Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone

Lainščak, Mitja; Pelliccia, Francesco; Rosano, Giuseppe M.C.; Vitale, Cristiana; Schiariti, Michele; Greco, Cesare; Saglio, Giuseppe; Gaudio, Carlo

doi:10.1016/j.ijcard.2015.05.127

Cited by 142 publications

(95 citation statements)

References 37 publications

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“…Spironolactone is currently used as a potassium-sparing diuretic, in clinics, to treat hypertension, hyperaldosteronism, and heart failure (Lainscak et al, 2015). Very recently, this drug has been reported to inhibit acute HIV-1 infection through the inhibition of Tat-mediated HIV-1 transcription (Lacombe et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

et al. 2017

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Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged “block and lock” approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clinical use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compound library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.

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Section: Discussionmentioning

confidence: 99%

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

et al. 2017

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“…Although SPR has been used clinically for decades as a diuretic and to treat heart failure, hyperaldosteronism, and edematous states, several side effects limit its use (22,23). These include effects on reproductive and other metabolic functions.…”

Section: Discussionmentioning

confidence: 99%

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Verma

Thompson

Swaminathan

2016

Proc. Natl. Acad. Sci. U.S.A.

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Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses. . EBV infects the majority of humans worldwide and establishes a persistent, lifelong latent infection in memory B cells. Occasional reactivation from latency occurs, and EBV enters a lytic phase of replication, during which a tightly regulated series of lytic genes is expressed, culminating in lysis of the host cell and release of infectious viral progeny. All herpesviruses share these abilities to establish asymptomatic latent infection and reactivate intermittently.All herpesviruses also express a regulatory protein early in lytic replication that is essential for efficient gene expression and infectious virion production. The EBV member of this family, which includes herpes simplex virus ICP27, cytomegalovirus (CMV) UL69, and Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57, is known as SM (2). SM acts posttranscriptionally to enhance accumulation of many lytic EBV transcripts. SM activity is highly gene-specific and preferentially enhances expression of several late lytic transcripts, including those encoding the major viral capsid antigen (VCA) and gp350, which is required for infection of B lymphocytes (3-5). SM and its homologs in other herpesviruses may also enhance transcription and translation of specific viral genes (6).Currently, all available antiherpesvirus drugs target viral DNA polymerases and are usually highly effective, but toxicity and development of resistance limits their use (7). To discover potential novel therapeutic compounds, we applied a cell-based screening assay to identify compounds that would specifically target SM function (8). Using this assay, spironolactone (SPR), a drug in clinical use for over 50 y, was identified as inhibiting SM function and EBV virion production. SPR is an aldosterone antagonis...

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“…The MRAs administered in the included trials were spironolactone or eplerenone, both of which have been proved efficacious in the treatment of heart failure and hypertension. 44 Compared to spironolactone, eplerenone is a selective aldosterone antagonist with lower incidence of sexual side effects due to lower affinity for progesterone and androgen receptors. 45 However, highly polymorphic cytochrome dependent metabolism makes eplerenone susceptible to drug interactions.…”

Section: Discussionmentioning

confidence: 99%

Safety and cardiovascular effects of mineralocorticoid receptor antagonists for patients receiving hemodialysis: a systematic review and meta-analysis

et al. 2016

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Introduction Cardiovascular disease is an important factor in the mortality and morbidity of patients with end-stage renal disease receiving hemodialysis. Although mineralocorticoid receptor antagonists may have potential benefits on the cardiovascular system, their safety for patients on hemodialysis remains unclear, considering the differences between the results of already performed clinical trials. Methods MEDLINE, EMBASE, Cochrane, ClinicalTrials.gov and PubMed databases were searched for relevant clinical trials. The Cochrane Collaboration assessment tool was employed to evaluate the quality of the randomized controlled trials. Revman 5.3 was used to perform the meta-analysis. Results Eleven studies (n¼379) were included in the systematic review and five randomized controlled trials were included in the meta-analysis (n¼248). Mineralocorticoid antagonists (MRAs) did not increase predialysis potassium levels significantly (0.11, 95% confidence interval À0.03 to 0.25, p ¼ 0.11). However, the studies included in this review reported inconsistently with respect to effects of mineralocorticoid receptor antagonists on blood pressure, left ventricular ejection fraction and left ventricular hypertrophy, and quantitative analysis was not performed due to insufficient data. One trial showed that the mineralocorticoid receptor antagonists were associated with decreased carotid intima-media thickness and other articles concluded that mineralocorticoid receptor antagonists had no effect on aortic stiffness. Conclusion It is safe to use low dose mineralocorticoid receptor antagonists on patients receiving hemodialysis, at the end of each session of hemodialysis, and close monitoring of serum potassium levels and possible side effects is necessary. The cardiovascular actions still need to be explored and large scale RCTs are in progress.

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Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone

Cited by 142 publications

References 37 publications

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Safety and cardiovascular effects of mineralocorticoid receptor antagonists for patients receiving hemodialysis: a systematic review and meta-analysis

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