The Spla2 Inhibition to Decrease Enzyme Release After Percutaneous Coronary Intervention (Spider-Pci) Trial.

Džavík, Vladimir; Cantor, Warren J.; Overgaard, Christopher B.; Thorpe, Kevin E.; Lavi, Shahar; Lan, Julie; Horlick, Eric; Ross, John; Daly, Paul; Barolet, Alan; Ing, Douglas; Planté, Sylvain; Robbins, Kim; Goldman, Lorne; Harsdorf, Rüdiger von; Atchison, Deborah J.; Schwartz, Leonard; Seidelin, Peter H.

doi:10.1016/s0735-1097(10)61953-5

Cited by 5 publications

(4 citation statements)

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“…Recently, two clinical trials with a nonselective sPLA 2 inhibitor, varespladib, have been completed, one in patients with acute coronary syndromes and the other in patients going to percutaneous coronary intervention. 9,10 Neither of these trials were positive. A third trial is recruiting patients with vaso-occlusive crisis from sickle cell disease.…”

Section: Introductionmentioning

confidence: 92%

Cytosolic Phospholipase A2α Protects against Ischemia/Reperfusion Injury in the Heart

Kerkelä

Boucher

Zaka

et al. 2011

Clinical and Translational Science

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Studies with sPLA2 Group X and cPLA2α gene-targeted mice suggest that absence of sPLA2 Group X results in protection from ischemia/reperfusion (I/R) injury in the heart, and absence of cPLA2α Group IV is protective in the brain. Although the latter studies might suggest a similar deleterious role for cPLA2α in I/R injury in the heart, the pathophysiology of stroke is intricately related to excitotoxicity, and can not necessarily be extrapolated to the heart. We report here that unlike findings in the brain, cPLA2α(−/−)mice have exaggerated injury following ischemia/reperfusion in vivo. In contrast, there is no difference in injury induced by simulated ischemia in cardiomyocytes isolated from cPLA2α(−/−)vs. cPLA2α(+/+)mice. This suggests that cPLA2α does not have an important cardiomyocyte autonomous effect on ischemic injury. Prostaglandin E2 (PGE2) levels are significantly reduced in the hearts of the cPLA2α(−/−) mice, and the enhanced injury is ameliorated by treatment with the PGE analog, misoprostol. We demonstrate that cPLA2α is cardioprotective in vivo, and this is likely via cPLA2α-mediated production of cardioprotective eicosanoids. These studies are the first to identify a protective role for cPLA2 in I/R injury in any organ and raise concerns over long-term inhibition of cPLA2.

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Section: Introductionmentioning

confidence: 92%

Cytosolic Phospholipase A2α Protects against Ischemia/Reperfusion Injury in the Heart

Kerkelä

Boucher

Zaka

et al. 2011

Clinical and Translational Science

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“…The small-molecule indole-based sPLA 2 inhibitor has IC 50 as low as 9-14 nM for human sPLA 2 -IIA [93] and was found to mechanistically inhibit surfactant degradation [94]. Having wide existing pharmacological data, Varespladib has already undertaken phase II and III clinical studies in adults (both orally and intravenously) for a variety of clinical symptoms, such as sepsis, acute coronary syndrome, and sickle cell disease-induced acute chest syndrome (IMPACTS trial, NCT00434473) [9,[95][96][97][98][99][100]. However, the oral pro-drug of Varespladib sodium, Varespladib-methyl (LY333013) has been found to have varying efficacies in the treatment of coronary artery disease (CAD) [96][97][98] as well as been ineffective in treatment of rheumatoid arthritis, leading researchers to believe that Varespladib has limited efficacy in clinical studies [101].…”

Section: The Search For Effective Inhibitors With High Specificity To Spla 2 -Iiamentioning

confidence: 99%

The need for Group IIA secretory phospholipase A2 (sPLA2-IIA) inhibitors in inflammatory ocular disease treatment

Liu¹,

Lv²,

Feng³

et al. 2018

Med Dent Res

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The highly cationic nature of sPLA 2 -IIA allows the enzyme to bind and hydrolyze an anionic phospholipid on the cell membrane, especially when damaged and stressed, causing the release of lysophospholipid and free fatty acid. These products are eventually converted into eicosanoids such as arachidonic acid, leukotrienes, and prostaglandins, leading to inflammation. Recent studies have shown that a high level of sPLA 2 -IIA is associated with ocular inflammatory diseases, including dry eye disease, chronic blepharitis and allergic conjunctivitis. Therefore, inhibition of sPLA 2 -IIA may serve as a promising strategy to alleviate ocular inflammation. In this review, we survey the current literature of sPLA 2 -IIA on inflammatory diseases and aim to provide new insight into the study of sPLA 2 -IIA inhibition for inflammatory ocular diseases.

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“…The Fewer Recurrent Acute coronary events with Near‐term Coronary Inflammation Suppression‐ACS (FRANCIS‐ACS) study investigated the safety and efficacy of varespladib (A‐002; Anthera Pharmaceuticals) in 625 patients with acute coronary syndromes and showed an 8% reduction in LDL‐C and 70–80% reductions in CRP and sPLA2 levels (120). The PhosphoLipase And Serological Markers of Atherosclerosis‐2 (PLASMA‐2) study showed an improvement in LDL subfractions (121) but no benefit was seen on myonecrosis with pretreatment prior to percutaneous coronary intervention in the SPIDER‐PCI trial (122). The Vascular Inflammation Suppression to Treat Acute Coronary Syndrome‐16 Weeks (VISTA‐16) trial is investigating the role of varespladib added to statins in 6500 patients with acute coronary syndromes (123).…”

Section: Other Approachesmentioning

confidence: 99%

New lipid-lowering drugs: an update

Wierzbicki

Hardman²,

Viljoen

2012

International Journal of Clinical Practice

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Summary Lipid lowering is established as a proven intervention to reduce atherosclerosis and its complications. Statins form the basis of care but are not able to treat all aspects of dyslipidaemia. Many novel therapeutic compounds are being developed. These include additional therapeutics for low‐density lipoprotein cholesterol, for example, thyroid mimetics (thyroid receptor beta‐agonists), antisense oligonucleotides or microsomal transfer protein inhibitors (MTPI); triglycerides, for example, novel peroxosimal proliferator activating receptors agonists, MTPIs, diacylglycerol acyl transferase‐1 inhibitors and high‐density lipoprotein cholesterol (HDL‐C), for example, mimetic peptides; HDL delipidation strategies and cholesterol ester transfer protein inhibitors and modulators of inflammation, for example, phospholipase inhibitors. Gene therapy for specific rare disorders, for example, lipoprotein lipase deficiency using alipogene tiparvovec is also in clinical trials. Lipid‐lowering drugs are likely to prove a fast‐developing area for novel treatments as possible synergies exist between new and established compounds for the treatment of atherosclerosis.

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The Spla2 Inhibition to Decrease Enzyme Release After Percutaneous Coronary Intervention (Spider-Pci) Trial.

Cited by 5 publications

References 0 publications

Cytosolic Phospholipase A2α Protects against Ischemia/Reperfusion Injury in the Heart

Cytosolic Phospholipase A2α Protects against Ischemia/Reperfusion Injury in the Heart

The need for Group IIA secretory phospholipase A2 (sPLA2-IIA) inhibitors in inflammatory ocular disease treatment

New lipid-lowering drugs: an update

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