Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial

American Heart Journal

Volumn 169, Issue 5, 2015, Pages 622-630.e6

  O'Donoghue, Michelle L ^a   Glaser, Ruchira ^b   Aylward, Philip E ^c   Cavender, Matthew A ^a   Crisp, Adam ^b   Fox, Keith A A ^d   Laws, Ian ^b   Lopez Sendon, Jose L ^e   Steg, P Gabriel ^f,g   Theroux, Pierre ^h   Sabatine, Marc S ^a   Morrow, David A ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b GLAXOSMITHKLINE   (United States)

^c FLINDERS UNIVERSITY   (Australia)

^d UNIVERSITY OF EDINBURGH   (United Kingdom)

^e HOSPITAL UNIVERSITARIO LA PAZ   (Spain)

^f UNIVERSITÉ PARIS DESCARTES   (France)

^g ROYAL BROMPTON HOSPITAL   (United Kingdom)

^h MONTREAL HEART INSTITUTE   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO TERMINAL PRO BRAIN NATRIURETIC PEPTIDE; BIOLOGICAL MARKER; C REACTIVE PROTEIN; LOSMAPIMOD; PLACEBO; 6-(5-((CYCLOPROPYLAMINO)CARBONYL)-3-FLUORO-2-METHYLPHENYL)-N-(2,2-DIMETHYLPRPYL)-3-PYRIDINECARBOXAMIDE; CYCLOPROPANE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE P38; PROTEIN KINASE INHIBITOR; PYRIDINE DERIVATIVE;

ACUTE CORONARY SYNDROME; ARTICLE; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG SAFETY; FOLLOW UP; HEART MUSCLE REVASCULARIZATION; HOSPITAL PATIENT; HUMAN; MAJOR CLINICAL STUDY; MULTICENTER STUDY; NON ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; OUTCOME ASSESSMENT; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; TREATMENT DURATION; ADULT; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; COMPARATIVE STUDY; FEMALE; MALE; METHODOLOGY; MIDDLE AGED;

ACUTE CORONARY SYNDROME; ADULT; CYCLOPROPANES; DOUBLE-BLIND METHOD; FEMALE; HUMANS; MALE; MIDDLE AGED; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PLACEBOS; PROTEIN KINASE INHIBITORS; PYRIDINES; RESEARCH DESIGN;

EID: 84929278429     PISSN: 00028703     EISSN: 10976744     Source Type: Journal    
DOI: 10.1016/j.ahj.2015.02.012     Document Type: Article

References (24)

1. K.A. Fox, K.F. Carruthers, and D.R. Dunbar Underestimated and under-recognized: the late consequences of acute coronary syndrome (GRACE UK-Belgian Study) Eur Heart J 31 2010 2755 2764
2. P. Libby Inflammation in atherosclerosis Nature 420 2002 868 874
3. M.S. Marber, B. Rose, and Y. Wang The p38 mitogen-activated protein kinase pathway - a potential target for intervention in infarction, hypertrophy, and heart failure J Mol Cell Cardiol 51 2011 485 490
4. E. Denise Martin, G.F. De Nicola, and M.S. Marber New therapeutic targets in cardiology: p38 alpha mitogen-activated protein kinase for ischemic heart disease Circulation 126 2012 357 368
5. R. Kerkela, and T. Force p38 mitogen-activated protein kinase: a future target for heart failure therapy? J Am Coll Cardiol 48 2006 556 558
6. G. Schett, J. Zwerina, and G. Firestein The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis Ann Rheum Dis 67 2008 909 916
7. F.H. Seeger, D. Sedding, and A.C. Langheinrich Inhibition of the p38 MAP kinase in vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression Basic Res Cardiol 105 2010 389 397
8. X.L. Ma, S. Kumar, and F. Gao Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion Circulation 99 1999 1685 1691
9. Z. Shao, K. Bhattacharya, and E. Hsich c-Jun N-terminal kinases mediate reactivation of Akt and cardiomyocyte survival after hypoxic injury in vitro and in vivo Circ Res 98 2006 111 118
10. B.G. Petrich, and Y. Wang Stress-activated MAP kinases in cardiac remodeling and heart failure; new insights from transgenic studies Trends Cardiovasc Med 14 2004 50 55
11. J. Ren, S. Zhang, and A. Kovacs Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction J Mol Cell Cardiol 38 2005 617 623
12. L. Sarov-Blat, J.M. Morgan, and P. Fernandez Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans Arterioscler Thromb Vasc Biol 30 2010 2256 2263
13. C. Ding Drug evaluation: VX-702, a MAP kinase inhibitor for rheumatoid arthritis and acute coronary syndrome Curr Opin Investig Drugs 7 2006 1020 1025
14. M. Elkhawad, J.H. Rudd, and L. Sarov-Blat Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis JACC Cardiovasc Imaging 5 2012 911 922
15. J. Cheriyan, A.J. Webb, and L. Sarov-Blat Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia Circulation 123 2011 515 523
16. L.K. Newby, M.S. Marber, and C. Melloni Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial Lancet 384 2014 1187 1195
17. K. Thygesen, J.S. Alpert, and A.S. Jaffe Third universal definition of myocardial infarction Circulation 126 2012 2020 2035
18. K.A. Hicks, H.M.J. Hung, and K.W. Mahaffey Standardized Definitions for Cardiovascular and Stroke Endpoint Events in Clinical Trials Available at http://www.cdisc.org/system/files/all/standard/Draft%20Definitions%20for%20CDISC%20August%2020%2C%202014.pdf [Accessed November 25, 2014]
19. P.M. Ridker, and T.F. Luscher Anti-inflammatory therapies for cardiovascular disease Eur Heart J 35 2014 1782 1791
20. A.D. Hingorani, and J.P. Casas The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis Lancet 379 2012 1214 1224
21. N. Sarwar, A.S. Butterworth, and D.F. Freitag Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies Lancet 379 2012 1205 1213
22. P.M. Ridker, N. Rifai, and M. Clearfield Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events N Engl J Med 344 2001 1959 1965
23. P. Cohen Targeting protein kinases for the development of anti-inflammatory drugs Curr Opin Cell Biol 21 2009 317 324
24. M.L. O'Donoghue, E. Braunwald, and H.D. White Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial JAMA 312 2014 1006 1015