Mechanism of Sodium Channel Blockade in the Cardiotoxic Action of Emetine Dihydrochloride in Isolated Cardiac Preparations and Ventricular Myocytes of Guinea Pigs

Lemmens‐Gruber, Rosa; Studenik, Christian; Karkhaneh, Azam; Heistracher, P.

doi:10.1097/00005344-199711000-00004

Cited by 9 publications

(6 citation statements)

References 26 publications

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“…Nevertheless, this amoebicide drug has been found to be cardiotoxic. Its cardiotoxicity was attributed to the inhibitory effects on sodium and calcium conductances (Lemmens‐Gruber et al ., 1996; 1997).…”

Section: Discussionmentioning

confidence: 99%

Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres

Champéroux¹,

Viaud²,

Amrani³

et al. 2005

British J Pharmacology

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1 Torsade de Pointes (TdP) is a well-described major risk associated with various kinds of drugs. However, prediction of this risk is still uncertain both in preclinical and clinical trials. We tested 45 reference compounds on the model of isolated canine Purkinje fibres. Of them, 22 are clearly associated and/or labelled with a risk of TdP, and 13 others are drugs with published clinical evidence of QT prolongation, with only one or two exceptional cases of TdP. The 10 remaining drugs are without reports of TdP and QT prolongation. 2 The relevance of different indicators such as APD 90 increase, reverse use dependency, action potential triangulation or effect on V max was evaluated by comparison with available clinical data. Finally, a complex algorithm called TDPscreent and based on two subalgorithms corresponding to particular electrophysiological patterns was defined. 3 This latter algorithm enabled a clear separation of drugs into three groups: (A) drugs with numerous or several reports (42 cases) of TdP, (B) drugs causing QT prolongation and/or TdP only, the latter at a very low frequency (p2 cases), (C) drugs without reports of TdP or QT prolongation. 4 The use of such an algorithm combined with a database accrued from reference compounds with available clinical data is suggested as a basis for testing new candidate drugs in the early stages of development for proarrhythmic risk prediction.

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Section: Discussionmentioning

confidence: 99%

Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres

Champéroux¹,

Viaud²,

Amrani³

et al. 2005

British J Pharmacology

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“…1E. All the other compounds, cephaeline [42], emetine [42], pyrvinium, me oquine [43], and felodipine [44] are reported as inhibitors of voltage-gated sodium (Nav) channels, with the exception of compounds pyrvinium and cycloheximide, which have no known impact on voltage-gated sodium channels (Fig. 1E).…”

Section: Resultsmentioning

confidence: 99%

Discovery of maslinic acid being a Nav1.7 inhibitor with analgesic efficacy in rodent pain models

Dai

Osafo

Wang

et al. 2023

Preprint

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Background Voltage gated sodium channels are essential for the generation of exceptional pain signals after peripheral nerve injury. Among them, voltage-gated sodium (Nav) subtype Nav1.7 is a powerful target for a broad range of pain conditions. Maslinic acid, one of the most common pentacyclic triterpenes widely distributed in medicinal plants, showed pharmacologic safety and potent pharmacological action. Herein, we present maslinic acid (MA) as an inhibitor of Nav1.7 with analgesic efficacy in rodent pain models. Methods We first explored the target of maslinic acid using the CMap method and patch clamp recording. Maslin acid and its inactive analogue (oleanolic acid as negative controls) was used to culture MCF-7 cells. Then, we performed RNA-seq of the cultured MCF-7 cells and analyzed the transcriptome data. The differential genes were identified and used as an input for CMap. The CMap result was further confirmed by patch clamp recording. Results The CMap result suggested that maslinic acid was an agonist of Nav channels. Further whole cell patch-clamp experiments revealed that maslinic acid inhibited the Nav1.7 channel with an IC50 value of 6.1 µM. Conclusion Maslinic acid showed a potent analgesic effect in two rodent models of formaldehyde and acid-induced pain. Our findings show novel insights into the new target of maslinic acid in complex neurological disorders. Maslinic acid targeting Nav1.7 is a new analgesic lead.

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“…19,20 From the structure activity relationship studies of in vivo toxicity of emetine and its derivatives (prodrugs), it is conclusive that the solution phase conformation of emetine is a critical factor in eliminating the in vivo cardiotoxicity. Thus, we hypothesize that to obtain a prodrug of emetine that will not present acute in vivo toxicity, we need to modify emetine on the aromatic ring of the tetrahydroisoquinoline ring (position C-5′, C-6′, C-7′, or C-8′, Fig.…”

Section: Resultsmentioning

confidence: 99%

Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives

Akinboye

Rosen

Bakare

et al. 2017

Bioorganic & Medicinal Chemistry

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Emetine is a small molecule protein synthesis inhibitor that is toxic to all cell types and therefore suitable for complete killing of all types of heterogeneous cancer cells within a tumor. It becomes significantly inactive (non-toxic) when derivatized at its N-2′ secondary amine. This provides a strategy for targeting emetine to cancerous tumor without killing normal cells. In this report, PSA activatable peptide prodrugs of emetine were synthesized. To overcome steric hindrances and enhance protease specific cleavage, a 2-stage prodrug activation process was needed to release emetine in cancer cells. In this 2-stage process, emetine prodrug intermediates are coupled to PSA peptide substrate (Ac-His-Ser-Ser-Lys-Leu-Gln) to obtain the full prodrug. Both prodrug intermediates 10 (Ala-Pro-PABC-Emetine) and 14 (Ser-Leu-PABC-Emetine) were evaluated for kinetics of hydrolysis to emetine and potency [Where PABC = p-aminobenzyloxycarbonyl]. While both intermediates quantitatively liberate emetine when incubated under appropriate conditions, upon coupling of PSA substrate to give the full prodrugs, only prodrug 16, the prodrug obtained from 14 was hydrolyzable by PSA. Cytotoxicity studies in PSA producing LNCaP and CWR22Rv1 confirm the activation of the prodrug by PSA with an IC50 of 75 nM and 59 nM respectively. The cytotoxicity of 16 is significantly reduced in cell lines that do not produce PSA. Further, in vivo toxicity studies are done on these prodrugs and other derivatives of emetine. The results show the significance of conformational modulation in obtaining safe emetine prodrugs.

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Mechanism of Sodium Channel Blockade in the Cardiotoxic Action of Emetine Dihydrochloride in Isolated Cardiac Preparations and Ventricular Myocytes of Guinea Pigs

Cited by 9 publications

References 26 publications

Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres

Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres

Discovery of maslinic acid being a Nav1.7 inhibitor with analgesic efficacy in rodent pain models

Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives

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