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The KCa2 Channel In...
The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs
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Diness, J. G. (author)
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Kirchhoff, J. E. (author)
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Speerschneider, T. (author)
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Abildgaard, L. (author)
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- Edvardsson, Nils, 1942 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Sørensen, U. S. (author)
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Grunnet, M. (author)
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Bentzen, B. H. (author)
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(creator_code:org_t)
- 2020-02-28
- 2020
- English.
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In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Abstract
Subject headings
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- Aims: To describe the effects of the KCa2 channel inhibitor AP30663 in pigs regarding tolerability, cardiac electrophysiology, pharmacokinetics, atrial functional selectivity, effectiveness in cardioversion of tachy-pacing induced vernakalant-resistant atrial fibrillation (AF), and prevention of reinduction of AF. Methods and Results: Six healthy pigs with implanted pacemakers and equipped with a Holter monitor were used to compare the effects of increasing doses (0, 5, 10, 15, 20, and 25 mg/kg) of AP30663 on the right atrial effective refractory period (AERP) and on various ECG parameters, including the QT interval. Ten pigs with implanted neurostimulators were long-term atrially tachypaced (A-TP) until sustained vernakalant-resistant AF was present. 20 mg/kg AP30663 was tested to discover if it could successfully convert vernakalant-resistant AF to sinus rhythm (SR) and protect against reinduction of AF. Seven anesthetized pigs were used for pharmacokinetic experiments. Two pigs received an infusion of 20 mg/kg AP30663 over 60 min while five pigs received 5 mg/kg AP30663 over 30 min. Blood samples were collected before, during, and after infusion on AP30663. AP30663 was well-tolerated and prominently increased the AERP in pigs with little effect on ventricular repolarization. Furthermore, it converted A-TP induced AF that had become unresponsive to vernakalant, and it prevented reinduction of AF in pigs. Both a >30 ms increase of the AERP and conversion of AF occurred in different pigs at a free plasma concentration level of around 1.0–1.4 µM of AP30663, which was achieved at a dose level of 5 mg/kg. Conclusion: AP30663 has shown properties in animals that would be of clinical interest in man. © Copyright © 2020 Diness, Kirchhoff, Speerschneider, Abildgaard, Edvardsson, Sørensen, Grunnet and Bentzen.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- antiarrhythmic drugs
- atrial fibrillation
- ion channels
- KCa2
- SK channels
- antiarrhythmic agent
- ap 30663
- small conductance calcium activated potassium channel
- unclassified drug
- vernakalant
- animal experiment
- animal model
- Article
- cardioversion
- controlled study
- drug distribution
- drug efficacy
- drug elimination
- drug half life
- drug metabolism
- drug tolerability
- electrocardiography
- female
- heart muscle refractory period
- heart pacing
- heart repolarization
- Landrace pig
- maximum concentration
- nerve stimulation
- nonhuman
Publication and Content Type
- ref (subject category)
- art (subject category)
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