Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison

Abstract

Aconitine (AC) is well‐known as the main toxic ingredient and active compound of Aconitum species, of which several aconites are essential herbal medicines of Traditional Chinese Medicine (TCM) and widely applied to treat diverse diseases for their excellent anti‐inflammatory, analgesic, and cardiotonic effects. However, the cardiotoxicity and neurotoxicity of AC attracted a lot of attention and made it a favorite botanic poison in history. Nowadays, the narrow therapeutic window of AC limits the clinical application of AC‐containing herbal medicines; overdosing on AC always induces ventricular tachyarrhythmia and heart arrest, both of which are potentially lethal. But the underlying cardiotoxic mechanisms remained chaos. Recently, beyond its cardiotoxic effects, emerging evidence shows that low doses of AC or its metabolites could generate cardioprotective effects and are necessary to aconite's clinical efficacy. Consistent with TCM's theory that even toxic substances are powerful medicines, AC thus could not be simply identified as a toxicant or a drug. To prevent cardiotoxicity while digging the unique value of AC in cardiac pharmacology, there exists a huge urge to better know the characteristic of AC being a cardiotoxic agent or a potential heart drug. Here, this article reviews the advances of AC metabolism and focuses on the latest mechanistic findings of cardiac efficacy and toxicity of this aconite alkaloid or its metabolites. We also discuss how to prevent AC‐related cardiotoxicity, as well as the issues before the development of AC‐based medicines that should be solved, to provide new insight into the paradoxical nature of this ancient poison.

Revealing the efficacy-toxicity relationship of Fuzi in treating rheumatoid arthritis by systems pharmacology

“…To fully explore the toxic mechanism of Fuzi, all the targets of Fuzi were subjected to KEGG analysis. Because the main toxicity of Fuzi includes cardiotoxicity and neurotoxicity, and disturbance of ion channels such as voltage-gated Na + channel is responsible for toxicity 26 , therefore calcium signaling, adrenergic signaling in cardiomyocytes, neuroactive ligand-receptor interaction, and dopaminergic synapse were considered as the toxic pathways of Fuzi. To help visualize the comprehensive toxic mechanism of Fuzi, a compound-target-pathway network was constructed (Fig.…”

“…8 ). Noteworthy is that disturbance of ion flow including Na + , Ca 2+ , and K + is the main reason for the toxicity of Fuzi 26 . Here we showed that Fuzi can act on multiple targets that directly modulate the flow of Na + , Ca 2+ , and K + .…”

“…To obtain the targets and mechanisms of the toxicity of Fuzi, all the target genes were subjected to DAVID. Because the main toxicity of Fuzi is cardiac toxicity and neurotoxicity, and ion channels are involved in the onset of toxicity 26 , the enriched pathways including calcium signaling, adrenergic signaling in cardiomyocytes, neuroactive ligand-receptor interaction, dopaminergic synapse were considered as the toxic pathways of Fuzi, and all the target genes on those pathways were reserved.…”

Mechanisms and Efficacy of Traditional Chinese Medicine in Heart Failure

“…Aconitum carmichaelii Debx is a TCM that is, used extensively in HF as the processed product of Aconitum carmichaelii Debeaux tubers ( Zhou W et al, 2021 ). Aconitum alkaloids, which include C19-diterpenoid alkaloids (mainly comprising aconitine, mesaconitine, and hypaconitine) and C20-diterpenoid alkaloids (predominantly benzoylmesaconitine, benzoylaconitine, and benzoylhypacoitine) and other alkaloids (mainly comprising higenamine and salsolinol) have versatile chemical structures ( Zhou et al, 2015 ).…”

Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

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