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British journal of pharmacology2020; 177(16); 3778-3794; doi: 10.1111/bph.15100

Effect of selective IK,ACh inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation.

Abstract: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, IK,ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific IK,ACh inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in horses with persistent AF. The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction. XAF-1407 potently and selectively inhibited Kir 3.1/3.4 and Kir 3.4/3.4, underlying the IK,ACh current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia. XAF-1407 efficiently cardioverted sustained tachypacing-induced AF of short duration in horses without notable side effects. This supports IK,ACh inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.
© 2020 The British Pharmacological Society.
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Publication Date: 2020-06-24 PubMed ID: 32436234PubMed Central: PMC7393200DOI: 10.1111/bph.15100Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research paper investigates the anti-arrhythmic and electrophysiological properties of a new compound, XAF-1407, in treating atrial fibrillation in horses. The study found that XAF-1407 efficiently treats sustained tachypacing-induced atrial fibrillation in horses with minimal side effects, suggesting potential use in other species including humans.

Explanation of the Research Paper

The research paper explains a study conducted on the properties of a new compound, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), especially its inhibitory effect on specific ion channels involved in atrial fibrillation.

  • The first section of the research covers the investigation into the pharmacological ion channel profile of XAF-1407. The research team used cell lines displaying the relevant ion channels to test the effectiveness of the compound in inhibiting these channels.
  • The study then applies this understanding to practical experiments involving eleven horses. The horses are implanted with cardioverter defibrillators which are used to induce atrial fibrillation. The effect of XAF-1407 is then tested in these horses over a one-month period.
  • The results of these tests revealed that XAF-1407 has the ability to inhibit certain channels — specifically K 3.1/3.4 and K 3.4/3.4 which underlay the IK,ACh current — effectively. Treatment with XAF-1407 resulted in slowing down the atrial fibrillatory rate and led to successful cardioversion — the process of restoring the heart’s normal rhythm.
  • The compound was also found to cause minor QTc prolongation (an extension of the electrical recovery phase of the heart) within 15 minutes of drug infusion, but this observation did not result in any ventricular arrhythmia, suggesting the safety of the drug.

Significance of the Findings

These findings are significant as they suggest XAF-1407 as a potential treatment for atrial fibrillation. Specifically, the findings imply:

  • The ability of XAF-1407 to efficiently treat atrial fibrillation induced by tachypacing (rapid heartbeat) in horses. There were minimal side effects detected during the study period.
  • The study also suggests the potential of the compound for use in treating paroxysmal atrial fibrillation in horses, and implies potential clinical value in treating the condition in other species, including humans.

Cite This Article

APA
Fenner MF, Carstensen H, Dalgas Nissen S, Melis Hesselkilde E, Scott Lunddahl C, Adler Hess Jensen M, Loft-Andersen AV, Sattler SM, Platonov P, El-Haou S, Jackson C, Tang R, Kirby R, Ford J, Schotten U, Milnes J, Svane Sørensen U, Jespersen T, Buhl R. (2020). Effect of selective IK,ACh inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation. Br J Pharmacol, 177(16), 3778-3794. https://doi.org/10.1111/bph.15100

Publication

British journal of pharmacology
ISSN: 1476-5381
NlmUniqueID: 7502536
Country: England
Language: English
Volume: 177
Issue: 16
Pages: 3778-3794

Researcher Affiliations

Fenner, Merle Friederike
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Carstensen, Helena
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Dalgas Nissen, Sarah
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Melis Hesselkilde, Eva
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Scott Lunddahl, Christine
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Adler Hess Jensen, Maja
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Loft-Andersen, Ameli Victoria
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Sattler, Stefan Michael
  • Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark.
  • Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians University Munich (LMU), Munich, Germany.
Platonov, Pyotr
  • Arrhythmia Clinic, Skåne University Hospital and Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden.
El-Haou, Said
  • Xention Ltd., Newmarket, UK.
Jackson, Claire
  • Xention Ltd., Newmarket, UK.
Tang, Raymond
  • Xention Ltd., Newmarket, UK.
Kirby, Robert
  • Xention Ltd., Newmarket, UK.
Ford, John
  • Xention Ltd., Newmarket, UK.
Schotten, Ulrich
  • Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
Milnes, James
  • Xention Ltd., Newmarket, UK.
Svane Sørensen, Ulrik
  • Acesion A/S, Copenhagen, Denmark.
Jespersen, Thomas
  • Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Buhl, Rikke
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.

MeSH Terms

  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Atrial Fibrillation / drug therapy
  • Heart Atria
  • Horses
  • Potassium

Grant Funding

  • Oda og Hans Svenningsens Fond
  • Kirsten og Freddy Johansens Fond
  • The Kustos Foundation of 1881
  • DFF-7017-00050 / The Independent Research Fund Denmark
  • 675351 / European Union Horizon 2020 MSCA ITN

Conflict of Interest Statement

The authors S.E.‐H., C.J., R.T., R.K., J.F., and J.M. were employees of former Xention Ltd but no longer have financial interest in the experimental compound (XAF‐1407) mentioned within this article. The experimental compound XAF‐1407 was provided free of charge. The other authors (M.F.F., H.C., S.D.N., E.Z.H., C.L., M.A.J., A.V.L.‐A., S.M.S., P.G.P., U.S., U.S.S., T.J., and R.B.) report no conflicts of interest.

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Citations

This article has been cited 18 times.
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