Current Pharmaceutical Design - Volume 24, Issue 46, 2018

Background: Aldosterone, through its actions on Mineralcorticosteroid Receptors (MR), controls fluid and electrolyte balance, but also exerts various direct deleterious actions on the vasculature. A number of aldosterone antagonists have been manufactured to reverse these effects. Objective: A comprehensive review of the underlying mechanisms of the actions of aldosterone and its antagonists in cardiovascular disease. Method: The relevant studies indexed in PubMed, Scopus and Google Scholar databases, published from 2003 to May 2018 were identified and reported. Results: Aldosterone binds to MR, activating them as intracellular transcription factors. Moreover, aldosterone, through its actions on MR, as well as on another not fully explored class of receptors, triggers several signaling pathways that produce rapid, non-genomic actions. In the vasculature, all these changes favor the establishment of inflammation and cardiovascular dysfunction, which, in turn, lead to or exacerbate various cardiovascular diseases. Mineralcorticosteroid Antagonists (MRA) are compounds that antagonize the action of aldosterone on MR. Spironolactone was the first steroidal MRA to be commercially used. It showed beneficial clinical results, but also a number of adverse effects. The next generation of steroidal MRA, exhibited lower potency but did not induce many of these adverse reactions, due to their high selectivity for MR. The third generation of MRA compromises the newly introduced non-steroidal MRA, which have a completely different chemical structure, they induce different and more drastic changes to MR, they are much more specific and currently under clinical trials. Conclusion: New MRA, which block the aldosterone induced pathways in the vasculature, hold promising results for the treatment of cardiovascular disease.

Background: Mineralocorticoid receptor antagonists are a second-line class of antihypertensive drugs, which have been accounted for as the optimal add-on therapy in the triple algorithm for the management of resistant hypertension. Objectives: To assess the effects of mineralocorticoid receptor antagonists in the treatment of patients with essential hypertension and resistant hypertension. Method: We conducted a meticulous review of the literature and comprehensive identification of the clinical trials assessing the efficacy of mineralocorticoid receptor antagonists in individuals with primary and resistant hypertension. Results: MRAs have been thoroughly tested in several clinical studies in relevance to blood pressure lowering effects, over the last six decades. Accumulating data observed that MRAs resulted in a significant reduction in blood pressure level in patients with resistant hypertension. In addition, spironolactone was found to beneficially affect the management of resistant hypertension. Conclusion: Mineralocorticoid receptor antagonists exert a significant antihypertensive effect. Future welldesigned randomized controlled studies are greatly needed to address crucial clinical aspects in the field.

Background: Primary aldosteronism is the most common causes of secondary hypertension. Patients suffering from this clinical syndrome have an increased cardiovascular risk and target organ damage. Mineralocorticoid receptor antagonists are the optimal pharmaceutical option for the management of such patients. Objectives: The study aimed to assess the effects of mineralocorticoid receptor antagonist in the treatment of patients with primary aldosteronism. Method: We conducted an in-depth review of the literature and comprehensive identification of the clinical studies investigating the efficacy of mineralocorticoid receptor antagonists in individuals with primary aldosteronism. Results: Mineralocorticoid receptor antagonists result in significant improvement in blood pressure and serum potassium level among patients with primary aldosteronism. Moreover, mineralocorticoid receptor antagonists reverse left ventricular hypertrophy, albuminuria, and carotid intima-media thickness. However, a high risk for atrial fibrillation remains among subject with primary aldosteronism in such agents. Conclusion: Mineralocorticoid receptor antagonists are recommended as the first-line treatment in patients with bilateral primary aldosteronism. In patients with unilateral aldosterone-producing adenoma, adrenalectomy should be preferred. However, existing data presents significant limitations and is rather inconclusive. Future randomized control trials are required in order to illustrate the field.

Background: Heart failure (HF) is a worldwide modern epidemic, associated with significant morbidity and mortality. Several causes have been identified for the syndrome, most of which share common pathophysiologic pathways, including neurohormonal activation. Central to the latter lies activation of the reninangiotensin- aldosterone system, and its effects on cardiovascular disease progression. Objectives: The aim of this review is to summarize the pathophysiology of aldosterone and the effects of its blockage in the failing heart, as well as to provide state-of-the-art evidence, and address future perspectives regarding the use of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction. Method: Literature was reviewed for studies that assess the pathophysiology of aldosterone in HF with reduced ejection fraction (HFrEF), and the effects of mineralocorticoid receptor antagonists (MRAs) in this condition. Results: Several major society guidelines have synthesized the available evidence on HFrEF management, and drugs that block the renin-angiotensin-aldosterone system at different levels continue to form the key component of standard of care for these patients. Mineralocorticoid receptor antagonists are an important part of HFrEF pharmacologic treatment, and their use is supported by a high level of evidence studies. This class of drugs demonstrated significant benefits for morbidity and mortality, across the spectrum oh HFrEF, including patients after acute myocardial infarction. Conclusion: Current evidence supports the central role of aldosterone in HFrEF progression, and the significant benefits on outcomes with the use of MRAs.

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with increased risk for hospitalization and all-cause mortality. Currently, there is no established treatment to improve the survival of these patients. Aldosterone appears to play a role in the pathogenesis of HFpEF. Objective: To discuss the findings of studies that evaluated the effects of mineralocorticoid receptor (MR) antagonists on the outcome of patients with HFpEF. Methods: PubMed was searched for relevant papers. References of retrieved articles were also evaluated for pertinent material. Results: Accumulating data suggest that MR antagonists might be useful in the management of patients with HFpEF. However, existing evidence is limited and conflicting. Conclusions: More studies are needed to clearly define the therapeutic potential of MR antagonists in HFpEF. Given the heterogeneity of this disease and the low specificity of the criteria used for its diagnosis, it is also important to improve the definition of HFpEF and include appropriately selected patients in these studies.

Background: The use of single RAS-blockade is currently the recommended first-line treatment for proteinuric diabetic or non-diabetic nephropathy, as these agents were repeatedly shown in studies with hard renal outcomes to retard the progression of renal injury. However, CKD will continue to progress on optimum single RAS-blockade, and other options to ameliorate renal injury were explored. Dual RAS-blockade was associated with an increased risk of adverse-events with no apparent benefits and, therefore, is currently abandoned. Based on the phenomenon of aldosterone escape and the well-documented harmful effects of aldosterone on renal tissue, several randomized trials have studied the effects of a MRA in diabetic and non-diabetic nephropathy. Method: This is a review of the literature in relevance to data evaluating the effect of MRA on renal outcomes. Results: Studies with spironolactone and eplerenone added to single RAS-blockade showed that these agents are associated with greater reductions in urine albumin or protein excretion compared to either placebo or dual RASblockade. However, studies with these agents on hard renal outcomes are currently missing and the reasonable skepticism of physicians on the real-world incidence of hyperkalemia in CKD patients are limiting their use. A non-steroidal MRA, finerenone, has also great potency in decreasing albuminuria in diabetic nephropathy with possibly lower rates of hyperkalemia. Two multi-center clinical trials examining the effect of finerenone on hard cardiovascular and renal outcomes are currently ongoing. Conclusion: MRAs are able to reduce albuminuria and proteinuria on top of single RAS-blockade in patients with proteinuric CKD. Ongoing clinical trials are expected to clarify whether such an effect is accompanied by delay in CKD progression.

Background: Mineralocorticoid receptor antagonists consist of a class of drugs with pleiotropic beneficial effects in several cardiovascular diseases. However, physicians frequently overlook their use due to the adverse effects of such agents. Objectives: To determine the adverse effects of mineralocorticoid receptor antagonists and to suggest clinically meaningful options. We present data on the two most administered agents of this class: spironolactone and eplerenone. Method: We conducted an in-depth review of the existing international literature to draft a mini review about the mineralocorticoid receptor antagonists-related side effects. Result: Mineralocorticoid receptor antagonists are associated with increased risk of hyperkalemia and acute deterioration of renal function. Of note, these adverse effects are dose-dependent, more common during the initial period of treatment, and are usually reversed after the withdrawal of therapy. Sex-related adverse events are noted mainly in spironolactone while switching to eplerenone could attenuate those. Conclusion: Mineralocorticoid receptor antagonists therapy is significantly limited due to their side effects. The development of novel non-steroidal mineralocorticoid receptor antagonists could substantially widen the use of such agents.

Background: Hyperkalemia is an important clinical problem that is associated with significant lifethreatening complications. Several conditions are associated with increased risk for hyperkalemia such as chronic kidney disease, diabetes mellitus, heart failure, and the use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Objective: The purpose of this review is to present and critically discuss treatment options for the management of hyperkalemia. Method: A comprehensive review of the literature was performed to identify studies assessing the drug-induced management of hyperkalemia. Results: The management of chronic hyperkalemia seems to be challenging and includes a variety of traditional interventions, such as restriction in the intake of the dietary potassium, loop diuretics or sodium polystyrene sulfonate. In the last few years, several new agents have emerged as promising options to reduce potassium levels in hyperkalemic patients. Patiromer and sodium zirconium cyclosilicate 9 (ZS-9) have been examined in hyperkalemic patients and were found to be efficient and safe. Importantly, the efficacy of these novel drugs might allow the continuation of the use of RAAS inhibitors, morbidity- and mortality-wise beneficial class of drugs in the setting of chronic kidney disease and heart failure. Conclusion: Data support that the recently emerged patiromer and ZS-9 offer significant hyperkalemia-related benefits. Larger trials are needed to unveil the impact of these drugs in other patients’ subpopulations, as well.

Background: Targeting the renin-angiotensin-aldosterone axis is one of the most important therapeutic pathways for blood pressure control, renal and cardiovascular protection. Objective: In this review, the new nonsteroidal mineralcorticoid receptor antagonists will be presented with a special focus on finerenone and its randomized controlled trials along with an introduction to the clinically promising aldosterone synthase inhibitors. Method: We conducted an in-detail review of the literature in order to draft a narrative review on the field. Results: Development of new anti-aldosterone agents focusing on the diverse components of aldosterone production and action is now taking place. Nonsteroidal mineralcorticoid receptor antagonists are safe and effective therapeutic solutions with finerenone being the most well-studied agent with promising clinical data extending its efficacy in diabetes mellitus, chronic kidney disease and heart failure. Aldosterone synthase inhibitors impact the hormonal balance but there are still limitations regarding the duration of action and adverse effect of the glycolcorticoid axis. Conclusion: Novel third-generation, nonsteroidal mineralocorticoid receptor antagonists seem to offer great advantages, which may lead to a wider use of mineralocorticoid receptor antagonists. Future randomized controlled trials are needed to evaluate significant perspectives.

Background: Besides the numerous biologic and pharmacologic functions in the human body that act as potent antioxidants, flavonoids (flavones, flavanones, flavonols, flavanols and isoflavones) are noted as cancer preventive or therapeutic agents. Methods: This review summarizes the published data using PubMed, Science Direct, and Scopus. Results: In this context, recognition and introduction of the most active cytotoxic flavonoids as promising agents for cancer therapy gives insight for further evaluations. However, there are some critical points that may affect the entering of flavonoids as active cytotoxic phytochemicals in the clinical phase. Issues such as the abundance of active species in nature, the methods of extraction and purification, solubility, pharmacokinetic profile, presence of the chiral moieties, method of synthesis, and structure modification may limit the entry of a selected compound for use in humans. Although plenty of basic evidence exists for cytotoxic/antitumor activity of the versatility of flavonoids for entry into clinical trials, the above-mentioned concerns must be considered. Conclusion: This review is an effort to introduce cytotoxic natural flavonoids (IC50< 10 μM) that may have the potential to be used against various tumor cells. Also, active constituents, molecular mechanisms, and related clinical trials have been discussed as well as the limitations and challenges of using flavonoids in clinic.

Background: Among polyphenolic compounds suggested to prevent cardiovascular diseases (CVDs) and to explain the “French paradox”, the anthocyanidin delphinidin (Dp) has been reported to support at least partly the vascular beneficial effects of dietary polyphenolic compounds including those from fruits and related products as red wine. It has also been highlighted that Dp interacts directly with the active site of estrogen receptor α (ERα), leading to activation of endothelial NO synthase (eNOS) pathway thus contributing to the prevention of endothelial dysfunction in mice aorta. However, anthocyanidins have very low bioavailability and despite a well described in vitro efficacy, the very high hydrophilicity and physicochemical instability of Dp might explain the lack of in vivo reported effects. Objective: The aim of this study was to identify new Dp analogues with increased lipophilicity and vasorelaxation potential by a chemical modulation of its structure and to characterize the signaling pathway notably in relation with ERα signaling and nitric oxide (NO) production. Method: OCH3-substituted delphinidin analogues were obtained through the coupling of the corresponding acetophenones with substituted benzaldehydes. Prediction of resorption of the flavylium derivatives was performed with the calculated logP and induction of vasorelaxation was performed by myography on WT and ERαKO mice thoracic aorta rings and compared to Dp. NO production was evaluated in vitro on human primary endothelial cells. Results: Eight Dp analogues were synthesized including four new flavylium derivatives. Two compounds (9 and 11) showed a strong increase of vasorelaxation potential and a theoretically increased bioavailability compared to Dp. Interestingly, 9 and 11 induced increased O2 - or NO endothelial production respectively and revealed a novel NO-dependent ERα-independent relaxation compared to Dp. We suggested that this mechanism may be at least in part supported by the inhibition of vascular cyclic nucleotide phosphodiesterase (PDEs). Conclusion: The current study demonstrated that pharmacomodulation of the Dp backbone by replacement of OH groups by OCH3 groups of the A and B rings led to the identification and characterization of two compounds (9 and 11) with enhanced physio-chemical properties that could be associated to higher permeability capability and pharmacological activity for the prevention of CVDs compared to Dp.

Background: The effect of drugs on ATP-binding cassette transporters, especially permeabilityglycoprotein (P-gp), is an important consideration during new anti-cancer drug development. Objective: In this context, the effects of a newly synthesized artemisinin derivative, 10-(4-phenyl-1H-1,2,3- triazol)-artemisinin (5a), were evaluated on P-gp expression and function. Methods: Reverse transcript polymerase chain reaction and immunoblotting techniques were used to determine the effect of 5a on P-gp expression in LS174T cells. In addition, the ability of 5a to work as either a substrate or an inhibitor of P-gp was investigated through different methods. Results: The results revealed that 5a acts as a novel P-gp inhibitor that dually suppresses the overexpression and function of P-glycoprotein. Co-treatment of LS174T cell line, human colon adenocarcinoma cell line, with 5a and paclitaxel recovered the anticancer effect of paclitaxel by controlling the acquired drug resistance pathway. The overexpression of P-gp induced by rifampin and paclitaxel in a colorectal cell line was suppressed by 5a which could be a novel inhibitory substrate inhibiting the transport of paclitaxel by P-gp. Conclusion: The results revealed that 5a can be classified as a type B P-gp inhibitor (with both substrate and inhibitor activities) with an additional function of suppressing P-gp overexpression. The results might be clinically useful in the development of anticancer drugs against cancers with multidrug resistance.