Clinical efficacy of potassium canreonate-canrenone in sinus rhythm restoration among patients with atrial fibrillation - a protocol of a pilot, randomized, double -blind, placebo-controlled study (CANREN-AF trial)

Dąbrowski, Rafał; Syska, Paweł; Mączyńska, Justyna; Farkowski, Michał M.; Sawicki, Stefan; Kubaszek-Kornatowska, Agata; Michałek, Piotr; Kowalik, Ilona; Szwed, Hanna; Hryniewiecki, Tomasz

doi:10.1186/s13063-020-04277-3

Cited by 4 publications

(4 citation statements)

References 16 publications

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“…The mechanisms leading to RAAS toxicity also include (i) modulation of the production of pro-inflammatory status, potentially leading to recruitment of mono/macrophages; (ii) induction of fibrosis (through AT1R); (iii) induction of vascular toxicity and modulation of angiogenesis [ 15 ]. Of note, among the RAAS-inhibiting agents, only canrenone (potassium canreonate), the active metabolite of spironolactone, can be administered intravenously [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

The Efficacy of the Mineralcorticoid Receptor Antagonist Canrenone in COVID-19 Patients

Vicenzi

Ruscica

Iodice

et al. 2020

JCM

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Background: In COVID-19 patients, aldosterone via angiotensin-converting enzyme-2 deregulation may be responsible for systemic and pulmonary vasoconstriction, inflammation, and oxidative organ damage. Aim: To verify retrospectively the impact of the mineralcorticoid receptor antagonist canrenone i.v. on the need of invasive ventilatory support and/or all-cause in-hospital mortality. Methods: Sixty-nine consecutive COVID-19 patients, hospitalized for moderate to severe respiratory failure at Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico of Milan, received two different therapeutic approaches in usual care according to the personal skills and pharmacological management experience of the referral medical team. Group A (n = 39) were given vasodilator agents or renin–angiotensin–aldosterone system (RAAS) inhibitors and group B (n = 30) were given canrenone i.v. Results: Among the 69 consecutive COVID-19 patients, those not receiving canrenone i.v. (group A) had an event-free rate of 51% and a survival rate of 64%. Group B (given a mean dose of 200 mg/q.d. of canrenone for at least two days of continuous administration) showed an event-free rate of 80% with a survival rate of 87%. Kaplan–Meier analysis for composite outcomes and mortality showed log rank statistics of 0.0004 and 0.0052, respectively. Conclusions: The novelty of our observation relies on the independent positive impact of canrenone on the all-cause mortality and clinical improvement of COVID-19 patients ranging from moderate to severe diseases.

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Section: Discussionmentioning

confidence: 99%

The Efficacy of the Mineralcorticoid Receptor Antagonist Canrenone in COVID-19 Patients

Vicenzi

Ruscica

Iodice

et al. 2020

JCM

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“…This favorable response may rely on the activity of canrenone that can antagonize the disequilibrium of RAAS pathway. Among the RAAS-inhibiting agents, only canrenone (potassium canreonate), the active metabolite of spironolactone, can be administered intravenously [9].…”

Section: Discussionmentioning

confidence: 99%

“…ACE2 serves a counterbalancing role in Renin-Angiotensin-Aldosterone System (RAAS), i.e. it cleaves away (i) phenylalanine from angiotensin (Ang) II, converting it to Ang-(1-7), and (ii) leucine from Ang I, converting it to Ang- (1)(2)(3)(4)(5)(6)(7)(8)(9). SARS-CoV-2 infection appears to downregulate ACE2 possibly making unable the enzyme to exert protective effects in organs.…”

Section: Introductionmentioning

confidence: 99%

The efficacy of mineral corticoid receptor antagonist, canrenone, in COVID-19 patients

Vicenzi

Ruscica

Iodice

et al. 2020

Preprint

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Purpose: Despite the spread of SARS-CoV-2 global pandemic and the volume of clinical trials launched, no specific therapeutic drug approaches improving outcomes have been so far approved. In COVID-19 patients, aldosterone via ACE2 deregulation may be responsible for systemic and pulmonary vasoconstriction, inflammation and oxidative organ damage.Aim: To verify retrospectively the impact of the mineral corticoid receptor antagonist canrerone i.v. on the need of invasive ventilatory support and/or all-cause in-hospital mortality.Study design: In this retrospective study (CARDIOVID-19, ID-107162), COVID-19 patients hospitalized for severe respiratory failure were taken care by pneumologists or cardiologists and received two different therapeutic approaches according to personal skill of referral medical team on pharmacological management. Group 1 (n=39) were given vasodilator agents or RAAS-inhibitors and group 2 (n=30) were given canrenone i.v.Results: Among 69 consecutive COVID-19 patients, enrolled in COVID-19 NETWORK registry, the group given canrenone (200 mg/q.d. for a median of 14±11) showed a free event rate of 83% with a survival percentage of 90%. In group 1, not receiving canrenone, free event rate was 51% and survival 64%. Kaplan-Meier analysis for composite outcomes showed a Log Rank of 0.0004 and for mortality, Log Rank was 0.005.Conclusions: The novelty of our observation relies on the independent positive impact of the canrenone, a mineral corticoid receptor antagonist, on all-cause mortality and clinical improvement in COVID-19 patients.

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“…The aldosterone synthesis and secretion pathway were only shown in conjunction with ZT, but is related to renin secretion and adrenergic signaling in cardiomyocytes. A randomized, double-blind, placebo-controlled study showed that excess aldosterone secretion resulted in proarrhythmic effects and moreover confirmed that drugs affecting the renin-angiotensinaldosterone system (RAAS) were of benefit for arrhythmia and its comorbidities (56). A systematic review provided evidence that ACEI/ARB and aldosterone inhibitors could prevent the recurrence of AF (57).…”

Section: Shared Signaling Pathways Of Pharmacogeneticsmentioning

confidence: 92%

Integrated Pharmacogenetics Analysis of the Three Fangjis Decoctions for Treating Arrhythmias Based on Molecular Network Patterns

Wei

Long

Tan

et al. 2021

Front. Cardiovasc. Med.

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Aim: To explore the diverse target distribution and variable mechanisms of different fangjis prescriptions when treating arrhythmias based on the systems pharmacology.Methods: The active ingredients and their corresponding targets were acquired from the three fangjis [Zhigancao Tang (ZT), Guizhigancao Longgumuli Tang (GLT), and Huanglian E'jiao Tang (HET)] and the arrhythmia-related genes were identified based on comprehensive database screening. Networks were constructed between the fangjis and arrhythmia and used to define arrhythmia modules. Common and differential gene targets were identified within the arrhythmia network modules and the cover rate (CR) matrix was applied to compare the contributions of the fangjis to the network and modules. Comparative pharmacogenetics analyses were then conducted to define the arrhythmia-related signaling pathways regulated by the fangjis prescriptions. Finally, the divergence and convergence points of the arrhythmia pathways were deciphered based on databases and the published literature.Results: A total of 187, 105, and 68 active ingredients and 1,139, 1,195, and 811 corresponding gene targets of the three fangjis were obtained and 102 arrhythmia-related genes were acquired. An arrhythmia network was constructed and subdivided into 4 modules. For the target distribution analysis, 65.4% of genes were regulated by the three fangjis within the arrhythmia network. ZT and GLT were more similar to each other, mainly regulated by module two, whereas HET was divided among all the modules. From the perspective of signal transduction, calcium-related pathways [calcium, cyclic guanosine 3′,5′-monophosphate (cGMP)-PKG, and cyclic adenosine 3′,5′-monophosphate (cAMP)] and endocrine system-related pathways (oxytocin signaling pathway and renin secretion pathways) were associated with all the three fangjis prescriptions. Nevertheless, heterogeneity existed between the biological processes and pathway distribution among the three prescriptions. GLT and HET were particularly inclined toward the conditions involving abnormal hormone secretion, whereas ZT tended toward renin-angiotensin-aldosterone system (RAAS) disorders. However, calcium signaling-related pathways prominently feature in the pharmacological activities of the decoctions. Experimental validation indicated that ZT, GLT, and HET significantly shortened the duration of ventricular arrhythmia (VA) and downregulated the expression of CALM2 and interleukin-6 (IL-6) messenger RNAs (mRNAs); GLT and HET downregulated the expression of CALM1 and NOS3 mRNAs; HET downregulated the expression of CRP mRNA.Conclusion: Comparing the various distributions of the three fangjis, pathways provide evidence with respect to precise applications toward individualized arrhythmia treatments.

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Clinical efficacy of potassium canreonate-canrenone in sinus rhythm restoration among patients with atrial fibrillation - a protocol of a pilot, randomized, double -blind, placebo-controlled study (CANREN-AF trial)

Cited by 4 publications

References 16 publications

The Efficacy of the Mineralcorticoid Receptor Antagonist Canrenone in COVID-19 Patients

The Efficacy of the Mineralcorticoid Receptor Antagonist Canrenone in COVID-19 Patients

The efficacy of mineral corticoid receptor antagonist, canrenone, in COVID-19 patients

Integrated Pharmacogenetics Analysis of the Three Fangjis Decoctions for Treating Arrhythmias Based on Molecular Network Patterns

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