{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T02:06:29Z","timestamp":1789005989829,"version":"build-2803163510"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              We evaluated the viability of I\n              <jats:sub>Kur<\/jats:sub>\n              as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel I\n              <jats:sub>Kur<\/jats:sub>\n              inhibitor.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              In vitro MK-0448 studies demonstrated strong inhibition of I\n              <jats:sub>Kur<\/jats:sub>\n              with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained atrial fibrillation was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg\/kg. These data led to a 2-part first-in-human study: Part I evaluated safety and pharmacokinetics, and part II was an invasive electrophysiological study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the electrophysiological study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected, despite achieving plasma concentrations in excess of 2 \u03bcmol\/L. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of I\n              <jats:sub>Kur<\/jats:sub>\n              blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              The contribution of I\n              <jats:sub>Kur<\/jats:sub>\n              to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.111.969782","type":"journal-article","created":{"date-parts":[[2012,10,31]],"date-time":"2012-10-31T14:11:39Z","timestamp":1351692699000},"page":"1193-1201","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":47,"title":["MK-0448, a Specific Kv1.5 Inhibitor"],"prefix":"10.1161","volume":"5","author":[{"given":"Behzad B.","family":"Pavri","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard E.","family":"Greenberg","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter K.","family":"Kraft","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Lazarus","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Lynch","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Salata","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Bilodeau","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Regan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Stump","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Fan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anish","family":"Mehta","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Wagner","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Gutstein","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bloomfield","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiology (B.B.P.), and Department of Pharmacology and Experimental Therapeutics (H.E.G., W.K.K.), Thomas Jefferson University, Philadelphia, PA; and Merck Sharp and Dohme Corp, Whitehouse Station, NJ (N.L., J.J.L., J.J.S., M.T.B., C.P.R., G.S., L.F., A.M., J.A.W., D.E.G., D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(02)01253-6"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000072767.89944.6e"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(02)01236-6"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.07.009"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200464240-00003"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11936-004-0019-2"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1993.03510200057032"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1542-474X.2009.00305.x"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.73.6.1061"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.127654"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl143"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2008.05.020"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000145155.60288.71"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2112"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0b013e3180325b2a"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(03)00332-2"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000121736.16643.11"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)03230-X"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.126.2.476"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021375"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0b013e3181719b0c"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/eun130"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1540-8167.2005.04117.x"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1838(91)90113-H"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(91)90445-Q"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1993.sp019958"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2009"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.10.043"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.07.034"}],"container-title":["Circulation: Arrhythmia and Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCEP.111.969782","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:53:28Z","timestamp":1715558008000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCEP.111.969782"}},"subtitle":["Safety, Pharmacokinetics, and Pharmacodynamic Electrophysiology in Experimental Animal Models and Humans"],"short-title":[],"issued":{"date-parts":[[2012,12]]},"references-count":29,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["10.1161\/CIRCEP.111.969782"],"URL":"https:\/\/doi.org\/10.1161\/circep.111.969782","relation":{},"ISSN":["1941-3149","1941-3084"],"issn-type":[{"value":"1941-3149","type":"print"},{"value":"1941-3084","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,12]]},"assertion":[{"value":"2011-12-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-09-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-10-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}