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

David A. Morrow; Chaim M. Brickman; Sabina A. Murphy; Kenneth Baran; Ricardo Krakover; Harold Dauerman; Sujatha Kumar; Natanya Slomowitz; Laura Grip; Carolyn H. McCabe; Andrew L. Salzman

doi:10.1007/s11239-008-0230-1

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

David A. Morrow^*, Chaim M. Brickman, Sabina A. Murphy, Kenneth Baran, Ricardo Krakover, Harold Dauerman, Sujatha Kumar, Natanya Slomowitz, Laura Grip, Carolyn H. McCabe, Andrew L. Salzman

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

85 Scopus citations

Abstract

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. Methods & 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.

Original language	English
Pages (from-to)	359-364
Number of pages	6
Journal	Journal of Thrombosis and Thrombolysis
Volume	27
Issue number	4
DOIs	https://doi.org/10.1007/s11239-008-0230-1
State	Published - 2009
Externally published	Yes

Funding

Funders	Funder number
Inotek Pharmaceuticals Corporation
National Institutes of Health
National Heart, Lung, and Blood Institute	R44HL074684

Keywords

Clinical trials
Myocardial infarction
Poly(ADP-ribose) polymerase
Reperfusion injury

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s11239-008-0230-1

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Morrow, D. A., Brickman, C. M., Murphy, S. A., Baran, K., Krakover, R., Dauerman, H., Kumar, S., Slomowitz, N., Grip, L., McCabe, C. H., & Salzman, A. L. (2009). 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. Journal of Thrombosis and Thrombolysis, 27(4), 359-364. https://doi.org/10.1007/s11239-008-0230-1

Morrow, David A. ; Brickman, Chaim M. ; Murphy, Sabina A. et al. / 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. In: Journal of Thrombosis and Thrombolysis. 2009 ; Vol. 27, No. 4. pp. 359-364.

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title = "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",

abstract = "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. Methods & 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 (t1/2) 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.",

keywords = "Clinical trials, Myocardial infarction, Poly(ADP-ribose) polymerase, Reperfusion injury",

author = "Morrow, {David A.} and Brickman, {Chaim M.} and Murphy, {Sabina A.} and Kenneth Baran and Ricardo Krakover and Harold Dauerman and Sujatha Kumar and Natanya Slomowitz and Laura Grip and McCabe, {Carolyn H.} and Salzman, {Andrew L.}",

note = "Funding Information: Acknowledgments TIMI 37A was supported by the NIH R44 HL074684-01 and by Inotek Pharmaceuticals Corporation.",

year = "2009",

doi = "10.1007/s11239-008-0230-1",

language = "אנגלית",

volume = "27",

pages = "359--364",

journal = "Journal of Thrombosis and Thrombolysis",

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Morrow, DA, Brickman, CM, Murphy, SA, Baran, K, Krakover, R, Dauerman, H, Kumar, S, Slomowitz, N, Grip, L, McCabe, CH & Salzman, AL 2009, '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', Journal of Thrombosis and Thrombolysis, vol. 27, no. 4, pp. 359-364. https://doi.org/10.1007/s11239-008-0230-1

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. / Morrow, David A.; Brickman, Chaim M.; Murphy, Sabina A. et al.
In: Journal of Thrombosis and Thrombolysis, Vol. 27, No. 4, 2009, p. 359-364.

Research output: Contribution to journal › Article › peer-review

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T1 - 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

T2 - Results of the TIMI 37 trial

AU - Morrow, David A.

AU - Brickman, Chaim M.

AU - Murphy, Sabina A.

AU - Baran, Kenneth

AU - Krakover, Ricardo

AU - Dauerman, Harold

AU - Kumar, Sujatha

AU - Slomowitz, Natanya

AU - Grip, Laura

AU - McCabe, Carolyn H.

AU - Salzman, Andrew L.

N1 - Funding Information: Acknowledgments TIMI 37A was supported by the NIH R44 HL074684-01 and by Inotek Pharmaceuticals Corporation.

PY - 2009

Y1 - 2009

N2 - 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. Methods & 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 (t1/2) 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.

AB - 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. Methods & 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 (t1/2) 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.

KW - Clinical trials

KW - Myocardial infarction

KW - Poly(ADP-ribose) polymerase

KW - Reperfusion injury

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Morrow DA, Brickman CM, Murphy SA, Baran K, Krakover R, Dauerman H et al. 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. Journal of Thrombosis and Thrombolysis. 2009;27(4):359-364. doi: 10.1007/s11239-008-0230-1