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.; Baran, Kenneth W.; Krakover, Ricardo; Dauerman, Harold L.; Kumar, Sujatha; Slomowitz, Natanya; Grip, Laura T.; McCabe, Carolyn H.; Salzman, Andrew L.

doi:10.1007/s11239-008-0230-1

Cited by 76 publications

(52 citation statements)

References 15 publications

(24 reference statements)

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“…This single randomized trial assessed the effect of the PARP1 inhibitor INO-1001 in 40 patients with myocardial infarction, undergoing percutaneous coronary revascularization (Morrow et al, 2009). While this study was not powered to assess clinical efficacy, there was a trend towards blunting of inflammatory response, as assessed by serial plasma c-reactive protein and IL-6 levels, with the addition of the PARP1 inhibitor.…”

Section: Parp1 Inhbitors As a Strategy For Selective Modulation Of Trmentioning

confidence: 99%

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function

et al. 2015

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Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed.

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Section: Parp1 Inhbitors As a Strategy For Selective Modulation Of Trmentioning

confidence: 99%

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function

et al. 2015

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“…Multiple lines of follow-up studies have confirmed and extended these findings and demonstrated the protective effects of PARP1 genetic deficiency, as well as of various classes of PARP inhibitors (including 3-aminobenzamide, nicotinamide, PJ34 and INO-1001) in various models of acute and chronic myocardial insults, including ischaemia/reperfusion injury, transplantation and chronic heart failure (see: Szabó et al, 2004;Booz, 2007;Pacher and Szabó, 2008;Berger et al, 2018). The concept of cardioprotection mediated by PARP inhibition has also been tested in a small clinical trial, where trends for anti-inflammatory and cardioprotective effects were noted in patients with myocardial infarction (Morrow et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

Korkmaz‐Icöz

Szczesny

Marcatti

et al. 2017

British J Pharmacology

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*Equally contributed. BACKGROUND AND PURPOSEOlaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) are approved as anti-cancer drugs in humans. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effects of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in vivo model of cardiac transplantation. EXPERIMENTAL APPROACHH9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen peroxide (H 2 O 2 ) or with glucose oxidase (GOx, which generates H 2 O 2 in the tissue culture medium). Cell viability assays (MTT, lactate dehydrogenase) and Western blotting for PARP and its product, PAR was performed. Heterotopic heart transplantation was performed in Lewis rats; recipients were treated either with vehicle or olaparib (10 mg kg -1 ). Left ventricular function of transplanted hearts was monitored via a Millar catheter. Multiple gene expression in the graft was measured by qPCR. KEY RESULTSOlaparib blocked autoPARylation of PARP1 and attenuated the rapid onset of death in H9c2 cells, induced by H 2 O 2 , but did not affect cell death following chronic, prolonged oxidative stress induced by GOx. In rats, after transplantation, left ventricular systolic and diastolic function were improved by olaparib. In the transplanted hearts, olaparib also reduced gene expression for c-jun, caspase-12, catalase, and NADPH oxidase-2. CONCLUSIONS AND IMPLICATIONSOlaparib protected cardiomyocytes against oxidative stress and improved graft contractility in a rat model of heart transplantation. These findings raise the possibility of repurposing this clinically approved oncology drug, to be used in heart transplantation. LINKED ARTICLES

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“…In a pig model, INO-1001 improved functional recovery after ischemia but did not affect infarct size (97). In humans, this agent reduced C-reactive and interleukin-6 levels in myocardial infarction (98) and caused myelosuppression and transaminitis when combined with temozolamide in patients with advanced melanoma (99).…”

Section: Clinical Datamentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase-1 Inhibition: Preclinical and Clinical Development of Synthetic Lethality

Leung

Rosen

Fields

et al. 2011

Mol Med

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The hereditary forms of breast cancer identified by BRCA1 and BRCA2 genes have a defect in homologous DNA repair and demonstrate a dependence on alternate DNA repair processes by base excision repair, which requires poly(ADP-ribose) polymerase 1 (PARP-1). siRNA and deletion mutations demonstrate that interference with PARP-1 function results in enhanced cell death when the malignancy has a defect in homologous recombination. These findings resulted in a plethora of agents in clinical trials that interfere with DNA repair, and these agents offer the potential of being more selective in their effects than classic chemotherapeutic drugs. An electronic search of the National Library of Medicine for published articles written in English used the terms "PARP inhibitors" and "breast cancer" to find prospective, retrospective and review articles. Additional searches were done for articles dealing with mechanism of action. A total of 152 articles dealing with breast cancer and PARP inhibition were identified. PARP inhibition not only affects nonhomologous repair, but also has several other nongenomic functions. Mutational resistance to these agents was seen in preclinical studies. To date, PARP-1 inhibitors were shown to enhance cytotoxic effects of some chemotherapy agents. This new class of agents may offer more therapeutic specificity by exploiting a DNA repair defect seen in some human tumors with initial clinical trials demonstrating antitumor activity. Although PARP inhibitors may offer a therapeutic option for selected malignancies, the long-term effects of these agents have not yet been defined.

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Abstract: The results from this first trial of INO-1001 in STEMI support future investigation of INO-1001 as a novel treatment for reperfusion injury.

Cited by 76 publications

References 15 publications

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

Poly(ADP-Ribose) Polymerase-1 Inhibition: Preclinical and Clinical Development of Synthetic Lethality

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