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Sample records for spironolactone

  1. Spironolactone-Induced Unilateral Gynecomastia

    PubMed Central

    Veeregowda, Sahana Hadihalli; Krishnamurthy, Jayakumar Jyothinagaram; Krishnaswamy, Bhuvana; Narayana, Sarala

    2018-01-01

    Gynecomastia is benign enlargement of male breast, drug-induced gynecomastia accounts for about 25%. We are reporting a case of spironolactone-induced unilateral gynecomastia. A 52-year-old male patient receiving multiple antihypertensives including hydrochlorothiazide presented with muscle weakness and easy fatigability. Investigations revealed hypokalemia; he was advised to stop hydrochlorothiazide and consume potassium-rich diet; since he did not respond to this, spironolactone was added. The patient improved symptomatically but developed painful swelling of the right breast after 12 months of treatment which was suspected to be spironolactone-induced gynecomastia. Within a month of stopping the drug, pain in the right breast subsided followed by decrease in size of swelling. Literature search indicates bilateral gynecomastia by spironolactone, but when clinician encounters unilateral presentation, they should consider the possibility of drug-induced etiology. Patients should be educated about this while prescribing, and eplerenone can be a safe alternative. PMID:29552536

  2. Spironolactone-Induced Unilateral Gynecomastia.

    PubMed

    Veeregowda, Sahana Hadihalli; Krishnamurthy, Jayakumar Jyothinagaram; Krishnaswamy, Bhuvana; Narayana, Sarala

    2018-01-01

    Gynecomastia is benign enlargement of male breast, drug-induced gynecomastia accounts for about 25%. We are reporting a case of spironolactone-induced unilateral gynecomastia. A 52-year-old male patient receiving multiple antihypertensives including hydrochlorothiazide presented with muscle weakness and easy fatigability. Investigations revealed hypokalemia; he was advised to stop hydrochlorothiazide and consume potassium-rich diet; since he did not respond to this, spironolactone was added. The patient improved symptomatically but developed painful swelling of the right breast after 12 months of treatment which was suspected to be spironolactone-induced gynecomastia. Within a month of stopping the drug, pain in the right breast subsided followed by decrease in size of swelling. Literature search indicates bilateral gynecomastia by spironolactone, but when clinician encounters unilateral presentation, they should consider the possibility of drug-induced etiology. Patients should be educated about this while prescribing, and eplerenone can be a safe alternative.

  3. Spironolactone in cardiovascular disease: an expanding universe?

    PubMed

    Funder, John W

    2017-01-01

    Spironolactone has been marketed for over half a century as a 'potassium-sparing diuretic', used primarily in patients with ascites. With the realization that primary aldosteronism is the most common (5-13%) form of secondary hypertension, it has become widely used as a mineralocorticoid receptor antagonist. More recently, in the wake of the RALES trial, spironolactone in addition to standard therapy has been shown to be very beneficial in heart failure with a reduced ejection fraction. Despite the failure of the TOPCAT trial, spironolactone is being increasingly used in diastolic heart failure (i.e. with a preserved ejection fraction). The third currently accepted role for spironolactone is in hypertension resistant to three conventional antihypertensives including a diuretic, where it has been proven to be effective, in contra-distinction to renal artery denervation. Finally, brief consideration will be given to 'areas in waiting' - pulmonary hypertension/fibrosis, cancer - where spironolactone may play very useful roles.

  4. Spironolactone and doxazosin treatment in patients with resistant hypertension.

    PubMed

    Rodilla, Enrique; Costa, José A; Pérez-Lahiguera, Francisco; Baldó, Emilio; González, Carmen; Pascual, José M

    2009-02-01

    The aim of this study was to evaluate the use of spironolactone and doxazosin as treatment for patients with resistant hypertension. This retrospective study involved 181 outpatients with resistant hypertension (defined as a failure of blood pressure [BP] control despite treatment with three drugs, one of which was a diuretic) who received additional spironolactone (n=88) or doxazosin (n=93). Mean systolic BP in the spironolactone group fell by 28 mmHg (95% confidence interval [CI], 24-32 mmHg; P< .001) and mean diastolic BP fell by 12 mmHg (95% CI, 9-14 mmHg; P< .001). The corresponding falls in the doxazosin group were 16 mmHg (95% CI, 13-20 mmHg; P< .001) and 7 mmHg (95% CI, 5-9 mmHg; P< .001), respectively. The decrease was significantly greater with spironolactone for both systolic (P< .001) and diastolic (P=.003) pressures. At the end of follow-up, 30% of all patients had achieved BP control, with control being more frequent with spironolactone (39%) than doxazosin (23%; P=.02). Multivariate logistic regression analysis showed that the only factors that significantly influenced the achievement of BP control were diabetes (odds ratio=0.17; 95% CI, 0.08-0.39; P< .001) and baseline systolic BP <165 mmHg (odds ratio=2.56; 95% CI, 1.11-5.90; P=.03). In patients with resistant hypertension, the addition of either spironolactone or doxazosin resulted in a significant decrease in BP, though the decrease appeared to be greater with spironolactone. The presence of diabetes complicated BP control.

  5. Spironolactone for heart failure with preserved ejection fraction.

    PubMed

    Pitt, Bertram; Pfeffer, Marc A; Assmann, Susan F; Boineau, Robin; Anand, Inder S; Claggett, Brian; Clausell, Nadine; Desai, Akshay S; Diaz, Rafael; Fleg, Jerome L; Gordeev, Ivan; Harty, Brian; Heitner, John F; Kenwood, Christopher T; Lewis, Eldrin F; O'Meara, Eileen; Probstfield, Jeffrey L; Shaburishvili, Tamaz; Shah, Sanjiv J; Solomon, Scott D; Sweitzer, Nancy K; Yang, Song; McKinlay, Sonja M

    2014-04-10

    Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P=0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood

  6. Central serous chorioretinopathy treatment with spironolactone: a challenge-rechallenge case.

    PubMed

    Ryan, Edwin H; Pulido, Christine M

    2015-01-01

    To present a case of central serous chorioretinopathy (CSC) treatment with spironolactone in a challenge-rechallenge pattern. At presentation, fundus photography, fluorescein angiography, spectral domain optical coherence tomography, and enhanced depth imaging ocular coherence tomography were performed in both eyes. The patient was prescribed 25 mg spironolactone daily along with serum potassium monitoring. At follow-ups, spectral domain optical coherence tomography and enhanced depth imaging ocular coherence tomography were performed. A 37-year-old white male accountant presenting with CSC. Spironolactone treatment resolved the CSC. After the patient discontinued treatment, it returned. After returning to daily treatment, the CSC again resolved. Spironolactone was an effective treatment of CSC in this case. Other groups have reported similar findings with eplerenone, a similar drug.

  7. Long-Term Effects of Spironolactone in Peritoneal Dialysis Patients

    PubMed Central

    Mizuno, Masashi; Suzuki, Yasuhiro; Tamai, Hirofumi; Hiramatsu, Takeyuki; Ohashi, Hiroshige; Ito, Isao; Kasuga, Hirotake; Horie, Masanobu; Maruyama, Shoichi; Yuzawa, Yukio; Matsubara, Tatsuaki; Matsuo, Seiichi

    2014-01-01

    ESRD treated with dialysis is associated with increased left ventricular hypertrophy, which, in turn, is related to high mortality. Mineralocorticoid receptor antagonists improve survival in patients with chronic heart failure; however, the effects in patients undergoing dialysis remain uncertain. We conducted a multicenter, open-label, prospective, randomized trial with 158 patients receiving angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist and undergoing peritoneal dialysis with and without (control group) spironolactone for 2 years. As a primary endpoint, rate of change in left ventricular mass index assessed by echocardiography improved significantly at 6 (P=0.03), 18 (P=0.004), and 24 (P=0.01) months in patients taking spironolactone compared with the control group. Rate of change in left ventricular ejection fraction improved significantly at 24 weeks with spironolactone compared with nontreatment (P=0.02). The benefits of spironolactone were clear in patients with reduced residual renal function. As secondary endpoints, renal Kt/V and dialysate-to-plasma creatinine ratio did not differ significantly between groups during the observation period. No serious adverse effects, such as hyperkalemia, occurred. In this trial, spironolactone prevented cardiac hypertrophy and decreases in left ventricular ejection fraction in patients undergoing peritoneal dialysis, without significant adverse effects. Further studies, including those to determine relative effectiveness in women and men and to evaluate additional secondary endpoints, should confirm these data in a larger cohort. PMID:24335969

  8. The acute effects of different spironolactone doses on cardiac function in streptozotocin-induced diabetic rats.

    PubMed

    Vranic, Aleksandra; Simovic, Stefan; Ristic, Petar; Nikolic, Tamara; Stojic, Isidora; Srejovic, Ivan; Zivkovic, Vladimir; Jakovljevic, Vladimir; Djuric, Dusan

    2017-11-01

    Currently, cardiovascular diseases are the leading cause of global mortality, while diabetes mellitus remains an important cause of cardiovascular morbidity. A recent study showed that patients with diabetes mellitus treated with mineralocorticoid receptor antagonists have improved coronary microvascular function, leading to improved diastolic dysfunction. In this study, we evaluated the influence of acute administration of spironolactone on myocardial function in rats with streptozotocin-induced diabetes mellitus, with special emphasis on cardiodynamic parameters in diabetic rat hearts. The present study was carried out on 40 adult male Wistar albino rats (8 weeks old). Rats were randomly divided into 4 groups (10 animals per group): healthy rats treated with 0.1 μmol/L of spironolactone, diabetic rats treated with 0.1 μmol/L of spironolactone, healthy rats treated with 3 μmol/L of spironolactone, and diabetic rats treated with 3 μmol/L of spironolactone. Different, dose-dependent, acute responses of spironolactone treatment on isolated, working diabetic and healthy rat heart were observed in our study. In healthy rats, better systolic function was achieved with higher spironolactone dose, while in diabetic rats, similar effects of low and high spironolactone dose were observed.

  9. Effect of spironolactone on 30-day death and heart failure rehospitalization (from the COACH Study).

    PubMed

    Maisel, Alan; Xue, Yang; van Veldhuisen, Dirk J; Voors, Adriaan A; Jaarsma, Tiny; Pang, Peter S; Butler, Javed; Pitt, Bertram; Clopton, Paul; de Boer, Rudolf A

    2014-09-01

    The aim of our study is to investigate the effect of spironolactone on 30-day outcomes in patients with acute heart failure (AHF) and the association between treatment and outcomes stratified by biomarkers. We conducted a secondary analysis of the biomarker substudy of the multicenter COACH (Co-ordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure) trial involving 534 AHF patients for 30-day mortality and HF rehospitalizations. Spironolactone therapy was initiated and terminated at the discretion of the treating physician; 30-day outcomes were compared between patients who were treated with spironolactone and those who were not. Outcomes with spironolactone therapy were explored based on N-terminal pro-B-type natriuretic peptide, ST2, galectin-3, and creatinine levels. Spironolactone was prescribed to 297 (55.6%) patients at discharge (158 new and 139 continued). There were 19 deaths and 30 HF rehospitalizations among 46 patients by 30 days. Patients discharged on spironolactone had significantly less 30-day event (hazard ratio 0.538, p = 0.039) after adjustment for multiple risk factors. Initiation of spironolactone in patients who were not on spironolactone before admission was associated with a significant reduction in event rate (hazard ratio 0.362, p = 0.027). The survival benefit of spironolactone was more prominent in patient groups with elevations of creatinine, N-terminal pro-B-type natriuretic peptide, ST2, or galectin-3. In conclusion, AHF patients who received spironolactone during hospitalization had significantly fewer 30-day mortality and HF rehospitalizations, especially in high-risk patients. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Spironolactone Add-on for Preventing or Slowing the Progression of Diabetic Nephropathy: A Meta-analysis.

    PubMed

    Hou, Jing; Xiong, Weiquan; Cao, Ling; Wen, Xiangqiong; Li, Ailing

    2015-09-01

    The aim of this meta-analysis was to evaluate the benefits and potential adverse effects of adding spironolactone to standard antidiabetic/renoprotective/antihypertensive (AD/RP/AHT) treatment in patients with diabetic nephropathy (DN). PubMed/MEDLINE and Web of Knowledge were searched for relevant randomized, controlled studies (RCTs) or quasi-RCTs of the effects of adding spironolactone to standard AD/RP/AHT treatment in patients with DN. Results were summarized with a random-effects model or a fixed-effects model. According to the outcomes measured (benefits and risks of adding spironolactone to standard AD/RP/AHT treatment), compared with controls, the addition of spironolactone significantly decreased end-of-treatment (EOT) 24-hour urinary albumin/protein excretion and significantly increased percentage reduction from baseline in urinary albumin/creatinine ratio (UACR), although it did not significantly affect EOT UACR. The addition of spironolactone further led to a significantly greater reduction from baseline in glomerular filtration rate (GFR)/estimated (e) GFR, although it did not significantly affect EOT GFR/eGFR. Further, the addition of spironolactone significantly reduced EOT in-office, 24-hour, and daytime systolic and diastolic blood pressure (SBP and DBP, respectively) and led to significantly greater reductions from baseline in in-office SBP and DBP, although it did not significantly affect nighttime SBP or DBP. Finally, the addition of spironolactone significantly increased mean serum/plasma potassium levels and the risk for hyperkalemia. Spironolactone could be added to preexisting AD/RP/AHT therapy in patients with DN to prevent or slow DN progression by reducing proteinuria. The addition of spironolactone would likely provide even more beneficial effect in patients with DN and hypertension due to the BP reduction associated with spironolactone use. However, the beneficial effects of spironolactone add-on should be weighed against its potential

  11. Spironolactone in patients with heart failure and preserved ejection fraction.

    PubMed

    Sánchez-Sánchez, C; Mendoza-Ruiz de Zuazu, H F; Formiga, F; Manzano, L; Ceresuela, L M; Carrera-Izquierdo, M; González Franco, Á; Epelde-Gonzalo, F; Cerqueiro-González, J M; Montero-Pérez-Barquero, M

    2015-01-01

    Aldosterone inhibitors have been shown to be beneficial for patients with systolic heart failure. However, the evidence from patients with heart failure and preserved ejection fraction (HFPEF) is limited. We evaluated the role of spironolactone in the prognosis of a cohort of patients with HFPEF. We analyzed the outcomes of patients hospitalized for HFPEF in 52 departments of internal medicine of the Spanish RICA registry according to those who did and did not take spironolactone. We recorded the posthospital mortality rate and readmissions at 1 year and performed a multivariate survival analysis. We included 1212 patients with HFPEF, with a mean age of 79 years (standard deviation, 7.9), (64.1% women), the majority of whom had hypertensive heart disease (50.7%). The patients treated with spironolactone, compared with those who were not treated with this diuretic, had a more advanced functional class, a higher number of readmissions (44.3 vs. 29.1%; p<0.001) and a higher rate in the combined variable of readmissions/mortality (39.0 vs. 29.0%; p=0.001). In the multivariate analysis, the administration of spironolactone was associated with an increase in readmissions (RR, 1.4; 95% CI, 1.16-1.78; p=0.001). For patients with HFPEF, the administration of spironolactone was associated with an increase in all-cause readmission, perhaps due to the higher rate of hyperpotassemia. Copyright © 2015. Published by Elsevier España, S.L.U.

  12. [Spironolactone in patients with resistant hypertension].

    PubMed

    Rodilla, Enrique; Costa, José A; Pérez-Lahiguera, Francisco; González, Carmen; Pascual, José M

    2008-10-04

    The aim of the study was to assess the effect of adding spironolactone to hypertensive resistant (HTR) patients and characterize those who respond effectively. Observational retrospective study on outpatients with HTR (being treated with at least 3 drugs at full doses, one of these being a diuretic) not achieving blood pressure (BP) goals, with normal creatinine values (< 1.6 mg/dl for males and < 1.4 mg/dl in women). A total of 95 patients (70% male), average (standard deviation) age of 66 (12) years (40% diabetics), were treated with spironolactone during 4 months (range: 2-13). Mean systolic and diastolic BP fell from 170/86 (20/14) mmHg, by 29/12 mmHg (95% confidence interval [CI], 25 to 33/10 to 14 mmHg; p = 0.001). At the end of follow-up, 38% of all patients achieved the goal of BP control. Initial systolic BP < 165 mmHg (odds ratio [OR] = 3,97; 95% CI, 1.52-10.37; p = 0.005), and diabetes (OR = 0.33; 95% CI, 0.13-0.86; p = 0.02) were the only independent factors related to BP control in a logistic regression analysis. The addition of spironolactone effectively lowers BP in patients with HTR treated with 3 drugs. BP control is more difficult to achieve in diabetics.

  13. Stability of Spironolactone Oral Suspension in PCCA Base, SuspendIt.

    PubMed

    Graves, Richard; Phan, Kelly V; Bostanian, Levon A; Mandal, Tarun K; Pramar, Yashoda V

    2017-01-01

    Spironolactone (Aldactone) is a potassium-sparing diuretic used to treat hypertension and heart failure and may also be used to treat edema resulting from kidney disease, low potassium levels, or excess aldosterone. No commercial liquid dosage form of spironolactone exists. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide an alternative option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of spironolactone in the PCCA base SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. It thickens upon standing to minimize settling of any insoluble drug particles and becomes fluid upon shaking to allow convenient pouring during administration to the patient. A robust stability-indicating highperformance liquid chromatographic assay for the determination of spironolactone in PCCA base SuspendIt was developed and validated. This assay was used to determine the chemical stability of the drug in SuspendIt. Samples were prepared and stored under three different temperature conditions (5°C, 25°C, 40°C) and assayed using the high-performance liquid chromatographic assay at pre-determined intervals over an extended period of time as follows: 0, 7, 14, 29, 46, 60, 90, 120, and 180 days at each designated temperature. Physical data such as pH, viscosity, and appearance were also monitored. The study showed that drug concentration did not go below 90% of the label claim (initial drug concentration) at all three temperatures studied. Viscosity and pH values also did not change significantly. This study demonstrates that spironolactone is physically and chemically stable in SuspendIt for 180 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for spironolactone in a liquid dosage form, with an extended beyond-use date to meet

  14. Treatment of dogs with compensated myxomatous mitral valve disease with spironolactone-a pilot study.

    PubMed

    Hezzell, M J; Boswood, A; López-Alvarez, J; Lötter, N; Elliott, J

    2017-08-01

    Spironolactone improves outcome in dogs with advanced myxomatous mitral valve disease (MMVD). Its efficacy in preclinical MMVD is unknown. The hypothesis was the administration of spironolactone to dogs with compensated MMVD demonstrating risk factors for poorer prognosis will decrease the rate of disease progression. The aim was to provide pilot data to evaluate preliminary effects and sample size calculation for a definitive clinical trial. Twenty-five client-owned dogs with MMVD with at least one of the following; left atrial to aortic ratio (LA:Ao) ≥ 1.5, normalized left ventricular internal diameter in diastole ≥ 1.6), N-terminal pro-B-type natriuretic peptide (NT-proBNP) > 550 pmol/L, cardiac troponin I > 0.025 ng/mL. Prospective, single-center, equally randomized, placebo-controlled, double-blinded, parallel grouped pilot study. No dogs were receiving medications for cardiac disease before the enrollment. Twelve dogs received placebo; 13 received spironolactone. One dog in the spironolactone group died suddenly, 1 developed congestive heart failure, and 2 received suboptimal spironolactone doses. At enrollment, NT-proBNP was significantly higher in the spironolactone group (p=0.005). Left atrial to aortic ratio (p=0.002) and left ventricular internal diameter in diastole (p=0.005) increased over time in the placebo group, but not the spironolactone group; the change did not differ significantly between groups. The change in biomarker concentrations did not differ significantly between groups; there was a tendency toward an increase in NT-proBNP over time in the placebo group. Enrollment of 76 dogs would be necessary to demonstrate a difference in the change in LA:Ao over 6 months between the groups. Preliminary results support undertaking a larger clinical trial of treatment of dogs with preclinical MMVD with spironolactone. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Spironolactone differently influences remodeling of the left ventricle and aorta in L-NAME-induced hypertension.

    PubMed

    Simko, F; Matúsková, J; Lupták, I; Pincíková, T; Krajcírovicová, K; Stvrtina, S; Pomsár, J; Pelouch, V; Paulis, L; Pechánová, O

    2007-01-01

    Aldosterone receptor antagonist, spironolactone, has been shown to prevent remodeling of the heart in several models of left ventricular hypertrophy. The aim of the present study was to determine whether the treatment with spironolactone can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) and aortic remodeling in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Four groups of rats were investigated: control, spironolactone (200 mg/kg), L-NAME (40 mg/kg) and L-NAME + spironolactone (in corresponding dosage). Animals were studied after 5 weeks of treatment. The decrease of NO-synthase activity in the LV and kidney was associated with the development of hypertension and LV hypertrophy, with increased DNA concentration in the LV, and remodeling of the aorta in the L-NAME group. Spironolactone prevented the inhibition of NO-synthase activity in the LV and kidney and partially attenuated hypertension and LVH development and the increase in DNA concentration. However, remodeling of the aorta was not prevented by spironolactone treatment. We conclude that the aldosterone receptor antagonist spironolactone improved nitric oxide production and partially prevented hypertension and LVH development without preventing hypertrophy of the aorta in NO-deficient hypertension. The reactive growth of the heart and aorta seems to be controlled by different mechanisms in L-NAME-induced hypertension.

  16. Spironolactone Treatment and Effect on Survival in Chronic Heart Failure Patients with Reduced Renal Function: A Propensity-Matched Study

    PubMed Central

    Stubnova, Viera; Os, Ingrid; Grundtvig, Morten; Atar, Dan; Waldum-Grevbo, Bård

    2017-01-01

    Background/Aims Spironolactone may be hazardous in heart failure (HF) patients with renal dysfunction due to risk of hyperkalemia and worsened renal function. We aimed to evaluate the effect of spironolactone on all-cause mortality in HF outpatients with renal dysfunction in a propensity-score-matched study. Methods A total of 2,077 patients from the Norwegian Heart Failure Registry with renal dysfunction (eGFR <60 mL/min/1.73 m2) not treated with spironolactone at the first visit at the HF clinic were eligible for the study. Patients started on spironolactone at the outpatient HF clinics (n = 206) were propensity-score-matched 1:1 with patients not started on spironolactone, based on 16 measured baseline characteristics. Kaplan-Meier and Cox regression analyses were used to investigate the independent effect of spironolactone on 2-year all-cause mortality. Results Propensity score matching identified 170 pairs of patients, one group receiving spironolactone and the other not. The two groups were well matched (mean age 76.7 ± 8.1 years, 66.4% males, and eGFR 46.2 ± 10.2 mL/min/1.73 m2). Treatment with spironolactone was associated with increased potassium (delta potassium 0.31 ± 0.55 vs. 0.05 ± 0.41 mmol/L, p < 0.001) and decreased eGFR (delta eGFR −4.12 ± 12.2 vs. −0.98 ± 7.88 mL/min/1.73 m2, p = 0.006) compared to the non-spironolactone group. After 2 years, 84% of patients were alive in the spironolactone group and 73% of patients in the non-spironolactone group (HR 0.59, 95% CI 0.37-0.92, p = 0.020). Conclusion In HF outpatients with renal dysfunction, treatment with spironolactone was associated with improved 2-year survival compared to well-matched patients not treated with spironolactone. Favorable survival was observed despite worsened renal function and increased potassium in the spironolactone group. PMID:28611786

  17. Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial.

    PubMed

    Cusan, L; Dupont, A; Gomez, J L; Tremblay, R R; Labrie, F

    1994-02-01

    To compare the clinical efficacy and safety of the pure antiandrogen flutamide and the steroidal derivative spironolactone in the treatment of hirsutism in women. Fifty-three premenopausal women suffering from moderate to severe hirsutism were randomized into two groups and received either flutamide or spironolactone in association with a triphasic oral contraceptive (OC) pill. Hirsutism, acne, seborrhea, alopecia, and side effects were monitored monthly for a treatment period of 9 months and a follow-up after treatment period of 6 months. Blood samples were taken at each visit for assessment of endocrine, biochemical, and hematologic parameters. After only 6 months of therapy, flutamide caused a maximal reduction in the hirsutism score to a value within almost normal range; during the same period, spironolactone caused only a 30% reduction of the hirsutism score. Whereas flutamide caused a dramatic (80%) decrease in total acne, seborrhea, and hair loss score after only 3 months of therapy, spironolactone caused only a 50% reduction in acne and seborrhea, with no significant effect on the hair loss score. Four patients in the spironolactone group but only one in the flutamide group stopped the medication because of adverse side effects. The present data obtained in a randomized prospective study clearly demonstrate that the pure antiandrogen flutamide is superior to spironolactone in the treatment of female hirsutism and its related androgen-dependent symptoms and signs in women.

  18. Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial.

    PubMed

    Kato, Sawako; Maruyama, Shoichi; Makino, Hirofumi; Wada, Jun; Ogawa, Daisuke; Uzu, Takashi; Araki, Hisazumi; Koya, Daisuke; Kanasaki, Keizo; Oiso, Yutaka; Goto, Motomitsu; Nishiyama, Akira; Kobori, Hiroyuki; Imai, Enyu; Ando, Masahiko; Matsuo, Seiichi

    2015-12-01

    Several studies have demonstrated that spironolactone has an anti-albuminuric property in diabetic nephropathy. As an adverse event, spironolactone often induces the elevation of creatinine levels with hypotension and hyperkalemia. Therefore, we aimed to evaluate the efficacy and safety of spironolactone in Japanese patients with type 2 diabetes treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Fifty-two Japanese patients with diabetic nephropathy and albuminuria (100 mg/gCr-2000 mg/gCr) treated with renin-angiotensin system (RAS) blockade were enrolled in a prospective, randomized, open-label study. The patients were subjected to add-on treatment with spironolactone 25 mg once daily and compared with matched controls for 8 weeks. The primary outcome was a reduction in the rate of albuminuria at 8 weeks compared with the baseline value. This study was registered with UMIN Clinical Trials Registry (000008016). Albuminuria was reduced by 33 % (95 % confidence interval: 22-54; P = 0.0002) at 8 weeks with spironolactone. In the spironolactone group, blood pressure tended to lower and the estimated glomerular filtration rate (eGFR) was significantly decreased compared to those in the control group. When adjusted by systolic blood pressure and eGFR, spironolactone treatment still showed a significant effect on albuminuria reduction in a linear mixed model (coefficient ± standard error; 514.4 ± 137.6 mg/gCr, P < 0.0005). No patient was excluded from the study because of hyperkalemia. Spironolactone reduced albuminuria along with conventional RAS inhibitors in patients with diabetic nephropathy. Our study suggests that spironolactone exerts anti-albuminuric effects independent of systemic hemodynamic alterations.

  19. Effect of metformin and spironolactone therapy on OGTT in patients with polycystic ovarian syndrome - a retrospective analysis.

    PubMed

    Kulshreshtha, Bindu; Gupta, Nandita; Ganie, Mohd Ashraf; Ammini, Ariachery C

    2012-10-01

    Metformin (an insulin sensitizer) and spironolactone (an antiandrogen) are both used for treatment of polycystic ovary syndrome. We analyzed the effect of 6 months of therapy with these drugs on body weight and glucose tolerance. This was a retrospective analysis of polycystic ovarian syndrome (PCOS) cases on treatment. There were 88 patients with PCOS-42 were on metformin 1 g daily and 46 were taking spironolactone 50-75 mg daily. 21 of 42 had abnormal glucose tolerance (AGT) in the metformin group and 13 of 46 had AGT in the spironolactone group. Patients on metformin reported a greater reduction in body weight, whereas there was no change in body weight with spironolactone therapy (67.6-63.7 versus 59.6-59.2 kg). There was a significant reduction in the 1 and 2 h glucose and insulin levels with metformin therapy in those with AGT. However, fasting glucose increased in those with normal glucose tolerance. There was no change in either body weight or insulin levels with spironolactone. But, there was a significant reduction in both the 0 and 2 h glucose with spironolactone also in those with AGT. Spironolactone and metformin had similar effect in reducing the glucose levels in PCOS patients with AGT. PCOS patients with normal glucose tolerance had higher fasting plasma glucose at the end of 6 months of metformin therapy inspite of weight reduction.

  20. Low-dose spironolactone ameliorates insulin resistance and suppresses elevated plasminogen activator inhibitor-1 during gestational testosterone exposure.

    PubMed

    Olatunji, Lawrence A; Usman, Taofeek O; Akinade, Aminat I; Adeyanju, Oluwaseun A; Kim, InKyeom; Soladoye, Ayodele O

    2017-12-01

    Elevated gestational circulating testosterone has been associated with pathological pregnancies that increase the risk of development of cardiometabolic disorder in later life. We hypothesised that gestational testosterone exposure, in late pregnancy, causes glucose deregulation and atherogenic dyslipidaemia that would be accompanied by high plasminogen activator inhibitor-1 (PAI-1). The study also hypothesise that low-dose spironolactone treatment would ameliorate these effects. Pregnant Wistar rats received vehicle, testosterone (0.5 mg/kg; sc), spironolactone (0.5 mg/kg, po) or testosterone and spironolactone daily between gestational days 15 and 19. Gestational testosterone exposure led to increased HOMA-IR, circulating insulin, testosterone, 1-h post-load glucose, atherogenic dyslipidaemia, PLR, PAI-1 and MDA. However, all these effects, except that of circulating testosterone, were ameliorated by spironolactone. These results demonstrate that low-dose spironolactone ameliorates glucose deregulation and atherogenic dyslipidaemia during elevated gestational testosterone exposure, at least in part, by suppressing elevated PAI-1.

  1. Fine structure and morphogenesis of spironolactone bodies in the zona glomerulosa of the human adrenal cortex

    PubMed Central

    Kovacs, K.; Horvath, E.; Singer, W.

    1973-01-01

    Numerous spironolactone bodies have been detected in the zona glomerulosa cells of the adrenal cortex of a 36-year-old spironolactone-treated woman whose non-tumorous right adrenal gland was removed surgically because of primary hyperaldosteronism. Electron microscopy revealed spherical laminated whorls which consisted of a central core composed of an amorphous electron-dense material surrounded by numerous smooth-walled concentric membranes. Continuous with and deriving from the endoplasmic reticulum, they were present in viable cells and were not associated with ultrastructural features indicating cellular injury. Cytoplasmic inclusions similar to spironolactone bodies can be detected in other organs after the administration of various compounds. Thus, they can be regarded as neither specific to spironolactone treatment nor exclusively inducible in the zona glomerulosa of the adrenal cortex. Images PMID:4131694

  2. Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone.

    PubMed

    Mulder, Paul; Mellin, Virginie; Favre, Julie; Vercauteren, Magali; Remy-Jouet, Isabelle; Monteil, Christelle; Richard, Vincent; Renet, Sylvanie; Henry, Jean Paul; Jeng, Arco Y; Webb, Randy L; Thuillez, Christian

    2008-09-01

    Inhibition of aldosterone synthase, the key enzyme in aldosterone formation, could be an alternative strategy for mineralocorticoid-receptor antagonists in congestive heart failure (CHF), but its effect in CHF is unknown. We compared, in rats with CHF, the effects of a 7 day and a 12 week treatment with the aldosterone synthase inhibitor FAD286 (4 mg kg(-1) day(-1)) with those induced by spironolactone (80 mg kg(-1) day(-1)). FAD286/spironolactone increased cardiac output without modifying arterial pressure. Long-term FAD286 and spironolactone reduced left ventricular (LV) end-diastolic pressure, LV relaxation constant, and LV dilatation, and these effects were more marked with FAD286, whereas both drugs reduced LV hypertrophy and collagen accumulation to the same extent. Long-term FAD286/spironolactone prevented CHF-related enhancement in LV ACE and reduction in LV ACE-2, but only FAD286 prevented the reduction in LV AT(2) receptors. FAD286, but not long-term spironolactone, reduced the CHF-related enhancements in LV reactive oxygen species, reduced-oxidized glutathione ratio, and aortic nicotinamide adenine dinucleotide phosphate oxidase activity. FAD286 normalized the CHF-induced impairment of endothelium-dependent vasodilatation. In experimental CHF, FAD286 and spironolactone improve LV haemodynamics, remodelling, and function, but only FAD286 persistently normalizes LV 'redox status'. These results suggest that aldosterone synthase inhibition is a potential therapeutic strategy for the treatment of CHF.

  3. Preformulation experiences and in vitro model studies with spironolactone-containing suppositories.

    PubMed

    Regdon, G; Deák, D; Regdon, G; Muskó, Z; Erös, I

    2001-01-01

    The optimal suppository base for the formulation of rectal suppositories containing diuretic spironolactone was selected experimentally. Model studies were carried out about the effect of solubility-increasing additives on the release of the drug from the suppositories. During the in vitro examinations acceptor phases of different pH values were used, and both diffusion time and the number of samplings were changed. Among the lipophilic and hydrophilic suppository bases studied the hydrophilic Macrogolum 1540 was found to be optimal. The release and diffusion of spironolactone was the most favourable from these suppositories. During storage these suppositories remained stable and the values of release did not decrease significantly (p < 0.05).

  4. Spontaneous, L-arginine-induced and spironolactone-induced regression of protein remodeling of the left ventricle in L-NAME-induced hypertension.

    PubMed

    Simko, F; Potácová, A; Pelouch, V; Paulis, L; Matúsková, J; Krajcírovicová, K; Pechánová, O; Adamcová, M

    2007-01-01

    N(G)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension is associated with protein remodeling of the left ventricle. The aim of the study was to show, whether aldosterone receptor blocker spironolactone and precursor of NO-production L-arginine were able to reverse the protein rebuilding of the left ventricle. Six groups of male Wistar rats were investigated: control 4 (4 weeks placebo), L-NAME (4 weeks L-NAME), spontaneous-regression (4 weeks L-NAME + 3 weeks placebo), spironolactone-regression (4 weeks L-NAME + 3 weeks spironolactone), L-arginine-regression (4 weeks L-NAME + 3 weeks arginine), control 7 (7 weeks placebo). L-NAME administration induced hypertension, hypertrophy of the left ventricle (LV), and the increase of metabolic and contractile as well as soluble and insoluble collagenous protein concentration. The systolic blood pressure and relative weight of the LV decreased in all three groups with regression, while the most prominent attenuation of the LVH was observed after spironolactone treatment. In the spontaneous-regression and L-arginine-regression groups the concentrations of individual proteins were not significantly different from the control value. However, in the spironolactone-regression group the concentration of metabolic, contractile and insoluble collagenous proteins remained significantly increased in comparison with the control group. The persistence of the increased protein concentration in the spironolactone group may be related to the more prominent reduction of myocardial water content by spironolactone.

  5. Functional assessment of four types of disintegrants and their effect on the spironolactone release properties.

    PubMed

    Rojas, John; Guisao, Santiago; Ruge, Vanesa

    2012-12-01

    Spironolactone is a drug derived from sterols that exhibits an incomplete oral absorption due to its low water solubility and slow dissolution rate. In this study, formulations of spironolactone with four disintegrants named as croscarmellose sodium, crospovidone, sodium starch glycolate and microcrystalline cellulose II (MCCII) were conducted. The effect of those disintegrants on the tensile strength, disintegration time and dissolution rate of spironolactone-based compacts was evaluated using a factorial design with three categorical factors (filler, lubricant, and disintegrant). The swelling values, water uptake and water sorption studies of these disintegrants all suggested that MCCII compacts disintegrate by a wicking mechanism similar to that of crospovidone, whereas a swelling mechanism was dominant for sodium starch glycolate and croscarmellose sodium. The disintegration time of MCCII and sodium starch glycolate remained unchanged with magnesium stearate. However, this lubricant delayed the disintegration time of crospovidone and croscarmellose sodium. MCCII presented the fastest disintegration time independent of the medium and lubricant employed. The water sorption ratio and swelling values determined sodium starch glycolate followed by croscarmellose sodium as the largest swelling materials, whereas crospovidone and MCCII where the least swelling disintegrants. The swelling property of sodium starch glycolate and croscarmellose sodium was strongly affected by the medium pH. The disintegration time of spironolactone compacts was faster when starch was used as a filler due to the formation of soft compacts. In this case, the type of filler employed rather than the disintegrant had a major effect on the disintegration and dissolution times of spironolactone.

  6. Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect.

    PubMed

    Ferreira, João Pedro; Girerd, Nicolas; Medeiros, Pedro Bettencourt; Santos, Mário; Carvalho, Henrique Cyrne; Bettencourt, Paulo; Kénizou, David; Butler, Javed; Zannad, Faiez; Rossignol, Patrick

    2016-06-01

    Loop diuretic resistance characterized by inefficient sodium excretion complicates many patients with acutely decompensated heart failure (ADHF). Mineralocorticoid receptor antagonists (MRAs) in natriuretic doses may improve spot urine sodium excretion and outcomes. Our primary aim was to assess the association of high-dose spironolactone with short-term spot urine sodium excretion, and our secondary aim was to determine if this higher short-term spot urine sodium excretion is associated with reduction in the composite clinical outcome (of cardiovascular mortality and/or ADHF hospitalization) event rate at 180 days. Single-centre, non-randomized, open-label study enrolling 100 patients with ADHF. Patients were treated with standard ADHF therapy alone (n = 50) or oral spironolactone 100 mg/day plus standard ADHF therapy (n = 50). Spot urine samples were collected at day 1 and day 3 of hospitalization. Spironolactone group had significantly higher spot urine sodium levels compared to standard care group at day 3 (84.13 ± 28.71 mmol/L vs 70.74 ± 34.43 mmol/L, p = 0.04). The proportion of patients with spot urinary sodium <60 mmol/L was lower in spironolactone group at day 3 (18.8 vs 45.7, p = 0.01). In multivariate analysis, spironolactone was independently associated with increased spot urinary sodium and urinary sodium/potassium ratio of >2 at day 3 (both, p < 0.05). Higher spot urine sodium levels were associated with a lower event rate [HR for urinary sodium >100 mmol/L = 0.16 (0.06-0.42), p < 0.01, compared to <60], and provided a significant prognostic gain measured by net reclassification indexes. Spot urinary sodium levels >60 mmol/L and urinary sodium/potassium ratio >2 measured at day 3 of hospitalization for ADHF are associated with improved mid-term outcomes. Spironolactone is associated with increased spot urinary sodium and sodium/potassium ratio >2.

  7. Efficacy and Safety of Spironolactone in Patients with Resistant Hypertension: A Meta-analysis of Randomised Controlled Trials.

    PubMed

    Wang, Chunbin; Xiong, Bo; Huang, Jing

    2016-10-01

    The treatment of resistant hypertension (RH) is challenging. Several observational studies have suggested that the addition of spironolactone to triple-drug therapy might have a promising anti-hypertensive effect on RH. To provide more definite evidence for the benefit of spironolactone, we performed a meta-analysis of randomised controlled trials (RCTs) to evaluate the efficacy and safety of spironolactone in RH patients. Articles were searched from PubMed, EMBASE and Cochrane Library. Randomised controlled trials investigating the effect of additional spironolactone on office blood pressure (BP), ambulatory BP or adverse events in RH patients were included for analysis. Then quality assessment, subgroup, sensitivity, and publication bias analyses were performed. Five RCTs involving a total of 553 patients were eligible for inclusion. Compared with control therapies, additional spironolactone treatment in RH patients significantly decreased 24-h ambulatory systolic BP (ASBP, weight mean difference [WMD]= -10.50, 95% confidence interval [CI] = -12.30 to -8.71, P<0.001), 24-h ambulatory diastolic BP (ADBP, WMD = -4.09, 95% CI = -5.28 to -2.91, P<0.001), daytime ASBP (WMD = -10.20, 95% CI = -12.41 to -7.99, P<0.001), daytime ADBP (WMD = -4.14, 95% CI = -5.50 to -2.78, P<0.001), night-time ASBP (WMD = -10.02, 95% CI = -12.63 to -7.41), night-time ADBP (WMD=-3.21, 95% CI=-4.84 to -1.58, P<0.001), office systolic BP (WMD=-16.99, 95% CI=-25.04 to -8.95, P<0.001) and office diastolic BP (WMD=-6.18, 95% CI=-9.30 to -3.05, P<0.001). However, serum potassium might be slightly elevated by additional spironolactone (WMD=0.181, 95% CI=0.042 to 0.319, P=0.011). Spironolactone combined with triple-drug therapy may be an effective and relatively safe strategy for the management of RH patients. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All

  8. Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment).

    PubMed

    Krieger, Eduardo M; Drager, Luciano F; Giorgi, Dante M A; Pereira, Alexandre C; Barreto-Filho, José Augusto Soares; Nogueira, Armando R; Mill, José Geraldo; Lotufo, Paulo A; Amodeo, Celso; Batista, Marcelo C; Bodanese, Luiz C; Carvalho, Antônio C C; Castro, Iran; Chaves, Hilton; Costa, Eduardo A S; Feitosa, Gilson S; Franco, Roberto J S; Fuchs, Flávio D; Guimarães, Armênio C; Jardim, Paulo C; Machado, Carlos A; Magalhães, Maria E; Mion, Décio; Nascimento, Raimundo M; Nobre, Fernando; Nóbrega, Antônio C; Ribeiro, Antônio L P; Rodrigues-Sobrinho, Carlos R; Sanjuliani, Antônio F; Teixeira, Maria do Carmo B; Krieger, Jose E

    2018-04-01

    The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5-50 mg QD) or clonidine (0.1-0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55-1.88]; P =1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01643434. © 2018 American Heart Association, Inc.

  9. Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study.

    PubMed

    Krum, Henry; Mohacsi, Paul; Katus, Hugo A; Tendera, Michael; Rouleau, Jean-Lucien; Fowler, Michael B; Coats, Andrew J; Roecker, Ellen B; Packer, Milton

    2006-01-01

    The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of

  10. The effect of spironolactone in patients with resistant arterial hypertension in relation to baseline blood pressure and secondary causes of hypertension.

    PubMed

    Vaclavik, Jan; Sedlak, Richard; Jarkovsky, Jiri; Kocianova, Eva; Taborsky, Milos

    2013-03-01

    There are currently limited data about whether the effect of spironolactone in patients with resistant arterial hypertension depends on baseline blood pressure and the presence of a secondary cause of hypertension. Patients with office systolic blood pressure (BP) >140 mmHg or diastolic BP >90 mmHg, despite treatment with at least 3 antihypertensive drugs including a diuretic, were randomly assigned to receive spironolactone or a placebo for 8 weeks in a double-blind, placebo-controlled, multicentre trial (ASPIRANT). Analyses were done with 55 patients treated with spironolactone. The degree of BP reduction after 8 weeks of spironolactone treatment did not differ significantly between the three tertiles of baseline systolic BP and patients with and without a secondary cause of hypertension. The reduction of office systolic, office diastolic BP and office pulse pressure was significantly lower in the highest tertile with baseline diastolic BP > 97 mmHg. Spironolactone treatment is effective to a similar extent both in patients with and without a secondary cause of hypertension and regardless of the baseline value of systolic BP. Less effect of spironolactone was found in patients with the highest baseline diastolic BP.

  11. Comparative study of acetazolamide and spironolactone on body fluid compartments on induction to high altitude

    NASA Astrophysics Data System (ADS)

    Singh, M. V.; Jain, S. C.; Rawal, S. B.; Divekar, H. M.; Parshad, Rajinder; Tyagi, A. K.; Sinha, K. C.

    1986-03-01

    Studies were conducted on 29 male healthy subjects having no previous experience of living at high altitude. These subjects were divided into three groups, i.e., subjects treated with placebo, acetazolamide and spironolactone. These subjects were first studied in Delhi. The drug schedule was started 24 hour prior to the airlift of these subjects to an altitude of 3,500 m and was continued for 48 hour after arrival at high altitude. Total body water, extra cellular water, plasma volume, blood electrolytes, pH, pO2, pCO2 and blood viscosity were determined on 3rd and 12th day of their stay at high altitude. Total body water, extra cellular water intracellular water and plasma volume decreased on high altitude exposure. There was a further slight decrease in these compartments with acetazolamide and spironolactone. It was also observed that spironolactone drives out more water from the extracellular compartment. Loss of plasma water was also confirmed by increased plasma osmolality. Increase in arterial blood pH was noticed on hypoxic exposure but the increase was found less in acetazolamide and spironolactone cases. This decrease in pH is expected to result in better oxygen delivery to the tissues at the low oxygen tension. It was also confirmed because blood pO2 increased in both the groups. No significant change in plasma electrolytes was observed in subjects of various groups. Blood viscosity slightly increased on exposure to high altitude. The degree of rise was found less in the group treated with spironolactone. This study suggests that both the drugs are likely to be beneficial in ameliorating/prevention of AMS syndrome.

  12. Renal Denervation vs. Spironolactone in Resistant Hypertension: Effects on Circadian Patterns and Blood Pressure Variability.

    PubMed

    de la Sierra, Alejandro; Pareja, Julia; Armario, Pedro; Barrera, Ángela; Yun, Sergi; Vázquez, Susana; Sans, Laia; Pascual, Julio; Oliveras, Anna

    2017-01-01

    Sympathetic renal denervation (SRD) has been proposed as a therapeutic alternative for patients with resistant hypertension not controlled on pharmacological therapy. Two studies have suggested an effect of SRD in reducing short-term blood pressure variability (BPV). However, this has not been addressed in a randomized comparative trial. We aimed to compare the effects of spironolactone and SRD on circadian BP and BPV. This is a post-hoc analysis of a randomized trial in 24 true resistant hypertensive patients (15 men, 9 women; mean age 64 years) comparing 50mg of spironolactone (n = 13) vs. SRD (n = 11) on 24-hour BP. We report here the comparative effects on daytime (8 am-10 pm) and nighttime (0 am-6 am) BP, night-to-day ratios and BP and heart rate variabilities (SD and coefficient of variation of 24-hour, day and night, as well as weighted SD and average real variability (ARV)). Spironolactone was more effective than SRD in reducing daytime systolic (P = 0.006), daytime diastolic (P = 0.006), and nighttime systolic (P = 0.050) BP. No differences were observed in the night-to-day ratios. In contrast, SRD-reduced diastolic BPV (24 hours, daytime, nighttime, weighted, and ARV; all P < 0.05) with respect to spironolactone, without significant differences in systolic BPV. Spironolactone is more effective than SRD in reducing ambulatory BP. However, BPV is significantly more reduced with SRD. This effect could be important in terms of potential prevention beyond BP reduction and deserves further investigation. © American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Long-term results and recurrence rates after spironolactone treatment in non-resolving central serous chorio-retinopathy (CSCR).

    PubMed

    Herold, Tina Rike; Rist, Kristina; Priglinger, Siegfried Georg; Ulbig, Michael Werner; Wolf, Armin

    2017-02-01

    To evaluate the long-term results of spironolactone in non-resolving central serous chorio-retinopathy (CSCR) and recurrence rates of CSCR. Interventional uncontrolled open-label prospective clinical trial of patients with non-resolving CSCR who were treated with spironolactone 50 mg daily (Spironolacton AL® 50 mg, ALIUD PHARMA) for up to 16 weeks. Follow-up visits were performed at 3, 6, 9, and 12 months. Retreatment criteria for recurrence were: gain in sub-retinal fluid (SRF) of more than 25 % plus/or increase of central retinal thickness (CRT) of more than 50 μm plus visual symptoms compared to last visit. 12-month efficacy of upload treatment with spironolactone. Secondary outcome measure was the recurrence rate at 6, 9, and 12 months. Of the 21 study eyes treated, 71 % (n = 15) showed significant improvement or complete regression on OCT examination over 12 months. Nineteen percent of the patients (n = 4) showed a stable course from visit 1 to visit 12. The overall reduction of sub-retinal fluid from visit 1 (156 μm ± 131 SD) to visit 12 (53 μm ± 93 SD) was statistically significant (p = 0.003). The change of mean visual acuity (log MAR) from 0.25 (± 0.17 SD) at baseline to 0.17 (± 0.18 SD) at visit 12 was statistically significant, with p = 0.044. Our results confirm a positive effect of spironolactone in non-resolving CSCR in 71 % of cases. Evaluation of recurrence rates and retreatments showed good results in patients who responded to spironolactone primarily. A prospective randomized trial may provide better data about this non-invasive treatment.

  14. Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease.

    PubMed

    Bernay, F; Bland, J M; Häggström, J; Baduel, L; Combes, B; Lopez, A; Kaltsatos, V

    2010-01-01

    Spironolactone, an aldosterone antagonist, has been demonstrated to decrease mortality in human patients when added to other cardiac therapies. Spironolactone in addition to conventional therapy increases survival compared with conventional therapy in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Between February 2003 and March 2005, 221 dogs were recruited in Europe. Nine dogs were excluded from analysis, leaving 212 dogs with moderate to severe mitral regurgitation (MR) caused by MMVD (International Small Animal Cardiac Health Council classification classes II [n = 190] and III [n = 21]). Double-blinded, field study conducted with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin converting enzyme inhibitor, plus furosemide and digoxin if needed). Primary endpoint was a composite of cardiac-related death, euthanasia, or severe worsening of MR. Primary endpoint reached by 11/102 dogs (10.8%) in the spironolactone group (6 deaths, 5 worsening) versus 28/110 (25.5%) in control group (14 deaths, 8 euthanasia, 6 worsening). Risk of reaching the composite endpoint significantly decreased by 55% (hazard ratio [HR] = 0.45; 95% confidence limits [CL], 0.22-0.90; log rank test, P = .017). Risk of cardiac-related death or euthanasia significantly reduced by 69% (HR = 0.31; 95% CL, 0.13-0.76; P = .0071). Number of dogs not completing the study for cardiac and other miscellaneous reasons similar in spironolactone (67/102) and control groups (66/110). Spironolactone added to conventional cardiac therapy decreases the risk of reaching the primary endpoint (ie, cardiac-related death, euthanasia, or severe worsening) in dogs with moderate to severe MR caused by MMVD.

  15. Association between spironolactone added to beta-blockers and ACE inhibition and survival in heart failure patients with reduced ejection fraction: a propensity score-matched cohort study.

    PubMed

    Frankenstein, L; Katus, H A; Grundtvig, M; Hole, T; de Blois, J; Schellberg, D; Atar, D; Zugck, C; Agewall, S

    2013-10-01

    Heart failure (CHF) guidelines recommend mineralocorticoid receptor antagonists for all symptomatic patients treated with a combination of ACE inhibitors/angiotensin receptor blockers (ARBs) and beta-blockers. As opposed to both eplerenone trials, patients in RALES (spironolactone) received almost no beta-blockers. Since pharmacological properties differ between eplerenone and spironolactone, the prognostic benefit of spironolactone added to this baseline combination therapy needs clarification. We included 4,832 CHF patients with chronic systolic dysfunction from the Norwegian Heart Failure Registry and the heart failure outpatients' clinic of the University of Heidelberg. Propensity scores for spironolactone receipt were calculated for each patient and used for matching to patients without spironolactone. During a total follow-up of 17,869 patient-years, 881 patients (27.0 %) died in the non-spironolactone group and 445 (28.4 %) in the spironolactone group. Spironolactone was not associated with improved survival, neither in the complete sample (HR 0.82; 95 % CI 0.64-1.07; HR 1.03; 95 % CI 0.88-1.20; multivariate and propensity score adjusted respectively), nor in the propensity-matched cohort (HR 0.98; 95 % CI 0.82-1.18). In CHF outpatients we were unable to observe an association between the use of spironolactone and improved survival when administered in addition to a combination of ACE/ARB and beta-blockers.

  16. Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study

    PubMed Central

    Gomes, Tara; Mamdani, Muhammad M; Yao, Zhan; Hellings, Chelsea; Garg, Amit X; Weir, Matthew A; Juurlink, David N

    2011-01-01

    Objectives To characterise the risk of admission to hospital for hyperkalaemia in elderly patients treated with trimethoprim-sulfamethoxazole in combination with spironolactone. Design Population based nested case-control study. Setting Ontario, Canada, from 1 April 1992 to 1 March 2010. Participants Cases were residents of Ontario aged 66 years or above receiving chronic treatment with spironolactone and admitted to hospital with hyperkalaemia within 14 days of receiving a prescription for either trimethoprim-sulfamethoxazole, amoxicillin, norfloxacin, or nitrofurantoin. Up to four controls for each case were identified from the same cohort, matched on age, sex, and presence or absence of chronic kidney disease and diabetes, and required to have received one of the study antibiotics within 14 days before the case’s index date. Main outcome measures Odds ratio for association between admission to hospital with hyperkalaemia and receipt of a study antibiotic in the preceding 14 days, adjusted for conditions and drugs that may influence risk of hyperkalaemia. Results During the 18 year study period, 6903 admissions for hyperkalaemia were identified, 306 of which occurred within 14 days of antibiotic use. Of these, 248 (81%) cases were matched to 783 controls. 10.8% (17 859/165 754) of spironolactone users received at least one prescription for trimethoprim-sulfamethoxazole. Compared with amoxicillin, prescription of trimethoprim-sulfamethoxazole was associated with a marked increase in the risk of admission to hospital for hyperkalaemia (adjusted odds ratio 12.4, 95% confidence interval 7.1 to 21.6). The population attributable fraction was 59.7%, suggesting that approximately 60% of all cases of hyperkalaemia in older patients taking spironolactone and treated with an antibiotic for a urinary tract infection could be avoided if trimethoprim-sulfamethoxazole was not prescribed. Treatment with nitrofurantoin was also associated with an increase in the risk of

  17. Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study.

    PubMed

    Antoniou, Tony; Gomes, Tara; Mamdani, Muhammad M; Yao, Zhan; Hellings, Chelsea; Garg, Amit X; Weir, Matthew A; Juurlink, David N

    2011-09-12

    To characterise the risk of admission to hospital for hyperkalaemia in elderly patients treated with trimethoprim-sulfamethoxazole in combination with spironolactone. Population based nested case-control study. Ontario, Canada, from 1 April 1992 to 1 March 2010. Cases were residents of Ontario aged 66 years or above receiving chronic treatment with spironolactone and admitted to hospital with hyperkalaemia within 14 days of receiving a prescription for either trimethoprim-sulfamethoxazole, amoxicillin, norfloxacin, or nitrofurantoin. Up to four controls for each case were identified from the same cohort, matched on age, sex, and presence or absence of chronic kidney disease and diabetes, and required to have received one of the study antibiotics within 14 days before the case's index date. Odds ratio for association between admission to hospital with hyperkalaemia and receipt of a study antibiotic in the preceding 14 days, adjusted for conditions and drugs that may influence risk of hyperkalaemia. During the 18 year study period, 6903 admissions for hyperkalaemia were identified, 306 of which occurred within 14 days of antibiotic use. Of these, 248 (81%) cases were matched to 783 controls. 10.8% (17,859/165,754) of spironolactone users received at least one prescription for trimethoprim-sulfamethoxazole. Compared with amoxicillin, prescription of trimethoprim-sulfamethoxazole was associated with a marked increase in the risk of admission to hospital for hyperkalaemia (adjusted odds ratio 12.4, 95% confidence interval 7.1 to 21.6). The population attributable fraction was 59.7%, suggesting that approximately 60% of all cases of hyperkalaemia in older patients taking spironolactone and treated with an antibiotic for a urinary tract infection could be avoided if trimethoprim-sulfamethoxazole was not prescribed. Treatment with nitrofurantoin was also associated with an increase in the risk of hyperkalaemia (adjusted odds ratio 2.4, 1.3 to 4.6), but no such risk was

  18. Improved bioavailability and clinical response in patients with chronic liver disease following the administration of a spironolactone: β-cyclodextrin complex

    PubMed Central

    Abosehmah-Albidy, A. Z. M.; York, P.; Wong, V.; Losowsky, M. S.; Chrystyn, H.

    1997-01-01

    Aims To compare the absorption and clinical effect of spironolactone from an inclusion complex with β-cyclodextrin (SP-COMP) to Aldactone tablets (ALD) in chronic liver disease. Methods Patients, admitted with chronic liver disease, completed a randomized crossover steady state study. They received their spironolactone dose as either daily SP-COMP or ALD for 7 days. Serial blood samples were drawn over a 24 h period from day 7 of each therapy. Accurate fluid balance was recorded on days 5–7 and 12–14. Thirteen (six females) whose mean (s.d.) age and weight was 58.4(9.3) years and 74.3(19.0) kg completed the study. Results The mean (95% confidence limits) relative bioavailability for SP-COMP (compared with ALD) from steady state serum concentrations of canrenone, 6β-hydroxyl 7α-thiomethyl spironolactone and 7α-thiomethyl spironolactone was 310.0 (265.4, 336.7), 233.4(212.9, 250.8) and 254.8(230.8, 279.0)%, respectively. Improvements in clinical status and fluid balance occurred over the last 3 days of SP-COMP with a mean (s.d.) net loss, in fluid balance, of 1370(860)ml compared with a gain of 228(936)ml during ALD. Conclusions Better absorption of spironolactone from the spironolactone: β-cyclodextrin complex formulation should lead to a reduction in dosage and perhaps a more consistent effect in patients with chronic liver disease. PMID:9241094

  19. Delineating the Effects of Spironolactone on Two Small Fish Species

    EPA Science Inventory

    Spironolactone is a pharmaceutical that acts as an anti-androgen in humans to treat certain conditions such as hirsutism and female pattern hair loss. This drug is also used to treat hypertension, various dermatologic conditions, and as a diuretic. With its common usage for vario...

  20. Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results from the DENERVHTA study - a randomized controlled trial.

    PubMed

    Oliveras, Anna; Armario, Pedro; Clarà, Albert; Sans-Atxer, Laia; Vázquez, Susana; Pascual, Julio; De la Sierra, Alejandro

    2016-09-01

    Both renal denervation (RDN) and spironolactone have been proposed for the treatment of resistant hypertension. However, they have not been compared in a randomized clinical trial. We aimed to compare the efficacy of spironolactone versus RDN in patients with resistant hypertension. A total of 24 patients with office SBP at least 150 mmHg and 24-h SBP at least 140 mmHg despite receiving at least three full-dose antihypertensive drugs, one a diuretic, but without aldosterone antagonists, were randomized to receive RDN or spironolactone (50 mg) as add-on therapy. Primary endpoint was change in 24-h SBP at 6 months. Comparisons between treatment groups were performed using generalized linear models adjusted by age, sex, and baseline values. Spironolactone was more effective than RDN in reducing 24-h SBP and 24-h DBP: mean baseline-adjusted differences between the two groups were -17.9 mmHg (95%CI -30.9 to -4.9); P = 0.010 and -6.6 mmHg (95%CI -12.9 to -0.3); P = 0.041, for 24-h SBP and 24-h DBP, respectively. As regards changes in office blood pressure, mean baseline-adjusted differences between the two groups were -12.1 mmHg (95%CI -29.1 to 5.1); P = 0.158 and of -5.3 mmHg (95%CI -16.3 to 5.8); P = 0.332, for office SBP and office DBP, respectively. Otherwise, the decrease of estimated glomerular filtration rate was greater in the spironolactone group; mean baseline-adjusted difference between the two groups was -10.7 ml/min per 1.73 m (95%CI -20.1 to -1.4); P = 0.027. We conclude that spironolactone is more effective than RDN to reduce 24-h SBP and 24-h DBP in patients with resistant hypertension. Therefore, spironolactone should be the fourth antihypertensive drug to prescribe if deemed well tolerated' in all patients with resistant hypertension before considering RDN.

  1. [Benefits of spironolactone as the optimal treatment for drug resistant hypertension. Pathway-2 trial review].

    PubMed

    Prado, J C; Ruilope, L M; Segura, J

    Pathway-2 is the first randomised, double-blind and crossover trial that compares spironolactone as a fourth drug with alfa-blocker, beta-blocker and placebo. This study shows that spironolactone is the drug with more possibilities of success for the management of patients with difficult-to-treat hypertension in patients with a combination of three drugs and poor control. The results validate the widespread treatment with mineralocorticoid receptor antagonists in resistant hypertension. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Changes in the composition of the thoracic aortic wall in spontaneously hypertensive rats treated with losartan or spironolactone.

    PubMed

    Han, Wei-Qing; Wu, Ling-Yun; Zhou, Hai-Yan; Zhang, Jia; Che, Zai-Qian; Wu, Yong-Jie; Liu, Jian-Jun; Zhu, Ding-Liang; Gao, Ping-Jin

    2009-05-01

    1. In the present study, we compared the elastin and collagen content of thoracic aortic medial and adventitial layers from Wistar-kyoto (WKY) and spontaneously hypertensive rats (SHR). In addition, the effects of losartan, an angiotensin II receptor antagonist, and spironolactone, a mineralocorticoid receptor antagonist, on collagen and elastin content were determined. 2. Prehypertensive (4-week-old) and hypertensive (16-week-old) SHR were randomly divided into three groups treated with either 0.9% NaCl, losartan (20 mg/kg per day) or spironolactone (200 mg/kg per day). Prehypertensive and hypertensive SHR were treated for 12 and 16 weeks, respectively. Age-matched WKY rats were not treated with NaCl, losartan or spironolactone and served as the control group. 3. The medial and adventitial layers of the thoracic aorta were composed mainly of elastin and collagen, respectively, in both SHR and WKY rats. Compared with WKY rats, SHR exhibited greater collagen and elastin content in the media, but decreased collagen and elastin content in the adventitial layer. Both medial and adventitial collagen and elastin content increased significantly with age in both strains and was greater in 32-week-old rats compared with 16-week-old rats. Spironolactone treatment decreased collagen content in the media of thoracic aortas from prehypertensive SHR, whereas losartan decreased collagen content in the media of aortas from hypertensive SHR. In contrast, neither spironolactone nor losartan had any effect on adventitial collagen content in prehypertensive and hypertensive SHR. Medial collagen and elastin were positively related to pulse pressure (PP), but there was no correlation between adventitial mass or collagen content and PP or mean arterial pressure in untreated and treated SHR and WKY rats. 4. In conclusion, the composition of the medial and adventitial layers of the thoracic aorta differs and treatment of SHR with losartan and spironolactone decreases collagen content when

  3. Preparation and characterization of spironolactone-loaded nano-emulsions for extemporaneous applications.

    PubMed

    Hallouard, François; Dollo, Gilles; Brandhonneur, Nolwenn; Grasset, Fabien; Corre, Pascal Le

    2015-01-15

    In neonates as well as in adults having swallowing difficulty, oral medication is given through a nasogastric tube making liquid formulations preferable. In this study, we present the high potential of nanometric emulsions formulated by spontaneous surfactant diffusion, as extemporaneous formulations of hydrophobic drug. Spironolactone used as hydrophobic drug model, was incorporated in oil before formulation at a concentration of 13.5mg/g oil. Then, all formulations were evaluated from pharmacotechnical and clinical standpoints, for their use in hospital or community pharmacy. The strength of this new liquid formulation lies on the simplicity, efficiency and reproducibility of their low energy process as on clinical aspects: high dose uniformity, facility to be administered through in nasogastric tube without any retention and a stability of 2 months at least compatible for an extemporaneous use. Moreover, this emulsion presented spironolactone content of 3.75 mg/ml among the most concentrated formulations published. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Combined oral contraceptives plus spironolactone compared with metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial.

    PubMed

    Alpañés, Macarena; Álvarez-Blasco, Francisco; Fernández-Durán, Elena; Luque-Ramírez, Manuel; Escobar-Morreale, Héctor F

    2017-11-01

    We aimed to compare a combined oral contraceptive (COC) plus the antiandrogen spironolactone with the insulin sensitizer metformin in women with polycystic ovary syndrome (PCOS). We conducted a randomized, parallel, open-label, clinical trial comparing COC (30 μg of ethinylestradiol and 150 μg of desogestrel) plus spironolactone (100 mg/day) with metformin (850 mg b.i.d.) for one year in women with PCOS (EudraCT2008-004531-38). The composite primary outcome included efficacy (amelioration of hirsutism, androgen excess and menstrual dysfunction) and cardiometabolic safety (changes in the frequencies of disorders of glucose tolerance, dyslipidemia and hypertension). A complete anthropometric, biochemical, hormonal and metabolic evaluation was conducted every three months and data were submitted to intention-to-treat analyses. Twenty-four patients were assigned to COC plus spironolactone and 22 patients to metformin. Compared with metformin, COC plus spironolactone caused larger decreases in hirsutism score (mean difference 4.6 points, 95% CI: 2.6-6.7), total testosterone (1.1 nmol/L, 0.4-1.7), free testosterone (25 pmol/L, 12-39), androstenedione (5.5 nmol/L, 1.8-9.2) and dehydroepiandrosterone sulfate (2.7 μmol/L, 1.4-4.0). Menstrual dysfunction was less frequent with COC plus spironolactone (OR: 0.06, 95% CI: 0.02-0.23). No differences were found in frequencies of abnormal glucose tolerance (OR: 1.7, 95% CI: 0.7-4.4), dyslipidemia (OR: 0.6, 95% CI: 0.2-1.8) or hypertension (OR: 0.3, 95% CI: 0.5-2.0). No major adverse events occurred and biochemical markers were similarly safe with both treatments. COC plus spironolactone was more effective than metformin for symptoms of PCOS showing similar safety and overall neutral effects on cardiometabolic risk factors. © 2017 European Society of Endocrinology.

  5. Effects of spironolactone on residual renal function and peritoneal function in peritoneal dialysis patients.

    PubMed

    Yelken, Berna; Gorgulu, Numan; Gursu, Meltem; Yazici, Halil; Caliskan, Yasar; Telci, Aysegul; Ozturk, Savas; Kazancioglu, Rumeyza; Ecder, Tevfik; Bozfakioglu, Semra

    2014-01-01

    There is increasing evidence that long-term peritoneal dialysis (PD) is associated with structural changes in the peritoneal membrane. Inhibition of the renin-angiotensin system has been demonstrated to lessen peritoneal injury and to slow the decline in residual renal function. Whether spironolactone affects residual renal function in addition to the peritoneal membrane is unknown. We evaluated 23 patients (13 women) with a glomerular filtration rate of 2 mL/min/1.73 m2 or more who were receiving PD. Patients with an active infection or peritonitis episode were excluded. Baseline measurements were obtained for serum high-sensitivity C-reactive protein (hs-CRP), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta), and connective tissue growth factor (CTGF); for daily ultrafiltration (in milliliters); for end-to-initial dialysate concentration of glucose (4/D0 glucose), Kt/V, and peritoneal transport status; and for dialysate cancer antigen 125 (CA125). Spironolactone therapy (25 mg) was given daily for 6 months, after which all measurements were repeated. Mean age of the patients was 46 +/- 13 years. Duration of PD was 15 +/- 21 months (range: 2-88 months). After spironolactone therapy, mean dialysate CA125 was significantly increased compared with baseline (20.52 +/- 12.06 U/mL vs. 24.44 +/- 13.97 U/mL, p = 0.028). Serum hs-CRP, VEGF, TGF-beta, CTGF, daily ultrafiltration, D/Do glucose, Kt/V and peritoneal transport status were similar at both times. At the end of the study period, residual glomerular filtration rate in the patients was lower. In PD patients, treatment with spironolactone seems to slow the decline of peritoneal function, suppress the elevation of profibrotic markers, and increase mesothelial cell mass.

  6. PROLACTIN LEVELS DO NOT RISE AMONG TRANSGENDER WOMEN TREATED WITH ESTRADIOL AND SPIRONOLACTONE.

    PubMed

    Bisson, Jason R; Chan, Kelly J; Safer, Joshua D

    2018-04-30

    Existing transgender treatment guidelines suggest that for transfeminine hormone treatment there is a need to monitor prolactin levels. Also, recent studies suggest that use of cyproterone acetate as an adjunctive anti-androgen during transgender hormone treatment may elevate serum prolactin. We sought to determine whether the reported relationship between transfeminine estradiol treatment and hyperprolactinemia would be evident when the regimen used spironolactone as the adjunctive anti-androgen. Estradiol levels, testosterone levels, prolactin levels, and BMI as well as prescribed spironolactone dosage were extracted from the electronic medical records of 98 de-identified transgender women treated with estrogen therapy at the Endocrinology Clinic at Boston Medical Center. Up to 6 years of data were available for some patients. We found no statistically significant relationship between prolactin and any of the other measures. No estrogen dose associated elevations in prolactin were found. None of the patients were diagnosed with prolactinoma. Our data suggest that there may be no significant rise in prolactin when transgender women are treated with estrogen along with spironolactone as the adjunct anti-androgen, and that it may be unnecessary to monitor prolactin in women on this treatment combination. BMI = body mass index; BMC = Boston Medical Center; HT = hormone therapy; ENIGI = European Network for the Investigation of Gender Incongruence; E2 = estradiol; LCMS/MS = liquid chromatography tandem mass spectrometry; T = testosterone.

  7. Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results from the DENERVHTA study – a randomized controlled trial

    PubMed Central

    Oliveras, Anna; Armario, Pedro; Clarà, Albert; Sans-Atxer, Laia; Vázquez, Susana; Pascual, Julio; De la Sierra, Alejandro

    2016-01-01

    Objective: Both renal denervation (RDN) and spironolactone have been proposed for the treatment of resistant hypertension. However, they have not been compared in a randomized clinical trial. We aimed to compare the efficacy of spironolactone versus RDN in patients with resistant hypertension. Methods: A total of 24 patients with office SBP at least 150 mmHg and 24-h SBP at least 140 mmHg despite receiving at least three full-dose antihypertensive drugs, one a diuretic, but without aldosterone antagonists, were randomized to receive RDN or spironolactone (50 mg) as add-on therapy. Primary endpoint was change in 24-h SBP at 6 months. Comparisons between treatment groups were performed using generalized linear models adjusted by age, sex, and baseline values. Results: Spironolactone was more effective than RDN in reducing 24-h SBP and 24-h DBP: mean baseline-adjusted differences between the two groups were −17.9 mmHg (95%CI −30.9 to −4.9); P = 0.010 and −6.6 mmHg (95%CI −12.9 to −0.3); P = 0.041, for 24-h SBP and 24-h DBP, respectively. As regards changes in office blood pressure, mean baseline-adjusted differences between the two groups were −12.1 mmHg (95%CI −29.1 to 5.1); P = 0.158 and of −5.3 mmHg (95%CI −16.3 to 5.8); P = 0.332, for office SBP and office DBP, respectively. Otherwise, the decrease of estimated glomerular filtration rate was greater in the spironolactone group; mean baseline-adjusted difference between the two groups was −10.7 ml/min per 1.73 m2 (95%CI −20.1 to −1.4); P = 0.027. Conclusion: We conclude that spironolactone is more effective than RDN to reduce 24-h SBP and 24-h DBP in patients with resistant hypertension. Therefore, spironolactone should be the fourth antihypertensive drug to prescribe if deemed well tolerated’ in all patients with resistant hypertension before considering RDN. PMID:27327441

  8. Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs.

    PubMed

    Li, Wennan; Chen, Xingjuan; Riley, Ashley M; Hiett, S Christopher; Temm, Constance J; Beli, Eleni; Long, Xin; Chakraborty, Saikat; Alloosh, Mouhamad; White, Fletcher A; Grant, Maria B; Sturek, Michael; Obukhov, Alexander G

    2017-09-01

    Coronary transient receptor potential canonical (TRPC) channel expression is elevated in metabolic syndrome (MetS). However, differential contribution of TRPCs to coronary pathology in MetS is not fully elucidated. We investigated the roles of TRPC1 and TRPC6 isoforms in coronary arteries of MetS pigs and determined whether long-term treatment with a mineralocorticoid receptor inhibitor, spironolactone, attenuates coronary TRPC expression and associated dysfunctions. MetS coronary arteries exhibited significant atherosclerosis, endothelial dysfunction, and increased histamine-induced contractions. Immunohistochemical studies revealed that TRPC6 immunostaining was significantly greater in the medial layer of MetS pig coronary arteries compared to that in Lean pigs, whereas little TRPC6 immunostaining was found in atheromas. Conversely, TRPC1 immunostaining was weak in the medial layer but strong in MetS atheromas, where it was predominantly localized to macrophages. Spironolactone treatment significantly decreased coronary TRPC expression and dysfunctions in MetS pigs. In vivo targeted delivery of the dominant-negative (DN)-TRPC6 cDNA to the coronary wall reduced histamine-induced calcium transients in the MetS coronary artery medial layer, implying a role for TRPC6 in mediating calcium influx in MetS coronary smooth muscles. Monocyte adhesion was increased in Lean pig coronary arteries cultured in the presence of aldosterone; and spironolactone antagonized this effect, suggesting that coronary mineralocorticoid receptor activation may regulate macrophage infiltration. TRPC1 expression in atheroma macrophages was associated with advanced atherosclerosis, whereas medial TRPC6 upregulation correlated with increased histamine-induced calcium transients and coronary contractility. We propose that long-term spironolactone treatment may be a therapeutic strategy to decrease TRPC expression and coronary pathology associated with MetS.

  9. Effect of Spironolactone and Amiloride on Thiazolidinedione-Induced Fluid Retention in South Indian Patients with Type 2 Diabetes

    PubMed Central

    Viswanathan, Vijay; Mohan, Viswanathan; Subramani, Poongothai; Parthasarathy, Nandakumar; Subramaniyam, Gayathri; Manoharan, Deepa; Sundaramoorthy, Chandru; Gnudi, Luigi; Viberti, Giancarlo

    2013-01-01

    Summary Background and objectives Thiazolidinediones (pioglitazone and rosiglitazone) induce renal epithelial sodium channel (ENaC)–mediated sodium reabsorption, resulting in plasma volume (PV) expansion. Incidence and long-term management of fluid retention induced by thiazolidinediones remain unclear. Design, setting, participants, & measurements In a 4-week run-in period, rosiglitazone, 4 mg twice daily, was added to a background anti-diabetic therapy in 260 South Indian patients with type 2 diabetes mellitus. Patients with PV expansion (absolute reduction in hematocrit in run-in, ≥1.5 percentage points) entered a randomized, placebo-controlled study to evaluate effects of amiloride and spironolactone on attenuating rosiglitazone-induced fluid retention. Primary endpoint was change in hematocrit in each diuretic group versus placebo (control group). Results Of the 260 patients, 70% (n=180) had PV expansion. These 180 patients (70% male; mean age, 47.8 years [range, 30–80 years]) were randomly assigned to rosiglitazone, 4 mg twice daily, plus spironolactone, 50 mg once daily; rosiglitazone, 4 mg twice daily, plus amiloride, 10 mg once daily; or rosiglitazone, 4 mg twice daily, plus placebo for 24 weeks. Hematocrit continued to decrease significantly in control and spironolactone groups (mean absolute change, −1.2 [P=0.01] and −0.7 [P=0.02] percentage points, respectively), suggesting continued PV expansion. No change occurred with amiloride (mean change, 0.0 percentage points). Amiloride, but not spironolactone, was superior to control (mean hematocrit difference [95% confidence interval] relative to control, 1.27 [0.21–2.55] and 0.49 [−0.79–1.77] percentage points [P=0.04 and P=0.61], respectively). Conclusions Prevalence of rosiglitazone-induced fluid retention in South Indian patients with type 2 diabetes is high. Amiloride, a direct ENaC blocker, but not spironolactone, prevented protracted fluid retention in these patients. PMID:23184569

  10. Controlled treatment of primary hypertension with propranolol and spironolactone. A crossover study with special reference to initial plasma renin activity.

    PubMed

    Karlberg, B E; Kågedal, B; Tegler, L; Tolagen, K; Bergman, B

    1976-03-31

    Twenty-seven patients with hypertension were randomly allocated to a 10 month crossover study. Treatment consisted of spironolactone (200 mg/day for 2 months), propranolol (320 mg/day for 2 months) and combined administration of both drugs at half the dosage. Between treatment periods placebo was given for 2 months. Fourteen patients were previously untreated. The average pretreatment blood pressure for the entire group was 188/114 +/- 16/7(mean +/- standard deviation) mm Hg supine and 188/118 +/- 20/9 mm Hg standing. Both spironolactone and propranolol reduced blood pressure significantly in both the supine and standing positions. Upright plasma renin activity was determined by radioimmunoassay of angiotensin I. The average initial level was 1.9 +/- 1.2 (range 0.4 to 5.0) ng/ml/hr. There was a close correlation between plasma renin activity and the effects of the drugs: With increasing renin level the response to propranolol was better whereas the opposite was true for spironolactone. The combination of spironolactone and propranolol decreased the blood pressure still further in the supine and standing positions, irrespective of initial plasma renin activity. All patients achieved a normal supine pressure. Blood pressure and plasma renin activity returned toward pretreatment values during placebo administration. It is concluded that pretreatment levels of plasma renin activity can predict the antihypertensive response to propranolol and spironolactone. The combination of the two drugs, which have different modes of action, will effectively reduce blood pressure in hypertension. The results support the concept that the renin-angiotensin-aldo-sterone system may be involved in primary hypertension.

  11. The influence of enalapril and spironolactone on electrolyte concentrations in Doberman pinschers with dilated cardiomyopathy.

    PubMed

    Thomason, J D; Rapoport, G; Fallaw, T; Calvert, C A

    2014-12-01

    The combination of an angiotensin-converting enzyme inhibitor (ACEI) with an aldosterone receptor antagonist can increase serum potassium and magnesium and lower serum sodium concentrations. The objective of this study was to retrospectively determine whether an ACEI and spironolactone can be co-administered to Doberman pinschers with occult dilated cardiomyopathy without serious adverse influences on serum electrolyte concentrations. Between 2001 and 2007, 26 client-owned Doberman pinschers were given enalapril, spironolactone, and carvedilol and followed for at least 6 months. Most dogs had been prescribed mexiletine for ventricular tachyarrhythmia suppression. Dogs were treated with pimobendan when congestive heart failure was imminent. Baseline and follow-up (3-10 visits) color-flow Doppler echocardiograms, serum urea nitrogen (SUN), creatinine, sodium, potassium, and magnesium concentration data were tabulated. Compared to baseline data, there were no significant changes in serum sodium or serum creatinine concentrations. Serum magnesium (P = 0.003), serum potassium (P = 0.0001), and SUN (P = 0.0001) concentrations increased significantly with time. Although the combination of ACEI and spironolactone was associated with significant increases in magnesium, potassium, and SUN concentrations, these changes were of no apparent clinical relevance. At the dosages used in this study, this combination of drugs appears safe. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Effect of low-dose spironolactone on resistant hypertension in type 2 diabetes mellitus: a randomized controlled trial in a sub-Saharan African population.

    PubMed

    Djoumessi, Romance Nguetse; Noubiap, Jean Jacques N; Kaze, Francois Folefack; Essouma, Mickael; Menanga, Alain Patrick; Kengne, Andre Pascal; Mbanya, Jean Claude; Sobngwi, Eugene

    2016-03-23

    Low-dose spironolactone has been proven to be effective for resistant hypertension in the general population, but this has yet to be confirmed in type 2 diabetic (T2DM) patients. We assessed the efficacy of a low-dose spironolactone on resistant hypertension in a sub-Saharan African population of T2DM patients from Cameroon. This was a four-week single blinded randomized controlled trial in 17 subjects presenting with resistant hypertension in specialized diabetes care units in Cameroon. They were randomly assigned to treatment with a daily 25 mg of spironolactone (n = 9) or to an alternative antihypertensive regimen (n = 8), on top of any ongoing regimen and prevailing lifestyle prescriptions. They were seen at the start of the treatment, then 2 and 4 weeks later. The primary outcome was change in office and self-measured blood pressure (BP) during follow-up, and secondary outcomes were changes in serum potassium, sodium, and creatinine levels. Compared with alternative treatment, low-dose spironolactone was associated with significant decrease in office systolic BP (-33 vs. -14 mmHg; p = 0.024), and in diastolic BP (-14 vs. -5 mmHg; p = 0.006). After 1 month of spironolactone, all the patients were controlled based on BP below 130/80 mmHg, with significant office BP reduction from 158 ± 17/86 ± 11 to 125 ± 11/72 ± 8, vs. 158 ± 8/94 ± 8 to 144 ± 17/89 ± 12 mmHg in the alternative treatment group. There was no significant variation in sodium and creatinine levels in both groups, but a mild increase of potassium levels in the spironolactone group. Add-on low-dose spironolactone was effective in reducing BP to optimal levels in T2DM Cameroonian patients despite mild increase in serum potassium. Trial registration ClinicalTrials.gov Identifier NCT02426099. Date of registration April 2015.

  13. Female pattern hair loss: a pilot study investigating combination therapy with low-dose oral minoxidil and spironolactone.

    PubMed

    Sinclair, Rodney D

    2018-01-01

    Minoxidil and spironolactone are oral antihypertensives known to stimulate hair growth. To report on a case series of women with pattern hair loss (PHL) treated with once daily minoxidil 0.25 mg and spironolactone 25 mg. Women newly diagnosed with a Sinclair stage 2-5 PHL were scored for hair shedding and hair density before and after 12 months of treatment with oral minoxidil 0.25 mg and spironolactone 25 mg. A total of 100 women were included in this observational pilot study. Mean age was 48.44 years (range 18-80). Mean hair loss severity at baseline was Sinclair 2.79 (range 2-5). Mean hair shedding score at baseline was 4.82. Mean duration of diagnosis was 6.5 years (range 0.5-30). Mean reduction in hair loss severity score was 0.85 at 6 months and 1.3 at 12 months. Mean reduction in hair shedding score was 2.3 at 6 months and 2.6 at 12 months. Mean change in blood pressure was -4.52 mmHg systolic and -6.48 mmHg diastolic. Side effects were seen in eight women but were generally mild. No patients developed hyperkalemia or any other blood test abnormality. Six of these women continued treatment, and two women who developed urticaria discontinued treatment. Prospective, uncontrolled, open-label observational study. Once daily capsules containing minoxidil 0.25 mg and spironolactone 25 mg appear to be safe and effective in the treatment of FPHL. Placebo-controlled studies to investigate this further are warranted. © 2017 The International Society of Dermatology.

  14. Successive ratio subtraction as a novel manipulation of ratio spectra for quantitative determination of a mixture of furosemide, spironolactone and canrenone

    NASA Astrophysics Data System (ADS)

    Emam, Aml A.; Abdelaleem, Eglal A.; Naguib, Ibrahim A.; Abdallah, Fatma F.; Ali, Nouruddin W.

    2018-03-01

    Furosemide and spironolactone are commonly prescribed antihypertensive drugs. Canrenone is the main degradation product and main metabolite of spironolactone. Ratio subtraction and extended ratio subtraction spectrophotometric methods were previously applied for quantitation of only binary mixtures. An extension of the above mentioned methods; successive ratio subtraction, is introduced in the presented work for quantitative determination of ternary mixtures exemplified by furosemide, spironolactone and canrenone. Manipulating the ratio spectra of the ternary mixture allowed their determination at 273.6 nm, 285 nm and 240 nm and in the concentration ranges of (2-16 μg mL- 1), (4-32 μg mL- 1) and (1-18 μg mL- 1) for furosemide, spironolactone and canrenone, respectively. Method specificity was ensured by the application to laboratory prepared mixtures. The introduced method was ensured to be accurate and precise. Validation of the developed method was done with respect to ICH guidelines and its validity was further ensured by the application to the pharmaceutical formulation. Statistical comparison between the obtained results and those obtained from the reported HPLC method was achieved concerning student's t-test and F ratio test where no significant difference was observed.

  15. Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: a preliminary report.

    PubMed

    Gaddam, K; Pimenta, E; Thomas, S J; Cofield, S S; Oparil, S; Harding, S M; Calhoun, D A

    2010-08-01

    Obstructive sleep apnoea (OSA) and hyperaldosteronism are very common in subjects with resistant hypertension. We hypothesized that aldosterone-mediated chronic fluid retention may influence OSA severity in patients with resistant hypertension. We tested this in an open-label evaluation by assessing the changes in the severity of OSA in patients with resistant hypertension after treatment with spironolactone. Subjects with resistant hypertension (clinical blood pressure (BP) >or=140/90 mm Hg on >or=3 antihypertensive medications, including a thiazide diuretic and OSA (defined as an apnoea-hypopnoea index (AHI) >or=15) had full diagnostic, polysomnography before and 8 weeks after spironolactone (25-50 mg a day) was added to their ongoing antihypertensive therapy. In all, 12 patients (mean age 56 years and body mass index 36.8 kg m(-2)) were evaluated. After treatment with spironolactone, the AHI (39.8+/-19.5 vs 22.0+/-6.8 events/h; P<0.05) and hypoxic index (13.6+/-10.8 vs 6.7+/-6.6 events/h; P<0.05), weight and clinic and ambulatory BP were significantly reduced. Plasma renin activity (PRA) and serum creatinine were significantly higher. This study provides preliminary evidence that treatment with a mineralocorticoid receptor antagonist substantially reduces the severity of OSA. If confirmed in a randomized assessment, it will support aldosterone-mediated chronic fluid retention as an important mediator of OSA severity in patients with resistant hypertension.

  16. Do Diuretics have Antinociceptive Actions: Studies of Spironolactone, Eplerenone, Furosemide and Chlorothiazide, Individually and with Oxycodone and Morphine.

    PubMed

    Jokinen, Viljami; Lilius, Tuomas; Laitila, Jouko; Niemi, Mikko; Kambur, Oleg; Kalso, Eija; Rauhala, Pekka

    2017-01-01

    Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co-administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)- and morphine (3 mg/kg, s.c.)-induced antinociception using tail-flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  17. Cross species sensitivity to a novel androgen receptor agonist of potential environmental concern, spironolactone

    EPA Science Inventory

    Spironolactone (SPL) is a pharmaceutical that is used in humans as an androgen receptor (AR) antagonist to treat conditions like hirsutism, various dermatologic afflictions, and female pattern hair loss, in addition to its common usage as a diuretic to treat hypertension. Althoug...

  18. Role of Adding Spironolactone and Renal Denervation in True Resistant Hypertension: One-Year Outcomes of Randomized PRAGUE-15 Study.

    PubMed

    Rosa, Ján; Widimský, Petr; Waldauf, Petr; Lambert, Lukáš; Zelinka, Tomáš; Táborský, Miloš; Branny, Marian; Toušek, Petr; Petrák, Ondřej; Čurila, Karol; Bednář, František; Holaj, Robert; Štrauch, Branislav; Václavík, Jan; Nykl, Igor; Krátká, Zuzana; Kociánová, Eva; Jiravský, Otakar; Rappová, Gabriela; Indra, Tomáš; Widimský, Jiří

    2016-02-01

    This randomized, multicenter study compared the relative efficacy of renal denervation (RDN) versus pharmacotherapy alone in patients with true resistant hypertension and assessed the effect of spironolactone addition. We present here the 12-month data. A total of 106 patients with true resistant hypertension were enrolled in this study: 52 patients were randomized to RDN and 54 patients to the spironolactone addition, with baseline systolic blood pressure of 159±17 and 155±17 mm Hg and average number of drugs 5.1 and 5.4, respectively. Twelve-month results are available in 101 patients. The intention-to-treat analysis found a comparable mean 24-hour systolic blood pressure decline of 6.4 mm Hg, P=0.001 in RDN versus 8.2 mm Hg, P=0.002 in the pharmacotherapy group. Per-protocol analysis revealed a significant difference of 24-hour systolic blood pressure decline between complete RDN (6.3 mm Hg, P=0.004) and the subgroup where spironolactone was added, and this continued within the 12 months (15 mm Hg, P= 0.003). Renal artery computed tomography angiograms before and after 1 year post-RDN did not reveal any relevant changes. This study shows that over a period of 12 months, RDN is safe, with no serious side effects and no major changes in the renal arteries. RDN in the settings of true resistant hypertension with confirmed compliance is not superior to intensified pharmacological treatment. Spironolactone addition (if tolerated) seems to be more effective in blood pressure reduction. © 2015 American Heart Association, Inc.

  19. Identification of a novel androgen receptor agonist (or “androgen mimic”) of environmental concern: spironolactone

    EPA Science Inventory

    Spironolactone is a pharmaceutical that acts as an androgen receptor (AR) antagonist in humans to treat certain conditions such as hirsutism, various dermatologic afflictions, and female pattern hair loss. The drug is also used to treat hypertension as a diuretic. With this commo...

  20. The Effect of Spironolactone on the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Cardiac Catheterization: Study Design and Rationale.

    PubMed

    Mujtaba, Alhasan; Taher, Mohammed A; Hazza, Mazin A; Al-Rubaye, Hassan M; Kata, Asaad H; AbdulWahab, Hamid; AbdulBari, AbdulAmeer; AlRubay, Hayder K

    2018-05-21

    Patients undergoing coronary catheterization are at high risk of developing contrast-induced nephropathy (CIN) acute kidney injury (AKI). Several approaches have been supposed to limit such an effect but with mixed results or non-practical methods. Spironolactone is supposed to be effective as a nephroprotective agent in animal studies. This study will try to measure the effect of spironolactone on the incidence of CIN-AKI in patients undergoing coronary catheterization (angiography angioplasty). This study is a single-center, investigator-driven, double-blinded randomized controlled study in Iraq-Basra. More than 400 patients admitted for coronary angio unit in our center will be allocated in a 1:1 ratio to receive either spironolactone 200 mg single dose or placebo in addition to their usual premedication. Primary end point will be CIN defined as more than 25% or 0.3 mg/dl elevation in serum creatinine (S.Cr.) from baseline during the first 2-3 days after the procedure. We hope to identify or answer an important question regarding CIN in such high-risk patients. ClinicalTrials.gov Identifier, NCT03329443.

  1. Antifailure therapy including spironolactone improves left ventricular energy supply-demand relations in nonischemic dilated cardiomyopathy.

    PubMed

    Bell, Susan P; Adkisson, Douglas W; Lawson, Mark A; Wang, Li; Ooi, Henry; Sawyer, Douglas B; Kronenberg, Marvin W

    2014-08-27

    Left ventricular (LV) energy supply-demand imbalance is postulated to cause "energy starvation" and contribute to heart failure (HF) in nonischemic dilated cardiomyopathy (NIDCM). Using cardiac magnetic resonance (CMR) and [(11)C] acetate positron emission tomography (PET), we evaluated LV perfusion and oxidative metabolism in NIDCM and the effects of spironolactone on LV supply-demand relations. Twelve patients with NIDCM underwent CMR and PET at baseline and after ≥6 months of spironolactone therapy added to a standard HF regimen. The myocardial perfusion reserve index (MPRI) was calculated after gadolinium injection during adenosine, as compared to rest. The monoexponential clearance rate of [(11)C] acetate (kmono) was used to calculate the work metabolic index (WMI), an index of LV mechanical efficiency, and kmono/RPP (rate-pressure product), an index of energy supply/demand. At baseline, the subendocardium was hypoperfused versus the subepicardium (median MPRI, 1.63 vs. 1.80; P<0.001), but improved to 1.80 (P<0.001) after spironolactone. The WMI increased (P=0.001), as did kmono/RPP (P=0.003). These improvements were associated with reverse remodeling, increased LV ejection fraction, and decreases in LV mass and systolic wall stress (all P<0.002). NIDCM is associated with subendocardial hypoperfusion and impaired myocardial oxidative metabolism, consistent with energy starvation. Antifailure therapy improves parameters of energy starvation and is associated with augmented LV performance. http://www.clinicaltrials.gov/ Unique identifier: ID NCT00574119. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  2. Regression of left ventricular hypertrophy and aortic remodelling in NO-deficient hypertensive rats: effect of L-arginine and spironolactone.

    PubMed

    Paulis, L; Matuskova, J; Adamcova, M; Pelouch, V; Simko, J; Krajcirovicova, K; Potacova, A; Hulin, I; Janega, P; Pechanova, O; Simko, F

    2008-09-01

    We investigated, whether the substrate for nitric oxide (NO) formation -L-arginine - and the aldosterone receptor antagonist - spironolactone - are able to reverse alterations of the left ventricle (LV) and aorta in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Six groups of male adult Wistar rats were investigated: controls after 4 and 7 weeks of experiment, rats treated with L-NAME for 4 weeks and three recovery groups: spontaneous-reversion (4 weeks L-NAME + 3 weeks placebo), spironolactone-induced reversion (4 weeks L-NAME + 3 weeks spironolactone) and L-arginine-induced reversion (4 weeks L-NAME+ 3 weeks L-arginine). Blood pressure was measured by tail-cuff plethysmography. Relative weight of the LV, myocardial fibrosis (based upon histomorphometry and hydroxyproline determination) and conjugated dienes in the LV and aortic cross-sectional area, inner diameter and wall thickness were determined. NO-synthase activity was investigated in the LV and aorta. L-NAME administration induced hypertension, left ventricular hypertrophy (LVH), LV fibrosis, aortic thickening and diminution of NO-synthase activity in the LV and aorta. Reduction in blood pressure and regression of LVH were observed in all recovery groups, yet reduction in LV fibrosis and aortic thickening were not. NO-synthase activity was restored only in the L-arginine and spironolactone group. In our study, the reversion of hypertension and LVH was not dependent on the restoration of NO-synthase activity. Moreover, LV fibrosis and aortic remodelling seem to be more resistant to conditions resulting in regression of LVH. Preserved level of fibrosis in the initial period of LVH regression might result in loss of structural homogeneity and possible functional alterations of the LV.

  3. Effects of Different Doses of Irbesartan Combined With Spironolactone on Urinary Albumin Excretion Rate in Elderly Patients With Early Type 2 Diabetic Nephropathy.

    PubMed

    Chen, Yingying; Liu, Peng; Chen, Xia; Li, Yanan; Zhang, Fengmei; Wang, Yangang

    2018-05-01

    There is a lack of research on the effect of low dose of angiotensin receptor blockers combined with spironolactone, and the effect of high dose of angiotensin receptor blockers alone on the urinary albumin excretion rate (UAER) in elderly patients with early type 2 diabetic nephropathy (DN). We conducted a prospective, randomized, open-label, parallel-controlled study that included 244 elderly patients with early DN and mild-to-moderate essential hypertension. Patients were randomly divided into 4 groups: low-dose irbesartan (group A), high-dose irbesartan (group B), low-dose irbesartan combined with spironolactone (group C) and high-dose irbesartan combined with spironolactone (group D). Changes in UAER, serum potassium and blood pressure were compared. There were no statistical differences in the baseline characteristics among groups. Furthermore, no significant difference in blood pressure before and after treatment was found among different groups. After 72-week treatment, UAER in group D was lower compared to group A and B (P < 0.05). Meanwhile, compared with group B, UAER in group C decreased significantly (P < 0.05). Additionally, significantly higher serum potassium was found in group D compared to other groups (P < 0.05). Also, group D had the highest count of patients who withdrew from the study due to hyperkalemia compared to other groups (P < 0.05). Our results indicate high-dose irbesartan combined with spironolactone may be more efficient in reducing UAER in elderly patients with early DN, but this treatment could cause hyperkalemia. Low-dose irbesartan combined with spironolactone was shown to be safer and more effective in decreasing UAER compared to high-dose irbesartan. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  4. National quality assessment evaluating spironolactone use during hospitalization for acute myocardial infarction (AMI) in China: China Patient-centered Evaluation Assessment of Cardiac Events (PEACE)-Retrospective AMI Study, 2001, 2006, and 2011.

    PubMed

    Guan, Wenchi; Murugiah, Karthik; Downing, Nicholas; Li, Jing; Wang, Qing; Ross, Joseph S; Desai, Nihar R; Masoudi, Frederick A; Spertus, John A; Li, Xi; Krumholz, Harlan M; Jiang, Lixin

    2015-06-12

    Spironolactone, the only aldosterone antagonist available in China, improves outcomes in acute myocardial infarction (AMI) among patients with systolic dysfunction and either diabetes or heart failure (HF). However, national practice patterns in the use of spironolactone in China are unknown. From a nationally representative sample of AMI patients from in 2001, 2006, and 2011, we identified 6906 patients with either diabetes or HF and classified them into 1 of 4 groups according to their eligibility for spironolactone-"ideal"(left ventricular ejection fraction [LVEF] ≤40% and without contraindications), "contraindicated," "not indicated" (neither ideal nor contraindicated), and "unknown indications" (LVEF unmeasured)-to determine how frequently patient eligibility for this drug is assessed in the hospital, how it is used in several groups, and to identify factors associated with the use in these groups. From 2001 to 2011, the proportion of patients whose eligibility for spironolactone was not assessed decreased (66.9% in 2001 to 32.8% in 2011). Spironolactone use significantly increased among ideal patients over this period (28.6% to 72.4%; P<0.001 for trend), but also in contraindicated patients (11.4% to 27.5%; P=0.002 for trend) and in other patients groups (not indicated: 27.5% to 38.3%; unknown indications: 21.3% to 35.1%; both P<0.01 for trend). In all 4 groups, patients presenting with HF on admission were more likely to receive spironolactone. Although the appropriate use of spironolactone and assessment of eligibility increased in China over the past decade, there remains marked opportunities for improvement. URL: http://www.clinicaltrials.gov Unique identifier: NCT01624883. © 2015 The Authors. Published on behalf of the American Heart Association, Inc, by Wiley Blackwell.

  5. Biotransformation of the mineralocorticoid receptor antagonists spironolactone and canrenone by human CYP11B1 and CYP11B2: Characterization of the products and their influence on mineralocorticoid receptor transactivation.

    PubMed

    Schiffer, Lina; Müller, Anne-Rose; Hobler, Anna; Brixius-Anderko, Simone; Zapp, Josef; Hannemann, Frank; Bernhardt, Rita

    2016-10-01

    Spironolactone and its major metabolite canrenone are potent mineralocorticoid receptor antagonists and are, therefore, applied as drugs for the treatment of primary aldosteronism and essential hypertension. We report that both compounds can be converted by the purified adrenocortical cytochromes P450 CYP11B1 and CYP11B2, while no conversion of the selective mineralocorticoid receptor antagonist eplerenone was observed. As their natural function, CYP11B1 and CYP11B2 carry out the final steps in the biosynthesis of gluco- and mineralocorticoids. Dissociation constants for the new exogenous substrates were determined by a spectroscopic binding assay and demonstrated to be comparable to those of the natural substrates, 11-deoxycortisol and 11-deoxycorticosterone. Metabolites were produced at preparative scale with a CYP11B2-dependent Escherichia coli whole-cell system and purified by HPLC. Using NMR spectroscopy, the metabolites of spironolactone were identified as 11β-OH-spironolactone, 18-OH-spironolactone and 19-OH-spironolactone. Canrenone was converted to 11β-OH-canrenone, 18-OH-canrenone as well as to the CYP11B2-specific product 11β,18-diOH-canrenone. Therefore, a contribution of CYP11B1 and CYP11B2 to the biotransformation of drugs should be taken into account and the metabolites should be tested for their potential toxic and pharmacological effects. A mineralocorticoid receptor transactivation assay in antagonist mode revealed 11β-OH-spironolactone as pharmaceutically active metabolite, whereas all other hydroxylation products negate the antagonist properties of spironolactone and canrenone. Thus, human CYP11B1 and CYP11B2 turned out to metabolize steroid-based drugs additionally to the liver-dependent biotransformation of drugs. Compared with the action of the parental drug, changed properties of the metabolites at the target site have been observed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Pulmonary vein isolation combined with spironolactone or renal sympathetic denervation in patients with chronic kidney disease, uncontrolled hypertension, paroxysmal atrial fibrillation, and a pacemaker.

    PubMed

    Kiuchi, Márcio Galindo; Chen, Shaojie; Hoye, Neil Alexander; Pürerfellner, Helmut

    2018-01-01

    Atrial fibrillation (AF) commonly occurs in chronic kidney disease (CKD), occasioning adverse outcomes. Merging pulmonary vein isolation (PVI) and renal sympathetic denervation (RSD) may decrease the recurrence of AF in subjects with CKD and uncontrolled hypertension. We considered that RSD could reduce the recurrence of AF in patients with CKD by modulating sympathetic hyperactivity. We aimed to evaluate the impact of RSD or spironolactone 50 mg/day associated with PVI in reducing systolic blood pressure (BP), AF recurrence, and AF burden in patients with a history of paroxysmal AF and mild CKD. This was a single-center, prospective, longitudinal, randomized, double-blind study. The individuals were randomly divided into two groups (PVI + spironolactone, n = 36, and PVI + RSD, n = 33). All of them were followed for exactly 1 year to assess maintenance of sinus rhythm and to monitor the other variables. Ambulatory BP measurements were reduced in both groups and at the 12th month also differed between groups. Significantly more patients in the PVI + RSD (61%) than in the PVI + spironolactone group (36%) were AF-free at the 12th month of follow-up, P = 0.0242. Toward the end of the study, the mean AF burden was lower in the PVI + RSD group as compared to PVI + spironolactone group, at the 9th month: ∆ = - 10% (P < 0.0001), and at the 12th month: ∆ = - 12% (P < 0.0001), respectively. PVI + RSD is safe and appears to be superior to PVI + spironolactone in BP reduction, augmentation of AF event-free rate, reduction of AF burden, and improvement of renal function.

  7. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies.

    PubMed

    Williams, Bryan; MacDonald, Thomas M; Morant, Steve V; Webb, David J; Sever, Peter; McInnes, Gordon T; Ford, Ian; Cruickshank, J Kennedy; Caulfield, Mark J; Padmanabhan, Sandosh; Mackenzie, Isla S; Salsbury, Jackie; Brown, Morris J

    2018-06-01

    In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081. Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r 2 =0·13, p<0·0001) and plasma renin (r 2 =0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from

  8. The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease

    PubMed Central

    Edwards, Nicola C; Steeds, Richard P; Chue, Colin D; Stewart, Paul M; Ferro, Charles J; Townend, Jonathan N

    2012-01-01

    AIM Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30–89 ml/min/1.73m2) received 25 mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed. RESULTS After 40 weeks of treatment the incidence of serious hyperkalaemia (K+≥6.0 mmol/L) was <1%. A potassium 5.5–5.9 mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0 mmol/L and eGFR ≤45 ml/min/1.73m2. Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks. CONCLUSION Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested. PMID:21950312

  9. The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease.

    PubMed

    Edwards, Nicola C; Steeds, Richard P; Chue, Colin D; Stewart, Paul M; Ferro, Charles J; Townend, Jonathan N

    2012-03-01

    Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30-89ml/min/1.73m(2) ) received 25mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed. After 40 weeks of treatment the incidence of serious hyperkalaemia (K(+) ≥6.0mmol/L) was <1%. A potassium 5.5-5.9mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0mmol/L and eGFR ≤45 ml/min/1.73m(2) . Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks. Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  10. Optimization and Validation of a Sensitive Method for HPLC-PDA Simultaneous Determination of Torasemide and Spironolactone in Human Plasma using Central Composite Design.

    PubMed

    Subramanian, Venkatesan; Nagappan, Kannappan; Sandeep Mannemala, Sai

    2015-01-01

    A sensitive, accurate, precise and rapid HPLC-PDA method was developed and validated for the simultaneous determination of torasemide and spironolactone in human plasma using Design of experiments. Central composite design was used to optimize the method using content of acetonitrile, concentration of buffer and pH of mobile phase as independent variables, while the retention factor of spironolactone, resolution between torasemide and phenobarbitone; and retention time of phenobarbitone were chosen as dependent variables. The chromatographic separation was achieved on Phenomenex C(18) column and the mobile phase comprising 20 mM potassium dihydrogen ortho phosphate buffer (pH-3.2) and acetonitrile in 82.5:17.5 v/v pumped at a flow rate of 1.0 mL min(-1). The method was validated according to USFDA guidelines in terms of selectivity, linearity, accuracy, precision, recovery and stability. The limit of quantitation values were 80 and 50 ng mL(-1) for torasemide and spironolactone respectively. Furthermore, the sensitivity and simplicity of the method suggests the validity of method for routine clinical studies.

  11. A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial.

    PubMed

    Elinoff, Jason M; Rame, J Eduardo; Forfia, Paul R; Hall, Mary K; Sun, Junfeng; Gharib, Ahmed M; Abd-Elmoniem, Khaled; Graninger, Grace; Harper, Bonnie; Danner, Robert L; Solomon, Michael A

    2013-04-02

    Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction plays a central role in the pathogenesis and progression of pulmonary arterial hypertension. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic and disease-associated pulmonary arterial hypertension. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular failure and death has not been tested. Spironolactone, a mineralocorticoid and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with pulmonary arterial hypertension and symptoms of right heart failure includes use of mineralocorticoid receptor antagonists for their diuretic and natriuretic effects. We hypothesize that initiating spironolactone therapy at an earlier stage of disease in patients with pulmonary arterial hypertension could provide additional benefits through anti-inflammatory effects and improvements in pulmonary vascular function. Seventy patients with pulmonary arterial hypertension without clinical evidence of right ventricular failure will be enrolled in a randomized, double-blinded, placebo-controlled trial to investigate the effect of early treatment with spironolactone on exercise capacity, clinical worsening and vascular inflammation in vivo. Our primary endpoint is change in placebo-corrected 6-minute walk distance at 24 weeks and the incidence of clinical worsening in the spironolactone group compared to placebo. At a two-sided alpha level of 0.05, we will have at least 84% power to detect an effect size (group mean difference divided by standard deviation) of 0.9 for the difference in the change of 6-minute walk distance from baseline between the two groups. Secondary endpoints include the effect of

  12. A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction plays a central role in the pathogenesis and progression of pulmonary arterial hypertension. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic and disease-associated pulmonary arterial hypertension. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular failure and death has not been tested. Spironolactone, a mineralocorticoid and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with pulmonary arterial hypertension and symptoms of right heart failure includes use of mineralocorticoid receptor antagonists for their diuretic and natriuretic effects. We hypothesize that initiating spironolactone therapy at an earlier stage of disease in patients with pulmonary arterial hypertension could provide additional benefits through anti-inflammatory effects and improvements in pulmonary vascular function. Methods/Design Seventy patients with pulmonary arterial hypertension without clinical evidence of right ventricular failure will be enrolled in a randomized, double-blinded, placebo-controlled trial to investigate the effect of early treatment with spironolactone on exercise capacity, clinical worsening and vascular inflammation in vivo. Our primary endpoint is change in placebo-corrected 6-minute walk distance at 24 weeks and the incidence of clinical worsening in the spironolactone group compared to placebo. At a two-sided alpha level of 0.05, we will have at least 84% power to detect an effect size (group mean difference divided by standard deviation) of 0.9 for the difference in the change of 6-minute walk distance from baseline between the two groups. Secondary endpoints include

  13. Organ damage changes in patients with resistant hypertension randomized to renal denervation or spironolactone: The DENERVHTA (Denervación en Hipertensión Arterial) study.

    PubMed

    Oliveras, Anna; Armario, Pedro; Sans, Laia; Clarà, Albert; Vázquez, Susana; Molina, Luis; Pareja, Júlia; de la Sierra, Alejandro; Pascual, Julio

    2018-01-01

    Renal denervation and spironolactone have both been proposed for the treatment of resistant hypertension, but their effects on preclinical target organ damage have not been compared. Twenty-four patients with 24-hour systolic blood pressure ≥140 mm Hg despite receiving three or more full-dose antihypertensive drugs, one a diuretic, were randomized to receive spironolactone or renal denervation. Changes in 24-hour blood pressure, urine albumin excretion, arterial stiffness, carotid intima-media thickness, and left ventricular mass index were evaluated at 6 months. Mean baseline-adjusted difference between the two groups (spironolactone vs renal denervation) at 6 months in 24-hour systolic blood pressure was -17.9 mm Hg (95% confidence interval [CI], -30.9 to -4.9; P = .01). Mean baseline-adjusted change in urine albumin excretion was -87.2 (95% CI, -164.5 to -9.9) and -23.8 (95% CI, -104.5 to 56.9), respectively (P = .028). Mean baseline-adjusted variation of 24-hour pulse pressure was -13.5 (95% CI, -18.8 to -8.2) and -2.1 (95% CI, -7.9 to 3.7), respectively (P = .006). The correlation of change in 24-hour systolic blood pressure with change in log-transformed urine albumin excretion was r = .713 (P < .001). At 6 months there was a reduction in albuminuria in patients with resistant hypertension treated with spironolactone as compared with renal denervation. ©2018 Wiley Periodicals, Inc.

  14. Effect of losartan and spironolactone on triglyceride-rich lipoproteins in diabetic nephropathy

    PubMed Central

    Srivastava, Anand; Adams-Huet, Beverley; Vega, Gloria L; Toto, Robert D

    2016-01-01

    Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can improve dyslipidemia in patients with diabetes and albuminuria. Whether combined ACEi+ARB or ACEi+mineralocorticoid receptor blockade improves dyslipidemia is not known. We hypothesized long-term administration of either losartan 100 mg or spironolactone 25 mg once daily added onto lisinopril 80 mg once daily would improve dyslipidemia in diabetic nephropathy (DN). We measured lipid levels, very-low-density (V), intermediate-density (I), low-density (LDL), high-density (HDL) lipoprotein, LDL particle size with their respective cholesterol (C) and apolipoprotein B levels (ApoB), and urine albumin/creatinine ratio (UACR) at 12-week interval during a 48-week randomized, double-blind placebo-controlled trial in 81 patients with DN. Plasma lipids and lipoprotein C were analyzed enzymatically and Apo B was determined chemically. Data were analyzed by mixed model repeated measures. ΔUACR differed among treatment arms (placebo −24.6%, los −38.2%, spiro −51.6%, p=0.02). No correlation existed between ΔUACR and ΔTG or any of the lipid or lipoprotein measurements. Compared with placebo losartan, but not spironolactone, decreased TG (−20.9% vs +34.3%, p<0.01), V+I C(−18.8% vs +21.3%, p<0.01), and V+I-ApoB (−13.2% vs +21%, p<0.01). There were no significant changes in body weight, HbA1c or other lipoprotein variables. We conclude losartan improves dyslipidemia in patients with DN. We speculate the mechanism improved clearance of VLDL and remnant lipoproteins. Trial registration number NCT00381134; Results. PMID:27388615

  15. Nanostructured DPA-MPC-DPA triblock copolymer gel for controlled drug release of ketoprofen and spironolactone.

    PubMed

    Azmy, Bahaa; Standen, Guy; Kristova, Petra; Flint, Andrew; Lewis, Andrew L; Salvage, Jonathan P

    2017-08-01

    Uncontrolled rapid release of drugs can reduce their therapeutic efficacy and cause undesirable toxicity; however, controlled release from reservoir materials helps overcome this issue. The aims of this study were to determine the release profiles of ketoprofen and spironolactone from a pH-responsive self-assembling DPA-MPC-DPA triblock copolymer gel and elucidate underlying physiochemical properties. Drug release profiles from DPA 50 -MPC 250 -DPA 50 gel (pH 7.5), over 32 h (37 °C), were determined using UV-Vis spectroscopy. Nanoparticle size was measured by dynamic light scattering (DLS) and critical micelle concentration (CMC) by pyrene fluorescence. Polymer gel viscosity was examined via rheology, nanoparticle morphology investigated using scanning transmission electron microscopy (STEM) and the gel matrix observed using cryo-scanning electron microscopy (Cryo-SEM). DPA 50 -MPC 250 -DPA 50 copolymer (15% w/v) formed a free-standing gel (pH 7.5) that controlled drug release relative to free drugs. The copolymer possessed a low CMC, nanoparticle size increased with copolymer concentration, and DLS data were consistent with STEM. The gel displayed thermostable viscosity at physiological temperatures, and the gel matrix was a nanostructured aggregation of smaller nanoparticles. The DPA 50 -MPC 250 -DPA 50 copolymer gel could be used as a drug delivery system to provide the controlled drug release of ketoprofen and spironolactone. © 2017 Royal Pharmaceutical Society.

  16. Fungal biotransformation of diuretic and antihypertensive drug spironolactone with Gibberella fujikuroi, Curvularia lunata, Fusarium lini, and Aspergillus alliaceus.

    PubMed

    Al-Aboudi, Amal; Kana'an, Belal Muneeb; Zarga, Musa Abu; Bano, Saira; Atia-Tul-Wahab; Javed, Kulsoom; Choudhary, M Iqbal

    2017-12-01

    Derivatives of spironolactone (1), a diuretic and antihypertensive drug, were synthesized by using fungal cells for the first time. Ten different fungi were screened for their ability to biotransform 1, four of which were able to produce metabolites 2-8. Gibberella fujikuroi produced canrenone (2), 1-dehydrocanrenone (3), Curvularia lunuta provided compound 2, and 7α-thio-spironolactone (4), Fusarium lini yielded compounds 2, 3, 1β-hydroxycanrenone (5), 1α-hydroxycanrenone (6), 1-dehydro-15α-hydroxycanrenone (7), and 15α-hydroxycanrenone (8), while Aspergillus alliaceus was able to produce all the seven metabolites. Metabolites 5, 6, and 7 were identified as new compounds. Their structures were elucidated by using different spectroscopic techniques. Substrate 1 and its metabolites 2, 3, and 5-8 were also evaluated for α-glucosidase inhibitory activity in vitro. Substrate 1 was found to be strongly active with IC 50  = 335 ± 4.3 μM as compared to the standard drug acarbose IC 50  = 840 ± 1.73 μM, whereas all of resulting metabolites were found to be inactive. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. [Dissociation of antihypertensive and metabolic response to losartan and spironolactone in experimental rats with metabolic sindrome].

    PubMed

    Machado, Hussen; Pinheiro, Helady Sanders; Terra, Marcella Martins; Guerra, Martha de Oliveira; de Paula, Rogerio Baumgratz; Peters, Vera Maria

    2012-01-01

    The treatment of arterial hypertension (AH) in patients with metabolic syndrome (MS) is a challenge, since non drug therapies are difficult to implement and optimal pharmacological treatment is not fully established. To assess the blockade of the rennin angiotensin aldosterone system (RAAS) in blood pressure (BP) in renal function and morphology in an experimental model of MS induced by high fat diet. Wistar rats were fed on high fat diet from the fourth week of life, for 20 weeks. The groups received Losartan or Spironolactone from the eighth week of life. We weekly evaluated the body weight and BP by tail plethysmography. At the end of the experiment oral glucose tolerance, lipid profile, creatinine clearance tests, and the direct measurement of BP were performed. A morphometric kidney analysis was performed. The administration of high-fat diet was associated with the development of MS, characterized by central fat accumulation, hypertension, hyperglycemia and hypertriglyceridemia. In this model there were no changes in renal histomorphometry. The blockade of angiotensin II (Ang II) receptor AT1 prevented the development of hypertension. The mineralocorticoid blockage did not have antihypertensive efficacy but was associated with reduction of abdominal fat. The dissociation of the antihypertensive response to the blockades of Ang II receptors and mineralocorticoid indicates the involvement of Ang II in the pathogenesis of hypertension associated with obesity. Reduction of central obesity with Spironolactone suggests the presence of mineralocorticoid adipogenic effect.

  18. Follicular delivery of spironolactone via nanostructured lipid carriers for management of alopecia.

    PubMed

    Shamma, Rehab Nabil; Aburahma, Mona Hassan

    2014-01-01

    Spironolactone (SL) is a US Food and Drug Administration-approved drug for the treatment of hypertension and various edematous conditions. SL has gained a lot of attention for treating androgenic alopecia due to its potent antiandrogenic properties. Recently, there has been growing interest for follicular targeting of drug molecules for treatment of hair and scalp disorders using nanocolloidal lipid-based delivery systems to minimize unnecessary systemic side effects associated with oral drug administration. Accordingly, the objective of this study is to improve SL efficiency and safety in treating alopecia through the preparation of colloidal nanostructured lipid carriers (NLCs) for follicular drug delivery. SL-loaded NLCs were prepared by an emulsion solvent diffusion and evaporation method using 23 full factorial design. All of the prepared formulations were spherical in shape with nanometric size range (215.6-834.3 nm) and entrapment efficiency >74%. Differential scanning calorimetry thermograms and X-ray diffractograms revealed that SL exists in amorphous form within the NLC matrices. The drug release behavior from the NLCs displayed an initial burst release phase followed by sustained release of SL. Confocal laser scanning microscopy confirmed the potential of delivering the fluorolabeled NLCs within the follicles, suggesting the possibility of using SL-loaded NLCs for localized delivery of SL into the scalp hair follicles.

  19. Follicular delivery of spironolactone via nanostructured lipid carriers for management of alopecia

    PubMed Central

    Shamma, Rehab Nabil; Aburahma, Mona Hassan

    2014-01-01

    Spironolactone (SL) is a US Food and Drug Administration-approved drug for the treatment of hypertension and various edematous conditions. SL has gained a lot of attention for treating androgenic alopecia due to its potent antiandrogenic properties. Recently, there has been growing interest for follicular targeting of drug molecules for treatment of hair and scalp disorders using nanocolloidal lipid-based delivery systems to minimize unnecessary systemic side effects associated with oral drug administration. Accordingly, the objective of this study is to improve SL efficiency and safety in treating alopecia through the preparation of colloidal nanostructured lipid carriers (NLCs) for follicular drug delivery. SL-loaded NLCs were prepared by an emulsion solvent diffusion and evaporation method using 23 full factorial design. All of the prepared formulations were spherical in shape with nanometric size range (215.6–834.3 nm) and entrapment efficiency >74%. Differential scanning calorimetry thermograms and X-ray diffractograms revealed that SL exists in amorphous form within the NLC matrices. The drug release behavior from the NLCs displayed an initial burst release phase followed by sustained release of SL. Confocal laser scanning microscopy confirmed the potential of delivering the fluorolabeled NLCs within the follicles, suggesting the possibility of using SL-loaded NLCs for localized delivery of SL into the scalp hair follicles. PMID:25473283

  20. Spironolactone loaded nanostructured lipid carrier gel for effective treatment of mild and moderate acne vulgaris: A randomized, double-blind, prospective trial.

    PubMed

    Kelidari, Hamid Reza; Saeedi, Majid; Hajheydari, Zohreh; Akbari, Jafar; Morteza-Semnani, Katayoun; Akhtari, Javad; Valizadeh, Hadi; Asare-Addo, Kofi; Nokhodchi, Ali

    2016-10-01

    Spironolactone (SP) known as an anti-androgen drug, has been proven to be effective in treatment of acne. The quest to minimize the unnecessary systemic side effects associated with the oral drug administration of spironolactone, has led to a growing interest of loading SP on lipid nanoparticles to deliver the drug in a topical formulation. The aim of the current investigation was to prepare and compare the performance of SP loaded nanostructured lipid carrier (SP-NLC) and SP alcoholic gels (SP-ALC) on two groups of respective patient populations, group A and group B in the treatment of mild to moderate acne vulgaris. The results showed that SP-NLCs were spherical in shape with an average diameter of ∼240nm. The polydispersity index (PI) and zeta potential of these nanoparticles were 0.286 and -21.4 respectively. The gels showed non-Newtonian independent pseudoplastic and shear thinning behavior. The SP-NLCs was not toxic to fibroblast cell strains at the 24 and 48h periods. Results showed that the mean number of total lesions (37.66±9.27) and non-inflammatory lesions (29.26±7.99) in group A significantly decreased to 20.31±6.58 (p<0.05) and to 13.95±5.22 (p<0.05) respectively. A similar pattern was observed for group B where the mean number of total lesions and non-inflammatory lesions reduced from 33.73±9.40 to 19.13±5.53 (p<0.05) and from 25.65±8.12 to 13.45±4.48 (p<0.05) respectively. The total lesion count (TLC) was significantly decreased from 37.16±9.28 to 19.63±6.36 (for group A; p<0.071) and 32.60±9.32 to 18.33±5.55 (for group B; p<0.05) respectively. After treatment with SP-NLC for 8 weeks, the water content of the skin significantly (p<0.05) increased from 37.44±8.85 to 45.69±19.34 instrumental units. Therefore, the SP-NLC gel may help in controlling acne vulgaris with skin care benefits. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. In-vitro and in-vivo study of amorphous spironolactone prepared by adsorption method using supercritical CO2.

    PubMed

    Jiang, Qikun; Li, Yuanyuan; Fu, Qiang; Geng, Yajie; Zhao, Juanhang; Ma, Panqin; Zhang, Tianhong

    2015-02-01

    The aim of this study was to improve the oral bioavailability of spironolactone (SP). SP was adsorbed on the fumed silica using supercritical CO2 (scCO2) technology and further compressed into tablets. The morphology was observed by scanning electron microscopy (SEM), and the crystalline form was investigated by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution test was performed in water, 0.1 M HCl solution, pH 4.5 acetate buffers and pH 6.8 phosphate buffers using the paddle method. The pharmacokinetics was undertaken in six dogs in a crossover fashion. SP was successfully prepared into tablets and presented in amorphous state. SP-silica scCO2 tablets displayed higher dissolution profiles than SP-silica physical mixtures tablets in different media. The AUC0-t and Cmax of SP-silica supercritical CO2 was 1.61- and 1.52-fold greater than those of SP-silica physical mixtures (p < 0.05), respectively. It is a promising method in improving dissolution and bioavailability by adsorbing SP, a poorly soluble drug, on the fumed silica using rapid expansion of supercritical solutions.

  2. Comparison of desogestrel/ethinyl estradiol plus spironolactone versus cyproterone acetate/ethinyl estradiol in the treatment of polycystic ovary syndrome: a randomized controlled trial.

    PubMed

    Leelaphiwat, Supatra; Jongwutiwes, Theerayut; Lertvikool, Srithean; Tabcharoen, Chotika; Sukprasert, Matchuporn; Rattanasiri, Sasivimol; Weerakiet, Sawaek

    2015-03-01

    To compare the effects of ethinyl estradiol (EE) 30 mcg/desogestrel 150 mcg plus spironolactone 25 mg/day (group A) versus EE 35 mcg/cyproterone acetate 2 mg (group B) on hyperandrogenism and metabolism in PCOS. This was a randomized clinical study. Eighteen women in groups A and B received medications for three cycles. Acne score, androgens and metabolic parameters were assessed before and after treatment. One and two women in groups A and B, respectively, were excluded from the study. Both groups had significantly decreased acne score and free androgen index, and increased sex hormone-binding globulin levels. Cholesterol and high-density lipoprotein were significantly increased in group B, and androstenedione was significantly decreased in group A. The regular withdrawal bleeding was obtained in both groups. Both regimens had quite similar efficacy on hyperandrogenism after three cycles of therapy and without any changes in metabolic parameters. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

  3. Renal denervation in comparison with intensified pharmacotherapy in true resistant hypertension: 2-year outcomes of randomized PRAGUE-15 study.

    PubMed

    Rosa, Ján; Widimský, Petr; Waldauf, Petr; Zelinka, Tomáš; Petrák, Ondřej; Táborský, Miloš; Branny, Marian; Toušek, Petr; Čurila, Karol; Lambert, Lukáš; Bednář, František; Holaj, Robert; Štrauch, Branislav; Václavík, Jan; Kociánová, Eva; Nykl, Igor; Jiravský, Otakar; Rappová, Gabriela; Indra, Tomáš; Krátká, Zuzana; Widimský, Jiří

    2017-05-01

    The randomized, multicentre study compared the efficacy of renal denervation (RDN) versus spironolactone addition in patients with true resistant hypertension. We present the 24-month data. A total of 106 patients with true resistant hypertension were enrolled in this study: 52 patients were randomized to RDN and 54 patients to the spironolactone addition, with baseline SBP of 159 ± 17 and 155 ± 17 mmHg and average number of drugs 5.1 and 5.4, respectively. Two-year data are available in 86 patients. Spironolactone addition, as crossover after 1 year, was performed in 23 patients after RDN, and spironolactone addition followed by RDN was performed in five patients. Similar and comparable reduction of 24-h SBP after RDN or spironolactone addition after randomization was observed, 9.1 mmHg (P = 0.001) and 10.9 mmHg (P = 0.001), respectively. Similar decrease of office blood pressure (BP) was observed, 17.7 mmHg (P < 0.001) versus 14.1 mmHg (P < 0.001), whereas the number of antihypertensive drugs did not differ significantly between groups. Crossover analysis showed nonsignificantly better efficacy of spironolactone addition in 24-h SBP and office SBP reduction than RDN (3.7 mmHg, P = 0.27 and 4.6 mmHg, P = 0.28 in favour of spironolactone addition, respectively). Meanwhile, the number of antihypertensive drugs was significantly increased after spironolactone addition (+0.7, P = 0.001). In the settings of true resistant hypertension, spironolactone addition (if tolerated) seems to be of better efficacy than RDN in BP reduction over a period of 24 months. However, by contrast to the 12-month results, BP changes were not significantly greater.

  4. Spironolactone

    MedlinePlus

    ... causes the kidneys to eliminate unneeded water and sodium from the body into the urine but reduces ... your meals, including advice for a reduced-salt (sodium) diet and daily exercise program. Avoid potassium-containing ...

  5. The Prognostic Importance of Impaired Systolic Function in Heart Failure with Preserved Ejection Fraction and the Impact of Spironolactone

    PubMed Central

    Shah, Amil M.; Claggett, Brian; Sweitzer, Nancy K.; Shah, Sanjiv J.; Anand, Inder S.; Liu, Li; Pitt, Bertram; Pfeffer, Marc A.; Solomon, Scott D.

    2015-01-01

    Background Impairment in left ventricular (LV) systolic function has been described in heart failure with preserved ejection fraction (HFpEF), but its prognostic relevance is not known. We determined whether LV longitudinal strain (LS) is predictive of cardiovascular (CV) outcomes in HFpEF beyond clinical and conventional echocardiographic measures. Methods and Results LS was assessed by 2D speckle-tracking echocardiography at baseline in 447 HFpEF patients enrolled in the Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. At a median follow-up of 2.6 (IQR 1.5–3.9) years, 115 patients experienced the primary composite outcome of CV death, HF hospitalization, or aborted cardiac arrest. Impaired LS, defined as an absolute LS<15.8%, was present in 52% of patients and was predictive of the composite outcome (adjusted HR 2.14, 95% CI 1.26–3.66; p=0.005), CV death alone (adjusted HR 3.20, 95% CI 1.44–7.12; p=0.004), and HF hospitalization alone (adjusted HR 2.23, 95% CI 1.16–4.28; p=0.016) after adjusting for clinical and conventional echocardiographic variables. LS was the strongest echocardiographic predictor of the composite outcome. Exploratory analysis in a subset of 131 patients with follow-up LS assessed after 12–18 months demonstrated a trend towards improvement in LS associated with spironolactone in patients enrolled in the Americas but not in Russia or Georgia. Conclusions Impaired LV systolic function is a powerful predictor of HF hospitalization, CV death, or aborted cardiac arrest in HFpEF, independent of clinical predictors. Impaired LS represents a novel imaging biomarker to identify HFpEF patients at particularly high risk for CV morbidity and mortality. Clinical Trial Registration Information Clinicaltrials.gov. Identifier NCT00094302. PMID:26130119

  6. Environmental Xenobiotics and the Antihormones Cyproterone Acetate and Spironolactone Use the Nuclear Hormone Pregnenolone X Receptor to Activate the CYP3A23 Hormone Response Element

    PubMed Central

    SCHUETZ, ERIN G.; BRIMER, CYNTHIA; SCHUETZ, JOHN D.

    2013-01-01

    The pregnenolone X receptor (PXR), a new member of the nuclear hormone receptor superfamily, was recently demonstrated to mediate glucocorticoid agonist and antagonist activation of a hormone response element spaced by three nucleotides (DR-3) within the rat CYP3A23 promoter. Because many other steroids and xenobiotics can up-regulate CYP3A23 expression, we determined whether some of these other regulators used PXR to activate the CYP3A23 DR-3. Transient cotransfection of LLC-PK1 cells with (CYP3A23)2-tk-CAT and mouse PXR demonstrated that the organochlorine pesticides transnonachlor and chlordane and the nonplanar polychlorinated biphenyls (PCBs) each induced the CYP3A23 DR-3 element, and this activation required PXR. Additionally, this study found that PXR is activated to induce (CYP3A23)2-tk-CAT by antihormones of several steroid classes including the antimineralocorticoid spironolactone and the antiandrogen cyproterone acetate. These studies reveal that PXR is involved in the induction of CYP3A23 by pharmacologically and structurally distinct steroids and xenobiotics. Moreover, PXR-mediated PCB activation of the (CYP3A23)2-tk-CAT may serve as a rapid assay for effects of nonplanar PCBs. PMID:9855641

  7. Potassium handling with dual renin-angiotensin system inhibition in diabetic nephropathy.

    PubMed

    Van Buren, Peter N; Adams-Huet, Beverley; Nguyen, Mark; Molina, Christopher; Toto, Robert D

    2014-02-01

    Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation. In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models. Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P<0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P<0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study. Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of

  8. [Drug-induced gynecomastia].

    PubMed

    Schirren, U; Hinz, B; Schirren, C

    1986-01-01

    Concerning four own observations by men in the age of 41-69 years it has been reported about the drug-induced gynecomastia. It can be demonstrated that the spironolactone induced gynecomastia disappeared after stopping this drug. The knowledge of such side effects is the condition for a pre-information of the patient at the beginning of therapy. The mode of action of spironolactone is discussed. It is referred about the important role of the disturbance of the relation androgen: estrogens under spironolactone as well as the peripheral antiandrogen effect of this substance.

  9. Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: six-month results from the Prague-15 study.

    PubMed

    Rosa, Ján; Widimský, Petr; Toušek, Petr; Petrák, Ondřej; Čurila, Karol; Waldauf, Petr; Bednář, František; Zelinka, Tomáš; Holaj, Robert; Štrauch, Branislav; Šomlóová, Zuzana; Táborský, Miloš; Václavík, Jan; Kociánová, Eva; Branny, Marian; Nykl, Igor; Jiravský, Otakar; Widimský, Jiří

    2015-02-01

    This prospective, randomized, open-label multicenter trial evaluated the efficacy of catheter-based renal denervation (Symplicity, Medtronic) versus intensified pharmacological treatment including spironolactone (if tolerated) in patients with true-resistant hypertension. This was confirmed by 24-hour ambulatory blood pressure monitoring after excluding secondary hypertension and confirmation of adherence to therapy by measurement of plasma antihypertensive drug levels before enrollment. One-hundred six patients were randomized to renal denervation (n=52), or intensified pharmacological treatment (n=54) with baseline systolic blood pressure of 159±17 and 155±17 mm Hg and average number of drugs 5.1 and 5.4, respectively. A significant reduction in 24-hour average systolic blood pressure after 6 months (-8.6 [95% cofidence interval: -11.8, -5.3] mm Hg; P<0.001 in renal denervation versus -8.1 [95% cofidence interval: -12.7, -3.4] mm Hg; P=0.001 in pharmacological group) was observed, which was comparable in both groups. Similarly, a significant reduction in systolic office blood pressure (-12.4 [95% cofidence interval: -17.0, -7.8] mm Hg; P<0.001 in renal denervation versus -14.3 [95% cofidence interval: -19.7, -8.9] mm Hg; P<0.001 in pharmacological group) was present. Between-group differences in change were not significant. The average number of antihypertensive drugs used after 6 months was significantly higher in the pharmacological group (+0.3 drugs; P<0.001). A significant increase in serum creatinine and a parallel decrease of creatinine clearance were observed in the pharmacological group; between-group difference were borderline significant. The 6-month results of this study confirmed the safety of renal denervation. In conclusion, renal denervation achieved reduction of blood pressure comparable with intensified pharmacotherapy. © 2014 American Heart Association, Inc.

  10. The association between drospirenone and hyperkalemia: a comparative-safety study

    PubMed Central

    2011-01-01

    Background Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia. Methods A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone Results The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy. Conclusions A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert. PMID:22208934

  11. The association between drospirenone and hyperkalemia: a comparative-safety study.

    PubMed

    Bird, Steven T; Pepe, Salvatore R; Etminan, Mahyar; Liu, Xinyue; Brophy, James M; Delaney, Joseph Ac

    2011-12-30

    Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia. A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy. A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.

  12. Spironolactone and Hydrochlorothiazide

    MedlinePlus

    ... antagonists. It causes the kidneys to eliminate unneeded water and sodium from the body into the urine, ... is in a class of medications called diuretics (''water pills''). It works by causing the kidneys to ...

  13. A randomized trial on mineralocorticoid receptor blockade in men: effects on stress responses, selective attention, and memory.

    PubMed

    Cornelisse, Sandra; Joëls, Marian; Smeets, Tom

    2011-12-01

    Corticosteroids, released in high amounts after stress, exert their effects via two different receptors in the brain: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). GRs have a role in normalizing stress-induced effects and promoting consolidation, while MRs are thought to be important in determining the threshold for activation of the hypothalamic-pituitary-adrenal (HPA) axis. We investigated the effects of MR blockade on HPA axis responses to stress and stress-induced changes in cognitive function. In a double-blind, placebo-controlled study, 64 healthy young men received 400 mg of the MR antagonist spironolactone or placebo. After 1.5 h, they were exposed to either a Trier Social Stress Test or a non-stressful control task. Responses to stress were evaluated by hormonal, subjective, and physiological measurements. Afterwards, selective attention, working memory, and long-term memory performance were assessed. Spironolactone increased basal salivary cortisol levels as well as cortisol levels in response to stress. Furthermore, spironolactone significantly impaired selective attention, but only in the control group. The stress group receiving spironolactone showed impaired working memory performance. By contrast, long-term memory was enhanced in this group. These data support a role of MRs in the regulation of the HPA axis under basal conditions as well as in response to stress. The increased availability of cortisol after spironolactone treatment implies enhanced GR activation, which, in combination with MR blockade, presumably resulted in a decreased MR/GR activation ratio. This condition influences both selective attention and performance in various memory tasks.

  14. TESTOSTERONE LEVELS ACHIEVED BY MEDICALLY TREATED TRANSGENDER WOMEN IN A UNITED STATES ENDOCRINOLOGY CLINIC COHORT.

    PubMed

    Liang, Jennifer J; Jolly, Divya; Chan, Kelly J; Safer, Joshua D

    2018-02-01

    Most transgender women depend on medical treatment alone to lower testosterone levels in order to align physical appearance with gender identity. The medical regimen in the United States typically includes spironolactone and estrogens. The purpose of this cross-sectional study was to assess the testosterone suppression achieved among transgender women treated with spironolactone and estrogens. Testosterone and estradiol levels were extracted from the electronic medical records of 98 anonymized transgender women treated with oral spironolactone and oral estrogen therapy at the Endocrinology Clinic at Boston Medical Center. Patients starting therapy required about 9 months to reach a steady-state testosterone, with significant heterogeneity of levels achieved among patients. Patients with normal body mass index (BMI) had higher testosterone levels, whereas patients with obese BMI had lower testosterone levels throughout treatment. Stratification of patients by age or spironolactone dosage revealed no significant difference in testosterone levels achieved. At steady state, patients in the highest suppressing quartile were able to achieve testosterone levels of 27 ng/dL, with a standard deviation of 21 ng/dL. Measured serum estradiol levels did not change over time and did not correlate with dosage of estradiol administered. Among a cohort of transgender women treated with spironolactone and estrogen, the highest suppressing quartile could reliably achieve testosterone levels in the female range at virtually all times. The second highest suppressing quartile could not achieve female levels but remained below the male range virtually all of the time. One quartile was unable to achieve any significant suppression. BMC = Boston Medical Center BMI = body mass index CPY = cyproterone acetate LC-MS/MS = liquid chromatography-tandem mass spectrometry Q = quartile.

  15. Diuretic exposure in premature infants from 1997–2011

    PubMed Central

    Laughon, Matthew M.; Chantala, Kim; Aliaga, Sofia; Herring, Amy H.; Hornik, Christoph P.; Hughes, Rachel; Clark, Reese H.; Smith, P. Brian

    2014-01-01

    Objective Diuretics are often prescribed off-label to premature infants, particularly to prevent or treat bronchopulmonary dysplasia (BPD). We examined their use and safety in this group. Study Design Retrospective cohort study of infants <32 weeks gestation and <1500 g birth weight exposed to diuretics in 333 neonatal intensive care units from 1997–2011. We examined use of acetazolamide, amiloride, bumetanide, chlorothiazide, diazoxide, ethacrynic acid, furosemide, hydrochlorothiazide, mannitol, metolazone, or spironolactone combination. Respiratory support and FiO2 on the first day of each course of diuretic use were identified. Results Thirty-seven percent (39,357/107,542) of infants were exposed to at least 1 diuretic; furosemide was the most commonly used (93% with ≥1 recorded dose), followed by spironolactone, chlorothiazide, hydrochlorothiazide, bumetanide, and acetazolamide. Seventy-four percent were exposed to 1 diuretic at a time, 19% to 2 diuretics simultaneously, and 6% to 3 diuretics simultaneously. The most common combination was furosemide/spironolactone, followed by furosemide/chlorothiazide and chlorothiazide/spironolactone. Many infants were not receiving mechanical ventilation on the first day of each new course of furosemide (47%), spironolactone (69%), chlorothiazide (61%), and hydrochlorothiazide (68%). Any adverse event occurred on 42 per 1000 infant-days for any diuretic and 35 per 1000 infant-days for furosemide. Any serious adverse event occurred in 3.8 for any diuretic and 3.2 per 1000 infant-days for furosemide. The most common laboratory abnormality associated with diuretic exposure was thrombocytopenia. Conclusion Despite no FDA indication and little safety data, over one third of premature infants in our population were exposed to a diuretic, many with minimal respiratory support. PMID:24801161

  16. Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response.

    PubMed

    Martin-Lorenzo, Marta; Martinez, Paula J; Baldan-Martin, Montserrat; Ruiz-Hurtado, Gema; Prado, Jose Carlos; Segura, Julian; de la Cuesta, Fernando; Barderas, Maria G; Vivanco, Fernando; Ruilope, Luis Miguel; Alvarez-Llamas, Gloria

    2017-11-01

    Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered ( P <0.0001). Metabolic concentrations were quantified and ranged from ng/mL malate to μg/mL citrate. Citrate and oxaloacetate increased in RH versus pseudoresistant. Together with α-ketoglutarate and malate, they were able to discriminate between responders and nonresponders, being the 4 metabolites increased in nonresponders. Combined as a prediction panel, they showed receiver operating characteristiccurve with area under the curve of 0.96. We show that citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone. © 2017 American Heart Association, Inc.

  17. Impact of worsening renal function related to medication in heart failure.

    PubMed

    Brunner-La Rocca, Hans-Peter; Knackstedt, Christian; Eurlings, Luc; Rolny, Vinzent; Krause, Friedemann; Pfisterer, Matthias E; Tobler, Daniel; Rickenbacher, Peter; Maeder, Micha T

    2015-02-01

    Renal failure is a major challenge in treating heart failure (HF) patients. HF medication may deteriorate renal function, but the impact thereof on outcome is unknown. We investigated the effects of HF medication on worsening renal function (WRF) and the relationship to outcome. This post-hoc analysis of TIME-CHF (NT-proBNP-guided vs. symptom-guided management in chronic HF) included patients with LVEF ≤45% and ≥1 follow-up visit (n = 462). WRF III was defined as a rise in serum creatinine ≥0.5 mg/dL (i.e. 44.2 µmol/L) at any time during the first 6 months. Four classes of medication were considered: loop diuretics, beta-blockers, renin-angiotensin system (RAS)-blockers, and spironolactone. Functional principal component analysis of daily doses was used to comprehend medication over time. All-cause mortality after 18 months was the primary outcome. Interactions between WRF, medication, and outcome were tested. Patients with WRF III received on average higher loop diuretic doses (P = 0.0002) and more spironolactone (P = 0.02), whereas beta-blockers (P = 0.69) did not differ and lower doses of RAS-blockers were given (P = 0.09). There were significant interactions between WRF III, medicationn and outcome. Thus, WRF III was associated with poor prognosis if high loop diuretic doses were given (P = 0.001), but not with low doses (P = 0.29). The opposite was found for spironolactone (poor prognosis in the case of WRF III with no spironolactone, P <0.0001; but not with spironolactone, P = 0.31). Beta-blockers were protective in all patients (P <0.001), but most in those with WRF III (P <0.05 for interaction). RAS-blockade was associated with improved outcome (P = 0.006), irrespective of WRF III. Based on this analysis, it may be hypothesized that high doses of loop diuretics might have detrimental effects, particularly in combination with significant WRF, whereas spironolactone and beta-blockers might be protective in patients with WRF. © 2014 The Authors

  18. Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease

    PubMed Central

    Bushinsky, David A.; Kitzman, Dalane W.; Ruschitzka, Frank; Metra, Marco; Filippatos, Gerasimos; Rossignol, Patrick; Du Mond, Charles; Garza, Dahlia; Berman, Lance; Lainscak, Mitja

    2018-01-01

    Abstract Aims Hyperkalaemia risk precludes optimal renin–angiotensin–aldosterone system inhibitor use in patients with heart failure (HF), particularly those with chronic kidney disease (CKD). Patiromer is a sodium‐free, non‐absorbed potassium (K+)‐binding polymer approved for the treatment of hyperkalaemia. In PEARL‐HF, patiromer 25.2 g (fixed dose) prevented hyperkalaemia in HF patients with or without CKD initiating spironolactone. The current study evaluated the effectiveness of a lower starting dose of patiromer (16.4 g/day) followed by individualized titration in preventing hyperkalaemia and hypokalaemia when initiating spironolactone. Methods and results This open‐label 8‐week study enrolled 63 patients with CKD, serum K+ 4.3–5.1 mEq/L, and chronic HF, who, based on investigator opinion, should receive spironolactone. Eligible patients started spironolactone 25 mg/day and patiromer 16.8 g/day (divided into two doses), with patiromer titrated to maintain serum K+ 4.0–5.1 mEq/L. Mean (standard deviation) serum K+ was 4.78 (0.51) mEq/L at baseline; weekly values were 4.48–4.70 mEq/L during treatment. Serum K+ of 3.5–5.5 mEq/L at the end of study treatment (primary endpoint) was achieved by 57 (90.5%) patients; 53 (84.1%) had serum K+ 4.0–5.1 mEq/L. One patient (1.6%) developed hypokalaemia, and two patients (3.2%) developed hypomagnesaemia. Spironolactone was increased to 50 mg/day in all patients; 43 (68%) patients required one or more patiromer dose titration. Adverse events (AEs) occurred in 36 (57.1%) patients, with a low rate of discontinuations [four (6.3%) patients]. The most common AE was mild to moderate abdominal discomfort [four (6.3%) patients]. Conclusions In this open‐label study, patiromer 16.8 g/day followed by individualized titration maintained serum K+ within the target range in the majority of patients with HF and CKD, all of whom were uptitrated to spironolactone 50 mg/day, patiromer was well

  19. A study comparing the efficacy of antimicrobial agents versus enzyme (P-gp) inducers in the treatment of 2,4,6 trinitrobenzenesulfonic acid-induced colitis in rats.

    PubMed

    Toklu, H Z; Kabasakal, L; Imeryuz, N; Kan, B; Celikel, C; Cetinel, S; Orun, O; Yuksel, M; Dulger, G A

    2013-08-01

    The intestinal microflora is an important cofactor in the pathogenesis of intestinal inflammation; and the epithelial cell barrier function is critical in providing protection against the stimulation of mucosal immune system by the microflora. In the present study, therapeutic role of the antibacterial drugs rifampicin and ciprofloxacine were investigated in comparison to spironolactone, an enzyme inducer, in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis of the rats. Drugs were administered for 14 days following induction of colitis. All drug treatments ameliorated the clinical hallmarks of colitis as determined by body weight loss and assessment of diarrhea, colon length, and histology. Oxidative damage and neutrophil infiltration as well as nuclear factor κB (NF-κB) and tumor necrosis factor α (TNF-α) expressions that were increased during colitis, were decreased significantly. Rifampicin and ciprofloxacin were probably effective due to their antibacterial and immunomodulating properties. The multidrug resistence gene (MDR1) and its product p-glycoprotein (P-gp) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). In the present study, findings of the P-gp expression were inconclusive but regarding previous studies, it can be suggested that the beneficial effects of rifampicin and spironolactone may be partly due to their action as a P-gp ligand. Spironolactone has been reported to supress the transcription of proinflamatory cytokines that are considered to be of importance in immunoinflammatory diseases. It is also a powerful pregnane X receptor (PXR) inducer; thus, inhibition of the expression of NF-κB and TNF-α, and amelioration of inflammation by spironolactone suggest that this may have been through the activation of PXR. However, our findings regarding PXR expression were inconclusive. Activation of PXR by spironolactone probably also contributed to the induction of P-gp, resulting in extrusion of noxious substances

  20. Aldosterone Induces Renal Fibrosis and Inflammatory M1-Macrophage Subtype via Mineralocorticoid Receptor in Rats

    PubMed Central

    Martín-Fernández, Beatriz; Rubio-Navarro, Alfonso; Cortegano, Isabel; Ballesteros, Sandra; Alía, Mario; Cannata-Ortiz, Pablo; Olivares-Álvaro, Elena; Egido, Jesús; de Andrés, Belén; Gaspar, María Luisa; de las Heras, Natalia; Lahera, Vicente; Moreno, Juan Antonio

    2016-01-01

    We aimed to evaluate macrophages heterogeneity and structural, functional and inflammatory alterations in rat kidney by aldosterone + salt administration. The effects of treatment with spironolactone on above parameters were also analyzed. Male Wistar rats received aldosterone (1 mgkg-1d-1) + 1% NaCl for 3 weeks. Half of the animals were treated with spironolactone (200 mg kg-1d-1). Systolic and diastolic blood pressures were elevated (p<0.05) in aldosterone + salt–treated rats. Relative kidney weight, collagen content, fibronectin, macrophage infiltrate, CTGF, Col I, MMP2, TNF-α, CD68, Arg2, and SGK-1 were increased (p<0.05) in aldosterone + salt–treated rats, being reduced by spironolactone (p<0.05). Increased iNOS and IFN-γ mRNA gene expression (M1 macrophage markers) was observed in aldosterone + salt rats, whereas no significant differences were observed in IL-10 and gene ArgI mRNA expression or ED2 protein content (M2 macrophage markers). All the observed changes were blocked with spironolactone treatment. Macrophage depletion with liposomal clodronate reduced macrophage influx and inflammatory M1 markers (INF-γ or iNOS), whereas interstitial fibrosis was only partially reduced after this intervention, in aldosterone plus salt-treated rats. In conclusion, aldosterone + salt administration mediates inflammatory M1 macrophage phenotype and increased fibrosis throughout mineralocorticoid receptors activation. PMID:26730742

  1. Prevention of liver cancer cachexia-induced cardiac wasting and heart failure.

    PubMed

    Springer, Jochen; Tschirner, Anika; Haghikia, Arash; von Haehling, Stephan; Lal, Hind; Grzesiak, Aleksandra; Kaschina, Elena; Palus, Sandra; Pötsch, Mareike; von Websky, Karoline; Hocher, Berthold; Latouche, Celine; Jaisser, Frederic; Morawietz, Lars; Coats, Andrew J S; Beadle, John; Argiles, Josep M; Thum, Thomas; Földes, Gabor; Doehner, Wolfram; Hilfiker-Kleiner, Denise; Force, Thomas; Anker, Stefan D

    2014-04-01

    Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.

  2. Prevention of liver cancer cachexia-induced cardiac wasting and heart failure

    PubMed Central

    Springer, Jochen; Tschirner, Anika; Haghikia, Arash; von Haehling, Stephan; Lal, Hind; Grzesiak, Aleksandra; Kaschina, Elena; Palus, Sandra; Pötsch, Mareike; von Websky, Karoline; Hocher, Berthold; Latouche, Celine; Jaisser, Frederic; Morawietz, Lars; Coats, Andrew J.S.; Beadle, John; Argiles, Josep M.; Thum, Thomas; Földes, Gabor; Doehner, Wolfram; Hilfiker-Kleiner, Denise; Force, Thomas; Anker, Stefan D.

    2014-01-01

    Aims Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). Methods and results Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. Conclusion Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer. PMID:23990596

  3. Ethics and eplerenone.

    PubMed

    Gupta, Shruti; Fugh-Berman, Adriane J; Scialli, Anthony

    2013-02-01

    The use of a placebo arm in clinical trials is unethical if there is an active comparator that is acceptably safe and effective. We argue that reasonable evidence of effectiveness and safety of an inexpensive alternative to an expensive therapy is sufficient to require that the inexpensive therapy be included as a comparator when the expensive therapy is tested, and that use of an inactive placebo comparator only is not ethical. For example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of unnecessary cost in medical care as an example of non-maleficence. Several ethical actors in the design, conduct, and publication of clinical trials and their results bear responsibility for the appropriate conduct of clinical trials. That responsibility includes protecting study subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and expensive therapies.

  4. Hormonal Treatment of Transgender Women with Oral Estradiol.

    PubMed

    Leinung, Matthew C; Feustel, Paul J; Joseph, Jalaja

    2018-01-01

    Purpose: Maintaining cross-sex hormone levels in the normal physiologic range for the desired gender is the cornerstone of transgender hormonal therapy, but there are limited data on how to achieve this. We investigated the effectiveness of oral estradiol therapy in achieving this goal. Methods: We analyzed data on all transgender females seen in our clinic since 2008 treated with oral estradiol. We looked at the success of achieving serum levels of testosterone and 17-β estradiol in the normal range on various doses of estradiol (with and without antiandrogens spironolactone and finasteride). Results: There was a positive correlation between estradiol dose and 17-β estradiol, but testosterone suppression was less well correlated. Over 70% achieved treatment goals (adequate 17-β estradiol levels and testosterone suppression) on 4 mg daily or more. Nearly a third of patients did not achieve adequate treatment goals on 6 or even 8 mg daily of estradiol. Spironolactone, but not finasteride, use was associated with impairment of obtaining desired 17-β estradiol levels. Spironolactone did not enhance testosterone suppression, and finasteride was associated with higher testosterone levels. Conclusions: Oral estradiol was effective in achieving desired serum levels of 17-β estradiol, but there was wide individual variability in the amount required. Oral estradiol alone was not infrequently unable to achieve adequate testosterone suppression. Spironolactone did not aid testosterone suppression and seemed to impair achievement of goal serum 17-β estradiol levels. Testosterone levels were higher with finasteride use. We recommend that transgender women receiving estradiol therapy have hormone levels monitored so that therapy can be individualized.

  5. Albuminuria is associated with an increased prostasin in urine while aldosterone has no direct effect on urine and kidney tissue abundance of prostasin.

    PubMed

    Oxlund, Christina; Kurt, Birgül; Schwarzensteiner, Ilona; Hansen, Mie R; Stæhr, Mette; Svenningsen, Per; Jacobsen, Ib A; Hansen, Pernille B; Thuesen, Anne D; Toft, Anja; Hinrichs, Gitte R; Bistrup, Claus; Jensen, Boye L

    2017-06-01

    The proteinase prostasin is a candidate mediator for aldosterone-driven proteolytic activation of the epithelial sodium channel (ENaC). It was hypothesized that the aldosterone-mineralocorticoid receptor (MR) pathway stimulates prostasin abundance in kidney and urine. Prostasin was measured in plasma and urine from type 2 diabetic patients with resistant hypertension (n = 112) randomized to spironolactone/placebo in a clinical trial. Prostasin protein level was assessed by immunoblotting in (1) human and rat urines with/without nephrotic syndrome, (2) human nephrectomy tissue, (3) urine and kidney from aldosterone synthase-deficient (AS -/- ) mice and ANGII- and aldosterone-infused mice, and in (4) kidney from adrenalectomized rats. Serum aldosterone concentration related to prostasin concentration in urine but not in plasma. Plasma prostasin concentration increased significantly after spironolactone compared to control. Urinary prostasin and albumin related directly and were reduced by spironolactone. In patients with nephrotic syndrome, urinary prostasin protein was elevated compared to controls. In rat nephrosis, proteinuria coincided with increased urinary prostasin, unchanged kidney tissue prostasin, and decreased plasma prostasin while plasma aldosterone was suppressed. Prostasin protein abundance in human nephrectomy tissue was similar across gender and ANGII inhibition regimens. Prostasin urine abundance was not different in AS -/- and aldosterone-infused mice. Prostasin kidney level was not different from control in adrenalectomized rats and AS -/- mice. We found no evidence for a direct relationship between mineralocorticoid receptor signaling and kidney and urine prostasin abundance. The reduction of urinary prostasin in spironolactone-treated patients is most likely the result of an improved glomerular filtration barrier function and generally reduced proteinuria.

  6. Effects of mineralocorticoid receptor blockade on empathy in patients with major depressive disorder.

    PubMed

    Wingenfeld, Katja; Kuehl, Linn K; Dziobek, Isabel; Roepke, Stefan; Otte, Christian; Hinkelmann, Kim

    2016-10-01

    The mineralocorticoid receptor (MR) is highly expressed in the hippocampus and prefrontal cortex and is involved in social cognition. We recently found that pharmacological stimulation of the MR enhances emotional empathy but does not affect cognitive empathy. In the current study, we examined whether blockade of the MR impairs empathy in patients with major depressive disorder (MDD) and healthy individuals. In a placebo-controlled study, we randomized 28 patients with MDD without psychotropic medication and 43 healthy individuals to either placebo or 300 mg spironolactone, a MR antagonist. Subsequently, all participants underwent two tests of social cognition, the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC), measuring cognitive and emotional facets of empathy. In the MET, we found no significant main effect of treatment or main effect of group for cognitive empathy but a highly significant treatment by group interaction (p < 0.01). Patients had higher cognitive empathy scores compared to controls in the placebo condition but not after spironolactone. Furthermore, in the spironolactone condition reduced cognitive empathy was seen in MDD patients but not in controls. Emotional empathy was not affected by MR blockade. In the MASC, no effect of spironolactone could be revealed. Depressed patients appear to exhibit greater cognitive empathy compared to healthy individuals. Blockade of MR reduced cognitive empathy in MDD patients to the level of healthy individuals. Future studies should further clarify the impact of MR functioning on different domains of social cognition in psychiatric patients.

  7. Successful diuretics treatment of protein-losing enteropathy in Noonan syndrome.

    PubMed

    Mizuochi, Tatsuki; Suda, Kenji; Seki, Yoshitaka; Yanagi, Tadahiro; Yoshimoto, Hironaga; Kudo, Yoshiyuki; Iemura, Motofumi; Tanikawa, Ken; Matsuishi, Toyojiro

    2015-04-01

    There are few reports on successful high-dose spironolactone treatment of refractory protein-losing enteropathy (PLE) caused by Fontan procedure. We report successful diuretics treatment with spironolactone and furosemide at standard dose, of refractory PLE in a patient with Noonan syndrome and repaired congenital heart disease. This is the first successful application of diuretics treatment in a patient with refractory PLE without Fontan procedure. This case illustrates that diuretics treatment can be the first-line treatment of PLE regardless of the causative physiology, and can be effective in refractory PLE with Noonan syndrome. © 2015 Japan Pediatric Society.

  8. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.

    PubMed

    Pitt, Bertram; Kober, Lars; Ponikowski, Piotr; Gheorghiade, Mihai; Filippatos, Gerasimos; Krum, Henry; Nowack, Christina; Kolkhof, Peter; Kim, So-Young; Zannad, Faiez

    2013-08-01

    Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), but their use is limited by hyperkalaemia and/or worsening renal function (WRF). BAY 94-8862 is a highly selective and strongly potent non-steroidal MRA. We investigated its safety and tolerability in patients with HFrEF associated with mild or moderate chronic kidney disease (CKD). This randomized, controlled, phase II trial consisted of two parts. In part A, the safety and tolerability of oral BAY 94-8862 [2.5, 5, or 10 mg once daily (q.d.)] was assessed in 65 patients with HFrEF and mild CKD. In part B, BAY 94-8862 (2.5, 5, or 10 mg q.d., or 5 mg twice daily) was compared with placebo and open-label spironolactone (25 or 50 mg/day) in 392 patients with HFrEF and moderate CKD. BAY 94-8862 was associated with significantly smaller mean increases in serum potassium concentration than spironolactone (0.04-0.30 and 0.45 mmol/L, respectively, P < 0.0001-0.0107) and lower incidences of hyperkalaemia (5.3 and 12.7%, respectively, P = 0.048) and WRF. BAY 94-8862 decreased the levels of B-type natriuretic peptide (BNP), amino-terminal proBNP, and albuminuria at least as much as spironolactone. Adverse events related to BAY 94-8862 were infrequent and mostly mild. In patients with HFrEF and moderate CKD, BAY 94-8862 5-10 mg/day was at least as effective as spironolactone 25 or 50 mg/day in decreasing biomarkers of haemodynamic stress, but it was associated with lower incidences of hyperkalaemia and WRF.

  9. Resistant hypertension optimal treatment trial: a randomized controlled trial.

    PubMed

    Krieger, Eduardo M; Drager, Luciano F; Giorgi, Dante Marcelo Artigas; Krieger, Jose Eduardo; Pereira, Alexandre Costa; Barreto-Filho, José Augusto Soares; da Rocha Nogueira, Armando; Mill, José Geraldo

    2014-01-01

    The prevalence of resistant hypertension (ReHy) is not well established. Furthermore, diuretics, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and calcium channel blockers are largely used as the first 3-drug combinations for treating ReHy. However, the fourth drug to be added to the triple regimen is still controversial and guided by empirical choices. We sought (1) to determine the prevalence of ReHy in patients with stage II hypertension; (2) to compare the effects of spironolactone vs clonidine, when added to the triple regimen; and (3) to evaluate the role of measuring sympathetic and renin-angiotensin-aldosterone activities in predicting blood pressure response to spironolactone or clonidine. The Resistant Hypertension Optimal Treatment (ReHOT) study (ClinicalTrials.gov NCT01643434) is a prospective, multicenter, randomized trial comprising 26 sites in Brazil. In step 1, 2000 patients will be treated according to hypertension guidelines for 12 weeks, to detect the prevalence of ReHy. Medical therapy adherence will be checked by pill count monitoring. In step 2, patients with confirmed ReHy will be randomized to an open label 3-month treatment with spironolactone (titrating dose, 12.5-50 mg once daily) or clonidine (titrating dose, 0.1-0.3 mg twice daily). The primary endpoint is the effective control of blood pressure after a 12-week randomized period of treatment. The ReHOT study will disseminate results about the prevalence of ReHy in stage II hypertension and the comparison of spironolactone vs clonidine for blood pressure control in patients with ReHy under 3-drug standard regimen. © 2013 Wiley Periodicals, Inc.

  10. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.

    PubMed

    Arai, Kiyoshi; Homma, Tsuyoshi; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiyoyuki; Aoki, Kazumasa; Ishikawa, Hirokazu; Mizuno, Makoto; Sada, Toshio

    2015-08-15

    The present study was designed to characterize the pharmacological profile of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited (3)H-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 36 and 713nM, respectively. CS-3150 also showed at least 1000-fold higher selectivity for mineralocorticoid receptor over other steroid hormone receptors, glucocorticoid receptor, androgen receptor and progesterone receptor. In the reporter gene assay, CS-3150 inhibited aldosterone-induced transcriptional activation of human mineralocorticoid receptor with an IC50 value of 3.7nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 66 and 970nM, respectively. CS-3150 had no agonistic effect on mineralocorticoid receptor and did not show any antagonistic or agonistic effect on glucocorticoid receptor, androgen receptor and progesterone receptor even at the high concentration of 5μM. In adrenalectomized rats, single oral administration of CS-3150 suppressed aldosterone-induced decrease in urinary Na(+)/K(+) ratio, an index of in vivo mineralocorticoid receptor activation, and this suppressive effect was more potent and longer-lasting than that of spironolactone and eplerenone. Chronic treatment with CS-3150 inhibited blood pressure elevation induced by deoxycorticosterone acetate (DOCA)/salt-loading to rats, and this antihypertensive effect was more potent than that of spironolactone and eplerenone. These findings indicate that CS-3150 is a selective and highly potent mineralocorticoid receptor antagonist with long-lasting oral activity. This agent could be useful for the treatment of hypertension, cardiovascular and renal disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Oral contraceptive plus antiandrogen therapy and cardiometabolic risk in polycystic ovary syndrome.

    PubMed

    Harmanci, Ayla; Cinar, Nese; Bayraktar, Miyase; Yildiz, Bulent Okan

    2013-01-01

    Oral contraceptives alone or in combination with antiandrogens are commonly used in the treatment for polycystic ovary syndrome (PCOS). We aimed to determine the effects of ethinyl estradiol/drospirenone (EE-DRSP) plus spironolactone therapy on inflammation and cardiometabolic risk in PCOS. Prospective cohort study. Twenty-three lean, normal glucose-tolerant patients with PCOS and 23 age- and body mass index (BMI)-matched healthy control women. Androgens, high-sensitivity C-reactive protein (hsCRP), homocysteine, lipids, fasting insulin, and glucose levels during a standard 75-g, 2-h oral glucose tolerance test were measured. Patients with PCOS were evaluated before and after receiving EE-DRSP (3 mg/30 μg) plus spironolactone (100 mg/day) for 6 months. Healthy controls were evaluated at baseline only. hsCRP, homocysteine, lipids, insulin and glucose levels were similar between patient and control groups at baseline. EE-DRSP plus spironolactone increased hsCRP and homocysteine levels in patients with PCOS (0.50 ± 0.28 vs 1.5 ± 1.3 mg/l, P < 0.05 and 13.1 ± 5.2 vs 17.6 ± 5.3 μm, P < 0.05, respectively). BMI, waist-to-hip ratio, LDL, HDL cholesterol and triglycerides, and glucose tolerance did not change. Modified Ferriman-Gallwey hirsutism scores, testosterone levels and free androgen index improved (9.1 ± 4.2 vs 6.2 ± 3.4, P = 0.001; 80.6 ± 31.1 47.8 ± 20.3 ng/dl, P < 0.05; and 10.5 ± 7.4 vs 1.1 ± 0.8, P < 0.001, respectively). EE-DRSP plus spironolactone therapy in 6 months improves androgen excess in lean PCOS women without any adverse effects on adiposity, glucose tolerance status or lipid profile. However, this combination increases hsCRP and homocysteine levels. © 2012 Blackwell Publishing Ltd.

  12. Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans.

    PubMed

    Laffer, Cheryl L; Elijovich, Fernando; Eckert, George J; Tu, Wanzhu; Pratt, J Howard; Brown, Nancy J

    2014-07-01

    An rs3890011 variant of CYP4A11, which is in linkage disequilibrium with the loss-of-function variant rs1126742, is associated with hypertension in humans. In mice, Cyp4a deficiency results in salt-sensitive hypertension through activation of ENaC. We tested the hypothesis that the rs3890011 variant is associated with blood pressure response to drugs acting via the ENaC pathway. African Americans with volume-dependent, resistant hypertension were randomized to treatment with placebo, spironolactone, amiloride, or combination. Blood pressure responses were analyzed by CYP4A11 genotypes. Rs3890011 (GG:GC:CC = 20:35:28) and rs1126742 (TT:TC:CC = 45:31:7) were in linkage disequilibrium (D' = 1, r = 0.561). Expected small number of rs1126742 CC homozygotes precluded analysis of the effect of this genotype on treatment responses. Spironolactone reduced blood pressure in rs3890011 GG and GC individuals, but not in CC homozygotes (P = .002), whereas amiloride reduced blood pressure similarly in all rs3890011 genotypes. The antihypertensive effects of spironolactone and amiloride were comparable in GG and GC participants, but only amiloride reduced pressure in CC homozygotes (-6.3 ± 7.3/-3.2 ± 4.0 vs. +6.8 ± 7.9/+4.8 ± 8.6 mm Hg, P < .01/<.05). The aldosterone response to spironolactone was also blunted in the CC genotype. In individuals homozygous for the CYP4A11 rs3890011 C allele, blood pressure is resistant to mineralocorticoid receptor antagonism, but sensitive to ENaC inhibition, consistent with ENaC activation. Studies in a larger population are needed to replicate these findings. Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  13. Rapid effects of aldosterone in primary cultures of cardiomyocytes - do they suggest the existence of a membrane-bound receptor?

    PubMed

    Araujo, Carolina Morais; Hermidorff, Milla Marques; Amancio, Gabriela de Cassia Sousa; Lemos, Denise da Silveira; Silva, Marcelo Estáquio; de Assis, Leonardo Vinícius Monteiro; Isoldi, Mauro César

    2016-10-01

    Aldosterone acts on its target tissue through a classical mechanism or through the rapid pathway through a putative membrane-bound receptor. Our goal here was to better understand the molecular and biochemical rapid mechanisms responsible for aldosterone-induced cardiomyocyte hypertrophy. We have evaluated the hypertrophic process through the levels of ANP, which was confirmed by the analysis of the superficial area of cardiomyocytes. Aldosterone increased the levels of ANP and the cellular area of the cardiomyocytes; spironolactone reduced the aldosterone-increased ANP level and cellular area of cardiomyocytes. Aldosterone or spironolactone alone did not increase the level of cyclic 3',5'-adenosine monophosphate (cAMP), but aldosterone plus spironolactone led to increased cAMP level; the treatment with aldosterone + spironolactone + BAPTA-AM reduced the levels of cAMP. These data suggest that aldosterone-induced cAMP increase is independent of mineralocorticoid receptor (MR) and dependent on Ca(2+). Next, we have evaluated the role of A-kinase anchor proteins (AKAP) in the aldosterone-induced hypertrophic response. We have found that St-Ht31 (AKAP inhibitor) reduced the increased level of ANP which was induced by aldosterone; in addition, we have found an increase on protein kinase C (PKC) and extracellular signal-regulated kinase 5 (ERK5) activity when cells were treated with aldosterone alone, spironolactone alone and with a combination of both. Our data suggest that PKC could be responsible for ERK5 aldosterone-induced phosphorylation. Our study suggests that the aldosterone through its rapid effects promotes a hypertrophic response in cardiomyocytes that is controlled by an AKAP, being dependent on ERK5 and PKC, but not on cAMP/cAMP-dependent protein kinase signaling pathways. Lastly, we provide evidence that the targeting of AKAPs could be relevant in patients with aldosterone-induced cardiac hypertrophy and heart failure.

  14. AT1 and aldosterone receptors blockade prevents the chronic effect of nandrolone on the exercise-induced cardioprotection in perfused rat heart subjected to ischemia and reperfusion.

    PubMed

    Marques-Neto, Silvio Rodrigues; Ferraz, Emanuelle Baptista; Rodrigues, Deivid Carvalho; Njaine, Brian; Rondinelli, Edson; Campos de Carvalho, Antônio Carlos; Nascimento, Jose Hamilton Matheus

    2014-04-01

    Myocardial tolerance to ischaemia/reperfusion (I/R) injury is improved by exercise training, but this cardioprotection is impaired by the chronic use of anabolic androgenic steroids (AAS). The present study evaluated whether blockade of angiotensin II receptor (AT1-R) with losartan and aldosterone receptor (mineralocorticoid receptor, MR) with spironolactone could prevent the deleterious effect of AAS on the exercise-induced cardioprotection. Male Wistar rats were exercised and treated with either vehicle, nandrolone decanoate (10 mg/kg/week i.m.) or the same dose of nandrolone plus losartan or spironolactone (20 mg/kg/day orally) for 8 weeks. Langendorff-perfused hearts were subjected to I/R and evaluated for the postischaemic recovery of left ventricle (LV) function and infarct size. mRNA and protein expression of angiotensin II type 1 receptor (AT1-R), mineralocorticoid receptor (MR), and KATP channels were determined by reverse-transcriptase polymerase chain reaction and Western blotting. Postischaemic recovery of LV function was better and infarct size was smaller in the exercised rat hearts than in the sedentary rat hearts. Nandrolone impaired the exercise-induced cardioprotection, but this effect was prevented by losartan (AT1-R antagonist) and spironolactone (MR antagonist) treatments. Myocardial AT1-R and MR expression levels were increased, and the expression of the KATP channel subunits SUR2a and Kir6.1 was decreased and Kir6.2 increased in the nandrolone-treated rat hearts. The nandrolone-induced changes of AT1-R, MR, and KATP subunits expression was normalized by the losartan and spironolactone treatments. The chronic nandrolone treatment impairs the exercise-induced cardioprotection against ischaemia/reperfusion injury by activating the cardiac renin-angiotensin-aldosterone system and downregulating KATP channel expression.

  15. Renal calculi in primary hyperaldosteronism.

    PubMed Central

    Kabadi, U. M.

    1995-01-01

    Increased urinary calcium (Ca++) excretion and the presence of negative Ca++ balance is well documented in primary hyperaldosteronism. However, renal calculi as a major manifestation of this disorder has not previously been described. This report describes a patient who presented with renal calculi in association with primary hyperaldosteronism. We believe that primary hyperaldosteronism was a major pathogenetic factor in the formation of renal calculi since the increased urinary excretion of Ca++ and uric acid noted at onset declined following a short-term spironolactone administration and remission from renal calculi has persisted following initial nephrolithotomy and continued spironolactone therapy, which also corrected hypertension and hypokalemia, a hallmark of this disorder. Images Figure PMID:7479473

  16. The role of hepatic transport and metabolism in the interactions between pravastatin or repaglinide and two rOatp inhibitors in rats.

    PubMed

    Badolo, Lassina; Bundgaard, Christoffer; Garmer, Mats; Jensen, Bente

    2013-07-16

    A change in the function or expression of hepatic drug transporters may have significant effect on the efficacy or safety of orally administered drugs. Although a number of clinical drug-drug interactions associated with hepatic transport proteins have been reported, in practice it is not always straightforward to discriminate other pathways (e.g. drug metabolism) from being involved in these interactions. The present study was designed to assess the interactions between organic anion transporting polypeptide (Oatp) substrates (pravastatin or repaglinide) and inhibitors (spironolactone or diphenhydramine) in vivo in rats. The mechanisms behind the interactions were then investigated using in vitro tools (isolated hepatocytes and rat liver microsomes). The results showed a significant increase in the systemic exposures of pravastatin (2.5-fold increase in AUC) and repaglinide (1.8-fold increase in AUC) after co-administration of spironolactone to rats. Diphenhydramine increased the AUC of repaglinide by 1.4-fold. The in vivo interactions observed in rats between Oatp substrates and inhibitors may a priori be classified as transport-mediated drug-drug interactions. However, mechanistic studies performed in vitro using both isolated rat hepatocytes and rat liver microsomes showed that the interaction between pravastatin and spironolactone may be solely linked to the inhibition of pravastatin uptake in liver. On the contrary, the inhibition of cytochrome P450 seemed to be the reason for the interactions observed between repaglinide and spironolactone. Although the function and structure of transport proteins may vary between rats and humans, the approach used in the present study can be applied to humans and help to understand the role of drug transport and drug metabolism in a given drug-drug interaction. This is important to predict and mitigate the risk of drug-drug interactions for a candidate drug in pre-clinical development, it is also important for the optimal

  17. Drug Does Not Improve Set of Cardiovascular Outcomes for Diastolic Heart Failure

    MedlinePlus

    ... preserved systolic function, is a common heart condition accounting for about half of all heart failure cases. ... study showed that participants enrolled via elevated BNP measurements who received spironolactone fared better in the composite ...

  18. Polycystic ovary syndrome

    MedlinePlus

    ... regular. These medicines may also help reduce abnormal hair growth and acne after you take them for several ... nurse may also suggest other treatments for abnormal hair growth. Some are: Spironolactone or flutamide pills Eflornithine cream ...

  19. Polycystic ovary syndrome and combined oral contraceptive use: a comparison of clinical practice in the United States to treatment guidelines.

    PubMed

    Bird, Steven T; Hartzema, Abraham G; Etminan, Mahyar; Brophy, James M; Delaney, Joseph A C

    2013-04-01

    The October 2010 ESHRE/ASRM polycystic ovary syndrome (PCOS) workshop concluded: (1) all combined oral contraceptives (COC) appear to have equal efficacy for PCOS, (2) addition of antiandrogens (spironolactone) to COCs has little treatment benefit and (3) metformin does not improve the live-birth rate and should only be used with impaired glucose tolerance. We compared these guidelines to current practice in the United States IMS claims-database. Time-series analyses were conducted by calendar-year in women with PCOS to evaluate prescribing preferences for COCs, concomitant use of spironolactone, and utilization of metformin. Trends were analyzed with linear regression. Our cohort included 1.6 million women taking COCs, 46 780 with a PCOS claim. Drospirenone utilization increased by 1.52% (SE:0.48%, p = 0.007) per-year more in women with PCOS (4.16%, SE:0.45%, p < 0.001) than in women without PCOS (2.64%, SE:0.17%, p < 0.001)). Concomitant use of drospirenone and spironolactone was common (14.26%) and increased by 0.75% (SE:0.15%, p = 0.002) per-year. Although plasma glucose tests were unavailable, women with PCOS were more likely to take metformin than have a diabetes claim (45.8% versus 15.2%, p < 0.001), indicating some women likely receive metformin solely for PCOS. Our data suggests further attention is needed to medication management of PCOS to bridge the gap between guidelines and practice.

  20. SciTech Connect

    Jaggi, Jaspreet Singh; Seshan, Surya V.; McDevitt, Michael R.

    Purpose: Internal irradiation of kidneys as a consequence of radioimmunotherapy, radiation accidents, or nuclear terrorism can result in radiation nephropathy. We attempted to modify pharmacologically, the functional and morphologic changes in mouse kidneys after injection with the actinium ({sup 225}Ac) nanogenerator, an in vivo generator of {alpha}- and {beta}-particle emitting elements. Methods and Materials: The animals were injected with 0.35 {mu}Ci of the {sup 225}Ac nanogenerator, which delivers a dose of 27.6 Gy to the kidneys. Then, they were randomized to receive captopril (angiotensin-converting enzyme inhibitor), L-158,809 (angiotensin II receptor-1 blocker), spironolactone (aldosterone receptor antagonist), or a placebo. Results: Fortymore » weeks after the {sup 225}Ac injection, the placebo-control mice showed a significant increase in blood urea nitrogen (BUN) (87.6 {+-} 6.9 mg/dL), dilated Bowman spaces, and tubulolysis with basement membrane thickening. Captopril treatment accentuated the functional (BUN 119.0 {+-} 4.0 mg/dL; p <0.01 vs. placebo controls) and histopathologic damage. In contrast, L-158,809 offered moderate protection (BUN 66.6 {+-} 3.9 mg/dL; p = 0.02 vs. placebo controls). Spironolactone treatment, however, significantly prevented the development of histopathologic and functional changes (BUN 31.2 {+-} 2.5 mg/dL; p <0.001 vs. placebo controls). Conclusions: Low-dose spironolactone and, to a lesser extent, angiotensin receptor-1 blockade can offer renal protection in a mouse model of internal {alpha}-particle irradiation.« less

  1. The Relationship Between the Renin-Angiotensin-Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death.

    PubMed

    Kobayashi, Mamoru; Hirooka, Kazuyuki; Ono, Aoi; Nakano, Yuki; Nishiyama, Akira; Tsujikawa, Akitaka

    2017-03-01

    Excitotoxicity, which is due to glutamate-induced toxic effects on the retinal ganglion cell (RGC), is one of several mechanisms of RGC loss. The renin-angiotensin-aldosterone system (RAAS) has also been implicated in RGC death. Therefore, it is important to determine the exact relationship between the RAAS and N-methyl-d-aspartate (NMDA) receptor-mediated signal in order to prevent RGC death. N-methyl-d-aspartate or aldosterone was injected into the vitreous body. After intravitreal injection of NMDA or aldosterone, animals were treated with spironolactone or memantine. Retinal damage was evaluated by measuring the number of RGCs at 4 weeks after local administration of aldosterone or at 2 weeks after local administration of NMDA. Vitreous humor levels of aldosterone were measured using enzyme immunoassay kits. A significantly decreased number of RGCs were observed after intravitreal injection of NMDA. Although spironolactone did not show any neuroprotective effects, memantine significantly reduced NMDA-induced degeneration in the retina. Furthermore, a significant decrease in the number of RGCs was observed after an intravitreal injection of aldosterone. While memantine did not exhibit any neuroprotective effects, spironolactone caused a significant reduction in the aldosterone-induced degeneration in the retina. There was no change in the aldosterone concentration in the vitreous humor after an NMDA injection. Our findings indirectly show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.

  2. [Effects and mechanisms of ursodeoxycholic acid on isoprenaline-Induced myocardial fibrosis in mice].

    PubMed

    Li, X; Han, K Q; Shi, Y N; Men, S Z; Li, S; Sun, M H; Dong, H; Lu, J J; Ma, L J; Zhao, M; Li, D; Liu, W

    2017-02-07

    Objective: To investigate the effects and possible mechanisms of ursodeoxycholic acid (UDCA) on myocardial fibrosis in mice. Method: To observe the expression of transforming growth factor(TGF) -β1, CTGF, MMPs and the degree of myocardial fibrosis, 61 male Kunming mice were randomly divided into normal group, low dose UDCA group, high dose of UDCA group, spironolactone group, and the control group.Isoproterenol (ISO) injection was given subcutaneously (30 d) to make the model of myocardial fibrosis.Corresponding anti-fibrosis drugs (UDCA or spironolactone) were given by gavage.HE staining and Masson staining were performed to explore the inflammation and fibrosis in the myocardium.The expression of collagen Ⅰ and collagen Ⅲ protein was detected by immunohistochemistry to evaluate the degree of fibrosis among the groups.Western blot was used to detect the expression of transforming growth factor, (TGF)-β1, connective tissue growth factor (CTGF), matrix metalloproteinase (MMP)-2, -9, tissue inhibitor of metalloproteinase (TIMP)-4, -1 and anti-phospho-NFKBIA (p-IκB-α) inhibitor of NF-κB (IκB) protein in myocardium. Results: HE and Masson staining results showed that in the normal group, myocardial fibrosis is less, while the control group showed a large amount of fibrotic tissue ( P <0.05). Tissue fibrosis in the low/high dose UDCA group and spironolactone group was significantly reduced compared with the control group ( P <0.05), in which high dose of UDCA reduces fibrosis more significantly.Immunohistochemistry results showed that collagen Ⅰ and collagen Ⅲ protein expression was significantly increased ( P <0.05). Whereas in the low/high UDCA dose group and spironolactone group, collagen Ⅰ and collagen Ⅲ expression were significantly decreased ( P <0.05), the high UDCA dose group decreased more significantly.Western blot results suggest that TGFβ-1 expression in the myocardial tissue was significantly increased compared to the normal group ( P <0

  3. Female Pattern Hair Loss

    MedlinePlus

    ... susceptible women, but is most commonly seen after menopause. In female pattern hair loss some excess loss of hair is noted, but ... all. Spironolactone pills help many women, especially whose hair loss starts before menopause but takes many months. Hormone replacement pills, such ...

  4. Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice.

    PubMed

    Lowe, Jeovanna; Floyd, Kyle T; Rastogi, Neha; Schultz, Eric J; Chadwick, Jessica A; Swager, Sarah A; Zins, Jonathan G; Kadakia, Feni K; Smart, Suzanne; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E; Raman, Subha V; Janssen, Paul M L; Rafael-Fortney, Jill A

    2016-01-01

    Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus , and cardiac papillary muscle force was measured ex vivo , followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

  5. Comparison of the anticonvulsant potency of various diuretic drugs in the maximal electroshock-induced seizure threshold test in mice.

    PubMed

    Załuska, Katarzyna; Kondrat-Wróbel, Maria W; Łuszczki, Jarogniew J

    2018-05-01

    The coexistence of seizures and arterial hypertension requires an adequate and efficacious treatment involving both protection from seizures and reduction of high arterial blood pressure. Accumulating evidence indicates that some diuretic drugs (with a well-established position in the treatment of arterial hypertension) also possess anticonvulsant properties in various experimental models of epilepsy. The aim of this study was to assess the anticonvulsant potency of 6 commonly used diuretic drugs (i.e., amiloride, ethacrynic acid, furosemide, hydrochlorothiazide, indapamide, and spironolactone) in the maximal electroshock-induced seizure threshold (MEST) test in mice. Doses of the studied diuretics and their corresponding threshold increases were linearly related, allowing for the determination of doses which increase the threshold for electroconvulsions in drug-treated animals by 20% (TID20 values) over the threshold in control animals. Amiloride, hydrochlorothiazide and indapamide administered systemically (intraperitoneally - i.p.) increased the threshold for maximal electroconvulsions in mice, and the experimentally-derived TID20 values in the maximal electroshock seizure threshold test were 30.2 mg/kg for amiloride, 68.2 mg/kg for hydrochlorothiazide and 3.9 mg/kg for indapamide. In contrast, ethacrynic acid (up to 100 mg/kg), furosemide (up to 100 mg/kg) and spironolactone (up to 50 mg/kg) administered i.p. had no significant impact on the threshold for electroconvulsions in mice. The studied diuretics can be arranged with respect to their anticonvulsant potency in the MEST test as follows: indapamide > amiloride > hydrochlorothiazide. No anticonvulsant effects were observed for ethacrynic acid, furosemide or spironolactone in the MEST test in mice.

  6. Effect of Spironolactone on Acute Mountain Sickness,

    DTIC Science & Technology

    1985-04-11

    RD-RI53 788 EFFECT OF SPIRONOLRCTONE ON ACU TE MOUNTAIN SICKNESS(U) 1 / 1 -5 ARMY RESEARCH INST OF ENVIRONMENTAL MEDICINE NATICK MR U~c~asIFEDR F...LARSEN ET AL. ii APR 85 USARIEM-M-26/85 /615 N MNCSS E N 06/SN 14, 1128 1112. 11W2 11112. 14.0I 1.8 1 .H󈧝 11111_L.4 6 MICROCOPY RESOLUTION TEST CHART...PROGRAM ELEMENT. PROJECT. TASK USAREM AREA & WORK UNIT NUMBERS Natick, MA 01760-5007 3EI62777A879 I 54683304126 1 . CONTROLLING OFFICE NAME AND ADDRESS 12

  7. Menstrual cyclicity post OC withdrawal in PCOS: Use of non-hormonal options.

    PubMed

    Kulshreshtha, Bindu; Arora, Arpita; Pahuja, Isha; Sharma, Neera; Pant, Shubhi

    2016-08-01

    There is no data on menstrual cyclicity post oral contraceptive (OC) withdrawal with nonhormonal options in PCOS patients. OC could affect obesity, insulin and gonadotropins factors integral to pathogenesis of PCOS, thereby adversely affecting the HPG axis. Menstrual cycles of PCOS patients were retrospectively studied post OCP. Patients developing regular versus irregular cycles post OC were compared. Forty-eight PCOS patients were followed for an average of 1.9 years post OC. Thirty-six (75%) achieved regular cycles over a period of one year with other nonhormonal options like spironolactone and metformin. Seven patients required no treatment. Patients who continued to have irregular cycles had a longer pre OC cycle length (p < 0.01) and a greater duration of menstrual irregularity (p < 0.02), though age, BMI and hormones were similar in the two groups. In conclusion, spironolactone and metformin are effective nonhormonal options for regular periods post OC. Around 15% PCOS may not require any treatment post OC.

  8. Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial.

    PubMed

    Rajagopalan, Sanjay; Alaiti, M Amer; Broadwater, Kylene; Goud, Aditya; Gaztanaga, Juan; Connelly, Kim; Fares, Anas; Shirazian, Shayan; Kreatsoulas, Catherine; Farkouh, Michael; Dobre, Mirela; Fink, Jeffrey C; Weir, Matthew R

    2017-09-01

    Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher-risk patients who otherwise may not be candidates for such a therapeutic approach. In this double-blind, randomized, placebo-controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). The co-primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24-hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA-IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event-based trials. © 2017 Wiley Periodicals, Inc.

  9. Community-acquired hyperkalemia in elderly patients: risk factors and clinical outcomes.

    PubMed

    Turgutalp, Kenan; Bardak, Simge; Helvacı, Ilter; İşgüzar, Gizem; Payas, Ezgi; Demir, Serap; Kıykım, Ahmet

    2016-10-01

    Although the risk and related factors of hyperkalemia developed in the hospital are known in elderly, risk and related factors of community-acquired hyperkalemia (CAH) in this population are not well known. This study was performed to investigate the risk of CAH in elderly and evaluate the related factors and clinical outcomes. Study design, setting and participants, intervention: Patients (aged ≥65 years) with hyperkalemia were screened. Group 1 (young-old); 65-74 years/old, Group 2 (middle-old); 75-84 years/old, Group 3 (oldest-old); ≥85 years/old, and Group 4 (control group); ≥65 years/old (normal serum potassium levels). The relation between CAH and hospital expenses (HE), the number of comorbid diseases (NCD), and all-cause of mortality rates (MR) were evaluated. We also investigated whether drugs, sex, and NCD are risk factors for the development of CAH. There was a positive correlation between serum potassium levels and length of hospital stay, MR, HE, and NCD (p < 0.001). Risk factors for CAH were the use of non-steroidal-anti inflammatory drugs (NSAIDs) (Odds Ratio [OR]: 2.679), spironolactone (OR: 2.530), and angiotensin converting enzyme inhibitors (ACEI) (OR: 2.242), angiotensin receptor blockers (ARB) (OR: 2.679), ≥2 comorbid diseases (OR: 2.221), female gender (OR: 2.112), and renal injury (OR: 5.55). CAH risk was found to be increased 30.03 times when any of ACEI, ARB, NSAIDs, or spironolactone is given to a patient with a renal injury. Use of NSAIDs, ACEI, ARB, spironolactone and increased NCD are all independent risk factors for CAH in the elderly, especially in patients with kidney diseases.

  10. Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma

    PubMed Central

    Pitha, Ian F.; Nguyen, Cathy; Steinhart, Matthew R.; Nguyen, Thao D.; Pease, Mary Ellen; Oglesby, Ericka N.; Berlinicke, Cynthia A.; Mitchell, Katherine L.; Kim, Jessica; Jefferys, Joan J.

    2015-01-01

    Purpose To determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice. Methods We produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by β-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. Results Losartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP. Conclusions The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes

  11. [Diuretics and their potential effect on breath-alcohol concentration--a case report].

    PubMed

    Schmitt, Georg; Skopp, Gisela

    2015-01-01

    Many objections were raised to breath-alcohol analysis upon its introduction in the field of traffic law enforcement in Germany, but in the meantime this issue has become less relevant in forensic routine work. In the present case, the defending lawyer claimed that the ethanol concentration in the blood and hence in the breath of his client, which was 0.35 mg/l according to the Dräger Alcotest 7110® Evidential and thus above the legal limit of 0.25 mg/l, had been changed by diuretics taken 4 hours before the breath alcohol test, viz. 10 mg of torasemide, a loop diuretic, and 50 mg of spironolactone, a competitive aldosterone antagonist. According to the literature, the maximum urinary output in healthy subjects within the first 4 hours after 10 mg torasemide was 1450 ml. In patients suffering from heart failure, the urinary volume was reduced by a factor of 2.5-3; after chronic intake of torasemide, water loss did not differ from placebo. Spironolactone, which acts on the distal tubule, has little effect on urinary output. In a publication, the loss of water in excess within 24 hours was 90 ml. Co-administration of 100 mg spironolactone and 20 mg furosemide, which roughly compares to 10 mg torasemide, resulted in a mean urinary volume of 1566 ml within the first 4 hours. In terms of the reported case and provided that no compensatory fluid had been taken, a purely theoretical maximum shift of 0.007 mg/ may occur in the breath-alcohol concentration due to the smaller distribution volume even considering maximum urinary excretion values. On the other hand, already mild levels of dehydration may be associated with negative symptoms affecting driving ability.

  12. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells.

    PubMed

    Min, Li-Juan; Mogi, Masaki; Li, Jian-Mei; Iwanami, Jun; Iwai, Masaru; Horiuchi, Masatsugu

    2005-09-02

    Interaction between aldosterone (Aldo) and angiotensin II (Ang II) in the cardiovascular system has been highlighted; however, its detailed signaling mechanism is poorly understood. Here, we examined the cross-talk of growth-promoting signaling between Aldo and Ang II in vascular smooth muscle cells (VSMC). Treatment with a lower dose of Aldo (10(-12) mol/L) and with a lower dose of Ang II (10(-10) mol/L) significantly enhanced DNA synthesis, whereas Aldo or Ang II alone at these doses did not affect VSMC proliferation. This effect of a combination of Aldo and Ang II was markedly inhibited by a selective AT1 receptor blocker, olmesartan, a mineralocorticoid receptor antagonist, spironolactone, an MEK inhibitor, PD98059, or an EGF receptor tyrosine kinase inhibitor, AG1478. Treatment with Aldo together with Ang II, even at noneffective doses, respectively, synergistically increased extracellular signal-regulated kinase (ERK) activation, reaching 2 peaks at 10 to 15 minutes and 2 to 4 hours. The early ERK peak was effectively blocked by olmesartan or an EGF receptor kinase inhibitor, AG1478, but not by spironolactone, whereas the late ERK peak was completely inhibited by not only olmesartan, but also spironolactone. Combined treatment with Aldo and Ang II attenuated mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and increased Ki-ras2A expression. The late ERK peak was not observed in VSMC treated with Ki-ras2A-siRNA. Interestingly, the decrease in MKP-1 expression and the increase in Ki-ras2A expression were restored by PD98059 or AG1478. These results suggest that Aldo exerts a synergistic mitogenic effect with Ang II and support the notion that blockade of both Aldo and Ang II could be more effective to prevent vascular remodeling.

  13. Predicting final product properties of melt extruded solid dispersions from process parameters using Raman spectrometry.

    PubMed

    Vigh, Tamás; Drávavölgyi, Gábor; Sóti, Péter L; Pataki, Hajnalka; Igricz, Tamás; Wagner, István; Vajna, Balázs; Madarász, János; Marosi, György; Nagy, Zsombor K

    2014-09-01

    Raman spectrometry was utilized to estimate degraded drug percentage, residual drug crystallinity and glass-transition temperature in the case of melt-extruded pharmaceutical products. Tight correlation was shown between the results obtained by confocal Raman mapping and transmission Raman spectrometry, a PAT-compatible potential in-line analytical tool. Immediate-release spironolactone-Eudragit E solid dispersions were the model system, owing to the achievable amorphization and the heat-sensitivity of the drug compound. The deep investigation of the relationship between process parameters, residual drug crystallinity and degradation was performed using statistical tools and a factorial experimental design defining 54 different circumstances for the preparation of solid dispersions. From the examined factors, drug content (10, 20 and 30%), temperature (110, 130 and 150°C) and residence time (2.75, 11.00 and 24.75min) were found to have significant and considerable effect. By forming physically stable homogeneous dispersions, the originally very slow dissolution of the lipophilic and poorly water-soluble spironolactone was reasonably improved, making 3minute release possible in acidic medium. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Both mineralocorticoid and glucocorticoid receptors regulate emotional memory in mice.

    PubMed

    Zhou, Ming; Bakker, Eveline H M; Velzing, Els H; Berger, Stefan; Oitzl, Melly; Joëls, Marian; Krugers, Harm J

    2010-11-01

    Corticosteroid hormones are thought to promote optimal behavioral adaptation under fearful conditions, primarily via glucocorticoid receptors (GRs). Here, we examined - using pharmacological and genetic approaches in mice - if mineralocorticoid receptors (MRs) also play a role in fearful memory formation. As expected, administration of the GR-antagonist RU38486 prior to training in a fear conditioning paradigm impaired contextual memory when tested 24 (but not when tested 3) h after training. Tone-cue memory was enhanced by RU38486 when tested at 4 (but not 25) h after training. Interestingly, pre (but not post)-training administration of MR antagonist spironolactone impaired contextual memory, both at 3 and 24h after training. Similar effects were also found in forebrain-specific MR knockout mice. Spironolactone also impaired tone-cue memory, but only at 4h after training. These results reveal that - in addition to GRs - MRs also play a critical role in establishing fear memories, particularly in the early phase of memory formation. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Nonsteroidal mineralocorticoid antagonists in diabetic kidney disease.

    PubMed

    Dojki, Farheen K; Bakris, George

    2017-09-01

    Current data highlight the pathological aspects of excess aldosterone in promoting glomerular hypertrophy, glomerulosclerosis, and proteinuria in diabetic kidney disease (DKD). The role of nonsteroidal mineralocorticoid receptor antagonists (MRAs) in DKD is being evaluated in ongoing clinical trials. Recent studies demonstrate beneficial effects of adding MRAs to the treatment regimen of patients with type 2 diabetes with nephropathy. The MRAs spironolactone and eplerenone can protect against organ damage caused by elevated levels of serum aldosterone in patients with heart failure and DKD but are limited by their side effects, for example, hyperkalemia. Finerenone is more selective for the mineralocorticoid receptor than spironolactone and has greater affinity for the mineralocorticoid receptor than eplerenone. It reduces the concentration of aldosterone without causing significant elevation in serum potassium. MRAs have a clear role in reducing albuminuria when used with other renin-angiotensin system blockers in DKD; however, hyperkalemia limits their use. This article provides an overview of clinical studies with a novel MRA, finerenone, and several nonsteroidal MRAs being studied for treatment in DKD.

  16. Finerenone : third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease.

    PubMed

    Liu, Licette C Y; Schutte, Elise; Gansevoort, Ron T; van der Meer, Peter; Voors, Adriaan A

    2015-01-01

    The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone reduce the risk of hospitalizations and mortality in patients with heart failure (HF) with reduced ejection fraction (HFrEF), and attenuate progression of diabetic kidney disease. However, their use is limited by the fear of inducing hyperkalemia, especially in patients with renal dysfunction. Finerenone is a novel nonsteroidal MRA, with higher selectivity toward the mineralocorticoid receptor (MR) compared to spironolactone and stronger MR-binding affinity than eplerenone. This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of finerenone. The selectivity and greater binding affinity of finerenone to the MR may reduce the risk of hyperkalemia and renal dysfunction and thereby overcome the reluctance to start and uptitrate MRAs in patients with HF and diabetic kidney disease. Studies conducted in patients with HFrEF and moderate chronic kidney disease and diabetic kidney disease, showed promising results. Phase III trials will have to show whether finerenone might become the third-generation MRA for the treatment of HF and diabetic kidney disease.

  17. Physicochemical and microbiological stability studies of extemporaneous antihypertensive pediatric suspensions for hospital use.

    PubMed

    Mendes, Cassiana; Costa, Ana Paula; Oliveira, Paulo Renato; Tagliari, Monika Piazzon; Silva, Marcos Antônio Segatto

    2013-01-01

    Extemporaneous suspensions of the antihypertensive agents furosemide, spironolactone and hydrochlorothiazide for pediatric use have been prepared at University Hospital (Federal University of Santa Catarina - Brazil). The aim of this work was to investigate the physicochemical and microbiological stability of these suspensions over the estimated shelf-life period of seven days and, if necessary, to optimize the formulations by improving the chemical stability. The pediatric suspensions were prepared using drug raw material and were stored at 25 ± 2°C and 5 ± 3°C. Chemical stability was evaluated by HPLC assay of the suspensions for drug content. Physical stability was evaluated by sedimentation volume, redispersibility, particle size, and zeta potential. Viable bacterial and fungal contaminations were assessed according to the official compendium. Furosemide and spironolactone suspensions as prepared herein can be stored for 7 days. However, the hydrochlorothiazide suspension formulation at pH 6.5 demonstrated poor chemical stability and was optimized by adjusting the pH to 3.3 where the drug exhibited acceptable stability. The optimized formulation demonstrated to be stable over the required period of 7 days.

  18. Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: a retrospective study of 21 cases.

    PubMed

    de Madron, Eric; King, Jonathan N; Strehlau, Günther; White, Regina Valle

    2011-11-01

    This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m(2) for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate.

  19. Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: A retrospective study of 21 cases

    PubMed Central

    de Madron, Eric; King, Jonathan N.; Strehlau, Günther; White, Regina Valle

    2011-01-01

    This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m2 for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate. PMID:22547843

  20. Spironolactone Therapy in Chronic Stable Right HF Trial

    ClinicalTrials.gov

    2018-04-12

    Chronic Right-Sided Heart Failure; Pulmonary Arterial Hypertension; Pulmonary Hypertension, Primary, 2; Pulmonary Hypertension, Primary, 3; Pulmonary Hypertension, Primary, 4; Cardiomyopathy Right Ventricular

  1. Benefits of Aldosterone Receptor Antagonism in Chronic Kidney Disease (BARACK D) trial-a multi-centre, prospective, randomised, open, blinded end-point, 36-month study of 2,616 patients within primary care with stage 3b chronic kidney disease to compare the efficacy of spironolactone 25 mg once daily in addition to routine care on mortality and cardiovascular outcomes versus routine care alone: study protocol for a randomized controlled trial.

    PubMed

    Hill, Nathan R; Lasserson, Daniel; Thompson, Ben; Perera-Salazar, Rafael; Wolstenholme, Jane; Bower, Peter; Blakeman, Thomas; Fitzmaurice, David; Little, Paul; Feder, Gene; Qureshi, Nadeem; Taal, Maarten; Townend, Jonathan; Ferro, Charles; McManus, Richard; Hobbs, Fd Richard

    2014-05-08

    Chronic kidney disease (CKD) is common and increasing in prevalence. Cardiovascular disease (CVD) is a major cause of morbidity and death in CKD, though of a different phenotype to the general CVD population. Few therapies have proved effective in modifying the increased CVD risk or rate of renal decline in CKD. There are accumulating data that aldosterone receptor antagonists (ARA) may offer cardio-protection and delay renal impairment in patients with the CV phenotype in CKD. The use of ARA in CKD has therefore been increasingly advocated. However, no large study of ARA with renal or CVD outcomes is underway. The study is a prospective randomised open blinded endpoint (PROBE) trial set in primary care where patients will mainly be identified by their GPs or from existing CKD lists. They will be invited if they have been formally diagnosed with CKD stage 3b or there is evidence of stage 3b CKD from blood results (eGFR 30-44 mL/min/1.73 m2) and fulfil the other inclusion/exclusion criteria. Patients will be randomised to either spironolactone 25 mg once daily in addition to routine care or routine care alone and followed-up for 36 months. BARACK D is a PROBE trial to determine the effect of ARA on mortality and cardiovascular outcomes (onset or progression of CVD) in patients with stage 3b CKD. EudraCT: 2012-002672-13ISRTN: ISRCTN44522369.

  2. The Use of Hormonal Antiandrogen Therapy in Female Patients with Acne: A 10-Year Retrospective Study.

    PubMed

    Park, Joyce H; Bienenfeld, Amanda; Orlow, Seth J; Nagler, Arielle R

    2018-06-01

    Little is known about how dermatologists prescribe hormonal antiandrogen acne treatment (HAAT). The aim of this study was to investigate dermatologists' HAAT-prescribing habits and HAAT's impact on systemic antibiotic use in women with acne. We performed a retrospective study at an academic medical center of female patients receiving HAAT (combined oral contraceptive [COC], spironolactone) for acne from January 2005 to October 2015. Data from a control group of female acne patients who never received HAAT were also collected. A total of 672 female patients received HAAT. Out of all systemic medications for acne, antibiotics were used as first-line treatment in 39% of patients, COCs in 12%, and spironolactone in 21%. Mean antibiotic durations in patients who initiated HAAT for the first time at the study site (250.4 days) were significantly longer than in patients who received HAAT prior to presentation and continued HAAT at the study site (192.0 days) (p = 0.021). A statistically significant inverse association was found between HAAT use and mean antibiotic duration (p = 0.016). HAAT is not typically used as a first-line systemic therapy in women with acne. HAAT usage is associated with shorter cumulative antibiotic durations and early HAAT initiation can decrease systemic antibiotic use in acne treatment.

  3. Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease.

    PubMed

    Ames, M K; Atkins, C E; Eriksson, A; Hess, A M

    2017-06-01

    Aldosterone breakthrough (ABT) is the condition in which angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers fail to effectively suppress the activity of the renin angiotensin aldosterone system. The objective of this study was to determine if ABT occurs in dogs with naturally occurring myxomatous mitral valve disease receiving an ACEI, using the urine aldosterone to creatinine ratio (UAldo:C) as a measure of renin angiotensin aldosterone system activation. This study includes 39 dogs with myxomatous mitral valve disease. A UAldo:C cut-off definition (derived from a normal population of healthy, adult, and client-owned dogs) was used to determine the prevalence of ABT in this population. Spearman analysis and univariate logistic regression were used to evaluate the relationship between UAldo:C and ABT (yes/no) and eight variables (age, serum K + concentration, serum creatinine concentration, ACEI therapy duration and ACEI dosage, furosemide therapy duration and furosemide dosage, and urine sample storage time). Finally, the UAldo:C in dogs receiving spironolactone, as part congestive heart failure (CHF) therapy, was compared to dogs with CHF that were not receiving spironolactone. The prevalence of ABT was 32% in dogs with CHF and 30% in dogs without CHF. There was no relationship between either the UAldo:C or the likelihood of ABT and the eight variables. Therapy with spironolactone lead to a significant elevation of the UAldo:C. Using the UAldo:C and a relatively stringent definition of ABT, it appears that incomplete RAAS blockade is common in dogs with MMVD receiving an ACEI. The prevalence of ABT in this canine population mirrors that reported in humans. While the mechanism of ABT is likely multifactorial and still poorly understood, the proven existence of ABT in dogs offers the potential to improve the prognosis for MMVD with the addition of a mineralocorticoid receptor blocker to current therapeutic regimens

  4. Adrenalectomy prevents renal ischemia-reperfusion injury.

    PubMed

    Ramírez, Victoria; Trujillo, Joyce; Valdes, Rafael; Uribe, Norma; Cruz, Cristino; Gamba, Gerardo; Bobadilla, Norma A

    2009-10-01

    Spironolactone treatment prevents renal damage induced by ischemia-reperfusion (I/R), suggesting that renoprotection conferred by spironolactone is mediated by mineralocorticoid receptor (MR) blockade. It is possible, however, that this effect is due to other mechanisms. Therefore, this study evaluated whether adrenalectomy prevented renal damage induced by I/R. Three groups of Wistar rats were studied: 1) a group subjected to a sham surgery, 2) a group subjected to bilateral I/R, and 3) a group of rats in which adrenal glands were removed 3 days before induction of I/R. As expected, I/R resulted in renal dysfunction and severe tubular injury that was associated with a significant increase in tubular damage markers. In contrast, there was no renal dysfunction or tubular injury in rats that were adrenalectomized before I/R. These effects were demonstrated by normalization of glomerular filtration rate, markers of oxidative stress, and tubular injury markers in adrenalectomized rats. The renoprotection observed was associated with the reestablishment of nitric oxide metabolites, increased endothelial nitric oxide synthase expression and its activating phosphorylation, as well as normalization of Rho-kinase expression and ET(A) mRNA levels. Our results show that aldosterone plays a central role in the pathogenesis of renal damage induced by I/R and that MR blockade may be a promising strategy that opens a new therapeutic option for preventing acute renal injury.

  5. Aldosterone induces rapid sodium intake by a nongenomic mechanism in the nucleus tractus solitarius.

    PubMed

    Qiao, Hu; Hu, Bo; Zhou, Hong; Yan, Jianqun; Jia, Ru; Lu, Bo; Sun, Bo; Luo, Xiao; Fan, Yuanyuan; Wang, Nan

    2016-12-09

    The purpose of this study was to determine whether aldosterone has a rapid action in the nucleus tractus solitarius (NTS) that increases sodium intake, and to examine whether this effect of aldosterone, if present, is mediated by G protein-coupled estrogen receptor (GPER). Adult male Sprague-Dawley rats with a stainless-steel cannula in the NTS were used. Aldosterone was injected into the NTS at the doses of 1, 5, 10 and 20 ng 0.1 μl -1 . A rapid dose-related increase of 0.3 M NaCl intake was induced within 30 min and this increase was not suppressed by the mineralocorticoid receptor (MR) antagonist spironolactone (10 ng 0.1 μl -1 ). Water intake was not affected by aldosterone. The GPER agonist G-1 produced a parallel and significant increase in sodium intake, while pre-treatment with GPER antagonist G15 (10 ng 0.1 μl -1 ) blocked the G-1 or aldosterone-induced rapid sodium intake. In addition, sodium intake induced by sodium depletion or low-sodium diet fell within 30 min after injection into the NTS of the MR antagonist spironolactone, while G15 had no effect. Our results confirm previous reports, and support the hypothesis that aldosterone evokes rapid sodium intake through a non-genomic mechanism involving GPER in NTS.

  6. [Investigation of gestagenic effect of raw drone milk in rats].

    PubMed

    Seres, Adrienn; Ducza, Eszter; Gáspár, Róbert

    2014-01-01

    Numerous honeybee products are used in traditional medicine. The best-known honeybee products are the honey, the propolis and the royal jelly. Drone milk is a relatively little-known honeybee product. Although, drone milk is traditionally used to treat infertility and to promote vitality in both men and women in certain countries, the literature furnishes no information concerning effects of the drone milk. The oestrogenic and androgenic effects of drone milk have recently been reported in rats and the effective compounds have also been identified. The aim of this study was to determine the putative gestagenic effect of raw drone milk in rats. Maintenance of pregnancy assays revealed that drone milk was able to increase the number of surviving fetuses. This results suggested some gestagenic effects. This effect was confirmed by RT-PCR and Western blot methods in which the mRNA and protein expressions of gestagen-dependent CRLR (Calcitonin Receptor-Like Receptor) peptide were determined. To determine the efficacy of gestagenic effect of drone milk, spironolactone (weak gestagen compound) was used. The combination of drone milk and spironolactone showed more potent gestagenic effect. These results lead us to suppose that raw drone milk shows weak gestagenic effect and this effect can be increased by another weak gestagen. Further studies are required to clarify the gestagenic mechanisms of action of drone milk.

  7. Study of Acute Kidney Injury on 309 Hypertensive Inpatients with ACEI/ARB - Diuretic Treatment.

    PubMed

    Chen, Qiaochao; Zhu, Shaofang; Liao, Jianjun; He, Wen

    2018-06-01

    The present study investigated risk factors for acute kidney injury (AKI) in patients found to be hypertensive during hospitalization who were prescribed angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor antagonists (ARB) + diuretic combinations, in order to determine which type of diuretic or combination of diuretics used in ACE/ARB-treated patients leads to a higher risk of acute kidney injury. Data on basic information, medical history, diagnostic information and medications prescribed were obtained from the patients' medical records. Retrospective analysis of potential risk factors and ACEI/ARB + diuretic use with AKI was performed. Multivariate analysis showed initial risk factors for AKI to be chronic kidney disease and poor cardiac function. In univariate analysis, patients whose baseline serum creatinine was between 115 and 265 μmol/L also had a higher risk of AKI. The combination of furosemide and spironolactone produced only approximately a third of the risk of AKI as the combination of hydrochlorothiazide and spironolactone. Chronic kidney disease and poor cardiac function are major risk factors for AKI in hypertensive inpatients using ACEI/ARB + diuretic therapy. The combination of thiazide diuretic and aldosterone antagonist had a higher risk of AKI than other single diuretics or diuretic combinations. Copyright © 2017 National Medical Association. Published by Elsevier Inc. All rights reserved.

  8. Oily Skin: A review of Treatment Options

    PubMed Central

    Miller, Richard A.

    2017-01-01

    One of the most common dermatologic concerns is oily skin, and the demand for effective treatment options is ever apparent. This review article addresses numerous topical treatment options such as retinoids, olumacostat glasaretil, and various cosmeceutical agents. several systemic and procedural techniques that incorporate isotretinoin, spironolactone, oral contraceptives, botulinum toxin, photodynamic therapy, and lasers are reviewed as well. Each treatment option is analyzed in terms of the proposed mechanism of action, efficacy reported in the literature, and potential adverse effects. PMID:28979664

  9. Drug-induced gynecomastia.

    PubMed

    Thompson, D F; Carter, J R

    1993-01-01

    Gynecomastia is a relatively common physical finding in men. A wide variety of drugs have been implicated in its cause. Sufficient evidence in the literature suggests that calcium-channel blockers, cancer chemotherapeutic agents, and histamine2-receptor blockers may play a role in the disorder. Evidence for digitalis glycosides and neuroleptic agents is insufficient. Ketoconazole and spironolactone can also produce gynecomastia, and data for marijuana are contradictory. Large numbers of drugs have only case reports of temporal association with the disorder.

  10. Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2 signaling in left ventricular systolic dysfunction after acute myocardial infarction.

    PubMed

    Lax, Antonio; Sanchez-Mas, Jesus; Asensio-Lopez, Maria C; Fernandez-Del Palacio, Maria J; Caballero, Luis; Garrido, Iris P; Pastor-Perez, Francisco J; Januzzi, James L; Pascual-Figal, Domingo A

    2015-01-01

    This study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, on the modulation of galectin-3 (Gal-3) and interleukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI). The molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not well understood. MI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 male Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either eplerenone (n = 15) or spironolactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal-3 including transforming growth factor (TGF)-β and SMAD3, as well as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription polymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-α, monocyte chemotactic protein-1) was also examined. In the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-β, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-β, and SMAD3 and enhanced IL-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between eplerenone and spironolactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of

  11. Influence of antihypertensive drugs on aortic and coronary effects of Ang-(1-7) in pressure-overloaded rats

    PubMed Central

    Nunes, A.D.C.; Souza, A.P.S.; Macedo, L.M.; Alves, P.H.; Pedrino, G.R.; Colugnati, D.B.; Mendes, E.P.; Santos, R.A.S.; Castro, C.H.

    2017-01-01

    This study investigated the influence of antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (ACEIs), AT1 receptor blockers (ARBs), voltage-gated L-type calcium channel blockers, and mineralocorticoid receptor antagonists (MRAs), on the effects of angiotensin-(1-7) [Ang-(1-7)] on aorta and coronary arteries from pressure-overloaded rats. Pressure overload was induced by abdominal aortic banding (AB). To evaluate the role of antihypertensive drugs on the effect of Ang-(1-7), AB male Wistar rats weighing 250–300 g were treated with vehicle or low doses (5 mg·kg-1·day-1, gavage) of losartan, captopril, amlodipine, or spironolactone. Isolated aortic rings and isolated perfused hearts under constant flow were used to evaluate the effect of Ang-(1-7) in thoracic aorta and coronary arteries, respectively. Ang-(1-7) induced a significant relaxation in the aorta of sham animals, but this effect was reduced in the aortas of AB rats. Chronic treatments with losartan, captopril or amlodipine, but not with spironolactone, restored the Ang-(1-7)-induced aorta relaxation in AB rats. The coronary vasodilatation evoked by Ang-(1-7) in sham rats was blunted in hypertrophic rats. Only the treatment with losartan restored the coronary vasodilatory effect of Ang-(1-7) in AB rat hearts. These data support a beneficial vascular effect of an association of Ang-(1-7) and some antihypertensive drugs. Thus, this association may have potential as a new therapeutic strategy for cardiovascular diseases. PMID:28355350

  12. Influence of antihypertensive drugs on aortic and coronary effects of Ang-(1-7) in pressure-overloaded rats.

    PubMed

    Nunes, A D C; Souza, A P S; Macedo, L M; Alves, P H; Pedrino, G R; Colugnati, D B; Mendes, E P; Santos, R A S; Castro, C H

    2017-03-23

    This study investigated the influence of antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (ACEIs), AT1 receptor blockers (ARBs), voltage-gated L-type calcium channel blockers, and mineralocorticoid receptor antagonists (MRAs), on the effects of angiotensin-(1-7) [Ang-(1-7)] on aorta and coronary arteries from pressure-overloaded rats. Pressure overload was induced by abdominal aortic banding (AB). To evaluate the role of antihypertensive drugs on the effect of Ang-(1-7), AB male Wistar rats weighing 250-300 g were treated with vehicle or low doses (5 mg·kg-1·day-1, gavage) of losartan, captopril, amlodipine, or spironolactone. Isolated aortic rings and isolated perfused hearts under constant flow were used to evaluate the effect of Ang-(1-7) in thoracic aorta and coronary arteries, respectively. Ang-(1-7) induced a significant relaxation in the aorta of sham animals, but this effect was reduced in the aortas of AB rats. Chronic treatments with losartan, captopril or amlodipine, but not with spironolactone, restored the Ang-(1-7)-induced aorta relaxation in AB rats. The coronary vasodilatation evoked by Ang-(1-7) in sham rats was blunted in hypertrophic rats. Only the treatment with losartan restored the coronary vasodilatory effect of Ang-(1-7) in AB rat hearts. These data support a beneficial vascular effect of an association of Ang-(1-7) and some antihypertensive drugs. Thus, this association may have potential as a new therapeutic strategy for cardiovascular diseases.

  13. Apparent mineralocorticoid excess and the long term treatment of genetic hypertension.

    PubMed

    Razzaghy-Azar, Maryam; Yau, Mabel; Khattab, Ahmed; New, Maria I

    2017-01-01

    Apparent mineralocorticoid excess (AME) is a genetic disorder causing severe hypertension, hypokalemia, and hyporeninemic hypoaldosteronism owing to deficient 11 beta-hydroxysteroid dehydrogenase type-2 (11βHSD2) enzyme activity. The 11βHSD2 enzyme confers mineralocorticoid receptor specificity for aldosterone by converting cortisol to its inactive metabolite, cortisone and inactivating the cortisol-mineralocorticoid receptor complex. The 20year follow-up of a consanguineous Iranian family with three sibs affected with AME shows the successes and pitfalls of medical therapy with spironolactone. The three sibs, (female, male, female) were diagnosed at the ages of 14, 11, and 4 years, respectively. At diagnosis, hypertensive retinopathy and left ventricular hypertrophy were present in the eldest female and retinopathy was noted in the male sib. Spironolactone treatment resulted in decreased blood pressure and rise in serum potassium levels. The older female, age 36, developed reduced left ventricular function with mitral and tricuspid regurgitation and renal failure after her second pregnancy. She was treated with renal transplantation resulting in cure of AME with decreased blood pressure and weaning from antihypertensives. Her younger sibs, age 34 and 26, do not have end organ damage. Early and vigilant treatment improves morbidity in patients with AME. Mineralocorticoid receptor antagonists normalize blood pressure, correct hypokalemia and reduce hypertensive end-organ damage in patients with AME. Low dose dexamethasone can be considered, though the response may be variable. Future directions of therapy include selective mineralocorticoid antagonists. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Misdiagnosis of resistant hypertension: Real frequency of true resistant hypertension in patients with suspected resistance to treatment.

    PubMed

    Doménech, Mónica; Sastre, Enric; Camafort, Miguel; Sierra, Cristina; Coca, Antonio

    2018-01-12

    Resistant hypertension(RH) has been defined as failure to control office blood pressure (BP) despite the use of≥3 different antihypertensive agents at optimal doses, including, ideally, a diuretic. Apparent RH, defines patients with an incorrect diagnosis of RH due to different causes. The objective was to determine whether most patients with RH in fact have apparent but not true RH. Observational study involving 93 patients with suspected RH, being 60 patients finally included. Screening for secondary causes of hypertension was perfomed. True RH was defined as office BP>140/90mmHg despite full doses of 3 antihypertensive drugs including a diuretic. Mean age 63.7±9.8years, 68.3%were male. Office BP 154.3±14.4/84.4±13.7mmHg. Of the 60 patients, 23.3% had white coat effect, 3.3% didn't have a diuretic and 8.3% were non-adherent-to-treatment. Accordingly, 58.3% were classified as true RH. Spironolactone was added in 62.5% of patients of whom 78.4% achieved ambulatory BP control. Almost half of the patients with suspected RH were not really true RH. We provide more evidence of excess of fluid retention as an underlying cause of lack of BP control in patients with RH, reinforce the relevant paper of spironolactone for the management in those patients. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  15. Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

    PubMed Central

    Feldman, D; Couropmitree, C

    1976-01-01

    Because some nonsteroidal anti-inflammatory drugs (NSAID) induce salt and water retention and exhibit other steroid-like actions, studies were performed to ascertain whether these drugs possess intrinsic mineralocorticoid agonist activity. In vitro competitive binding assays utilizing tissue from adrenalectomized rats demonstrated that some NSAID can displace [3H]-aldosterone from renal cytoplasmic mineralocorticoid receptors. Displacement potency for these sites was in the sequence: aldosterone greater than spironolactone greater than phenylbutazone (PBZ) greater than aspirin (ASA) greater than indomethacin (IDM). Concentration ratios required to obtain significant displacement of [3H]aldosterone were high but clearly within the therapeutic range for PBZ and ASA but not IDM. The analogues oxyphenbutazone (OBZ) and sodium salicylate (SS) were similar in binding activity to PBZ and ASA, respectively. Lineweaver-Burk analysis revealed that the inhibition of [3H]aldosterone binding was competitive in nature. In addition, PBZ was shown to prevent the nuclear binding of [3H]aldosterone. In vivo injection of PBZ and ASA resulted in competition for [3H]aldosterone renal binding comparable to the in vitro studies. Administration of PBZ and OBZ to adrenalectomized rats resulted in significant salt retention whereas ASA and SS did not differ significantly from controls. Salt retention elicited by PBZ and OBZ was inhibited by spironolactone, a competitive mineralocorticoid antagonist. These data suggest that, despite nonsteroidal structures, PBZ and OBZ induce salt retention via a receptor-mediated mineralocorticoid pathway analogous to aldosterone action. PMID:173739

  16. Type IV neonatal Bartter syndrome complicated with congenital chloride diarrhea.

    PubMed

    Sakallı, Hale; Bucak, Hakan İbrahim

    2012-01-01

    Pseudo-Bartter syndrome encompasses a heterogenous group of disorders similar to Bartter syndrome. Sometimes a few status may be nested, as in our case presented here. An 8-month-old boy was referred to our hospital with of intractable diarrhea, polyuria, persistent hypokalemia, abdominal distension and failure to thrive. He was born in the 34 6/7 gestational week (GW) to consanguineous parents. In the 30(th) GW polyhydramnios was verified by ultrasonography. The laboratory results showed hypokalemic-hypochloremic metabolic alkalosis, hyponatremia, and increased urinary loss of chloride, potassium and calcium. An audiogram test revealed complete sensorineural deafness. Ultrasonography revealed medullary nephrocalcinosis in both kidneys. Elevated plasma renin activity and aldosterone were found and a provisional diagnosis of type-IV neonatal Bartter syndrome was made. Treatment with indomethacin, spironolactone and additional intake of NaCl/KCl was initiated. Despite these therapies, the child's diarrhea persisted but serum potassium concentration normalized, and hypercalciuria and urine output reduced. After determining the high fecal chloride concentration, there was an immediate decompensation of the disease on indomethacin withdrawal, thus a diagnosis of type IV neonatal Bartter syndrome complicated with congenital chloride diarrhea was considered. Indomethacin, spironolactone and supplementary therapies with NaCl/KCl were continued, which resulted in the normalization of serum electrolytes as well as his physical development, but high contents of chloride in urine and faeces and nephrocalcinosis remains unchanged during 1-year follow-up. Because of the clinical and laboratory simulations between the various diseases that lead to hypokalemic-hypochloremic metabolic alkalosis, patients must be evaluated carefully.

  17. Effects of aldosterone blockade on left ventricular function and clinical status during acute myocardial infarction.

    PubMed

    Uzunhasan, Isil; Yildiz, Ahmet; Coskun, Ugur; Kalyoncuoglu, Muhsin; Baskurt, Murat; Cakar, Mehmet Akif; Kaya, Aysem; Pehlivanoglu, Seckin; Enar, Rasim; Okcun, Baris

    2009-01-01

    Heart failure is frequently a serious complication of acute myocardial infarction (AMI). ACE inhibitors, Angiotensin II receptor blockers, beta-blockers and aldosterone receptor blockers have been shown to improve outcomes in this setting. This study aimed to determine the effect of spironolactone on the frequency of clinical heart failure, mortality, rehospitalization and left ventricular functions determined by echocardiography. A total of 82 patients with STEMI hospitalized within 6-12 h of debut of symptoms were included in the study. The patients were randomly assigned into spironolactone (group A) or placebo (group B) groups after informed consent had been obtained. All patients were followed for 6 months. There were no statistically significant differences between the two groups when demographic criteria were compared. The incidence of post-MI angina pectoris, rhythm and conduction disturbance during hospitalization was significantly higher in Group B than in Group A. Although not statistically significant, the incidence of clinical heart failure was slightly lower in Group A than in Group B (5% versus 11%). Left ventricular end-diastolic volumes were slightly lower in Group A than in Group B, although statistically this was not significant. In concordance with these findings, the ejection fraction was slightly higher in Group A than in Group B, although this was not statistically significant (47% versus 44%). This trend continued during a 6-month follow-up after randomization. Our findings suggest that early administration of aldosterone blockers provides additional benefits after AMI, reducing the incidence of post-MI angina pectoris and rhythm and conduction disturbances.

  18. Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene-expression profiles in dystrophic skeletal muscles.

    PubMed

    Chadwick, Jessica A; Bhattacharya, Sayak; Lowe, Jeovanna; Weisleder, Noah; Rafael-Fortney, Jill A

    2017-02-01

    Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD. Copyright © 2017 the American Physiological Society.

  19. [Adherence to pharmaceutical guidance in patients over 85 years of age with chronic heart failure-stage C. Effects on 12-month mortality].

    PubMed

    Esteve Arríen, Ainhoa; Domínguez de Pablos, Gema; Minaya Saiz, Jesús

    2009-01-01

    To describe factors related to prescription on discharge of treatment for Chronic Heart Failure(CHF)-Stage C and to analyse whether this is related to 12month-mortality. Observational follow-up study of patients over 85 hospitalized during 2006/7 with Stage C-Chronic Heart Failure in an outskirt support hospital. Drug-prescription adherence was assessed according to the American Heart Society 2005-Guidelines and recommendations of the American Geriatrics Society-2007. A multivariate analysis of logistic regression was performed to obtain odds for 12-month mortality for each recommended therapy, adjusting by mortality risk factors. 104 patients aged 90+/-3yr were followed on discharge, 85% of which were women. NYHA-classes were distributed NYHA I-28,2%, II-37,9%, III-30,1%, IV-3,9%. Most frequently prescribed drugs were loop diuretics (83,3%) and IACEs/ARB (62%), and the less frequent beta-blockers (19,1%). IACEs/ARB were prescribed to those with lower functional impairment (p=0.04), and beta-blockers to those with worse NYHA class (p=0.02). All recommended prescriptions had a tendency to 12 month mortality risk reduction, even adjusted by age, functional status, co-morbidity, NYHA class and co-morbid atrial fibrillation, except for spironolactone (OR-1,8; IC95% 0,48-17,19). Treatment with CHF disease-modifying therapies except for spironolactone can reduce 12 month risk mortality, also in the oldest old. There exists room for improvement in frequency of drug prescription in this group of age.

  20. Intestinal organoids: A model of intestinal fibrosis for evaluating anti-fibrotic drugs

    PubMed Central

    Rodansky, Eva S.; Johnson, Laura A.; Huang, Sha; Spence, Jason R.; Higgins, Peter D. R.

    2016-01-01

    Background & Aims Intestinal fibrosis is a critical complication of Crohn’s disease (CD). Current in vitro models of intestinal fibrosis cannot model the complex intestinal architecture, while in vivo rodent models do not fully recapitulate human disease and have limited utility for large-scale screening. Here, we exploit recent advances in stem cell derived human intestinal organoids (HIOs) as a new human model of fibrosis in CD. Methods Human pluripotent stem cells were differentiated into HIOs. We identified myofibroblasts, the key effector cells of fibrosis, by immunofluorescence staining for alpha-smooth muscle actin (αSMA), vimentin, and desmin. We examined the fibrogenic response of HIOs by treatment with transforming growth factor beta (TGFβ) in the presence or absence of the anti-fibrotic drug spironolactone. Fibrotic response was assayed by expression of fibrogenic genes (COL1A1 (collagen, type I, alpha 1), ACTA2 (alpha smooth muscle actin), FN1 (fibronectin 1), MYLK (myosin light chain kinase), and MKL1 (megakaryoblastic leukemia (translocation) 1)) and proteins (αSMA). Results Immunofluorescent staining of organoids identified a population of myofibroblasts within the HIO mesenchyme. TGFβ stimulation of HIOs produced a dose-dependent pro-fibrotic response. Spironolactone treatment blocked the fibrogenic response of HIOs to TGFβ. Conclusions HIOs contain myofibroblasts and respond to a pro-fibrotic stimulus in a manner that is consistent with isolated human myofibroblasts. HIOs are a promising model system that might bridge the gap between current in vitro and in vivo models of intestinal fibrosis in IBD. PMID:25828392

  1. Aldosterone rapidly activates Src kinase in M-1 cells involving the mineralocorticoid receptor and HSP84.

    PubMed

    Braun, Sabine; Lösel, Ralf; Wehling, Martin; Boldyreff, Brigitte

    2004-07-16

    We investigated the effect of aldosterone on Src kinase. In the kidney cell line, M-1 aldosterone leads to a >2-fold transient activation of Src kinase seen as early as 2 min after aldosterone administration. Maximal Src kinase activation was measured at an aldosterone concentration of 1 nM. In parallel to activation, autophosphorylation at Tyr-416 of Src kinase increased. Src kinase activation was blocked by spironolactone. Aldosterone led to increased association of Src with HSP84. Furthermore, rapamycin blocked aldosterone-induced Src activation. We conclude that Src activation by aldosterone is mediated through the mineralocorticoid receptor and HSP84.

  2. [Drug-induced gynecomastia].

    PubMed

    Hugues, F C; Gourlot, C; Le Jeunne, C

    2000-02-01

    Drugs are a very common cause of gynecomastia and should always be entertained as the possible causal agent of such a condition. This drug side-effect is due to an impaired balance in the serum estrogen/serum androgen ratio, whatever the mechanism, or a rise in prolactin level. Sex hormones, antiandrogens, are frequently involved as well as spironolactone, cimetidine, verapamil and cancer chemotherapy (especially alkylating agents). Diazepam, tricyclic antidepressants, neuroleptics, calcium channel blockers, captopril, digitalis glycosides, omeprazole, some antibiotics and growth hormone are all possibly, but less often, the responsible agent. Criteria of the French method for determining drug causality are discussed.

  3. Prescribing Habits for Androgenic Alopecia Among Dermatologists in Spain in 2017: A Cross-Sectional Study.

    PubMed

    Pindado-Ortega, C; Saceda-Corralo, D; Buendía-Castaño, D; Fernández-González, P; Moreno-Arrones, Ó M; Fonda-Pascual, P; Alegre-Sánchez, A; Rodrigues-Barata, A R; Vañó-Galván, S

    2018-04-12

    Topical minoxidil and oral finasteride are the only drugs approved for the treatment of androgenetic alopecia (AGA) in Spain. However, the management of this condition is highly variable because numerous treatments are used off-label. The main aim of this study was to describe the prescribing habits of dermatologists in Spain for male AGA (MAGA) and female AGA (FAGA). Descriptive cross-sectional study using online questionnaires completed by dermatologists working in Spain. The responses of 241 dermatologists were analyzed. The most common treatments prescribed for MAGA were minoxidil (98%), oral finasteride (96%), nutricosmetics (44%), topical finasteride (37%), oral dutasteride (33%), platelet-rich plasma (14%), and low-level laser therapy (8%). For premenopausal FAGA, the most common treatments were topical minoxidil (98%), oral contraceptives (81%), nutricosmetics (72%), cyproterone acetate (58%), oral finasteride (39%), topical finasteride (39%), spironolactone (27%), platelet-rich plasma (20%), oral dutasteride (20%), oral flutamide (18%), and low-level laser therapy (7%). Finally, for postmenopausal FAGA, the most common treatments prescribed were topical minoxidil (98%), oral finasteride (84%), nutricosmetics (68%), topical finasteride (50%), oral dutasteride (35%), platelet-rich plasma (21%), spironolactone (16%), cyproterone acetate (16%), oral flutamide (9%), and low-level laser therapy (9%). A limitation of our study is that we did not analyze novel AGA treatments such as oral minoxidil and dutasteride mesotherapy. The most common treatments prescribed for AGA by dermatologists in Spain are topical minoxidil, oral finasteride, and nutricosmetics for MAGA and postmenopausal FAGA and topical minoxidil, oral contraceptives, and nutricosmetics for premenopausal FAGA. Copyright © 2018 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.

    PubMed

    Calvier, Laurent; Martinez-Martinez, Ernesto; Miana, Maria; Cachofeiro, Victoria; Rousseau, Elodie; Sádaba, J Rafael; Zannad, Faiez; Rossignol, Patrick; López-Andrés, Natalia

    2015-01-01

    This study investigated whether galectin (Gal)-3 inhibition could block aldosterone-induced cardiac and renal fibrosis and improve cardiorenal dysfunction. Aldosterone is involved in cardiac and renal fibrosis that is associated with the development of cardiorenal injury. However, the mechanisms of these interactions remain unclear. Gal-3, a β-galactoside-binding lectin, is increased in heart failure and kidney injury. Rats were treated with aldosterone-salt combined with spironolactone (a mineralocorticoid receptor antagonist) or modified citrus pectin (a Gal-3 inhibitor), for 3 weeks. Wild-type and Gal-3 knockout mice were treated with aldosterone for 3 weeks. Hemodynamic, cardiac, and renal parameters were analyzed. Hypertensive aldosterone-salt-treated rats presented cardiac and renal hypertrophy (at morphometric, cellular, and molecular levels) and dysfunction. Cardiac and renal expressions of Gal-3 as well as levels of molecular markers attesting fibrosis were also augmented by aldosterone-salt treatment. Spironolactone or modified citrus pectin treatment reversed all of these effects. In wild-type mice, aldosterone did not alter blood pressure levels but increased cardiac and renal Gal-3 expression, fibrosis, and renal epithelial-mesenchymal transition. Gal-3 knockout mice were resistant to aldosterone effects. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction but was prevented by pharmacological inhibition (modified citrus pectin) or genetic disruption of Gal-3. These data suggest a key role for Gal-3 in cardiorenal remodeling and dysfunction induced by aldosterone. Gal-3 could be used as a new biotarget for specific pharmacological interventions. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  5. Type IV neonatal Bartter syndrome complicated with congenital chloride diarrhea

    PubMed Central

    Sakallı, Hale; Bucak, Hakan İbrahim

    2012-01-01

    Summary Background: Pseudo-Bartter syndrome encompasses a heterogenous group of disorders similar to Bartter syndrome. Sometimes a few status may be nested, as in our case presented here. Case Report: An 8-month-old boy was referred to our hospital with of intractable diarrhea, polyuria, persistent hypokalemia, abdominal distension and failure to thrive. He was born in the 34 6/7 gestational week (GW) to consanguineous parents. In the 30th GW polyhydramnios was verified by ultrasonography. The laboratory results showed hypokalemic-hypochloremic metabolic alkalosis, hyponatremia, and increased urinary loss of chloride, potassium and calcium. An audiogram test revealed complete sensorineural deafness. Ultrasonography revealed medullary nephrocalcinosis in both kidneys. Elevated plasma renin activity and aldosterone were found and a provisional diagnosis of type-IV neonatal Bartter syndrome was made. Treatment with indomethacin, spironolactone and additional intake of NaCl/KCl was initiated. Despite these therapies, the child’s diarrhea persisted but serum potassium concentration normalized, and hypercalciuria and urine output reduced. After determining the high fecal chloride concentration, there was an immediate decompensation of the disease on indomethacin withdrawal, thus a diagnosis of type IV neonatal Bartter syndrome complicated with congenital chloride diarrhea was considered. Indomethacin, spironolactone and supplementary therapies with NaCl/KCl were continued, which resulted in the normalization of serum electrolytes as well as his physical development, but high contents of chloride in urine and faeces and nephrocalcinosis remains unchanged during 1-year follow-up. Conclusions: Because of the clinical and laboratory simulations between the various diseases that lead to hypokalemic-hypochloremic metabolic alkalosis, patients must be evaluated carefully. PMID:23569535

  6. Role of Nongenomic Signaling Pathways Activated by Aldosterone During Cardiac Reperfusion Injury.

    PubMed

    Ashton, Anthony W; Le, Thi Y L; Gomez-Sanchez, Celso E; Morel-Kopp, Marie-Christine; McWhinney, Brett; Hudson, Amanda; Mihailidou, Anastasia S

    2015-08-01

    Aldosterone (Aldo) activates both genomic and nongenomic signaling pathways in the cardiovascular system. Activation of genomic signaling pathways contributes to the adverse cardiac actions of Aldo during reperfusion injury; however, the extent nongenomic signaling pathways contribute has been difficult to identify due to lack of a specific ligand that activates only nongenomic signaling pathways. Using a pegylated aldosterone analog, aldosterone-3-carboxymethoxylamine-TFP ester conjugated to methoxypegylated amine (Aldo-PEG), we are able for the first time to distinguish between nongenomic and genomic cardiac actions of Aldo. We confirm Aldo-PEG activates phosphorylation of ERK1/2 in rat cardiomyocyte H9c2 cells similar to Aldo and G protein-coupled receptor 30 (GPR30 or GPER) agonist G1. GPER antagonist, G36, but not mineralocorticoid receptor (MR) antagonist spironolactone, prevented ERK1/2 phosphorylation by Aldo, Aldo-PEG, and G1. The selective nongenomic actions of Aldo-PEG are confirmed, with Aldo-PEG increasing superoxide production in H9c2 cells to similar levels as Aldo but having no effect on subcellular localization of MR. Striatin serves as a scaffold for GPER and MR, with GPER antagonist G36, but not spironolactone, restoring MR-striatin complexes. Aldo-PEG had no effect on MR-dependent transcriptional activation, whereas Aldo increased transcript levels of serum-regulated kinase 1 and plasminogen activator inhibitor-1. Using our ex vivo experimental rat model of myocardial infarction, we found aggravated infarct size and apoptosis by Aldo but not Aldo-PEG. Our studies confirm that in the heart, activation of nongenomic signaling pathways alone are not sufficient to trigger the deleterious effects of aldosterone during myocardial reperfusion injury.

  7. Rapid actions of aldosterone revisited: Receptors in the limelight.

    PubMed

    Wehling, Martin

    2018-02-01

    Steroid hormones like aldosterone have been conclusively shown to elicit both late genomic and rapid, nongenomically initiated responses. Aldosterone was among the first for which rapid, clinically relevant effects were even shown in humans. Yet, after over 30 years of research, the nature of receptors involved in rapid actions of aldosterone is still unclear. Such effects may be assigned to the classical, intracellular steroid receptors, in this case mineralocorticoid receptors (MR, class IIa action Mannheim classification). They typically disappear in knockout models and are blocked by MR-antagonists such as spironolactone, as shown for several cellular and physiological, e.g. renal or cardiovascular effects. In contrast, there is also consistent evidence suggesting type IIb effects involving structurally different receptors ("membrane receptors") being insensitive to classic antagonists and persistent in knockout models; IIb effects have lately even been confirmed by atomic force detection of surface receptors which bind aldosterone but not spironolactone. Type IIa and b may coexist in the same cell with IIa often augmenting early IIb effects. So far cloning of IIb receptors was unsuccessful; therefore results on G-protein coupled estrogen receptor 1 (GPER1) being potentially involved in rapid aldosterone action raised considerable interest. Surprisingly, GPER1 does not bind aldosterone. Though under these circumstances GPER1 should not yet be considered as IIb-receptor, it might be an intermediary signaling enhancer of mineralocorticoid action as shown for epithelial growth factor receptors reconciling those results. We still seem to be left without IIb-receptors whose identification would however be highly desirable and essential for clinical translation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. White-Coat Effect Is Uncommon in Patients With Refractory Hypertension.

    PubMed

    Siddiqui, Mohammed; Judd, Eric K; Oparil, Suzanne; Calhoun, David A

    2017-09-01

    Refractory hypertension is a recently described phenotype of antihypertensive treatment failure defined as uncontrolled blood pressure (BP) despite the use of ≥5 different antihypertensive agents, including chlorthalidone and spironolactone. Recent studies indicate that refractory hypertension is uncommon, with a prevalence of ≈5% to 10% of patients referred to a hypertension specialty clinic for uncontrolled hypertension. The prevalence of white-coat effect, that is, uncontrolled automated office BP ≥135/85 mm Hg and controlled out-of-office BP <135/85 mm Hg, by awake ambulatory BP monitor in hypertensive patients overall is ≈30% to 40%. The prevalence of white-coat effect among patients with refractory hypertension has not been previously reported. In this prospective evaluation, consecutive patients referred to the University of Alabama at Birmingham Hypertension Clinic for uncontrolled hypertension were enrolled. Refractory hypertension was defined as uncontrolled automated office BP ≥135/85 mm Hg with the use of ≥5 antihypertensive agents, including chlorthalidone and spironolactone. Automated office BP measurements were based on 6 serial readings, done automatically with the use of a BpTRU device unobserved in the clinic. Out-of-office BP measurements were done by 24-hour ambulatory BP monitor. Thirty-four patients were diagnosed with refractory hypertension, of whom 31 had adequate ambulatory BP monitor readings. White-coat effect was present in only 2 patients, or 6.5% of the 31 patients with refractory hypertension, suggesting that white-coat effect is largely absent in patients with refractory hypertension. These findings suggest that white-coat effect is not a common cause of apparent lack of BP control in patients failing maximal antihypertensive treatment. © 2017 American Heart Association, Inc.

  9. Hyperkalaemia in the age of aldosterone antagonism.

    PubMed

    Chapagain, A; Ashman, N

    2012-11-01

    Hyperkalaemia is well recognized as a medical emergency. However, with the publication of trials showing benefit with renin-aldosterone axis suppression in heart failure, the epidemiology of patients presenting with hyperkalaemia has changed. The reported incidence of rate of serious hyperkalaemia (>6.0 mEq/l of potassium) ranges from 6 to 12% in patients on spironolactone with congestive cardiac failure (CCF). A rational choice of therapy based on present evidence is different from the traditionally used algorithm, given our understanding of the physiology relevant to this patient group. This article discusses the changing face of hyperkalaemia and the present evidence and discusses options in treatment of hyperkalaemia.

  10. [Primary and secondary arterial hypertension - update 2016].

    PubMed

    Sanner, Bernd; Hausberg, Martin

    2016-06-01

    In patients with hypertension without diabetes and with an increased risk of cardiovascular complications a blood pressure of below 130 mmHg should be targeted. Hypertensive patients with an age above 80 years should be treated in the same way as younger hypertensive patients if they are otherwise healthy and functionally independent. On the other hand frail elderly patients could have an increased morbidity and mortality with intensive blood pressure control. In patients with resistant hypertension spironolactone was the most effective drug when given in addition to their baseline drugs (ACE-inhibitor/angiotensin receptor antagonist, calcium channel blocker and thiazide diuretic). © Georg Thieme Verlag KG Stuttgart · New York.

  11. Improving cardiovascular disease management in Australia: NPS MedicineWise.

    PubMed

    Gadzhanova, Svetla V; Roughead, Elizabeth E; Bartlett, Mark J

    2013-08-05

    To determine the impact of four NPS MedicineWise programs targeting quality use of medicines in cardiovascular management in primary care. Interrupted time-series analysis using the Department of Veterans' Affairs (DVA) claims dataset from 1 January 2002 to 31 August 2010. We examined the use of antithrombotics in people with atrial fibrillation and in those who had had a stroke, and the use of echocardiography and spironolactone in the population with heart failure. All veterans and their dependants in Australia who had received cardiovascular medicines or health services related to the targeted intervention. NPS MedicineWise national programs to improve cardiovascular management in primary care, which included prescriber feedback, academic detailing, case studies and audits as well as printed educational materials. Changes in medication and health service use before and after the interventions. All national programs were positively associated with significant improvements in related prescribing or test request practice. The interventions to improve the use of antithrombotics resulted in a 1.27% (95% CI, 1.26%-1.28%) and 0.63% (95% CI, 0.62%-0.64%) relative increase in the use of aspirin or warfarin in the population with atrial fibrillation 6 and 12 months after the program, respectively, and in a 1.51% (95% CI, 1.49%-1.53%) relative increase in the use of aspirin as monotherapy for secondary stroke prevention 12 months after the intervention. The heart failure programs resulted in a 3.69% (95% CI, 3.67%-3.71%) relative increase in the use of low-dose spironolactone and a 4.31% (95% CI, 4.27%-4.35%) relative increase in the use of echocardiogram tests 12 months after the intervention. NPS MedicineWise programs were effective in achieving positive changes in medicine and health service use for patients with cardiovascular diseases.

  12. Reduction of diuretics and analysis of water and muscle volumes to prevent falls and fall-related fractures in older adults.

    PubMed

    Okada, Kosuke; Okada, Masahiro; Kamada, Nanao; Yamaguchi, Yumiko; Kakehashi, Masayuki; Sasaki, Hidemi; Katoh, Shigeko; Morita, Katsuya

    2017-02-01

    In an attempt to decrease the incidence of falls and fall-related fractures at a special geriatric nursing home, we endeavored to reduce diuretic doses, and examined the relationship between the effectiveness of this approach with the body compositions and activities of daily living of the study cohort. We enrolled 93 participants living in the community, 60 residents of an intermediate geriatric nursing home and 50 residents of the 100-bed Kandayama Yasuragien special geriatric nursing home. We recorded body composition using a multifrequency bioelectrical impedance analyzer. Daily loop diuretic and other diuretic regimens of those in the special geriatric nursing home were reduced or replaced with "NY-mode" diuretic therapy, namely, spironolactone 12.5 mg orally once on alternate days. The incidence of falls fell from 53 in 2011 to 29 in 2012, and there were no fall-related proximal femoral fractures for 3 years after the introduction of NY-mode diuretic therapy. We also found statistically significant differences in muscle and intracellular water volumes in our elderly participants: those with higher care requirements or lower levels of independence had lower muscle or water volumes. We found that reducing or replacing daily diuretics with NY-mode therapy appeared to reduce the incidence of falls and fall-related proximal femoral fracture, likely by preserving intracellular and extracellular body water volumes. Low-dose spironolactone (12.5 mg on alternate days) appears to be an effective means of treating elderly individuals with chronic heart failure or other edematous states, while preventing falls and fall-related fractures. Geriatr Gerontol Int 2017; 17: 262-269. © 2016 The Authors. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.

  13. Assessing the impact of heart failure specialist services on patient populations.

    PubMed

    Lyratzopoulos, Georgios; Cook, Gary A; McElduff, Patrick; Havely, Daniel; Edwards, Richard; Heller, Richard F

    2004-05-24

    The assessment of the impact of healthcare interventions may help commissioners of healthcare services to make optimal decisions. This can be particularly the case if the impact assessment relates to specific patient populations and uses timely local data. We examined the potential impact on readmissions and mortality of specialist heart failure services capable of delivering treatments such as b-blockers and Nurse-Led Educational Intervention (N-LEI). Statistical modelling of prevented or postponed events among previously hospitalised patients, using estimates of: treatment uptake and contraindications (based on local audit data); treatment effectiveness and intolerance (based on literature); and annual number of hospitalization per patient and annual risk of death (based on routine data). Optimal treatment uptake among eligible but untreated patients would over one year prevent or postpone 11% of all expected readmissions and 18% of all expected deaths for spironolactone, 13% of all expected readmisisons and 22% of all expected deaths for b-blockers (carvedilol) and 20% of all expected readmissions and an uncertain number of deaths for N-LEI. Optimal combined treatment uptake for all three interventions during one year among all eligible but untreated patients would prevent or postpone 37% of all expected readmissions and a minimum of 36% of all expected deaths. In a population of previously hospitalised patients with low previous uptake of b-blockers and no uptake of N-LEI, optimal combined uptake of interventions through specialist heart failure services can potentially help prevent or postpone approximately four times as many readmissions and a minimum of twice as many deaths compared with simply optimising uptake of spironolactone (not necessarily requiring specialist services). Examination of the impact of different heart failure interventions can inform rational planning of relevant healthcare services.

  14. Premicroalbuminuria in women with polycystic ovary syndrome: a metabolic risk marker.

    PubMed

    Patel, Arti A; Bloomgarden, Zachary T; Futterweit, Walter

    2008-03-01

    To determine the relationship between urinary albumin excretion and features of the metabolic syndrome in women with polycystic ovary syndrome (PCOS). We retrospectively analyzed the medical records of 189 premenopausal women (mean age +/- SD, 28.9 +/- 7.7 years) with PCOS and 81 control patients (mean age +/- SD, 37.9 +/- 8.6 years) from a single endocrinology practice. Exclusion criteria were diabetes, heart disease, kidney disease, use of lipid-lowering agents, and use of antihypertensive agents (except spironolactone). The urine albumin-to-creatinine ratio (ACR) was measured in a random single-voided urine sample. Premicroalbuminuria was defined as an ACR >7 mg/g. The prevalence of ACR >7 mg/g was 31.2% in the PCOS group (N = 189) and 35.8% in the control group (N = 81). The metabolic syndrome was noted in 16.3% (27 of 166) of patients with PCOS and in 2.9% (2 of 69) of control subjects. Nine percent of patients with PCOS who had an ACR 7 mg/g had the metabolic syndrome. Patients with PCOS who had an ACR >7 mg/g had significantly higher blood pressure and alanine aminotransferase levels than did those with an ACR 7 mg/g, no significant difference was found in frequency of use of metformin, spironolactone, or oral contraceptives. In women with PCOS, an ACR >7 mg/g was strongly associated with the metabolic syndrome, high blood pressure, and elevated alanine aminotransferase levels. It may be useful to consider ACR >7 mg/g as an associated sign of the presence of metabolic syndrome in women with PCOS.

  15. Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone.

    PubMed

    Brown, Jenifer M; Williams, Jonathan S; Luther, James M; Garg, Rajesh; Garza, Amanda E; Pojoga, Luminita H; Ruan, Daniel T; Williams, Gordon H; Adler, Gail K; Vaidya, Anand

    2014-02-01

    Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.

  16. Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

    SciTech Connect

    Tocchetti, Guillermo Nicolás

    The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a groupmore » of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs. - Highlights: • Intestinal MRP2 (ABCC2) expression and activity can be regulated by xenobiotics. • PXR and CAR are major MRP2 modulators through a transcriptional mechanism.

  17. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension

    PubMed Central

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E.; Arons, Elena; Zaman, Paula; Polach, Kevin J.; Matar, Majed; Yung, Lai-Ming; Yu, Paul B.; Bowman, Frederick P.; Opotowsky, Alexander R.; Waxman, Aaron B.; Loscalzo, Joseph; Leopold, Jane A.; Maron, Bradley A.

    2016-01-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10−9 to 10−7 M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor–small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro. Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo. Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.—Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery

  18. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes

    SciTech Connect

    Queisser, Nina; Happ, Kathrin; Link, Samuel

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague–Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure.more » To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased. - Highlights: • Aldosterone has direct profibrotic effects on the liver independent of blood pressure. • Fibrosis is mediated by the mineralocorticoid

  19. Aldosterone mediates metastatic spread of renal cancer via the G protein-coupled estrogen receptor (GPER).

    PubMed

    Feldman, Ross D; Ding, Qingming; Hussain, Yasin; Limbird, Lee E; Pickering, J Geoffrey; Gros, Robert

    2016-06-01

    Although aldosterone is a known regulator of renal and cardiovascular function, its role as a regulator of cancer growth and spread has not been widely considered. This study tested the hypothesis that aldosterone regulates cancer cell growth/spread via G protein-coupled estrogen receptor (GPER) activation. In vitro in murine renal cortical adenocarcinoma (RENCA) cells, a widely used murine in vitro model for the study of renal cell adenocarcinoma, aldosterone increased RENCA cell proliferation to a maximum of 125 ± 3% of control at a concentration of 10 nM, an effect blocked by the GPER antagonist G15 or by GPER knockdown using short interfering (sh) RNA techniques. Further, aldosterone increased RENCA cell migration to a maximum of 170 ± 20% of control at a concentration of 100 nM, an effect also blocked by G15 or by GPER down-regulation. In vivo, after orthotopic RENCA cell renal transplantation, pulmonary tumor spread was inhibited by pharmacologic blockade of aldosterone effects with spironolactone (percentage of lung occupied by metastasis: control = 68 ± 13, spironolactone = 26 ± 8, P < 0.05) or inhibition of aldosterone synthesis with a high dietary salt diet (percentage of lung: control = 44 ± 6, high salt = 12 ± 3, P < 0.05), without reducing primary tumor size. Additionally, adrenalectomy significantly reduced the extent of pulmonary tumor spread, whereas aldosterone infusion recovered pulmonary metastatic spread toward baseline levels. Finally, inhibition of GPER either with the GPER antagonist G15 or by GPER knockdown comparably inhibited RENCA cell pulmonary metastatic cancer spread. Taken together, these findings provide strong evidence for aldosterone serving a causal role in renal cell cancer regulation via its GPER receptor; thus, antagonism of GPER represents a potential new target for treatment to reduce metastatic spread.-Feldman, R. D., Ding, Q., Hussain, Y., Limbird, L. E., Pickering, J. G., Gros, R. Aldosterone mediates metastatic

  20. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    PubMed

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  1. Treatment of female pattern hair loss with oral antiandrogens.

    PubMed

    Sinclair, R; Wewerinke, M; Jolley, D

    2005-03-01

    It has not been conclusively established that female pattern hair loss (FPHL) is either due to androgens or responsive to oral antiandrogen therapy. To evaluate the efficacy of oral antiandrogen therapy in the management of women with FPHL using standardized photographic techniques (Canfield Scientific), and to identify clinical and histological parameters predictive of clinical response. For this single-centre, before-after, open intervention study, 80 women aged between 12 and 79 years, with FPHL and biopsy-confirmed hair follicle miniaturization [terminal/vellus (T/V) hair ratio < or = 4 : 1] were photographed at baseline and again after receiving a minimum of 12 months of oral antiandrogen therapy. Forty women received spironolactone 200 mg daily and 40 women received cyproterone acetate, either 50 mg daily or 100 mg for 10 days per month if premenopausal. Women using topical minoxidil were excluded. Standardized photographs of the midfrontal and vertex scalp were taken with the head positioned in a stereotactic device. Images were evaluated by a panel of three clinicians experienced in the assessment of FPHL, blinded to patient details and treatment and using a three-point scale. As there was no significant difference in the results or the trend between spironolactone and cyproterone acetate the results were combined. Thirty-five (44%) women had hair regrowth, 35 (44%) had no clear change in hair density before and after treatment, and 10 (12%) experienced continuing hair loss during the treatment period. Ordinal logistic regression analysis to identify predictors of response revealed no influence of patient age, menopause status, serum ferritin, serum hormone levels, clinical stage (Ludwig) or histological parameters such as T/V ratio or fibrosis. The only significant predictor was midscalp clinical grade, with higher-scale values associated with a greater response (P = 0.013). Eighty-eight percent of women receiving oral antiandrogens could expect to see no

  2. Elevated Potassium Levels in Patients With Congestive Heart Failure: Occurrence, Risk Factors, and Clinical Outcomes: A Danish Population-Based Cohort Study.

    PubMed

    Thomsen, Reimar Wernich; Nicolaisen, Sia Kromann; Hasvold, Pål; Garcia-Sanchez, Ricardo; Pedersen, Lars; Adelborg, Kasper; Egfjord, Martin; Egstrup, Kenneth; Sørensen, Henrik Toft

    2018-05-22

    Data on the true burden of hyperkalemia in patients with heart failure (HF) in a real-world setting are limited. Incidence rates of hyperkalemia (first blood test with a potassium level >5.0 mmol/L) in primary or hospital care were assessed in a population-based cohort of patients with incident HF diagnoses in northern Denmark from 2000 to 2012. Risk factors and clinical outcomes were compared in patients with HF with versus without hyperkalemia. Of 31 649 patients with HF, 39% experienced hyperkalemia (mean follow-up, 2.2 years). Risks of experiencing a second, third, or fourth event were 43%, 54%, and 60%, respectively. Among patients with HF with stage 3A, 3B, 4, or 5 kidney dysfunction, 26%, 35%, 44%, and 48% experienced hyperkalemia within the first year. Important hyperkalemia risk factors included chronic kidney disease (prevalence ratio, 1.46; 95% confidence interval [CI], 1.43-1.49), diabetes mellitus (prevalence ratio, 1.38; 95% CI, 1.32-1.45), and spironolactone use (prevalence ratio, 1.48; 95% CI, 1.42-1.54). In patients with HF who developed hyperkalemia, 53% had any acute-care hospitalization 6 months before the hyperkalemia event, increasing to 74% 6 months after hyperkalemia (before-after risk ratio, 1.41; 95% CI, 1.38-1.44). Compared with matched patients with HF without hyperkalemia, adjusted 6-month hazard ratios in patients with hyperkalemia were 2.75-fold (95% CI, 2.65-2.85) higher for acute-care hospitalization and 3.39-fold (95% CI, 3.19-3.61) higher for death. Almost 4 in 10 patients with HF develop hyperkalemia, and many patients have recurrent hyperkalemia episodes. Hyperkalemia risk is strongly associated with degree of reduced kidney function and use of spironolactone. Hyperkalemia is associated with severe clinical outcomes and death in HF. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  3. A determination of the current causes of hyperkalaemia and whether they have changed over the past 25 years.

    PubMed

    Muschart, X; Boulouffe, C; Jamart, J; Nougon, G; Gérard, V; de Cannière, L; Vanpee, D

    2014-08-01

    Hyperkalaemia is a potentially lethal electrolyte disorder. The objective of this study was to determine if the causes of hyperkalaemia-related visits to the emergency department (ED) have changed since 25 years. All patients presenting to the ED with hyperkalaemia between January 2009 and August 2011 were included in this retrospective, single-centre study. Patients were divided into one of these three categories: mild (5·2≤ K(+)<5·8 mEq/l), moderate (5·8≤K(+)<7·0 mEq/l) or severe hyperkalaemia (K(+)≥7·0 mEq/l). The causes of hyperkalaemia were divided into three groups: renal failure (RF), potassium-increasing drugs (PIDs) or others. Overall, 139 patients with hyperkalaemia were included in the study (mean K(+) of 6·2 mEq/l): 35% with mild, 49% with moderate and 16% with severe hyperkalaemia. Eighty-three per cent of patients (n = 115) had RF with creatinine levels ≥1·25 mg/dl or estimated glomerular filtration rate (eGFR) levels ≤60 ml/min/1·73 m(2). Serum potassium levels were significantly related with creatinine and eGFR values (P<0·001). The severity of hyperkalaemia was significantly related with creatinine levels ≥1·25 mg/dl (P = 0·002) and eGFR values ≤60 ml/min/1·73 m(2) (P = 0·005). Seventy-five per cent of patients (n = 105) were taking PIDs. Potassium levels were significantly related with PIDs (P<0·001), in particularly spironolactone (P = 0·001) and angiotensin-converting enzyme inhibitors (P = 0·008). The category 'others' included 7% of patients (n = 10). RF (83%) and PIDs (75%) remain common causes of hyperkalaemia. Hyperkalaemia is significantly related with four variables: creatinine levels, spironolactone, ACEIs and beta-blocker intake. The causes of hyperkalaemia have not changed in recent years.

  4. Consumption and costs of antihypertensive drugs in Mexico: are diuretic agents a standing technological trajectory?

    PubMed

    Altagracia-Martínez, M; Kravzov-Jinich, J; Guadarrama-Atrizco, M D; Rubio-Poo, C; Wertheimer, A I

    2006-03-01

    Little is known about hypertension medication consumption and costs in Mexico. Hypertension control is a pharmacological challenge and a public health issue. (a) To compare drug sales, number of written prescriptions, and monthly treatment costs among 5 classes of antihypertensive drugs and (b) to analyze diuretic drug sales and prescriptions to determine whether these antihypertensive agents represent an established technological trajectory. A retrospective time series data study from 1999 to 2003. Data sources used were International Marketing Services of Mexico drug sales and the Mexico Prescription Audit databases. The 5 different classes of antihypertensive drugs were accommodated into 4 main technological trajectories according to their main biological mechanisms of action. Each technological trajectory was assessed using consumption and prescription data. Daily defined dose was used to calculate drug treatment costs. The market for cardiovascular agents is one of the largest, and in 2003 accounted for a value market share of 59 billion US dollar and a unit share of 40.7 million. Among cardiovascular agents, antihypertensive drugs made up a large percentage of market shares. Calcium channel blockers and angiotensin-converting enzyme inhibitors I had the biggest share value of the total cardiovascular market. Amlodipine had the highest share among calcium channel blockers, and enalapril and captopril had the largest share among angiotensin-converting enzyme inhibitors I. The top-selling diuretic drug was furosemide. The trend in number of prescriptions was parallel to that in sales. The diuretic spironolactone was the most expensive drug treatment (59 US dollar). Treatment with spironolactone might represent 47% of the income of a Mexican family if their household income was close to minimum wage (124 US dollar). The most effective and least expensive drugs-diuretics-had the smallest market share of all antihypertensive agents in Mexico. Nevertheless, diuretic

  5. Zumba-induced Takotsubo cardiomyopathy: a case report.

    PubMed

    Chams, Sana; El Sayegh, Skye; Hamdon, Mulham; Kumar, Sarwan; Kulairi, Zain

    2018-06-10

    Takotsubo cardiomyopathy or stress cardiomyopathy is characterized by transient left ventricular apical ballooning in the absence of coronary occlusion. The underlying pathophysiological mechanism is still unclear but possible causes have been proposed mainly catecholamine cardiotoxicity, followed by metabolic disturbance, coronary microvascular impairment, and multivessel epicardial coronary artery vasospasm. Takotsubo cardiomyopathy accounts for 1-2% of patients presenting with acute coronary syndrome with the majority of patients diagnosed with Takotsubo cardiomyopathy being women > 55 years of age. Here, we discuss the case of a 38-year-old woman presenting with typical chest pain, electrocardiography changes and cardiac markers consistent with acute coronary syndrome, who was subsequently diagnosed with Takotsubo cardiomyopathy. A 38-year-old healthy American woman with negative past medical history presented to our Emergency Department with chest pain developing while participating in intense outdoor physical activities (Zumba) at a fundraising event. Our patient had typical substernal chest pain induced with exercise and was relieved by sublingual nitroglycerin in the Emergency Department. The pain started after 2 h of intensive Zumba workout. On review of her history, our patient was noted to be taking spironolactone 125 mg once daily for hirsutism for the past year. Our patient denied any family history of cardiac disease or heart failure. She admitted to being a former occasional smoker and to drinking alcohol socially. She denied any illicit drug use. She works as a social worker, and reported that she does not experience much stress in her life and denied any "one big life-changing event" or any major stressful news. While in the Emergency Department, our patient was hemodynamically stable and an electrocardiography was performed and showed sinus rhythm with no ST elevation/depression but noted T-wave inversion in leads I and aVL, and T wave

  6. Compound heterozygous mutation of aquaporin 2 gene in woman patient with congenital nephrogenic diabetes insipidus.

    PubMed

    Tsutsumi, Zenta; Inokuchi, Taku; Tamada, Daisuke; Moriwaki, Yuji; Ka, Tsuneyoshi; Takahashi, Sumio; Yamamoto, Tetsuya

    2009-01-01

    We performed mutational analyses of a woman patient with congenital nephrogenic diabetes insipidus referred to us during pregnancy. The diagnosis was made during the neonatal period, after which she was treated with spironolactone and hydrochlorothiazide. Our examination showed the patient to be apparently in good health without definite evidence of dehydration. Serum and urine osmolality were 220 mOsm/L and 50 mOsm/L, respectively, and the serum concentration of AVP was 2.7 pg/mL. Results of a water-deprivation test performed after delivery were compatible with nephrogenic diabetes insipidus. Mutational analyses showed that the patient was a compound heterozygote with point mutations at nucleotide position 298 (G to A; G100R) in exon 1 and nucleotide position 374 (C to T; T125M) in exon 2 of the aquaporin 2 gene, which have been previously described.

  7. Drug-induced gynecomastia.

    PubMed

    Bowman, John D; Kim, Hyunah; Bustamante, Juan J

    2012-12-01

    Drugs account for about 20% of gynecomastia cases in men. As a number of factors can alter the estrogen:androgen ratio, several pathophysiologic mechanisms are associated with drugs causing this disorder. Antiandrogens, protease inhibitors, and nucleoside reverse transcriptase inhibitors are the most common drug causes of gynecomastia, whereas first-generation antipsychotics, spironolactone, verapamil, and cimetidine are less common causes. Other drugs have been reported rarely as causes. Treatment may involve switching to an alternative agent or may require surgery or irradiation if the causative agent cannot be discontinued. We reviewed the literature on drug-induced gynecomastia and provided another perspective by reviewing data from the United States Food and Drug Administration's Adverse Event Reporting System. Epidemiologic studies are needed to provide a more accurate description of the frequency of drug-induced gynecomastia. © 2012 Pharmacotherapy Publications, Inc.

  8. Management of transgenderism.

    PubMed

    Spack, Norman P

    2013-02-06

    Gender identity disorder (transgenderism) is poorly understood from both mechanistic and clinical standpoints. Awareness of the condition appears to be increasing, probably because of greater societal acceptance and available hormonal treatment. Therapeutic options include hormone and surgical treatments but may be limited by insurance coverage because costs are high. For patients seeking male-to-female (MTF) change, hormone treatment includes estrogens, finasteride, spironolactone, and gonadotropin-releasing hormone (GnRH) analogs. Surgical options include feminizing genital and facial surgery, breast augmentation, and various fat transplantations. For patients seeking a female-to-male (FTM) gender change, medical therapy includes testosterone and GnRH analogs and surgical therapy includes mammoplasty and phalloplasty. Medical therapy for both FTM and MTF can be started in early puberty, although long-term effects are not known. All patients considering treatment need counseling and medical monitoring.

  9. Action of ANP on the nongenomic dose-dependent biphasic effect of aldosterone on NHE1 in proximal S3 segment.

    PubMed

    Braga-Sobrinho, C; Leite-Dellova, D C A; Mello-Aires, M

    2012-02-01

    The rapid (2 min) nongenomic effects of aldosterone (ALDO) and/or spironolactone (MR antagonist), RU 486 (GR antagonist), atrial natriuretic peptide (ANP) and dimethyl-BAPTA (BAPTA) on the intracellular pH recovery rate (pHirr) via NHE1 (basolateral Na⁺/H⁺ exchanger isoform), after the acid load induced by NH₄Cl, and on the cytosolic free calcium concentration ([Ca²⁺](i)) were investigated in the proximal S3 segment isolated from rats, by the probes BCECF-AM and FLUO-4-AM, respectively. The basal pHi was 7.15±0.008 and the basal pHirr was 0.195±0.012 pH units/min (number of tubules/number of tubular areas=16/96). Our results confirmed the rapid biphasic effect of ALDO on NHE1: ALDO (10⁻¹² M) increases the pHirr to approximately 59% of control value, and ALDO (10⁻⁶ M) decreases it to approximately 49%. Spironolactone did not change these effects, but RU 486 inhibited the stimulatory effect and maintained the inhibitory effect. ANP (10⁻⁶ M) or BAPTA (5×10⁻⁵ M) alone had no significant effect on NHE1 but prevented both effects of ALDO on this exchanger. The basal [Ca²⁺](i) was 104±3 nM (15), and ALDO (10⁻¹² or 10⁻⁶ M) increased the basal [Ca²⁺](i) to approximately 50% or 124%, respectively. RU 486, ANP and BAPTA decreased the [Ca²⁺](i) and inhibited the stimulatory effect of both doses of ALDO. The results suggest the involvement of GR on the nongenomic effects of ALDO and indicate a pHirr-regulating role for [Ca²⁺](i) that is mediated by NHE1, stimulated/impaired by ALDO, and affected by ANP or BAPTA with ALDO. The observed nongenomic hormonal interaction in the S3 segment may represent a rapid and physiologically relevant regulatory mechanism in the intact animal under conditions of volume alterations. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. Aldosterone Induces Apoptosis in Rat Podocytes: Role of PI3-K/Akt and p38MAPK Signaling Pathways

    PubMed Central

    Chen, Cheng; Liang, Wei; Jia, Junya; van Goor, Harry; Singhal, Pravin C.; Ding, Guohua

    2009-01-01

    Background Podocytes play a critical role in the pathogenesis of glomerulosclerosis. Increasing evidence suggests that aldosterone (ALD) is involved in the initiation and progression of glomerular damage. It is, however, unknown whether there is a direct injurious effect of ALD on podocytes. Therefore, in the present study, we evaluated the effect of ALD on podocyte apoptosis and studied the role of phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways in this process. Methods Podocytes were incubated in media containing either buffer or increasing concentrations of ALD (10–9∼10–5M) for variable time periods. The cells were also treated with either wortmannin (inhibitor of PI3-K, 100 nM), SB202190 (SB20, inhibitor of p38MAPK, 10 μM) or buffer. All treatments were performed with or without ALD (10–7M) for 24 h. At the end of the incubation period, apoptosis was evaluated by cell nucleus staining and flow cytometric analyses. Activation of PI3-K/Akt and p38MAPK phosphorylation of cultured rat podocytes was evaluated by performing Akt kinase assay and Western blot, respectively. Results Apoptosis of cultured rat podocytes was induced by ALD in a dose- and time-dependent manner. ALD inhibited the activity of PI3-K/Akt and increased the activation of p38MAPK. PI3-K/Akt activity was further inhibited by the addition of wortmannin to the cells in the presence of ALD. This was accompanied by a significant increase in apoptosis. ALD-induced p38MAPK phosphorylation and apoptosis were inhibited when the cells were pretreated with SB20. Furthermore, treatment with spironolactone not only attenuated the proapoptotic effect of ALD, but also significantly reversed its effects on PI3-K/Akt and p38MAPK signaling pathways. Conclusion ALD induces apoptosis in rat podocytes through inhibition of PI3-K/Akt and stimulation of p38 MAPK signaling pathways. Spironolactone attenuates ALD-induced podocyte apoptosis

  11. Synergy between publication and promotion: comparing adoption of new evidence in Canada and the United States.

    PubMed

    Majumdar, Sumit R; McAlister, Finlay A; Soumerai, Stephen B

    2003-10-15

    Few studies have examined the effect of new evidence from clinical trials on physician practice. We took advantage of differences in promotional activity in Canada and the United States for the Heart Outcomes Prevention and Evaluation (HOPE) study and the Randomized Aldactone Evaluation Study (RALES) to determine if publication of new evidence changes practice, and the extent to which promotion influences adoption of new evidence. We used longitudinal dispensing data, collected from 1998 to 2001, to examine changes in prescribing patterns for ramipril and other angiotensin-converting enzyme (ACE) inhibitors before and after the HOPE study. We also obtained estimates for promotional expenditures. We stratified analyses by country, to isolate the effect of promotion, and used interrupted time series methods to adjust for pre-existing prescribing trends. Similar analyses were conducted for spironolactone use before and after RALES. Publication of the HOPE study results was associated with rapid increases in the use of ramipril. After adjusting for pre-existing prescribing trends, ramipril prescribing increased by 12% per month (P = 0.001) in Canada versus 5% per month (P = 0.001) in the United States after the study results were presented and published. One year later, ramipril accounted for 30% of the ACE inhibitor market in Canada versus 6% in the United States. The year before publication of these results, expenditures for detailing increased by 20% in Canada (to 18 US dollars per physician) but decreased by 7% in the United States (to 13 US dollars per physician); the year after publication, spending increased to 27 US dollars per physician in Canada versus 23 US dollars per physician in the United States. In the absence of promotional activity for RALES in either country, publication of results was associated with more modest but similar increases of 2% per month (P = 0.001) in spironolactone use in both countries. Publication of new evidence is associated with

  12. Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial.

    PubMed

    Lindhardt, Morten; Persson, Frederik; Currie, Gemma; Pontillo, Claudia; Beige, Joachim; Delles, Christian; von der Leyen, Heiko; Mischak, Harald; Navis, Gerjan; Noutsou, Marina; Ortiz, Alberto; Ruggenenti, Piero Luigi; Rychlik, Ivan; Spasovski, Goce; Rossing, Peter

    2016-03-02

    Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years.The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. The study will be conducted under International Conference on Harmonisation - Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws

  13. Diuretic effect of compounds from Hibiscus sabdariffa by modulation of the aldosterone activity.

    PubMed

    Jiménez-Ferrer, Enrique; Alarcón-Alonso, Javier; Aguilar-Rojas, Arturo; Zamilpa, Alejandro; Jiménez-Ferrer C, Itzia; Tortoriello, Jaime; Herrera-Ruiz, Maribel

    2012-12-01

    Recent studies of Hibiscus sabdariffa Linn. have demonstrated that it presents diuretic, natriuretic, and potassium sparing effects. However, the mechanism that induces these effects has not yet been elucidated. The aim of this study was to explore the possible mechanism of action for the diuretic effect of Hibiscus sabdariffa extract and its fractions.The aqueous extract from this plant and the fractions obtained with solvents of different polarities were administered to adrenalectomized rats, and the diuretic effect was measured in the presence of deoxycorticosterone acetate (aldosterone analog).The effect on renal filtration was also evaluated in an in situ kidney model, and finally, the effect of diuretic active extracts on gene expression of the alpha subunit from the transporter (αENaC) of renal epithelial cell was quantified. The subsequent results were obtained: The aqueous extract of Hibiscus sabdariffa presented the following chemical composition, 32.4 mg/g delphinidin-3-O-sambubioside, 11.5 mg/g cyanidin-3-O-sambubioside, 11.5 mg/g quercetin, and chlorogenic acid 2.7 mg/g. The concentration of anthocyanins was diminished until disappearance due to decrease of the polarity of the solvents used in the extraction process, in contrast to the flavonoids and chlorogenic acid, which had their concentration increased. The diuretic effect caused by adrenalectomy in rats was reversed by deoxycorticosterone acetate activity. However, the effect of deoxycorticosterone acetate was antagonized by spironolactone, the aqueous extract of Hibiscus sabdariffa, and the acetonitrile : methanol 5 : 5 mixture extract, administered orally. A similar effect was observed on renal filtration obtained from the isolated kidney model.When the gene expression levels of αENaC was measured in adrenalectomized rats, it was observed that spironolactone, the aqueous extract of Hibiscus sabdariffa, the acetonitrile : methanol 5 : 5 mixture, as well as the

  14. Managing resistant hypertension: focus on mineralocorticoid-receptor antagonists

    PubMed Central

    Yugar-Toledo, Juan Carlos; Modolo, Rodrigo; de Faria, Ana Paula; Moreno, Heitor

    2017-01-01

    Mineralocorticoid-receptor antagonists (MRAs) have proven to be effective in some types of hypertension, especially in resistant hypertension (RHTN). In this phenotype of hypertension, the renin–angiotensin–aldosterone pathway plays an important role, with MRAs being especially effective in reducing blood pressure. In this review, we show the relevance of aldosterone in RHTN, as well as some clinical characteristics of this condition and the main concepts involving its pathophysiology and cardiovascular damage. We analyzed the mechanisms of action and clinical effects of two current MRAs – spironolactone and eplerenone – both of which are useful in RHTN, with special attention to the former. RHTN represents a significant minority (10%–15%) of hypertension cases. However, primary-care physicians, cardiologists, nephrologists, neurologists, and geriatricians face this health problem on a daily basis. MRAs are likely one of the best pharmacological options in RHTN patients; however, they are still underused. PMID:29081661

  15. Simultaneous Determination of Eight Hypotensive Drugs of Various Chemical Groups in Pharmaceutical Preparations by HPLC-DAD.

    PubMed

    Stolarczyk, Mariusz; Hubicka, Urszula; Żuromska-Witek, Barbara; Krzek, Jan

    2015-01-01

    A new sensitive, simple, rapid, and precise HPLC method with diode array detection has been developed for separation and simultaneous determination of hydrochlorothiazide, furosemide, torasemide, losartane, quinapril, valsartan, spironolactone, and canrenone in combined pharmaceutical dosage forms. The chromatographic analysis of the tested drugs was performed on an ACE C18, 100 Å, 250×4.6 mm, 5 μm particle size column with 0.0.05 M phosphate buffer (pH=3.00)-acetonitrile-methanol (30+20+50 v/v/v) mobile phase at a flow rate of 1.0 mL/min. The column was thermostatted at 25°C. UV detection was performed at 230 nm. Analysis time was 10 min. The elaborated method meets the acceptance criteria for specificity, linearity, sensitivity, accuracy, and precision. The proposed method was successfully applied for the determination of the studied drugs in the selected combined dosage forms.

  16. Symptomatic Cushing's syndrome and hyperandrogenemia in a steroid cell ovarian neoplasm: a case report.

    PubMed

    Sedhom, Ramy; Hu, Sophia; Ohri, Anupam; Infantino, Dorian; Lubitz, Sara

    2016-10-12

    Malignant steroid cell tumors of the ovary are rare and frequently associated with hormonal abnormalities. There are no guidelines on how to treat rapidly progressive Cushing's syndrome, a medical emergency. A 67-year-old white woman presented to our hospital with rapidly developing signs and symptoms of Cushing's syndrome secondary to a steroid-secreting tumor. Her physical and biochemical manifestations of Cushing's syndrome progressed, and she was not amenable to undergoing conventional chemotherapy secondary to the debilitating effects of high cortisol. Her rapidly progressive Cushing's syndrome ultimately led to her death, despite aggressive medical management with spironolactone, ketoconazole, mitotane, and mifepristone. We report an unusual and rare case of Cushing's syndrome secondary to a malignant steroid cell tumor of the ovary. The case is highlighted to discuss the complications of rapidly progressive Cushing's syndrome, an underreported and often unrecognized endocrine emergency, and the best available evidence for treatment.

  17. Use of aldosterone antagonists in resistant hypertension.

    PubMed

    Calhoun, David A

    2006-01-01

    Resistant hypertension is defined as an elevated blood pressure in spite of treatment with 3 different antihypertensive agents. The prevalence of resistant hypertension is unknown, but recent cross-sectional analyses and hypertension outcome studies suggest it is a common clinical problem and will become even more so with an aging and increasingly heavy population. Secondary causes of hypertension are common in patients with resistant hypertension, in particular, obstructive sleep apnea and hyperaldosteronism. Treatment of resistant hypertension is predicated upon identification and reversal of secondary causes of hypertension, as possible, and effective use of multidrug regimens. Recent clinical studies indicate that aldosterone antagonists, spironolactone and amiloride, provide significant additional blood pressure reduction when added to treatment regimens of patients with resistant hypertension. Both agents are generally well tolerated. Hyperkalemia is an uncommon complication of aldosterone antagonists, but it can occur; therefore, biochemical monitoring is necessary, particularly in high-risk patients.

  18. Pay attention to cardiac remodeling in cancer cachexia.

    PubMed

    Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

    2016-07-01

    Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival.

  19. Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions.

    PubMed

    Thommes, Markus; Ely, David R; Carvajal, M Teresa; Pinal, Rodolfo

    2011-06-06

    We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.

  20. Role of 11beta-hydroxysteroid dehydrogenase 2 renal activity in potassium homeostasis in rats with chronic renal failure.

    PubMed

    Yeyati, N L; Altuna, M E; Damasco, M C; Mac Laughlin, M A

    2010-01-01

    Aldosterone concentrations vary in advanced chronic renal failure (CRF). The isozyme 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2), which confers aldosterone specificity for mineralocorticoid receptors in distal tubules and collecting ducts, has been reported to be decreased or normal in patients with renal diseases. Our objective was to determine the role of aldosterone and 11beta-HSD2 renal microsome activity, normalized for glomerular filtration rate (GFR), in maintaining K+ homeostasis in 5/6 nephrectomized rats. Male Wistar rats weighing 180-220 g at the beginning of the study were used. Rats with experimental CRF obtained by 5/6 nephrectomy (N = 9) and sham rats (N = 10) were maintained for 4 months. Systolic blood pressure and plasma creatinine (Pcr) concentration were measured at the end of the experiment. Sodium and potassium excretion and GFR were evaluated before and after spironolactone administration (10 mg.kg-1.day-1 for 7 days) and 11beta-HSD2 activity on renal microsomes was determined. Systolic blood pressure (means +/- SEM; Sham = 105 +/- 8 and CRF = 149 +/- 10 mmHg) and Pcr (Sham = 0.42 +/- 0.03 and CRF = 2.53 +/- 0.26 mg/dL) were higher (P < 0.05) while GFR (Sham = 1.46 +/- 0.26 and CRF = 0.61 +/- 0.06 mL/min) was lower (P < 0.05) in CRF, and plasma aldosterone (Pald) was the same in the two groups. Urinary sodium and potassium excretion was similar in the two groups under basal conditions but, after spironolactone treatment, only potassium excretion was decreased in CRF rats (sham = 0.95 +/- 0.090 (before) vs 0.89 +/- 0.09 microEq/min (after) and CRF = 1.05 +/- 0.05 (before) vs 0.37 +/- 0.07 microEq/min (after); P < 0.05). 11beta-HSD2 activity on renal microsomes was lower in CRF rats (sham = 0.807 +/- 0.09 and CRF = 0.217 +/- 0.07 nmol.min-1.mg protein-1; P < 0.05), although when normalized for mL GFR it was similar in both groups. We conclude that K+ homeostasis is maintained during CRF development despite normal Pald levels. This

  1. Cardioprotective effect of cerium oxide nanoparticles in monocrotaline rat model of pulmonary hypertension: A possible implication of endothelin-1.

    PubMed

    Nassar, Seham Zakaria; Hassaan, Passainte S; Abdelmonsif, Doaa A; ElAchy, Samar Nabil

    2018-05-15

    Cerium oxide nanoparticles (CeO 2 NPs) have been recently introduced into the medical field for their antioxidant properties. The ability of CeO 2 NPs alone or in combination with spironolactone (SP) to attenuate monocrotaline (MCT)-induced pulmonary hypertension and associated right ventricular hypertrophy was studied in rats. A special emphasis was given to endothelin-1 pathway. Pulmonary hypertension was induced in albino rats by a single subcutaneous injection of MCT (60 mg/kg). Rats received either single CeO 2 NPs therapy or combined therapy with SP for 2 weeks. CeO 2 NPs improved pulmonary function tests with concomitant decrease in serum endothelin-1 and pulmonary expression of endothelin-1 and its receptor ETAR. Besides, CeO 2 NPs diminished MCT-induced right ventricular hypertrophy and reduced cardiac oxidative stress and apoptosis. CeO 2 NPs could improve pulmonary hypertension and associated right ventricular hypertrophy with no additive value for SP. Besides being an antioxidant, CeO 2 NPs work through endothelin-1 pathway to improve pulmonary hypertension. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Use of Diuretics is not associated with mortality in patients admitted to the emergency department: results from a cross-sectional study.

    PubMed

    Haider, Dominik G; Lindner, Gregor; Wolzt, Michael; Leichtle, Alexander Benedikt; Fiedler, Georg-Martin; Sauter, Thomas C; Fuhrmann, Valentin; Exadaktylos, Aristomenis K

    2016-02-01

    Patients with diuretic therapy are at risk for drug-induced adverse reactions. It is unknown if presence of diuretic therapy at hospital emergency room admission is associated with mortality. In this cross sectional analysis, all emergency room patients 2010 and 2011 at the Inselspital Bern, Switzerland were included. A multivariable logistic regression model was performed to assess the association between pre-existing diuretic medication and 28 day mortality. Twenty-two thousand two hundred thirty-nine subjects were included in the analysis. A total of 8.5%, 2.5%, and 0.4% of patients used one, two, or three or more diuretics. In univariate analysis spironolactone, torasemide and chlortalidone use were associated with 28 day mortality (all p < 0.05). In a multivariate cox regression model no association with mortality was detectable (p > 0.05). No difference existed between patients with or without diuretic therapy (P > 0.05). Age and creatinine were independent risk factors for mortaliy (both p < 0.05). Use of diuretics is not associated with mortality in an unselected cohort of patients presenting in an emergency room.

  3. Gitelman or Bartter type 3 syndrome? A case of distal convoluted tubulopathy caused by CLCNKB gene mutation

    PubMed Central

    Cruz, António José; Castro, Alexandra

    2013-01-01

    A 32-year-old woman with no significant medical history was sent to our consultation due to hypokalaemia (<3.0 mmol/l). Her main complaints were longstanding polyuria and nocturia. Physical examination was normal. Basic investigations showed normal renal function, low serum potassium (2.7 mmol/l) and magnesium (0.79 mmol/l), metabolic alkalosis (pH 7.54; bicarbonate 32.5 mmol/l), elevated urinary potassium (185 mmol/24 h) and normal urinary calcium (246 mg/24 h). Thiazide test revealed blunted response. Chronic vomiting and the abuse of diuretics were excluded. Genetic tests for SLC12A3 gene mutation described in Gitelman syndrome (GS) came negative. CLCNKB gene mutation analysis present in both GS and Bartter (BS) type 3 syndromes was positive. The patient is now being treated with potassium and magnesium oral supplements, ramipril and spironolactone with stable near-normal potassium and magnesium levels. This article presents the case of a patient with hypokalaemia caused by CLCNKB gene mutation hard to categorise as GS or BS type 3. PMID:23345488

  4. Gitelman or Bartter type 3 syndrome? A case of distal convoluted tubulopathy caused by CLCNKB gene mutation.

    PubMed

    Cruz, António José; Castro, Alexandra

    2013-01-22

    A 32-year-old woman with no significant medical history was sent to our consultation due to hypokalaemia (<3.0 mmol/l). Her main complaints were longstanding polyuria and nocturia. Physical examination was normal. Basic investigations showed normal renal function, low serum potassium (2.7 mmol/l) and magnesium (0.79 mmol/l), metabolic alkalosis (pH 7.54; bicarbonate 32.5 mmol/l), elevated urinary potassium (185 mmol/24 h) and normal urinary calcium (246 mg/24 h). Thiazide test revealed blunted response. Chronic vomiting and the abuse of diuretics were excluded. Genetic tests for SLC12A3 gene mutation described in Gitelman syndrome (GS) came negative. CLCNKB gene mutation analysis present in both GS and Bartter (BS) type 3 syndromes was positive. The patient is now being treated with potassium and magnesium oral supplements, ramipril and spironolactone with stable near-normal potassium and magnesium levels. This article presents the case of a patient with hypokalaemia caused by CLCNKB gene mutation hard to categorise as GS or BS type 3.

  5. Cardiovascular risk and subclinical cardiovascular disease in polycystic ovary syndrome.

    PubMed

    Bajuk Studen, Katica; Jensterle Sever, Mojca; Pfeifer, Marija

    2013-01-01

    In addition to its effects on reproductive health, it is now well recognized that polycystic ovary syndrome (PCOS) is a metabolic disorder, characterized by decreased insulin sensitivity which leads to an excess lifetime risk of type 2 diabetes and cardiovascular disease. PCOS patients are often obese, hypertensive, dyslipidemic and insulin resistant; they have obstructive sleep apnea and have been reported to have higher aldosterone levels in comparison to normal healthy controls. These are all components of an adverse cardiovascular risk profile. Many studies exploring subclinical atherosclerosis using different methods (flow-mediated dilatation, intima media thickness, arterial stiffness, coronary artery calcification) as well as assessing circulating cardiovascular risk markers, point toward an increased cardiovascular risk and early atherogenesis in PCOS. The risk and early features of subclinical atherosclerosis can be reversed by non-medical (normalization of weight, healthy lifestyle) and medical (metformin, thiazolidinediones, spironolactone, and statins) interventions. However, the long-term risk for cardiovascular morbidity and mortality as well as the clinical significance of different interventions still need to be properly addressed in a large prospective study. Copyright © 2013 S. Karger AG, Basel.

  6. Combining neuroendocrine inhibitors in heart failure: reflections on safety and efficacy.

    PubMed

    Jneid, Hani; Moukarbel, George V; Dawson, Bart; Hajjar, Roger J; Francis, Gary S

    2007-12-01

    Neuroendocrine activation in heart failure has become the major target of pharmacotherapy for this growing epidemic. Agents targeting the renin-angiotensin-aldosterone and sympathetic nervous systems have shown cardiovascular and survival benefits in clinical trials. Beta-blockers and angiotensin-converting enzyme (ACE) inhibitors remain the mainstream initial therapy. The benefits of aldosterone antagonists have been demonstrated in advanced heart failure (spironolactone) and after myocardial infarction complicated by left ventricular dysfunction and heart failure (eplerenone). Emerging clinical evidence demonstrated that angiotensin receptor blockers may be a reasonable alternative to ACE inhibitors in patients with heart failure (candesartan) and following myocardial infarction complicated by heart failure or left ventricular dysfunction (valsartan). Angiotensin receptor blockers (candesartan) also provided incremental benefits when added to ACE inhibitors in chronic heart failure. Thus, combining neuroendocrine inhibitors in heart failure appears both biologically plausible and evidence-based. However, this approach raised concerns about side effects, such as hypotension, renal insufficiency, hyperkalemia, and others. Close follow-up and implementation of evidence-based medicine (ie, using agents and doses proven beneficial in clinical trials) should therefore be undertaken when combining neuroendocrine inhibitors.

  7. Life-threatening hyperkalemia – an overlooked acute kidney injury with a serum creatinine rise in the ‘normal’ range

    PubMed Central

    Latus, Joerg; Braun, Niko; Alscher, M Dominik; Kimmel, Martin

    2012-01-01

    A 76-year-old woman (51 kg, 158 cm, body mass index 20.5) was admitted to the hospital because of an acute kidney injury with hyperkalemia. On admission, she reported progredient muscle weakness of all limbs for several days. Serum potassium level was dramatically elevated and ECG showed QRS with a ‘sine-wave’ pattern and haemodialysis was started. 45 days ago, Hartmann’s operation was done because of stenosing sigmoid diverticulitis. At this time, the serum creatinine was 0.4 mg/dl (‘normal’ 0.5–1.2). Thereafter, she got severe ‘high output-ileostoma’ with severe intestinal fluid losses and treatment with potassium supplementation and spironolactone was started by the surgeons. She was discharged with elevated serum potassium levels and serum creatinine of 1.0 mg/dl (‘normal’ range (0.5–1.2 mg/dl)). This case illustrates impressively the lack of serum creatinine as an ideal kidney function test, because it is depending on muscle mass and there is no interindividual normal range. PMID:22605836

  8. Genetic Ablation of Fgf23 or Klotho Does not Modulate Experimental Heart Hypertrophy Induced by Pressure Overload.

    PubMed

    Slavic, Svetlana; Ford, Kristopher; Modert, Magalie; Becirovic, Amarela; Handschuh, Stephan; Baierl, Andreas; Katica, Nejla; Zeitz, Ute; Erben, Reinhold G; Andrukhova, Olena

    2017-09-12

    Left ventricular hypertrophy (LVH) ultimately leads to heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac hypertrophy.

  9. Cholestyramine induced hyperchloremic metabolic acidosis.

    PubMed

    Eaves, E R; Korman, M G

    1984-10-01

    The first reported case, in an adult, of cholestyramine induced hyperchloremic metabolic acidosis is a 70 year old female with a two year history of primary biliary cirrhosis confirmed by histologic and immunologic criteria. After taking cholestyramine II sachets twice daily for two months she presented with lethargy, confusion and drowsiness. Examination revealed confusion, jaundice, signs of chronic liver disease, portal hypertension and hepatic encephalopathy. Laboratory investigations confirmed a metabolic acidosis (pH 7.15) and hyperchloremia. Multiple cultures failed to reveal sepsis and a urinary pH of 4.85 together with tests of renal acidification, excluded renal tubular acidosis. She received 600 mEq of sodium bicarbonate intravenously over 36 hours by which time her mentation, electrolytes and pH were normal. It is presumed that her hyperchloremic metabolic acidosis was secondary to cholestyramine because of the similarity to pediatric reports; the rapid and lasting response to intravenous sodium bicarbonate; the absence of another etiology; normal serum potassium, chloride and bicarbonate despite continued spironolactone therapy after recovery.

  10. Molecular genetics of Liddle's syndrome.

    PubMed

    Yang, Kun-Qi; Xiao, Yan; Tian, Tao; Gao, Ling-Gen; Zhou, Xian-Liang

    2014-09-25

    Liddle's syndrome, an autosomal dominant form of monogenic hypertension, is characterized by salt-sensitive hypertension with early penetrance, hypokalemia, metabolic alkalosis, suppression of plasma rennin activity and aldosterone secretion, and a clear-cut response to epithelial sodium channel (ENaC) blockers but not spironolactone therapy. Our understanding of ENaCs and Na(+) transport defects has expanded greatly over the past two decades and provides detailed insight into the molecular basis of Liddle's syndrome. In this review, we offer an overview of recent advances in understanding the molecular genetics of Liddle's syndrome, involving mutation analysis, molecular mechanisms and genetic testing. The ENaC in the distal nephron is composed of α, β and γ subunits that share similar structures. Mutations associated with Liddle's syndrome are positioned in either β or γ subunits and disturb or truncate a conserved proline-rich sequence (i.e., PY motif), leading to constitutive activation of the ENaC. Genetic testing has made it possible to make accurate diagnoses and develop tailored therapies for mutation carriers. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Pathophysiology and management of pediatric ascites.

    PubMed

    Sabri, Mahmoud; Saps, Miguel; Peters, John M

    2003-06-01

    Ascites accumulation is the product of a complex process involving hepatic, renal, systemic, hemodynamic, and neurohormonal factors. The main pathophysiologic theories of ascites formation include the "underfill," "overflow," and peripheral arterial vasodilation hypotheses. These theories are not necessarily mutually exclusive and are linked at some level by a common pathophysiologic thread: The body senses a decreased effective arterial blood volume, leading to stimulation of the sympathetic nervous system, arginine-vasopressin feedback loops, and the renin-angiotensin-aldosterone system. Cornerstones of ascites management include dietary sodium restriction and diuretics. Spironolactone is generally tried initially, with furosemide added if clinical response is suboptimal. More refractory patients require large-volume paracentesis (LVP) accompanied by volume expansion with albumin. Placement of a transjugular intrahepatic portosystemic shunt is reserved for individuals with compensated liver function who require very frequent sessions of LVP. Peritoneovenous shunts are not used in contemporary ascites management. Liver transplantation remains the definitive therapy for refractory ascites. Although treatment of ascites fails to improve survival, it benefits quality of life and limits the development of such complications as spontaneous bacterial peritonitis.

  12. Female pattern alopecia: current perspectives

    PubMed Central

    Levy, Lauren L; Emer, Jason J

    2013-01-01

    Hair loss is a commonly encountered problem in clinical practice, with men presenting with a distinctive pattern involving hairline recession and vertex balding (Norwood-Hamilton classification) and women exhibiting diffuse hair thinning over the crown (increased part width) and sparing of the frontal hairline (Ludwig classification). Female pattern hair loss has a strikingly overwhelming psychological effect; thus, successful treatments are necessary. Difficulty lies in successful treatment interventions, as only two medications – minoxidil and finasteride – are approved for the treatment of androgenetic alopecia, and these medications offer mediocre results, lack of a permanent cure, and potential complications. Hair transplantation is the only current successful permanent option, and it requires surgical procedures. Several other medical options, such as antiandrogens (eg, spironolactone, oral contraceptives, cyproterone, flutamide, dutasteride), prostaglandin analogs (eg, bimatoprost, latanoprost), and ketoconazole are reported to be beneficial. Laser and light therapies have also become popular despite the lack of a profound benefit. Management of expectations is crucial, and the aim of therapy, given the current therapeutic options, is to slow or stop disease progression with contentment despite patient expectations of permanent hair regrowth. This article reviews current perspectives on therapeutic options for female pattern hair loss. PMID:24039457

  13. Update in diagnosis and management of primary aldosteronism.

    PubMed

    Dick, Sofia M; Queiroz, Marina; Bernardi, Bárbara L; Dall'Agnol, Angélica; Brondani, Letícia A; Silveiro, Sandra P

    2018-02-23

    Primary aldosteronism (PA) is a group of disorders in which aldosterone is excessively produced. These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis. The prevalence of PA ranges from 5% to 12% around the globe, and the most common causes are adrenal adenoma and adrenal hyperplasia. The importance of PA recognition arises from the fact that it can have a remarkably adverse cardiovascular and renal impact, which can even result in death. The aldosterone-to-renin ratio (ARR) is the election test for screening PA, and one of the confirmatory tests, such as oral sodium loading (OSL) or saline infusion test (SIT), is in general necessary to confirm the diagnosis. The distinction between adrenal hyperplasia (AH) or aldosterone-producing adenoma (APA) is essential to select the appropriate treatment. Therefore, in order to identify the subtype of PA, imaging exams such as computed tomography or magnetic ressonance imaging, and/or invasive investigation such as adrenal catheterization must be performed. According to the subtype of PA, optimal treatment - surgical for APA or pharmacological for AH, with drugs like spironolactone and amiloride - must be offered.

  14. Changes in body fluid compartments on re-induction to high altitude and effect of diuretics

    NASA Astrophysics Data System (ADS)

    Singh, M. V.; Rawal, S. B.; Tyagi, A. K.; Bhagat, Maj J. K.; Parshad, R.; Divekar, H. M.

    1988-03-01

    Studies were carried out in 29 healthy young adults in the Indian Army stationed in the plains and posted at an elevation of 3500 m for more than 6 months. After exposure to a low elevation in Delhi (260 m) for 3 weeks they were reinduced to a height of 3500 m. The subjects were divided into three groups, each of which was treated with either placebo or acetazolamide or spironolactone. The drug treatment was started immediately after their landing at high altitude and continued for 2 days only. Total body water, extracellular fluid, intracellular fluid, plasma volume, blood pH, PaO2, PaCO2 and blood viscosity were determined on exposure at Delhi and on re-induction to high altitude. Plasma volume was increased after the descent from high altitude and remained high for up to 21 day's study. This increased plasma volume may have some significance in the pathogenesis of pulmonary oedema. Total body water and intracellular fluid content were increased at 260 m elevation, while extracellular fluid decreased. On re-induction there was a decrease in total body water with no change in the extracellular fluid content.

  15. Differential effects of glucocorticoid and mineralocorticoid antagonism on anxiety behavior in mild traumatic brain injury.

    PubMed

    Fox, Laura C; Davies, Daniel R; Scholl, Jamie L; Watt, Michael J; Forster, Gina L

    2016-10-01

    Mild traumatic brain injuries (TBIs) comprise three-quarters of all TBIs occurring in the United States annually, and psychological symptoms arising from them can last years after injury. One commonly observed symptom following mild TBI is generalized anxiety. Most mild TBIs happen in stressful situations (sports, war, domestic violence, etc.) when glucocorticoids are elevated in the brain at the time of impact, and glucocorticoids have negative effects on neuronal health following TBI. Therefore, blocking glucocorticoid receptors might prevent emergence of anxiety symptoms post-injury. Adult male rats received mifepristone (20mg/kg) or spironolactone (50mg/kg) to block glucocorticoid and mineralocorticoid receptors, respectively, 40min prior to being exposed to acute social defeat stress followed immediately by mild TBI. In defeated rats with concomitant mild TBI, mifepristone restored time spent in the open arms of an elevated plus maze to control levels, demonstrating for the first time that glucocorticoid receptors play a critical role in the development of anxiety after mild TBI. Future treatments could target these receptors, alleviating anxiety as a major side effect in victims of mild TBI sustained in stressful situations. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. PCOS.

    PubMed

    Cahill, David

    2009-01-15

    Polycystic ovary syndrome (PCOS) is diagnosed in up to 10% of women attending gynaecology clinics, but the prevalence in the population as a whole is unclear. PCOS has been associated with hirsutism, infertility, acne, weight gain, type 2 diabetes, cardiovascular disease (CVD), and endometrial hyperplasia. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: finasteride, flutamide, metformin, spironolactone, cyproterone acetate-ethinylestradiol (co-cyprindiol), interventions to achieve weight loss, ketoconazole, and mechanical hair removal.

  17. Treatment of premenstrual dysphoric disorder (PMDD) with a novel formulation of drospirenone and ethinyl estradiol.

    PubMed

    De Berardis, Domenico; Serroni, Nicola; Salerno, Rosa Maria; Ferro, Filippo Maria

    2007-08-01

    Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS). Pharmacologic options studied for treating severe PMS and PMDD may include selective serotonin reuptake inhibitors, anxiolytic agents, gonadotropin-releasing hormone agonists and the diuretic spironolactone. However, the use of combined oral contraceptives (COC) may be a therapeutic option in treating PMS and PMDD. The combination of drospirenone with ethinylestradiol (EE/drospirenone) was approved for marketing as an oral contraceptive in Europe and the United States. The preparation is characterized by a high contraceptive efficacy in combination with excellent cycle control, good tolerability, and a favourable impact on lipid and glucose metabolism. Recently, some placebo-controlled, randomized studies have tested clinical efficacy and tolerability of this COC in the treatment of PMDD. The aim of the present review was to elucidate the possible benefits or disadvantages of PMDD treatment with this novel formulation of EE/drospirenone. The results of trials evaluating the use of EE/drospirenone combination in the treatment of PMDD are encouraging but further studies are needed. However, the reported clinical efficacy and the relative good tolerability of EE/drospirenone may contribute to widen the therapeutic spectrum of PMDD.

  18. Treatment of premenstrual dysphoric disorder (PMDD) with a novel formulation of drospirenone and ethinyl estradiol

    PubMed Central

    De Berardis, Domenico; Serroni, Nicola; Salerno, Rosa Maria; Ferro, Filippo Maria

    2007-01-01

    Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS). Pharmacologic options studied for treating severe PMS and PMDD may include selective serotonin reuptake inhibitors, anxiolytic agents, gonadotropin-releasing hormone agonists and the diuretic spironolactone. However, the use of combined oral contraceptives (COC) may be a therapeutic option in treating PMS and PMDD. The combination of drospirenone with ethinylestradiol (EE/drospirenone) was approved for marketing as an oral contraceptive in Europe and the United States. The preparation is characterized by a high contraceptive efficacy in combination with excellent cycle control, good tolerability, and a favourable impact on lipid and glucose metabolism. Recently, some placebo-controlled, randomized studies have tested clinical efficacy and tolerability of this COC in the treatment of PMDD. The aim of the present review was to elucidate the possible benefits or disadvantages of PMDD treatment with this novel formulation of EE/drospirenone. The results of trials evaluating the use of EE/drospirenone combination in the treatment of PMDD are encouraging but further studies are needed. However, the reported clinical efficacy and the relative good tolerability of EE/drospirenone may contribute to widen the therapeutic spectrum of PMDD. PMID:18472980

  19. [In-vitro evaluation of cinnarizine as a competing agent to beta-cyclodextrin inclusion complexes: effect of cinnarizine on the membrane permeation rate of progesterone from its beta-cyclodextrin inclusion complex].

    PubMed

    Muraoka, Atsushi; Tokumura, Tadakazu; Machida, Yoshiharu

    2008-01-01

    The use of competing agents is considered a powerful tool for the development of a drug-delivery system with drug/cyclodextrin inclusion complexes. However, there are very few studies examining this issue. To explain this phenomenon, it was thought that a competing agent with a sufficiently high stability constant had not yet been reported. In this study, cinnarizine (CN), which has a high stability constant with beta-cyclodextrin (beta-CD) and unique solubility characteristics, was selected, and its ability as a competing agent was examined in a membrane permeability study. The permeability study showed that the permeation rates of the drugs flurbiprofen, progesterone, and spironolactone decreased with their stability constants with the addition of beta-CD. In one of the drugs, progesterone (Pro), the decrease was restored by the addition of CN. The amount of CN added was a 1:1 molar ratio to the amount of Pro. However, no similar action was induced with the addition of DL-phenylalanine (Phe) in the permeation study at the 1:5 (Pro:Phe) molar ratio. These finding indicate that CN acts as a competing agent, and its action is much stronger than that of Phe.

  20. [Familial male-limited precocious puberty due to Asp578His mutations in the LHCGR gene: clinical characteristics and gene analysis in an infant].

    PubMed

    Wang, Min; Li, Min; Liu, Yue-Sheng; Lei, Si-Min; Xiao, Yan-Feng

    2017-11-01

    The aim of the study was to provide a descriptive analysis of familial male-limited precocious puberty (FMPP), which is a rare inherited disease caused by heterozygous constitutively activating mutations of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR). The patient was a ten-month-old boy, presenting with penile enlargement, pubic hair formation, and spontaneous erections. Based on the clinical manifestations and laboratory data, including sexual characteristics, serum testosterone levels, GnRH stimulation test, and bone age, this boy was diagnosed with peripheral precocious puberty. Subsequently the precocious puberty-related genes were analyzed by direct DNA sequencing of amplified PCR products from the patient and his parents. Genetic analysis revealed a novel heterozygous missense mutation c.1732G>C (Asp578His) of the LHCGR gene exon11 in the patient, which had never been reported. His parents had no mutations. After combined treatment with aromatase inhibitor letrozole and anti-androgen spironolactone for six months, the patient's symptoms were controlled. The findings in this study expand the mutation spectrum of the LHCGR gene, and provide molecular evidence for the etiologic diagnosis as well as for the genetic counseling and prenatal diagnosis in the family.

  1. Mineralocorticoid receptor antagonism prevents hedonic deficits induced by a chronic sodium appetite.

    PubMed

    Morris, Michael J; Na, Elisa S; Johnson, Alan Kim

    2010-04-01

    Our laboratory has reported that manipulations that provoke a robust sodium appetite (e.g., sodium depletion, deoxycorticosterone acetate) decrease lateral hypothalamic self-stimulation (LHSS) reward if rats are denied access to hypertonic saline solutions. The following studies investigated the interaction between chronic sodium appetite and the renin-angiotensin-aldosterone system on LHSS reward. In Experiment 1, animals treated with the diuretic furosemide (20 mg/kg) when denied access to saline exhibited an increase in the current required to produce 50% of the maximum LHSS response rate (ECu50) 48 hr after extracellular volume depletion. Furosemide-depleted rats that were allowed to drink 0.3 M saline after depletion, or that were treated with the selective mineralocorticoid receptor (MR) antagonist spironolactone, which significantly reduced sodium appetite, did not show ECu50 changes. In Experiment 2 chronic intracerebroventricular administration of the selective MR antagonist RU 28318 (10 microg/microl/hr) prevented decreases in the ECu50 induced by deoxycorticosterone acetate-no salt treatment. We conclude that an unresolved sodium appetite will reduce responding for rewards and that experimental manipulations that reduce sodium appetite (e.g., access to saline or blockade of MR) decrease hedonic deficits.

  2. Resistant hypertension and aldosterone: an update.

    PubMed

    Clark, Donald; Ahmed, Mustafa I; Calhoun, David A

    2012-05-01

    Resistant hypertension (RHTN) is defined as a blood pressure remaining above goal despite the concurrent use of 3 antihypertensive medications of different classes, including, ideally a diuretic. RHTN is an important health problem with a prevalence rate expected to increase as populations become older, more obese, and at higher risk of having diabetes and chronic kidney disease, all of which are important risk factors for development of RHTN. The role of aldosterone has gained increasing recognition as a significant contributor to antihypertensive treatment resistance. In prospective studies, the prevalence of primary aldosteronism (PA) has ranged from 14%-21% in patients with RHTN, which is considerably higher than in the general hypertensive population. Furthermore, marked antihypertensive effects are seen when mineralocorticoid antagonists are added to the treatment regimen of patients with RHTN, further supporting aldosterone excess as an important cause of RHTN. A close association exists between hyperaldosteronism, RHTN, and obstructive sleep apnea (OSA) based upon recent studies which indicate that OSA is worsened by aldosterone-mediated fluid retention. This interaction is supported by preliminary data which demonstrates improvement in OSA severity after treatment with spironolactone. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  3. Incidence of and risk factors for severe acute kidney injury in children with heart failure treated with renin-angiotensin system inhibitors.

    PubMed

    Terano, Chikako; Ishikura, Kenji; Miura, Masaru; Hamada, Riku; Harada, Ryoko; Sakai, Tomoyuki; Hamasaki, Yuko; Hataya, Hiroshi; Ando, Takashi; Honda, Masataka

    2016-05-01

    No large cohort study has yet determined the incidence of acute kidney injury (AKI) in children with heart failure treated with renin-angiotensin system (RAS) inhibitors. We thus retrospectively analyzed the incidence and risk factors for severe AKI (stages 2-3 according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines) at our institutions from 2008 to 2011. Among 312 children (162 boys; median age, 7.3 months), 59 cases of AKI occurred in 45 children. The incidence of AKI was 14.3 cases per 100 person-years overall (follow-up 413.6 person-years), or 27.3, 16.8, and 4.5 cases per 100 person-years in children aged <1, 1-3, and ≥4 years, respectively. Among them, 23 (39.0 %) children had metabolic acidosis and 14 (23.7 %) had hyperkalemia. Younger age, myocardial disease, cyanotic congenital heart disease, use of spironolactone, and cardiac surgery were independent risk factors for AKI. Furthermore, 37.3 % of children suffered dehydration during AKI. AKI incidence is relatively high in children, particularly younger children, with heart failure treated using RAS inhibitors. Careful monitoring of renal function and serum electrolytes is essential. Proper management of fluid balance after infection and cardiac surgery may reduce the risk of AKI. Temporary discontinuation in RAS inhibitors should be considered during dehydration or surgery. • Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the two main classes of renin-angiotensin system (RAS) inhibitors used to treat hypertension, heart failure, and chronic kidney disease. Acute kidney injury (AKI) and hyperkalemia are potentially life-threatening complications associated with the use of ACEIs and ARBs. Some reports have suggested that dehydration and cardiac surgery are risk factors for AKI in children. However, no large-scale cohort studies have determined the incidence of AKI, its risk factors, and its outcomes in children with heart failure treated

  4. Efficacy of tolvaptan in patients with refractory ascites in a clinical setting

    PubMed Central

    Ohki, Takamasa; Sato, Koki; Yamada, Tomoharu; Yamagami, Mari; Ito, Daisaku; Kawanishi, Koki; Kojima, Kentaro; Seki, Michiharu; Toda, Nobuo; Tagawa, Kazumi

    2015-01-01

    AIM: To elucidate the efficacies of tolvaptan (TLV) as a treatment for refractory ascites compared with conventional treatment. METHODS: We retrospectively enrolled 120 refractory ascites patients between January 1, 2009 and September 31, 2014. Sixty patients were treated with oral TLV at a starting dose of 3.75 mg/d in addition to sodium restriction (> 7 g/d), albumin infusion (10-20 g/wk), and standard diuretic therapy (20-60 mg/d furosemide and 25-50 mg/d spironolactone) and 60 patients with large volume paracentesis in addition to sodium restriction (less than 7 g/d), albumin infusion (10-20 g/wk), and standard diuretic therapy (20-120 mg/d furosemide and 25-150 mg/d spironolactone). Patient demographics and laboratory data, including liver function, were not matched due to the small number of patients. Continuous variables were analyzed by unpaired t-test or paired t-test. Fisher’s exact test was applied in cases comparing two nominal variables. We analyzed factors affecting clinical outcomes using receiver operating characteristic curves and multivariate regression analysis. We also used multivariate Cox’s proportional hazard regression analysis to elucidate the risk factors that contributed to the increased incidence of ascites. RESULTS: TLV was effective in 38 (63.3%) patients. The best cut-off values for urine output and reduced urine osmolality as measures of refractory ascites improvement were > 1800 mL within the first 24 h and > 30%, respectively. Multivariate regression analysis indicated that > 25% reduced urine osmolality [odds ratio (OR) = 20.7; P < 0.01] and positive hepatitis C viral antibodies (OR = 5.93; P = 0.05) were positively correlated with an improvement of refractory ascites, while the total bilirubin level per 1.0 mg/dL (OR = 0.57; P = 0.02) was negatively correlated with improvement. In comparing the TLV group and controls, only the serum sodium level was significantly lower in the TLV group (133 mEq/L vs 136 mEq/L; P = 0

  5. Applying high resolution mass spectrometry and network analysis to assess exposure to a novel androgen, spironolactone, on metabolic pathways in fish

    EPA Science Inventory

    Although metabolomics can successfully detect effects from overall contaminant exposure, its ability to elucidate specific metabolic pathways impacted by those exposures can be hindered by bottlenecks in metabolite identification. However, improved analytical approaches that com...

  6. Blocking mineralocorticoid receptors impairs, blocking glucocorticoid receptors enhances memory retrieval in humans.

    PubMed

    Rimmele, Ulrike; Besedovsky, Luciana; Lange, Tanja; Born, Jan

    2013-04-01

    Memory retrieval is impaired at very low as well as very high cortisol levels, but not at intermediate levels. This inverted-U-shaped relationship between cortisol levels and memory retrieval may originate from different roles of the mineralocorticoid (MR) and glucocorticoid receptor (GR) that bind cortisol with distinctly different affinity. Here, we examined the role of MRs and GRs in human memory retrieval using specific receptor antagonists. In two double-blind within-subject, cross-over designed studies, young healthy men were asked to retrieve emotional and neutral texts and pictures (learnt 3 days earlier) between 0745 and 0915 hours in the morning, either after administration of 400 mg of the MR blocker spironolactone vs placebo (200 mg at 2300 hours and 200 mg at 0400 hours, Study I) or after administration of the GR blocker mifepristone vs placebo (200 mg at 2300 hours, Study II). Blockade of MRs impaired free recall of both texts and pictures particularly for emotional material. In contrast, blockade of GRs resulted in better memory retrieval for pictures, with the effect being more pronounced for neutral than emotional materials. These findings indicate indeed opposing roles of MRs and GRs in memory retrieval, with optimal retrieval at intermediate cortisol levels likely mediated by high MR but concurrently low GR activation.

  7. CONGESTIVE HEART FAILURE ASSOCIATED WITH PREGNANCY IN OKAPI (OKAPIA JOHNSTONI).

    PubMed

    Warren, Joshua D; Aitken-Palmer, Copper; Weldon, Alan D; Flanagan, Joseph P; Howard, Lauren L; Garner, Michael M; Citino, Scott B

    2017-03-01

    Acute signs associated with cardiovascular disease occurred in three pregnant okapi ( Okapia johnstoni ) during early to midgestation and progressed to congestive heart failure. Congestive heart failure was diagnosed antemortem using echocardiography and plasma cardiac troponin levels. Clinical signs included decreased activity, hyporexia, tachypnea, dyspnea, flared nostrils, and productive coughing with copious amounts of foamy nasal discharge. Parenteral and oral treatment with furosemide, enalapril, and spironolactone controlled clinical signs in the three okapi allowing each to carry out one pregnancy to term. Two okapi carried the first pregnancy to term after showing signs, while one okapi aborted the first calf and gave birth to a healthy calf in a subsequent pregnancy. Subsequent pregnancy in one okapi ended with abortion and associated dystocia and endometritis. Following parturition, clinical signs associated with heart failure resolved in all three individuals; serial echocardiography in two individuals showed improvement in fractional shortening and left atrial size and all three okapi showed markedly decreased pleural effusion and resolution of pulmonary edema. However, subsequent pregnancies in all three okapi induced respiratory distress and recurrence of congestive heart failure; one okapi died from congestive heart failure associated with subsequent pregnancy. This case series describes the clinical presentation and pathologic findings of congestive heart failure during pregnancy in adult okapi.

  8. Are diuretics harmful in the management of acute kidney injury?

    PubMed

    Ejaz, A Ahsan; Mohandas, Rajesh

    2014-03-01

    To assess the role of diuretics in acute kidney injury (AKI) and their effectiveness in preventing AKI, achieving fluid balance, and decreasing progression to chronic kidney disease (CKD). Diuretics are associated with increased risk for AKI. The theoretical advantage of diuretic-induced preservation of renal medullary oxygenation to prevent AKI has not been proven. A higher cumulative diuretic dose during the dialysis period can cause hypotension and increase mortality in a dose-dependent manner. Data on the use of forced euvolemic diuresis to prevent AKI remains controversial. Positive fluid balance has emerged as an independent predictor of adverse outcomes. Post-AKI furosemide dose had a favorable effect on mortality due in part to the reduction of positive fluid balance. There are exciting experimental data suggesting that spironolactone may prevent AKI once an ischemic insult has occurred and thus prevent the progression to CKD. Diuretics are ineffective and even detrimental in the prevention and treatment of AKI, and neither shorten the duration of AKI, nor reduce the need for renal replacement therapy. Diuretics have an important role in volume management in AKI, but they are not recommended for the prevention of AKI. There is increased emphasis on the prevention of progression of AKI to CKD.

  9. [Clinical analysis of 6 cases of Bartter syndrome].

    PubMed

    Yin, Fang-mei; Zheng, Fang-qiu; Zhang, Xin; Wu, Mei-jun; Wei, Hong-yan; Ma, Zhong-shu; Lu, Biao; Qiu, Ming-cai

    2011-03-01

    To summarize the clinical characteristics of Bartter syndrome and investigate its pathogenesis. The clinical data of 6 cases of Bartter syndrome at our hospital from November 2006 to May 2010 were analyzed retrospectively. The onset age of Bartter syndrome was 13-35 years old. The main symptoms included weakness (6/6), paralysis (1/6), numbness (5/6) and tetany (4/6). All patients had normal blood pressure. The biochemical tests showed persistent hypokalemia, metabolic alkalosis (6/6) and hyperreninemia. The pathological examination of deltoid muscle biopsy showed the swelling, degeneration and necrosis of myocytes and the deposition of immunocomplex in myolemma. And the pathological examination of renal biopsy showed the hyperplasia of juxtaglomerular apparatus (5/6) and the deposition of immunocomplex. All symptoms were relieved after a therapy of potassium supplementation or a combination of indomethacin, spironolactone and immunosuppressant. When such clinical features as weakness, paralysis, tetany, hypokalemic alkalosis and normotension are encountered, Bartter syndrome should be suspected. Serum electrolytes, blood gas analysis and activation of the renin-angiotensin-aldosterone system should be examined for a definite diagnosis. The treatment of choice includes potassium and magnesium supplementation or in combination with prostaglandin synthetase inhibitor, aldosterone antagonist and immunosuppressant. Immunologic mechanism may participate in the course of Bartter syndrome.

  10. Distal Renal Tubules Are Deficient in Aggresome Formation and Autophagy upon Aldosterone Administration

    PubMed Central

    Cheema, Muhammad Umar; Damkier, Helle Hasager; Nielsen, Jakob; Poulsen, Ebbe Toftgaard; Enghild, Jan J.; Fenton, Robert A.; Praetorius, Jeppe

    2014-01-01

    Prolonged elevations of plasma aldosterone levels are associated with renal pathogenesis. We hypothesized that renal distress could be imposed by an augmented aldosterone-induced protein turnover challenging cellular protein degradation systems of the renal tubular cells. Cellular accumulation of specific protein aggregates in rat kidneys was assessed after 7 days of aldosterone administration. Aldosterone induced intracellular accumulation of 60 s ribosomal protein L22 in protein aggregates, specifically in the distal convoluted tubules. The mineralocorticoid receptor inhibitor spironolactone abolished aldosterone-induced accumulation of these aggregates. The aldosterone-induced protein aggregates also contained proteasome 20 s subunits. The partial de-ubiquitinase ataxin-3 was not localized to the distal renal tubule protein aggregates, and the aggregates only modestly colocalized with aggresome transfer proteins dynactin p62 and histone deacetylase 6. Intracellular protein aggregation in distal renal tubules did not lead to development of classical juxta-nuclear aggresomes or to autophagosome formation. Finally, aldosterone treatment induced foci in renal cortex of epithelial vimentin expression and a loss of E-cadherin expression, as signs of cellular stress. The cellular changes occurred within high, but physiological aldosterone concentrations. We conclude that aldosterone induces protein accumulation in distal renal tubules; these aggregates are not cleared by autophagy that may lead to early renal tubular damage. PMID:25000288

  11. Permanent scalp alopecia related to breast cancer chemotherapy by sequential fluorouracil/epirubicin/cyclophosphamide (FEC) and docetaxel: a prospective study of 20 patients.

    PubMed

    Kluger, N; Jacot, W; Frouin, E; Rigau, V; Poujol, S; Dereure, O; Guillot, B; Romieu, G; Bessis, D

    2012-11-01

    To analyze the clinical and histological features of permanent alopecia following a sequential fluorouracil/epirubicin/cyclophosphamide (FEC) and docetaxel regimen for adjuvant breast cancer treatment. Women treated for breast cancer by a sequential adjuvant FEC and docetaxel regimen who developed permanent alopecia diagnosed between 2007 and 2011 were identified from the Department of Dermatology (Saint-Eloi Hospital, Montpellier, France) and the Department of Medical Oncology (CRLC Val d'Aurelle, Montpellier, France). Data were collected regarding demographics, type of cancer, delay of onset after chemotherapy, Dermatology Life Quality Index (DLQI), clinical description of the lesions, scalp biopsies, laboratory explorations investigating steroid hormonal, iron, zinc and thyroid status, therapy and outcome. Twenty white Caucasian females were included. Hair loss presented with a moderate or intense androgenetic-like pattern of scalp alopecia. Biopsy specimen examinations were normal or displayed the androgenetic-like pattern. Laboratory explorations ruled out iron or zinc deficiency and thyroid disorders and confirmed hormonal menopause without hyperandrogenism. The overall mean DLQI score reflected the distressing psychological consequences in the patients' lives. No spontaneous regrowth of the scalp hair was noted. Treatment including vitamins, minoxidil, psoralen and ultraviolet A therapy and spironolactone proved to be ineffective. Permanent and severe alopecia is a newly reported complication of the FEC 100-docetaxel breast cancer regimen.

  12. Gynaecomastia--pathophysiology, diagnosis and treatment.

    PubMed

    Narula, Harmeet S; Carlson, Harold E

    2014-11-01

    Gynaecomastia (enlargement of the male breast tissue) is a common finding in the general population. Most cases of gynaecomastia are benign and of cosmetic, rather than clinical, importance. However, the condition might cause local pain and tenderness, could occasionally be the result of a serious underlying illness or a medication, or be inherited. Breast cancer in men is much less common than benign gynaecomastia, and the two conditions can usually be distinguished by a careful physical examination. Estrogens are known to stimulate the growth of breast tissue, whereas androgens inhibit it; most cases of gynaecomastia result from deficient androgen action or excessive estrogen action in the breast tissue. In some cases, such as pubertal gynaecomastia, the breast enlargement resolves spontaneously. In other situations, more active treatment might be required to correct an underlying condition (such as hyperthyroidism or a benign Leydig cell tumour of the testis) or medications that could cause breast enlargement (such as spironolactone) might need to be discontinued. For men with hypogonadism, administration of androgens might be helpful, as might antiestrogen therapy in men with endogenous overproduction of estrogens. Surgery to remove the enlarged breast tissue might be necessary when gynaecomastia does not resolve spontaneously or with medical therapy.

  13. Drug-induced gynecomastia: an evidence-based review.

    PubMed

    Deepinder, Fnu; Braunstein, Glenn D

    2012-09-01

    Drugs are estimated to cause about 10 - 25% of all cases of gynecomastia. Over the course of several decades, multiple medications have been implicated in the development of gynecomastia mostly in the form of case reports and case series. However, these reports suffer from a multitude of deficiencies, including poor quality of evidence. Studies were selected for this review by performing an extensive electronic and hand-search using BIOSIS, EMBASE and Medline, from 1940 to present, for all reported drug associations of gynecomastia and their possible pathophysiology. Quality of evidence was assessed on a three-point scale: good, fair and poor, and each of the drugs reported to cause gynecomastia was assigned a level of strength. The pathophysiology of gynecomastia is also discussed in detail for each of the drugs found to have a good or fair evidence of association with gynecomastia. Most of the reported drug-gynecomastia associations were based on poor quality evidence. The drugs definitely associated with the onset of gynecomastia are spironolactone, cimetidine, ketoconazole, hGH, estrogens, hCG, anti-androgens, GnRH analogs and 5-α reductase inhibitors. Medications probably associated with gynecomastia include risperidone, verapamil, nifedipine, omeprazole, alkylating agents, HIV medications (efavirenz), anabolic steroids, alcohol and opioids.

  14. Establishment of cocrystal cocktail grinding method for rational screening of pharmaceutical cocrystals.

    PubMed

    Yamamoto, Katsuhiko; Tsutsumi, Shunichirou; Ikeda, Yukihiro

    2012-11-01

    Cocrystals (CCs) used in the pharmaceutical industry are defined as complex crystals formed by reaction between an API and a cocrystal former (CCF); unlike salts, CCs do not show proton transfer. Recently, pharmaceutical CCs have been used to improve the drug-likeness of APIs, such as solubility and stability. Grinding is more effective for CC synthesis than crystallization from solution because in the former case, the API can predominantly interact with the CCF without being affected by solvents. However, this method is tedious because the API is ground with only one CCF at a time. We developed a cocktail cocrystal grinding (CCG) method, in which a mixture of CCFs having the same functional group was used. No false negatives/positives were observed in CCG when carbamazepine was used as the model compound. This method could be used to obtain CCs of piroxicam and spironolactone. False negatives were observed for only one compound from among three model compounds, indicating that CCG facilitates efficient CC detection and that it has higher throughput than does the conventional method. Further, CCG is fast and suitable for rational CC screening, and it helps identify the partial structure of CCFs that forms synthons with an API. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Evaluation and management of the patient with difficult-to-control or resistant hypertension.

    PubMed

    Viera, Anthony J; Hinderliter, Alan L

    2009-05-15

    High blood pressure is often difficult to control. Resistant hypertension is blood pressure above goal despite adherence to a combination of at least three antihypertensive medications of different classes, optimally dosed and usually including a diuretic. The approach to blood pressure that is apparently difficult to control begins with an assessment of the patient's adherence to the management plan, including lifestyle modifications and medications. White-coat hypertension may need to be ruled out. Suboptimal therapy is the most common reason for failure to reach the blood pressure goal. Once-daily fixed-dose combination pills may improve control through the synergism of antihypertensive agents from different classes and improved adherence. Truly drug-resistant hypertension is commonly caused by chronic kidney disease, obstructive sleep apnea, or hyperaldosteronism, all of which can lead to fluid retention. Higher doses of diuretics (or a change to a loop diuretic) are usually needed. Other strategies include adding an alpha blocker, alpha-beta blocker, clonidine, or an aldosterone antagonist (e.g., spironolactone). Particularly in patients with diabetes or renal disease, combining a long-acting nondihydropyridine with a dihydropyridine calcium channel . blocker can also be considered. Obesity, heavy alcohol intake, high levels of dietary sodium, and interfering substances (especially nonsteroidal anti-inflammatory drugs) contribute to hypertension that is resistant or difficult to control.

  16. Blocking Mineralocorticoid Receptors Impairs, Blocking Glucocorticoid Receptors Enhances Memory Retrieval in Humans

    PubMed Central

    Rimmele, Ulrike; Besedovsky, Luciana; Lange, Tanja; Born, Jan

    2013-01-01

    Memory retrieval is impaired at very low as well as very high cortisol levels, but not at intermediate levels. This inverted-U-shaped relationship between cortisol levels and memory retrieval may originate from different roles of the mineralocorticoid (MR) and glucocorticoid receptor (GR) that bind cortisol with distinctly different affinity. Here, we examined the role of MRs and GRs in human memory retrieval using specific receptor antagonists. In two double-blind within-subject, cross-over designed studies, young healthy men were asked to retrieve emotional and neutral texts and pictures (learnt 3 days earlier) between 0745 and 0915 hours in the morning, either after administration of 400 mg of the MR blocker spironolactone vs placebo (200 mg at 2300 hours and 200 mg at 0400 hours, Study I) or after administration of the GR blocker mifepristone vs placebo (200 mg at 2300 hours, Study II). Blockade of MRs impaired free recall of both texts and pictures particularly for emotional material. In contrast, blockade of GRs resulted in better memory retrieval for pictures, with the effect being more pronounced for neutral than emotional materials. These findings indicate indeed opposing roles of MRs and GRs in memory retrieval, with optimal retrieval at intermediate cortisol levels likely mediated by high MR but concurrently low GR activation. PMID:23303058

  17. Prevalence of primary hyperaldosteronism in a systemic arterial hypertension league.

    PubMed

    Ribeiro, Maria Jacqueline Silva; Figueiredo Neto, José Albuquerque de; Memória, Edson Viriato; Lopes, Maíra de Castro; Faria, Manuel dos Santos; Salgado Filho, Natalino; Oliveira, Thiara Castro de

    2009-01-01

    Until recently, primary hyperaldosteronism was considered a rare cause of secondary hypertension. However, in recent years, many studies have suggested that this disease can affect up to 20% of hypertensive individuals. To determine the prevalence of primary hyperaldosteronism in hypertensive patients treated at the hypertension league of a university hospital. Serum aldosterone and plasma renin activity levels were measured in 105 patients while they were undergoing standard antihypertensive treatment, with the exception of those using betablockers and spironolactone, in fasting condition and after rest in the supine position for 20 minutes. Those with an aldosterone/plasma renin activity ratio > 25 were submitted to the saline suppression test and, after the confirmation of the autonomy of aldosterone secretion, a computed tomography of the adrenals was performed. The results are presented as percentages and means and standard deviations. Of the 105 patients, 6.54% presented refractory hypertension. Nine presented an aldosterone/plasma renin activity ratio > 25 (8.5% of the total). Of these, 08 were submitted to the saline suppression test and 01 (with refractory hypertension) had the diagnosis of primary hyperaldosteronism confirmed (0.96% of the total). A computed tomography of the adrenals was performed, which showed normal results. The prevalence of primary hyperaldosteronism in the studied sample was 0.96% of the total. However, when only the patients with refractory hypertension were evaluated, the prevalence was 14.3%.

  18. High-performance liquid chromatography-diode array and electrospray-mass spectrometry analysis of non-allowed substances in cosmetic products for preventing hair loss and other hormone-dependent skin diseases.

    PubMed

    De Orsi, Daniela; Pellegrini, Manuela; Pichini, Simona; Mattioli, Donatella; Marchei, Emilia; Gagliardi, Luigi

    2008-11-04

    A simple high-performance liquid chromatography (HPLC) method with ultraviolet diode array (UV-DAD) and electrospray ionisation mass spectrometry (ESI-MS) detection has been developed for the determination of minoxidil, progesterone, estrone, spironolactone, canrenone, hydrocortisone and triamcinolone acetonide in cosmetic products. The presence of these substances in commercial cosmetic samples is prohibited. The compounds were separated by reversed phase chromatography with water (0.1% trifluoroacetic acid) and acetonitrile gradient elution and detected by UV-DAD at 230, 254 and 280 nm and by ESI-MS positive ionisation mode. Benzoic acid was used as internal standard. Linearity was studied with UV-DAD detection from 1.50 to 1,000 microg/ml or mug/g range, depending on the different compounds and type of cosmetic preparation and with ESI-MS in the 50-1,000 ng/ml or ng/g range. Good determination coefficients (r(2)>or=0.99) were found in both UV and ESI-MS. At three concentrations spanning the linear dynamic ranges of both UV-DAD and ESI-MS assay, mean recoveries were always higher than 90% for the different analytes. This method was successfully applied to the analysis of substances under investigations illegally added in cosmetic cream and lotions, sold on internet web sites to prevent hair loss and other hormone-dependent skin diseases, like acne and hirsutism.

  19. Aromatase gene polymorphism does not influence clinical phenotype and response to oral contraceptive pills in polycystic ovary syndrome women.

    PubMed

    Maier, Polyana S; Spritzer, Poli Mara

    2012-01-01

    To assess whether a single nucleotide polymorphism (SNP50) of the aromatase gene (CYP19) is associated with polycystic ovary syndrome (PCOS) phenotypes and to investigate the influence of this polymorphism on the response of PCOS to treatment with oral contraceptive pills (OCP). 162 hirsute women were stratified into a classic PCOS group (hyperandrogenism, ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS). 51 women completed a 6-month OCP trial (20 µg ethinyl estradiol + 75 µg gestodene, 21/28 days per cycle, plus 100 mg spironolactone in 32 women with moderate to severe hirsutism). We considered the presence of the polymorphic allele A (AG+AA) in comparison to the absence of the polymorphism (GG) to express results and to perform the comparisons regarding clinical variables. Mean age was 23.3 ± 6.9 years. Hirsutism score was similar in c-PCOS and ov-PCOS (15 (11-20) vs. 13 (11-20)). The differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A. In the OCP trial subsample, no differences were observed between genotypes after 6 months' treatment. The differences between c-PCOS and ov-PCOS cannot be explained by the genetic variation at SNP50 in the CYP19 gene. Copyright © 2012 S. Karger AG, Basel.

  20. Evaluation of effects of an oral contraceptive containing ethinylestradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome.

    PubMed

    De Leo, Vincenzo; Morgante, Giuseppe; Piomboni, Paola; Musacchio, Maria Concetta; Petraglia, Felice; Cianci, Antonio

    2007-07-01

    To investigate whether the administration of an oral contraceptive containing the new antiandrogenic drospirenone is associated with reduced adrenal androgen synthesis in hyperandrogenic women with diagnosis of polycystic ovary syndrome. Drospirenone, an analogue of spironolactone and aldosterone antagonist, is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. Prospective study. Healthy volunteers in University Department of Obstetrics and Gynecology. Fifteen women ages 18 to 28 years with the diagnosis of polycystic ovary syndrome. Three months of contraceptive use (30 mcg ethinylestradiol, 3 mg drospirenone). An adrenocorticotropic hormone test was performed before and after the study. Adrenal production of cortisol was unchanged after therapy with oral contraceptives. An interesting observation was reduced basal concentrations of androgens such as androstenedione, dehydroepiandrosterone sulfate, testosterone, and free testosterone during therapy. The ratios of the areas of substrates to products before and after oral contraceptive administration were compared for differences in 17alpha-hydroxylase (17-hydroxyprogesterone/progesterone) and 17,20-lyase (androstenedione/17-hydroxyprogesterone); activities were significantly reduced, indicating a reduction in the activities of these enzymes. The present results show for the first time that oral contraceptives containing drospirenone affect adrenal steroidogenesis by reducing synthesis and release of androgens in response to adrenocorticotropic hormone, leaving adrenal production of cortisol unchanged.

  1. [Simultaneous analysis of four diuretic drugs by HPLC and its application to health food supplements advertising weight reduction].

    PubMed

    Goto, Tomomi; Mikami, Eiichi; Ohno, Tsutomu; Matsumoto, Hiroshi

    2002-04-01

    A high-performance liquid chromatographic (HPLC) method for the simultaneous analysis of triamterene, trichlormethiazide, furosemide and spironolactone is presented for application in the examination of health food supplements advertising weight reduction and in the analysis of pharmaceuticals. The HPLC assay was performed under gradient conditions using a Wakosil ODS 5C18 column (5 microns, 150 x 4.6 mm i.d.). The mobile phase consisted of a gradient program with a mixture of water and acetonitrile containing 0.1% triethylamine adjusted with phosphoric acid to pH 3.0: from 0 to 6 min, 15% acetonitrile; from 6 to 20 min, linear gradient from 15 to 50% acetonitrile; and from 20 to 40 min, 50% acetonitrile. The column effluent was monitored from 0 to 20 min at 260 nm and from 20 to 40 min at 235 nm. The calibration curves of the four drugs showed good linearity and the correlation coefficients were better than 0.999 in all cases. The lower limits of detection were approximately 40 ng for each drug. Commercially available health food supplements and pharmaceuticals were analyzed after extraction with a mixture of methanol and acetic acid (99:1). The procedure described here is suitable for the screening of four diuretic drugs in adulterated supplements and for the quality control of pharmaceuticals with minimal sample preparation.

  2. State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)

    PubMed Central

    2011-01-01

    PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy. PMID:21899727

  3. Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome.

    PubMed

    Polfus, Linda M; Boerwinkle, Eric; Gibbs, Richard A; Metcalf, Ginger; Muzny, Donna; Veeraraghavan, Narayanan; Grove, Megan; Shete, Sanjay; Wallace, Stephanie; Milewicz, Dianna; Hanchard, Neil; Lupski, James R; Hashmi, Syed Shahrukh; Gupta-Malhotra, Monesha

    2016-11-01

    To comprehensively evaluate a European-American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), SCNN1B , an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, SCNN1A , possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566*) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine.

  4. State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS).

    PubMed

    Geller, David H; Pacaud, Danièle; Gordon, Catherine M; Misra, Madhusmita

    2011-08-26

    PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy.

  5. Mortality in two recent reports of clinical trials on patients with congestive heart failure compared with mortality in three previous clinical trials.

    PubMed

    Singer, R B

    2000-01-01

    Several clinical trials of drug treatment of patients with congestive heart failure (CHF) have previously been reported as Mortality Abstracts in the Journal of Insurance Medicine. Results are presented here for two similar clinical trials reported in September 1999 and compared with the previous results. In a recent international multicenter clinical trial, excess mortality in terms of excess death rates (EDRs) was reduced from 195 per 1000 per year in the placebo group to 139 in the group treated with Spironolactone. There was no significant reduction in the Danish multicenter study of Dofetilide to convert the atrial fibrillation (AF) to a normal rhythm in the 25% of the CHF patients who had AF (EDR was 224 in the placebo group and 216 in the Dofetilide group). In both of these studies, there were more patients with severe CHF than in the previous studies and the EDR values were higher. Results from the Danish study by severity according to the New York Heart Association (NYHA) classification show a progressive increase in EDR from 173 in class 2 to 237 in class 3 to 392 in class 4. Excess mortality in symptomatic CHF is far outside the issue limits for individual life insurance, but these results are of potential utility for the underwriting of such cases for structured settlement annuities.

  6. Adult-onset acne: prevalence, impact, and management challenges

    PubMed Central

    Bagatin, Ediléia

    2018-01-01

    Acne is a multifactorial and inflammatory disease of pilosebaceous follicles, which affects most adolescents. Recent epidemiological data revealed a difference in adults affected by this disease. Women have a high prevalence and incidence when compared with men, especially after 25 years of age. In contrast to what was initially thought, most of these patients do not present endocrinopathy capable of leading to the development of the lesions. When present, polycystic ovarian syndrome is the main cause. However, in these cases, acne is rarely the only dermatological manifestation; hirsutism and acanthosis nigricans are often present. The majority of the normoandrogenic acne patients present a history since adolescence, but in many cases the lesion distribution and intensity change with time. There is often a typical localization of the lesions in the lower third of the face and lateral region of the neck. Another interesting feature is related to the impact on quality of life (QoL), which is always intense. Often there are signs of depression, even when the lesions are mild. As most adult patients are women, in addition to the conventional options, there is also hormone treatment. Combined oral contraceptives and spironolactone are good options. Knowing more about the particularities in etiopathogenesis, impact on QoL, and specific treatment options is important to all dermatologists who face the challenge of treating acne in adults. PMID:29440921

  7. Hypertension Update: Resistant Hypertension.

    PubMed

    Viera, Anthony J

    2018-06-01

    Resistant hypertension is a blood pressure (BP) level that remains above the goal level despite adherence to at least three appropriately dosed antihypertensive drugs of different classes, one of which is a diuretic. Evaluation of suspected resistant hypertension starts with confirming adherence to the drug regimen. White coat hypertension should be ruled out with out-of-office BP level measurements, ideally using 24-hour ambulatory BP monitoring. Obesity, significant alcohol intake, and interfering drugs and other substances can contribute to resistant hypertension. Lifestyle modifications, including exercise and dietary sodium restriction, can be useful in management. Resistant hypertension may be due to secondary etiologies (eg, parenchymal kidney disease, obstructive sleep apnea, hyperaldosteronism). Adequate diuretic treatment is a key part of therapy. In addition to a diuretic, patients with resistant hypertension should take a dihydropyridine calcium channel blocker and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. Spironolactone is an effective fourth drug. Other drug options include a beta blocker, a long-acting nondihydropyridine calcium channel blocker, or clonidine or guanfacine. When the BP level is not controlled despite adherence to a four-drug regimen, referral to a hypertension subspecialist should be considered. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

  8. Safety, efficacy, actions, and patient acceptability of drospirenone/ethinyl estradiol contraceptive pills in the treatment of premenstrual dysphoric disorder.

    PubMed

    Breech, Lesley L; Braverman, Paula K

    2010-08-09

    Premenstrual dysphoric disorder (PMDD) is estimated to affect 3%-8% of reproductive age women. Multiple therapeutic modalities have been evaluated with varying efficacy for the associated somatic and mood symptoms. The majority of older studies had shown that oral contraceptive pills (OCs) were most effective for the physical symptoms. However, newer OCs containing a novel progestin, drospirenone, have shown promise in alleviating both the somatic and affective/behavioral symptoms. This progestin, which is a derivative of spironolactone, has both antimineralocorticoid and antiandrogenic activity. A 24/4 formulation containing 20 μg of ethinyl estradiol has been found effective in randomized double-blind placebo-controlled trials utilizing established scales documenting symptoms associated with PMDD. Multiple studies have shown that drospirenone-containing OCs are safe without evidence of clinically adverse effects on carbohydrate metabolism, lipids, blood pressure, weight, serum potassium or increased thrombotic events compared to other low dose OCs. In addition, significant improvements have been demonstrated in acne, hirsutism, and fluid retention symptoms. Several open label studies demonstrated good patient compliance and reported satisfaction with the method. Because of the significant placebo effect demonstrated in the blinded placebo-controlled trials, additional large randomized placebo-controlled trials are needed to confirm the efficacy of the drospirenone OCs in the treatment of PMDD. However, this OC formulation appears to be a promising therapeutic modality.

  9. Safety, efficacy, actions, and patient acceptability of drospirenone/ethinyl estradiol contraceptive pills in the treatment of premenstrual dysphoric disorder

    PubMed Central

    Breech, Lesley L; Braverman, Paula K

    2010-01-01

    Premenstrual dysphoric disorder (PMDD) is estimated to affect 3%–8% of reproductive age women. Multiple therapeutic modalities have been evaluated with varying efficacy for the associated somatic and mood symptoms. The majority of older studies had shown that oral contraceptive pills (OCs) were most effective for the physical symptoms. However, newer OCs containing a novel progestin, drospirenone, have shown promise in alleviating both the somatic and affective/behavioral symptoms. This progestin, which is a derivative of spironolactone, has both antimineralocorticoid and antiandrogenic activity. A 24/4 formulation containing 20 μg of ethinyl estradiol has been found effective in randomized double-blind placebo-controlled trials utilizing established scales documenting symptoms associated with PMDD. Multiple studies have shown that drospirenone-containing OCs are safe without evidence of clinically adverse effects on carbohydrate metabolism, lipids, blood pressure, weight, serum potassium or increased thrombotic events compared to other low dose OCs. In addition, significant improvements have been demonstrated in acne, hirsutism, and fluid retention symptoms. Several open label studies demonstrated good patient compliance and reported satisfaction with the method. Because of the significant placebo effect demonstrated in the blinded placebo-controlled trials, additional large randomized placebo-controlled trials are needed to confirm the efficacy of the drospirenone OCs in the treatment of PMDD. However, this OC formulation appears to be a promising therapeutic modality. PMID:21072278

  10. Drospirenone/ethinylestradiol 3mg/20microg (24/4 day regimen): a review of its use in contraception, premenstrual dysphoric disorder and moderate acne vulgaris.

    PubMed

    Fenton, Caroline; Wellington, Keri; Moen, Marit D; Robinson, Dean M

    2007-01-01

    Drospirenone 3mg with ethinylestradiol 20microg (Yaz) is a low-dose combined oral contraceptive (COC) administered in a regimen of 24 days of active tablets followed by a short hormone-free interval (4 days; 24/4 regimen). Drospirenone, unlike other synthetic progestogens used in COCs, is a 17alpha-spirolactone derivative and a 17alpha-spironolactone analogue with antimineralocorticoid and antiandrogenic properties. Drospirenone/ethinylestradiol 3mg/20microg (24/4) is approved in the US for the prevention of pregnancy in women, for the treatment of the symptoms of premenstrual dysphoric disorder (PMDD) and for the treatment of moderate acne vulgaris in women who wish to use an oral contraceptive for contraception.Drospirenone/ethinylestradiol 3mg/20microg (24/4) provided 99% contraceptive protection over 1 year of treatment in two large studies. The same treatment regimen over three treatment cycles also significantly improved the emotional and physical symptoms associated with PMDD, and improved moderate acne vulgaris over six treatment cycles in double-blind trials. It was generally well tolerated, with adverse events generally typical of those experienced with other COCs and which were most likely to occur in the first few cycles. Clinical trials indicate that drospirenone/ethinylestradiol 3mg/20microg (24/4) is a good long-term contraceptive option, and additionally offers relief of symptoms that characterise PMDD and has a favourable effect on moderate acne vulgaris.

  11. Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus.

    PubMed

    Osborne, Danielle M; O'Leary, Kelsey E; Fitzgerald, Dennis P; George, Alvin J; Vidal, Michael M; Anderson, Brian M; McNay, Ewan C

    2017-01-01

    Recurrent hypoglycaemia is primarily caused by repeated over-administration of insulin to patients with diabetes. Although cognition is impaired during hypoglycaemia, restoration of euglycaemia after recurrent hypoglycaemia is associated with improved hippocampally mediated memory. Recurrent hypoglycaemia alters glucocorticoid secretion in response to hypoglycaemia; glucocorticoids are well established to regulate hippocampal processes, suggesting a possible mechanism for recurrent hypoglycaemia modulation of subsequent cognition. We tested the hypothesis that glucocorticoids within the dorsal hippocampus might mediate the impact of recurrent hypoglycaemia on hippocampal cognitive processes. We characterised changes in the dorsal hippocampus at several time points to identify specific mechanisms affected by recurrent hypoglycaemia, using a well-validated 3 day model of recurrent hypoglycaemia either alone or with intrahippocampal delivery of glucocorticoid (mifepristone) and mineralocorticoid (spironolactone) receptor antagonists prior to each hypoglycaemic episode. Recurrent hypoglycaemia enhanced learning and also increased hippocampal expression of glucocorticoid receptors, serum/glucocorticoid-regulated kinase 1, cyclic AMP response element binding (CREB) phosphorylation, and plasma membrane levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors. Both hippocampus-dependent memory enhancement and the molecular changes were reversed by glucocorticoid receptor antagonist treatment. These results indicate that increased glucocorticoid signalling during recurrent hypoglycaemia produces several changes in the dorsal hippocampus that are conducive to enhanced hippocampus-dependent contextual learning. These changes appear to be adaptive, and in addition to supporting cognition may reduce damage otherwise caused by repeated exposure to severe hypoglycaemia.

  12. Management of hypertension and heart failure in patients with Addison's disease.

    PubMed

    Inder, Warrick J; Meyer, Caroline; Hunt, Penny J

    2015-06-01

    Addison's disease may be complicated by hypertension and less commonly by heart failure. We review the pathophysiology of the renin-angiotensin-aldosterone axis in Addison's disease and how this is altered in the setting of hypertension and heart failure. An essential first step in management in both conditions is optimizing glucocorticoid replacement and considering dose reduction if excessive. Following this, if a patient with Addison's disease remains hypertensive, the fludrocortisone dose should be reviewed and reduced if there are clinical and/or biochemical signs of mineralocorticoid excess. In the absence of such signs, where the renin is towards the upper end of the normal range or elevated, an angiotensin II (AII) receptor antagonist or angiotensin converting enzyme (ACE) inhibitor is the treatment of choice, and the fludrocortisone dose should remain unchanged. Dihydropyridine calcium channel blockers are clinically useful as second line agents, but diuretics should be avoided. In the setting of heart failure, there is an increase in total body sodium and water; therefore, it is appropriate to reduce and rarely consider ceasing the fludrocortisone. Loop diuretics may be used, but not aldosterone antagonists such as spironolactone or eplerenone. Standard treatment with ACE inhibitors, or as an alternative, AII receptor antagonists, are appropriate. Measurements of renin are no longer helpful in heart failure to determine the volume status but plasma levels of brain natriuretic peptide (BNP/proBNP) may help guide therapy. © 2014 John Wiley & Sons Ltd.

  13. A patient with Bartter syndrome accompanying severe growth hormone deficiency and focal segmental glomerulosclerosis.

    PubMed

    Akil, Ipek; Ozen, Serkan; Kandiloglu, Ali Riza; Ersoy, Betul

    2010-06-01

    Bartter syndrome is a rare autosomal recessive, salt-losing disorder characterized by hypokalemic hypochloremic metabolic alkalosis. A 10-year-old boy had severe growth retardation (height standard deviation score -8.15). He had a thin, triangular face, prominent ears and forehead, and big eyes. Megacystis, bilateral hydroureteronephrosis, and residual urine were detected in ultrasonography, but there was no vesicoureteral reflux. Lumbosacral magnetic resonance (MR) showed posterior disc bulging at L4-5. Serum sodium and chloride levels were normal, but mild hypokalemia was overlooked initially. During follow-up, hypokalemic hypochloremic metabolic alkalosis developed, with high urinary chloride and potassium excretion (52 and 43 mEq/L, respectively). The patient, with renal salt loss, was thought to have classic Bartter syndrome due to absence of nephrocalcinosis, presence of persistent hypercalciuria and sensorineural deafness, and presence of relatively mild clinical and laboratory findings, except polyuria initially. The child was treated with indomethacin, spironolactone, and oral potassium in addition to growth hormone (GH). During treatment, he had considerable increase in weight and height compared with the period of GH therapy only. We present this case because, although growth retardation is a major feature of Bartter syndrome, associated GH deficiency is rarely reported in the literature. Diagnosis of Bartter syndrome was made later, as our patient was followed for megacystis and megaureter secondary to the neurogenic bladder and GH deficiency initially; and proteinuria associated with focal segmental glomerulosclerosis responded to treatment for Bartter syndrome.

  14. The role of polyester interstitium and aldosterone during structural development of renal tubules in serum-free medium.

    PubMed

    Minuth, Will W; Denk, Lucia; Hu, Kanghong

    2007-10-01

    Little knowledge is available regarding the development of renal stem/progenitor cells into functional parenchyme. To investigate the environmental mechanisms during this maturation process, we elaborated an advanced culture technique to follow renal tubule development. Embryonic stem/progenitor cells derived from neonatal rabbit kidney were placed in a perfusion culture container at the interphase of an artificial polyester interstitium. Tissue culture was carried out in IMDM without serum or protein supplementation and without coating with extracellular matrix proteins. Development of tubules was registered histochemically on cryosections labeled with soybean agglutinin (SBA) and tissue-specific antibodies. The experiments revealed that the development of renal tubules depends exclusively on the administration of aldosterone. The use of 1x10(-7) M aldosterone for 13 days generated numerous SBA-labeled tubules, while no tubules developed in the absence of the steroid hormone. To obtain further information about the action of the hormone on the cognate receptor, molecular precursors of the aldosterone synthesis pathway were tested. Surprisingly, application of cholesterol, pregnenolone, progesterone, 11-deoxycorticosterone (DOCA) and corticosterone failed to form numerous tubules. Only 11-DOCA and progesterone induced a few tubules, which were barely SBA-labeled. Furthermore, application of aldosterone antagonists such as 1x10(-4) M spironolactone and 1x10(-4) M canrenoate completely inhibited the development of tubules. We conclude that specifically aldosterone promotes the development of tubules via the mineralocorticoid receptor whereas its precursors have no effect.

  15. Epidemiology, diagnosis, and management of polycystic ovary syndrome.

    PubMed

    Sirmans, Susan M; Pate, Kristen A

    2013-12-18

    Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder characterized by irregular menses, hyperandrogenism, and polycystic ovaries. The prevalence of PCOS varies depending on which criteria are used to make the diagnosis, but is as high as 15%-20% when the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine criteria are used. Clinical manifestations include oligomenorrhea or amenorrhea, hirsutism, and frequently infertility. Risk factors for PCOS in adults includes type 1 diabetes, type 2 diabetes, and gestational diabetes. Insulin resistance affects 50%-70% of women with PCOS leading to a number of comorbidities including metabolic syndrome, hypertension, dyslipidemia, glucose intolerance, and diabetes. Studies show that women with PCOS are more likely to have increased coronary artery calcium scores and increased carotid intima-media thickness. Mental health disorders including depression, anxiety, bipolar disorder and binge eating disorder also occur more frequently in women with PCOS. Weight loss improves menstrual irregularities, symptoms of androgen excess, and infertility. Management of clinical manifestations of PCOS includes oral contraceptives for menstrual irregularities and hirsutism. Spironolactone and finasteride are used to treat symptoms of androgen excess. Treatment options for infertility include clomiphene, laparoscopic ovarian drilling, gonadotropins, and assisted reproductive technology. Recent data suggest that letrozole and metformin may play an important role in ovulation induction. Proper diagnosis and management of PCOS is essential to address patient concerns but also to prevent future metabolic, endocrine, psychiatric, and cardiovascular complications.

  16. Epidemiology, diagnosis, and management of polycystic ovary syndrome

    PubMed Central

    Sirmans, Susan M; Pate, Kristen A

    2014-01-01

    Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder characterized by irregular menses, hyperandrogenism, and polycystic ovaries. The prevalence of PCOS varies depending on which criteria are used to make the diagnosis, but is as high as 15%–20% when the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine criteria are used. Clinical manifestations include oligomenorrhea or amenorrhea, hirsutism, and frequently infertility. Risk factors for PCOS in adults includes type 1 diabetes, type 2 diabetes, and gestational diabetes. Insulin resistance affects 50%–70% of women with PCOS leading to a number of comorbidities including metabolic syndrome, hypertension, dyslipidemia, glucose intolerance, and diabetes. Studies show that women with PCOS are more likely to have increased coronary artery calcium scores and increased carotid intima-media thickness. Mental health disorders including depression, anxiety, bipolar disorder and binge eating disorder also occur more frequently in women with PCOS. Weight loss improves menstrual irregularities, symptoms of androgen excess, and infertility. Management of clinical manifestations of PCOS includes oral contraceptives for menstrual irregularities and hirsutism. Spironolactone and finasteride are used to treat symptoms of androgen excess. Treatment options for infertility include clomiphene, laparoscopic ovarian drilling, gonadotropins, and assisted reproductive technology. Recent data suggest that letrozole and metformin may play an important role in ovulation induction. Proper diagnosis and management of PCOS is essential to address patient concerns but also to prevent future metabolic, endocrine, psychiatric, and cardiovascular complications. PMID:24379699

  17. Dual blockade of aldosterone and angiotensin II additively suppresses TGF-beta and NADPH oxidase in the hypertensive kidney.

    PubMed

    Onozato, Maristela Lika; Tojo, Akihiro; Kobayashi, Naohiko; Goto, Atsuo; Matsuoka, Hiroaki; Fujita, Toshiro

    2007-05-01

    Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF). Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks. DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.

  18. Investigation of aldosterone-synthase inhibition in rats.

    PubMed

    Ménard, Joël; Gonzalez, Marie-Françoise; Guyene, Thanh-Tam; Bissery, Alvine

    2006-06-01

    In-vivo investigation of aldosterone-synthase inhibitors requires experimental models to characterize the biological effects of these compounds. Seven successive experiments were performed in groups of 2-month-old male spontaneously hypertensive rats. Urinary free aldosterone was the main end-point measured during two contrasted diets: low sodium-high potassium (LS), inducing high urinary aldosterone (839 pmol/24 h, 95% confidence interval 654-1077), and high sodium-normal potassium (HS), inducing low urinary aldosterone (38.1 pmol/24 h; 95% confidence interval, 32.4-44.9). FAD 286 A (10 and 30 mg/kg) decreased urinary free aldosterone by 53 and 87% on the LS diet, and 50 and 75% on the HS. Plasma renin concentration increased three-fold after a 4-week treatment of 30 mg/kg FAD 286 A on the LS diet and did not change on the HS. The combination of FAD 286 A (30 mg/kg) and spironolactone (30 mg/kg) on the LS diet induced a biological picture of severe hypoaldosteronism and was not tolerated, whereas the HS diet prevented these abnormalities. The combination of FAD 286 A (30 mg/kg) and furosemide (30 mg/kg) on the HS diet corrected the diuretic-induced hypokalemia (4.1 +/- 0.2 versus 3.7 +/- 2.2 mEq/l, P < 0.033). This experimental model will be useful to screen future aldosterone-synthase inhibitors and study their biological effects in various experimental conditions.

  19. Cytokine modulation by stress hormones and antagonist specific hormonal inhibition in rainbow trout (Oncorhynchus mykiss) and gilthead sea bream (Sparus aurata) head kidney primary cell culture.

    PubMed

    Khansari, Ali Reza; Parra, David; Reyes-López, Felipe E; Tort, Lluís

    2017-09-01

    A tight interaction between endocrine and immune systems takes place mainly due to the key role of head kidney in both hormone and cytokine secretion, particularly under stress situations in which the physiological response promotes the synthesis and release of stress hormones which may lead into immunomodulation as side effect. Although such interaction has been previously investigated, this study evaluated for the first time the effect of stress-associated hormones together with their receptor antagonists on the expression of cytokine genes in head kidney primary cell culture (HKPCC) of the freshwater rainbow trout (Oncorhynchus mykiss) and the seawater gilthead sea bream (Sparus aurata). The results showed a striking difference when comparing the response obtained in trout and seabream. Cortisol and adrenocorticotropic hormone (ACTH) decreased the expression of immune-related genes in sea bream but not in rainbow trout and this cortisol effect was reverted by the antagonist mifepristone but not spironolactone. On the other hand, while adrenaline reduced the expression of pro-inflammatory cytokines (IL-1β, IL-6) in rainbow trout, the opposite effect was observed in sea bream showing an increased expression (IL-1β, IL-6). Interestingly, this effect was reverted by antagonist propranolol but not phentolamine. Overall, our results confirm the regional interaction between endocrine and cytokine messengers and a clear difference in the sensitivity to the hormonal stimuli between the two species. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Statin Medications and the Risk of Gynecomastia.

    PubMed

    Skeldon, Sean C; Carleton, Bruce; Brophy, James; Sodhi, Mohit; Etminan, Mahyar

    2018-06-19

    Case reports have suggested an increased risk of gynecomastia with HMG-CoA reductase inhibitors (i.e. statins). A recent meta-analysis also found that statins decrease circulating testosterone levels in men. We investigated whether statin use was associated with an increased risk of gynecomastia. Case control study. A cohort of patients from a random sample of 9,053,240 US subjects from the PharMetrics Plus ™ health claims database from 2006 to 2016 was created. New cases of gynecomastia requiring at least two ICD-9 codes were identified from the cohort and matched to 10 controls by follow-up time and age using density-based sampling. Rate ratios (RRs) for past users of statins were computed using conditional logistic regression adjusting for alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, obesity, hypogonadism, hyperprolactinemia and use of spironolactone, ketoconazole, H 2 receptor antagonists (H 2 blockers), risperidone, testosterone and androgen deprivation therapy. Our cohort included 6,147 cases of gynecomastia and 61,470 corresponding matched controls. The adjusted RR for current, recent and past statin use with respect to gynecomastia was 1.19 (1.04-1.36), 1.38 (1.15-1.65) and 1.20 (1.03-1.40) respectively. Statin use is associated with an increased risk of developing gynecomastia. Clinicians should be cognizant of this effect and educate patients accordingly. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  1. Heart failure.

    PubMed

    Metra, Marco; Teerlink, John R

    2017-10-28

    Heart failure is common in adults, accounting for substantial morbidity and mortality worldwide. Its prevalence is increasing because of ageing of the population and improved treatment of acute cardiovascular events, despite the efficacy of many therapies for patients with heart failure with reduced ejection fraction, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β blockers, and mineralocorticoid receptor antagonists, and advanced device therapies. Combined angiotensin receptor blocker neprilysin inhibitors (ARNIs) have been associated with improvements in hospital admissions and mortality from heart failure compared with enalapril, and guidelines now recommend substitution of ACE inhibitors or ARBs with ARNIs in appropriate patients. Improved safety of left ventricular assist devices means that these are becoming more commonly used in patients with severe symptoms. Antidiabetic therapies might further improve outcomes in patients with heart failure. New drugs with novel mechanisms of action, such as cardiac myosin activators, are under investigation for patients with heart failure with reduced left ventricular ejection fraction. Heart failure with preserved ejection fraction is a heterogeneous disorder that remains incompletely understood and will continue to increase in prevalence with the ageing population. Although some data suggest that spironolactone might improve outcomes in these patients, no therapy has conclusively shown a significant effect. Hopefully, future studies will address these unmet needs for patients with heart failure. Admissions for acute heart failure continue to increase but, to date, no new therapies have improved clinical outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Resistant Hypertension: Time to Consider the Best Fifth Anti-Hypertensive Treatment.

    PubMed

    Pio-Abreu, Andrea; Drager, Luciano F

    2018-06-16

    Resistant hypertension (RH) is a growing clinical condition worldwide associated with target-organ damage and poor prognosis compared to non-resistant counterparts. The purpose of this review is to perform a critical evaluation of preferable drug choices for managing RH highlighting the evidence that significant proportion of patients remained uncontrolled despite using four anti-hypertensive drugs. Until recently, the fourth drug therapy was main derived from personal opinion or small interventional studies. The recent data derived from two multicentric randomized trials, namely PATHWAY-2 and ReHOT, pointed spironolactone as the preferable fourth drug therapy in patients with confirmed RH as compared to bisoprolol and doxazosin (PATHWAY-2) as well as clonidine (ReHOT). However, significant proportion of patients (especially observed in ReHOT trial that used 24-h ambulatory blood pressure monitoring) did not achieve optimal blood pressure with the fourth drug. This finding underscores the need of new approaches and treatment options in this important research area. The current evidence pointed that significant proportion of RH patients are requiring more than four drugs for controlling BP. This statement is particularly true considering the new criteria proposed by the 2017 Guidelines for diagnosing RH (> 130 × 80 mmHg). New combinations, drugs, or treatments should be tested aiming to reduce the RH burden. Based on the aforementioned multicentric trials, we proposed the first five preferable anti-hypertensive classes in the overall context of RH.

  3. A short review of primary aldosteronism in a question and answer fashion.

    PubMed

    Farrugia, Frederick-Anthony; Zavras, Nicolaos; Martikos, Georgios; Tzanetis, Panagiotis; Charalampopoulos, Anestis; Misiakos, Evangelos P; Sotiropoulos, Dimitrios; Koliakos, Nikolaos

    2018-01-01

    The aim of this study was to present up to date information concerning the diagnosis and treatment of primary aldosteronism (PA). PA is the most common cause of endocrine hypertension. It has been reported up to 24% of selective referred hypertensive patients. We did a search in Pub-Med and Google Scholar using the terms: PA, hyperaldosteronism, idiopathic adrenal hyperplasia, diagnosis of PA, mineralocorticoid receptor antagonists, adrenalectomy, and surgery. We also did cross-referencing search with the above terms. We had divided our study into five sections: Introduction, Diagnosis, Genetics, Treatment, and Conclusions. We present our results in a question and answer fashion in order to make reading more interesting. PA should be searched in all high-risk populations. The gold standard for diagnosis PA is the plasma aldosterone/plasma renin ratio (ARR). If this test is positive, then we proceed with one of the four confirmatory tests. If positive, then we proceed with a localizing technique like adrenal vein sampling (AVS) and CT scan. If the lesion is unilateral, after proper preoperative preparation, we proceed, in adrenalectomy. If the lesion is bilateral or the patient refuses or is not fit for surgery, we treat them with mineralocorticoid receptor antagonists, usually spironolactone. Primary aldosteronism is the most common and a treatable case of secondary hypertension. Only patients with unilateral adrenal diseases are eligible for surgery, while patients with bilateral and non-surgically correctable PA are usually treated by mineralocorticoid receptor antagonist (MRA). Thus, the distinction between unilateral and bilateral aldosterone hypersecretion is crucial.

  4. Treatment of Severe Edema in Children with Nephrotic Syndrome with Diuretics Alone — A Prospective Study

    PubMed Central

    Kapur, Gaurav; Valentini, Rudolph P.; Imam, Abubakr A.; Mattoo, Tej K.

    2009-01-01

    Background and objective: Severe edema in children with nephrotic syndrome (NS) may be associated with volume contraction (VC) or volume expansion (VE). Usually, severe edema in children is treated with intravenous (IV) albumin and diuretics, which is appropriate for VC patients. However, in VE patients, this can precipitate fluid overload. The objective of this study was to evaluate treatment of severe edema in NS with diuretics alone. Design, setting, participants, & measurements: Thirty NS patients with severe edema were enrolled in this prospective study in two phases. VC was diagnosed based on fractional excretion of sodium (FeNa) <1%. VC patients received IV albumin and furosemide. VE patients received IV furosemide and oral spironolactone. On the basis of phase 1 observations, FeNa <0.2% identified VC in 20 phase 2 patients. Results: All phase 1 patients had FeNa <1%. Phase 1 patients when reanalyzed based on a FeNa cutoff of 0.2%; it was noted that VC patients had higher BUN, BUN/creatinine ratio, urine osmolality, and lower FeNa and urine sodium compared with VE patients. Similar results were observed in phase 2. VC patients had significantly higher renin, aldosterone, and antidiuretic hormone levels. In phase 2, 11 VE patients received diuretics alone and 9 VC patients received albumin and furosemide. There was no difference in hospital stay and weight loss in VC and VE groups after treatment. Conclusions: FeNa is useful in distinguishing VC versus VE in NS children with severe edema. The use of diuretics alone in VE patients is safe and effective. PMID:19406963

  5. Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease.

    PubMed

    Tomaschitz, Andreas; Ritz, Eberhard; Pieske, Burkert; Rus-Machan, Jutta; Kienreich, Katharina; Verheyen, Nicolas; Gaksch, Martin; Grübler, Martin; Fahrleitner-Pammer, Astrid; Mrak, Peter; Toplak, Hermann; Kraigher-Krainer, Elisabeth; März, Winfried; Pilz, Stefan

    2014-01-01

    Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon. © 2013.

  6. Pattern of extemporaneous prescriptions and preparations in a tertiary health institution: a five-year assessment.

    PubMed

    Aghahowa, S E; Egharevba, J O; Erhagbe, B E; Okoh, F

    2013-01-01

    Due to the increasing rate in the demand of extemporaneous formulations, it became necessary to assess the pattern of prescription and preparation in a developing institution. The purpose of this study was to assess the pattern of extemporaneous prescription and preparation in the University of Benin Teaching Hospital, Benin City, Nigeria. Records of prescription and preparation of extemporaneous formulations were assessed retrospectively between 2007 and 2011. Fifty-nine different types of drugs were prescribed with a frequency of 6,882 times during the period. These were indicated for eight classes of systemic disease. Eighteen drugs were indicated for central nervous diseases, followed by 16 drugs for cardiovascular diseases. Of the 18 drugs indicated for central nervous diseases, pyridoxine was the most common. Rifampicin for tuberculosis was the most frequently formulated, followed by spironolactone for cardiovascular disorders. Most preparations were labeled to be used for a maximum of two weeks. They were all liquid preparations packaged in amber-colored bottles. Distilled water was the most common vehicle utilized for trituration; while ascorbic acid syrup was commonly used to bulk the solution and as a sweetening agent. None of the patients reported with any form of pharmaceutical degradation or toxicity within two weeks of expected use. There were reports of spillages due to poor handling. Maximum volume prepared was 75 mL. The study suggests an adequate setup of a quality-control unit in the institution to meet the increasing demand for specific agents. This will enhance an effective healthcare delivery among patients.

  7. Roles of mineralocorticoid and glucocorticoid receptors in the regulation of progenitor proliferation in the adult hippocampus.

    PubMed

    Wong, Edmund Y H; Herbert, Joe

    2005-08-01

    New neurons are produced continually in the dentate gyrus of the hippocampus. Numerous factors modulate the rate of neuron production. One of the most important is the adrenal-derived corticoids. Raised levels of corticoids suppress proliferation of progenitor cells, while removal of corticoids by adrenalectomy reverses this. The exact mechanisms by which corticoids mediate such regulation are unknown, but corticoids are believed to act through the receptors for mineralocorticoids (MR) and glucocorticoids (GR). Previous reports regarding the roles of these receptors in regulating cell proliferation came to contrasting conclusions. Here we use both agonists and antagonists to these receptors in adult male rats to investigate and clarify their roles. Blockade of MR with spironolactone in adrenalectomised male rats implanted with a corticosterone pellet to reproduce basal levels enhanced proliferation, whereas treatment with the GR antagonist mifepristone had no effect. However, mifepristone reversed the suppressive effect of additional corticosterone in intact rats. Both aldosterone and RU362, agonists of MR and GR, respectively, reduced proliferation in adrenalectomised rats, and combined treatment with both agonists had an additional suppressive action. These results clearly show that occupancies of both receptors act in the same direction on progenitor proliferation. The existence of two receptors with different affinities for corticoids may ensure that proliferation of progenitor cells in the adult dentate gyrus is regulated across the range of adrenal corticoid activity, including both basal and stressful contexts. Although a small proportion of newly formed cells may express GR and MR, corticosterone probably regulates proliferation indirectly through other local cells.

  8. Classic Bartter syndrome complicated with profound growth hormone deficiency: a case report

    PubMed Central

    2013-01-01

    Introduction Classic Bartter syndrome is a salt-wasting tubulopathy caused by mutations in the CLCNKB (chloride channel Kb) gene. Although growth hormone deficiency has been suggested as a cause for persistent growth failure in patients with classic Bartter syndrome, in our opinion the diagnoses of growth hormone deficiency has been unconvincing in some reports. Moreover, Gitelman syndrome seems to have been confused with Bartter syndrome in some cases in the literature. In the present work, we describe a new case with CLCNKB gene mutations and review the reported cases of classic Bartter syndrome associated with growth hormone deficiency. Case presentation Our patient was a Japanese boy diagnosed as having classic Bartter syndrome at eight months of age. The diagnosis of Bartter syndrome was confirmed by CLCNKB gene analysis, which revealed compound heterozygous mutations with deletion of exons 1 to 3 (derived from his mother) and ΔL130 (derived from his father). His medical therapy consisted of potassium (K), sodium chloride, spironolactone, and anti-inflammatory agents; this regime was started at eight months of age. Our patient was very short (131.1cm, -4.9 standard deviation) at 14.3 years and showed profoundly impaired growth hormone responses to pharmacological stimulants: 0.15μg/L to insulin-induced hypoglycemia and 0.39μg/L to arginine. His growth response to growth hormone therapy was excellent. Conclusions The present case strengthens the association between classic Bartter syndrome and growth hormone deficiency. We propose that growth hormone status should be considered while treating children with classic Bartter syndrome. PMID:24377430

  9. Classic Bartter syndrome complicated with profound growth hormone deficiency: a case report.

    PubMed

    Adachi, Masanori; Tajima, Toshihiro; Muroya, Koji; Asakura, Yumi

    2013-12-30

    Classic Bartter syndrome is a salt-wasting tubulopathy caused by mutations in the CLCNKB (chloride channel Kb) gene. Although growth hormone deficiency has been suggested as a cause for persistent growth failure in patients with classic Bartter syndrome, in our opinion the diagnoses of growth hormone deficiency has been unconvincing in some reports. Moreover, Gitelman syndrome seems to have been confused with Bartter syndrome in some cases in the literature. In the present work, we describe a new case with CLCNKB gene mutations and review the reported cases of classic Bartter syndrome associated with growth hormone deficiency. Our patient was a Japanese boy diagnosed as having classic Bartter syndrome at eight months of age. The diagnosis of Bartter syndrome was confirmed by CLCNKB gene analysis, which revealed compound heterozygous mutations with deletion of exons 1 to 3 (derived from his mother) and ΔL130 (derived from his father). His medical therapy consisted of potassium (K), sodium chloride, spironolactone, and anti-inflammatory agents; this regime was started at eight months of age. Our patient was very short (131.1cm, -4.9 standard deviation) at 14.3 years and showed profoundly impaired growth hormone responses to pharmacological stimulants: 0.15μg/L to insulin-induced hypoglycemia and 0.39μg/L to arginine. His growth response to growth hormone therapy was excellent. The present case strengthens the association between classic Bartter syndrome and growth hormone deficiency. We propose that growth hormone status should be considered while treating children with classic Bartter syndrome.

  10. Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist.

    PubMed

    Yamamura, Y; Ogawa, H; Yamashita, H; Chihara, T; Miyamoto, H; Nakamura, S; Onogawa, T; Yamashita, T; Hosokawa, T; Mori, T

    1992-04-01

    1. OPC-31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol-anaesthetized rats and for diuretic action in conscious normal rats. 2. OPC-31260 caused a competitive displacement of [3H]-AVP binding to both V1 and V2 receptors with IC50 values of 1.2 +/- 0.2 x 10(-6) M and 1.4 +/- 0.2 x 10(-8) M, respectively. 3. OPC-31260 at doses of 10 to 100 micrograms kg-1, i.v., inhibited the antidiuretic action of exogenously administered AVP in water-loaded, alcohol-anaesthetized rats in a dose-dependent manner. OPC-31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist. 4. After oral administration at doses of 1 to 30 mg kg-1 in normal conscious rats, OPC-31260 dose-dependently increased urine flow and decreased urine osmolality. The diuretic action of OPC-31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone. 5. The results indicate that OPC-31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC-31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention.

  11. Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist

    PubMed Central

    Yamamura, Yoshitaka; Ogawa, Hidenori; Yamashita, Hiroshi; Chihara, Tomihiko; Miyamoto, Hisashi; Nakamura, Shigeki; Onogawa, Toshiyuki; Yamashita, Tatsuya; Hosokawa, Tetsumi; Mori, Toyoki; Tominaga, Michiaki; Yabuuchi, Youichi

    1992-01-01

    1 OPC-31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol-anaesthetized rats and for diuretic action in conscious normal rats. 2 OPC-31260 caused a competitive displacement of [3H]-AVP binding to both V1 and V2 receptors with IC50 values of 1.2 ± 0.2 × 10-6 M and 1.4 ± 0.2 × 10-8 M, respectively. 3 OPC-31260 at doses of 10 to 100 μg kg-1, i.v., inhibited the antidiuretic action of exogenously administered AVP in water-loaded, alcohol-anaesthetized rats in a dose-dependent manner. OPC-31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist. 4 After oral administration at doses of 1 to 30 mg kg-1 in normal conscious rats, OPC-31260 dose-dependently increased urine flow and decreased urine osmolality. The diuretic action of OPC-31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone. 5 The results indicate that OPC-31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC-31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention. PMID:1387020

  12. Clinical and prognostic value of spot urinary creatinine in chronic heart failure-An analysis from GISSI-HF.

    PubMed

    Ter Maaten, Jozine M; Maggioni, Aldo Pietro; Latini, Roberto; Masson, Serge; Tognoni, Gianni; Tavazzi, Luigi; Signorini, Stefano; Voors, Adriaan A; Damman, Kevin

    2017-06-01

    This study aimed to identify patient characteristics associated with low urinary creatinine in morning spot urine and investigate its association with clinical outcome. Twenty-four-hour creatinine excretion is an established marker of muscle mass in heart failure and other populations. Spot urine creatinine might be an easy obtainable, cheap marker of muscle wasting and prognosis in heart failure (HF) patients. Spot urine creatinine concentration was measured in 2130 patients included in the GISSI-HF trial. We evaluated the prognostic value of urinary creatinine and its relation with clinical variables. Median spot urinary creatinine was 0.80 (IQR 0.50-1.10) g/L. Lower spot urinary creatinine was associated with older age, smaller height and weight, higher NYHA class, worse renal function and more frequent spironolactone and diuretic use (all P<.02). During a median follow-up of 2.8 years, 655 patients (31%) experienced the combined endpoint of all-cause mortality or HF hospitalization. Lower urinary creatinine was independently associated with an increased risk of all-cause mortality or HF hospitalization (HR, 1.59 [1.21-2.08] per log decrease, P=.001), and all-cause mortality (HR, 1.75 [1.25-2.45] per log decrease, P=.001). Lower urinary creatinine, measured in morning spot urine in patients with chronic HF, is associated with worse renal function, smaller body size, more severe HF and is independently associated with an increased risk of all-cause death and HF hospitalization. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients.

    PubMed

    Scheinfeld, Noah

    2013-04-15

    Hidradenitis suppurativa (HS), a pathological follicular disease, impacts patients' lives profoundly. HS most commonly involves cutaneous intertriginous areas, such as the axilla, inner thighs, groin and buttocks, and pendulous breasts, but can appear on any follicular skin. Protean, HS manifests with variations of abscesses, folliculitis, pyogenic granulomas, scars (oval honeycombed), comedones, tracts, fistulas, and keloids. The pathophysiology might involve both defects of the innate follicular immunity and overreaction to coagulase negative Staphylococcus. Treatment depends on the morphology, extent, severity, and duration. Topical clindamycin and dapsone are often adequate for treating mild HS. For Stage 1 and 2 HS, first line treatment combines rifampin with either oral clindamycin or minocycline. Other HS treatments include: fluoroquinolones with metronidazole and rifampin, oral dapsone, zinc, acitretin, hormone blockers (oral contraceptive pills, spironolactone, finasteride, and dutasteride), and oral prednisone. For severe HS, cyclosporine, adalimumab, or infliximab (used at double psoriatic doses) and intravenous carbapenems or cephalosporins are often required. Isotretinoin, etanercept, isoniazid, lymecycline, sulfasalazine, methotrexate, metformin, colchicine, clarithromycin, IVIG, and thalidomide are less favored treatments. The role of botulinum toxin is uncertain. The most important life style modification is weight loss. De-roofing fluctuant nodules and injection of intralesional corticosteroids ameliorates the disease and perhaps, if done at regular intervals, improves HS more permanently. Surgical excision and CO2 laser ablation are more definitive treatments. The 1064 nm laser for hair removal aids in the treatment of HS. This article centers on medical therapies and will only passingly mention surgical and laser treatments. This article summarizes my treatment experience with over 350 HS patients.

  14. Intravenous hypertonic saline solution (7.5%) and oral electrolytes to treat of calves with noninfectious diarrhea and metabolic acidosis.

    PubMed

    Leal, M L R; Fialho, S S; Cyrillo, F C; Bertagnon, H G; Ortolani, E L; Benesi, F J

    2012-01-01

    The aim of this study was to compare the efficacy of treating osmotic diarrhea and dehydration in calves with hypertonic saline solution (HSS) IV, isotonic electrolyte solution (IES) PO, and a combination of these 2 solutions (HSS + IES). Eighteen male calves 8-30 days of age were used to evaluate the efficacy of 3 methods of fluid therapy after induction of osmotic diarrhea and dehydration. The diarrhea and dehydration were induced by administration of saccharose, spironolactone, and hydrochlorothiazide for 48 hours. The animals were randomly divided into 3 experimental groups: Group 1: 7.2% hypertonic saline solution-HSS (5 mL/kg IV); Group 2: oral isotonic electrolyte solution IES (60 mL/kg PO); or Group 3: HSS+IES. Clinical signs and laboratory finding observed 48 hours post-induction (Time 0) included diarrhea, dehydration, lethargy, and metabolic acidosis. Calves treated with HSS + IES experienced decreases in hematocrit, total protein concentration, albumin concentration, urea nitrogen concentration, and plasma volume as well as increases in blood pH, blood bicarbonate concentration, and central venous pressure between 1 and 3 hours post-treatment. These findings also were observed in animals treated with IES, however, at a slower rate than in the HSS + IES-treated animals. Animals treated with HSS continued to display signs of dehydration, lethargy, and metabolic acidosis 24 hours post-treatment. Treatment with a combination of HSS and IES produced rapid and sustainable correction of hypovolemia and metabolic acidosis in calves with noninfections diarrhea and dehydration. Copyright © 2012 by the American College of Veterinary Internal Medicine.

  15. Reliability of a Bayesian network to predict an elevated aldosterone-to-renin ratio.

    PubMed

    Ducher, Michel; Mounier-Véhier, Claire; Lantelme, Pierre; Vaisse, Bernard; Baguet, Jean-Philippe; Fauvel, Jean-Pierre

    2015-05-01

    Resistant hypertension is common, mainly idiopathic, but sometimes related to primary aldosteronism. Thus, most hypertension specialists recommend screening for primary aldosteronism. To optimize the selection of patients whose aldosterone-to-renin ratio (ARR) is elevated from simple clinical and biological characteristics. Data from consecutive patients referred between 1 June 2008 and 30 May 2009 were collected retrospectively from five French 'European excellence hypertension centres' institutional registers. Patients were included if they had at least one of: onset of hypertension before age 40 years, resistant hypertension, history of hypokalaemia, efficient treatment by spironolactone, and potassium supplementation. An ARR>32 ng/L and aldosterone>160 ng/L in patients treated without agents altering the renin-angiotensin system was considered as elevated. Bayesian network and stepwise logistic regression were used to predict an elevated ARR. Of 334 patients, 89 were excluded (31 for incomplete data, 32 for taking agents that alter the renin-angiotensin system and 26 for other reasons). Among 245 included patients, 110 had an elevated ARR. Sensitivity reached 100% or 63.3% using Bayesian network or logistic regression, respectively, and specificity reached 89.6% or 67.2%, respectively. The area under the receiver-operating-characteristic curve obtained with the Bayesian network was significantly higher than that obtained by stepwise regression (0.93±0.02 vs. 0.70±0.03; P<0.001). In hypertension centres, Bayesian network efficiently detected patients with an elevated ARR. An external validation study is required before use in primary clinical settings. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  16. Aldosterone increases cardiac vagal tone via G protein-coupled oestrogen receptor activation

    PubMed Central

    Brailoiu, G Cristina; Benamar, Khalid; Arterburn, Jeffrey B; Gao, Erhe; Rabinowitz, Joseph E; Koch, Walter J; Brailoiu, Eugen

    2013-01-01

    In addition to acting on mineralocorticoid receptors, aldosterone has been recently shown to activate the G protein-coupled oestrogen receptor (GPER) in vascular cells. In light of the newly identified role for GPER in vagal cardiac control, we examined whether or not aldosterone activates GPER in rat nucleus ambiguus. Aldosterone produced a dose-dependent increase in cytosolic Ca2+ concentration in retrogradely labelled cardiac vagal neurons of nucleus ambiguus; the response was abolished by pretreatment with the GPER antagonist G-36, but was not affected by the mineralocorticoid receptor antagonists, spironolactone and eplerenone. In Ca2+-free saline, the response to aldosterone was insensitive to blockade of the Ca2+ release from lysosomes, while it was reduced by blocking the Ca2+ release via ryanodine receptors and abolished by blocking the IP3 receptors. Aldosterone induced Ca2+ influx via P/Q-type Ca2+ channels, but not via L-type and N-type Ca2+ channels. Aldosterone induced depolarization of cardiac vagal neurons of nucleus ambiguus that was sensitive to antagonism of GPER but not of mineralocorticoid receptor. in vivo studies, using telemetric measurement of heart rate, indicate that microinjection of aldosterone into the nucleus ambiguus produced a dose-dependent bradycardia in conscious, freely moving rats. Aldosterone-induced bradycardia was blocked by the GPER antagonist, but not by the mineralocorticoid receptor antagonists. In summary, we report for the first time that aldosterone decreases heart rate by activating GPER in cardiac vagal neurons of nucleus ambiguus. PMID:23878371

  17. Endolymphatic Sodium Homeostasis by Extramacular Epithelium of the Saccule

    PubMed Central

    Kim, Sung Huhn

    2009-01-01

    The saccule is a vestibular sensory organ that depends upon regulation of its luminal fluid, endolymph, for normal transduction of linear acceleration into afferent neural transmission. Previous studies suggested that endolymph in the saccule was merely derived from cochlear endolymph. We developed and used a preparation of isolated mouse saccule to measure transepithelial currents from the extramacular epithelium with a current density probe. The direction and pharmacology of transepithelial current was consistent with Na+ absorption by the epithelial Na+ channel (ENaC) and was blocked by the ENaC-specific inhibitors benzamil and amiloride. Involvement of Na+,K+-ATPase and K+ channels was demonstrated by reduction of the current by ouabain and the K+ channel blockers Ba2+, XE991, and 4-AP. Glucocorticoids upregulated the current via glucocorticoid receptors. Dexamethasone stimulated the current after 24 h and the stimulation was blocked by mifepristone but not spironolactone. No acute response was observed to elevated cAMP in the presence of amiloride nor to bumetanide, a blocker of Na+,K+,2Cl− cotransporter. The results are consistent with a canonical model of corticosteroid-regulated Na+ absorption that includes entry of luminal Na+ through apical membrane Na+ channels and active basolateral exit of Na+ via a Na+ pump, with recycling of K+ at the basolateral membrane via K+-permeable channels. These observations provide our first understanding of the active role played by saccular epithelium in the local regulation of the [Na+] of endolymph for maintenance of our sense of balance. PMID:20016101

  18. Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus

    PubMed Central

    Osborne, Danielle M.; O'Leary, Kelsey E.; Fitzgerald, Dennis P.; George, Alvin J.; Vidal, Michael M.; Anderson, Brian M.; McNay, Ewan C.

    2016-01-01

    Aims/hypothesis Recurrent hypoglycaemia is primarily caused by repeated over-administration of insulin to patients with diabetes. Although cognition is impaired during hypoglycaemia, restoration of euglycaemia after recurrent hypoglycaemia is associated with improved hippocampally mediated memory. Recurrent hypoglycaemia alters glucocorticoid secretion in response to hypoglycaemia; glucocorticoids are well established to regulate hippocampal processes, suggesting a possible mechanism for recurrent hypoglycaemia modulation of subsequent cognition. We tested the hypothesis that glucocorticoids within the dorsal hippocampus might mediate the impact of recurrent hypoglycaemia on hippocampal cognitive processes. Methods We characterised changes in the dorsal hippocampus at several time points to identify specific mechanisms affected by recurrent hypoglycaemia, using a well-validated 3 day model of recurrent hypoglycaemia either alone or with intrahippocampal delivery of glucocorticoid (mifepristone) and mineralocorticoid (spironolactone) receptor antagonists prior to each hypoglycaemic episode. Results Recurrent hypoglycaemia enhanced learning and also increased hippocampal expression of glucocorticoid receptors, serum/glucocorticoid-regulated kinase 1, cyclic AMP response element binding (CREB) phosphorylation, and plasma membrane levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors. Both hippocampus-dependent memory enhancement and the molecular changes were reversed by glucocorticoid receptor antagonist treatment. Conclusions/interpretation These results indicate that increased glucocorticoid signalling during recurrent hypoglycaemia produces several changes in the dorsal hippocampus that are conducive to enhanced hippocampus-dependent contextual learning. These changes appear to be adaptive, and in addition to supporting cognition may reduce damage otherwise caused by repeated exposure to severe

  19. Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods

    NASA Astrophysics Data System (ADS)

    Roos, Katarina; Hogner, Anders; Ogg, Derek; Packer, Martin J.; Hansson, Eva; Granberg, Kenneth L.; Evertsson, Emma; Nordqvist, Anneli

    2015-12-01

    In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory using core fragments and a protein model with only the first shell residues surrounding the core, to predict relative binding affinity of a matched series of mineralocorticoid receptor (MR) antagonists. Antagonists of MR are used for treatment of chronic heart failure and hypertension. Marketed MR antagonists, spironolactone and eplerenone, are also believed to be highly efficacious in treatment of chronic kidney disease in diabetes patients, but is contra-indicated due to the increased risk for hyperkalemia. These findings and a significant unmet medical need among patients with chronic kidney disease continues to stimulate efforts in the discovery of new MR antagonist with maintained efficacy but low or no risk for hyperkalemia. Applied on a matched series of MR antagonists the quantum mechanical based method gave an R2 = 0.76 for the experimental lipophilic ligand efficiency versus relative predicted binding affinity calculated with the M06-2X functional in gas phase and an R2 = 0.64 for experimental binding affinity versus relative predicted binding affinity calculated with the M06-2X functional including an implicit solvation model. The quantum mechanical approach using core fragments was compared to free energy perturbation calculations using the full sized compound structures.

  20. Eplerenone: a selective aldosterone receptor antagonist for patients with heart failure.

    PubMed

    Barnes, Brian J; Howard, Patricia A

    2005-01-01

    To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF). English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles. Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated. Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence. The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.

  1. Hormetic effects by exercise on hippocampal neurogenesis with glucocorticoid signaling

    PubMed Central

    Okamoto, Masahiro; Yamamura, Yuhei; Liu, Yu-Fan; Min-Chul, Lee; Matsui, Takashi; Shima, Takeru; Soya, Mariko; Takahashi, Kanako; Soya, Shingo; McEwen, Bruce S.; Soya, Hideaki

    2015-01-01

    Abstract Exercise enhances adult hippocampal neurogenesis (AHN), although the exact nature of how this happens remains controversial. The beneficial effects of exercise vary depending upon the exercise condition, especially intensity. Most animal studies, however, have used wheel running, which only evaluates running distance (exercise volume) and does not consider intensity. In our rat model, we have found that exercise-induced neurogenesis varies depending on the intensity of the exercise and have found that exercise-enhanced neurogenesis is more pronounced with mild exercise than with moderate and/or intense exercise. This may be due, at least in part, to increased glucocorticoid (CORT) secretion. To test this hypothesis, we used our special exercise model in mice, with and without a stress response, based on the lactate threshold (LT) in which moderate exercise above the LT increases lactate and adrenocorticotropic hormone (ACTH) release, while mild exercise does not. Adult male C57BL/6J mice were subjected to two weeks of exercise training and AHN was measured with a 5-Bromo-2-deoxyuridine (BrdU) pre-injection and immunohistochemistry. The role of glucocorticoid signaling was examined using intrapertioneal injections of antagonists for the glucocorticoid receptor (GR), mifepristone, and the mineralocorticoid receptor (MR), spironolactone. We found that, while mild exercise increased AHN without elevating CORT blood levels, both MR and GR antagonists abolished mild-exercise-induced AHN, but did not affect AHN under intense exercise. This suggests a facilitative, permissive role of glucocorticoid and mineralocorticoid receptors in AHN during mild exercise (234/250)

  2. Characteristics of Saudi patients with congestive heart failure and adherence to management guidelines in a tertiary hospital in Riyadh.

    PubMed

    Alqahtani, Mohammad; Alanazi, Thari; Binsalih, Salih; Aljohani, Naji; Alshammari, Mohammed; Ashagag, Ali; Abdullah, Mohammed; Buabbas, Sara; Abdulbaqi, Manar

    2012-01-01

    There is limited data available on the characteristics of local Saudi patients diagnosed with congestive heart failure (CHF) and on their adherence to guidelines for managing the disease. This study aimed to fill this gap. Retrospective study of patients treated at King Abdulaziz Medical City from 20022008. The records were reviewed of subjects admitted secondary to heart failure (defined as systolic heart failure [ejection fraction < 55%] and/or heart failure with preserved ejection fraction diagnosed either clinically and/or by echocardiogram and/or cardiac catheterization) or who visited the outpatient department for the same complaint. Of 392 CHF cases, the mean age was 67.8 (12.8) years and the majority were males (53.1%). Hypertension was the predominant comorbid illness, accounting for 84.9% of cases, followed by diabetes mellitus type 2 and hyperlipidemia. Almost three-fourths (73.7%) of the subjects had mild to severe left ventricular dysfunction, with 68.5% of the cases having right ischemic cardiomyopathy. Spironolactone, exercise and vaccination were the the least least adhered to recommendations (30.0%, 20.5% and 15.2%, respectively). The study highlights the need for proper education of patients and caregivers to increase compliance to medications. Physicians are also encouraged to undergo continuing medical education and training courses to properly implement current recommendations in the management of heart failure. Further studies are needed on a larger scale in order to formulate an effective management scheme that will address the current challenges faced by both clinicians and CHF patients.

  3. Effectiveness and safety of tolvaptan in liver cirrhosis patients with edema: Interim results of post-marketing surveillance of tolvaptan in liver cirrhosis (START study).

    PubMed

    Sakaida, Isao; Terai, Shuji; Kurosaki, Masayuki; Yasuda, Moriyoshi; Okada, Mitsuru; Bando, Kosuke; Fukuta, Yasuhiko

    2017-10-01

    Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings. Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6 months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure. Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were -2.38 kg on day 7 and -3.52 kg on day 14. Ascites and bloated feeling was significantly improved within 14 days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of ≥146 mEq/L was observed in 12 patients (2.7%). In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained. © 2016 The Japan Society of Hepatology.

  4. Shakuyaku-kanzo-to induces pseudoaldosteronism characterized by hypokalemia, rhabdomyolysis, metabolic alkalosis with respiratory compensation, and increased urinary cortisol levels.

    PubMed

    Kinoshita, Hiroyuki; Okabayashi, Misako; Kaneko, Masakazu; Yasuda, Mutsuko; Abe, Keisuke; Machida, Akira; Ohkubo, Takuya; Kamata, Tomoyuki; Yakushiji, Fumiatsu

    2009-04-01

    Licorice, the primary ingredient of the Japanese herbal medicine shakuyaku-kanzo-to, can cause pseudoaldosteronism. Thus, shakuyaku-kanzo-to can cause this condition. A 79-year-old woman was brought to the emergency room. She had been experiencing general fatigue, numbness in the hands, and weakness in the lower limbs and could not stand up without assistance. She presented with hypokalemia (potassium level, 1.7 mEq/L), increased urinary excretion of potassium (fractional excretion of K, 21.2%), abnormalities on an electrocardiogram (flat T waves in II, III, AVF, and V1-6), rhabdomyolysis (creatine kinase level, 28,376 U/L), myopathy, metabolic alkalosis with respiratory compensation (O(2) flow rate, 2 L/min; pH, 7.473; pco(2), 61.0 mm Hg; po(2), 78.0 mm Hg; HCO(3), 44.1 mmol/L), hypertension (174/93 mm Hg), hyperglycemia (blood glucose level, 200-300 mg/dL), frequent urination, suppressed plasma renin activity (0.1 ng/mL/hour), decreased aldosterone levels (2.6 ng/dL), and increased urinary cortisol levels (600.6 microg/day; reference range, 26.0-187.0 microg/day). In this case, the observed reduction in the urinary cortisol levels, from 600.6 to 37.8 microg/day, led to a definitive diagnosis of pseudoaldosteronism instead of the apparent mineralocorticoid excess syndrome. Discontinuing shakuyaku-kanzo-to treatment and administering spironolactone and potassium proved effective in improving the patient's condition. Medical practitioners prescribing shakuyaku-kanzo-to should take into account the association between licorice, which is its main ingredient, and pseudoaldosteronism.

  5. Ventilatory effects of gap junction blockade in the RTN in awake rats.

    PubMed

    Hewitt, Amy; Barrie, Rachel; Graham, Michael; Bogus, Kara; Leiter, J C; Erlichman, Joseph S

    2004-12-01

    We tested the hypothesis that carbenoxolone, a pharmacological inhibitor of gap junctions, would reduce the ventilatory response to CO(2) when focally perfused within the retrotrapezoid nucleus (RTN). We tested this hypothesis by measuring minute ventilation (V(E)), tidal volume (V(T)), and respiratory frequency (F(R)) responses to increasing concentrations of inspired CO(2) (Fi(CO(2)) = 0-8%) in rats during wakefulness. We confirmed that the RTN was chemosensitive by perfusing the RTN unilaterally with either acetazolamide (AZ; 10 microM) or hypercapnic artificial cerebrospinal fluid equilibrated with 50% CO(2) (pH approximately 6.5). Focal perfusion of AZ or hypercapnic aCSF increased V(E), V(T), and F(R) during exposure to room air. Carbenoxolone (300 microM) focally perfused into the RTN decreased V(E) and V(T) in animals <11 wk of age, but V(E) and V(T) were increased in animals >12 wk of age. Glyzyrrhizic acid, a congener of carbenoxolone, did not change V(E), V(T), or F(R) when focally perfused into the RTN. Carbenoxolone binds to the mineralocorticoid receptor, but spironolactone (10 microM) did not block the disinhibition of V(E) or V(T) in older animals when combined with carbenoxolone. Thus the RTN is a CO(2) chemosensory site in all ages tested, but the function of gap junctions in the chemosensory process varies substantially among animals of different ages: gap junctions amplify the ventilatory response to CO(2) in younger animals, but appear to inhibit the ventilatory response to CO(2) in older animals.

  6. An Investigation of Drug-Drug Interaction Alert Overrides at a Pediatric Hospital.

    PubMed

    Humphrey, Kate; Jorina, Maria; Harper, Marvin; Dodson, Brenda; Kim, Seung-Yeon; Ozonoff, Al

    2018-05-01

    Drug-drug interactions (DDIs) can result in patient harm. DDI alerts are intended to help prevent harm; when the majority of alerts presented to providers are being overridden, their value is diminished. Our objective was to evaluate the overall rates of DDI alert overrides and how rates varied by specialty, clinician type, and patient complexity. A retrospective study of DDI alert overrides that occurred during 2012 and 2013 within the inpatient setting described at the medication-, hospital-, provider-, and patient encounter-specific levels was performed at an urban, quaternary-care, pediatric hospital. There were >41 000 DDI alerts presented to clinicians; ∼90% were overridden. The 5 DDI pairs that were most frequently presented and overridden included the following: potassium chloride-spironolactone, methadone-ondansetron, ketorolac-ibuprofen, cyclosporine-fluconazole, and potassium chloride-enalapril, each with an alert override rate of ≥0.89. Override rates across provider groups ranged between 0.84 and 0.97. In general, patients with high complexity had a higher frequency of alert overrides, but the rates of alert overrides for each DDI pairing did not differ significantly. High rates of DDI alert overrides occur across medications, provider groups, and patient encounters. Methods to decrease DDI alerts which are likely to be overridden exist, but it is also clear that more robust and intelligent tools are needed. Characteristics exist at the medication, hospital, provider, and patient levels that can be used to help specialize and enhance information transmission. Copyright © 2018 by the American Academy of Pediatrics.

  7. Aldosterone down-regulates the slowly activated delayed rectifier potassium current in adult guinea pig cardiomyocytes.

    PubMed

    Lv, Yankun; Bai, Song; Zhang, Hua; Zhang, Hongxue; Meng, Jing; Li, Li; Xu, Yanfang

    2015-12-01

    There is emerging evidence that the mineralocorticoid hormone aldosterone is associated with arrhythmias in cardiovascular disease. However, the effect of aldosterone on the slowly activated delayed rectifier potassium current (IK s ) remains poorly understood. The present study was designed to investigate the modulation of IK s by aldosterone. Adult guinea pigs were treated with aldosterone for 28 days via osmotic pumps. Standard glass microelectrode recordings and whole-cell patch-clamp techniques were used to record action potentials in papillary muscles and IK s in ventricular cardiomyocytes. The aldosterone-treated animals exhibited a prolongation of the QT interval and action potential duration with a higher incidence of early afterdepolarizations. Patch-clamp recordings showed a significant down-regulation of IK s density in the ventricular myocytes of these treated animals. These aldosterone-induced electrophysiological changes were fully prevented by a combined treatment with spironolactone, a mineralocorticoid receptor (MR) antagonist. In addition, in in vitro cultured ventricular cardiomyocytes, treatment with aldosterone (sustained exposure for 24 h) decreased the IK s density in a concentration-dependent manner. Furthermore, a significant corresponding reduction in the mRNA/protein expression of IKs channel pore and auxiliary subunits, KCNQ1 and KCNE1 was detected in ventricular tissue from the aldosterone-treated animals. Aldosterone down-regulates IK s by inhibiting the expression of KCNQ1 and KCNE1, thus delaying the ventricular repolarization. These results provide new insights into the mechanism underlying K(+) channel remodelling in heart disease and may explain the highly beneficial effects of MR antagonists in HF. © 2015 The British Pharmacological Society.

  8. Mineralocorticoid receptor antagonism treats obesity-associated cardiac diastolic dysfunction.

    PubMed

    Bender, Shawn B; DeMarco, Vincent G; Padilla, Jaume; Jenkins, Nathan T; Habibi, Javad; Garro, Mona; Pulakat, Lakshmi; Aroor, Annayya R; Jaffe, Iris Z; Sowers, James R

    2015-05-01

    Patients with obesity and diabetes mellitus exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin-aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure-independent low-dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide-independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling, with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. In addition, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure-independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance. © 2015 American Heart Association, Inc.

  9. Apparent mineralocorticoid excess syndrome: report of one family with three affected children.

    PubMed

    Al-Harbi, Taiba; Al-Shaikh, Adnan

    2012-01-01

    The syndrome of apparent mineralocorticoid excess (AME) is an autosomal recessive disorder characterized by hypertension, hypokalemia, low renin, and hypoaldosteronism. It is caused by deficiency of 11β-hydroxysteroid dehydrogenase, which results in a defect of the peripheral metabolism of cortisol to cortisone. As a consequence, the serum cortisol half-life (T½) is prolonged, ACTH is suppressed, and serum cortisol concentration is normal. The hormonal diagnosis of the disorder is made by the increased ratio of urine-free cortisol to cortisone. In patients with AME, this ratio is 5-18, while in normal individuals it is <0.5. These studies suggest that an abnormality in cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid and causing the syndrome of AME. We report three siblings - two female and one male - with the syndrome of apparent mineralocorticoid excess who presented with hypertension, hypokalemia, low renin, and low aldosterone levels. The finding of abnormally high ratios of 24-h urine-free cortisol to cortisone in our three patients (case 1, 8.4; case 2, 25; and case 3, 7.5) confirmed the diagnosis of apparent mineralocorticoid excess syndrome in these children. They were treated with oral potassium supplements. The addition of spironolactone resulted in a decrease in blood pressure, rise in serum potassium and a gradual increase in plasma renin activity in all three. In this study, the genetic testing of those three siblings with the typical clinical features of AME has detected missense mutation c.662C>T (p.Arg208Cys) in exon 3 of the HSD11B2 gene in the homozygous state.

  10. Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms

    PubMed Central

    De Silva, Deepa S.; Wilson, Richard M.; Hutchinson, Christoph; Ip, Peter C.; Garcia, Anthony G.; Lancel, Steve; Ito, Masa; Pimentel, David R.; Sam, Flora

    2009-01-01

    Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat ventricular myocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured ARVM and whether fenofibrate ameliorated the apoptosis. Aldosterone (1 μM) induced apoptosis by increasing terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei in ARVM. Spironolactone (100 nM), an aldosterone receptor antagonist, but not RU-486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis, indicating that the mineralocorticoid receptor (MR) plays a role. SP-600125 (3 μM)—a selective inhibitor of c-Jun NH2-terminal kinase (JNK)—inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress-activated protein kinases, pretreatment with fenofibrate (10 μM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53, and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100 mg·kg body wt−1·day−1) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly, eplerenone, a selective MR inhibitor, used in chronic pressure-overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Therefore, involvement of JNK MAPK-dependent mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a peroxisome proliferator-activated receptor (PPAR)α ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases. PMID:19395558

  11. Mineralocorticoid receptor antagonist pretreatment to MINIMISE reperfusion injury after ST-elevation myocardial infarction (the MINIMISE STEMI Trial): rationale and study design.

    PubMed

    Bulluck, Heerajnarain; Fröhlich, Georg M; Mohdnazri, Shah; Gamma, Reto A; Davies, John R; Clesham, Gerald J; Sayer, Jeremy W; Aggarwal, Rajesh K; Tang, Kare H; Kelly, Paul A; Jagathesan, Rohan; Kabir, Alamgir; Robinson, Nicholas M; Sirker, Alex; Mathur, Anthony; Blackman, Daniel J; Ariti, Cono; Krishnamurthy, Arvindra; White, Steven K; Meier, Pascal; Moon, James C; Greenwood, John P; Hausenloy, Derek J

    2015-05-01

    Novel therapies capable of reducing myocardial infarct (MI) size when administered prior to reperfusion are required to prevent the onset of heart failure in ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI). Experimental animal studies have demonstrated that mineralocorticoid receptor antagonist (MRA) therapy administered prior to reperfusion can reduce MI size, and MRA therapy prevents adverse left ventricular (LV) remodeling in post-MI patients with LV impairment. With these 2 benefits in mind, we hypothesize that initiating MRA therapy prior to PPCI, followed by 3 months of oral MRA therapy, will reduce MI size and prevent adverse LV remodeling in STEMI patients. The MINIMISE-STEMI trial is a prospective, randomized, double-blind, placebo-controlled trial that will recruit 150 STEMI patients from four centers in the United Kingdom. Patients will be randomized to receive either an intravenous bolus of MRA therapy (potassium canrenoate 200 mg) or matching placebo prior to PPCI, followed by oral spironolactone 50 mg once daily or matching placebo for 3 months. A cardiac magnetic resonance imaging scan will be performed within 1 week of PPCI and repeated at 3 months to assess MI size and LV remodeling. Enzymatic MI size will be estimated by the 48-hour area-under-the-curve serum cardiac enzymes. The primary endpoint of the study will be MI size on the 3-month cardiac magnetic resonance imaging scan. The MINIMISE STEMI trial will investigate whether early MRA therapy, initiated prior to reperfusion, can reduce MI size and prevent adverse post-MI LV remodeling. © 2015 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.

  12. Blocking the mineralocorticoid receptor in humans prevents the stress-induced enhancement of centromedial amygdala connectivity with the dorsal striatum.

    PubMed

    Vogel, Susanne; Klumpers, Floris; Krugers, Harm J; Fang, Zhou; Oplaat, Krista T; Oitzl, Melly S; Joëls, Marian; Fernández, Guillén

    2015-03-01

    Two research lines argue for rapid stress-induced reallocations of neural network activity involving the amygdala. One focuses on the role of norepinephrine (NE) in mediating a shift towards the salience network and improving vigilance processing, whereas the other focuses on the role of cortisol in enhancing automatic, habitual responses. It has been suggested that the mineralocorticoid receptor (MR) is critical in shifting towards habitual responses, which are supported by the dorsal striatum. However, until now it remained unclear whether these two reallocations of neural recourses might be part of the same phenomenon and develop immediately after stress onset. We combined methods used in both approaches and hypothesized specifically that stress would lead to rapidly enhanced involvement of the striatum as assessed by amygala-striatal connectivity. Furthermore, we tested the hypothesis that this shift depends on cortisol interacting with the MR, by using a randomized, placebo-controlled, full-factorial, between-subjects design with the factors stress and MR-blockade (spironolactone). We investigated 101 young, healthy men using functional magnetic resonance imaging after stress induction, which led to increased negative mood, heart rate, and cortisol levels. We confirmed our hypothesis by revealing a stress-by-MR-blockade interaction on the functional connectivity between the centromedial amygdala (CMA) and the dorsal striatum. Stress rapidly enhanced CMA-striatal connectivity and this effect was correlated with the stress-induced cortisol response, but required MR availability. This finding might suggest that the stress-induced shift described by distinct research lines might capture different aspects of the same phenomenon, ie, a reallocation of neural resources coordinated by both NE and cortisol.

  13. Pseudo-Bartter syndrome in an infant with congenital chloride diarrhoea.

    PubMed

    Igrutinović, Zoran; Peco-Antić, Amira; Radlović, Nedeljko; Vuletić, Biljana; Marković, Slavica; Vujić, Ana; Rasković, Zorica

    2011-01-01

    Pseudo-Bartter syndrome encompasses a heterogenous group of disorders similar to Bartter syndrome. We are presenting an infant with pseudo-Bartter syndrome caused by congenital chloride diarrhoea. A male newborn born in the 37th gestational week (GW) to young healthy and non-consanguineous parents. In the 35th GW a polyhydramnios with bowel dilatation was verified by ultrasonography. After birth he manifested several episodes of hyponatremic dehydration with hypochloraemia, hypokalaemia and metabolic alkalosis, so as Bartter syndrome was suspected treatment with indomethacin, spironolactone and additional intake of NaCl was initiated. However, this therapy gave no results, so that at age six months he was rehospitalized under the features of persistent watery diarrhoea, vomiting, dehydration and acute renal failure (serum creatinine 123 micromol/L). The laboratory results showed hyponatraemia (123 mmol/L), hypokalaemia (3.1 mmol/L), severe hypochloraemia (43 mmol/L), alcalosis (blood pH 7.64, bicarbonate 50.6 mmol/L), high plasma renin (20.6 ng/ml) and aldosterone (232.9 ng/ml), but a low urinary chloride concentration (2.1 mmol/L). Based on these findings, as well as the stool chloride concentration of 110 mmol/L, the patient was diagnosed congenital chloride diarrhoea. In further course, the patient was treated by intensive fluid, sodium and potassium supplementation which resulted in the normalization of serum electrolytes, renal function, as well as his mental and physical development during 10 months of follow-up. Persistent watery diarrhoea with a high concentration of chloride in stool is the key finding in the differentiation of congenital chloride diarrhoea from Bartter syndrome. The treatment of congenital chloride diarrhoea consists primarily of adequate water and electrolytes replacement.

  14. Feedforward activation of endothelial ENaC by high sodium

    PubMed Central

    Korte, Stefanie; Sträter, Alexandra S.; Drüppel, Verena; Oberleithner, Hans; Jeggle, Pia; Grossmann, Claudia; Fobker, Manfred; Nofer, Jerzy-Roch; Brand, Eva; Kusche-Vihrog, Kristina

    2014-01-01

    Kidney epithelial sodium channels (ENaCs) are known to be inactivated by high sodium concentrations (feedback inhibition). Recently, the endothelial sodium channel (EnNaC) was identified to control the nanomechanical properties of the endothelium. EnNaC-dependent endothelial stiffening reduces the release of nitric oxide, the hallmark of endothelial dysfunction. To study the regulatory impact of sodium on EnNaC, endothelial cells (EA.hy926 and ex vivo mouse endothelium) were incubated in aldosterone-free solutions containing either low (130 mM) or high (150 mM) sodium concentrations. By applying atomic force microscopy-based nanoindentation, an unexpected positive correlation between increasing sodium concentrations and cortical endothelial stiffness was observed, which can be attributed to functional EnNaC. In particular, an acute rise in sodium concentration (+20 mM) was sufficient to increase EnNaC membrane abundance by 90% and stiffening of the endothelial cortex by 18%. Despite the absence of exogenous aldosterone, these effects were prevented by the aldosterone synthase inhibitor FAD286 (100 nM) or the mineralocorticoid receptor (MR)-antagonist spironolactone (100 nM), indicating endogenous aldosterone synthesis and MR-dependent signaling. Interestingly, in the presence of high-sodium concentrations, FAD286 increased the transcription of the MR by 69%. Taken together, a novel feedforward activation of EnNaC by sodium is proposed that contrasts ENaC feedback inhibition in kidney.—Korte, S., Sträter, A. S., Drüppel, V., Oberleithner, H., Jeggle, P., Grossmann, C., Fobker, M., Nofer, J.-R., Brand, E., Kusche-Vihrog, K. Feedforward activation of endothelial ENaC by high sodium. PMID:24868010

  15. Resistant hypertension: Renal denervation or intensified medical treatment?

    PubMed

    Morganti, Alberto; Mancia, Giuseppe

    2018-04-01

    Resistant hypertension (RH) can be diagnosed if blood pressure (BP) is not controlled with the combination of three antihypertensive drugs, including a diuretic, all at effective doses. Patients affected by this condition exhibit a marked increase in the risk of cardiovascular and renal morbid and fatal events. They also exhibit an increased activity of the sympathetic nervous system which is likely to importantly contribute at the renal and other vascular levels to the hypertensive state. Almost 10years ago renal denervation (RDN) by radiofrequency thermal energy delivery to the walls of the renal arteries was proposed for the treatment of RH. Several uncontrolled studies initially reported that this procedure substantially reduced the elevated BP values but this conclusion has not been supported by a recent randomized control trial, which has almost marginalized this therapeutic approach. A revival, however, is under way because of recent positive findings and technical improvement that hold promise to make renal denervation more complete. The antihypertensive efficacy and overall validity of RDN will have to be tested against drug treatment of RH. Several studies indicate that an excess of aldosterone production contributes to RH and recent evidence documents indisputably that anti-aldosterone agents such as spironolactone can effectively control BP in many RH patients, although with some side effects that require close patients' monitoring. At present, it is advisable to treat RH with the addition of an anti-aldosterone agent. If BP control is not achieved or serious side effects become manifest RDN may then be considered. Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  16. Aldosterone signaling regulates the over-expression of claudin-4 and -8 at the distal nephron from type 1 diabetic rats.

    PubMed

    Molina-Jijón, Eduardo; Rodríguez-Muñoz, Rafael; González-Ramírez, Ricardo; Namorado-Tónix, Carmen; Pedraza-Chaverri, José; Reyes, Jose L

    2017-01-01

    Hyperglycemia in diabetes alters tight junction (TJ) proteins in the kidney. We evaluated the participation of aldosterone (ALD), and the effect of spironolactone (SPL), a mineralocorticoid receptor antagonist, on the expressions of claudin-2, -4, -5 and -8, and occludin in glomeruli, proximal and distal tubules isolated from diabetic rats. Type 1 diabetes was induced in female Wistar rats by a single tail vein injection of streptozotocin (STZ), and SPL was administrated daily by gavage, from days 3-21. Twenty-one days after STZ injection the rats were sacrificed. In diabetic rats, the serum ALD levels were increased, and SPL-treatment did not have effect on these levels or in hyperglycemia, however, proteinuria decreased in SPL-treated diabetic rats. Glomerular damage, evaluated by nephrin and Wilm's tumor 1 (WT1) protein expressions, and proximal tubular damage, evaluated by kidney injury molecule 1 (Kim-1) and heat shock protein 72 kDa (Hsp72) expressions, were ameliorated by SPL. Also, SPL prevented decrement in claudin-5 in glomeruli, and claudin-2 and occludin in proximal tubules by decreasing oxidative stress, evaluated by superoxide anion (O2●-) production, and oxidative stress markers. In distal tubules, SPL ameliorated increase in mRNA, protein expression, and phosphorylation in threonine residues of claudin-4 and -8, through a serum and glucocorticoid-induced kinase 1 (SGK1), and with-no-lysine kinase 4 (WNK4) signaling pathway. In conclusion, this is the first study that demonstrates that ALD modulates the expression of renal TJ proteins in diabetes, and that the blockade of its actions with SPL, may be a promising therapeutic strategy to prevent alterations of TJ proteins in diabetic nephropathy.

  17. Successful long-term treatment of Cushing disease with mifepristone (RU486).

    PubMed

    Basina, Marina; Liu, Hau; Hoffman, Andrew R; Feldman, David

    2012-01-01

    We describe a girl with Cushing disease for whom surgery and radiation treatments failed and the subsequent clinical course with mifepristone therapy. We present the patient's clinical, biochemical, and imaging findings. A 16-year-old girl presented with classic Cushing disease. After transsphenoidal surgery, Cyberknife radiosurgery, ketoconazole, and metyrapone did not control her disease, and she was prescribed mifepristone, which was titrated to a maximal dosage of 1200 mg daily with subsequent symptom improvement. Mifepristone (RU486) is a high-affinity, nonselective antagonist of the glucocorticoid receptor. There is limited literature on its use as an off-label medication to treat refractory Cushing disease. Over her 8-year treatment with mifepristone, her therapy was complicated by hypertension and hypokalemia requiring spironolactone and potassium chloride. She received a 2-month drug holiday every 4 to 6 months to allow for withdrawal menstrual bleeding with medroxyprogesterone acetate. Urinary cortisol, serum cortisol, and corticotropin levels remained elevated during mifepristone drug holidays. While on mifepristone, her signs and symptoms of Cushing disease resolved. Repeated magnetic resonance imaging demonstrated stable appearance of the residual pituitary mass. Bilateral adrenalectomy was performed, and mifepristone was discontinued after 95 months of medical therapy. We describe the longest duration of mifepristone therapy thus reported for the treatment of refractory Cushing disease. Mifepristone effectively controlled all signs and symptoms of hypercortisolism. Menstruating women who take the drug on a long-term basis should receive periodic drug holidays to allow for menses. The lack of reliable serum biomarkers to monitor the success of mifepristone therapy requires careful clinical judgment and may make its use difficult in Cushing disease.

  18. Stressor and Glucocorticoid-Dependent Induction of the Immediate Early Gene Krüppel-Like Factor 9: Implications for Neural Development and Plasticity

    PubMed Central

    Bonett, Ronald M.; Hu, Fang; Bagamasbad, Pia; Denver, Robert J.

    2009-01-01

    Krüppel-like factor 9 (KLF9) is a thyroid hormone-induced, immediate early gene implicated in neural development in vertebrates. We analyzed stressor and glucocorticoid (GC)-dependent regulation of KLF9 expression in the brain of the frog Xenopus laevis, and investigated a possible role for KLF9 in neuronal differentiation. Exposure to shaking/confinement stressor increased plasma corticosterone (CORT) concentration, and KLF9 immunoreactivity in several brain regions, which included the medial amygdala and bed nucleus of the stria terminalis, anterior preoptic area (homologous to the mammalian paraventricular nucleus), and optic tectum (homologous to the mammalian superior colliculus). The stressor-induced KLF9 mRNA expression in the brain was blocked by pretreatment with the GC receptor antagonist RU486, or mimicked by injection of CORT. Treatment with CORT also caused a rapid and dose-dependent increase in KLF9 mRNA in X. laevis XTC-2 cells that was resistant to inhibition of protein synthesis. The action of CORT on KLF9 expression in XTC-2 cells was blocked by RU486, but not by the mineralocorticoid receptor antagonist spironolactone. To test for functional consequences of up-regulation of KLF9, we introduced a KLF9 expression plasmid into living tadpole brain by electroporation-mediated gene transfer. Forced expression of KLF9 in tadpole brain caused an increase in Golgi-stained cells, reflective of neuronal differentiation/maturation. Our results support that KLF9 is a direct, GC receptor target gene that is induced by stress, and functions as an intermediary in the actions of GCs on brain gene expression and neuronal structure. PMID:19036875

  19. Treatment of Bartter syndrome. Unsolved issue.

    PubMed

    Nascimento, Carla Lessa Pena; Garcia, Cecilia Lopes; Schvartsman, Benita Galassi Soares; Vaisbich, Maria Helena

    2014-01-01

    To describe the results of a long-term follow-up of Bartter syndrome patients treated with different drugs. Patients were diagnosed according to clinical and laboratory data. Treatment protocol was potassium supplementation, sodium, spironolactone, and non-steroidal anti-inflammatory drug. Patients who developed proteinuria were converted to angiotensin conversion enzyme inhibitor. The variables evaluated for each drug were Z-score for weight and stature, proteinuria, creatinine clearance, gastrointestinal complaints, amount of potassium supplementation, serum potassium and bicarbonate levels, and findings of upper digestive endoscopy. 20 patients were included. Follow-up was 10.1 ± 5.2 years. 17 patients received indomethacin for 5.9 ± 5.3 years; 19 received celecoxib, median of 35 months; and five received enalapril, median of 23 months. During indomethacin, a statistically significant increase was observed in the Z-score for stature and weight, without a change in the creatinine clearance. Seven of 17 patients had gastrointestinal symptoms, and upper digestive endoscopy evidenced gastritis in three patients and gastric ulcer in four patients. During celecoxib use, a significant increase was detected in the Z-score for stature and weight and a reduction of hyperfiltration; seven patients presented gastrointestinal symptoms, and upper digestive endoscopy evidenced mild gastritis in three. During enalapril use, no significant changes were observed in the Z-score for stature, weight and creatinine clearance. The conversion to enalapril resulted in a significant reduction in proteinuria. The authors suggest starting the treatment with celecoxib, and replacing by ACEi if necessary, monitoring the renal function. The safety and efficacy of celecoxib need to be assessed in larger controlled studies. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  20. Are we missing a mineralocorticoid in teleost fish? Effects of cortisol, deoxycorticosterone and aldosterone on osmoregulation, gill Na+,K+-ATPase activity and isoform mRNA levels in Atlantic salmon

    USGS Publications Warehouse

    McCormick, S.D.; Regish, A.; O'Dea, M. F.; Shrimpton, J.M.

    2008-01-01

    It has long been held that cortisol, acting through a single receptor, carries out both glucocorticoid and mineralocorticoid actions in teleost fish. The recent finding that fish express a gene with high sequence similarity to the mammalian mineralocorticoid receptor (MR) suggests the possibility that a hormone other than cortisol carries out some mineralocorticoid functions in fish. To test for this possibility, we examined the effect of in vivo cortisol, 11-deoxycorticosterone (DOC) and aldosterone on salinity tolerance, gill Na+,K+-ATPase (NKA) activity and mRNA levels of NKA α1a and α1b in Atlantic salmon. Cortisol treatment for 6–14 days resulted in increased, physiological levels of cortisol, increased gill NKA activity and improved salinity tolerance (lower plasma chloride after a 24 h seawater challenge), whereas DOC and aldosterone had no effect on either NKA activity or salinity tolerance. NKA α1a and α1b mRNA levels, which increase in response to fresh water and seawater acclimation, respectively, were both upregulated by cortisol, whereas DOC and aldosterone were without effect. Cortisol, DOC and aldosterone had no effect on gill glucocorticoid receptor GR1, GR2 and MR mRNA levels, although there was some indication of possible upregulation of GR1 by cortisol (p = 0.07). The putative GR blocker RU486 inhibited cortisol-induced increases in salinity tolerance, NKA activity and NKA α1a and α1b transcription, whereas the putative MR blocker spironolactone had no effect. The results provide support that cortisol, and not DOC or aldosterone, is involved in regulating the mineralocorticoid functions of ion uptake and salt secretion in teleost fish.

  1. True rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials: A meta-analysis.

    PubMed

    Vukadinović, Davor; Lavall, Daniel; Vukadinović, Aleksandra Nikolovska; Pitt, Bertram; Wagenpfeil, Stefan; Böhm, Michael

    2017-06-01

    Mineralocorticoid receptor antagonists (MRA) improve survival in heart failure with reduced ejection fraction but are often underused, mostly due to concerns of hyperkalemia. Because hyperkalemia occurs also on placebo, we aimed to determine the truly MRA-related rate of hyperkalemia. We performed a meta-analysis including randomized, placebo-controlled trials reporting hyperkalemia on MRAs in patients after myocardial infarction or with chronic heart failure. We evaluated the truly MRA-related rate of hyperkalemia that represents hyperkalemia on MRA, corrected for hyperkalemia on placebo (Pla), according to the equation: True MRA (%)=(MRA (%) - Pla (%))/MRA (%). A total number of 16,065 patients from 7 trials were analyzed. Hyperkalemia was more frequently observed on MRA (9.3%) vs placebo (4.3%) (risk ratio 2.17, 95% CI 1.92-2.45, P<.0001). Truly MRA-related hyperkalemia was 54%, whereas 46% were non-MRA related. In trials using eplerenone, hyperkalemia was documented in 5.0% on eplerenone and in 2.6% on placebo (P<.0001). In spironolactone trials, hyperkalemia was documented in 17.5% and in 7.5% of patients on placebo (P=.0001). Hypokalemia occurred less frequently in patients on MRA (9.3%) compared with placebo (14.8%) (risk ratio 0.58, CI 0.47-0.72, P<.0001). This meta-analysis shows that in clinical trials, 54% of hyperkalemia cases were specifically related to the MRA treatment and 46% to other reasons. Therefore, non-MRA-related rises in potassium levels might be underestimated and should be rigorously explored before cessation of the evidence-based therapy with MRAs. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy: a systematic review.

    PubMed

    Mavrakanas, Thomas A; Gariani, Karim; Martin, Pierre-Yves

    2014-02-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) is a standard therapeutic intervention in diabetic patients with chronic kidney disease (CKD). Concomitant mineralocorticoid receptor blockade has been studied as a novel approach to further slow down CKD progression. We used PubMed and EMBASE databases to search for relevant literature. We included in our review eight studies in patients of at least 18 years of age, with a diagnosis of type 1 or type 2 diabetes mellitus and diabetic nephropathy, under an angiotensin converting enzyme inhibitor (ACEI) and/or an angiotensin II receptor blocker (ARB) as standard treatment. A subset of patients in each study also received a mineralocorticoid receptor blocker (MRB) (either spironolactone or eplerenone) in addition to standard treatment. Combined treatment with a mineralocorticoid receptor blocker further reduced albuminuria by 23 to 61% compared with standard treatment. Estimated glomerular filtration rate values upon study completion slightly decreased under combined treatment. Blood pressure levels upon study completion were significantly lower with combined treatment in three studies. Hyperkalemia prevalence increased in patients under combined treatment raising dropout rate up to 17%. Therefore, combined treatment by an ACEI/ARB and a MRB may further decrease albuminuria in diabetic nephropathy. This effect may be due to the specific properties of the MRB treatment. Clinicians should regularly check potassium levels because of the increased risk of hyperkalemia. Available evidence should be confirmed by an adequately powered comparative trial of the standard treatment (ACEI or ARB) versus combined treatment by an ACEI/ARB and a MRB. Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  3. Psychological gender of men with systolic heart failure: a neglected strategy to cope with the disease?

    PubMed

    Makowska, Agata; Rydlewska, Agnieszka; Krakowiak, Bartosz; Kuczyłska, Alicja; Sorokowski, Piotr; Danel, Dariusz; Pawłowski, Bogusław; Banasiak, Waldemar; Ponikowski, Piotr; Jankowska, Ewa A

    2014-05-01

    Diminished exercise capacity is a fundamental symptom of heart failure (HF), which is particularly disadvantageous for men for whom exercise capacity contributes significantly to their gender identity, self-esteem, and quality of life. In this study, we aimed to examine whether psychological gender would be different in men with systolic HF as compared with their healthy peers. The authors examined 48 men with systolic HF (age = 64 ± 10 years; body mass index = 28.3 ± 3.4 kg/m(2); NYHA I/II/III [%] = 25/65/10; left ventricular ejection fraction [LVEF] = 32.1 ± 7.8%) and 15 age-matched healthy men. Based on the results of the Polish version of the Bem Sex Role Inventory, the examined men were divided into four types of psychological gender: "masculine" (M), "feminine" (F), "unspecified" (U), and "androgynous" (A). None of the men with HF presented M type of psychological gender, whereas this type was found in 27% of the healthy men (p = .0002). The prevalence of both A (38% vs. 47%) and F (10% vs. 20%, both p > .05) types of psychological gender was similar between men with HF versus without HF. More men with HF fulfilled the criteria of the U type of psychological gender as compared with healthy peers (51% vs. 7%, p = .002). Men with HF and the F type of psychological gender were treated with spironolactone more frequently than those classified with the U and A types (both p < .05). The lack of "psychologically masculine" and the overrepresentation of "psychologically unspecified" gender types in the HF group suggests that psychological gender may be affected among men with HF.

  4. Adoption of Sacubitril/Valsartan for the Management of Patients With Heart Failure.

    PubMed

    Sangaralingham, Lindsey R; Sangaralingham, S Jeson; Shah, Nilay D; Yao, Xiaoxi; Dunlay, Shannon M

    2018-02-01

    The US Food and Drug Administration approved the use of sacubitril/valsartan in patients with heart failure with reduced ejection fraction in July 2015. We aimed to assess the adoption and prescription drug costs of sacubitril/valsartan in its first 18 months after Food and Drug Administration approval. Using a large US insurance database, we identified privately insured and Medicare Advantage beneficiaries who filled a first prescription for sacubitril/valsartan between July 1, 2015, and December 31, 2016. We compared them to patients treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Outcomes included adoption, prescription drug costs, and 180-day adherence, defined as a proportion of days covered ≥80%. A total of 2244 patients initiated sacubitril/valsartan. Although the number of users increased over time, the proportion of heart failure with reduced ejection fraction patients taking sacubitril/valsartan remained low (<3%). Patients prescribed sacubitril/valsartan were younger, more often male, with less comorbidity than those taking an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Although a majority of prescription costs were covered by the health plan (mean, $328.37; median, $362.44 per 30-day prescription), out-of-pocket costs were still high (mean, $71.16; median, $40.27). By comparison, median out-of-pocket costs were $2 to $3 for lisinopril, losartan, carvedilol, and spironolactone. Overall, 59.1% of patients were adherent to sacubitril/valsartan. Refill patterns suggested that nearly half of nonadherent patients discontinued sacubitril/valsartan within 180 days of starting. Adoption of sacubitril/valsartan after Food and Drug Administration approval has been slow and may be associated with the high cost. © 2018 American Heart Association, Inc.

  5. Actions of circulating angiotensin II and aldosterone in the brain contributing to hypertension.

    PubMed

    Leenen, Frans H H

    2014-08-01

    In the past 1-2 decades, it has become apparent that the brain renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the regulation of blood pressure (BP) by the circulating RAAS. In the brain, angiotensinergic sympatho-excitatory pathways do not contribute to acute, second-to-second regulation but play a major role in the more chronic regulation of the setpoint for sympathetic tone and BP. Increases in plasma angiotensin II (Ang II) or aldosterone and in cerebrospinal fluid [Na(+)] can directly activate these pathways and chronically further activate/maintain enhanced activity by a slow neuromodulatory pathway involving local aldosterone, mineralocorticoid receptors (MRs), epithelial sodium channels, and endogenous ouabain. Blockade of any step in this slow pathway prevents Ang II-, aldosterone-, or salt and renal injury-induced forms of hypertension. It appears that the renal and arterial actions of circulating aldosterone and Ang II act as amplifiers but are not sufficient to cause chronic hypertension if their central actions are prevented, except perhaps at high concentrations. From a clinical perspective, oral treatment with an angiotensin type 1 (AT1)-receptor blocker at high doses can cause central AT1-receptor blockade and, in humans, lower sympathetic nerve activity. Low doses of the MR blocker spironolactone appear sufficient to cause central MR blockade and a decrease in sympathetic nerve activity. Integrating the brain actions of the circulating RAAS with its direct renal and arterial actions provides a better framework to understand the role of the circulating RAAS in the pathophysiology of hypertension and heart failure and to direct therapeutic strategies. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Drospirenone/ethinyl estradiol.

    PubMed

    Rapkin, Andrea J; Sorger, Shelley N; Winer, Sharon A

    2008-02-01

    Drospirenone 3 mg/ethinyl estradiol 20 microg (24/4) is a new unique oral contraceptive formulation that combines in a novel dosing regimen the lowest dosage of ethinyl estradiol commonly used today with drospirenone, an innovative progestin. Drospirenone is a compound closely resembling progesterone, but with the antimineralocorticoid and antiandrogenic properties of a related therapeutic agent, the diuretic, antihypertensive and androgen receptor antagonist, 17alpha-spironolactone. The prolongation of hormonally active pills in the monthly drospirenone/ethinyl estradiol cycle from 21 days to 24 days, followed by 4 days of inactive pills, is an interesting variant of the recently developed extended pill regimens (1). Recent contraceptive research has focused on improving side effect profiles and providing noncontraceptive health and lifestyle advantages. Many of these benefits are now supported with evidence-based medicine (2). Most available oral contraceptives improve cycle regularity, menstrual pain, excessive menstrual flow and acne. However, weight gain, bloating, food cravings, breast tenderness and mood alterations (especially irritability and depression and the complex of affective, behavioral and somatic symptoms of premenstrual syndrome [PMS] and the severe form of PMS, premenstrual dysphoric disorder [PMDD]) are not generally improved with the traditional oral contraceptive formulations (3). Drospirenone/ethinyl estradiol 24/4 is currently the only hormonally based contraceptive regimen with large, randomized, controlled trials demonstrating efficacy for PMDD. It has received U.S. Food and Drug Administration (FDA) indications not only for the prevention of pregnancy but also for PMDD and for moderate acne vulgaris in women who choose oral contraception for birth control (4, 5). Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

  7. Antiapolipoprotein A-1 IgG chronotropic effects require nongenomic action of aldosterone on L-type calcium channels.

    PubMed

    Rossier, Michel F; Pagano, Sabrina; Python, Magaly; Maturana, Andres D; James, Richard W; Mach, François; Roux-Lombard, Pascale; Vuilleumier, Nicolas

    2012-03-01

    Autoantibodies to apolipoprotein A-1 (antiapoA-1 IgG) have been shown to be associated with higher resting heart rate and morbidity in myocardial infarction patients and to behave as a chronotropic agent in the presence of aldosterone on isolated neonatal rat ventricular cardiomyocytes (NRVC). We aimed at identifying the pathways accounting for this aldosterone-dependent antiapoA-1 IgG-positive chronotropic effect on NRVC. The rate of regular spontaneous contractions was determined on NRVC in the presence of different steroid hormones and antagonists. AntiapoA-1 IgG chronotropic response was maximal within 20 min and observed only in aldosterone-pretreated cells but not in those exposed to other steroids. The positive antiapoA-1 IgG chronotropic effect was already significant after 5 min aldosterone preincubation, was dependent on 3-kinase and protein kinase A activities, was not inhibited by actinomycin D, and was fully abrogated by eplerenone (but not by spironolactone), demonstrating the dependence on a nongenomic action of aldosterone elicited through the mineralocorticoid receptor (MR). Under oxidative conditions (but not under normal redox state), corticosterone mimicked the permissive action of aldosterone on the antiapoA-1 IgG chronotropic response. Pharmacological and patch-clamp studies identified L-type calcium channels as crucial effectors of antiapoA-1 IgG chronotropic action, involving two converging pathways that increase the channel activity. The first one involves the rapid, nongenomic activation of the phosphatidylinositol 3-kinase enzyme by MR, and the second one requires a constitutive basal protein kinase A activity. In conclusion, our results indicate that, on NRVC, the aldosterone-dependent chronotropic effects of antiapoA-1 IgG involve the nongenomic activation of L-type calcium channels.

  8. Clinical tolerability of generic versus brand beta blockers in heart failure with reduced left ventricular ejection fraction: a retrospective cohort from heart failure clinic.

    PubMed

    Chanchai, Rattanachai; Kanjanavanit, Rungsrit; Leemasawat, Krit; Amarittakomol, Anong; Topaiboon, Paleerat; Phrommintikul, Arintaya

    2018-01-01

    Background: Beta-blockers have been shown to decrease mortality and morbidity in heart failure with reduced ejection fraction (HFrEF) patients. However, the side effects are also dose-related, leading to the underdosing. Cost constraint may be one of the limitations of appropriate beta-blocker use; this can be improved with generic drugs. However, the effects in real life practice have not been investigated. Methods and results: This study aimed to compare the efficacy and safety of generic and brand beta-blockers in HFrEF patients. We performed a retrospective cohort analysis in HFrEF patients who received either generic or brand beta-blocker in Chiang Mai Heart Failure Clinic. The primary endpoint was the proportion of patients who received at least 50% target dose of beta-blocker between generic and brand beta-blockers. Adverse events were secondary endpoints. 217 patients (119 and 98 patients received generic and brand beta-blocker, respectively) were enrolled. There were no differences between groups regarding age, gender, etiology of heart failure, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), rate of receiving angiotensin converting enzyme inhibitor (ACEI), angiotensin recepter blocker (ARB), or spironolactone. Patients receiving brand beta-blockers had lower resting heart rate at baseline (74.9 and 84.2 bpm, p  = .001). Rate of achieved 50% target dose and target daily dose did not differ between groups (40.4 versus 44.5% and 48.0 versus 55.0%, p  > .05, respectively). Rate of side effects was not different between groups (32.3 versus 29.5%, p  > .05) and the most common side effect was hypotension. Conclusion: This study demonstrated that beta-blocker tolerability was comparable between brand and generic formulations. Generic or brand beta-blockers should be prescribed to HFrEF patients who have no contraindications.

  9. The effectiveness and safety of treatments used for polycystic ovarian syndrome management in adolescents: a systematic review and network meta-analysis protocol.

    PubMed

    Al Khalifah, Reem A; Flórez, Iván D; Dennis, Brittany; Neupane, Binod; Thabane, Lehana; Bassilious, Ereny

    2015-09-23

    Polycystic ovarian syndrome (PCOS) is a common reproductive endocrine disease that is seen among adolescent women. Currently, there is limited evidence to support treatment options leading to considerable variation in practice among healthcare specialists. The objective of this study is to review and synthesize all the available evidence on treatment options for PCOS among adolescent women. We will conduct a systematic review of all randomized controlled trials evaluating the use of metformin, oral contraceptive pills as monotherapy, or as combination with pioglitazone, spironolactone, flutamide, and lifestyle interventions in the treatment of PCOS in adolescent women ages 11 to 19 years. The primary outcome measures are menstrual regulation and change hirsutism scores. The secondary outcome measures include acne scores, prevalence of dysglycaemia, BMI, lipid profile, total testosterone level, and adverse events. We will perform literature searches through Ovid Medline, Ovid Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), and gray literature resources. Two reviewers will independently screen titles and abstracts of identified citations, review the full texts of potentially eligible trials, extract information from eligible trials, and assess the risk of bias and quality of the evidence independently. Results of this review will be summarized narratively and quantitatively as appropriate. We will perform a multiple treatment comparison using network meta-analysis to estimate the pooled direct and indirect effects for all PCOS interventions on outcomes if adequate data is available. PCOS treatment poses a clinical challenge to the patients and physicians. This is the first systematic review and network meta-analysis for PCOS treatment in adolescents. We expect that our results will help improve patient care, unify the treatment approaches among specialists, and encourage research for other therapeutic options. PROSPERO CRD42015016148.

  10. Impaired Endothelial Repair Capacity of Early Endothelial Progenitor Cells in Hypertensive Patients With Primary Hyperaldosteronemia: Role of 5,6,7,8-Tetrahydrobiopterin Oxidation and Endothelial Nitric Oxide Synthase Uncoupling.

    PubMed

    Chen, Long; Ding, Mei-Lin; Wu, Fang; He, Wen; Li, Jin; Zhang, Xiao-Yu; Xie, Wen-Li; Duan, Sheng-Zhong; Xia, Wen-Hao; Tao, Jun

    2016-02-01

    Although hyperaldosteronemia exerts detrimental impacts on vascular endothelium in addition to elevating blood pressure, the effects and molecular mechanisms of hyperaldosteronemia on early endothelial progenitor cell (EPC)-mediated endothelial repair after arterial damage are yet to be determined. The aim of this study was to investigate the endothelial repair capacity of early EPCs from hypertensive patients with primary hyperaldosteronemia (PHA). In vivo endothelial repair capacity of early EPCs from PHAs (n=20), age- and blood pressure-matched essential hypertension patients (n=20), and age-matched healthy subjects (n=20) was evaluated by transplantation into a nude mouse carotid endothelial denudation model. Endothelial function was evaluated by flow-mediated dilation of brachial artery in human subjects. In vivo endothelial repair capacity of early EPCs and flow-mediated dilation were impaired both in PHAs and in essential hypertension patients when compared with age-matched healthy subjects; however, the early EPC in vivo endothelial repair capacity and flow-mediated dilation of PHAs were impaired more severely than essential hypertension patients. Oral spironolactone improved early EPC in vivo endothelial repair capacity and flow-mediated dilation of PHAs. Increased oxidative stress, oxidative 5,6,7,8-tetrahydrobiopterin degradation, endothelial nitric oxide synthase uncoupling and decreased nitric oxide production were found in early EPCs from PHAs. Nicotinamide adenine dinucleotide phosphate oxidase subunit p47(phox) knockdown or 5,6,7,8-tetrahydrobiopterin supplementation attenuated endothelial nitric oxide synthase uncoupling and enhanced in vivo endothelial repair capacity of early EPCs from PHAs. In conclusion, PHAs exhibited more impaired endothelial repair capacity of early EPCs than did essential hypertension patients independent of blood pressure, which was associated with mineralocorticoid receptor-dependent oxidative stress and subsequently 5

  11. Diuretics for Hypertension: A Review and Update.

    PubMed

    Roush, George C; Sica, Domenic A

    2016-10-01

    This review and update focuses on the clinical features of hydrochlorothiazide (HCTZ), the thiazide-like agents chlorthalidone (CTDN) and indapamide (INDAP), potassium-sparing ENaC inhibitors and aldosterone receptor antagonists, and loop diuretics. Diuretics are the second most commonly prescribed class of antihypertensive medication, and thiazide-related diuretics have increased at a rate greater than that of antihypertensive medications as a whole. The latest hypertension guidelines have underscored the importance of diuretics for all patients, but particularly for those with salt-sensitive and resistant hypertension. HCTZ is 4.2-6.2 systolic mm Hg less potent than CTDN, angiotensin-converting enzyme inhibitors, beta blockers, and calcium channel blockers by 24-hour measurements and 5.1mm Hg systolic less potent than INDAP by office measurements. For reducing cardiovascular events (CVEs), HCTZ is less effective than enalapril and amlodipine in randomized trials, and, in network analysis of trials, it is less effective than CTDN and HCTZ-amiloride. Combined with thiazide-type diuretics, potassium-sparing agents decrease ventricular ectopy and reduce the risk for sudden cardiac death relative to thiazide-type diuretics used alone. A recent synthesis of 44 trials has shown that the relative potencies in milligrams among spironolactone (SPIR), amiloride, and eplerenone (EPLER) are approximately from 25 to 10 to 100, respectively, which may be important when SPIR is poorly tolerated. SPIR reduces proteinuria beyond that provided by other renin angiotensin aldosterone inhibitors. EPLER also reduces proteinuria and has beneficial effects on endothelial function. While guidelines often do not differentiate among specific diuretics, this review demonstrates that these distinctions are important for managing hypertension. © American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Route of steroid-activated macromolecules through nuclear pores imaged with atomic force microscopy.

    PubMed

    Oberleithner, H; Schäfer, C; Shahin, V; Albermann, L

    2003-02-01

    In eukaryotic cells, two concentric membranes, the nuclear envelope (NE), separate the nucleus from the cytoplasm. The NE is punctured by nuclear pore complexes (NPCs; molecular mass 120 MDa) that serve as regulated pathways for macromolecules entering and leaving the nuclear compartment. Transport across NPCs occurs through central channels. Such import and export of macromolecules through individual NPCs can be elicited in the Xenopus laevis oocyte by injecting the mineralocorticoid aldosterone and can be visualized with atomic force microscopy. The electrical NE resistance in intact cell nuclei can be measured in parallel. Resistance increases when macromolecules are engaged with the NPC. This article describe six observations made from these experiments and the conclusions that can be drawn from them. (i) A homogeneous population of macromolecules (approx. 100 kDa) attaches to the cytoplasmic face of the NPC 2 min after aldosterone injection. They are most likely to be aldosterone receptors. After a few minutes, they have disappeared. (ii) Large plugs (approx. molecular mass 1 MDa) appear in the central channels 20 min after hormone injection. They are most likely to be ribonucleoproteins exiting the nucleus. (iii) Electrical resistance measurements in isolated nuclei reveal transient electrical NE resistance peaks: an early (2 min) peak and a late (20 min) peak. Electrical peaks reflect macromolecule interaction with the NPC. (iv) Spironolactone blocks both the early and late peaks. This indicates that classic aldosterone receptors are involved in the pregenomic (early) and post-genomic (late) responses. (v) Actinomycin D and, independently, RNase A block the late electrical peak, confirming that plugs are genomic in nature. (vi) Intracellular calcium chelation blocks both early and late electrical peaks. Thus, the release of calcium from internal stores, which is known to be the first intracellular signal in response to aldosterone, is a prerequisite for the

  13. Renal Drug Dosing

    PubMed Central

    Vogel, Erin A.; Billups, Sarah J.; Herner, Sheryl J.

    2016-01-01

    Summary Objective The purpose of this study was to compare the effectiveness of an outpatient renal dose adjustment alert via a computerized provider order entry (CPOE) clinical decision support system (CDSS) versus a CDSS with alerts made to dispensing pharmacists. Methods This was a retrospective analysis of patients with renal impairment and 30 medications that are contraindicated or require dose-adjustment in such patients. The primary outcome was the rate of renal dosing errors for study medications that were dispensed between August and December 2013, when a pharmacist-based CDSS was in place, versus August through December 2014, when a prescriber-based CDSS was in place. A dosing error was defined as a prescription for one of the study medications dispensed to a patient where the medication was contraindicated or improperly dosed based on the patient’s renal function. The denominator was all prescriptions for the study medications dispensed during each respective study period. Results During the pharmacist- and prescriber-based CDSS study periods, 49,054 and 50,678 prescriptions, respectively, were dispensed for one of the included medications. Of these, 878 (1.8%) and 758 (1.5%) prescriptions were dispensed to patients with renal impairment in the respective study periods. Patients in each group were similar with respect to age, sex, and renal function stage. Overall, the five-month error rate was 0.38%. Error rates were similar between the two groups: 0.36% and 0.40% in the pharmacist- and prescriber-based CDSS, respectively (p=0.523). The medication with the highest error rate was dofetilide (0.51% overall) while the medications with the lowest error rate were dabigatran, fondaparinux, and spironolactone (0.00% overall). Conclusions Prescriber- and pharmacist-based CDSS provided comparable, low rates of potential medication errors. Future studies should be undertaken to examine patient benefits of the prescriber-based CDSS. PMID:27466041

  14. Hypokalemic paralysis in a middle-aged female with classic Bartter syndrome.

    PubMed

    Chiang, Wen-Fang; Lin, Shih-Hung; Chan, Jenq-Shyong; Lin, Shih-Hua

    2014-02-01

    Inherited classic Bartter syndrome (cBS) is an autosomal recessive renal tubular disorder resulting from inactivating mutations in the asolateral chloride channel (C1C-Kb) and usually presents in early infancy or childhood with mild to moderate hypokalemia. Profound hypokalemic paralysis in patients with cBS is extremely rare, especially in middle age. A 45-year-old Chinese female patient was referred for evaluation of chronic severe hypokalemia despite regular K+ supplementation (1 mmol/kg/d). She had had two episodes of muscle paralysis due to severe hypokalemia (K+ 1.9 - 2.1 mmol/l) in the past 3 years. She denied vomiting, diarrhea, or the use of laxatives or diuretics. Her blood pressure was normal. Biochemical studies showed hypokalemia (K+ 2.5 mmol/l) with renal potassium wasting, metabolic alkalosis (HCO3- 32 mmol/l), normomagnesemia (Mg2+ 0.8 mmol/l), hypercalciuria (calcium to creatinine ratio 0.5 mmol/mmol; normal < 0.22 mmol/mol), high plasma renin activity, but normal plasma aldosterone concentration. Abdominal sonography revealed neither renal stones nor nephrocalcinosis. Acquired causes of cBS such as autoimmune disease and drugs were all excluded. Molecular analysis of the CLCNKB gene, encoding ClC-Kb, and SLC12A3, encoding the thiazide-sensitive sodium chloride cotransporter (NCC), revealed compound heterozygous mutations in CLCNKB (L335P and G470E) inherited from her parents; her SLC12A3 was normal. These two mutations were not identified in 100 healthy subjects. Her plasma K+ concentration rose to 3 - 3.5 mmol/l after the addition of spironolactone. Inherited cBS may present with hypokalemic paralysis and should be considered in adult patients with hypokalemia and metabolic alkalosis.

  15. Hypophyseal corticosteroids stimulate somatotrope differentiation in the embryonic chicken pituitary gland.

    PubMed

    Zheng, Jun; Takagi, Hiroyasu; Tsutsui, Chihiro; Adachi, Akihito; Sakai, Takafumi

    2008-03-01

    Although it is known that glucocorticoids induce differentiation of growth hormone (GH)-producing cells in rodents and birds, the effect of mineralocorticoids on GH mRNA expression and the origin of corticosteroids affecting somatotrope differentiation have not been elucidated. In this study, we therefore carried out experiments to determine the effect of mineralocorticoids on GH mRNA expression in the chicken anterior pituitary gland in vitro and to determine whether corticosteroids are synthesized in the chicken embryonic pituitary gland. In a pituitary culture experiment with E11 embryos, both corticosterone and aldosterone stimulated GH mRNA expression and increased the number of GH cells in both lobes of the pituitary gland in a dose-dependent manner. These effects of the corticosteroids were significantly reversed by pretreatment with mifepristone, a glucocorticoid receptor (GR) antagonist, or spironolactone, a mineralocorticoid receptor (MR) antagonist. Interestingly, an in vitro serum-free culture experiment with an E11 pituitary gland showed that the GH mRNA level spontaneously increased during cultivation for 2 days without any extra stimulation, and this increase in GH mRNA level was completely suppressed by metyrapone, a corticosterone-producing enzyme P450C11 inhibitor. Moreover, progesterone, the corticosterone precursor, also stimulated GH mRNA expression in the cultured chicken pituitary gland, and this effect was blocked by pretreatment with metyrapone. We also detected mRNA expression of enzymes of cytochrome P450 cholesterol side chain cleavage (P450scc) and 3beta-hydroxysteroid dehydrogenase1 (3beta-HSD1) in the developmental chicken pituitary gland from E14 and E18, respectively. These results suggest that mineralocorticoids as well as glucocorticoids can stimulate GH mRNA expression and that corticosteroids generated in the embryonic pituitary gland by intrinsic steroidogenic enzymes stimulate somatotrope differentiation.

  16. [Influence of non-sodium restricted diet with diuretics on plasma rennin, renal blood flow and in patients with cirrhotic ascites].

    PubMed

    Zhu, Yin-fang; Gu, Xi-bing; Zhu, Hong-ying; Yang, Xiao-juan; Wang, Dong; Yu, Ping

    2013-02-01

    To explore influence of sodium restricted diet and non-sodium restricted diet on plasma rennin (PRA), angiotensin II (All), ALD, renal blood flow (RBF) and subside of ascites in patients with cirrhotic ascites. Eighty cases of hepatitis B with cirrhotic ascites were randomly divided into sodium restricted diet group and non-sodium restricted diet group. 39 cases were in non-sodium restricted diet group, taking sodium chloride 6500-8000 mg daily; 41 cases were in sodium restricted diet group, taking sodium chloride 5000 mg daily. Both groups received diuretics furosemide and spironolactone. Blood sodium, urine sodium, PRA, AII, ALD, RBF ascites subsiding were compared after treatment. In non-sodium restricted diet group, blood sodium and urine sodium increased 10 days after treatment compared with those before treatment, and compared with those of sodium restricted diet group 10 days after treatment, P <0. 01. RBF increased compared with that before treatment, and compared with that of sodium restricted diet group 10 days after treatment, P < 0. 01. Renal damage induced by low blood sodium after treatment was less in non-sodium restricted diet group than that in sodium restricted diet group, P <0. 05. Ascites disappearance upon discharge was more in sodium restricted diet group than that in non-sodium restricted diet group, P <0. 01. Time of ascites disappearance was shorter in non-sodium restricted diet group than that in sodium restricted diet group, P < 0. 01. Compared with sodium restricted diet, while using diuretics of both groups, non-sodium restricted diet can increase level of blood sodium, thus increasing excretion of urine sodium and diuretic effect. It can also decrease levels of PRA, AII and ALD, increase renal blood flow and prevent renal damage induced by low blood sodium and facilitate subsiding of ascites.

  17. Psychosis associated with usage of herbal slimming products adulterated with sibutramine: a case series.

    PubMed

    Chen, Sammy P L; Tang, Magdalene H Y; Ng, Sau Wah; Poon, Wing Tat; Chan, Albert Y W; Mak, Tony W L

    2010-10-01

    Sibutramine, or its structurally related analogs, is often found as an adulterant in proprietary herbal slimming products in Hong Kong. A few solitary case reports of sibutramine-associated psychosis have been published since 2000. As the only tertiary referral center for clinical toxicology analysis in Hong Kong, we noticed that psychosis was an unusually common feature in patients taking "herbal slimming products" adulterated with sibutramine or its structurally related analogs over the past 5 years. To examine the association between psychosis and the use of sibutramine-adulterated herbal products, in an attempt to elucidate this possible adverse drug reaction. This retrospective study reviewed all cases hospitalized with psychotic symptoms confirmed to have used herbal slimming products adulterated with sibutramine, or its analogs, between January 2004 and October 2009. The cases' clinical features, outcome, drug history, and analytical findings of the offending slimming products were studied. Results. Among the 16 confirmed cases, 15 (94%) were female; the median age was 19 years (range: 15-47). Auditory hallucination was documented in 10 (63%), visual hallucination in 6 (38%), persecutory ideas in 6 (38%), delusions in 4 (25%), and suicidal ideation in 2 (13%). For 20 "herbal" slimming products analyzed, 16 were found to have been adulterated with sibutramine, 2 with N-desmethyl-sibutramine, and 1 with N-bisdesmethyl-sibutramine. Other concomitant adulterants were also found and included phenolphthalein in 9, fenfluramine, mazindol, animal thyroid tissue in 2, hydrochlorothiazide and spironolactone in 1. Eight patients disclosed the source of the products: four through the Internet, one obtained over-the-counter locally, with three acquired outside Hong Kong. Slimming products claimed "herbal" in origin could often be adulterated with sibutramine and other Western medications. We observed an association between the use of these products and psychotic features

  18. Management strategies for premenstrual syndrome/premenstrual dysphoric disorder.

    PubMed

    Jarvis, Courtney I; Lynch, Ann M; Morin, Anna K

    2008-07-01

    To evaluate the current nonpharmacologic and pharmacologic treatment options for symptoms of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Literature was obtained through searches of MEDLINE Ovid (1950-March week 3, 2008) and EMBASE Drugs and Pharmacology (all years), as well as a bibliographic review of articles identified by the searches. Key terms included premenstrual syndrome, premenstrual dysphoric disorder, PMS, PMDD, and treatment. All pertinent clinical trials, retrospective studies, and case reports in human subjects published in the English language were identified and evaluated for the safety and efficacy of pharmacologic and nonpharmacologic treatments of PMS/PMDD. Data from these studies and information from review articles were included in this review. Selective serotonin-reuptake inhibitors (SSRIs) have been proven safe and effective for the treatment of PMDD and are recommended as first-line agents when pharmacotherapy is warranted. Currently fluoxetine, controlled-release paroxetine, and sertraline are the only Food and Drug Administration-approved agents for this indication. Suppression of ovulation using hormonal therapies is an alternative approach to treating PMDD when SSRIs or second-line psychotropic agents are ineffective; however, adverse effects limit their use. Anxiolytics, spironolactone, and nonsteroidal antiinflammatory drugs can be used as supportive care to relieve symptoms. Despite lack of specific evidence, lifestyle modifications and exercise are first-line recommendations for all women with PMS/PMDD and may be all that is needed to treat mild-to-moderate symptoms. Herbal and vitamin supplementation and complementary and alternative medicine have been evaluated for use in PMS/PMDD and have produced unclear or conflicting results. More controlled clinical trials are needed to determine their safety and efficacy and potential for drug interactions. Healthcare providers need to be aware of the symptoms of

  19. Advances in Clinical Cardiology 2016: A Summary of the Key Clinical Trials.

    PubMed

    Gray, Alastair; McQuillan, Conor; Menown, Ian B A

    2017-07-01

    The findings of many new cardiology clinical trials over the last year have been published or presented at major international meetings. This paper aims to describe and place in context a summary of the key clinical trials in cardiology presented between January and December 2016. The authors reviewed clinical trials presented at major cardiology conferences during 2016 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD), Transcatheter Cardiovascular Therapeutics (TCT), and the American Heart Association (AHA). Selection criteria were trials with a broad relevance to the cardiology community and those with potential to change current practice. A total of 57 key cardiology clinical trials were identified for inclusion. Here we describe and place in clinical context the key findings of new data relating to interventional and structural cardiology including delayed stenting following primary angioplasty, contrast-induced nephropathy, management of jailed wires, optimal duration of dual antiplatelet therapy (DAPT), stenting vs bypass for left main disease, new generation stents (BioFreedom, Orsiro, Absorb), transcatheter aortic valve implantation (Edwards Sapien XT, transcatheter embolic protection), and closure devices (Watchman, Amplatzer). New preventative cardiology data include trials of bariatric surgery, empagliflozin, liraglutide, semaglutide, PCSK9 inhibitors (evolocumab and alirocumab), and inclisiran. Antiplatelet therapy trials include platelet function monitoring and ticagrelor vs clopidogrel for peripheral vascular disease. New data are also presented in fields of heart failure (sacubitril/valsartan, aliskiren, spironolactone), atrial fibrillation (rivaroxaban in patients undergoing coronary intervention, edoxaban in DC cardioversion), cardiac devices (implantable cardioverter

  20. Caveolin 1-related autophagy initiated by aldosterone-induced oxidation promotes liver sinusoidal endothelial cells defenestration.

    PubMed

    Luo, Xiaoying; Dan Wang; Luo, Xuan; Zhu, Xintao; Wang, Guozhen; Ning, Zuowei; Li, Yang; Ma, Xiaoxin; Yang, Renqiang; Jin, Siyi; Huang, Yun; Meng, Ying; Li, Xu

    2017-10-01

    Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models. In vitro, fenestrae of primary LSECs gradually shrank, along with the down-regulation of the NO-dependent pathway and the augment of the AMPK-dependent autophagy; these effects were aggravated by rapamycin (an autophagy activator) or aldosterone treatment. Additionally, aldosterone increased oxidation mediated by Cav1, reduced ATP generation, and subsequently induced the AMPK-dependent autophagy, leading to the down-regulation of the NO-dependent pathway and LSECs defenestration. These effects were reversed by MR antagonist spironolactone, antioxidants or autophagy inhibitors. Besides, aldosterone enhanced the co-immunoprecipitation of Cav1 with p62 and ubiquitin, and induced Cav1 co-immunofluorescence staining with LC3, ubiquitin, and F-actin in the perinuclear area of LSECs. Furthermore, aldosterone treatment increased the membrane protein level of Cav1, whereas decrease the cytoplasmic protein level of Cav1, indicating that aldosterone induced Cav1-related selective autophagy and F-actin remodeling to promote defenestration. Consequently, Cav1-related selective autophagy initiated by aldosterone-induced oxidation promotes LSECs defenestration via activating the AMPK-ULK1 pathway and inhibiting the NO-dependent pathway. Copyright © 2017 The Authors

  1. Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice.

    PubMed

    Tanino, Akiko; Okura, Takafumi; Nagao, Tomoaki; Kukida, Masayoshi; Pei, Zuowei; Enomoto, Daijiro; Miyoshi, Ken-Ichi; Okamura, Haruki; Higaki, Jitsuo

    2016-10-01

    Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18(-/-) and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  2. Acute kidney injury in schistosomiasis: a retrospective cohort of 60 patients in Brazil.

    PubMed

    Duarte, Daniella Bezerra; Vanderlei, Lucas Alexandre; de Azevêdo Bispo, Raianne Kívia; Pinheiro, Maria Eliete; da Silva Junior, Geraldo Bezerra; De Francesco Daher, Elizabeth

    2015-04-01

    The aim of this study is to investigate renal involvement in schistosomiasis. This is a retrospective cohort of 60 consecutive patients with schistosomiasis admitted to a university hospital in Maceió, Brazil. The patients were divided into 2 groups: patients with and without acute kidney injury (AKI) according to the RIFLE criteria. We compared the groups for differences in clinical manifestations and laboratory tests. Patients' mean age was 58 ± 16 yr, and 56.7% were female. The average length of hospital stay was 16.4 ± 12.1 days. Patients with hypertension and diabetes were 35% and 21.7% respectively. The main clinical symptoms and signs presented were ascites (86.7%), splenomegaly (80%), and hepatomegaly (63.3%). Current or previous history of upper gastrointestinal bleeding was found in 45% of patients, esophageal varices on endoscopy were present in 92%, and periportal fibrosis on ultrasound examination in 81% of patients. AKI incidence was 43.3% during hospital stay. Mean age and length of hospitalization were higher in the AKI group. Diuretic use, such as furosemide and spironolactone, ascites, and AST levels were also associated with AKI. Death occurred in 5 cases (8.5%), 4 of them in the AKI group. The classifications Child-Pugh score (CHILD) and Model for End-Stage Liver Disease (MELD), used to assess the severity and prognosis of chronic liver disease, presented higher scores among patients with AKI (CHILD: 9.5 ± 1.5 vs. 8.4 ± 1.7, P = 0.02; MELD: 19 ± 5.8 vs. 13 ± 3.9, P < 0.001). Renal dysfunction is an important feature of schistosomiasis, which is associated with significant morbidity and possible increased mortality. Further studies are necessary to establish the mechanisms through which schistosomiasis can lead to renal dysfunction.

  3. Pharmacotherapy Evaluation and Utilization in Coronary Artery Bypass Grafting Patients in Kosovo during the Period 2016-2017

    PubMed Central

    Daci, Armond; Bozalija, Adnan; Cavolli, Raif; Alaj, Rame; Beretta, Giangiacomo; Krasniqi, Shaip

    2018-01-01

    BACKGROUND: Coronary Artery Bypass Grafting (CABG) is realised in patients with critical or advanced disease of coronary arteries. There are different pharmacotherapeutic approaches which are used as management, treatment and preventive therapy in cardiovascular disease or related comorbidities. Performing a successful surgery, pharmacotherapy, and increase of bypass patency rate remains a serious challenge. AIM: This study aims to analyse the patient characteristics undergoing CABG and evaluation of their drug utilisation rate and daily dosages in the perioperative period. MATERIAL AND METHODS: Data were collected from 102 patients in the period 2016-2017 and detailed therapeutic prescription and dosages, patient characteristics were analysed before the operation, after the operation and visit after operation in the Clinic of Cardiac surgery-University Clinical Center of Kosovo. RESULTS: Our findings had shown that patients provided to have normal biochemical parameters in the clinic before the operation, and were related to cardiovascular diseases and comorbidities and risk factors with mainly elective intervention. The, however, higher utilisation of cardiovascular drugs such as beta blockers, diuretics, anticoagulants, statins and lower calcium blockers, ACEi, ARBs, hydrochlorothiazide, amiodarone were founded. ARBs, beta blockers, statins, nitrates and nadroparin utilisation decreased after operation and visit after the operation, whereas amiodarone only in the visit after the operation. Diuretics are increased after the operation which decreases in the visit after the operation. Regarding the daily dosage, only metoprolol was increased in the visit after operation (P < 0.001) and visit after operation (P < 0.05) whereas losartan and furosemide were increased (P < 0.01) and (P < 0.05) respectively. CONCLUSION: The study showed that beta blockers, statins, aspirin, nitrates (before the operation), furosemide and spironolactone are the most utilised drugs

  4. Clinical tolerability of generic versus brand beta blockers in heart failure with reduced left ventricular ejection fraction: a retrospective cohort from heart failure clinic

    PubMed Central

    Chanchai, Rattanachai; Kanjanavanit, Rungsrit; Leemasawat, Krit; Amarittakomol, Anong; Topaiboon, Paleerat; Phrommintikul, Arintaya

    2018-01-01

    Abstract Background: Beta-blockers have been shown to decrease mortality and morbidity in heart failure with reduced ejection fraction (HFrEF) patients. However, the side effects are also dose-related, leading to the underdosing. Cost constraint may be one of the limitations of appropriate beta-blocker use; this can be improved with generic drugs. However, the effects in real life practice have not been investigated. Methods and results: This study aimed to compare the efficacy and safety of generic and brand beta-blockers in HFrEF patients. We performed a retrospective cohort analysis in HFrEF patients who received either generic or brand beta-blocker in Chiang Mai Heart Failure Clinic. The primary endpoint was the proportion of patients who received at least 50% target dose of beta-blocker between generic and brand beta-blockers. Adverse events were secondary endpoints. 217 patients (119 and 98 patients received generic and brand beta-blocker, respectively) were enrolled. There were no differences between groups regarding age, gender, etiology of heart failure, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), rate of receiving angiotensin converting enzyme inhibitor (ACEI), angiotensin recepter blocker (ARB), or spironolactone. Patients receiving brand beta-blockers had lower resting heart rate at baseline (74.9 and 84.2 bpm, p = .001). Rate of achieved 50% target dose and target daily dose did not differ between groups (40.4 versus 44.5% and 48.0 versus 55.0%, p > .05, respectively). Rate of side effects was not different between groups (32.3 versus 29.5%, p > .05) and the most common side effect was hypotension. Conclusion: This study demonstrated that beta-blocker tolerability was comparable between brand and generic formulations. Generic or brand beta-blockers should be prescribed to HFrEF patients who have no contraindications. PMID:29379674

  5. Angiotensin II receptor one (AT1) mediates dextrose induced endoplasmic reticulum stress and superoxide production in human coronary artery endothelial cells.

    PubMed

    Haas, Michael J; Onstead-Haas, Luisa; Lee, Tracey; Torfah, Maisoon; Mooradian, Arshag D

    2016-10-01

    Renin-angiotensin-aldosterone system (RAAS) has been implicated in diabetes-related vascular complications partly through oxidative stress. To determine the role of angiotensin II receptor subtype one (AT1) in dextrose induced endoplasmic reticulum (ER) stress, another cellular stress implicated in vascular disease. Human coronary artery endothelial cells with or without AT1 receptor knock down were treated with 27.5mM dextrose for 24h in the presence of various pharmacologic blockers of RAAS and ER stress and superoxide (SO) production were measured. Transfection of cells with AT1 antisense RNA knocked down cellular AT1 by approximately 80%. The ER stress was measured using the placental alkaline phosphatase (ES-TRAP) assay and western blot analysis of glucose regulated protein 78 (GRP78), c-jun-N-terminal kinase 1 (JNK1), phospho-JNK1, eukaryotic translation initiation factor 2α (eIF2α) and phospho-eIF2α measurements. Superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride (MCLA) chemiluminescence. In cells with AT1 knock down, dextrose induced ER stress was significantly blunted and treatment with 27.5mM dextrose resulted in significantly smaller increase in SO production compared to 27.5mM dextrose treated and sham transfected cells. Dextrose induced ER stress was reduced with pharmacologic blockers of AT1 (losartan and candesartan) and mineralocorticoid receptor blocker (spironolactone) but not with angiotensin converting enzyme inhibitors (captopril and lisinopril). The dextrose induced SO generation was inhibited by all pharmacologic blockers of RAAS tested. The results indicate that dextrose induced ER stress and SO production in endothelial cells are mediated at least partly through AT1 receptor activation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Selection of patients for heart transplantation in the current era of heart failure therapy.

    PubMed

    Butler, Javed; Khadim, Ghazanfar; Paul, Kimberly M; Davis, Stacy F; Kronenberg, Marvin W; Chomsky, Don B; Pierson, Richard N; Wilson, John R

    2004-03-03

    We sought to assess the relationship between survival, peak exercise oxygen consumption (VO(2)), and heart failure survival score (HFSS) in the current era of heart failure (HF) therapy. Based on predicted survival, HF patients with peak VO(2) <14 ml/min/kg or medium- to high-risk HFSS are currently considered eligible for heart transplantation. However, these criteria were developed before the widespread use of beta-blockers, spironolactone, and defibrillators-interventions known to improve the survival of HF patients. Peak VO(2) and HFSS were assessed in 320 patients followed from 1994 to 1997 (past era) and in 187 patients followed from 1999 to 2001 (current era). Outcomes were compared between these two groups of patients and those who underwent heart transplantation from 1993 to 2000. Survival in the past era was 78% at one year and 67% at two years, as compared with 88% and 79%, respectively, in the current era (both p < 0.01). One-year event-free survival (without urgent transplantation or left ventricular assist device) was improved in the current era, regardless of initial peak VO(2): 64% vs. 48% for peak VO(2) <10 ml/min/kg (p = 0.09), 81% vs. 70% for 10 to 14 ml/min/kg (p = 0.05), and 93% vs. 82% for >14 ml/min/kg (p = 0.04). Of the patients with peak VO(2) of 10 to 14 ml/min/kg, 55% had low-risk HFSS and exhibited 88% one-year event-free survival. One-year survival after transplantation was 88%, which is similar to the 85% rate reported by the United Network for Organ Sharing for 1999 to 2000. Survival for HF patients in the current era has improved significantly, necessitating re-evaluation of the listing criteria for heart transplantation.

  7. [Profile of heart failure according to the department of admission. Implications for multidisciplinary management].

    PubMed

    Vicent, Lourdes; Ayesta, Ana; Vidán, María Teresa; Miguel-Yanes, José María de; García, Jorge; Tamargo, María; Gómez, Víctor; Véliz, Samuel; Fernández-Avilés, Francisco; Martínez-Sellés, Manuel

    Population aging has led to notable changes in heart failure admissions. The aim of this study was to analyse the characteristics, comorbidity, management, and outcomes of this patient population in three hospital departments. An analysis was made of a prospective register that included all patients admitted due to heart failure in Internal Medicine, Cardiology, and Geriatrics over a period of 45 days. Of a total of 235 patients, 124 (52.7%) were admitted to Internal Medicine, 83 (35.3%) to Cardiology, and 28 (11.9%) to Geriatrics. Mean age was 77.0±20.2 years (Cardiology 71.5±13.5; Internal Medicine 79.2±21.1; Geriatrics 89.9±5.1; p<.001). Preserved ejection fraction was found in 121 (51.5%) patients, and this rate was higher in Internal Medicine (62.5%) and Geriatrics (70.0%) than in Cardiology (31.3%), p<.001. Comorbidity was frequent, especially atrial fibrillation (126; 53.6%), renal disease (89; 37.8%), and chronic obstructive pulmonary disease (65; 27.6%). Infections were the most common decompensating trigger in Internal Medicine (56; 45.2%), and there was often no trigger in Cardiology (45; 54.2%) and Geriatrics (14; 50.0%), p<.0001. The use of renin-angiotensin system inhibitors, beta-blockers, and spironolactone in patients with systolic dysfunction was higher in Cardiology. During the 45 days follow-up, 23 patients (9.9%) were readmitted, which was more frequent in Internal Medicine than in Cardiology (odds ratio 3.0 [95% confidence interval: 1.1 - 8.6], p=.03), with no other significant comparisons. Patients admitted due to decompensated heart failure are elderly and often have comorbidities. There are major differences between departments as regards age and clinical profile. Copyright © 2016 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension.

    PubMed

    Ueda, Kohei; Nishimoto, Mitsuhiro; Hirohama, Daigoro; Ayuzawa, Nobuhiro; Kawarazaki, Wakako; Watanabe, Atsushi; Shimosawa, Tatsuo; Loffing, Johannes; Zhang, Ming-Zhi; Marumo, Takeshi; Fujita, Toshiro

    2017-07-01

    Genome-wide analysis of renal sodium-transporting system has identified specific variations of Mendelian hypertensive disorders, including HSD11B2 gene variants in apparent mineralocorticoid excess. However, these genetic variations in extrarenal tissue can be involved in developing hypertension, as demonstrated in former studies using global and brain-specific Hsd11b2 knockout rodents. To re-examine the importance of renal dysfunction on developing hypertension, we generated kidney-specific Hsd11b2 knockout mice. The knockout mice exhibited systemic hypertension, which was abolished by reducing salt intake, suggesting its salt-dependency. In addition, we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-α and T53-phosphorylated Na + -Cl - cotransporter in the knockout mice. Acute intraperitoneal administration of amiloride-induced natriuresis and increased urinary sodium/potassium ratio more in the knockout mice compared with those in the wild-type control mice. Chronic administration of amiloride and high-KCl diet significantly decreased mean blood pressure in the knockout mice, which was accompanied with the correction of hypokalemia and the resultant decrease in Na + -Cl - cotransporter phosphorylation. Accordingly, a Na + -Cl - cotransporter blocker hydrochlorothiazide significantly decreased mean blood pressure in the knockout mice. Chronic administration of mineralocorticoid receptor antagonist spironolactone significantly decreased mean blood pressure of the knockout mice along with downregulation of cleaved epithelial sodium channel-α and phosphorylated Na + -Cl - cotransporter expression in the knockout kidney. Our data suggest that kidney-specific deficiency of 11β-HSD2 leads to salt-dependent hypertension, which is attributed to mineralocorticoid receptor-epithelial sodium channel-Na + -Cl - cotransporter activation in the kidney, and provides evidence that renal dysfunction is essential for developing the

  9. Modulatory in vitro effect of stress hormones on the cytokine response of rainbow trout and gilthead sea bream head kidney stimulated with Vibrio anguillarum bacterin.

    PubMed

    Khansari, Ali Reza; Parra, David; Reyes-López, Felipe E; Tort, Lluís

    2017-11-01

    In fish, the stress response and their consequences in the immune system have been widely described. Recently, a differential cytokine regulation between rainbow trout (Oncorhynchus mykiss) and gilthead sea bream (Sparus aurata) was reported after treatment with stress hormones together with their receptor antagonists. Nevertheless, there is no evidence of whether antagonists for stress hormone receptors may influence the interaction between hormones and cytokines after bacterial administration. Thus, the aim of our study was to evaluate the cytokine expression in the presence of stress hormones (cortisol, ACTH, adrenaline), hormone receptor antagonists and inactivated Vibrio anguillarum bacterin in rainbow trout and gilthead sea bream head kidney primary cell culture (HKPCC). Mifepristone, spironolactone, propranolol and phentolamine were used to block GR, MR, MC2R, and β-/α-adrenoreceptors. Our results showed an expected increase of the pro-inflammatory and anti-inflammatory response after inactivated V. anguillarum bacterin treatment in both species. Cortisol, ACTH and adrenaline did not modulate the expression of immune-related genes in rainbow trout, while in sea bream cortisol was able to reduce the stimulated gene expression of all cytokines. This effect was only restored to basal expression level in IL-1β and TNF-α by mifepristone. ACTH reduced both pro-inflammatory and anti-inflammatory cytokine expression, excluding IL-1β, only in sea bream. Adrenaline enhanced the expression of IL-1β and TGF-β1 stimulated by inactivated V. anguillarum in sea bream, and the effect was diminished by propranolol. In sum, our results confirm that the immunoendocrine differences reported at gene expression profile between two teleost species are also observed after exposure to inactivated V. anguillarum bacterin, suggesting that stress hormones would differentially modulate the immune response against pathogens in teleost species. Copyright © 2017 Elsevier Ltd. All

  10. Favorable surgical outcomes of aldosterone-producing adenoma based on lateralization by CT imaging and hypokalemia: a non-AVS-based strategy.

    PubMed

    Li, Hai; Liu, Jianbin; Feng, Xiujuan; Liu, Liehua; Wei, Guohong; Cao, Xiaopei; Li, Yanbing

    2017-12-01

    To test the efficacy of a strategy based on CT imaging and clinical characteristics on lateralizing origin of excess aldosterone secretion in primary aldosteronism. Consecutive patients with diagnosed primary hyperaldosteronism from June 2006 to July 2012 in our center underwent adrenal surgeries without pre-operational adrenal venous sampling (AVS) if all the three criteria were met: (1) round- or oval-shaped occupational lesion of low density after contrast enhancement with diameter >1 cm on CT scan was located in one adrenal gland; (2) unequivocally normal contralateral adrenal gland; (3) serum potassium level lower than 3.5 mmol/L. Subjects who had received operation were taken into analysis and follow-ups. One hundred and twenty-five patients fulfilled the criteria and were recruited into our research. One hundred and twenty-two operated patients (97.6%) experienced complete resolution of hypokalemia as well as resolution or improvement in hypertension with reduction in antihypertensive medication, while 3 patients (2.4%) failed to obtain normal kalemia and continued on spironolactone therapy. At a median of 65-month (range 21-93) follow-up of these 122 subjects, 27 patients dropped out (22.1%). The 95 responding patients reported no episodes of paralysis or confirmed hypokalemia or any supplementation of potassium. Multivariate linear correlation analysis showed that plasma potassium level was correlated inversely with tumor diameter (r = -0.258, 95% CI -0.076, -0.514, p = 0.037) and basal plasma aldosterone level (r = -0.251, 95% CI -0.040, -0.464, p = 0.042). Most patients with typical unilateral adrenal macroadenomas, normal contralateral glands and hypokalemia could attain favorable surgical therapeutic outcomes without pre-operational AVS lateralization.

  11. Enhancing the Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs Using Monoolein Cubosomes.

    PubMed

    Ali, Md Ashraf; Kataoka, Noriko; Ranneh, Abdul-Hackam; Iwao, Yasunori; Noguchi, Shuji; Oka, Toshihiko; Itai, Shigeru

    2017-01-01

    Monoolein cubosomes containing either spironolactone (SPI) or nifedipine (NI) were prepared using a high-pressure homogenization technique and characterized in terms of their solubility and oral bioavailability. The mean particle size, polydispersity index (PDI), zeta potential, solubility and encapsulation efficiency (EE) values of the SPI- and NI-loaded cubosomes were determined to be 90.4 nm, 0.187, -13.4 mV, 163 µg/mL and 90.2%, and 91.3 nm, 0.168, -12.8 mV, 189 µg/mL and 93.0%, respectively, which were almost identical to those of the blank cubosome. Small-angle X-ray scattering analyses confirmed that the SPI-loaded, NI-loaded and blank cubosomes existed in the cubic space group Im3̄m. The lattice parameters of the SPI- and NI-loaded cubosomes were 147.6 and 151.6 Å, respectively, making them almost identical to that of blank cubosome (151.0 Å). The in vitro release profiles of the SPI- and NI-loaded cubosomes showed that they released less than 5% of the drugs into various media over 12-48 h, indicating that most of the drug remained encapsulated within the cubic phase of their lipid bilayer. Furthermore, the in vivo pharmacokinetic results suggested that these cubosomes led to a considerable increase in the systemic oral bioavailability of the drugs compared with pure dispersions of the same materials. Notably, the stability results indicated that the mean particle size and PDI values of these cubosomes were stable for at least 4 weeks. Taken together, these results demonstrate that monoolein cubosomes represent promising drug carriers for enhancing the solubility and oral bioavailability of poorly water-soluble drugs.

  12. Estradiol and corticosterone stimulate the proliferation of a GH cell line, MtT/S: Proliferation of growth hormone cells.

    PubMed

    Nogami, Haruo; Hiraoka, Yoshiki; Aiso, Sadakazu

    2016-08-01

    Estrogens are known as a potent growth-stimulator of the anterior pituitary cells such as prolactin cells and somatomammotroph cell lines, while glucocorticoids often inhibit cellular proliferation in the pituitary gland as well as in the extra-pituitary tissues. In this study, the involvement of these steroid hormones in the regulation of proliferation was examined in the MtT/S cells, secreting growth hormone (GH). Effects of estrogens and glucocorticoids were examined in MtT/S cells grown in the medium containing dextran-coated charcoal treated serum. The relative cell density after culture was estimated by the Cell Titer-Glo Luminescent Cell Viability Assay System, and the proliferation rate was determined by the BrdU incorporation method. The mRNA levels were determined by real-time PCR. Estradiol and the specific agonist for both estrogen receptor (ER) α and ERβ stimulated MtT/S growth at a dose dependent manner. The membrane impermeable estrogen, 17β-estradiol-bovine serum albumin conjugate also stimulated the MtT/S proliferation. The effects of all estrogens were inhibited by an estrogen receptor antagonist, ICI182780. Corticosterone stimulated the proliferation of MtT/S cells at doses lower than 10nM without stimulating GH gene transcription, whereas it did not change the proliferation rate at 1μM. The effects of corticosterone were inhibited by glucocorticoid receptor inhibitor, RU486, but not by the mineralocorticoid receptor antagonist, spironolactone. Both estrogens and glucocorticoids were found to stimulate the proliferation of MtT/S, increasing the mRNA expression of cyclins D1, D3, and E. The results suggest that estrogens and glucocorticoids may be involved in the mechanisms responsible for the proliferation of GH cells in the course of pituitary development, to maintain the population of GH cells in the adult pituitary gland, and also in the promotion of GH cell tumors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Left ventricular assist device and drug therapy for the reversal of heart failure.

    PubMed

    Birks, Emma J; Tansley, Patrick D; Hardy, James; George, Robert S; Bowles, Christopher T; Burke, Margaret; Banner, Nicholas R; Khaghani, Asghar; Yacoub, Magdi H

    2006-11-02

    In patients with severe heart failure, prolonged unloading of the myocardium with the use of a left ventricular assist device has been reported to lead to myocardial recovery in small numbers of patients for varying periods of time. Increasing the frequency and durability of myocardial recovery could reduce or postpone the need for subsequent heart transplantation. We enrolled 15 patients with severe heart failure due to nonischemic cardiomyopathy and with no histologic evidence of active myocarditis. All had markedly reduced cardiac output and were receiving inotropes. The patients underwent implantation of left ventricular assist devices and were treated with lisinopril, carvedilol, spironolactone, and losartan to enhance reverse remodeling. Once regression of left ventricular enlargement had been achieved, the beta2-adrenergic-receptor agonist clenbuterol was administered to prevent myocardial atrophy. Eleven of the 15 patients had sufficient myocardial recovery to undergo explantation of the left ventricular assist device a mean (+/-SD) of 320+/-186 days after implantation of the device. One patient died of intractable arrhythmias 24 hours after explantation; another died of carcinoma of the lung 27 months after explantation. The cumulative rate of freedom from recurrent heart failure among the surviving patients was 100% and 88.9% 1 and 4 years after explantation, respectively. The quality of life as assessed by the Minnesota Living with Heart Failure Questionnaire score at 3 years was nearly normal. Fifty-nine months after explantation, the mean left ventricular ejection fraction was 64+/-12%, the mean left ventricular end-diastolic diameter was 59.4+/-12.1 mm, the mean left ventricular end-systolic diameter was 42.5+/-13.2 mm, and the mean maximal oxygen uptake with exercise was 26.3+/-6.0 ml per kilogram of body weight per minute. In this single-center study, we found that sustained reversal of severe heart failure secondary to nonischemic cardiomyopathy

  14. Implantation techniques and chronic lead parameters of biventricular pacing dual-chamber defibrillators.

    PubMed

    Daoud, Emile G; Kalbfleisch, Steven J; Hummel, John D; Weiss, Raul; Augustini, Ralph S; Duff, Steven B; Polsinelli, Georgia; Castor, John; Meta, Tejas

    2002-10-01

    The aim of this study is to describe implantation techniques and lead performance for biventricular pacing, dual-chamber implantable cardioverter defibrillators (ICDs). A dual-chamber ICD with biventricular pacing was implanted in 87 patients with congestive heart failure (ejection fraction: 0.21 +/- 0.09), prolonged QRS duration (161 +/- 22 msec), and an indication for ICD therapy. Left ventricular pacing was achieved with a thoracotomy approach (n = 21) or a nonthoracotomy approach (n = 66). With a thoracotomy, biventricular devices were implanted successfully in all patients. During follow-up (17 +/- 11 months), 9 patients died (43%), 2 underwent transplantation, and 2 required left ventricular lead revision. At last follow-up, biventricular sensing and capture threshold were 11 +/- 5 mV and 1.5 +/- 0.8 V, respectively. For nonthoracotomy procedures, two types of coronary sinus (CS) leads were implanted: an over-the-wire lead (n = 45) and a shaped lead (n = 21). The rate of successful implantation (overall: 89%) (over-the-wire 93% vs shaped 81%; P = 0.1) and durations for CS lead placement (66 +/- 50 vs 58 +/- 34 min, P = 0.6) and the procedure (133 +/- 58 vs 129 +/- 33 min, P = 0.8) were not different between the two CS leads. During follow-up (11 +/- 9 months), 9 patients died (14%), and the shaped CS lead dislodged in 3 patients (3 shaped vs 0 over-the-wire, P = 0.01). At last follow-up, biventricular sensing and capture threshold were 10 +/- 4 mV and 1.8 +/- 0.7 V, respectively, and there was no difference between over-the-wire and shaped leads. By multivariate analysis, mortality was associated with absence of spironolactone therapy but not procedural features. Nonthoracotomy CS lead implantation is feasible, with a success rate of about 90% and few adverse events. For the remaining 10%, a thoracotomy approach can be completed safely in these ill patients without increased risk for death.

  15. Diagnosis and management of polycystic ovary syndrome in the UK (2004–2014): a retrospective cohort study

    PubMed Central

    Ding, Tao; Baio, Gianluca; Hardiman, Paul J; Petersen, Irene; Sammon, Cormac

    2016-01-01

    Objective To estimate the incidence and prevalence of polycystic ovary syndrome (PCOS) in UK primary care and investigate prescribing patterns before and after a PCOS diagnosis. Design Retrospective cohort study. Setting UK primary care (2004–2014). Participants Women aged 15–45 years. Primary and secondary outcome measures The incidence and prevalence of diagnosed PCOS and probable PCOS (ie, those without a confirmed diagnosis but with at least 2 PCOS features recorded within 3 years). Among women with diagnosed or probable PCOS, the prevalence of prescribing of drugs typically used to treat PCOS was calculated prior to and in the 24 months after the diagnosis of PCOS. Results We identified 7233 women with PCOS diagnoses and 7057 women with records suggestive of probable PCOS, corresponding to incidence rates of 0.93 and 0.91 per 1000 person-years at risk (PYAR) and an overall rate of 1.84 per 1000 PYAR. Women aged 20–24 years and women living in deprived areas had the highest incidence of PCOS. The prevalence of PCOS in 2014 was ∼2%. The proportion of women with a prescription in the 24 months after their PCOS index date varied by drug type: 10.2% metformin, 15.2% combined oral contraceptives, 18.8% acne-related treatments, 1.93% clomiphene, 1.0% spironolactone, 0.28% cyproterone and 3.11% eflornithine. Acne-related treatments were more commonly used to treat probable (28.3%) than diagnosed (12.3%) cases, while metformin was prescribed much more commonly in diagnosed cases. Conclusions In conclusion, compared to rates estimated in community samples, the incidence and prevalence of women presenting in primary care with PCOS diagnoses and features are low, indicating that PCOS is an under-recognised condition. Although considerable variation is observed in treatments prescribed to women with PCOS, the treatments initiated following a confirmed diagnosis generally reflect the long-term prognostic concerns raised in PCOS consensuses. PMID:27401369

  16. Diagnosis and management of polycystic ovary syndrome in the UK (2004-2014): a retrospective cohort study.

    PubMed

    Ding, Tao; Baio, Gianluca; Hardiman, Paul J; Petersen, Irene; Sammon, Cormac

    2016-07-11

    To estimate the incidence and prevalence of polycystic ovary syndrome (PCOS) in UK primary care and investigate prescribing patterns before and after a PCOS diagnosis. Retrospective cohort study. UK primary care (2004-2014). Women aged 15-45 years. The incidence and prevalence of diagnosed PCOS and probable PCOS (ie, those without a confirmed diagnosis but with at least 2 PCOS features recorded within 3 years). Among women with diagnosed or probable PCOS, the prevalence of prescribing of drugs typically used to treat PCOS was calculated prior to and in the 24 months after the diagnosis of PCOS. We identified 7233 women with PCOS diagnoses and 7057 women with records suggestive of probable PCOS, corresponding to incidence rates of 0.93 and 0.91 per 1000 person-years at risk (PYAR) and an overall rate of 1.84 per 1000 PYAR. Women aged 20-24 years and women living in deprived areas had the highest incidence of PCOS. The prevalence of PCOS in 2014 was ∼2%. The proportion of women with a prescription in the 24 months after their PCOS index date varied by drug type: 10.2% metformin, 15.2% combined oral contraceptives, 18.8% acne-related treatments, 1.93% clomiphene, 1.0% spironolactone, 0.28% cyproterone and 3.11% eflornithine. Acne-related treatments were more commonly used to treat probable (28.3%) than diagnosed (12.3%) cases, while metformin was prescribed much more commonly in diagnosed cases. In conclusion, compared to rates estimated in community samples, the incidence and prevalence of women presenting in primary care with PCOS diagnoses and features are low, indicating that PCOS is an under-recognised condition. Although considerable variation is observed in treatments prescribed to women with PCOS, the treatments initiated following a confirmed diagnosis generally reflect the long-term prognostic concerns raised in PCOS consensuses. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please

  17. Rac1 GTPase regulates 11β hydroxysteroid dehydrogenase type 2 and fibrotic remodeling.

    PubMed

    Lavall, Daniel; Schuster, Pia; Jacobs, Nadine; Kazakov, Andrey; Böhm, Michael; Laufs, Ulrich

    2017-05-05

    The aim of the study was to characterize the role of Rac1 GTPase for the mineralocorticoid receptor (MR)-mediated pro-fibrotic remodeling. Transgenic mice with cardiac overexpression of constitutively active Rac1 (RacET) develop an age-dependent phenotype with atrial dilatation, fibrosis, and atrial fibrillation. Expression of MR was similar in RacET and WT mice. The expression of 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2) was age-dependently up-regulated in the atria and the left ventricles of RacET mice on mRNA and protein levels. Statin treatment inhibiting Rac1 geranylgeranylation reduced 11β-HSD2 up-regulation. Samples of human left atrial myocardium showed a positive correlation between Rac1 activity and 11β-HSD2 expression ( r = 0.7169). Immunoprecipitation showed enhanced Rac1-bound 11β-HSD2 relative to Rac1 expression in RacET mice that was diminished with statin treatment. Both basal and phorbol 12-myristate 13-acetate (PMA)-induced NADPH oxidase activity were increased in RacET and correlated positively with 11β-HSD2 expression ( r = 0.788 and r = 0.843, respectively). In cultured H9c2 cardiomyocytes, Rac1 activation with l-buthionine sulfoximine increased; Rac1 inhibition with NSC23766 decreased 11β-HSD2 mRNA and protein expression. Connective tissue growth factor (CTGF) up-regulation induced by aldosterone was prevented with NSC23766. Cardiomyocyte transfection with 11β-HSD2 siRNA abolished the aldosterone-induced CTGF up-regulation. Aldosterone-stimulated MR nuclear translocation was blocked by the 11β-HSD2 inhibitor carbenoxolone. In cardiac fibroblasts, nuclear MR translocation induced by aldosterone was inhibited with NSC23766 and spironolactone. NSC23766 prevented the aldosterone-induced proliferation and migration of cardiac fibroblasts and the up-regulation of CTGF and fibronectin. In conclusion, Rac1 GTPase regulates 11β-HSD2 expression, MR activation, and MR-mediated pro-fibrotic signaling. © 2017 by The American Society for

  18. Comparison of a commercially available oral nutritional supplement and intravenous fluid therapy for dehydration in dairy calves.

    PubMed

    Taylor, Jared D; Rodenburg, Merel; Snider, Timothy A

    2017-06-01

    Calf scours is a primary cause of morbidity and mortality in the dairy industry. Effective treatments are needed to minimize death, maximize welfare, and maintain growth and productivity. The objective of this trial was to compare the efficacy of a commercially available nutritional supplement (Diaque, Boehringer-Ingelheim Vetmedica Inc., St. Joseph, MO) and i.v. lactated Ringer's solution (LRS) in rehydrating, preventing acidemia, and correcting electrolyte imbalances in an experimental model for calf scours. Twenty-four colostrum-fed suckling dairy calves were used in a modified crossover design. An osmotic diarrhea was induced by orally feeding commercial milk replacer modified with high level of sucrose to create a hypertonic milk solution, and administering oral hydrochlorothiazide and spironolactone for 48 h. The intention was to create a challenge sufficient to result in moderately dehydrated, standing calves without producing severe depression or loss of suckle. The efficacy of i.v. fluid therapy and a commercial nutritional supplement were subsequently compared for reversing the effects of the diarrheal disease. Treatment A consisted of administering the nutritional supplement according to label directions (100 g in 1.9 L of warm water, 3 times a day), and treatment B consisted of i.v. LRS (2 L, once a day). Clinical signs and laboratory results were obtained once daily by a blinded observer. The induction method was effective in creating the desired effect, as demonstrated by weight loss and subjective health and hydration scores. Both treatment groups experienced increases in body weight, base excess, and bicarbonate, and decreases in total protein and packed cell volume following treatment. Both i.v. LRS and Diaque are effective methods to correct hypovolemia and control derangements in acid-base status in calves with diarrhea and dehydration. The Authors. Published by the Federation of Animal Science Societies and Elsevier Inc. on behalf of the

  19. Circulating aldosterone induces the apical accumulation of the proton pumping V-ATPase and increases proton secretion in clear cells in the caput epididymis.

    PubMed

    Roy, Jeremy W; Hill, Eric; Ruan, Ye Chun; Vedovelli, Luca; Păunescu, Teodor G; Brown, Dennis; Breton, Sylvie

    2013-08-15

    Clear cells express the vacuolar proton-pumping H(+)-ATPase (V-ATPase) and acidify the lumen of the epididymis, a process that is essential for male fertility. The renin-angiotensin-aldosterone system (RAAS) regulates fluid and electrolyte balance in the epididymis, and a previous study showed binding of aldosterone exclusively to epididymal clear cells (Hinton BT, Keefer DA. Steroid Biochem 23: 231-233, 1985). We examined here the role of aldosterone in the regulation of V-ATPase in the epididymis. RT-PCR showed expression of the mineralocorticoid receptor [MR; nuclear receptor subfamily 3, group C member 2 (NR3C2)] and 11-β-dehydrogenase isozyme 2 (HSD11β2) mRNAs specifically in clear cells, isolated by fluorescence-activated cell sorting from B1-enhanced green fluorescent protein (EGFP) mice. Tail vein injection of adult rats with aldosterone, 1,2-dioctanoyl-sn-glycerol (DOG), or 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) induced V-ATPase apical membrane accumulation and extension of V-ATPase-labeled microvilli in clear cells in the caput epididymis but not in the cauda. V-ATPase activity was measured in EGFP-expressing clear cells using the intracellular pH (pHi)-sensing dye seminaphthorhodafluor-5F-5-(and 6)-carboxylic acid, acetoxymethyl ester acetate (SNARF-5F). Aldosterone induced a rapid increase in the rate of Na(+)- and bicarbonate-independent pHi recovery following an NH4Cl-induced acid load in clear cells isolated from the caput but not the cauda. This effect was abolished by concanamycin A, spironolactone, and chelerythrine but not myristoylated-protein kinase inhibitor (mPKI) or mifepristone. Thus aldosterone increases V-ATPase-dependent proton secretion in clear cells in the caput epididymis via MR/NR3C2 and PKC activation. This study, therefore, identifies aldosterone as an active member of the RAAS for the regulation of luminal acidification in the proximal epididymis.

  20. Long-Term Response of Hirsutism and Other Hyperandrogenic Symptoms to Combination Therapy in Polycystic Ovary Syndrome.

    PubMed

    Ezeh, Uche; Huang, Andy; Landay, Melanie; Azziz, Ricardo

    2018-06-07

    Polycystic ovary syndrome (PCOS) affects 5%-15% of women and is the most common cause of hirsutism. Data on the time-course of improvement to suppressive therapy and predictors of that response in PCOS are lacking. The objectives of our study are to determine the long-term response and identify predictors of response in PCOS women treated with suppressive therapy, including spironolactone (SPL) + oral contraceptives (OCs). Retrospective cross-sectional analysis of 200 women with PCOS (1990 NIH criteria) treated with suppressive therapy in general, and a subgroup of 138 subjects treated with OCP+SPL who had been prospectively included in a biorepository. Main outcome measure included improvement rate per 100 person-month of follow-up for hirsutism, menstrual irregularity and acne measured qualitatively as "feeling better", and changes in the severity of hirsutism quantified by modified Ferriman-Gallwey [mF-G] score. During a mean follow-up of 34.2 months, 85.1%, 82.7%, and 79.3% of patients reported improvement in hirsutism, menstrual dysfunction, and acne, respectively. The modified Ferriman-Gallwey (mF-G) hirsutism score improved by 59.9%. The net reduction in mF-G score and the percent of patients reporting improvement in hirsutism were greater for OC+SPL than for either drug alone, with no difference in the percent of patients free of adverse effects. Among those treated with OC+SPL (n = 138), the initial mF-G and sex hormone-binding globulin (SHBG) independently predicted successful therapy for hirsutism. There is a high rate of patient satisfaction with suppressive therapy in PCOS. The efficacy of suppressive therapy for hirsutism was greater with OC+SPL than with either drug alone. Successful treatment of hirsutism with combination OC+SPL requires at least 6 months of therapy, with the proportion of satisfied patients continuing to increase with treatment duration. The probability of patient satisfaction with OC+SPL treatment for hirsutism can be

  1. A review of treatment of premenstrual syndrome and premenstrual dysphoric disorder.

    PubMed

    Rapkin, Andrea

    2003-08-01

    spironolactone analog, instead of a 19-nortestosterone derivative can reduce symptoms of water retention and other side effects related to estrogen excess. The studies are in progress, however, preliminary evidence suggests that the drospirenone-containing pill called Yasmin may be effective the treatment of PMDD.

  2. EVALUATION OF CASES WITH THE USAGE OF COMMERCIALLY AVAILABLE TABLETS IN THE PEDIATRIC FORMULA.

    PubMed

    Kuriata, Elżbieta; Sawicki, Wiesław

    2015-01-01

    Lack of availability, of either the medicinal product intended to be used for children, or such in a dose which is fitting for the individual child's needs, results in physicians administering medicines meant for the adult. The target of the thesis was to evaluate the cases with the usage of commercially avaible conventional tablet-formulated medicinal products intended for the adult in the pediatric formula. The subjects of the evaluation were the form of the pediatric drug, prepared from commercially available tablets and capsules, as well as the legitimacy of their usage in the treatment of the pediatric population. One hundred and fifty-four prescriptions filled in community pharmacies of Warminsko-Mazurskie Voivodeship in 2011 were chosen. A total of 5805 divided powders in starch capsules were prepared. The prescribing practice included 6 groups of manufactured medicinal products in the form of conventional tablets, containing as follows: anti-hypertensive medicines (ACE inhibitors--enalapril, captopril, ramipril, loop diuretics--furosemide, potassium sparing diuretics--spironolactone, β-adrenolytics--propranolol, α- and β-adrenolytics--carvedilol), medicines for heart failure (foxglove glycosides--digoxin, methyldigoxin), anti-clotting medicines (acetylsalicylic acid), peristalsis stimulating agents (metoclopramide), antibacterial medicines (furagin), and dopaminergic (carbidopa-levodopa). The only compounded forms ordered by the physicians were divided powders for an internal use. Starch capsules for powder preparation provided the only 'package' for the dose of the compounded powder, which after pouring, solving or suspending in water was administered to children. Such a shift of the form, between an oral tablet and divided powder for an internal use, did not cause a change in the method of administration. The information on indications and the way of dosage for children, inserted in the Summary of Product Characteristics, enables the administration

  3. Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials.

    PubMed

    Ezekowitz, Justin A; McAlister, Finlay A

    2009-02-01

    Aldosterone blockade has been used to treat acute myocardial infarction (MI) and chronic heart failure. The aim of this study is to summarize the evidence on the efficacy of spironolactone (SP), eplerenone (EP), or canrenoate (CAN) in patients with left ventricular dysfunction. A search of multiple electronic databases until June 2008 was supplemented by hand searches of reference lists of included studies and review articles, meeting abstracts, FDA reports, and contact with study authors and drug manufacturers. Studies were eligible for inclusion if they included patients with left ventricular systolic or diastolic dysfunction, treatment with SP, EP, or CAN vs. control, and reported clinical outcomes. Nineteen randomized controlled trials (four in acute MI and 15 in heart failure, n = 10 807 patients) were included -- 14 of SP, three of EP, and three of CAN. Analysis was performed using relative risks (RRs) with 95% confidence intervals (CIs) and a random effects model with statistical heterogeneity assessed by I(2). Aldosterone blockade reduced all-cause mortality by 20% (RR 0.80, 95% CI 0.74-0.87). All-cause mortality was reduced in both heart failure (RR = 0.75, 95% CI 0.67-0.84) and post-MI (RR 0.85, 95% CI 0.76-0.95) patients. Only nine trials reported hospitalizations, and the RR reduction was 23% (RR 0.77, 95% CI 0.68-0.87), although 98% of the outcomes came from two trials. Ejection fraction (EF) improved in the seven heart failure trials, which assessed this outcome (weighted mean difference 3.1%, 95% CI 1.6-4.5). We demonstrated a 20% reduction in all-cause mortality with the use of aldosterone blockade in a clinically heterogeneous group of clinical trial participants with heart failure and post-MI. In addition, we found a 3.1% improvement in EF. Further study in those with less severe symptoms or preserved systolic function is warranted.

  4. South African hypertension guideline 2011.

    PubMed

    Seedat, Y K; Rayner, B L

    2011-12-14

    Extensive data from randomised controlled trials have shown the benefit of treating hypertension. The target blood pressure (BP) for antihypertensive management is systolic <140 mmHg and diastolic <90 mmHg with minimal or no drug side-effects; however, stricter BP control is required for patients with end-organ damage, co-existing risk factors and co-morbidity, e.g. diabetes mellitus. The reduction of BP in the elderly and in those with severe hypertension should be achieved gradually over 1 month. Co-existent risk factors should also be controlled. Benefits of management include reduced risks of stroke, cardiac failure, chronic kidney disease and coronary heart disease. The correct BP measurement procedure is described, and evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated. The total cardiovascular disease risk profile should be determined for all patients to inform management strategies. Lifestyle modification and patient education are cornerstones in the management of every patient. Major indications, precautions and contra-indications to each recommended antihypertensive drug are listed. Combination therapy should be considered ab initio if the BP is ≥ 20/10 mmHg. First-line drug therapy for uncomplicated hypertension includes low-dose thiazide-like diuretics, calcium channel blockers (CCBs) or angiotensin-converting enzyme inhibitors (ACE-Is) (or ARBs - angiotensin II receptor blockers). If the target BP is not obtained, a second antihypertensive should be added from the aforementioned list. If the target BP is still not met, the third remaining antihypertensive agent should be used. In black patients either thiazide-like diuretics or CCBs can be used initially, because response rates are better than with ACE-Is or β-blockers. In treating resistant hypertension, a centrally acting drug, vasodilator, α-blocker, spironolactone or β-locker should be added. This guideline includes management of specific

  5. Class III antiarrhythmic agents in cardiac failure: lessons from clinical trials with a focus on the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA).

    PubMed

    Doval, H C

    1999-11-04

    The results of previous clinical trials, in a variety of clinical settings, showed that class I agents may consistently increase mortality in sharp contrast to the effects of beta blockers. Attention has therefore shifted to class III compounds for potential beneficial effects on long-term mortality among patients with underlying cardiac disease. Clinical trials with d-sotalol, the dextro isomer (devoid of beta blockade) of sotalol, showed increased mortality in patients with low ejection fraction after myocardial infarction and in those with heart failure; whereas in the case of dofetilide, the impact on mortality was neutral. Because of the complex effects of its actions as an alpha-adrenergic blocker and a class III agent, the impact on mortality of amiodarone in patients with heart failure is of particular interest. A meta-analysis of 13 clinical trials revealed significant reductions in all-cause and cardiac mortality among patients with heart failure or previous myocardial infarction. Among these were 5 controlled clinical trials that investigated the effects of amiodarone on mortality among patients with heart failure. None of these trials was large relative to the beta-blocker trials in the postinfarction patients. However, the larger 2 of the 5 amiodarone trials produced discordant effects on mortality, neutral in one and significantly positive in the other. Some of the differences may be accounted for by the differences in eligibility criteria and baseline characteristics. Future trials that may be undertaken to resolve the discrepancies may need to allow for the newer findings on the effects of concomitant beta blockers, implantable devices, and possibly, spironolactone. All these modalities of treatment have been shown in controlled clinical trials to augment survival in patients with impaired ventricular function or manifest heart failure. Additional trials, some of which are currently in progress, compare amiodarone with implantable devices and other

  6. Adherence to Antihypertensive Treatment and the Blood Pressure-Lowering Effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) Trial.

    PubMed

    Azizi, Michel; Pereira, Helena; Hamdidouche, Idir; Gosse, Philippe; Monge, Matthieu; Bobrie, Guillaume; Delsart, Pascal; Mounier-Véhier, Claire; Courand, Pierre-Yves; Lantelme, Pierre; Denolle, Thierry; Dourmap-Collas, Caroline; Girerd, Xavier; Michel Halimi, Jean; Zannad, Faiez; Ormezzano, Olivier; Vaïsse, Bernard; Herpin, Daniel; Ribstein, Jean; Chamontin, Bernard; Mourad, Jean-Jacques; Ferrari, Emile; Plouin, Pierre-François; Jullien, Vincent; Sapoval, Marc; Chatellier, Gilles

    2016-09-20

    The DENERHTN trial (Renal Denervation for Hypertension) confirmed the blood pressure-lowering efficacy of renal denervation added to a standardized stepped-care antihypertensive treatment for resistant hypertension at 6 months. We report the influence of adherence to antihypertensive treatment on blood pressure control. One hundred six patients with hypertension resistant to 4 weeks of treatment with indapamide 1.5 mg/d, ramipril 10 mg/d (or irbesartan 300 mg/d), and amlodipine 10 mg/d were randomly assigned to renal denervation plus standardized stepped-care antihypertensive treatment, or the same antihypertensive treatment alone. For standardized stepped-care antihypertensive treatment, spironolactone 25 mg/d, bisoprolol 10 mg/d, prazosin 5 mg/d, and rilmenidine 1 mg/d were sequentially added at monthly visits if home blood pressure was ≥135/85 mm Hg after randomization. We assessed adherence to antihypertensive treatment at 6 months by drug screening in urine/plasma samples from 85 patients. The numbers of fully adherent (20/40 versus 21/45), partially nonadherent (13/40 versus 20/45), or completely nonadherent patients (7/40 versus 4/45) to antihypertensive treatment were not different in the renal denervation and the control groups, respectively (P=0.3605). The difference in the change in daytime ambulatory systolic blood pressure from baseline to 6 months between the 2 groups was -6.7 mm Hg (P=0.0461) in fully adherent and -7.8 mm Hg (P=0.0996) in nonadherent (partially nonadherent plus completely nonadherent) patients. The between-patient variability of daytime ambulatory systolic blood pressure was greater for nonadherent than for fully adherent patients. In the DENERHTN trial, the prevalence of nonadherence to antihypertensive drugs at 6 months was high (≈50%) but not different in the renal denervation and control groups. Regardless of adherence to treatment, renal denervation plus standardized stepped-care antihypertensive treatment resulted in

  7. Influence of Physiological Gastrointestinal Surfactant Ratio on the Equilibrium Solubility of BCS Class II Drugs Investigated Using a Four Component Mixture Design

    PubMed Central

    2017-01-01

    The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced into dissolution testing including endogenous amphiphiles and digested lipids at physiological levels; however, in vivo individual variation exists in the concentrations of these components, which will alter drug absorption through an effect on solubility. The use of a factorial design of experiment and varying media by introducing different levels of bile, lecithin, and digested lipids has been previously reported, but here we investigate the solubility variation of poorly soluble drugs through more complex biorelevant amphiphile interactions. A four-component mixture design was conducted to understand the solubilization capacity and interactions of bile salt, lecithin, oleate, and monoglyceride with a constant total concentration (11.7 mM) but varying molar ratios. The equilibrium solubility of seven low solubility acidic (zafirlukast), basic (aprepitant, carvedilol), and neutral (fenofibrate, felodipine, griseofulvin, and spironolactone) drugs was investigated. Solubility results are comparable with literature values and also our own previously published design of experiment studies. Results indicate that solubilization is not a sum accumulation of individual amphiphile concentrations, but a drug specific effect through interactions of mixed amphiphile compositions with the drug. This is probably due to a combined interaction of drug characteristics; for example, lipophilicity, molecular shape, and ionization with amphiphile components, which can generate specific drug–micelle affinities. The proportion of each component can have a remarkable influence on solubility with, in some cases, the highest and lowest points close to each other. A single-point solubility measurement in a fixed composition simulated media or human intestinal fluid sample will therefore provide

  8. Greater efficacy of aldosterone blockade and diuretic reinforcement vs. dual renin-angiotensin blockade for left ventricular mass regression in patients with resistant hypertension.

    PubMed

    Azizi, Michel; Perdrix, Ludivine; Bobrie, Guillaume; Frank, Michael; Chatellier, Gilles; Ménard, Joël; Plouin, Pierre-François

    2014-10-01

    We report the results of an echocardiographic substudy carried out in a trial comparing the effects of two different treatment strategies - mineralocorticoid receptor blockade (MRB) and dual renin-angiotensin system blockade (RASB) - in patients with resistant hypertension. Both strategies reduce left ventricular mass index (LVMI), but they have not been compared in patients with resistant hypertension. After 4-week treatment with 300 mg irbesartan + 12.5 mg hydrochorothiazide + 5 mg amlodipine, 86 patients with resistant hypertension were randomized to the add-on 25 mg spironolactone (MRB group, n = 46) or 5 mg ramipril (RASB group, n = 40) groups for 12 weeks. Treatment intensity was increased at week 4, 8 or 10 if home blood pressure (BP) was equal to or above 135/85 mmHg, by sequentially adding 20-40 mg furosemide and 5 mg amiloride (MRB group), or 10 mg ramipril and 5-10 mg bisoprolol (RASB group). Transthoracic echography was performed at baseline and week 12. Daytime ambulatory BP decreased by 19 ± 12/11 ± 8 mmHg in the MRB group and by 8 ± 13/7 ± 7 mmHg in the RASB group (P = 0.0003/0.03). LVMI decreased by 8.2 ± 18.9 g/m in the MRB group, whereas it increased by 1.8 ± 19.1 g/m in the RASB group (P = 0.03). The decreases in posterior wall thickness, left ventricular (LV) end-systolic diameter, E/e' ratio and left atrial area were significantly greater with MRB than with RASB. The difference between groups remained significant after adjustment for the decrease in ambulatory BP. In patients with resistant hypertension, MRB-based treatment decreased both BP and LVMI more efficiently than a strategy based on dual RASB.

  9. Aldosterone Contributes to Sympathoexcitation in Renovascular Hypertension.

    PubMed

    Lincevicius, Gisele S; Shimoura, Caroline G; Nishi, Erika E; Perry, Juliana C; Casarini, Dulce E; Gomes, Guiomar N; Bergamaschi, Cássia T; Campos, Ruy R

    2015-09-01

    Although angiotensin II (Ang II) is essential to the development of renovascular hypertension, aldosterone plays a role as well. Recent studies have demonstrated a cross-talk between Ang II type 1 and mineralocorticoid receptors in the brain and kidneys. However, the role of aldosterone in the autonomic and renal dysfunction of renovascular hypertension is not well understood. The current study evaluated whether aldosterone contributes to cardiovascular and renal dysfunction in the 2 kidney-1 clip (2K1C) model. Mean arterial pressure (MAP) and baroreceptor reflex for control of the heart rate were evaluated in 2K1C treated or not treated with spironolactone (200mg/kg/day, 7 days). Tonic and reflex control of renal sympathetic nerve activity (rSNA) were assessed in urethane-anaesthetized rats. Plasma renin activity (PRA), kidney renin protein expression, renal injury, and central AT1 receptor protein expression were assessed. Spiro reduced MAP (198±4 vs. 170±9mm Hg; P < 0.05), normalized rSNA (147±9 vs. 96±10 pps; P < 0.05), and increased renal baroreceptor reflex sensitivity in the 2K1C rats. Spiro reduced α-smooth muscle actin expression in the nonclipped kidney in the 2K1C group (5±0.6 vs. 1.1±0.2%; P < 0.05). There was no change in PRA; however, a decrease in renin protein expression in the nonclipped kidney was found in the 2K1C treated group (217±30 vs. 160±19%; P < 0.05). Spiro treatment decreased AT1 receptor in the central nervous system (CNS) only in 2K1C rats (138±10 vs. 84±12%; P < 0.05). Aldosterone contributes to autonomic dysfunction and intrarenal injury in 2K1C, these effects are mediated by the CNS. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. Jejunal permeability to water and electrolytes in patients with chronic intrahepatic hypertension: evidence for a role of aldosterone.

    PubMed Central

    Duclos, B; Bories, P; Mathieu-Daude, J C; Michel, H

    1991-01-01

    Acute prehepatic portal hypertension induces intestinal secretion in animal models. In the course of chronic liver disease, however, these changes are not observed, despite higher portal pressures than those found in experimental studies. Eight patients without diarrhoea and with chronic alcoholic liver disease were examined for evidence of increased jejunal secretion; their suprahepatic wedge pressure was raised from 21 to 45 mmHg (mean 34.6 mmHg). Jejunal perfusion with a triple lumen catheter and a proximal occluding balloon was used to study net flows of water and chloride as well as net and unidirectional flows of sodium and potassium. No statistical difference in intestinal flows of water and electrolytes was noted between cirrhotic patients and control subjects after infusion with a 30 mmol/l glucose solution. Infusion with a 30 mmol/l mannitol solution resulted in a lower absorption of water, Na, K, and Cl than with the glucose solution. A higher rate of Na secretion was observed in cirrhotic patients than control subjects after infusion with 30 mmol/l mannitol (p less than 0.01). In addition, the rate of Na secretion was higher in cirrhotic patients than in control subjects (p less than 0.05). There was no correlation between the net flow of Na and the suprahepatic wedge pressure. A second perfusion with a 30 mmol/l glucose solution was given 75 minutes after a bolus injection of spironolactone (400 mg). Net flows of Na and Cl were lower in cirrhotic patients than in control subjects (p less than 0.05) because of a lower absorption of Na. Patients with gradually developing portal hypertension have moderate jejunal secretions of H2O and electrolytes which we assume are partly masked by increased absorption resulting from hyperaldosteronism. In contrast to animal models, this mechanism may be part of the jejunal adaptation to permeability in acute portal hypertension. PMID:2060871

  11. Diuretic or sodium-restricted diet for obstructive sleep apnea-a randomized trial.

    PubMed

    Fiori, Cintia Zappe; Martinez, Denis; Montanari, Carolina Caruccio; Lopez, Pedro; Camargo, Rodrigo; Sezerá, Lauren; Gonçalves, Sandro Cadaval; Fuchs, Flavio Danni

    2018-04-01

    Interventions that decrease leg fluid retention reduce obstructive sleep apnea (OSA) severity in nonrandomized experiments. We aimed to investigate in a randomized trial the effect of interventions that reduce fluid volume on OSA severity. Men diagnosed with severe OSA were randomized to receive daily spironolactone 100 mg + furosemide 20 mg or nutritional counseling to sodium-restricted diet plus placebo pill or placebo pill. All participants underwent home sleep apnea testing at baseline and after 1 week follow-up. The change in apnea-hypopnea index (AHI) was the primary outcome. The study included 54 participants and all were assessed at follow-up. The average baseline value of the AHI was similar among groups and from baseline to follow-up the AHI reduced 14.4 per cent (δ value -7.3 events per hour; 95% confidence interval, -13.8 to -0.9) in the diuretic group, 22.3 per cent (-10.7; 95% CI, -15.6 to -5.7) in the diet group, and 0.8 per cent (0.4; 95% CI, -2.5 to 3.2) in the placebo group (p = .001 for time × group interaction). None of the patients had their AHI returned to normal. The reduction in the total body water was 2.2 ± 2.2 L in the diuretic group (p < .001) and 1.0 ± 1.6 l in the low salt diet group (p = .002). Sleepiness and neck circumference were significantly reduced only in the diet group (p = .007 and p < .001 for the time × group interactions, respectively). Interventions to reduce bodily fluid content in men with severe OSA promoted a limited decrease of apnea frequency. This finding suggests that rostral fluid displacement affects only partially the OSA severity and/or that other factors prevail in determining pharyngeal collapsibility. Sodium-Restricted Diet and Diuretic in the Treatment of Severe Sleep Apnea (DESALT), https://clinicaltrials.gov/ct2/show/NCT01945801 ClinicalTrials.gov number: NCT01945801.

  12. Targeting NADPH oxidases in vascular pharmacology

    PubMed Central

    Schramm, Agata; Matusik, Paweł; Osmenda, Grzegorz; Guzik, Tomasz J

    2012-01-01

    Oxidative stress is a molecular dysregulation in reactive oxygen species (ROS) metabolism, which plays a key role in the pathogenesis of atherosclerosis, vascular inflammation and endothelial dysfunction. It is characterized by a loss of nitric oxide (NO) bioavailability. Large clinical trials such as HOPE and HPS have not shown a clinical benefit of antioxidant vitamin C or vitamin E treatment, putting into question the role of oxidative stress in cardiovascular disease. A change in the understanding of the molecular nature of oxidative stress has been driven by the results of these trials. Oxidative stress is no longer perceived as a simple imbalance between the production and scavenging of ROS, but as a dysfunction of enzymes involved in ROS production. NADPH oxidases are at the center of these events, underlying the dysfunction of other oxidases including eNOS uncoupling, xanthine oxidase and mitochondrial dysfunction. Thus NADPH oxidases are important therapeutic targets. Indeed, HMG-CoA reductase inhibitors (statins) as well as drugs interfering with the renin-angiotensin-aldosterone system inhibit NADPH oxidase activation and expression. Angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor antagonists (sartans) and aliskiren, as well as spironolactone or eplerenone, have been discussed. Molecular aspects of NADPH oxidase regulation must be considered, while thinking about novel pharmacological targeting of this family of enzymes consisting of several homologs Nox1, Nox2, Nox3, Nox4 and Nox5 in humans. In order to properly design trials of antioxidant therapies, we must develop reliable techniques for the assessment of local and systemic oxidative stress. Classical antioxidants could be combined with novel oxidase inhibitors. In this review, we discuss NADPH oxidase inhibitors such as VAS2870, VAS3947, GK-136901, S17834 or plumbagin. Therefore, our efforts must focus on generating small molecular weight inhibitors of NADPH oxidases, allowing the

  13. Heart failure with preserved left ventricular systolic function: a hospital cohort study

    PubMed Central

    Berry, C; Hogg, K; Norrie, J; Stevenson, K; Brett, M; McMurray, J

    2005-01-01

    Objective: To investigate how patients with heart failure with preserved left ventricular systolic function (LVSF) compare with patients with reduced LVSF. Design: Cohort study. Setting: Urban university hospital. Patients: 528 index emergency admissions with heart failure during the year 2000. Information on LVSF and follow up was available for 445 (84%) of these patients. Results: 130 (29%) patients had preserved LVSF (defined as an ejection fraction > 40%). The median follow up was 814 days (range 632–978 days). The average (SD) age was 72 (13) years. Women accounted for 62% and 45% of patients with preserved and reduced LVSF, respectively (p  =  0.001). Patients with preserved LVSF (compared with those with reduced LVSF) had a higher prevalence of left ventricular hypertrophy (56% v 29%) and aortic valve disease (mean gradient > 20 mm Hg; 31% v 9%). Fewer patients with preserved LVSF received an angiotensin converting enzyme inhibitor (65% v 78%, p  =  0.008) or spironolactone (12% v 21%, p  =  0.027). Anaemia tended to occur more often in patients with preserved LVSF than in those with reduced LVSF (43% v 33% for women, p  =  0.12; 59% v 49% for men, p  =  0.22). There was a similarly high prevalence of significant renal dysfunction in both groups (estimated glomerular filtration rate < 60 ml/min/1.73 m2 in 68% with preserved and 64% with reduced LVSF, p  =  0.40). Mortality was similar in both groups (preserved versus reduced 51 (39%) v 132 (42%), p  =  0.51). Compared with patients with reduced LVSF, patients with preserved LVSF tended to have a lower risk of death or hospital admission for heart failure (56 (42%) v 165 (53%), p  =  0.072) but a similar rate of death or readmission for any reason. Conclusion: Patients with preserved LVSF had more co-morbid problems than those with reduced LVSF; however, prognosis was similar for both groups. PMID:15958359

  14. Diuretics prevent Rho-kinase activation and expression of profibrotic/oxidative genes in the hypertensive aortic wall.

    PubMed

    Araos, Patricio; Mondaca, David; Jalil, Jorge E; Yañez, Cristián; Novoa, Ulises; Mora, Italo; Ocaranza, María Paz

    2016-12-01

    Diuretics are current antihypertensive drugs since they reduce blood pressure and cardiovascular risk. Increased vascular tone is modulated in a relevant way by the RhoA/Rho-kinase (ROCK) pathway, by acting on vascular smooth muscle cell contraction. This pathway has also proremodeling vascular effects. There are few data on the role of diuretics on both vascular ROCK activation and on proremodeling effects. We assessed the effects of hydrochlorothiazide (HCTZ) and spironolactone (spiro) alone and in combination with the ROCK inhibitor fasudil (FAS) on ROCK activation, gene expression of proremodeling markers and on hypertrophy in the aortic wall of hypertensive rats. Deoxycorticosterone acetate (DOCA)-salt hypertensive rats (male, Sprague-Dawley) were randomized to the specific ROCK inhibitor FAS, HCTZ, spiro or the combinations of FAS/HCTZ or FAS/spiro for 3 weeks. At the end of the study, ROCK activation (by western blot), gene expression of proremodeling markers (by reverse transcription polymerase chain reaction, RT-PCR) and vascular hypertrophy (by morphometry) were determined in the aortic wall. All treatments significantly reduced blood pressure. In the DOCA rats the p-myosin phosphatase target protein-1 (MYPT1)/t-MYPT1 ratio, index of ROCK activation was higher by 2.8 fold (p < 0.05) compared with control rats. All treatments reduced ROCK activation in the aortic wall to control levels (p < 0.05). Besides, significantly increased protein levels of transforming growth factor β1 (TGF-β 1 ), gene expression of TGF-β 1 , connective tissue growth factor (CTGF), p22 phox and gp91 phox subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, as well as increased media thickness and aortic media area/lumen area (AM/LA) in the untreated hypertensive rats were significantly reduced (p < 0.05) to control levels by all treatments. Similar effects were observed using both diuretics alone or in combination with FAS. In the aortic wall, both HCTZ and

  15. Diuretics prevent Rho-kinase activation and expression of profibrotic/oxidative genes in the hypertensive aortic wall

    PubMed Central

    Araos, Patricio; Mondaca, David; Jalil, Jorge E.; Yañez, Cristián; Novoa, Ulises; Mora, Italo; Ocaranza, María Paz

    2016-01-01

    Background: Diuretics are current antihypertensive drugs since they reduce blood pressure and cardiovascular risk. Increased vascular tone is modulated in a relevant way by the RhoA/Rho-kinase (ROCK) pathway, by acting on vascular smooth muscle cell contraction. This pathway has also proremodeling vascular effects. There are few data on the role of diuretics on both vascular ROCK activation and on proremodeling effects. We assessed the effects of hydrochlorothiazide (HCTZ) and spironolactone (spiro) alone and in combination with the ROCK inhibitor fasudil (FAS) on ROCK activation, gene expression of proremodeling markers and on hypertrophy in the aortic wall of hypertensive rats. Methods: Deoxycorticosterone acetate (DOCA)-salt hypertensive rats (male, Sprague–Dawley) were randomized to the specific ROCK inhibitor FAS, HCTZ, spiro or the combinations of FAS/HCTZ or FAS/spiro for 3 weeks. At the end of the study, ROCK activation (by western blot), gene expression of proremodeling markers (by reverse transcription polymerase chain reaction, RT-PCR) and vascular hypertrophy (by morphometry) were determined in the aortic wall. Results: All treatments significantly reduced blood pressure. In the DOCA rats the p-myosin phosphatase target protein-1 (MYPT1)/t-MYPT1 ratio, index of ROCK activation was higher by 2.8 fold (p < 0.05) compared with control rats. All treatments reduced ROCK activation in the aortic wall to control levels (p < 0.05). Besides, significantly increased protein levels of transforming growth factor β1 (TGF-β1), gene expression of TGF-β1, connective tissue growth factor (CTGF), p22 phox and gp91 phox subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, as well as increased media thickness and aortic media area/lumen area (AM/LA) in the untreated hypertensive rats were significantly reduced (p < 0.05) to control levels by all treatments. Similar effects were observed using both diuretics alone or in combination with FAS

  16. Computerized Tomography-Guided Paracentesis: An Effective Alternative to Bedside Paracentesis?

    PubMed

    Gaduputi, Vinaya; Tariq, Hassan; Chandrala, Chaitanya; Sakam, Sailaja; Abbas, Naeem; Chilimuri, Sridhar

    2017-02-01

    Ascites remains the most common cause of hospitalization among patients with decompensated cirrhosis. Paracentesis is a relatively safe procedure with low complication rates. Computerized tomography (CT)-guided therapeutic paracentesis could be a safe and effective alternative to unaided or aided (ultrasonogram-guided) bedside paracentesis. In this retrospective study, we aimed to compare the efficacy, safety, and cost-effectiveness of CT-guided paracentesis with bedside paracentesis. The period of study was from 2002 to 2012. All patients with cirrhosis who underwent therapeutic paracentesis were included in the study. These patients were divided into two groups. Group I consisted of patients who underwent CT-guided pigtail catheter insertion with ascitic fluid drainage. Group II consisted of patients who underwent beside therapeutic paracentesis after localization of fluid either by physical examination or sonographic localization. We measured the efficacy of CT-guided paracentesis and bedside paracentesis in terms of volume of fluid removed, length of stay, discharge doses of diuretics (spironolactone and furosemide) and number of days to readmission for symptomatic ascites. We also computed the cost-effectiveness of CT-guided therapeutic paracentesis when compared to a bedside procedure. Fischer exact test was used to analyze the distribution of categorical data and unpaired t -test was used for comparison of means. There were a total of 546 unique patients with diagnosed cirrhosis who were admitted to the hospital with symptomatic ascites and underwent therapeutic paracentesis. Two hundred and forty-seven patients underwent CT-guided paracentesis, while 272 patients underwent bedside paracentesis. There was significant inverse correlation between the amount of ascitic fluid removed and total length of stay in the hospital. We found that the volume of fluid removed via a CT-guided pigtail insertion and drainage (2.72 ± 2.02 L) is significantly higher when

  17. Gitelman syndrome manifesting in early childhood and leading to delayed puberty: a case report.

    PubMed

    Raza, Farhan; Sultan, Mubashar; Qamar, Khola; Jawad, Ali; Jawa, Ali

    2012-10-02

    Gitelman syndrome is an inherited autosomal recessive renal salt-wasting disorder. It presents with variable clinical symptoms including muscle weakness and fatigue, and the diagnosis is based on metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria. It is usually diagnosed incidentally in early adulthood. There are rare cases of Gitelman syndrome presenting in early childhood; however, to the best of our knowledge it has not previously been associated with delayed puberty. A 17-year-old South Asian man with recurrent episodes of generalized muscle weakness, fatigue and cramps from the age of two years was admitted for further workup. Before the age of 12 years, the episodes had been mild, but they then got progressively worse. Other symptoms include polyuria, polydipsia, nocturia, paresthesia and occasional watery diarrhea. He also had a history of short stature, poor weight gain and delayed developmental landmarks. His family history was unremarkable except for the consanguineous marriage of his parents. An examination revealed a thin and lean man with blood pressure of 95/60mmHg. His height and weight were below the third percentile and his sexual development was at Tanner Stage II. Laboratory work revealed serum sodium of 124mmol/L, potassium 2.4mmol/L, calcium 6.5mmol/L and magnesium of 1.2mg/dL. His testosterone level was low (0.85ng/mL, normal for his age 2.67 to 10.12ng/mL) with normal levels of luteinizing hormone and follicle-stimulating hormone. The sex hormone findings were attributed to delayed puberty. A 24-hour urinary analysis revealed decreased excretion of calcium (25.9mg/24 hours). Based on the findings of hypokalemic metabolic alkalosis without hypertension, severe hypomagnesemia and hypocalciuria, a diagnosis of Gitelman syndrome was made. Treatment was started with oral supplementation of potassium, magnesium and calcium along with spironolactone and liberal salt intake. Diagnosis of Gitelman syndrome is usually made incidentally

  18. Antihypertensive activities of the aqueous extract of Kalanchoe pinnata (Crassulaceae) in high salt-loaded rats.

    PubMed

    Bopda, Orelien Sylvain Mtopi; Longo, Frida; Bella, Thierry Ndzana; Edzah, Protais Marcellin Ohandja; Taïwe, Germain Sotoing; Bilanda, Danielle Claude; Tom, Esther Ngo Lemba; Kamtchouing, Pierre; Dimo, Theophile

    2014-04-28

    The leaves of Kalanchoe pinnata (Crassulaceae) are used in Cameroon folk medicine to manage many diseases such as cardiovascular dysfunctions. In this work, we aimed to evaluate the activities of aqueous leaf extract of Kalanchoe pinnata on the blood pressure of normotensive rat (NTR) and salt hypertensive rats (SHR), as well as its antioxidant properties. Hypertension was induced in rats by oral administration of 18% NaCl for 4 weeks. For the preventive study, three groups of rats received 18% NaCl solution and the plant extract at 25 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day by gavage. Two positive control groups received 18% NaCl solution and either spironolactone (0.71 mg/kg/day) or eupressyl (0.86 mg/kg/day) by gavage for 4 weeks. At the end of this experimental period, systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and heart rate (HR) were measured by the invasive method. Some oxidative stress biomarkers (reduced glutathione (GSH), superoxide dismutase (SOD), nitric monoxide (NO) were evaluated in heart, aorta, liver and kidney. NO level was indirectly evaluated by measuring nitrite concentration. Kalanchoe pinnata extract prevented significantly the increase of systolic and diastolic arterial pressures in high salt-loaded rats (SHR). In SHR, concomitant administration of Kalanchoe pinnata at 25, 50 and 100 mg/kg/day significantly prevented the increase in blood pressure by 32%, 24% and 47% (for SAP); 35%, 33% and 56% (for DAP), respectively. No significant change was recorded in heart rate of those rats. The plant extract improved antioxidant status in various organs, but more potently in aorta. Thus, antioxidant and modulatory effects of Kalanchoe pinnata at the vasculature might be of preponderant contribution to its overall antihypertensive activity. The work demonstrated that the concomitant administration of high-salt and the aqueous extract of Kalanchoe pinnata elicits prevention of salt-induced hypertension in rat. This

  19. Neurohormones and heart failure.

    PubMed

    Mendzef, Scott D; Slovinski, Jennifer R

    2004-12-01

    The management of several neurohormonal pathways is crucial to treating the progression of HF, in addition to improving the quality of life for patients diagnosed with HF. Stimulation of the sympathetic and retin-angiogensin-aldosterone systems begins the initial and primary neurohormonal stimulation associated with the progression of this disease. However, it is becoming increasingly evident that other systems, including the cellular immune, endothelin-NO pathway, kallikrein-kinin system, the arachidonic acid cascade, and the natriuretic peptides need to be considered by clinicians when treating HF. Once treated solely with nitrates, diuretics, and morphine, the management of HF is becoming a more complex and intricate balancing act among several interdependent neurohormonal systems. Understanding the complex nature and proper management of these systems are crucial if patients with HF are to enjoy a better quality of life and experience an improvement in their symptoms. Current recommendations for the treatment and management of HF use several medications, which affect multiple neurohormonal pathways. The Heart Failure Society of America and the American Heart Association both recommend in their recent guidelines for management of HF the use of beta-adrenergic receptor blockers (beta-blockers), loop diuretics, digitalis glycosides(digoxin), ACE-I, aldactone antagonists (spironolactone), and in selected instances, ARBs and the combination of hydralazine and isosorbide dinitrate. No discussion of HF is complete without mention of the larger challenges associated with the management of HF. It is a complex syndrome that requires a multidisciplinary approach with expertise in nutrition, exercise, pharmacology, education, and the basic pathophysiology of complex neurohormonal systems. Patients with uncompensated HF are frightened, vulnerable, and require frequent medication adjustments as well as substantial time dedicated to counseling, physical assessment, and

  20. Nemaline myopathy and heart failure: role of ivabradine; a case report.

    PubMed

    Sarullo, Filippo M; Vitale, Giuseppe; Di Franco, Antonino; Sarullo, Silvia; Salerno, Ylenia; Vassallo, Laura; Baviera, Emanuela Petrona; Marazia, Stefania; Mandalà, Giorgio; Lanza, Gaetano A

    2015-01-19

    Nemaline myopathy (NM) is a rare congenital myopathy characterized by muscle weakness, hypotonia and the presence in muscle fibers of inclusions known as nemaline bodies and a wide spectrum of clinical phenotypes, ranging from severe forms with neonatal onset to asymptomatic forms. The adult-onset form is heterogeneous in terms of clinical presentation and disease progression. Cardiac involvement occurs in the minority of cases and little is known about medical management in this subgroup of NM patients. We report a rare case of heart failure (HF) in a patient with adult-onset NM in whom ivabradine proved to be able to dramatically improve the clinical picture. We report a case of a 37-year-old man with adult-onset NM, presenting with weakness and hypotonia of the proximal limb muscles and shoulder girdle, severely limiting daily activities. He developed progressive HF over a period of 6 months while attending a rehabilitation program, with reduced left ventricular ejection fraction (LVEF = 20%), manifested by dyspnea and signs of systemic congestion. The patient was started HF therapy with enalapril, carvedilol, spironolactone and loop diuretics. Target HF doses of these drugs (including carvedilol) were not reached because of symptomatic hypotension causing a high resting heart rate (HR) ≥70 beats per minute (bpm). Further deterioration of the clinical picture occurred with several life-threatening arrhythmic episodes requiring external defibrillation. An implantable cardioverter defibrillator (ICD) was then implanted. Persistent high resting HR was successfully treated with ivabradine with HR lowering from 90 bpm to 55 bpm at 1 month follow up, LVEF rising to 50% at 3 month follow up and to 54% at 2,5 year follow up. To date no more hospitalizations for heart failure occurred. A single hospitalization due to aspiration pneumonia required insertion of a tracheostomy tube to protect airways from further aspiration. At present, the patient is attending

  1. Sudden Death in Heart Failure With Preserved Ejection Fraction: A Competing Risks Analysis From the TOPCAT Trial.

    PubMed

    Vaduganathan, Muthiah; Claggett, Brian L; Chatterjee, Neal A; Anand, Inder S; Sweitzer, Nancy K; Fang, James C; O'Meara, Eileen; Shah, Sanjiv J; Hegde, Sheila M; Desai, Akshay S; Lewis, Eldrin F; Rouleau, Jean; Pitt, Bertram; Pfeffer, Marc A; Solomon, Scott D

    2018-03-04

    This study investigated the rates and predictors of SD or aborted cardiac arrest (ACA) in HFpEF. Sudden death (SD) may be an important mode of death in heart failure with preserved ejection fraction (HFpEF). We studied 1,767 patients with HFpEF (EF ≥45%) enrolled in the Americas region of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. We identified independent predictors of composite SD/ACA with stepwise backward selection using competing risks regression analysis that accounted for nonsudden causes of death. During a median 3.0-year (25 th to 75 th percentile: 1.9 to 4.4 years) follow-up, 77 patients experienced SD/ACA, and 312 experienced non-SD/ACA. Corresponding incidence rates were 1.4 events/100 patient-years (25 th to 75 th percentile: 1.1 to 1.8 events/100 patient-years) and 5.8 events/100 patient-years (25 th to 75 th percentile: 5.1 to 6.4 events/100 patient-years). SD/ACA was numerically lower but not statistically reduced in those randomized to spironolactone: 1.2 events/100 patient-years (25 th to 75 th percentile: 0.9 to 1.7 events/100 patient-years) versus 1.6 events/100 patient-years (25 th to 75 th percentile: 1.2 to 2.2 events/100 patient-years); the subdistributional hazard ratio was 0.74 (95% confidence interval: 0.47 to 1.16; p = 0.19). After accounting for competing risks of non-SD/ACA, male sex and insulin-treated diabetes mellitus were independently predictive of composite SD/ACA (C-statistic = 0.65). Covariates, including eligibility criteria, age, ejection fraction, coronary artery disease, left bundle branch block, and baseline therapies, were not independently associated with SD/ACA. Sex and diabetes mellitus status remained independent predictors in sensitivity analyses, excluding patients with implantable cardioverter-defibrillators and when predicting SD alone. SD accounted for ∼20% of deaths in HFpEF. Male sex and insulin-treated diabetes mellitus identified

  2. Serum potassium monitoring for users of ethinyl estradiol/drospirenone taking medications predisposing to hyperkalemia: physician compliance and survey of knowledge and attitudes.

    PubMed

    Mona Eng, Patricia; Seeger, John D; Loughlin, Jeanne; Oh, Kelly; Walker, Alexander M

    2007-02-01

    Yasmin-28 [ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP)] contains drospirenone, a progestin component that possesses antimineralocorticoid activity with a potassium-sparing diuretic effect similar to that in spironolactone. Product labeling recommends potassium monitoring in the first month of use for women concurrently receiving medication that may increase serum potassium. We evaluated compliance with this recommendation by measuring monitoring around the date of oral contraceptive (OC) initiation in women who received EE/DRSP while being treated with medications predisposing to hyperkalemia and in similar women who received other OCs. Because preliminary analyses indicated incomplete compliance, we surveyed physicians who prescribed EE/DRSP to women receiving drugs predisposing to hyperkalemia on their knowledge and attitudes with regard to the recommendation. We conducted this study using data from the Ingenix Research Datamart, which includes insurance claims for reimbursement for medical services and prescription medications for approximately 8,000,000 members of a large nationally dispersed health plan. We used claims for pharmacy dispensings of prescription medications to identify all women aged 10-59 years old who initiated EE/DRSP or other OCs during the first 3 years of EE/DRSP availability (July 2001 to June 2004). The frequency of potassium monitoring was measured by identifying claims for serum potassium tests. We conducted a telephone survey of 58 physicians who had prescribed EE/DRSP up to June 2003 to women who received concomitant hyperkalemic drugs. Although potassium monitoring was generally more frequent among EE/DRSP initiators receiving concomitant hyperkalemic drugs than among other OC initiators receiving similar medications, only 40% of 466 EE/DRSP initiators with concurrent hyperkalemic treatment had potassium tests. More than 98% of surveyed physicians were aware of the potassium-sparing property of EE/DRSP. Compared with

  3. Different antihypertensive effect of beta-blocking drugs in low and normal-high renin hypertension.

    PubMed

    Kralberg, B E; Tolagen, K

    1976-05-31

    The treatment response to beta-adrenoceptor blocking drugs was compared in two groups of patients with primary (essential) hypertension and different renin levels. Each group consisted of 25 patients and was equally distributed regarding age, severity and stage of hypertension. In the first group (group 1), the mean upright plasma renin activity was 0.8 ng ml-1h-1 (range 0.3 to 1.5) and the patients were considered to have low renin hypertension. In the other group (group 2) the patients had a mean plasma renin activity of 2.1 ng ml-1h-1 (range 1.1 to 5.1) and were considered to have normal to high renin hypertension. In both groups the patients were initially treated with beta-blocking drugs; in group 1 with a beta-blocker corresponding to an average dose of 311 mg propranolol a day for at least eight weeks and in group 2 with propranolol 320 mg a day in a fixed dose for eight weeks. The hypotensive response differed significantly between the two groups (p less than 0.001). In group 1 the pretreatment blood pressure was 197/117 mm Hg supine and 198/120 mm Hg standing. During treatment blood pressure decreased only 5/3 mm Hg supine and 9/5 mm Hg standing. The pretreatment blood pressure in group 2 was 187/114 mm Hg supine and 186/117 mm Hg standing. Beta-blocking therapy reduced blood pressure 36/23 and 34/18 mm Hg, respectively (both p less than 0.001). Pulse rates fell significantly in the two groups, both in the lying and standing positions. In 17 patients with low renin hypertension (group 1), a volume-depleting drug was added (spironolactone, 14 patients; thiazides, 3 patients) and this achieved a marked fall in blood pressure levels of 38/16 mm Hg supine and 37/19 mm Hg standing (both p less than 0.001). These results suggest the following: (1) Most patients with normal to high plasma renin activity respond well to moderate doses of propranolol. (2) Propranolol given in the same doses is almost without antihypertensive effect in patients with low renin

  4. Eplerenone : a pharmacoeconomic review of its use in patients with post-myocardial infarction heart failure.

    PubMed

    Croom, Katherine F; Plosker, Greg L

    2005-01-01

    US, Dutch, French and Spanish analyses were 15,330-32,405 US dollars (18,089-38,238 euro), 12,148, 8,005-16,922 euro and 12,713-26, 873 euro, respectively. Clinical and pharmacoeconomic data comparing eplerenone with another active drug, such as spironolactone, in this patient population are not available. In conclusion, when added to standard therapy in patients with LV systolic dysfunction and heart failure after an acute MI, eplerenone was associated with significant reductions in mortality and morbidity compared with placebo. Despite some inherent limitations, available pharmacoeconomic data from Europe and the US indicate that eplerenone is a cost-effective treatment compared with placebo in terms of incremental cost per life-year gained in this patient population.

  5. Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress.

    PubMed

    Adamec, R; Muir, C; Grimes, M; Pearcey, K

    2007-05-16

    The roles of beta-NER (beta-noradrenergic receptor), GR (glucocorticoid) and mineral corticoid receptors (MR) in the consolidation of anxiogenic effects of predator stress were studied. One minute after predator stress, different groups of rats were injected (ip) with vehicle, propranolol (beta-NER blocker, 5 and 10 mg/kg), mifepristone (RU486, GR blocker, 20 mg/kg), spironolactone (MR blocker, 50 mg/kg), propranolol (5 mg/kg) plus RU486 (20 mg/kg) or the anxiolytic, chloradiazepoxide (CPZ, 10 mg/kg). One week later, rodent anxiety was assessed in elevated plus maze, hole board, light/dark box, social interaction and acoustic startle. Considering all tests except startle, propranolol dose dependently blocked consolidation of lasting anxiogenic effects of predator stress in all tests. GR receptor block alone was ineffective. However, GR block in combination with an ineffective dose of propranolol did blocked consolidation of predator stress effects in all tests, suggesting a synergism between beta-NER and GR. Surprisingly, MR block prevented consolidation of anxiogenic effects in all tests except the light/dark box. CPZ post stress was ineffective against the anxiogenic impact of predator stress. Study of startle was complicated by the fact that anxiogenic effects of stress on startle amplitude manifested as both an increase and a decrease in startle amplitude. Suppression of startle occurred in stressed plus vehicle injected groups handled three times prior to predator stress. In contrast, stressed plus vehicle rats handled five times prior to predator stress showed increases in startle, as did all predator stressed only groups. Mechanisms of consolidation of the different startle responses appear to differ. CPZ post stress blocked startle suppression but not enhancement of startle. Propranolol post stress had no effect on either suppression or enhancement of startle. GR block alone post stress prevented suppression of startle, but not enhancement. In contrast

  6. Persistent hypertension after adrenalectomy for an aldosterone-producing adenoma: weight as a critical prognostic factor for aldosterone’s lasting effect on the cardiac and vascular systems

    PubMed Central

    Carter, Yvette; Roy, Madhuchhanda; Sippel, Rebecca S.; Chen, Herbert

    2012-01-01

    lower BMI in women (27.6 ± 1.7 versus 33.4 ± 2.1 kg/m2, p=0.04). 90% of the cohort had at least a 20 mmHg decline in their systolic blood pressure post-operatively, placing them in the pre-hypertensive or normal blood pressure categories. 66% of the CURE patients required at least six months for resolution of their hypertension. All twenty patients who presented with hypokalemia, had immediate resolution post-operatively, and did not require continuance of the pre-operative spironolactone or potassium supplementation. Conclusions Laparoscopic adrenalectomy for aldosterone producing adenoma results in the normalization of, or more readily manageable blood pressure in 90% of patients, within six months. Metabolic disturbances are immediately corrected with tumor resection. Weight is an important contributing factor in resolving hypertension. PMID:22921664

  7. Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study

    PubMed Central

    Crellin, Elizabeth; Leyrat, Clémence; Nitsch, Dorothea; Douglas, Ian J; Root, Adrian; Williamson, Elizabeth; Smeeth, Liam; Tomlinson, Laurie A

    2018-01-01

    acute kidney injury, regardless of renin-angiotensin system blockade. However, for people taking renin-angiotensin system blockers and spironolactone treatment with trimethoprim instead of amoxicillin there were 18 additional cases of hyperkalaemia and 11 admissions with acute kidney injury. Conclusion Trimethoprim is associated with a greater risk of acute kidney injury and hyperkalaemia compared with other antibiotics used to treat UTIs, but not a greater risk of death. The relative risk increase is similar across population groups, but the higher baseline risk among those taking renin-angiotensin system blockers and potassium-sparing diuretics translates into higher absolute risks of acute kidney injury and hyperkalaemia in these groups. PMID:29438980

  8. Hair loss in women.

    PubMed

    Camacho-Martínez, Francisco M

    2009-03-01

    Female pattern hair loss (FPHL) is a clinical problem that is becoming more common in women. Female alopecia with androgen increase is called female androgenetic alopecia (FAGA) and without androgen increase is called female pattern hair loss. The clinical picture of typical FAGA begins with a specific "diffuse loss of hair from the parietal or frontovertical areas with an intact frontal hairline." Ludwig called this process "rarefaction." In Ludwig's classification of hair loss in women, progressive type of FAGA, 3 patterns were described: grade I or minimal, grade II or moderate, and grade III or severe. Ludwig also described female androgenetic alopecia with male pattern (FAGA.M) that should be subclassified according to Ebling's or Hamilton-Norwood's classification. FAGA.M may be present in 4 conditions: persistent adrenarche syndrome, alopecia caused by an adrenal or an ovarian tumor, posthysterectomy, and as an involutive alopecia. A more recent classification (Olsen's classification of FPHL) proposes 2 types: early- and late-onset with or without excess of androgens in each. The diagnosis of FPHL is made by clinical history, clinical examination, wash test, dermoscopy, trichoscan, trichograms and laboratory test, especially androgenic determinations. Topical treatment of FPHL is with minoxidil, 2-5% twice daily. When FPHL is associated with high levels of androgens, systemic antiandrogenic therapy is needed. Persistent adrenarche syndrome (adrenal SAHA) and alopecia of adrenal hyperandrogenism is treated with adrenal suppression and antiandrogens. Adrenal suppression is achieved with glucocorticosteroids. Antiandrogens therapy includes cyproterone acetate, drospirenone, spironolactone, flutamide, and finasteride. Excess release of ovarian androgens (ovarian SAHA) and alopecia of ovarian hyperandrogenism is treated with ovarian suppression and antiandrogens. Ovarian suppression includes the use of contraceptives containing an estrogen, ethinylestradiol, and a

  9. Hypertension Treatment in Patients with Metabolic Syndrome and/or Type 2 Diabetes Mellitus: Analysis of the Therapy Effectivity and the Therapeutic Inertia in Outpatient Study

    PubMed Central

    Strišková, Andrea; Borčin, Marián

    2018-01-01

    We have analysed the database of 1,595 consecutive patients visiting our department of cardiology and internal medicine clinic in 2005–2014. The analysis included 13,990 visit records, and the average number of visits per patient was 8.5 ± 7.0. Our goals were to evaluate the effectivity of hypertension treatment as for drug choice, decrease of sBP and dBP associated with a certain drug, a drug combination, and therapeutic inertia in patients with metabolic syndrome and/or diabetes mellitus. The final number of patients for analysis who fulfilled the inclusion criteria for interpenetration of both diagnostic circles was 570. Results. 15% of patients were treated using hypertension monotherapy, 70% of patients were treated using 2- to 4-drug combination therapy, and 15% of patients were treated using 5- to 6-drug combination. The drugs used most frequently were perindopril (perin), nitrendipine (nitre), amlodipine (amlo), telmisartan (telmi), hydrochlorothiazide (hydro), rilmenidine, and nebivolol (used in >100 patients). The most significant decrease of sBP was associated with treatment by nitre, hydro, telmi, and urapidil (>19 mmHg). The most significant decrease of dBP was associated with treatment by nitre, hydro, telmi, and verapamil (>10 mmHg). The most significant decrease of both sBP and dBP was associated with treatment using 3-drug combination of telmi + hydro + spironolactone (41 and 16 mmHg, resp.), telmi + hydro + nitre (34 and 15 mmHg, resp.), and telmi + hydro + urapidil (34 and 15 mmHg, resp.). At the last visit, 281 out of 413 patients at the first visit had sBP >140 mmHg (68%); that is, sBP control was 32%. At the last visit, 76 patients out of 217 at the first visit had dBP >90 mmHg (35%); that is, dBP control was 65%. Therapeutic inertia was calculated by evaluating the proportion of visits at which sBP was above the target for eligible visits minus the proportion of visits where the change was made in

  10. Prognostic value of a new cardiopulmonary exercise testing parameter in chronic heart failure: oxygen uptake efficiency at peak exercise - comparison with oxygen uptake efficiency slope.

    PubMed

    Toste, Alexandra; Soares, Rui; Feliciano, Joana; Andreozzi, Valeska; Silva, Sofia; Abreu, Ana; Ramos, Ruben; Santos, Ninel; Ferreira, Lurdes; Ferreira, Rui Cruz

    2011-10-01

    A growing body of evidence shows the prognostic value of oxygen uptake efficiency slope (OUES), a cardiopulmonary exercise test (CPET) parameter derived from the logarithmic relationship between O(2) consumption (VO(2)) and minute ventilation (VE) in patients with chronic heart failure (CHF). To evaluate the prognostic value of a new CPET parameter - peak oxygen uptake efficiency (POUE) - and to compare it with OUES in patients with CHF. We prospectively studied 206 consecutive patients with stable CHF due to dilated cardiomyopathy - 153 male, aged 53.3±13.0 years, 35.4% of ischemic etiology, left ventricular ejection fraction 27.7±8.0%, 81.1% in sinus rhythm, 97.1% receiving ACE-Is or ARBs, 78.2% beta-blockers and 60.2% spironolactone - who performed a first maximal symptom-limited treadmill CPET, using the modified Bruce protocol. In 33% of patients an cardioverter-defibrillator (ICD) or cardiac resynchronization therapy device (CRT-D) was implanted during follow-up. Peak VO(2), percentage of predicted peak VO(2), VE/VCO(2) slope, OUES and POUE were analyzed. OUES was calculated using the formula VO(2) (l/min) = OUES (log(10)VE) + b. POUE was calculated as pVO(2) (l/min) / log(10)peakVE (l/min). Correlation coefficients between the studied parameters were obtained. The prognosis of each variable adjusted for age was evaluated through Cox proportional hazard models and R2 percent (R2%) and V index (V6) were used as measures of the predictive accuracy of events of each of these variables. Receiver operating characteristic (ROC) curves from logistic regression models were used to determine the cut-offs for OUES and POUE. pVO(2): 20.5±5.9; percentage of predicted peak VO(2): 68.6±18.2; VE/VCO(2) slope: 30.6±8.3; OUES: 1.85±0.61; POUE: 0.88±0.27. During a mean follow-up of 33.1±14.8 months, 45 (21.8%) patients died, 10 (4.9%) underwent urgent heart transplantation and in three patients (1.5%) a left ventricular assist device was implanted. All variables proved

  11. Hypertension Treatment in Patients with Metabolic Syndrome and/or Type 2 Diabetes Mellitus: Analysis of the Therapy Effectivity and the Therapeutic Inertia in Outpatient Study.

    PubMed

    Farský, Štefan; Strišková, Andrea; Borčin, Marián

    2018-01-01

    We have analysed the database of 1,595 consecutive patients visiting our department of cardiology and internal medicine clinic in 2005-2014. The analysis included 13,990 visit records, and the average number of visits per patient was 8.5 ± 7.0. Our goals were to evaluate the effectivity of hypertension treatment as for drug choice, decrease of sBP and dBP associated with a certain drug, a drug combination, and therapeutic inertia in patients with metabolic syndrome and/or diabetes mellitus. The final number of patients for analysis who fulfilled the inclusion criteria for interpenetration of both diagnostic circles was 570. Results . 15% of patients were treated using hypertension monotherapy, 70% of patients were treated using 2- to 4-drug combination therapy, and 15% of patients were treated using 5- to 6-drug combination. The drugs used most frequently were perindopril (perin), nitrendipine (nitre), amlodipine (amlo), telmisartan (telmi), hydrochlorothiazide (hydro), rilmenidine, and nebivolol (used in >100 patients). The most significant decrease of sBP was associated with treatment by nitre, hydro, telmi, and urapidil (>19 mmHg). The most significant decrease of dBP was associated with treatment by nitre, hydro, telmi, and verapamil (>10 mmHg). The most significant decrease of both sBP and dBP was associated with treatment using 3-drug combination of telmi + hydro + spironolactone (41 and 16 mmHg, resp.), telmi + hydro + nitre (34 and 15 mmHg, resp.), and telmi + hydro + urapidil (34 and 15 mmHg, resp.). At the last visit, 281 out of 413 patients at the first visit had sBP >140 mmHg (68%); that is, sBP control was 32%. At the last visit, 76 patients out of 217 at the first visit had dBP >90 mmHg (35%); that is, dBP control was 65%. Therapeutic inertia was calculated by evaluating the proportion of visits at which sBP was above the target for eligible visits minus the proportion of visits where the change was made in

  12. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial.

    PubMed

    Azizi, Michel; Sapoval, Marc; Gosse, Philippe; Monge, Matthieu; Bobrie, Guillaume; Delsart, Pascal; Midulla, Marco; Mounier-Véhier, Claire; Courand, Pierre-Yves; Lantelme, Pierre; Denolle, Thierry; Dourmap-Collas, Caroline; Trillaud, Hervé; Pereira, Helena; Plouin, Pierre-François; Chatellier, Gilles

    2015-05-16

    Conflicting blood pressure-lowering effects of catheter-based renal artery denervation have been reported in patients with resistant hypertension. We compared the ambulatory blood pressure-lowering efficacy and safety of radiofrequency-based renal denervation added to a standardised stepped-care antihypertensive treatment (SSAHT) with the same SSAHT alone in patients with resistant hypertension. The Renal Denervation for Hypertension (DENERHTN) trial was a prospective, open-label randomised controlled trial with blinded endpoint evaluation in patients with resistant hypertension, done in 15 French tertiary care centres specialised in hypertension management. Eligible patients aged 18-75 years received indapamide 1·5 mg, ramipril 10 mg (or irbesartan 300 mg), and amlodipine 10 mg daily for 4 weeks to confirm treatment resistance by ambulatory blood pressure monitoring before randomisation. Patients were then randomly assigned (1:1) to receive either renal denervation plus an SSAHT regimen (renal denervation group) or the same SSAHT alone (control group). The randomisation sequence was generated by computer, and stratified by centres. For SSAHT, after randomisation, spironolactone 25 mg per day, bisoprolol 10 mg per day, prazosin 5 mg per day, and rilmenidine 1 mg per day were sequentially added from months two to five in both groups if home blood pressure was more than or equal to 135/85 mm Hg. The primary endpoint was the mean change in daytime systolic blood pressure from baseline to 6 months as assessed by ambulatory blood pressure monitoring. The primary endpoint was analysed blindly. The safety outcomes were the incidence of acute adverse events of the renal denervation procedure and the change in estimated glomerular filtration rate from baseline to 6 months. This trial is registered with ClinicalTrials.gov, number NCT01570777. Between May 22, 2012, and Oct 14, 2013, 1416 patients were screened for eligibility, 106 of those were randomly assigned to treatment

  13. Eplerenone for hypertension.

    PubMed

    Tam, Tina Sc; Wu, May Hy; Masson, Sarah C; Tsang, Matthew P; Stabler, Sarah N; Kinkade, Angus; Tung, Anthony; Tejani, Aaron M

    2017-02-28

    Eplerenone is an aldosterone receptor blocker that is chemically derived from spironolactone. In Canada, it is indicated for use as adjunctive therapy to reduce mortality for heart failure patients with New York Heart Association (NYHA) class II systolic chronic heart failure and left ventricular systolic dysfunction. It is also used as adjunctive therapy for patients with heart failure following myocardial infarction. Additionally, it is indicated for the treatment of mild and moderate essential hypertension for patients who cannot be treated adequately with other agents. It is important to determine the clinical impact of all antihypertensive medications, including aldosterone antagonists, to support their continued use in essential hypertension. No previous systematic reviews have evaluated the effect of eplerenone on cardiovascular morbidity, mortality, and magnitude of blood pressure lowering in patients with hypertension. To assess the effects of eplerenone monotherapy versus placebo for primary hypertension in adults. Outcomes of interest were all-cause mortality, cardiovascular events (fatal or non-fatal myocardial infarction), cerebrovascular events (fatal or non fatal strokes), adverse events or withdrawals due to adverse events, and systolic and diastolic blood pressure. We searched the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers up to 3 March 2016. We handsearched references from retrieved studies to identify any studies missed in the initial search. We also searched for unpublished data by contacting the corresponding authors of the included studies and pharmaceutical companies involved in conducting studies on eplerenone monotherapy in primary hypertension. The search had no language restrictions. We selected randomized placebo-controlled trials studying adult patients with primary hypertension. We excluded studies in people with secondary or gestational hypertension and studies where participants

  14. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME--PART 1.

    PubMed

    Goodman, Neil F; Cobin, Rhoda H; Futterweit, Walter; Glueck, Jennifer S; Legro, Richard S; Carmina, Enrico

    2015-11-01

    , alopecia, and acne. Cycle length >35 days suggests chronic anovulation, but cycle length slightly longer than normal (32 to 35 days) or slightly irregular (32 to 35-36 days) needs assessment for ovulatory dysfunction. Ovulatory dysfunction is associated with increased prevalence of endometrial hyperplasia and endometrial cancer, in addition to infertility. In PCOS, hirsutism develops gradually and intensifies with weight gain. In the neoplastic virilizing states, hirsutism is of rapid onset, usually associated with clitoromegaly and oligomenorrhea. Girls with severe acne or acne resistant to oral and topical agents, including isotretinoin (Accutane), may have a 40% likelihood of developing PCOS. Hair loss patterns are variable in women with hyperandrogenemia, typically the vertex, crown or diffuse pattern, whereas women with more severe hyperandrogenemia may see bitemporal hair loss and loss of the frontal hairline. Oral contraceptives (OCPs) can effectively lower androgens and block the effect of androgens via suppression of ovarian androgen production and by increasing sex hormone-binding globulin. Physiologic doses of dexamethasone or prednisone can directly lower adrenal androgen output. Anti-androgens can be used to block the effects of androgen in the pilosebaceous unit or in the hair follicle. Anti-androgen therapy works through competitive antagonism of the androgen receptor (spironolactone, cyproterone acetate, flutamide) or inhibition of 5α-reductase (finasteride) to prevent the conversion of T to its more potent form, 5α-dihydrotestosterone. The choice of antiandrogen therapy is guided by symptoms. The diagnosis of PCOS in adolescents is particularly challenging given significant age and developmental issues in this group. Management of infertility in women with PCOS requires an understanding of the pathophysiology of anovulation as well as currently available treatments. Many features of PCOS, including acne, menstrual irregularities, and hyperinsulinemia

  15. Interventions for central serous chorioretinopathy: a network meta-analysis

    PubMed Central

    Salehi, Mahsa; Wenick, Adam S; Law, Hua Andrew; Evans, Jennifer R; Gehlbach, Peter

    2016-01-01

    improvement in vision (MD −0.10 logMAR, 95% CI −0.18 to −0.02), less recurrence (risk ratio (RR) 0.10, 95% CI 0.01 to 0.81) and less persistent CSC (RR 0.12, 95% CI 0.01 to 1.02) at 12 months compared to sham treatment. There were no significant adverse events noted. Low quality evidence from two trials (56 participants) comparing anti-VEGF to low-fluence PDT in chronic CSC found little evidence for any difference in visual acuity at 12 months (MD 0.03 logMAR, 95% CI −0.08 to 0.15). There was some evidence that more people in the anti-VEGF group had recurrent CSC compared to people treated with PDT but, due to inconsistency between trials, it was difficult to estimate an effect. More people in the anti-VEGF group had persistent CSC at 12 months (RR 6.19, 95% CI 1.61 to 23.81; 34 participants). Two small trials of micropulse laser, one in people with acute CSC and one in people with chronic CSC, provided low quality evidence that laser treatment may lead to better visual acuity (MD −0.20 logMAR, 95% CI −0.30 to −0.11; 45 participants). There were no significant adverse effects noted. Other comparisons were largely inconclusive. We identified 12 ongoing trials covering the following interventions: aflibercept and eplerenone in acute CSC; spironolactone, eplerenone, lutein, PDT, and micropulse laser in chronic CSC; and micropulse laser and oral mifepristone in two trials where type of CSC not clearly specified. Authors’ conclusions CSC remains an enigmatic condition in large part due to a natural history of spontaneous improvement in a high proportion of people and also because no single treatment has provided overwhelming evidence of efficacy in published RCTs. While a number of interventions have been proposed as potentially efficacious, the quality of study design, execution of the study and the relatively small number of participants enrolled and followed to revealing endpoints limits the utility of existing data. It is not clear whether there is a clinically

  16. Interventions for female pattern hair loss.

    PubMed

    van Zuuren, Esther J; Fedorowicz, Zbys; Schoones, Jan

    2016-05-26

    L was not assessed. Only one study addressed adverse events (137 participants) (RR 1.03, 95% CI 0.45 to 2.34; low quality evidence). In two studies (219 participants) there was no clinically meaningful difference in change of hair count, whilst one study (12 participants) favoured finasteride (low quality evidence).Two studies (141 participants) evaluated low-level laser comb therapy compared to a sham device. According to the participants, the low-level laser comb was not more effective than the sham device (RR 1.54, 95% CI 0.96 to 2.49; and RR 1.18, 95% CI 0.74 to 1.89; moderate quality evidence). However, there was a difference in favour of low-level laser comb for change from baseline in hair count (MD 17.40, 95% CI 9.74 to 25.06; and MD 17.60, 95% CI 11.97 to 23.23; low quality evidence). These studies did not assess QoL and did not report adverse events per treatment arm and only in a generic way (low quality evidence). Low-level laser therapy against sham comparisons in two separate studies also showed an increase in total hair count but with limited further data.Single studies addressed the other comparisons and provided limited evidence of either the efficacy or safety of these interventions, or were unlikely to be examined in future trials. Although there was a predominance of included studies at unclear to high risk of bias, there was evidence to support the efficacy and safety of topical minoxidil in the treatment of FPHL (mainly moderate to low quality evidence). Furthermore, there was no difference in effect between the minoxidil 2% and 5% with the quality of evidence rated moderate to low for most outcomes. Finasteride was no more effective than placebo (low quality evidence). There were inconsistent results in the studies that evaluated laser devices (moderate to low quality evidence), but there was an improvement in total hair count measured from baseline.Further randomised controlled trials of other widely-used treatments, such as spironolactone