Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo

Baburin, Igor; Varkevisser, Rosanne; Schramm, Anja; Saxena, Priyanka; Beyl, Stanislav; Szkokan, Phillip; Linder, Tobias; Stary-Weinzinger, Anna; Heyden, Marcel A G van der; Houtman, Marien J C; Takanari, Hiroki; Jonsson, Malin K.B.; Beekman, Jet H.D.; Hamburger, Matthias; Vos, Marc A.; Hering, Steffen

doi:10.1016/j.phrs.2018.02.024

Cited by 26 publications

(10 citation statements)

References 48 publications

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“…We used commercial Cor.4U® human-induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMCs; Ncardia, Cologne, Germany) as described before (Baburin et al, 2018). Cells were transiently loaded with the voltage-sensitive dye FluoVolt, and the multiwell plate was placed in an environmentally controlled stage incubator (37°C, 5% CO 2 , water-saturated air atmosphere; Okolab Inc, Burlingame, CA, USA).…”

Section: Optical Action Potential Measurements In Hipsc-cmcsmentioning

confidence: 99%

LUF7244, an allosteric modulator/activator of K_v11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

Qile

Beekman

Sprenkeler

et al. 2019

British J Pharmacology

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Background and PurposeKv11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of Kv11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model.Experimental ApproachLUF7244 was tested in vitro for (a) increasing human IKv11.1 and canine IKr and (b) decreasing dofetilide‐induced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block.Key ResultsLUF7244 (0.5–10 μM) concentration dependently increased IKv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on IKIR2.1, INav1.5, ICa‐L, and IKs, doubled IKr, shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide‐induced early afterdepolarizations. LUF7244 (2.5 mg·kg−1·15 min−1) in dogs with sinus rhythm was not proarrhythmic and shortened, non‐significantly, repolarization parameters (QTc: −6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilide‐induced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75 ± 0.80 during sinus rhythm and 2.34 ± 1.57 μM after chronic atrioventricular block.Conclusions and ImplicationsLUF7244 counteracted dofetilide‐induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of Kv11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening.

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Section: Optical Action Potential Measurements In Hipsc-cmcsmentioning

confidence: 99%

LUF7244, an allosteric modulator/activator of K_v11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

Qile

Beekman

Sprenkeler

et al. 2019

British J Pharmacology

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“…A study on rabbits and dogs demonstrated that the prolongation of the QT interval subsequent to dehydroevodiamine usage could lead to the development of torsade de points. 79 …”

Section: Plants and Their Ingredients With Antiarhythmic Propertiesmentioning

confidence: 99%

“… 23 , 82 In addition, usage of dehydroevodiamine, one of the active principles isolated from the dried fruits of Evodia rutaecarpa, could lead to the development of torsade de points. 79 The arrhythmogenic effects of some other medicinal plants or their derivatives such as aconitum, Bitter orange, Echinacea, Ginkgo biloba, Guarana, Horny goat weed (Epimedium), Lily of the valley (Convallaria majalis), Night-blooming cereus, Oleander, Rhodiola and St. John’s wort (Hypericum perforatum) has also been reported. 23 , 109 , 110 The Lily of the valley, Night-blooming cereus, Oleander, and Strophanthus are using to treat congestive heart failure.…”

Section: Arrhythmogenesis Plants and Drug Interactionsmentioning

confidence: 99%

A review on plants and herbal components with antiarrhythmic activities and their interaction with current cardiac drugs

Beik

Joukar

Najafipour

2020

Journal of Traditional and Complementary Medicine

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This paper aimed to compile information on plants or their compounds which have experimentally shown antiarrhythmic effect and to scrutinize the efficacy and potency of them and their potential interaction with conventional cardiac drugs. Literature searches were accomplished by using numerous electronic databases, and the available knowledge on different parts of herbs and their ingredients with antiarrhythmic effects up to 2019 were identified and collected. The results indicate that 36 herbs or their derivatives can be effective in the treatment of arrhythmias, especially in animal and cellular models. They affect various ionic channels in different action potential phases. The alterations in ionic currents lead to changing in the amplitude and duration of the action potential, effective refractory period, maximum velocity, resting membrane potential, channel trafficking, or intracellular calcium concentration. The agents that prolong action potential duration and effective refractory period such as dauricine and sophocarpine seem to be more beneficial if more comprehensive studies confirm their efficacy and safety. It is noteworthy that the consumption of some herbal agents for cardiovascular (e.g. Hawthorn and Ginseng) or other (e.g. Ginseng and Licorice) therapeutic purposes may boost the pro-arrhythmogenic effect of current cardiovascular drugs such as cardiac glycosides. This study accentuates known plants or their derivatives with anti-arrhythmic effects, potential interaction with other cardiac drugs, and the possible mechanisms involved. It can assist clinicians and scientists in research and therapeutic approaches to the management of cardiac arrhythmias.

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“…It seems that the indole ring of DHE is able to arrange itself between Y652 and F656 in a sandwich type manner, thereby allowing π–π stacking interactions with both amino acids (Baburin et al. 2018).…”

Section: Characterization Of Compounds With Undesired Effects – Herg mentioning

confidence: 99%

HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples

Hamburger

2019

Pharmaceutical Biology

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Context: Discovery of pharmacologically active natural products as starting points for drug development remains important and, for reasons of consumer safety, the identification of toxicologically relevant compounds in herbal drugs. Objective: To explain, with the aid of relevant examples from our own research, how these goals can be achieved. Methods: An in-house technology platform comprising pre-formatted extract libraries in 96-well format, miniaturized tracking of activity in extracts via HPLC-activity profiling, structure elucidation with microprobe NMR, and in vitro and in vivo pharmacological methods were used. Results: Piperine was identified as a new scaffold for allosteric GABA A receptor modulators with in vivo activity that interacts at a benzodiazepine-independent binding site. Selectivity and potency were improved by iterative optimization towards synthetic piperine analogues. Dehydroevodiamine and hortiamine from the traditional Chinese herbal drug Evodiae fructus were identified as potent hERG channel blockers in vitro . The compounds induced torsades de pointes arrhythmia in animal models. Conclusions: The allosteric binding site for piperine analogues remains to be characterized and cardiac risks of herbal drugs need to be further evaluated to ensure consumer safety.

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Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo

Cited by 26 publications

References 48 publications

LUF7244, an allosteric modulator/activator of K_v11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

LUF7244, an allosteric modulator/activator of K_v11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

A review on plants and herbal components with antiarrhythmic activities and their interaction with current cardiac drugs

HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples

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Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo

Cited by 26 publications

References 48 publications

LUF7244, an allosteric modulator/activator of Kv11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

LUF7244, an allosteric modulator/activator of Kv11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

A review on plants and herbal components with antiarrhythmic activities and their interaction with current cardiac drugs

HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples

Contact Info

Product

Resources

About

LUF7244, an allosteric modulator/activator of K_v11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

LUF7244, an allosteric modulator/activator of K_v11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model