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

Purpose: Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7alpha-thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age. Methods: The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites, and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed‐effects modelling software Monolix 2018R2. Results: A total of 150 spironolactone, 158 TMS, and 158 CAN concentrations from 23 patients (ages: 3 days–21 months; median weight 4.3 kg (2.2–12.6)) were available for PK analysis. A one-compartment model for spironolactone, TMS, and CAN best fitted the data. The median (range) of individual estimated apparent clearance values were 47.7 (11.9–138.1) L/h for spironolactone, 9.7 (1.5–66.9) L/h for TMS, and 1.0 (0.2–5.9) L/h for CAN. The disposition of spironolactone and metabolites was mainly affected by size of the patient: body weight explained 22% of inter-individual variability of spironolactone clearance. None of the undesirable effects of spironolactone was documented during the study period. Conclusion: The pharmacokinetics of spironolactone and its metabolites was highly variable between patients below 2 years of age. Body weight explained a significant part of this variability; this highlights the need to take it into account for dosing prescription in this population. (Clinical trial Registration Number 2013–001189-40). [ABSTRACT FROM AUTHOR]

Introduction: Androgenic alopecia (AGA) is the most common cause of hair loss in women, affecting their quality of life. The present study was conducted with the aim of comparing the combined effect of topical minoxidil and oral spironolactone with the combined effect of topical minoxidil and oral finasteride in women with AGA, female and male hair loss patterns. Method: This clinical study was performed on 60 women suffering from AGA. The patients were divided into two groups receiving spironolactone 100 mg/day and finasteride 5 mg/day. In addition, a 2% minoxidil solution was used in all patients in addition to treatment with finasteride or spironolactone. At 2 months after initiation and at the end of treatment, patients were evaluated using the Ludwig/Norwood–Hamilton scale and the degree of physician and patient satisfaction. Results: After 2 months, hair density, hair thickness, and hair loss had improved in both groups; however, statistically, there was no significant difference between the two groups with respect to these parameters (p > 0.05). After 4 months, a significant difference was found between the two groups in terms of treatment response (physician satisfaction), hair density, and hair loss severity. So that, the drugs used were ineffective in 6.7% of cases in the minoxidil‐spironolactone group and in 16.7% of cases in the minoxidil‐finasteride group. In addition, 43.3% of cases in the minoxidil‐spironolactone group and 53% in the minoxidil‐finasteride group responded well to treatment. The treatment effect was excellent in 56.7% and 0% of the mentioned groups, respectively, and the mentioned difference was statistically significant (p: 0.01). The response to treatment in female pattern hair loss (FPHL) was not statistically significant (p: 0.52), but there was a significant difference in the response to both treatments in male pattern hair loss (MPHL; p: 0.007). In terms of patient satisfaction, minoxidil‐spironolactone treatment was significantly better than minoxidil‐finasteride regarding hair density and severity of hair loss (p: 0.01). Finally, in terms of treatment complications, the patients in two groups did not have any serious adverse effects. Conclusion: The combination of minoxidil and spironolactone could be considered a more effective treatment than the combination of minoxidil and finasteride in women with AGA, FPHL, and MPHL. [ABSTRACT FROM AUTHOR]

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

The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism. [ABSTRACT FROM AUTHOR]

Simultaneous measurement of spironolactone and canrenone in urine and plasma provides valuable insight into renal function, and therapeutic efficacy and can be utilized to identify potential health risks and ensure patient safety throughout treatment. By adopting greener methods to analyze these compounds, significant reductions in the environmental impact of such studies can be achieved. For this purpose, a sensitive and eco-friendly solvent bar microextraction method using natural deep eutectic solvent (NDE) followed by high-performance liquid chromatography-diode array detection (HPLC–DAD) was developed to determine spironolactone and canrenone in urine and plasma samples. The extraction solvents were synthesized using NDE-based terpenoids containing menthol and camphor in various ratios. The extraction efficiency percentage (EE%) of both drugs was measured using response surface methodology (RSM) based on central composite design (CCD), and 29 extraction tests were conducted to determine the optimum conditions. Although all parameters were found to be significant, the extraction and elution times were critical for isolating the target analytes. Under optimized conditions, the linear dynamic ranges for spironolactone (SPI)/canrenone (CAN) were 11.7–104/13.1–104 μg L−1 and 21.7–104/24.6–104 μg L−1 in urine and plasma samples, respectively with R2 ≥ 0.993. The ranges of intra-/interprecision (relative standard deviation (RSD) %, n = 5) were 1.31–9.17%/ 2.4–11% with extraction recovery ≥ 88.6% for both drugs. The comparison findings with previously published methods confirmed that the developed NDE-solvent bar microextraction (SBME)-HPLC–DAD method for spironolactone and canrenone analysis displayed confident sensitivity, feasible operation, and simple analysis. Furthermore, the method's applicability and effectiveness were proven by successfully analyzing spironolactone and its metabolite canrenone in patients' urine and plasma samples. [ABSTRACT FROM AUTHOR]

We aimed to determine the efficacy of the various available oral, topical, and procedural treatment options for hair loss in individuals with androgenic alopecia. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review of the National Library of Medicine was performed. Overall, 141 unique studies met our inclusion criteria. We demonstrate that many over the counter (e.g. topical minoxidil, supplements, low-level light treatment), prescription (e.g. oral minoxidil, finasteride, dutasteride), and procedural (e.g. platelet-rich plasma, fractionated lasers, hair transplantation) treatments successfully promote hair growth, highlighting the superiority of a multifaceted and individualized approach to management. [ABSTRACT FROM AUTHOR]

Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4 medications regardless of blood pressure, occurs in ≤ 15% of treated hypertensives. Apparent refractory hypertension, defined as uncontrolled office pressure despite use of 5 or more medications including a diuretic, occurs in ≤ 10% of resistant cases. Both are associated with increased comorbidity and enhanced cardiovascular risk. To rule out pseudo-resistant or pseudo-refractory hypertension, employ guideline-based methodology for obtaining pressure, maximize the regimen, rule out white-coat effect, and assess adherence. True resistant hypertension is characterized by volume overload and aldosterone excess, refractory by enhanced sympathetic tone. Spironolactone is the preferred agent for resistance, with lower doses. Spironolactone, potassium binders, or both, are preferred if the estimated glomerular filtration rate is below 45. If significant albuminuria, finerenone is indicated. The optimal treatment of refractory hypertension is unclear, but sympathetic inhibition (α-β blockade, centrally acting sympathoinhibitors, or both) seems reasonable. Renal denervation has shown minimal benefit for resistance, but its role in refractory hypertension remains to be defined. [ABSTRACT FROM AUTHOR]

The skin microbiome consists of the microorganisms populating the human skin. Cutibacterium acnes (C. acnes, formerly named Propionibacterium acnes) is recognized as a key factor in acne development, regulating inflammatory and immune pathways. Dysbiosis has been described as the imbalance in skin microbiome homeostasis and may play a role in acne pathogenesis. Microbial interference has been shown to be a contributor to healthy skin homeostasis and staphylococcal strains may exclude acne-associated C. acnes phylotypes. In this review we present an update on the skin microbiome in acne and discuss how current acne treatments such as benzoyl peroxide, orally administered isotretinoin, and antibiotics may affect the skin microbiome homeostasis. We highlight the collateral damage of acne antibiotics on the skin microbiome, including the risk of antimicrobial resistance and the dysregulation of the microbiome equilibrium that may occur even with short-term antibiotic courses. Consequently, the interest is shifting towards new non-antibiotic pharmacological acne treatments. Orally administered spironolactone is an emerging off-label treatment for adult female patients and topical peroxisome proliferator-activated receptor gamma (PPARγ) modulation is being studied for patients with acne. The potential application of topical or oral probiotics, bacteriotherapy, and phage therapy for acne are further promising areas of future research. [ABSTRACT FROM AUTHOR]

Purpose: Spironolactone (SPN), which is classified as an anti-androgen, has demonstrated efficacy in treating acne. This study aimed to utilize ultrasonication to create a chitosan-coated nano lipid carrier (NLC) for enhancing the delivery of SPN to the skin and treating acne. Methods: Various hydrophilic-lipophilic balance (HLB) values were investigated to optimize the SPN-NLCs. Photon correlation spectroscopy, attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), transmission electron microscopy (TEM), and differential scanning calorimetry (DSC) were employed to characterize the solid state of SPN in nanoparticle form. Additionally, the optimized formulation was used in a double-blind, randomized clinical trial. Results: Reducing the HLB of the surfactant mixtures resulted in a reduction in the size of SPNNLCs. The formula with the smallest particle diameter (238.4±0.74 nm) and the lowest HLB value (9.65) exhibited the highest encapsulation efficiency (EE) of 79.88±1.807%. Coating the optimized SPN-NLC with chitosan increased the diameter, polydispersity index (PDI), zeta potential (ZP), and EE. In vitro skin absorption studies demonstrated sustained release profiles for chitosan-coated SPN-NLC. In the double-blind trial, a gel containing chitosan-coated SPN-NLC effectively treated mild to moderate acne vulgaris, leading to improved healing and reduced lesion count after 8 weeks of therapy compared to the placebo. It successfully addressed both non-inflammatory and inflammatory lesions without adverse effects on the skin. Conclusion: The findings indicate that chitosan-coated SPN-NLCs have the potential as nanoparticles for targeted SPN delivery to the skin, offering novel options for the treatment of acne vulgaris. [ABSTRACT FROM AUTHOR]

Background & Objective: Heart failure (HF), as the final stage of cardiovascular disease, is a prevalent cause of mortality, disability, and recurrent hospitalization. Effective treatment of systolic HF is crucial for reducing patient disability and preventing repeated hospital admissions. In this context, we aimed to conduct a comparative study of spironolactone at doses of 25 mg and 50 mg in patients with systolic HF. Materials & Methods: This randomized clinical trial was performed on 100 patients with systolic HF. The patients were randomly divided into two treatment groups receiving 25 and 50 mg of spironolactone. Subsequently, changes in ejection fraction, frequency of hospitalization, performance capacity, quality of life, and electrolyte disorders were examined. Results: There was no significant difference between the groups in terms of age, sex, cardiovascular risk factors, history of cerebrovascular accidents, readmission rate, and EF changes (P>0.05). At the end of the study, the mean scores of performance capacity and quality of life in patients receiving 50 mg of spironolactone were 204.3±28 and 32±3.1, respectively. These values were statistically higher than those reported in patients receiving 25 mg of spironolactone (178.9±30 and 36.7±3.3, respectively) (P<0.001). In patients who received 50 mg of spironolactone, the average levels of potassium and blood urea nitrogen were 0.68±0.08 and 6.1±1.4, respectively. These levels were significantly higher compared to those in patients receiving a 25mg dose, where the levels were 0.39±0.17 and 4.7±2.8, respectively (P<0.05). However, it is important to note that the maximum values observed did not exceed the normal range for these parameters Conclusion: Compared to the 25mg dose, the 50mg dose of spironolactone was observed to enhance both the quality of life and performance capacity in patients with systolic HF. Therefore, it can be prescribed as the initial daily dosage for managing patients with HF. [ABSTRACT FROM AUTHOR]

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Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin–angiotensin system. In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However, the associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events. Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of hypertension in patients with CKD. [ABSTRACT FROM AUTHOR]

Introduction: Treatment of mood and cognitive symptoms of patients with bipolar disorder is associated with many complications and is generally not associated with therapeutic satisfaction. In this clinical trial, we evaluated the effectiveness of spironolactone in controlling mood and cognitive symptoms, sleep quality, appetite, and body mass index in patients with bipolar disorder in manic episodes. Methods: Sixty inpatients with bipolar disorder in manic episodes were treated with spironolactone/placebo in an 8‐week randomized, double‐blind, placebo‐controlled clinical trial. They were evaluated using the Young Mania Rating Scale (YMRS), mini‐mental state examination (MMSE), Pittsburgh sleep quality index, Simplified Nutritional Appetite Questionnaire, and body mass index in weeks 1, 4, and 8. Results: For cognitive impairment (MMSE), there were significant interaction effects of group and time at week 8 (B = −1.60, SE = 0.69, t = −2.33, p =.021) such that individuals in the spironolactone group experienced more improvement in their cognitive performance. For manic symptoms (YMRS), there were no significant interaction effects of group and time at week 8 (B = −2.53, SE = 1.46, t = −1.73, p =.085). Conclusions: Considering the promising findings in this clinical trial, further study of spironolactone as adjunctive therapy in bipolar disorder in manic episodes with larger sample sizes, multicenter settings, and longer follow‐ups are recommended. [ABSTRACT FROM AUTHOR]

There are mounting data that at least 30% of hypertensives who are appropriately screened have primary aldosteronism (PA), rather than the commonly reported figure of 5% to 10%. Second, there are similar data that undertreated patients with PA have a 3-fold higher risk profile than essential hypertensives with the same blood pressure levels. Third, clinicians managing hypertension measure success as sustainable lowering of blood pressure; untreated hypertensive patients with PA are thus in double jeopardy. Finally, and crucially, fewer than 1% of patients with hypertension are ever screened--let alone investigated--for PA. Accordingly, for "Who should we screen?" the answer is simple--all patients with hypertension. For "How they should be screened?" the answer is also simple--add spironolactone 25 mg/day for 4 weeks and measure the blood pressure response. In established hypertension, a fall of <10 mmHg means PA is unlikely; above 12 mm Hg PA, it is probable. Newly presenting hypertension is much the same--hold off on first-order antihypertensive(s) and prescribe spironolactone 25 mg/day for 4 weeks. If blood pressure falls into the normal range, continue; if it does not, prescribe a standard antihypertensive. It is likely that the above protocols--a first start, amenable to refinement--will find additional hypertensives with unilateral PA; it is probable that the overwhelming majority will have bilateral disease. What this means is that we have a major public health issue on our hands: how can this be the case? [ABSTRACT FROM AUTHOR]

IntroductionPolycystic ovary syndrome (PCOS) is often associated with metabolic-associated fatty liver disease (MAFLD). MAFLD has been associated with altered hepatic function, systemic dysmetabolism, and abnormal circulating levels of signaling molecules called organokines. Here, we assessed the effects of two randomized treatments on a set of organokines in adolescent girls with PCOS and without obesity, and report the associations with circulating biomarkers of liver damage, which were assessed longitudinally in the aforementioned studies as safety markers.Materials and methodsLiver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT)] were assessed as safety markers in previous randomized pilot studies comparing the effects of an oral contraceptive (OC) with those of a low-dose combination of spironolactone-pioglitazone-metformin (spiomet) for 1 year. As a post hoc endpoint, the organokines fibroblast growth factor-21 (FGF21), diazepam-binding protein-1 (DBI), and meteorin-like protein (METRNL) were assessed by ELISA after 6 months of OC (N = 26) or spiomet (N = 28). Auxological, endocrine-metabolic, body composition (using DXA), and abdominal fat partitioning (using MRI) were also evaluated. Healthy, age-matched adolescent girls (N = 17) served as controls.ResultsCirculating ALT and GGT levels increased during OC treatment and returned to baseline concentrations in the post-treatment phase; in contrast, spiomet treatment elicited no detectable changes in ALT and GGT concentrations. In relation to organokines after 6 months of treatment, (1) FGF21 levels were significantly higher in PCOS adolescents than in control girls; (2) DBI levels were lower in OC-treated girls than in controls and spiomet-treated girls; and (3) no differences were observed in METRNL concentrations between PCOS girls and controls. Serum ALT and GGT levels were directly correlated with circulating METRNL levels only in OC-treated girls (R = 0.449, P = 0.036 and R = 0.552, P = 0.004, respectively).ConclusionThe on-treatment increase in ALT and GGT levels occurring only in OC-treated girls is associated with circulating METRNL levels, suggesting enhanced METRNL synthesis as a reaction to the hepatic changes elicited by OC treatment.Clinical Trial Registrationhttps://doi.org, identifiers 10.1186/ISRCTN29234515, 10.1186/ISRCTN11062950.

The literature review is devoted to modern ideas about the role of hyperaldosteronism as one of the important pathophysiological links in hypertension (HTN) development. Data are presented on aldosterone synthesis mechanisms both in healthy and sick people, in particular in primary aldosteronism (PA), as well as in some cases of secondary aldosteronism. The results of modern studies are discussed, which established autonomous formation of aldosterone in elderly and senile people even without formal criteria for PA. The most important stages of studying and solving the hyperaldosteronism problem using surgical or conservative methods areconsidered. Data are presented on target organ damage caused by an increased blood concentration of aldosterone. The influence of the interaction between increased dietary sodium intake and the severity of cardiovascular damage is discussed. Separately, the role of subclinical hyperaldosteronism in the development of hypertension is considered, as well as the possibility of target organ damage in such cases, despite the normal blood pressure level. Modern data on the role of mineralocorticoid receptor antagonists (MRAs), in particular spironolactone, in the treatment of hyperaldosteronism and resistant hypertension are presented. The limitations of MRA use, which are mainly due to reduced kidney function, are considered. In particular, the results of the most important clinical studies are discussed, which became the basis for higher prescription rate of MRAs in the treatment of hypertensive patients.

In recent years, multiple novel and improved therapies have become available to treat alopecia disorders. Whereas many therapeutics are entirely new, some medications, such as oral minoxidil, have been available for years and are just now being revisited as potentially valuable hair loss treatments. This article discusses the risks, benefits, and potential side effects of the off-label use of low-dose oral minoxidil. It compares low-dose oral minoxidil with topical minoxidil, a well-established and FDA-approved treatment for androgenetic alopecia, but one that is often associated with poor overall adherence. Finally, nursing considerations in the education and care of patients with alopecia disorders and associated medications are discussed. [ABSTRACT FROM AUTHOR]

Quantitative systems pharmacology (QSP) models are rarely applied prospectively for decision-making in clinical practice. We therefore aimed to operationalize a QSP model for potas-sium homeostasis to predict potassium trajectories based on spironolactone administrations. For this purpose, we proposed a general workflow that was applied to electronic health records (EHR) from patients treated in a German tertiary care hospital. The workflow steps included model exploration, local and global sensitivity analyses (SA), identifiability analysis (IA) of model parameters, and specification of their inter-individual variability (IIV). Patient covariates, selected parameters, and IIV then defined prior information for the Bayesian a posteriori prediction of individual potassium trajectories of the following day. Following these steps, the successfully operationalized QSP model was interactively explored via a Shiny app. SA and IA yielded five influential and estimable parameters (extracellular fluid volume, hyperaldosteronism, mineral corticoid receptor abundance, potassium intake, sodium intake) for Bayesian prediction. The operationalized model was validated in nine pilot patients and showed satisfactory performance based on the (absolute) average fold error. This provides proof-of-principle for a Prescribing Monitoring of potassium concentrations in a hospital system, which could suggest preemptive clinical measures and therefore potentially avoid dangerous hyperkalemia or hypokalemia.

Introduction: Schizophrenia is a mental disorder in which the facts surrounding a person are interpreted as abnormal. The treatment aims to reduce symptoms and the possibility of disease recurrence. Aim: This study aimed to investigate the effectiveness of spironolactone on schizophrenia symptoms. Method: In this double-blind analytical and clinical study, 44 patients were randomly divided into two groups. The study was carried out in Quds Hospital and centers for psychiatric patients in Sanandaj city in 2019 and 2020. The number of patients decreased to 32 due to drug side effects and unwillingness to continue treatment. The instrument used was the scale test of positive and negative symptoms of schizophrenia. Datum were analyzed using chi-square and ANOVA with repeated measurements and independent t-tests by SPSS-23 software. Results: The results showed that out of 44 patients studied, 37 (84.1%) were men and 7 (15.9%) were women. The imbalance was due to the small sample size. There was no significant difference between the two groups in terms of sex distribution, literacy level, marital status, employment history, and background medication use (P>0.05). In addition, there was no significant difference between the two groups in terms of reducing negative symptoms (P=0.666), positive symptoms (P=0.748) and general symptoms (P=0.342). Conclusion: According to the finding, spironolactone has no significant effect on reducing negative, positive, and general symptoms. Therefore, it is suggested to carry out more studies using this drug (by removing the limitations of this study) and other drugs.

Acne in adult females is triggered mainly by hormones. Doxycycline is a reference treatment in acne. Spironolactone targets the androgen receptor of sebaceous glands and is prescribed off-label for female adult acne. This multicentre, controlled, randomized, double-blind prospective and parallel study assessed the efficacy of spironolactone compared with doxycycline in adult female acne. A total of 133 women with moderate acne were randomized to receive treatment with: (i) doxycycline and benzoyl peroxide for 3 months followed by a 3-month treatment with its placebo and benzoyl peroxide, or (ii) spironolactone and benzoyl peroxide for 6 months. Successfully treated patients continued with benzoyl peroxide or spironolactone alone for a further 6 months. Primary endpoints were treatment success at month 4 and month 6 with the AFAST score. At all visits, the ECLA score, lesion counts, local and systemic safety and quality of life were assessed. Spironolactone performed better at month 4 and showed a statistically significant better treatment success after 6 months than doxycycline (p = 0.007). Spironolactone was 1.37-times and 2.87-times more successful compared with doxycycline at respective time-points. AFAST and ECLA scores, as well as lesion counts always improved more with spironolactone. Patients’ quality of life was better with spironolactone at month 4 and month 6. Spironolactone was very well tolerated. This is the first study to show that, in female adults with moderate acne, treatment with spironolactone is significantly more successful than doxycycline and very well tolerated.

Madam, Heart failure (HF) is a multifaceted clinical syndrome arising from a functional or structural cardiac condition that hampers the adequate filling or expulsion of blood into the systemic circulation. It is estimated that heart failure affects around 26 million people globally and significantly adds to healthcare expenditures on a worldwide scale1. Furthermore, in 2016, approximately 16 percent of deaths in Pakistan were due to heart related disorders. This number grew to 29 percent in 20222. HF can greatly diminish the functional capability of a patient and heighten the risk of mortality. Therefore, it is essential to accurately diagnose and proficiently manage this condition to improve the quality of life of the patient. Spironolactone, the first mineralocorticoid receptor antagonist (MRA) to be developed, is prescribed for the management of hypertension, primary hyperaldosteronism, and peripheral oedema linked to cardiac failure3. When HF occurs and cardiac output decreases, it stimulates the renin-angiotensin-aldosterone system (RAAS) which in turn causes salt and water reabsorption and thus increases venous return to the heart which further contributes to congestive heart failure and heart fails to pump the additional fluid and pooling occurs. Here MRAs are very affective as they inhibit the function of aldosterone and hence fluid retention does not occur. Unfortunately, the beneficial effects of spironolactone do not occur without substantial adverse effects. Firstly, spironolactone is associated with sexual adverse events due to its affinity for androgen and progesterone receptors. There have been reports of male patients experiencing gynecomastia and breast pain. Secondly, spironolactone has been classified as potassium sparing diuretic hence hyperkalemia (defined as serum K+ > 5.5 mEq/L) is a common side effect3. Hyperkalemia can manifest as muscle weakness or paralysis, metabolic acidosis, cardiac conduction abnormalities, and life-threatening cardiac arrhythmias4. These cardiac arrythmias can have serious consequences, including cardiac arrest and stroke. In conclusion heart failure, if not treated immediately, can be fatal. Spironolactone is a drug used for management of heart failure; however, it has some detrimental effects on the cardiovascular system such as development of serious cardiac arrythmias. Hyperkalemia, due to potassium sparing nature of MRAs, is the primary cause of these life-threatening effects thus it is recommended to assess serum potassium levels and renal function of a patient with heart failure before prescribing spironolactone. Moreover, patients who are being treated with spironolactone should be periodically monitored to prevent any casualty.

Abstract Introduction Treatment of mood and cognitive symptoms of patients with bipolar disorder is associated with many complications and is generally not associated with therapeutic satisfaction. In this clinical trial, we evaluated the effectiveness of spironolactone in controlling mood and cognitive symptoms, sleep quality, appetite, and body mass index in patients with bipolar disorder in manic episodes. Methods Sixty inpatients with bipolar disorder in manic episodes were treated with spironolactone/placebo in an 8‐week randomized, double‐blind, placebo‐controlled clinical trial. They were evaluated using the Young Mania Rating Scale (YMRS), mini‐mental state examination (MMSE), Pittsburgh sleep quality index, Simplified Nutritional Appetite Questionnaire, and body mass index in weeks 1, 4, and 8. Results For cognitive impairment (MMSE), there were significant interaction effects of group and time at week 8 (B = −1.60, SE = 0.69, t = −2.33, p = .021) such that individuals in the spironolactone group experienced more improvement in their cognitive performance. For manic symptoms (YMRS), there were no significant interaction effects of group and time at week 8 (B = −2.53, SE = 1.46, t = −1.73, p = .085). Conclusions Considering the promising findings in this clinical trial, further study of spironolactone as adjunctive therapy in bipolar disorder in manic episodes with larger sample sizes, multicenter settings, and longer follow‐ups are recommended.

Background: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5–10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. Methods: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. Discussion: The present study will be the first to evaluate—in a randomised, double-blind, placebo-controlled way—the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. Trial registration: EudraCT 2021–003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58. [ABSTRACT FROM AUTHOR]

Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D) represents a major public health issue; it develops in about 30%–40% of patients with diabetes mellitus and is the most common cause of CKD worldwide. Patients with CKD and T2D are at high risk of both developing kidney failure and of cardiovascular events. Renin–angiotensin system (RAS) blockers were considered the cornerstone of treatment of albuminuric CKD in T2D for more than 20 years. However, the residual risk of progression to more advanced CKD stages under RAS blockade remains high, while in major studies with these agents in patients with CKD and T2D no significant reductions in cardiovascular events and mortality were evident. Steroidal mineralocorticoid receptor antagonists (MRAs) are known to reduce albuminuria in individuals on RAS monotherapy, but their wide clinical use has been curtailed by the significant risk of hyperkalemia and absence of trials with hard renal outcomes. In recent years, non-steroidal MRAs have received increasing interest due to their better pharmacologic profile. Finerenone, the first compound of this class, was shown to effectively reduce the progression of kidney disease and of cardiovascular outcomes in participants with T2D in phase 3 trials. This clinical practice document prepared from a task force of the European Renal Best Practice board summarizes current knowledge on the role of MRAs in the treatment of CKD in T2D aiming to support clinicians in decision-making and everyday management of patients with this condition. [ABSTRACT FROM AUTHOR]

Highly fluorescent nitrogen doped carbon quantum dots (N-CQDs) were prepared by a single-step method based on microwave heating of cane sugar and urea. The produced N-CQDs were applied as nano-sensors for the spectrofluorimetric determination of eplerenone and spironolactone. A strong emission band at 376 nm was obtained after excitation at 216 nm due to the produced N-CQDs. The native fluorescence of N-CQDs was obviously quenched upon adding increased concentrations of each drug. A strong correlation was found between the fluorescence quenching of N-CQDs and the concentration of each drug. The method was found to be linear over the range of 0.5 to 5.0 μg/mL for eplerenone and 0.5 to 6.0 μg/mL for spironolactone with LOQ of 0.383 μg/mL and 0.262 μg/mL. The developed method was further extended for determination of both drugs in their pharmaceutical tablets and spiked human plasma. The results obtained were statistically compared with those of reported methods. The mechanism of fluorescence quenching of N-CQDs by the two drugs was discussed. [ABSTRACT FROM AUTHOR]

Background: The use of decentralised clinical trials (which bring trials to patients through remote processes and technology versus central on-site visits) has been thought to be a potential solution to common recruitment and retention barriers. However, there is a lack of evidence to understand the experiences, needs and preferences of the public to inform trial methodologies that appeal to different populations. We report participant experiences of SAFA, a partially decentralised randomised clinical trial, to inform the methodology used in future dermatology trials that aim to appeal to women aged 18 and over. Methods: Participants of the SAFA (Spironolactone for Adult Female Acne) trial were invited to take part in a qualitative semi-structured interview to explore their experience and perspectives of taking part in the trial. Questions focused on their experience of using decentralised methods to access and enrol in the trial (e.g. social media advertising), in addition to the decentralised trial visit and data collection methods used throughout. Interviews were conducted remotely, recorded, and transcribed. Data were analysed using reflexive thematic analysis. Results: Twelve SAFA participants (all women, age range 22–36 years) were interviewed. Initially, participants were influenced to enrol by trusted online information, the feeling of validation the trial provided, and the convenience and flexibility offered by the decentralised methods and research staff made participants feel valued and enabled them to engage in the trial with minimal interference to existing commitments. SAFA participants were generally accepting of trial demands, such as the text-heavy paperwork and on-site visits for blood collection and highlighted several areas relevant for trial conduct going forwards including where decentralised methods may (and may not) be accepted and how trial accessibility and understanding could be improved. Conclusions: The study has shown that decentralised methods used by responsive and approachable staff were widely accepted in the SAFA trial. Interviewees found the methods adopted in the SAFA trial helped the trial to fit with their needs and promoted a sense of feeling valued that encouraged ongoing trial engagement. Decentralised methods should be considered favourably when designing a dermatology trial as they can potentially enhance both recruitment and retention. Trial registration number: ISRCTN 12892056. Registered on October 15, 2018. [ABSTRACT FROM AUTHOR]

Introduction and Objective: To determine the clinical characteristics and evolution of patients with hyperkalemia due to chronic prescription of angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACE inhibition/ARBs), plus spironolactone, documented in Internal Medicine-Nephrology outpatient service, inter-consultation, or recent hospitalization discharge report. Materials and Methods: Patients over 18 years of age were included, in whom serum potassium levels over 5.5 mEq/l were documented, associated with combined treatment of an ACE inhibitors or ARBs plus spironolactone. In addition, patients were grouped due to base diseases, predisposing factors, and previous medications related to the risk of hyperkalemia. The serum potassium and creatinine laboratory variables were included at the entrance and follow-up at 30 days. Additionally, the type of outpatient and hospitable management patients received, and interventions practiced were recorded. The statistical analysis was conducted with the SPSS 25.0V statistical program in Spanish licensed for the University of Caldas. Results: The study spanned 13 years. Seventy-two patients were identified, of whom 41 met the inclusion criteria, 3.15 patients per year: 22 women (54%), with a mean age of 74. The main reason for the combination prescription was difficult to manage arterial hypertension, followed by heart failure. Regarding medications, 54% were ACE inhibitors, enalapril the most common, with an average dose of 27.75 mg/d, ARBs losartan 105.5 mg/d, and spironolactone 35.37 mg/d. Other prescribed medications associated with hyperkalemia were Beta-blockers, NSAIDs, heparin, and no use of trimethoprim sulfa. The main precipitating for which hyperkalemia was triggered was decompensated heart failure (low cardiac output) and acute renal failure of various origins. None in 13 outpatients (32%), required further hospitalization, improving just with treatment discontinuation. In hospitalized patients, hemodialysis was required in five patients (12.2%), with an average of 2.4, performed every 24 hours. No patient died. Creatinine significantly declined over 30 days, changing GFR from a baseline average value of 27.82 mL/minute to 46.16 mL/minute at 30 days. In hospitalized patients, various interventions were chosen suspension of the causal medication, intravenous furosemide, B2 agonists, ion exchange resins, calcium gluconate, glucoseinsulin infusion, and intravenous bicarbonate. Conclusions: Severe hyperkalemia associated with combined ACE inhibitors/ARBs + spironolactone therapy is a pathology that continues to occur. Therefore, hydration status, renal function, and serum potassium should be monitored in frequent recipients. Elderly individuals with heart failure and renal failure are the highest-risk population. Henceforward, if possible, do not try to escalate to very high doses of medications when prescribing this combination. [ABSTRACT FROM AUTHOR]

Abnormal corneal wound healing can compromise corneal transparency and lead to visual impairment. Mineralocorticoid receptor antagonists (MRA) are promising candidates to promote corneal remodeling with anti-inflammatory properties and lack gluococorticoids-associated side effects. In this preclinical study, a new polymer-free hydroxypropyl-gamma-cyclodextrin-based eyedrop containing 0.1% spironolactone (SPL), a potent but non-water-soluble MRA, was investigated for its ocular surface tolerance and efficacy in a rat model of corneal wound healing. SPL eyedrops were stable for up to 9 months at 4 °C. The formulation was well-tolerated since no morphological changes or inflammatory reactions were observed in the rat cornea after multiple daily instillations over 7 days. SPL eyedrops accelerated rat corneal wound healing, reduced corneal edema and inflammation, enhanced epithelial integrity, and improved nerve regeneration, suggesting restoration of corneal homeostasis, while potassium canrenoate, an active and soluble metabolite of SPL, had no effect. SPL eyedrops could benefit patients with impaired corneal wound healing, including that secondary to glucocorticoid therapy. Repurposing known drugs with known excipients will expedite translation to the clinic. [ABSTRACT FROM AUTHOR]

Hereditary hemochromatosis (HH) is an autosomal recessive metabolic disorder. Mutations in different encoding genes, mostly HFE, lead to iron overload in different organs of the body. We herein report a case of HH caused by a novel variant in the HFE2 (HJV) gene. A 27- year-old man was admitted to the internal medicine ward of Shahid Rahimi Hospital in Khorramabad, Iran, on 6/6/2018. He first sought medical care for impotence and was diagnosed with increased serum iron. He ceased follow-up and was referred to our center with advanced symptoms of hemochromatosis, including central hypogonadism, heart failure, and ascites. The genetic test revealed that he was homozygote for a variant defined as c.950G>A (p.Cys317Tyr) in exon 4 of the HJV gene. The patient's symptoms improved following medical intervention. At a 4th year follow-up, he was alive and his clinical status was stable. [ABSTRACT FROM AUTHOR]