Potassium canrenoate 200mg/10ml solution for injection ampoules

What is known about this subject in regard to women and their families? Spironolactone is a medication commonly used off-label to treat androgenetic alopecia in women. There have long been concerns regarding the theoretical risk of the drug having the potential to increase the risk of breast cancer due to its antiandrogenetic effects. A case series reported in 1975 of 5 patients who developed breast cancer while on spironolactone was later proved to be statistically insignificant. In the early 1980s, studies in Japan and America showed that rats given potassium canrenoate, a metabolite of spironolactone, at doses greater than 100 times those given to humans, had an increase in mammary tumors. Further molecular studies in 1988 showed that potassium canrenoate produces mutagenic epoxy-canrenone derivatives, which are not produced by spironolactone. Spironolactone was subsequently reintroduced into clinical use after these studies cleared it of any association with breast cancer. Despite this, the drug has continued to be stigmatized and underutilized, and some patients are wary of using it as a therapeutic agent for their alopecia. What is new from this article as messages for women and their families? A 2022 large systematic review and meta-analysis by Bommaredy et al. has confirmed the absence of any association between spironolactone use and breast cancer risk. The Food and Drug Administration no longer lists “carcinoma of the breast” as a possible adverse effect of spironolactone since the 2018 spironolactone drug label revisions. Women with breast cancer may develop alopecia through several mechanisms, and spironolactone can be an effective treatment option. The historical association between breast cancer and spironolactone is unfounded, and women with breast cancer should not be discouraged from using spironolactone for their alopecia treatment. Spironolactone is an antihypertensive medication that is commonly used off-label to treat androgenetic alopecia (AGA) in women. However, due to its antiandrogenetic effects, there have long been concerns regarding a theorized risk of the drug having the potential to increase the risk of breast cancer. Since the 1980s, this association has been rebutted with molecular studies from 1988 by Cook et al.1 and Oppermann et al2. and recently as well by a 2022 large systematic review and meta-analysis by Bommaredy et al.3,4 Here, we review the historical background, assess why there has long been a perceived association between spironolactone use and breast cancer risk without evidence, and advocate for the role of spironolactone in the management of various alopecias in female breast cancer survivors. In 1975, a case series reported 5 patients who developed breast cancer while on spironolactone, but Jick and Armstrong5 later proved the association to be statistically insignificant. In the early 1980s, studies in Japan, followed by further testing in America, showed that rats given potassium canrenoate, a metabolite of spironolactone, at doses greater than 100 times those given to humans, had an increase in mammary tumors.6 These studies prompted a bulletin release calling for the withdrawal of spironolactone in the U.K. However, further molecular studies in 1988 showed that potassium canrenoate produces mutagenic epoxy-canrenone derivatives, which are not produced by spironolactone.1 Spironolactone was subsequently reintroduced into clinical use after these studies cleared it of any association with breast cancer. Despite this, the drug has continued to be stigmatized and underutilized. Since the 2018 spironolactone drug label revisions, the FDA no longer lists “carcinoma of the breast” as a possible adverse effect of spironolactone. This adverse effect was previously listed without a cause-and-effect relationship having been established. The historical association between breast cancer and spironolactone has led to some patients being wary of using spironolactone as a therapeutic agent for their alopecia. This unfounded association with breast cancer prevents women from receiving important alopecia treatment when they need it most, increasing the psychological burden these patients endure. Up to 14% of patients with cancer may consider rejecting curative cancer treatments if they are associated with hair loss.7 Women with breast cancer are more likely to suffer from alopecia through several mechanisms. Depending on their cancer therapy, they may develop anagen effluvium, AGA unmasked by telogen effluvium, or endocrine-induced alopecia, all of which can improve with spironolactone.7 Perceived negative associations with spironolactone may discourage some physicians from offering it as a treatment option for breast cancer survivors with AGA and endocrine-induced alopecia. Additionally, patients who learn about this historical association of spironolactone with increased breast cancer risk may have reservations regarding its use. In conclusion, this article aims to underscore the importance of considering the use of spironolactone for androgenetic and hormone-related alopecia in breast cancer patients without fear of increasing the risk of cancer recurrence. Conflicts of interest JS is a consultant for Lilly, Pfizer, and Replicel Life Sciences. Drs. JS and KLS have been investigators for Regen Lab and are investigators for Pfizer. KLS is a consultant for Pfizer and Aquis. Other authors have no conflicts to disclose. Funding None. Study approval N/A Author contributions All authors contributed to the design of the study. MGB and LA conducted the literature review and wrote the manuscript. All authors contributed to data analysis and interpretation. J.S. and K.L. provided critical revisions to the manuscript. All authors approved the final version of the manuscript for submission. Prior presentation This article has not been previously published and is not under consideration for publication elsewhere. Data availability There is no associated data being stored related to this study.

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Introduction Ischaemia/reperfusion injuries (IRIs) are associated with poorer survival of kidney grafts from expanded criteria donors. Preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) prevent acute and chronic post-ischaemic renal dysfunction by limiting IRI. However, data concerning the safety of MRAs in brain-dead donor patients are scarce. We seek to investigate the tolerance of MRAs on the haemodynamics in this population. Methods and analysis CANREO-PMO is a randomised, controlled, single-centre, double-blind study. Brain-dead organ donors hospitalised in intensive care are randomised 1:1 after consent to receive 200 mg potassium canrenoate or its matching placebo every 6 hours until organ procurement. The primary outcome is a hierarchical composite endpoint that includes: (1) cardiocirculatory arrest, (2) the impossibility of kidney procurement, (3) the average hourly dose of norepinephrine/epinephrine between randomisation and departure to the operating room, and (4) the average hourly volume of crystalloids and/or colloids received. Thirty-six patients will be included. The secondary endpoints evaluated among the graft recipients are the: (1) vital status of the kidney graft recipients and serum creatinine level with estimated glomerular filtration rate (GFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) at 3 months after renal transplantation, (2) percentage of patients dependent on dialysis and/or with an estimated GFR <20 mL/min/1.73 m 2 at 3 months, (3) vital status of the kidney graft recipients at 3 months, and (4) vital status of the kidney graft recipients and creatinine levels (in μmol/L), with the estimated GFR according to CKD-EPI (in mL/min/1.73 m 2 ), at 1 year, 3 years and 10 years after transplantation. Ethics and dissemination This trial has full ethical approval (Comité de Protection des Personnes: CPP Ouest II-ANGERS, France), and the written consent of relatives will be obtained. Results will be reported at conferences, peer-reviewed publications and using social media channels. Trial registration number NCT04714710 .

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In March 2020, the World Health Organization (WHO) announced a global pandemic of coronavirus disease 2019 (COVID-19) that presented mainly as an acute infection of the lower respiratory tract (pneumonia), with multiple long-term consequences, including lung fibrosis. The aim of this study was to evaluate the influence of potassium canrenoate on inflammatory markers in the treatment of COVID-19 pneumonia. A randomized clinical trial (RCT) of intravenous potassium canrenoate vs. placebo was performed between December 2020 and November 2021. This study is a secondary analysis of that RCT. In the final analysis, a total of 49 hospitalized patients were included (24 allocated to the potassium canrenoate group and 25 to the placebo group). Patients were assessed by serum testing and blood cell cytometry on day 1 and day 7 of the intervention. Age, sex, and body mass index were not significantly different between the placebo group and intervention group. Although there was a significantly higher rate of ischemic heart disease in the placebo group, rates of other preexisting comorbidities were not significantly different. There were no significant differences in the inflammatory parameters between the potassium canrenoate and placebo groups on day 1 and day 7. However, the intragroup comparisons using Wilcoxon’s test showed significant differences between day 1 and day 7. The CD3% for potassium canrenoate increased significantly between day 1 and day 7 (12.85 ± 9.46; 11.55 vs. 20.50 ± 14.40; 17.80; p = 0.022), while the change in the placebo group was not significant (15.66 ± 11.39; 12.65 vs. 21.16 ± 15.37; 16.40; p = 0.181). The IL-1ß total count [%] increased over time for both potassium canrenoate (0.68 ± 0.58; 0.45 vs. 1.27 ± 0.83; 1.20; p = 0.004) and placebo (0.61 ± 0.59; 0.40 vs. 1.16 ± 0.91; 1.00; p = 0.016). The TNF-α total count (%) decreased significantly between day 1 and day 7 for potassium canrenoate (0.54 ± 0.45; 0.40 vs. 0.25 ± 0.23; 0.10; p = 0.031), but not for placebo (0.53 ± 0.47; 0.35 vs. 0.26 ± 0.31; 0.20; p = 0.056). Interleukin-6 (pg/mL) showed a significant decrease between day 1 and day 7 for potassium canrenoate (64.97 ± 72.52; 41.00 vs. 24.20 ± 69.38; 5.30; p = 0.006), but not the placebo group. This RCT has shown that the administration of potassium canrenoate to patients with COVID-19-induced pneumonia may be associated with significant changes in certain inflammatory markers (interleukin-6, CD3%, TNF-α), potentially related to pulmonary fibrosis. Although some positive trends were observed in the potassium canrenoate group, none of these observations reached statistical significance. Any possible benefits from the use of potassium canrenoate as an anti-inflammatory or antifibrotic drug in COVID-19 patients require further investigation.

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In December 2019 the SARS-CoV-2 virus appeared in the world, mainly presenting as an acute infection of the lower respiratory tract, namely pneumonia. Nearly 10% of all patients show significant pulmonary fibrotic changes after the infection. The aim of this study was to evaluate the effectiveness and safety of potassium canrenoate in the treatment of COVID-19-associated pneumonia and pulmonary fibrosis. We performed a randomized clinical trial (RCT) of potassium canrenoate vs placebo. A total of 55 patients were randomized and 49 were included in the final analysis (24 allocated to the intervention group and 25 allocated to the control group). Patients were assessed by physical examination, lung ultrasound, CT imaging and blood samples that underwent biochemical analysis. This RCT has shown that the administration of potassium canrenoate to patients with COVID-19 induced pneumonia was not associated with shorter mechanical ventilation time, shorter passive oxygenation, shorter length of hospitalization or less fibrotic changes on CT imaging. The overall mortality rate was not significantly different between the two groups. Adverse events recorded in this study were not significantly increased by the administration of potassium canrenoate. The negative outcome of the study may be associated with the relatively small number of patients included. Any possible benefits from the use of potassium canrenoate as an antifibrotic drug in COVID-19 patients require further investigation.

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Abstract Inadequate blood supply to the expanding adipose tissue (AT) is involved in the unhealthy AT remodeling and cardiometabolic consequences of obesity. Because of the pathophysiological role of upregulated mineralocorticoid receptor (MR) signaling in the complications of obesity, this study tested the vasoactive properties of finerenone, a nonsteroidal MR antagonist, in arteries of human AT. Arteries isolated from the visceral AT of obese subjects were studied in a wire myograph. Finerenone resulted in a concentration‐dependent relaxation of arteries precontracted with either the thromboxane‐A2 analog U46619, ET‐1, or high‐K + solution; the steroidal MR antagonist potassium canrenoate, by contrast, did not relax arteries contracted with either U46619 or high‐K + solution. Finerenone‐induced relaxation after precontraction with U46619 was greater in the arteries of obese versus nonobese subjects. Mechanistically, the vasorelaxing response to finerenone was not influenced by preincubation with the nitric oxide synthase inhibitor L‐NAME or by endothelium removal. Interestingly, finerenone, like the dihydropyridine Ca 2+ ‐channel blocker nifedipine, relaxed arteries contracted with the L‐type Ca 2+ ‐channel agonist Bay K8644. In conclusion, finerenone relaxes arteries of human visceral AT, likely through antagonism of L‐type Ca 2+ channels. This finding identifies a novel mechanism by which finerenone may improve AT perfusion, hence protecting against the cardiometabolic complications of obesity.

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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.

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In Figure 4, the immunoblot band of Cox-2 (Figure 4A) and the bar chart of Cox-2 (Figure 4I) are incorrect.The correct Figure 4 is presented below.Corrected Figure 4 Additionally, the legend for Figure 4 is corrected (change is shown in bold):

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Abstract A post‐authorisation safety study (PASS) was conducted to assess the impact of LysaKare (2.5% Lysine‐Arginine solution) on serum potassium concentrations and its safety/tolerability profile in patients with gastroenteropancreatic neuroendocrine tumours (GEP‐NET) eligible for 177 Lu‐DOTATATE treatment. In a phase IV, multicentre, single‐arm, open‐label PASS, adults with somatostatin receptor‐positive GEP‐NET who were eligible for 177 Lu‐DOTATATE treatment received 1000 mL of LysaKare (monotherapy) intravenously over 4 h. The primary endpoint was the change in serum potassium levels over the course of 24 h. Secondary endpoints included the incidence of LysaKare‐related adverse events (AEs) and changes in laboratory parameters. Forty‐one patients were treated (median age, 57 years; 92.7% White and 7.3% Black; 53.7% male) and 40 completed post‐treatment follow‐up. Mean (standard deviation [SD]) serum potassium was 4.33 (0.397) mmol/L pre‐dose, increasing by 0.60 (0.666) mmol/L after 4 h (time to maximum change, range, 2–24 h) before decreasing to around the pre‐dose level: the mean (SD) increase after 24 h was 0.07 (0.396) mmol/L. Other electrolytes and blood gas components mostly showed transient changes that lasted ~24 h. A general trend of transient metabolic acidosis was also observed based on laboratory values. Serum potassium grade increased from baseline in 41.5% of patients. By comparison, five patients (12.2%) had a treatment‐related AE of hyperkalaemia (grade 3, n = 1); all resolved within 24 h, either without treatment ( n = 3) or following intravenous furosemide ( n = 2). There were no serious AEs and no AEs leading to treatment discontinuation/interruption. This PASS identified no new safety signals attributable to LysaKare. Trial registration: EudraCT, 2019‐004073‐76. Registered 20/08/2020.

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