Estradiol and Spironolactone Plasma Pharmacokinetics Among Brazilian Transgender Women Using HIV Pre-Exposure Prophylaxis: Analysis of Potential Interactions.

BACKGROUND AND OBJECTIVE: An important barrier to HIV prevention among transgender women (TGW) is the concern that oral pre-exposure prophylaxis (PrEP) negatively affects the efficacy of feminizing hormone therapy (FHT). We aimed to assess the impact of PrEP on FHT pharmacokinetics (PK) among TGW from Brazil. METHODS: We performed a drug-drug interaction sub-study among TGW enrolled in a daily oral PrEP demonstration study (PrEParadas, NCT03220152). Participants had a first PK assessment (PK1) 15 days after FHT (estradiol valerate 2-6 mg plus spironolactone 100-200 mg) initiation and then started PrEP (tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg). A second PK evaluation was performed 12 weeks later (PK2). Blood samples were collected prior and after the directly observed dosing (0, 0.5, 1, 2, 4, 6, 8, and 24 hours). Pharmacokinetic parameters of estradiol, spironolactone, and metabolites were estimated by non-compartmental analysis (Monolix 2021R2, Lixoft®) and compared as geometric mean ratios (GMRs, 90% confidence interval [CI]). RESULTS: Among 19 TGW who completed the substudy, median age was 26 years (interquartile range: 23-27.5). Estradiol area under the plasma concentration-time curve (AUCτ) and trough concentrations did not differ between PK1 and PK2 evaluations (GMR [90% CI]: 0.89 [0.76-1.04] and 1.06 [0.94-1.20], respectively). Spironolactone and canrenone AUCτ were statistically lower at PK2 than PK1 (0.76 [0.65-0.89] and 0.85 [0.78-0.94], respectively). Canrenone maximum concentration was also lower at PK2 than PK1 (0.82 [0.74-0.91]). CONCLUSION: Estradiol PK was not influenced by PrEP concomitant use. The small differences observed in some spironolactone and canrenone PK parameters should not prevent the concomitant use of estradiol-based FHT and PrEP. TRIAL REGISTRATION: This trial (NCT03220152) was registered on July 18, 2017.

Mineralocorticoid Receptor Antagonist Effect on Aldosterone to Renin Ratio in Patients With Primary Aldosteronism.

CONTEXT: Although current international guidelines recommend to avoid mineralocortcoid receptor antagonists in patients undergoing screening test for primary aldosteronism, a recent report suggested that mineralocorticoid receptor antagonist treatment can be continued without significant influence on screening results. OBJECTIVE: We aimed to evaluate the effect of mineralocorticoid receptor antagonists on the aldosterone to renin ratio in patients with primary aldosteronism. METHODS: We prospectively enrolled 121 patients with confirmed primary aldosteronism who started mineralocorticoid receptor antagonist (canrenone) treatment. Eighteen patients (11 with unilateral and 7 with bilateral primary aldosteronism) constituted the short-term study cohort and underwent aldosterone, renin, and potassium measurement after 2 and 8 weeks of canrenone therapy. The long-term cohort comprised 102 patients (16 with unilateral and 67 with bilateral primary aldosteronism, and 19 with undetermined subtype) who underwent hormonal and biochemical re-assessment after 2 to 12 months of canrenone therapy. RESULTS: Renin and potassium levels showed a significant increase, and the aldosterone to renin ratio displayed a significant reduction compared with baseline after both a short- and long-term treatment. These effects were progressively more evident with higher doses of canrenone and after longer periods of treatment. We demonstrated that canrenone exerted a deep impact on the diagnostic accuracy of the screening test for primary aldosteronism: the rate of false negative tests was raised to 16.7%, 38.9%, 54.5%, and 72.5% after 2 weeks, 8 weeks, 2 to 6 months, and 7 to 12 months of mineralocorticoid receptor antagonist treatment, respectively. CONCLUSION: Mineralocorticoid receptor antagonists should be avoided in patients with hypertension before measurement of renin and aldosterone for screening of primary aldosteronism.

Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.

BACKGROUND: Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a Cochrane review first published in 2009 and updated in 2014. OBJECTIVES: To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE. MAIN RESULTS: Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists. AUTHORS' CONCLUSIONS: The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.

Effects of Mineralocorticoid and AT1 Receptor Antagonism on The Aldosterone-Renin Ratio In Primary Aldosteronism-the EMIRA Study.

CONTEXT: While current guidelines recommend the withdrawal of mineralocorticoid receptor antagonist (MRA) and renin-angiotensin system blockers for the screening and detection of primary aldosteronism (PA), this can worsen hypokalemia and control of high blood pressure (BP) values. OBJECTIVE: To investigate whether aldosterone/renin ratio (ARR) values were affected by the MRA canrenone and/or by canrenone plus olmesartan treatment in patients with PA. DESIGN: Within-patient study. SETTING: The European Society of Hypertension center of excellence at the University of Padua. PATIENTS: Consecutive patients with an unambiguous diagnosis of PA subtyped by adrenal vein sampling. INTERVENTIONS: Patients were treated for 1 month with canrenone (50-100 mg orally), and for an additional month with canrenone plus olmesartan (10-20 mg orally). Canrenone and olmesartan were up-titrated over the first 2 weeks until BP values and hypokalemia were controlled. Patients with unilateral PA were adrenalectomized; those with bilateral PA were treated medically. MAIN OUTCOME MEASURES: BP, plasma levels of sodium and potassium, renin and aldosterone. RESULTS: Canrenone neither lowered plasma aldosterone nor increased renin; thus, the high ARR and true positive rate remained unaffected. Addition of the angiotensin type 1 receptor blocker raised renin and slightly lowered aldosterone, which reduced the ARR and increased the false negative rate. CONCLUSIONS: At doses that effectively controlled serum potassium and BP values, canrenone did not preclude an accurate diagnosis in patients with PA. Addition of the angiotensin type 1 receptor blocker olmesartan slightly raised the false negative rate. Hence, MRA did not seem to endanger the accuracy of the diagnosis of PA.

Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials.

This study aims to assess the comparative benefit and risk profile of treatment with mineralocorticoid receptor antagonists (MRAs) with regard to all-cause mortality (primary endpoint), cardiovascular mortality, or heart failure (HF)-related hospitalization (secondary endpoints) and the safety endpoints hyperkalemia, acute renal failure, and gynecomastia in patients with chronic HF. We conducted a systematic review and network meta-analysis following PRISMA-P and PRISMA-NMA guidelines. From 16 different sources, 14 randomized controlled trials totaling 12,213 patients testing an active treatment of either spironolactone, eplerenone, or canrenone/potassium-canreonate in adults with symptomatic HF due to systolic dysfunction reporting any of the above endpoints were retained. Efficacy in comparison to placebo/standard medical care with respect to all-cause mortality was confirmed for spironolactone and eplerenone while no conclusion could be drawn for canrenone (HR 0.69 (0.62; 0.77), 0.82 (0.75; 0.91), and 0.50 (0.17; 1.45), respectively). Indirect comparisons hint a potential (non-significant) preference of spironolactone over eplerenone (HR 0.84 (0.68; 1.03)). The overall risk of bias was low to intermediate. Results for secondary endpoints as well as sensitivity analyses essentially mirrored these findings. The beta-blocker adjusted meta-analysis for the primary endpoint showed the same tendency as the unadjusted one (HR 0.39 (0.07; 2.03)). Results need to be interpreted with caution, though, as the resultant mix of patient- and study-level covariates produced unstable statistical modeling. We found no significant and systematic superiority of either MRA regarding efficacy toward all endpoints considered in both direct and indirect comparisons.

Reliable and easy-to-use LC-MS/MS-method for simultaneous determination of the antihypertensives metoprolol, amlodipine, canrenone and hydrochlorothiazide in patients with therapy-refractory arterial hypertension.

BACKGROUND: Therapy-refractory arterial hypertension is defined as a blood pressure (BP) in a subset of patients who fail to achieve BP control despite a three-drug regimen (including a diuretic). Various factors have impact on loss of therapy response. Drug-drug-interactions (DDIs) may cause altered pharmacokinetics (PK) of antihypertensive drugs. Upregulation of activity and expression of cytochrome P450 (CYP) enzymes can result in decreased plasma drug levels. Besides these PK considerations a significant problem could be nonadherence to drug therapy. In this regard Therapeutic Drug Monitoring (TDM) is a useful tool for detecting nonadherence. Therefore a LC-MS/MS-method for determination of Metoprolol (MET), Amlodipine (AML), Canrenone (CAN) and Hydrochlorothiazide (HCT) was developed. METHODS: An UHPLC-MS/MS method was developed and validated for simultaneous determination of MET, AML, CAN and HCT in plasma matrix. Extraction of serum samples consisted of simple protein precipitation using acetonitrile. Stable isotope labeled analogues for each antihypertensive were obtained for internal standardization and quantitative analysis ([2H7]-MET, ([13C6]-AML, [2H4]-CAN, [13C6]-HCT). Calibrators and quality controls were prepared in plasma matrix of normal individuals. Sample preparation: protein precipitation with acetonitrile and addition of internal standard-mix. RESULTS: All analytes were eluted within a runtime of 2.5 min. Linearity experiments were demonstrated in plasma over following concentration ranges: MET: 5-750 µg/l, AML: 1-50 µg/l, CAN: 10-500 µg/l, HCT: 5-500 µg/l (R2 > 0.993). Chromatographic separation was achieved using a C18 column (50 × 2.1 mm, 1.9 µm particle size) and an isocratic elution. LC-MS/MS analyses were performed on a triple quadrupole mass spectrometer using positive and negative electrospray ionization in selected reaction monitoring (SRM) mode. Ion transitions monitored for quantitation were m/z 268.2 → 74.1 for MET, m/z 409.1 → 238.0 for AML, m/z 341.2 → 91.0 for CAN and m/z 296.0 → 205.1 for HCT. For all analytes, inter- and intra-day precision (CV, %) varied between 1.7 and 14.0 and inter- and intra-day accuracy values ranged from -2.5 to 7.1%. The lower limits of detection and quantification were: 0.08 and 0.23; 0.05 and 0.15; 2.82 and 8.54; and 0.02 and 0.05 µg/l for MET, AML, CAN and HCT, respectively. Results of stability experiments were within the required range of +/- 15%. CONCLUSIONS: Although the level of recommendation of TDM of antihypertensive drugs in patients with refractory hypertension is not yet established, the present LC-MS/MS-method can serve as an effective tool for detection of PK-alterations/nonadherence and may help to monitor antihypertensive pharmacotherapy.

Canrenone on cardiovascular mortality in congestive heart failure: CanrenOne eFFects on cardiovascular mortality in patiEnts with congEstIve hearT failure: The COFFEE-IT study.

AIM: To evaluate canrenone effects compared to other therapies on cardiovascular mortality in patients with chronic heart failure (CHF) and preserved systolic function after 10 years of evaluation. METHODS: We enrolled 532 patients with CHF and preserved systolic function. Patients were followed with a mean follow-up of 10 years: 166 patients were in therapy with canrenone, while 336 patients were in conventional therapy. We re-evaluated these data after 10 years, together with the rate of death and survival. RESULTS: Systolic and diastolic blood pressure were lower with canrenone compared to the group not treated with canrenone, both in supine and orthostatism. In the group treated with canrenone we recorded a lower value of fasting plasma glucose and glycated hemoglobin. Uric acid was lower in the group treated with canrenone, no differences were observed regarding creatinine, sodium, potassium, brain natriuretic peptide (BNP), pro-BNP or plasma renin activity (PRA), while aldosterone levels were reduced in canrenone group compared to control. After 10 years, left ventricular mass was lower in canrenone group. We recorded a more pronounced progression of NYHA class in controls compared to patients treated with canrenone, with also a higher number of deaths. A higher number of deaths was recorded in control group in the 68-83 years range compared to canrenone. A higher incidence of death was reported among patients without hypercholesterolemia in control group; this was not significant in patients treated with canrenone. A longer survival was observed in patients treated with canrenone. CONCLUSION: Administered to patients with CHF and preserved systolic fraction, reduced mortality and extended the life.

A randomized, double-blind clinical trial of canrenone vs hydrochlorothiazide in addition to angiotensin II receptor blockers in hypertensive type 2 diabetic patients.

AIM: The aim of this study was to evaluate the effects of canrenone compared to hydrochlorothiazide (HCTZ) added to angiotensin II receptor blockers (ARBs) on glycemia, lipid profile, potassium, aldosterone and renal function in patients with hypertension and type 2 diabetes mellitus. PATIENTS AND METHODS: The study enrolled 182 Caucasian patients with hypertension and type 2 diabetes mellitus. Patients were already taking ARBs and were randomized to canrenone, 50 mg once a day, or HCTZ, 12.5 mg once a day for 1 month. After the first month, patients not reaching an adequate blood pressure (BP) were up-titrated to canrenone 100 mg or HCTZ 25 mg once a day for 12 months. The following parameters were considered at 6 and 12 months: BP, body weight, body mass index (BMI), fasting plasma glucose (FPG), post-prandial glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin (HOMA-IR), lipid profile, potassium, plasma aldosterone, urine albumin excretion rate and estimated glomerular filtration rate (eGFR). RESULTS: We observed a similar decrease in BP with both treatments. Canrenone led to a significant decrease in FPG, PPG and HOMA index compared to baseline, while there was a significant increase in the same parameters with HCTZ. HCTZ also worsened glycated hemoglobin (HbA1c), while canrenone did not change it. No variations in lipid profile were recorded with canrenone, while there was a worsening of total cholesterol (TC) and triglycerides (Tg) with HCTZ. Potassium levels were decreased and uric acid levels were increased by HCTZ, but not by canrenone that had a neutral effect on these parameters. We recorded a slight decrease in eGFR with HCTZ and an improvement with canrenone; creatinine and eGFR were improved by canrenone compared to HCTZ. Plasma aldosterone levels were decreased by canrenone and increased by HCTZ. CONCLUSION: Canrenone and HCTZ have a similar effect on BP; however, canrenone seems to improve metabolic parameters, while HCTZ worsens them.

Galectin-3 and the Mineralocorticoid Receptor Antagonist Canrenone in Mild Heart Failure.

BACKGROUND: Galectin-3 (Gal-3) is involved in collagen deposition and inflammation and is a prognostic biomarker in heart failure (HF).Methods and Results:Gal-3 and other markers of fibrosis or cardiac stress were measured serially in 413 patients with mild HF randomized to the mineralocorticoid receptor antagonist canrenone or placebo to evaluate treatment effect and association with clinical outcome. Gal-3 increased slightly over 6 months in both arms of the study and was associated with clinical endpoints. CONCLUSIONS: Although Gal-3 showed prognostic value, the effect of canrenone on clinical outcomes was unaffected by baseline concentrations of biomarkers of fibrosis or cardiac stress.

A systematic review and meta-analysis of the impact of mineralocorticoid receptor antagonists on glucose homeostasis.

BACKGROUND: Spironolactone, a nonselective mineralocorticoid receptor antagonist (MRA), may have a deleterious effect on glycemia. The objective of this review was to assess current knowledge on MRAs' influence (spironolactone, eplerenone, and canrenone) on glucose homeostasis and the risk of diabetes. METHOD: A systematic review was conducted using the Medline database on articles published from 1946 to January 2017 that studied the effects of MRAs on any glucose-related endpoints, without any restrictions regarding the participants' characteristics.Study design, patient population, dose and duration of intervention, and the quantitative results on glycemic markers were extracted, interpreted for result synthesis, and evaluated for sources of bias. From the articles included in the qualitative analysis, a select number were used in a meta-analysis on studies having measured glycated hemoglobin (HbA1c) or risk of diabetes. RESULTS: Seventy-two articles were selected from the Medline database and references of articles. Results on spironolactone were heterogeneous, but seemed to be disease-specific. A potential negative effect on glucose regulation was mainly observed in heart failure and diabetes trials, while a neutral or positive effect was detected in diseases characterized by hyperandrogenism, and inconclusive for hypertension. Interpretation of data from heart failure trials was limited by the small number of studies. From a meta-analysis of 12 randomized controlled studies evaluating spironolactone's impact on HbA1c in diabetic patients, spironolactone had a nonsignificant effect in parallel-group studies (mean difference 0.03 [-0.20;0.26]), but significantly increased HbA1c in crossover studies (mean difference 0.24 [0.18;0.31]). Finally, eplerenone did not seem to influence glycemia, while limited data indicated that canrenone may exert a neutral or beneficial effect.The studies had important limitations regarding study design, sample size, duration of follow-up, and choice of glycemic markers. CONCLUSION: Spironolactone may induce disease-specific and modest alterations on glycemia. It is uncertain whether these effects are transient or not. Data from the most extensively studied population, individuals with diabetes, do not support a long-term glycemic impact in these patients. Further prospective studies are necessary to establish spironolactone's true biological effects and their clinical implications.

The effects of canrenone on inflammatory markers in patients with metabolic syndrome.

AIM: To evaluate the effects of canrenone compared to placebo on blood pressure control, some non-conventional biomarkers in cardiovascular stratification, and on metalloproteinases in patients affected by metabolic syndrome. METHODS: A total of 156 Caucasian patients were treated with placebo or canrenone, 50 mg once a day, for 3 months and then 50 mg twice a day, till the end of the study. We evaluated: systolic (SBP) and diastolic blood pressure (DBP), body weight, body mass index (BMI), fasting plasma glucose (FPG), lipid profile, plasma aldosterone, creatinine, potassium, brain natriuretic peptide (BNP), metalloproteinases 2 and 9 (MMP-2 and -9), lipoprotein (a) (Lp(a)), and serum myeloperoxidase (MPO). RESULTS: We observed a significant decrease of SBP and DBP in the canrenone group compared to baseline. Canrenone gave a significant decrease of MMP-2 and -9, Lp(a), and MPO compared to baseline, not observed with placebo. Plasma aldosterone, but not BNP, decreased with canrenone, both compared to baseline and to placebo. CONCLUSION: Canrenone seems to be effective in reducing blood pressure in patients with metabolic syndrome. Moreover, canrenone seems also to improve MPO, Lp(a), and metalloproteinases in these patients.

Mineralcorticoid antagonists in heart failure.

Mineralocorticoid receptor antagonists (MRAs) have become mandated therapy in patients with reduced ejection fraction (systolic) heart failure (HF) across all symptom classes. These agents should also be prescribed in the early post-myocardial infarction setting in those with reduced ejection fraction and either HF symptoms or diabetes. This article explores the pathophysiological role of aldosterone, an endogenous ligand for the mineralcorticoid receptor (MR), and summarizes the clinical data supporting guideline recommendations for these agents in systolic HF. The use of MRAs in novel areas beyond systolic HF ejection is also explored. Finally, the current status of newer agents will be examined.

Aldosterone receptor blockers spironolactone and canrenone: two multivalent drugs.

Canrenone is a derivative of spironolactone with lower antiandrogen activity. The drug is used only in few countries and can block all the side effects of aldosterone (ALDO). The drug is effective even in the presence of normal concentrations of ALDO. Mineralcorticoid receptor antagonists block the inflammatory activity of ALDO at the level of target tissues as heart, vessels and mononuclear leukocytes. Canrenone reduces the progression of insulin resistance and of microalbuminuria in type 2 diabetes and other related diseases. Both canrenone and hydrochlorothiazide can enhance the effect of treatment with ACE inhibitors and angiotensin II receptor blockers on microalbuminuria, but ALDO receptor blockers are more active. This different action is due to the fact that only canrenone blocks mineralocorticoid receptors. Serum potassium and renal function should be monitored before and during the treatment. ALDO receptor blockers are recommended in addition to polytherapy for resistant hypertension, but there are no studies on the effect of the drug as first-choice therapy.

Comparative effect of canrenone or hydrochlorothiazide addition to valsartan/amlodipine combination on urinary albumin excretion in well-controlled type 2 diabetic hypertensive patients with microalbuminuria.

OBJECTIVE: To compare the effect of adding canrenone or hydrochlorothiazide (HCTZ) to valsartan/amlodipine combination on urinary albumin excretion (UAE) in microalbuminuric type 2 diabetic hypertensives. RESEARCH DESIGN AND METHODS: After a 2-week placebo period and after 4 weeks of valsartan 160 mg plus amlodipine 5 mg combination, 120 patients whose blood pressure (BP) was not controlled (> 130/80 mmHg) were randomized to canrenone 25 mg or HCTZ 12.5 mg in addition to the previous therapy for 24 weeks. After the first 6 weeks of triple therapy, canrenone or HCTZ doses were doubled in the patients whose BP was yet uncontrolled. At the end of each period (placebo, dual combination and triple combination therapy), clinic and ambulatory BP measurements were recorded and 24 h UAE was evaluated. RESULTS: Both triple combinations produced greater clinical and ambulatory BP reduction than dual therapy, with no difference between the two groups. UAE was reduced by both regimens, but the decrease associated with canrenone add-on therapy was more pronounced. At week 24, UAE decreased by 45.3% in the canrenone group and by 20.3% in the HCTZ group (p < 0.01). CONCLUSIONS: These findings indicate that, despite similar BP-lowering effect, the addition of canrenone to valsartan/amlodipine combination was more effective in reducing UAE than HCTZ addition.

Effects of canrenone in patients with metabolic syndrome.

BACKGROUND: Metabolic syndrome is becoming a common disease due to a rise in obesity rates among adults. OBJECTIVES: The aim was to evaluate the effects of canrenone compared to placebo on metabolic and inflammatory parameters in patients affected by metabolic syndrome. A total of 145 patients were treated with placebo or canrenone, 50 mg/day, for 3 months and then 50 mg b.i.d. till the end of the study. Blood pressure, body weight, body mass index, fasting plasma glucose (FPG), fasting plasma insulin, HOMA-IR, lipid profile, plasma aldosterone, brain natriuretic peptide, high-sensitivity C-reactive protein (Hs-CRP), tumor necrosis factor-α (TNF-α) and M value were evaluated. RESULTS: A decrease of blood pressure was observed in canrenone group compared to baseline; moreover, systolic blood pressure value recorded after 6 months of canrenone therapy was lower than the one recorded with placebo. Canrenone gave a significant decrease of FPI and HOMA index, and an increase of M value both compared to baseline and to placebo. Canrenone also decreased triglycerides and FPG was not observed with placebo. Canrenone also decreased plasma aldosterone, Hs-CRP and TNF-α compared to baseline and to placebo. CONCLUSION: Canrenone seems to be effective in reducing some factors involved in metabolic syndrome and in improving insulin-resistance and the inflammatory state observed in these patients.

Additional use of an aldosterone antagonist in patients with mild to moderate chronic heart failure: a systematic review and meta-analysis.

AIMS: Aldosterone antagonists (AldoAs) have been used to treat severe chronic heart failure (CHF). There is uncertainty regarding the efficacy of using AldoAs in mild to moderate CHF with New York Heart Association (NYHA) classifications of I to II. This study summarizes the evidence for the efficacy of spironolactone (SP), eplerenone (EP) and canrenone in mild to moderate CHF patients. METHODS: PubMed, MEDLINE, EMBASE and OVID databases were searched before June 2012 for randomized and quasi-randomized controlled trials assessing AldoA treatment in CHF patients with NYHA classes I to II. Data concerning the study's design, patients' characteristics and outcomes were extracted. Risk ratio (RR) and weighted mean differences (WMD) or standardized mean difference were calculated using either fixed or random effects models. RESULTS: Eight trials involving 3929 CHF patients were included. AldoAs were superior to the control in all cause mortality (RR 0.79, 95% CI 0.66, 0.95) and in re-hospitalization for cardiac causes (RR 0.62, 95% CI 0.52, 0.74), the left ventricular ejection fraction was improved by AldoA treatment (WMD 2.94%, P = 0.52). Moreover, AldoA therapy decreased the left ventricular end-diastolic volume (WMD -14.04 ml, P < 0.00001), the left ventricular end-systolic volume (WMD -14.09 ml, P < 0.00001). A stratified analysis showed a statistical superiority in the benefits of SP over EP in reducing LVEDV and LVESV. AldoAs reduced B-type natriuretic peptide concentrations (WMD -37.76 pg ml(-1), P < 0.00001), increased serum creatinine (WMD 8.69 µmol l(-1), P = 0.0003) and occurrence of hyperkalaemia (RR 1.78, 95% CI 1.43, 2.23). CONCLUSIONS: Additional use of AldoAs in CHF patients may decrease mortality and re-hospitalization for cardiac reasons, improve cardiac function and simultaneously ameliorate LV reverse remodelling.

Eplerenone is not superior to older and less expensive aldosterone antagonists.

INTRODUCTION: Eplerenone is publicized to be extremely effective in reducing mortality from heart failure, with a reasonable side-effect profile. However, it is much more expensive compared with older aldosterone antagonists. We reviewed available evidence to assess whether increased expense was justified with outcomes data. METHODS AND RESULTS: The authors searched the PubMed, CENTRAL, CINAHL, and EMBASE databases for randomized controlled trials from 1966 through July 2011. Interventions included aldosterone antagonists (Aldactone [Pfizer, NY, NY], canrenone, eplerenone) in systolic heart failure. The comparator included standard medical therapy or placebo, or both. Outcomes assessed were mortality in the intervention versus the comparator groups, and rates of adverse events at the end of at least 8 weeks of follow-up. Event rates were compared using a forest plot of relative risk (RR) (95% confidence interval [CI]) using a random-effects model (Mantel-Haenszel) between the aldosterone antagonists and controls. We included 13 studies for aldosterone antagonists other than eplerenone, and 3 studies for eplerenone. There was significant reduction of mortality with all aldosterone antagonists, but eplerenone (15% mortality relative reduction; RR 0.85; 95% CI, 0.77-0.93; P=.0007) was outperformed by other aldosterone antagonists, namely, spironolactone and canrenone (26% mortality relative reduction; RR 0.74; 95% CI, 0.66-0.83; P <.0001). Reduction in cardiovascular mortality with eplerenone was 17% (RR 0.83; 95% CI, 0.75-0.92; P=.0005), while that with other aldosterone antagonists was 25% (RR 0.75; 95% CI, 0.67-0.84, P <.0001), without contributing significantly to an improved side-effect profile. CONCLUSION: Eplerenone does not appear to be more effective in reducing clinical events compared with older, less expensive aldosterone antagonists.

Polyuric-polydipsic syndrome in a pediatric case of non-glucocorticoid remediable familial hyperaldosteronism.

Familial hyperaldosteronism (FH) encompasses 3 types of autosomal dominant hyperaldosteronisms leading to inheritable hypertension. FH type II (FH-II), undistinguishable from sporadic hyperaldosteronism, represents the most frequent cause of inheritable hypertension and is believed to only manifest in adults. FH-III is a severe variety of PA resistant to pharmacotherapy and recently demonstrated to be caused by mutations in the gene encoding the potassium channel KCNJ5. In this report, we describe a FH pediatric patient, remarkable both for age at onset and unusual presentation: a two-years old girl with polyuric-polydipsic syndrome and severe hypertension, successfully treated with canrenone and amiloride. The girl had severe hypertension, hypokalemia, hypercalciuria, suppressed renin activity, high aldosterone, and unremarkable adrenal imaging. FH type I was ruled out by glucocorticoid suppression test, PCR test for CYP11B1/CYP11B2 gene, and urinary 18-oxo-cortisol and 18-hydroxy-cortisol excretion, which was in FH-II range. In spite of a clear-cut FH-II phenotype, the girl and her mother were found to harbor a FH-III genotype with KCNJ5 mutation (c.452G>A). Treatment with canrenone was started, resulting in prompt normalization of electrolytes and remission of polyuric-polydypsic syndrome. The addition of amiloride led to a complete normalization of blood pressure. This report expands the phenotypic spectrum of FH-III to a milder end, mimiking FH-II phenotype demonstrating that pharmacotherapy may be effective. This also implies that FH-II/III should be considered in the differential diagnosis of hypertensive children and, perhaps, that the offspring of patients with hyperaldosteronism should be screened for hypertension.

Potassium sparing diuretics as adjunct to mannitol therapy in neurocritical care patients with cerebral edema: effects on potassium homeostasis and cardiac arrhythmias.

BACKGROUND: Mannitol therapy to treat cerebral edema induces osmotic diuresis and electrolyte loss. In neurocritical care patients, potassium is the electrolyte that most often needs replacement. Objective of this study was to evaluate the effects of adding potassium sparing diuretic (canrenone) to mannitol therapy on potassium urinary excretion, potassium plasma levels, and incidence of new cardiac arrhythmias in patients receiving neurocritical care for cerebral edema. METHODS: Fifty-six patients were prospectively assigned to mannitol or mannitol plus i.v. canrenone. Potassium urinary excretion, potassium plasma levels, urinary volume, and the incidence of new cardiac arrhythmias were recorded during the first 8 days of therapy. RESULTS: In patients treated with mannitol the potassium urinary excretion was stable over the first 3 days and significantly increased, compared to baseline, on day 4th to 8th (baseline 20.3 ± 10.6 mEq/l/die, day 8th 24.6 ± 10.6 mEq/l/die, P < 0.05); while potassium plasma levels significantly decreased. In patients receiving mannitol plus canrenone potassium urinary excretion decreased from day 3rd to 8th (baseline 21.9 ± 11.6 mEq/l/die, day 8th 15.9 ± 10.9 mEq/l/die, P < 0.015) and potassium plasma levels increased but remained within normal values range. The incidence of new cardiac arrhythmias was higher in the mannitol group than the mannitol plus canrenone group (35.7 vs. 10.7%; P < 0.01). Urinary volumes, potassium balance, and sodium plasma concentration were similar in the 2 study groups. CONCLUSION: In patients receiving neurocritical care for cerebral edema, the adjunct of a potassium sparing diuretic (canrenone) to mannitol therapy reduces potassium urinary loss, prevents hypokalemia, and reduces the incidence of new cardiac arrhythmias.

Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: the AREA-in-CHF study.

BACKGROUND AND AIM: We analyzed the effect of the mineralocorticoid receptor antagonist canrenone on LV mechanics in patients with or without metabolic syndrome (MetS) and compensated (Class II NYHA) heart failure (HF) with reduced ejection fraction (EF≤45%) on optimal therapy (including ACE-i or ARB, and ß-blockers). METHODS AND RESULTS: From a randomized, double-blind placebo-controlled trial (AREA-in-CHF), patients with (73 on canrenone [Can] and 77 on placebo [Pla]), based on modified ATPIII definition (BMI≥30kg/m(2) instead of waist girth) or without MetS (146 by arm). In addition to traditional echocardiographic parameters, we also evaluated myocardial mechano-energetic efficiency (MME) based on a previously reported method. At baseline, Can and Pla did not differ in age, BMI, blood pressure (BP), metabolic profile, BNP, and PIIINP. Compared with MetS-Pla, and controlling for age, sex and diabetes, at the final control MetS-Can exhibited increased MME, preserved E/A ratio, and decreased atrial dimensions (0.04