A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial.
BACKGROUND
Reperfusion injury is a significant complication of the management of ST-elevation MI (STEMI). INO-1001 is a potent inhibitor of poly(ADP-ribose) polymerase (PARP), a mediator of oxidant-induced myocyte dysfunction during reperfusion.


RESULTS
We assessed the safety and pharmacokinetics of INO-1001 in a randomized, placebo-controlled, single-blind, dose-escalating trial in 40 patients with STEMI undergoing primary percutaneous coronary intervention within 24 h of onset. INO-1001 was well-tolerated. A trend toward more frequent transaminitis was observed with 800 mg. Plasma from INO1001-treated patients reduced in vitro PARP activity >90% at all doses. Serial C-reactive protein and IL-6 levels showed a trend toward blunting of inflammation with INO-1001. The apparent median terminal half-life (t(1/2)) of INO-1001 was 7.5 (25th, 75th: 5.9, 10.2) h.


CONCLUSIONS
The results from this first trial of INO-1001 in STEMI support future investigation of INO-1001 as a novel treatment for reperfusion injury.
TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. dmorrow@partners.org
David A
DA
Morrow
Chaim M
CM
Brickman
Sabina A
SA
Murphy
Kenneth
K
Baran
Ricardo
R
Krakover
Harold
H
Dauerman
Sujatha
S
Kumar
Natanya
N
Slomowitz
Laura
L
Grip
Carolyn H
CH
McCabe
Andrew L
AL
Salzman
D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D010865:Pilot Projects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000097:blood; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy / Q000201:enzymology
C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases