A Phase II Multicenter Double-Blind Placebo-Controlled Study of Ethyl Pyruvate in High-Risk Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

Bennett‐Guerrero, Elliott; Swaminathan, Madhav; Grigore, Alina M.; Roach, G.; Aberle, Laura H.; Johnston, Jeffrey M.; Fink, Mitchell P.

doi:10.1053/j.jvca.2008.08.005

Cited by 71 publications

(58 citation statements)

References 30 publications

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“…As an illustration, in a U.S.-based clinical trial (the only finished phase II trial on EP so far), six doses of 7.5 g EP were administered i.v. during 36 h (360 mg/kg/day) to high-risk patients undergoing cardiac surgery (48). Although this trial has not delivered clear clinical benefits in the prevention of sepsis and related conditions, it did show that EP is safe and well tolerated at high doses.…”

Section: Discussionmentioning

confidence: 87%

A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

Miljković

Blaževski

Petković

et al. 2015

The Journal of Immunology

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Dimethyl fumarate (DMF), a new drug for multiple sclerosis (MS) treatment, acts against neuroinflammation via mechanisms that are triggered by adduct formation with thiol redox switches. Ethyl pyruvate (EP), an off-the-shelf agent, appears to be a redox analog of DMF, but its immunomodulatory properties have not been put into the context of MS therapy. In this article, we examined and compared the effects of EP and DMF on MS-relevant activity/functions of T cells, macrophages, microglia, and astrocytes. EP efficiently suppressed the release of MS signature cytokines, IFN-γ and IL-17, from human PBMCs. Furthermore, the production of these cytokines was notably decreased in encephalitogenic T cells after in vivo application of EP to rats. Production of two other proinflammatory cytokines, IL-6 and TNF, and NO was suppressed by EP in macrophages and microglia. Reactive oxygen species production in macrophages, microglia activation, and the development of Ag-presenting phenotype in microglia and macrophages were constrained by EP. The release of IL-6 was reduced in astrocytes. Finally, EP inhibited the activation of transcription factor NF-κB in microglia and astrocytes. Most of these effects were also found for DMF, implying that EP and DMF share common targets and mechanisms of action. Importantly, EP had in vivo impact on experimental autoimmune encephalomyelitis, an animal model of MS. Treatment with EP resulted in delay and shortening of the first relapse, and lower clinical scores, whereas the second attack was annihilated. Further studies on the possibility to use EP as an MS therapeutic are warranted.

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Section: Discussionmentioning

confidence: 87%

A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

Miljković

Blaževski

Petković

et al. 2015

The Journal of Immunology

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“…EP has also been safely administered to humans in a randomized controlled clinical trial [15]. In addition, EP exerts pharmacological effects on ROS scavenging, inhibition of apoptosis, and cellular ATP synthesis [16].…”

Section: Introductionmentioning

confidence: 99%

Ethyl Pyruvate Attenuates CaCl<sub>2</sub>-Induced Tubular Epithelial Cell Injury by Inhibiting Autophagy and Inflammatory Responses

Zhao¹,

Cheng²,

Li³

et al. 2018

Kidney Blood Press Res

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Background/Aims: Nephrolithiasis is one of the most prevalent diseases of the urinary system. Approximately 80% of human kidney stones are composed of calcium oxalate (CaOx), and hypercalciuria is one of the most common metabolic disorders. Emerging evidence indicates that autophagy and inflammatory responses are related to the formation of CaOx nephrolithiasis. However, the roles of autophagy and inflammation in patients with hypercalciuria remain unclear. Ethyl pyruvate (EP) displays protective effects in experimental models of many illnesses. In this study, we investigated the protective effects of EP in vitro through its inhibition of autophagy and inflammatory responses after CaCl₂-induced tubular epithelial cell injury. Methods: First, we cultured human tubular epithelial (HK-2) cells in the presence of various concentrations of CaCl₂ (0, 0.1, 0.25, 0.5, 1.0, 1.5, and 2.0 mg/ml) for 12 h and EP (0, 1.0, 2.5, 5.0, and 10.0 mM) for 2 h to select the optimum concentration using the Cell Counting Kit-8 assay and lactate dehydrogenase (LDH) assay. Cells in culture were stimulated with CaCl₂ (1.0 mg/ml, 12 h) with or without EP pretreatment (2.5 mM, 2 h). After the exposure, we detected the expression of inflammation-related proteins using an enzyme-linked immunosorbent assay and Western blot analysis. Finally, the levels of autophagy-related proteins were determined through Western blot analysis, and the number of GFP-LC3 dots and autophagic vacuoles was detected under confocal microscopy. Results: With the use of the Cell Counting Kit-8 assay and the LDH assay, we identified the optimum concentration for CaCl₂ (1.0 mg/ml) treatment and EP pretreatment (2.5 mM). Our research indicated that CaCl₂ can induce autophagy and inflammatory responses in HK-2 cells. Furthermore, treatment with EP prior to CaCl₂ stimulation attenuated HK-2 cell injury by inhibiting autophagy and inflammation. Conclusion: Our results provide evidence that EP attenuates CaCl₂-induced injury of HK-2 cells by downregulating the expression of inflammation and autophagy proteins that may be associated with the inhibition of the high-mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4)/NF-κB pathway and the competitive interaction with Beclin-1 of HMGB1.

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“…The mechanism of this therapeutic benefit remains poorly defined. The only published clinical trial of ethyl pyruvate showed no therapeutic benefit in patients undergoing cardiopulmonary bypass [23]. Melatonin suppresses TLR4-mediated inflammation and is hepatoprotective in a murine LPS and galactosamine toxin model of liver injury [23] and [24].…”

Section: Introductionmentioning

confidence: 99%

“…The only published clinical trial of ethyl pyruvate showed no therapeutic benefit in patients undergoing cardiopulmonary bypass [23]. Melatonin suppresses TLR4-mediated inflammation and is hepatoprotective in a murine LPS and galactosamine toxin model of liver injury [23] and [24]. In a human clinical trial in NASH patients, oral melatonin administered for 12 weeks significantly reduced serum AST and GGT in patients at 12-week follow-up relative to placebo [25].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic strategies in inflammasome mediated diseases of the liver

Hoque

Vodovotz

Mehal

2013

Journal of Hepatology

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Summary Tissue stress and cell death result in inflammation even in the absence of pathogens. Such sterile inflammation is dependent on a cytosolic complex of proteins inside immune cells termed the inflammasome. This complex converts two groups of extracellular signals into an inflammatory response via activation of caspase-1 and secretion of IL-1β and IL-18. Group 1 signals are typically TOLL like receptor agonists and result in transcriptional upregulation of inflammasome components and pro-cytokines. Group 2 signals are diverse, ranging from uric acid to ATP, and lead to assembly and activation of the inflammasome complex. Inflammasome components are required for a wide range of acute and chronic pathologies, including experimental alcoholic and non-alcoholic steatohepatitis, and drug-induced liver injury. Collectively, group 1 and 2 signals, inflammasome components, and cytokine receptors provide a rich source of therapeutic targets. Many of the advances in the field have come from standard reductionist experiments. Progress in the understanding of complex human systems will, however, be dependent on novel strategies such as systems analysis, which analyze large data sets to provide new insights.

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A Phase II Multicenter Double-Blind Placebo-Controlled Study of Ethyl Pyruvate in High-Risk Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

Cited by 71 publications

References 30 publications

A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

Ethyl Pyruvate Attenuates CaCl<sub>2</sub>-Induced Tubular Epithelial Cell Injury by Inhibiting Autophagy and Inflammatory Responses

Therapeutic strategies in inflammasome mediated diseases of the liver

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