Efficacy of a novel P-selectin antagonist, rPSGL-Ig for reperfusion therapy in acute myocardial infarction: The RAPSODY trial

Tanguay, Jean‐François; Krucoff, Mitchell W.; Gibbons, Raymond J.; Chávez, Eduardo; Liprandi, Álvaro Sosa; Molina-Viamonte, Victor; Aylward, Philip E.; López‐Sendón, José; Holloway, Debra; Shields, K; Yu, Jason; Loh, Evan; Baran, Kenneth W.; Bethala, Vasanth K.; Vahanian, Alec; White, Harvey D.

doi:10.1016/s0735-1097(03)81179-8

Cited by 18 publications

(14 citation statements)

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“…Efficacy assessments explored trends of potential impact of rPSGL-Ig on early liver allograft function. Overall, the administration of rPSGL-Ig in all patients was uneventful and no specific safety concerns were raised from using this drug in the perioperative period, in agreement with previous clinical data (17,22,23). The distribution of the SAEs was similar between the rPSGL-Ig-treated and placebo arm, no SAE deemed related to study drug and all of them were expected in this patient population.…”

Section: Discussionsupporting

confidence: 86%

rPSGL-Ig for Improvement of Early Liver Allograft Function: A Double-Blind, Placebo-Controlled, Single-Center Phase II Study†

Busuttil¹,

Lipshutz²,

Kupiec‐Weglinski³

et al. 2011

American Journal of Transplantation

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The selectin antagonist known as recombinant Pselectin glycoprotein ligand IgG (rPSGL-Ig) blocks leukocyte adhesion and protects against transplantation ischemia reperfusion injury (IRI) in animal models. This randomized (1:1) single-center double-blind 47-patient phase 2 study with 6-month follow-up assessed rPSGL-Ig's safety and impact on early graft function at 1 mg/kg systemic dose with pretransplant allograft ex vivo treatment in deceased-donor liver transplant recipients. Safety was assessed in all patients, whereas efficacy was assessed in a prospectively defined per-protocol patient set (PP) by peak serum transaminase (TA) and bilirubin values, and normalization thereof. In PP patients, the incidence of poor early graft function (defined as peak TA >2500 U/L or bilirubin >10 mg/dL), average peak liver enzymes and bilirubin, normalization thereof and duration of primary and total hospitalization trended consistently lower in the rPSGL-Ig group compared to placebo. In patients with donor risk index above study-average, normalization of aspartate aminotransferase was significantly improved in the rPSGL-Ig group (p < 0.03). rPSGL-Ig treatment blunted postreperfusion induction versus placebo of IRI biomarker IP-10 (p < 0.1) and augmented cytoprotective IL-10 (p < 0.05). This is the first clinical trial of an adhesion molecule antagonist to demonstrate a beneficial effect on liver transplantation IRI and supported by therapeutic modulation of two hepatic IRI biomarkers.

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Section: Discussionsupporting

confidence: 86%

rPSGL-Ig for Improvement of Early Liver Allograft Function: A Double-Blind, Placebo-Controlled, Single-Center Phase II Study†

Busuttil¹,

Lipshutz²,

Kupiec‐Weglinski³

et al. 2011

American Journal of Transplantation

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“…Thus, pilot trials with anti-oxidants (a recombinant human SOD and edaravone, a ROS scavenger) in the setting of primary PCI for AMI failed to demonstrate efficacy (Table 3) [44,45]. In addition, despite equivocal experimental data regarding a causal role of PMNs in lethal RI, clinical trials were initiated using drugs that inhibit PMN tethering and activation [46][47][48][49][50][51], inhibit PMN adhesion molecules [52], or preserve endothelial function (Table 3) [53]. Disappointing results were reported in these 8 (predominantly phase II) clinical trials with agents that inhibit PMN activation and endothelial dysfunction [46][47][48][49][50][51][52][53].…”

Section: Clinical Trialsmentioning

confidence: 99%

“…In addition, despite equivocal experimental data regarding a causal role of PMNs in lethal RI, clinical trials were initiated using drugs that inhibit PMN tethering and activation [46][47][48][49][50][51], inhibit PMN adhesion molecules [52], or preserve endothelial function (Table 3) [53]. Disappointing results were reported in these 8 (predominantly phase II) clinical trials with agents that inhibit PMN activation and endothelial dysfunction [46][47][48][49][50][51][52][53]. Finally, complement inhibition with a monoclonal antibody (anti-C5), pexelizumab, was investigated in patients with AMI in the COMMA [54], the COMPLY [55] and the APEX-AMI trial [56].…”

Section: Clinical Trialsmentioning

confidence: 99%

Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies

Dirksen

Laarman

Simoons

et al. 2007

Cardiovascular Research

168

121

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The principal therapy in patients with myocardial infarction to limit infarct size is myocardial reperfusion by mechanical or pharmacological intervention. Reperfusion has been proposed to cause myocardial injury beyond that caused by the preceding ischaemia, termed "reperfusion injury" (RI). While the precise mechanism of RI is still incompletely understood, a large number of clinical studies have been performed over the past decade targeting some of the postulated mechanisms of RI. These clinical studies were based on experimental data demonstrating significant myocardial salvage. Nevertheless, clinical benefits were absent or very limited. The purpose of this review is to provide an overview of the various strategies that inhibit RI and to discuss potential mechanisms that may contribute to the discrepancy between the promising pre-clinical data and the rather disappointing results obtained from prospective clinical trials. There are numerous differences between the experimental models and clinical studies, including the fact that experimental studies typically use abrupt occlusion and reperfusion protocols in animals with previously healthy myocardium that apparently do not predict the therapeutic efficacy of novel cardioprotective agents in a clinical setting with pre-existing progressive coronary disease, intermittent coronary occlusion, and relatively late reperfusion. However, discrepancies also exist between experimental studies. Future experimental studies of reperfusion injury should use models that mimic the clinical situation more closely. Furthermore, future large clinical trials should only be performed in cases where the drug under investigation proved to reduce RI in a series of well-designed (possibly multicenter) experimental studies and in clinical trials with predefined subgroups.

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“…Together these data suggest that leukocytes can continue to roll in the absence of optimal P-selectin/PSGL-1 interaction using an alternative mechanism that involves P-selectin-, L-selectin-, and sLe Selectins and their ligands support early interactions between leukocytes and endothelium during inflammation 1 and present attractive targets for anti-inflammatory drugs. P-Selectin may be a good target for cardiovascular disease therapy, [2][3][4][5] although notable clinical trial disappointments 6,7 suggest that effective P-selectin inhibition may be more challenging than expected.…”

mentioning

confidence: 99%

L- and P-Selectins Collaborate to Support Leukocyte Rolling in Vivo When High-Affinity P-Selectin-P-Selectin Glycoprotein Ligand-1 Interaction Is Inhibited

Ridger¹,

Hellewell²,

Norman³

2005

The American Journal of Pathology

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P-selectin glycoprotein ligand-1 (PSGL-1) binding to Pselectin controls early leukocyte rolling during inflammation. Interestingly, antibodies and pharmacological inhibitors (eg, rPSGL-Ig) that target the N-terminus of PSGL-1 reduce but do not abolish P-selectin-dependent leukocyte rolling in vivo whereas PSGL-1-deficient mice have almost no P-selectin-dependent rolling. We have investigated mechanisms of P-selectin-dependent, PSGL-1-independent rolling using intravital microscopy. Initially we used fluorescent microspheres to study the potential of L-selectin and the minimal selectin ligand sialyl Lewis x (sLe x ) to interact with postcapillary venules in the absence of PSGL-1. Microspheres coated with combinations of L-selectin and sLe x interacted with surgically stimulated cremaster venules in a P-selectin-dependent manner. Microspheres coated with either L-selectin or sLe x alone showed less evidence of interaction. We also investigated leukocyte rolling in the presence of PSGL-1 antibody or inhibitor (rPSGL-Ig), both of which partially inhibited P-selectin-dependent leukocyte rolling. Residual rolling was substantially inhibited by L-selectin-blocking antibody or a previously described sLe x mimetic (CGP69669A). Together these data suggest that leukocytes can continue to roll in the absence of optimal P-selectin/PSGL-1 interaction using an alternative mechanism that involves P-selectin-, L-selectin-, and sLe and present attractive targets for anti-inflammatory drugs. P-Selectin may be a good target for cardiovascular disease therapy, 2-5 although notable clinical trial disappointments 6,7 suggest that effective P-selectin inhibition may be more challenging than expected.Natural ligand mimicry is a common drug development approach. Elements of PSGL-1 required for high-affinity P-selectin recognition include a sialylated, fucosylated O-glycan and tyrosine sulfation at appropriate positions near the N-terminus. 8 Drugs mimicking one or more of these elements could theoretically inhibit P-selectin. Inhibitors based on the carbohydrate selectin ligand, sLe x , are effective, albeit in high doses, against E-selectindependent leukocyte rolling in vivo but have no measurable effect on established P-selectin-dependent rolling.

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Efficacy of a novel P-selectin antagonist, rPSGL-Ig for reperfusion therapy in acute myocardial infarction: The RAPSODY trial

Cited by 18 publications

References 0 publications

rPSGL-Ig for Improvement of Early Liver Allograft Function: A Double-Blind, Placebo-Controlled, Single-Center Phase II Study†

rPSGL-Ig for Improvement of Early Liver Allograft Function: A Double-Blind, Placebo-Controlled, Single-Center Phase II Study†

Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies

L- and P-Selectins Collaborate to Support Leukocyte Rolling in Vivo When High-Affinity P-Selectin-P-Selectin Glycoprotein Ligand-1 Interaction Is Inhibited

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