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Dofetilide

Manufactured by Merck Group
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Sourced in Germany, United States

Dofetilide is a pharmaceutical drug product manufactured by Merck Group. It is a class III antiarrhythmic agent used for the treatment of certain types of cardiac arrhythmias. The core function of Dofetilide is to help regulate and maintain a normal heart rhythm in patients diagnosed with these specific cardiac conditions.

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Lab products found in correlation

Dimethyl sulfoxide (dmso), by Merck Group (6 mentions) Nifedipine, by Merck Group (5 mentions) E 4031, by Merck Group (4 mentions) Flecainide, by Merck Group (3 mentions) Quinidine, by Merck Group (3 mentions) Cisapride, by Merck Group (3 mentions) Verapamil, by Merck Group (2 mentions) Panobinostat, by Merck Group (2 mentions) Tubastatin a, by Merck Group (2 mentions) Trichostatin a, by Merck Group (2 mentions) Vanoxerine, by Merck Group (2 mentions) Blebbistatin, by Merck Group (1 mentions) Di 4 anepps, by Thermo Fisher Scientific (1 mentions) Prism 6 for mac os x, by GraphPad (1 mentions) Lidocaine, by Merck Group (1 mentions) Hmr 1556, by Bio-Techne (1 mentions) Bacl2, by Merck Group (1 mentions) S ketamine, by Pfizer (1 mentions) Xylazine, by Bayer (1 mentions) Ranolazine, by Merck Group (1 mentions)

22 protocols using dofetilide

1

Dofetilide and Derivative Preparation

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Dofetilide was obtained from Sigma, and its derivatives were prepared as previously described (Shagufta et al.,2009). All derivatives were dissolved in DMSO to prepare a 10 mM stock and stored at −20°C. Drug stocks were diluted to the required concentration in extracellular solution on the day of each experiment. The maximal DMSO concentration in the bath (1%) did not affect Cav1.2 or Nav1.5 currents in any of the preparations. (Supporting Information Fig. S1).
Saxena P., Hortigon‐Vinagre M.P., Beyl S., Baburin I., Andranovits S., Iqbal S.M., Costa A., IJzerman A.P., Kügler P., Timin E., Smith G.L, & Hering S. (2017). Correlation between human ether‐a‐go‐go‐related gene channel inhibition and action potential prolongation. British Journal of Pharmacology, 174(18), 3081-3093.
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2

Optical Mapping of Cardiac Arrhythmia

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We used the voltage sensitive dye AminoNaphthylEthenylPyridinium (Di-4-ANEPPS)(Life Technologies) at 10 μM24 (link). Blebbistatin 10 μM (Sigma-Aldrich) was employed to avoid motion artifact25 (link). Images were captured using an electron multiplying charge coupled device (EMCCD) camera (Cascade 128+, Cascade Evolve, Photometric, Tucson, AZ, U.S.A). Arrhythmia induction was carried out using rapid pacing protocols (median cycle length (CL) = 200 ms, range 150–300 ms) or burst pacing (CL of 50 ms for 30 seconds). The AADs flecainide (Sigma-Aldrich) and dofetilide (Sigma-Aldrich) were added to the culture dish in sequentially increasing concentrations after arrhythmia induction (see Supplement). Signal processing of the optically mapped data was performed using a custom IDL software program or Scroll software. Further details are provided in the Data Supplement.
Statistical Analysis was performed using Prism 6 for MacOS X (GraphPad Software Inc, 2014). Univariate testing was performed using the Student’s t -test or the Mann–Whitney U test. Paired data were compared using the paired t -test.
Laksman Z., Wauchop M., Lin E., Protze S., Lee J., Yang W., Izaddoustdar F., Shafaattalab S., Gepstein L., Tibbits G.F., Keller G, & Backx P.H. (2017). Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue. Scientific Reports, 7, 5268.
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3

Electrophysiological Profiling of Antiarrhythmic Drugs

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Nifedipine (Sigma), Quinidine (Sigma, Q3625), Lidocaine (Sigma, L7757), Flecainide (Sigma, F6777) were dissolved in DMSO to make 100 mM stock solutions; Dofetilide (Sigma) was dissolved in DMSO to make 10 mM stock solution. For each dose, the stock drug was diluted in measurement medium into 2x of the targeted dose and warmed up to 32 °C. Drug administration was performed by removing 500 μL from the 1 mL measurement medium and adding 500 μL of the ~2x dose. For single-dose experiments, the drug was administered 400 s after electroporation; and the recording lasted for ~30 min for each repeat. For multi-dose experiments, the drug administration started from 6 min after electroporation with 7 min apart between each dose.
Yang Y., Liu A., Tsai C.T., Liu C., Wu J.C, & Cui B. (2022). Cardiotoxicity drug screening based on whole-panel intracellular recording. Biosensors & bioelectronics, 216, 114617.
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4

Detailed Compound Sourcing for Studies

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The compounds used in these studies were supplied as follows: BaCl2 and dofetilide by Sigma‐Aldrich (Munich, Germany); heparin by Braun (Germany); HMR‐1556 by Tocris Bioscience (Bristol, UK); isoprenaline by Hospira Inc., (USA); S‐ketamine by Pfizer (USA); thiopental‐sodium by Inresa (Germany); xylazine by Bayer (Germany).
Hornyik T., Castiglione A., Franke G., Perez‐Feliz S., Major P., Hiripi L., Koren G., Bősze Z., Varró A., Zehender M., Brunner M., Bode C., Baczkó I, & Odening K.E. (2020). Transgenic LQT2, LQT5, and LQT2‐5 rabbit models with decreased repolarisation reserve for prediction of drug‐induced ventricular arrhythmias. British Journal of Pharmacology, 177(16), 3744-3759.
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5

Comprehensive Pharmacological Screening Protocol

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Tetrodotoxin (TTX), ranolazine, dofetilide, haloperidol, moxifloxacin, 4-aminopyridine (4-AP), erythromycin, thioridazine, verapamil, phosphatidylinositol 3,4,5-trisphosphate (PIP3), ATX-II, and LY294002 were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). E-4031 and d-sotalol were obtained from Tocris Bioscience (Minneapolis, MN, USA) and Bristol-Myers Squibb Co., respectively. Stock solutions for the tested drugs were prepared according to the vendors’ instructions and then diluted for studies as needed.
Yang T., Chun Y.W., Stroud D.M., Mosley J.D., Knollmann B.C., Hong C, & Roden D.M. (2014). Screening for Acute IKr Block is Insufficient to Detect Torsades de Pointes Liability: Role of Late Sodium Current. Circulation, 130(3), 224-234.
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6

Pharmacological Assay for Ion Channels

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Loperamide was supplied by Janssen Pharmaceutica N.V., (CAS number: 53179-11-6 (made in Beerse, Belgium for the hERG study, or purchased from Sigma-Aldrich, St. Louis, MO, USA), and verapamil (CAS number: 52-53-9) and dofetilide (CAS number: 115256-11-6) were obtained from Sigma (Sigma-Aldrich, St. Louis, MO, USA). Compounds were dissolved in dimethyl sulfoxide (DMSO) (Merck-Sigma Aldrich: CAS number: 67-68-5) with dilutions in the extracellular solution to obtain the final concentrations. The final DMSO concentration in hERG experiments was 0.1% and in Nav1.5 and Cav1.2, it was 0.3% (v/v). Samples were first stored at freezing, −80 °C, for later analysis.
Lu H.R., Damiano B.P., Kreir M., Rohrbacher J., van der Linde H., Saidov T., Teisman A, & Gallacher D.J. (2023). The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose. Biomolecules, 13(9), 1355.
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7

Cardiac Electrophysiology in Drosophila

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E-4031 and Dofetilide were obtained from Sigma-Aldrich. E-4031 stock solution (10 mM) was prepared by dissolving in distilled H2O; Dofetilide was dissolved in DMSO to make a 10mM stock. Hearts were dissected from both WtCS and seits1 mutant flies, allowed to equilibrate for 30 min in oxygenated AHL and were then filmed for 30sec (T0). The hemolymph was replaced with AHL containing either 1μM E-4031 or 1 μM Dofetilide. For E4032 experiments a second set of hearts were filmed using AHL as the “vehicle” and for Dofetilide an equivalent amount of DMSO without drug was added to the AHL. Hearts were filmed again for 30sec following a 15 min exposure to either drug or vehicle.
Ocorr K., Zambon A., Nudell Y., Pineda S., Diop S., Tang M., Akasaka T, & Taylor E. (2017). Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations. PLoS Genetics, 13(5), e1006786.
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8

Cardiac Effects of Antiarrhythmic Drugs

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In total, 30 heart preparations were used in this study, in order to examine effects produced by Dofetilide, quinidine, procainamide, and flecainide (7–8 experiments in each study group). For precise dosing, drug infusions were performed at a rate of 0.3 ml/min using a calibrated infusion pump, while perfusing the hearts with protein-free saline solution at a constant coronary flow rate (see above). Dofetilide (10 nM), quinidine (5 μM), procainamide (10 μM), and flecainide (1.5 μM) (all from Sigma-Aldrich, Germany) were infused over 30 min, at concentrations close to the maximum free (i.e. protein-unbound) therapeutic plasma levels [22 (link)–25 (link)] (S1 Table).
, & Osadchii O.E. (2018). Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals. PLoS ONE, 13(1), e0191514.
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9

Small Molecule Compound Synthesis and Evaluation

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L-673 was synthesized in house. Astemizole, E-4031, cisapride and dofetilide were
from Sigma-Aldrich (St. Louis, MO, USA). Test agent stock solutions were
prepared in 100% DMSO, and the final dilution was 1:1000 with culture media.
Zeng H., Wang J., Clouse H., Lagrutta A, & Sannajust F. (2019). Human-induced pluripotent stem cell-derived cardiomyocytes have limited IKs for repolarization reserve as revealed by specific KCNQ1/KCNE1 blocker. JRSM Cardiovascular Disease, 8, 2048004019854919.
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10

Comprehensive Pharmacological Compound Protocol

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2,6-Bis(2-benzimidazolyl)pyridine (BBP), dofetilide, bicuculline methiodide, paxilline, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) and 4-aminopyridine were purchased from Sigma-Aldrich (Germany). 2-(4-Chlorophenoxy)-2-methyl-N-[5-[(methylsulfonyl)amino]tricyclo[3.3.1.13,7]dec-2-yl]-propanamide (JNJ 303) was purchased from Tocris (United Kingdom) and N-(2-{[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]amino}-1H-1,3-benzodiazol-4-yl)acetamide (AP14145) was synthetized by Syngene Inc. (Bangalore, India). All compounds were dissolved in pure dimethyl sulfoxide (Sigma-Aldrich, Germany) into 10 mM stock solutions and stored at −20°C. On the day of the experiment, the stock solution was thawed and the corresponding amount of compound was added to the working solution.
Simó-Vicens R., Bomholtz S.H., Sørensen U.S, & Bentzen B.H. (2018). 2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels. Frontiers in Pharmacology, 9, 1409.
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