|
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
|
|
|
|||||||||
|
|||||||||||
|
J Am Coll Cardiol, 2001; 38:1644-1650 © 2001 by the American College of Cardiology Foundation |
* Medizinische Klinik II, Klinikum Kassel, Kassel, Germany
Ziekenhuis De Weezenlande, Zwolle, The Netherlands
Hopital Emile Muller, Mulhouse, France
Department and Clinic of Cardiology of the Medical Academy in Warsaw, Warszawa, Poland
|| Royal Gwent Hospital, Gwent, United Kingdom
¶ Huddinge Hospital, Huddinge, Sweden
# Twenteborg Ziekenhues, Amelo, The Netherlands
** Klinikum Lippe-Detmold, Detmold, Germany
Universitätsklinikum Benjamin Franklin, Berlin, Germany
Merck KGaA, Darmstadt, Germany
Manuscript received February 15, 2001; revised manuscript received July 18, 2001, accepted August 15, 2001.
* Address for correspondence: Dr. Uwe Zeymer, Klinikum Kassel, Medizinische Klinik II, Mönchebergstrasse 41-43, D-34125 Kassel, Germany
Uwe.Zeymer{at}t-online.de
OBJECTIVES
We conducted an international, prospective, randomized, double-blind, placebo-controlled phase 2 trial in patients undergoing thrombolytic therapy or primary angioplasty for acute ST-elevation myocardial infarction (MI) to investigate the effect of eniporide on infarct size and clinical outcome.
BACKGROUND
Experimental studies suggest that the activity of the Na+/H+ exchange (NHE) plays an important role in the unfavorable sequels of myocardial ischemia and reperfusion. Eniporide specifically inhibits the NHE-1 isoform and has been shown to limit infarct size in experimental models.
METHODS
The primary efficacy end point was the infarct size measured by the cumulative release of alpha-hydroxybutyrate dehydrogenase (alpha-HDBH) (area under the curve [AUC] 0 to 72 h). In stage 1, 50, 100, 150 or 200 mg eniporide given as a 10-min infusion before start of reperfusion therapy were compared with placebo in 430 patients, and in stage 2, 100 and 150 mg eniporide were compared with placebo in 959 patients.
RESULTS
In stage 1, the administration of 100 mg and 150 mg eniporide resulted in smaller infarct sizes (mean alpha-HBDH AUC in U/ml x h, placebo: 44.2, 100 mg eniporide: 40.2, 150 mg eniporide: 33.9), especially in the angioplasty group. In contrast, in stage 2 there was no difference in the enzymatic infarct size between the three groups (placebo: 41.2, 100 mg eniporide: 43.0, 150 mg eniporide: 41.5). Overall there was no effect of eniporide on clinical outcome (death, cardiogenic shock, heart failure, life-threatening arrhythmias). However, there was a significant reduction of the incidence of heart failure in patients reperfused late (>4 h).
CONCLUSIONS
In this large study administration of the NHE-1 inhibitor eniporide, before reperfusion therapy in patients with acute ST elevation MI, did not limit infarct size or improve clinical outcome.
| ||||||||||||||||||||
This article has been cited by other articles:
|
|
 |
|
  S. Kasama, M. Furuya, T. Toyama, S. Ichikawa, and M. Kurabayashi Effect of atrial natriuretic peptide on left ventricular remodelling in patients with acute myocardial infarction Eur. Heart J., June 2, 2008; 29(12): 1485 - 1494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Moncoq, G. Kemp, X. Li, L. Fliegel, and H. S. Young Dimeric Structure of Human Na+/H+ Exchanger Isoform 1 Overproduced in Saccharomyces cerevisiae J. Biol. Chem., February 15, 2008; 283(7): 4145 - 4154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Grayburn and J. W. Choi Advances in the assessment of no-reflow after successful primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: now that we can diagnose it, what do we do about it? J. Am. Coll. Cardiol., February 5, 2008; 51(5): 566 - 568. [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Yellon and D. J. Hausenloy Myocardial Reperfusion Injury N. Engl. J. Med., September 13, 2007; 357(11): 1121 - 1135. [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Dirksen, G. J. Laarman, M. L. Simoons, and D. J.G.M. Duncker Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies Cardiovasc Res, June 1, 2007; 74(3): 343 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Imahashi, F. Mraiche, C. Steenbergen, E. Murphy, and L. Fliegel Overexpression of the Na+/H+ exchanger and ischemia-reperfusion injury in the myocardium Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2237 - H2247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. Cingolani and I. L. Ennis Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy Circulation, March 6, 2007; 115(9): 1090 - 1100. [Full Text] [PDF]
|
|
|
|
|
|
M. E. Malo, L. Li, and L. Fliegel Mitogen-activated Protein Kinase-dependent Activation of the Na+/H+ Exchanger Is Mediated through Phosphorylation of Amino Acids Ser770 and Ser771 J. Biol. Chem., March 2, 2007; 282(9): 6292 - 6299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Wang, C. Zaragoza, and W. Holman Sodium-Hydrogen Exchange Inhibition and {beta}-Blockade Additively Decrease Infarct Size Ann. Thorac. Surg., March 1, 2007; 83(3): 1121 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. W. Bar, D. Tzivoni, M. T. Dirksen, A. Fernandez-Ortiz, G. R. Heyndrickx, J. Brachmann, J. H.C. Reiber, N. Avasthy, J. Tatsuno, M. Davies, et al. Results of the first clinical study of adjunctive CAldaret (MCC-135) in patients undergoing primary percutaneous coronary intervention for ST-Elevation Myocardial Infarction: the randomized multicentre CASTEMI study Eur. Heart J., November 1, 2006; 27(21): 2516 - 2523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. Mangano, Y. Miao, I. C. Tudor, C. Dietzel, for the Investigators of the Multicenter Study of, and and the Ischemia Research and Education Foundation Post-Reperfusion Myocardial Infarction: Long-Term Survival Improvement Using Adenosine Regulation With Acadesine J. Am. Coll. Cardiol., July 4, 2006; 48(1): 206 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Maekawa, J.-i. Abe, T. Shishido, S. Itoh, B. Ding, V. K. Sharma, S.-S. Sheu, B. C. Blaxall, and B. C. Berk Inhibiting p90 Ribosomal S6 Kinase Prevents Na+-H+ Exchanger-Mediated Cardiac Ischemia-Reperfusion Injury Circulation, May 30, 2006; 113(21): 2516 - 2523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. Bhattaram, N. V. Nagaraja, T. Peters, T. Machnig, S. Kroesser, A. Kovar, and H. Derendorf Population Pharmacokinetics of Eniporide and Its Metabolite in Healthy Subjects and Patients With Acute Myocardial Infarction J. Clin. Pharmacol., June 1, 2005; 45(6): 631 - 639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Juhaszova, C. Rabuel, D. B. Zorov, E. G. Lakatta, and S. J. Sollott Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res, May 1, 2005; 66(2): 233 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. P. Bouki, G. Pavlakis, and E. Papasteriadis Management of Cardiogenic Shock Due to Acute Coronary Syndromes Angiology, March 1, 2005; 56(2): 123 - 130. [Abstract] [PDF]
|
|
|
|
 |
|
 E. Kevelaitis, A. A. Qureshi, C. Mouas, F. Marotte, S. Kevelaitiene, M. Avkiran, and P. Menasche Na+/H+ exchange inhibition in hypertrophied myocardium subjected to cardioplegic arrest: an effective cardioprotective approach Eur. J. Cardiothorac. Surg., January 1, 2005; 27(1): 111 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Gibbons, U. S. Valeti, P. A. Araoz, and A. S. Jaffe The quantification of infarct size J. Am. Coll. Cardiol., October 19, 2004; 44(8): 1533 - 1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Bolli, L. Becker, G. Gross, R. Mentzer Jr, D. Balshaw, and D. A. Lathrop Myocardial Protection at a Crossroads: The Need for Translation Into Clinical Therapy Circ. Res., July 23, 2004; 95(2): 125 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kloner and S. H. Rezkalla Cardiac protection during acute myocardial infarction: Where do we stand in 2004? J. Am. Coll. Cardiol., July 21, 2004; 44(2): 276 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.M Piper, Y Abdallah, and C Schafer The first minutes of reperfusion: a window of opportunity for cardioprotection Cardiovasc Res, February 15, 2004; 61(3): 365 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ten Hove and C. J.A Van Echteld Limited effects of post-ischemic NHE blockade on [Na+]i and pHi in rat hearts explain its lack of cardioprotection Cardiovasc Res, February 15, 2004; 61(3): 522 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kupatt, R. Hinkel, J. Horstkotte, M. Deiss, M.-L. von Bruhl, M. Bilzer, and P. Boekstegers Selective retroinfusion of GSH and cariporide attenuates myocardial ischemia-reperfusion injury in a preclinical pig model Cardiovasc Res, February 15, 2004; 61(3): 530 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Chen, C. X. Chen, X. T. Gan, N. Beier, W. Scholz, and M. Karmazyn Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H381 - H387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Yarbrough, R. Mukherjee, G. P. Escobar, J. W. Hendrick, J. A. Sample, K. B. Dowdy, J. E. McLean, J. T. Mingoia, F. A. Crawford Jr, and F. G. Spinale Modulation of calcium transport improves myocardial contractility and enzyme profiles after prolonged ischemia-reperfusion Ann. Thorac. Surg., December 1, 2003; 76(6): 2054 - 2061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Teshima, M. Akao, S. P. Jones, and E. Marban Cariporide (HOE642), a Selective Na+-H+ Exchange Inhibitor, Inhibits the Mitochondrial Death Pathway Circulation, November 4, 2003; 108(18): 2275 - 2281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Corvera, Z.-Q. Zhao, L. S. Schmarkey, S. L. Katzmark, J. M. Budde, C. D. Morris, T. Ehring, R. A. Guyton, and J. Vinten-Johansen Optimal dose and mode of delivery of Na+/H+ exchange-1 inhibitor are critical for reducing postsurgical ischemia-reperfusion injury Ann. Thorac. Surg., November 1, 2003; 76(5): 1614 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Yarbrough, R. Mukherjee, G. P. Escobar, J. T. Mingoia, J. A. Sample, J. W. Hendrick, K. B. Dowdy, J. E. McLean, R. E. Stroud, and F. G. Spinale Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1489 - 1497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.E. Cingolani, I.L. Ennis, and S.M. Mosca NHE-1 and NHE-6 Activities: Ischemic and Reperfusion Injury Circ. Res., October 17, 2003; 93(8): 694 - 696. [Full Text] [PDF]
|
|
|
|
|
|
D. G Allen and X.-H. Xiao Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion Cardiovasc Res, March 15, 2003; 57(4): 934 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Piper, K. Meuter, and C. Schafer Cellular mechanisms of ischemia-reperfusion injury Ann. Thorac. Surg., February 1, 2003; 75(2): S644 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Mentzer Jr, R. D. Lasley, A. Jessel, and M. Karmazyn Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection Ann. Thorac. Surg., February 1, 2003; 75(2): S700 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Poole-Wilson Innovative treatments for myocardial infarction; design, purpose and consequences of early studies Eur. Heart J., November 1, 2002; 23(21): 1640 - 1642. [Full Text] [PDF]
|
|
|
|
|
|
M. Avkiran and M. S. Marber Na+/h+ exchange inhibitors for cardioprotective therapy: progress, problems and prospects J. Am. Coll. Cardiol., March 6, 2002; 39(5): 747 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. B. A. Menown and A. A. J. Adgey Cardioprotective therapy and sodium-hydrogen exchange inhibition: current concepts and future goals J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1651 - 1653. [Full Text] [PDF]
|
|
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
