inhibitor (SGLT2i), iron carboxymaltose, finerenone, omecamtiv mecarbil, and vericiguat have been shown to reduce hospitalization for heart failure. However, only SGLT2i, vericiguat, and omecamtiv mecarbil have been shown to reduce cardiovascular death. Finerenone has been shown to reduce cardiovascular events and renal adverse outcomes in patients with diabetes and kidney disease. Currently, only SGLT2i has been studied in patients beyond the heart failure with reduced ejection fraction population. CONCLUSION: The current quadruple therapy in the treatment of heart failure has demonstrated a reduction in the hospitalization of patients and a decrease in mortality associated with the condition. Individualized heart failure therapy research have shown some benefit in select heart failure patients. Further research on novel therapies will help improve heart failure patient outcomes.

Phenotyping patients with ischaemic heart disease at risk of developing heart failure: an analysis of the HOMAGE trial.

AIMS: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI). METHODS AND RESULTS: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months. CONCLUSIONS: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes.

Gene expression analysis to identify mechanisms underlying improvement of myocardial fibrosis by finerenone in SHR.

Both spironolactone and finerenone treatments significantly reduced SBP and there was no statistical difference in their antihypertensive effects. The differences in body weight (at the end of 1/2/3/4 week) to pre-dose body weight ratio and heart rate (at the end of 1/2/3/4 week) to pre-dose heart rate ratio were not statistically significant in the vehicle, spironolactone, finerenone, and control groups.There was no statistically significant difference in mortality among the vehicle, spironolactone, and finerenone groups. The relative heart mass, ANP, BNP, CVF, Col I, TGF-ß, and Casp-3 were gradually decreased in vehicle group, spironolactone group, and finerenone group. Among them, BNP, CVF, TGF-ß, and Casp-3 were significantly decreased in the finerenone group compared with the vehicle group. HE and Masson staining showed that the cardiomyocytes of rats in the vehicle group and spironolactone group were disorganized, with cell hypertrophy, significantly enlarged cell gaps and a large amount of collagen deposition, whereas the cardiomyocytes of rats in the finerenone group and the control group were more neatly arranged, with smaller cell gaps and a small amount of collagen tissue deposition. RNA sequencing (RNA-seq) showed that there was a total of 119 differentially expressed genes (DEGs) between finerenone treatment and vehicle treatment. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that the signaling pathways involved were mainly in drug metabolism-cytochrome P450, chemical carcinogenesis, IL-17 signaling pathway, axon guidance, and hematopoietic cell lineage. Protein-protein interaction (PPI) analysis showed that the core genes were Oaslf, Nos2, LOC687780, Rhobtb1, Ephb3, and Rps27a.

Combination of spironolactone and sitagliptin improves clinical outcomes of outpatients with COVID-19: a prospective cohort study.

BACKGROUND: There are evidences showing that sitagliptin and spironolactone can potentially improve the clinical outcomes of COVID-19 cases. In this observational study on acutely symptomatic outpatient COVID-19 cases, we investigated the effects of spironolactone and sitagliptin on the outcomes of the disease. METHODS: This is a prospective, naturally randomized cohort study. We followed mild to moderate symptomatic COVID-19 patients, who were treated with either combination (spironolactone 100 mg daily and sitagliptin 100 mg daily) or standard (steroid, antiviral and/or supportive care) therapy up to 30 days. The primary outcome was hospitalization rate. The secondary outcomes included ER visit, duration of disease, and complications, such as hypoglycemia, low blood pressure or altered mental status. RESULTS: Of the 206 patients referred to clinics randomly, 103 received standard therapy and 103 treated with combination therapy. There were no significant differences in baseline characteristics, except for slightly higher clinical score in control group (6.92 ± 4.01 control, 4.87 ± 2.92 combination; P < 0.0001). Treatment with combination therapy was associated with lower admission rate (5.8% combination, 22.3% control; P = 0.0011), ER visits (7.8% combination, 23.3% control; P = 0.0021) and average duration of symptoms (6.67 ± 2.30 days combination, 18.71 ± 6.49 days control; P ≤ 0.0001). CONCLUSIONS: The combination of sitagliptin and spironolactone reduced duration of COVID infection and hospital visits better than standard therapeutic approaches in outpatients with COVID-19. The effects of combination of sitagliptin and spironolactone in COVID-19 patients should be further verified in a double-blind, randomized, placebo-controlled trial.

Taming resistant hypertension: The promise of novel pharmacologic approaches and renal denervation.

Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline-recommended therapy. While spironolactone is widely considered as the preferable fourth-line drug, its broad application is limited by its side effect profile, especially off-target steroid receptor-mediated effects and hyperkalaemia in at-risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter-based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension.