Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: A randomised phase 2 trial

The Lancet

Volumn 384, Issue 9949, 2014, Pages 1187-1195

  Newby, L Kristin ^a   Marber, Michael S ^c   Melloni, Chiara ^a   Sarov Blat, Lea ^d   Aberle, Laura H ^a   Aylward, Philip E ^e   Cai, Gengqian ^g   De Winter, Robbert J ^f   Hamm, Christian W ^g   Heitner, John F ^h   Kim, Raymond ^b   Lerman, Amir ⁱ   Patel, Manesh R ^a   Tanguay, Jean Francois ^j   Lepore, John J ^d   Al Khalidi, Hussein R ^a   Sprecher, Dennis L ^d   Granger, Christopher B I ^a  

^a DUKE CLINICAL RESEARCH INSTITUTE   (United States)

^b DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c ST THOMAS HOSPITAL   (United Kingdom)

^d GLAXOSMITHKLINE   (United States)

^e FLINDERS UNIVERSITY   (Australia)

^f ACADEMIC MEDICAL CENTER   (Netherlands)

^g Kerckhoff Heart and Thorax Center   (Germany)

^h NEW YORK METHODIST HOSPITAL   (United States)

ⁱ MAYO CLINIC   (United States)

^j MONTREAL HEART INSTITUTE   (Canada)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; BRAIN NATRIURETIC PEPTIDE; C REACTIVE PROTEIN; LOSMAPIMOD; PLACEBO; TROPONIN I; 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;

ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; CEREBROVASCULAR ACCIDENT; CONTROLLED STUDY; DEATH; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG SAFETY; DYSPNEA; FATIGUE; FEMALE; HEART; HEART ATRIUM FIBRILLATION; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HEMATOMA; HUMAN; LOADING DRUG DOSE; MAJOR CLINICAL STUDY; MALE; NON ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; PHASE 2 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; THORAX PAIN; VERY ELDERLY; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; DRUG ADMINISTRATION; KAPLAN MEIER METHOD; MAGNETIC RESONANCE ANGIOGRAPHY; MIDDLE AGED; MORTALITY; MULTICENTER STUDY; MYOCARDIAL INFARCTION; TREATMENT OUTCOME;

AGED; AREA UNDER CURVE; CYCLOPROPANES; DOUBLE-BLIND METHOD; DRUG ADMINISTRATION SCHEDULE; FEMALE; HUMANS; KAPLAN-MEIER ESTIMATE; MAGNETIC RESONANCE ANGIOGRAPHY; MALE; MIDDLE AGED; MYOCARDIAL INFARCTION; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN KINASE INHIBITORS; PYRIDINES; TREATMENT OUTCOME;

EID: 84908310935     PISSN: 01406736     EISSN: 1474547X     Source Type: Journal    
DOI: 10.1016/S0140-6736(14)60417-7     Document Type: Article

References (18)

1. CW Hamm, JP Bassand, S Agewall for the the ESC Committee for Practice Guidelines ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC) Eur Heart J 32 2011 2999 3054
2. DE Martin, GF De Nicola, MS Marber New therapeutic targets in cardiology: p38α mitogen-activated protein kinase for ischemic heart disease Circulation 126 2012 357 368
3. MS Marber, B Rose, 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. MS Marber, JD Molkentin, T Force Developing small molecules to inhibit kinases unkind to the heart: p38 MAPK as a case in point Drug Discov Today Dis Mech 7 2010 e123 e127
5. GF De Nicola, ED Martin, A Chaikuad et al. Mechanism and consequence of the autoactivation of p38α mitogen-activated protein kinase promoted by TAB1 Nat Struct Mol Biol 20 2013 1182 1190
6. XL Ma, S Kumar, F Gao et al. Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion Circulation 99 1999 1685 1691
7. Z Li, JY Ma, I Kerr et al. Selective inhibition of p38α MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury Am J Physiol Heart Circ Physiol 291 2006 H1972 H1977
8. S Surinkaew, S Kumphune, S Chattipakorn, N Chattipakorn Inhibition of p38 MAPK during ischemia, but not reperfusion, effectively attenuates fatal arrhythmia in ischemia/reperfusion heart J Cardiovasc Pharmacol 61 2013 133 141
9. F See, W Thomas, K Way et al. p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat J Am Coll Cardiol 44 2004 1679 1689
10. FH Seeger, D Sedding, AC Langheinrich, J Haendeler, AM Zeiher, S Dimmeler 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
11. L Sarov-Blat, JM Morgan, P Fernandez et al. Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans Arterioscler Thromb Vasc Biol 30 2010 2256 2263
12. M Elkhawad, JH Rudd, L Sarov-Blat et al. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis JACC Cardiovasc Imaging 5 2012 911 922
13. J Cheriyan, AJ Webb, L Sarov-Blat et al. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia Circulation 123 2011 515 523
14. AM Barbour, L Sarov-Blat, G Cai et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers Br J Clin Pharmacol 76 2013 99 106
15. S Yang, M Beerahee Losmapimod concentration-QT relationship in healthy volunteers: meta-analysis of data from six clinical trials Eur J Clin Pharmacol 69 2013 1261 1267
16. C Melloni, DL Sprecher, L Sarov-Blat et al. The study of LoSmapimod treatment on inflammation and InfarCt SizE (SOLSTICE): design and rationale Am Heart J 164 2012 646 53.e3
17. AR Kompa, F See, DA Lewis et al. Long-term but not short-term p38 mitogen-activated protein kinase inhibition improves cardiac function and reduces cardiac remodeling post-myocardial infarction J Pharmacol Exp Ther 325 2008 741 750
18. YH Liu, D Wang, NE Rhaleb et al. Inhibition of p38 mitogen-activated protein kinase protects the heart against cardiac remodeling in mice with heart failure resulting from myocardial infarction J Card Fail 11 2005 74 81