Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: Combined results from the PRIMO-CABG I and II trials

Smith, Peter K.; Shernan, Stanton K.; Chen, John C.; Carrier, Michel; Verrier, Edward D.; Adams, Peter X.; Todaro, Thomas G.; Muhlbaier, Lawrence H.; Levy, Jerrold H.

doi:10.1016/j.jtcvs.2010.08.035

Cited by 67 publications

(49 citation statements)

References 19 publications

(21 reference statements)

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“…Specific complement inhibition has also been used in cardiovascular diseases, with promising results in animal models [50], but, as will be presented below, without convincing clinical results so far [51,52]. However, studies with inhibition of several complement factors simultaneously, or the combination of complement and TLR-system inhibition is yet to be performed.…”

Section: Clinical Use Of Complement Inhibitorsmentioning

confidence: 99%

“…Two early trials tested pexelizumab, a precursor of the recombinant anti-C5 antibody eculizumab, in coronary artery bypass grafting (CABG) with results indicating reduced mortality [177,178]. However, a recent study, combining results from the two trials including more than 7000 CABG patients found only a non-significant 6.7% reduction in 30-days mortality [52]. Nevertheless, there was a mortality benefit for high-risk surgical patients in an explanatory analysis of the combined data [179].…”

Section: Human Interventional Studiesmentioning

confidence: 99%

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The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

et al. 2015

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Despite recent medical advances, atherosclerosis is a global burden accounting for numerous deaths and hospital admissions. Immune-mediated inflammation is a major component of the atherosclerotic process, but earlier research focus on adaptive immunity has gradually switched towards the role of innate immunity. The complement system and toll-like receptors (TLRs), and the crosstalk between them, may be of particular interest both with respect to pathogenesis and as therapeutic targets in atherosclerosis. Animal studies indicate that inhibition of C3a and C5a reduces atherosclerosis. In humans modified LDL-cholesterol activate complement and TLRs leading to downstream inflammation, and histopathological studies indicate that the innate immune system is present in atherosclerotic lesions. Moreover, clinical studies have demonstrated that both complement and TLRs are upregulated in atherosclerotic diseases, although interventional trials have this far been disappointing. However, based on recent research showing an intimate interplay between complement and TLRs we propose a model in which combined inhibition of both complement and TLRs may represent a potent anti-inflammatory therapeutic approach to reduce atherosclerosis.

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Section: Clinical Use Of Complement Inhibitorsmentioning

confidence: 99%

Section: Human Interventional Studiesmentioning

confidence: 99%

The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

et al. 2015

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“…Targeting C5 with anti-C5 antibodies and the subsequent reduction in the anaphylatoxin C5a-mediated cellular infiltration was effective in the treatment of paroxysmal nocturnal hemoglobinuria (PNH), myocardial infarction (MI) and arthritis. [157][158][159][160] Eculizumab, an anti-C5 monoclonal antibody, is FDA approved for the treatment of PNH and aHUS. 161 The development of antibodies targeting factors of the complement pathways also offer additional tools to regulate complement activation and reduce inflammation.…”

Section: Strategic Approaches Of Complement Inhibitionmentioning

confidence: 99%

Viral-derived complement inhibitors: current status and potential role in immunomodulation

Zaraket

2016

Exp Biol Med (Maywood)

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The complement system is one of the body's major innate immune defense mechanisms in vertebrates. Its function is to detect foreign bodies and promote their elimination through opsonisation or lysis. Complement proteins play an important role in the immunopathogenesis of several disorders. However, excessive complement activation does not confer more protection but instead leads to several autoimmune and inflammatory diseases. With inappropriate activation of the complement system, activated complement proteins and glycoproteins may damage both healthy and diseased tissues. Development of complement inhibitors represents an effective approach in controlling dysregulated complement activity and reducing disease severity, yet few studies have investigated the nature and role of novel complement inhibitory proteins of viral origin. Viral complement inhibitors have important implications in understanding the importance of complement inhibition and their role as a promising novel therapeutic approach in diseases caused by dysregulated complement function. In this review, we discuss the role and importance of complement inhibitors derived from several viruses in the scope of human inflammatory and autoimmune diseases.

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“…Most clinical studies have focused on pexelizumab, a humanized single chain variable fragment (scFv) to complement C5. Although some favorable results of pexelizumab were reported as adjunctive therapy to reduce reperfusion injury in coronary artery bypass surgery [ 12 ], most of the clinical data, showed no benefi t in patients with AMI [ 13 ].…”

Section: Role Of Complement Activation In Post-infarction Infl Ammationmentioning

confidence: 99%

Repair of the Infarcted Myocardium

Wang

Frangogiannis

2014

Introduction to Translational Cardiovascular Research

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The adult mammalian heart has negligible regenerative capacity; thus, sudden death of a large number of cardiomyocytes in the infarcted myocardium leads to replacement of dead cells with collagen-based scar. Repair of the infarcted heart can be divided into three distinct, but overlapping phases: the infl ammatory phase, the proliferative phase and the maturation phase. Cardiomyocyte necrosis and matrix fragmentation in the infarcted myocardium release damage-associated molecular patterns (DAMPs) that activate innate immune cascades and trigger the infl ammatory reaction. Induction of chemokines and cytokines is a hallmark of the post-infarction infl ammatory response mediating recruitment of neutrophils and mononuclear cells in the myocardium. As infi ltrating leukocytes clear the wound from dead cells and matrix debris, pro-infl ammatory signaling is repressed and fi broblasts undergo myofi broblast conversion. Induction of specialized matricellular proteins that modulate growth factor and cytokine responses plays a critical role in activation of reparative cells and in formation of the scar. Cross-linking of the collagen-based matrix marks the end of the proliferative phase, as the scar matures and most fi broblasts and vascular cells in the wound undergo apoptosis. This chapter provides an overview of the phases of repair in the infarcted heart. Moreover, we discuss challenges and opportunities in targeting the infl ammatory and reparative response following infarction in order to attenuate adverse remodeling and to prevent progression of post-infarction heart failure.

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Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: Combined results from the PRIMO-CABG I and II trials

Cited by 67 publications

References 19 publications

The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

Viral-derived complement inhibitors: current status and potential role in immunomodulation

Repair of the Infarcted Myocardium

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