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- Bentzen, B. H., et al.
(author)
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Mechanisms of Action of the KCa2-Negative Modulator AP30663, a Novel Compound in Development for Treatment of Atrial Fibrillation in Man
- 2020
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In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Journal article (peer-reviewed)abstract
- Aims Small conductance Ca2+-activated K+ channels (SK channels, K(Ca)2) are a new target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of K(Ca)2 channels that is currently in clinical development for treatment of AF. The aim of this study is to present the electrophysiological profile and mechanism of action of AP30663 and its efficacy in prolonging atrial refractoriness in rodents, and by bioinformatic analysis investigate if genetic variants in KCNN2 or KCNN3 influence the expression level of these in human heart tissue. Methods and Results Whole-cell and inside-out patch-clamp recordings of heterologously expressed K(Ca)2 channels revealed that AP30663 inhibits K(Ca)2 channels with minor effects on other relevant cardiac ion channels. AP30663 modulates the K(Ca)2.3 channel by right-shifting the Ca2+-activation curve. In isolated guinea pig hearts AP30663 significantly prolonged the atrial effective refractory period (AERP) with minor effects on the QT-interval corrected for heart rate. Similarly, in anaesthetized rats 5 and 10 mg/kg of AP30663 changed the AERP to 130.7 +/- 5.4% and 189.9 +/- 18.6 of baseline values. The expression quantitative trait loci analyses revealed that the genome wide association studies for AF SNP rs13376333 in KCNN3 is associated with increased mRNA expression of KCNN3 in human atrial appendage tissue. Conclusions AP30663 is a novel negative allosteric modulator of K(Ca)2 channels that concentration-dependently prolonged rodent atrial refractoriness with minor effects on the QT-interval. Moreover, AF associated SNPs in KCNN3 influence KCNN3 mRNA expression in human atrial tissue. These properties support continued development of AP30663 for treatment of AF in man.
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- Holst, Anders G., et al.
(author)
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Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial
- 2023
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In: Nature Medicine. - 1078-8956 .- 1546-170X.
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Journal article (peer-reviewed)abstract
- Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg−1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg−1 AP30663, 5 mg kg−1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg−1 and 5 mg kg−1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg−1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .
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- Menon, C., et al.
(author)
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Defect density in non-selective and selective Si/SiGe structures
- 2002
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In: Journal of Crystal Growth. - 0022-0248 .- 1873-5002. ; 237, s. 259-263
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Journal article (peer-reviewed)abstract
- The epitaxial quality of Si (non-selective or selective epitaxy)/SiGe (non-selective or selective epitaxy) structures applying Si2H2Cl2 or SiH4 as the Si source has been studied. High-resolution reciprocal lattice mapping and X-ray reflectivity measurements have been used to characterise the epitaxial quality and the interfacial defects, respectively. The surface morphology of the structures was studied by atomic force microscopy. It is shown that the generation of defects in non-selective SiGe layers is strongly dependent oil the thickness of the buffer layer. Moreover, the selective growth of a Si buffer layer requires a growth temperature above 770degreesC in order to obtain a smooth layer surface, which is beneficial for the succeeding growth of the SiGe layer. The surface can also be smoothed by an annealing treatment at 900degreesC for 40 s. This annealing step is crucial to remove the interfacial defects in the case of Si/SiGe structures grown with different Si sources.
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- Radamson, H. H., et al.
(author)
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Growth of high frequency SiGe heterojunction bipolar transistors structures
- 2002
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In: Physica Scripta. - 0031-8949 .- 1402-4896. ; T101, s. 45-48
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Journal article (peer-reviewed)abstract
- The growth of heterojuntion bipolar transistor structures using chemical vapor deposition has been investigated. Generation of defects in selectively or nonselectively grown collector layers using arsenic as the dopant has been studied. Minimizing the defect density in SiGe base layers by optimizing the growth rate has also been investigated in detail. High resolution reciprocal lattice mapping, atomic force microscopy and secondary ion mass spectrometry have been used as the main characterization tools.
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- Radamson, H. H., et al.
(author)
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Observed critical thickness in selectively and non-selectively grown Si1-xGex layers on patterned substrates
- 2002
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In: Physica Scripta. - 0031-8949 .- 1402-4896. ; T101, s. 42-44
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Journal article (peer-reviewed)abstract
- Relaxation of SiGe layers grown selectively or non-selectively on oxide-patterned substrates using reduced pressure chemical vapor deposition was investigated. The influences of the buffer layer, the polycrystalline layer on the oxide and the opening size on the critical thickness for relaxation of SiGe layers have been studied in detail. High resolution reciprocal lattice mapping, atomic force microscopy and Normanski optical microscope have been used as the main characterization tools.
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