Nouvelle glycoproteine ligand de P-selectine, qui comporte la sequence d'acides amines presen... more Nouvelle glycoproteine ligand de P-selectine, qui comporte la sequence d'acides amines presentee dans SEQ ID NO:2 ou par la sequence d'acides amines presentee dans SEQ ID NO:4. Des sequences d'ADN codant la proteine ligand de P-selectine sont egalement decrites, ainsi que des vecteurs, des cellules hotes et des procedes permettant de fabriquer ladite proteine ligand de P-selectine. Des compositions pharmaceutiques contenant cette proteine et des procedes de traitement d'etats inflammatoires caracterises par des adherences intercellulaires induites par la P-selectine et la E-selectine sont egalement decrites.
SummaryThe interaction between von Willebrand factor (VWF) and platelet glycoprotein Ibα (GPIbα) ... more SummaryThe interaction between von Willebrand factor (VWF) and platelet glycoprotein Ibα (GPIbα) is a critical step that allows platelet adhesion, activation and subsequent thrombus formation to the injured vessel wall under high-shear conditions. In this study, we sought to investigate 1) whether GPG-290, a recombinant human GPIbα chimeric protein, would prevent thrombosis in a canine model of coronary thrombosis by blocking VWFGPIbα interaction; and 2) whether desmopressin (DDAVP), a VWF release stimulant, could reduce the prolonged bleeding time caused by a 10x efficacious dose of GPG-290. The antithrombotic efficacy of GPG-290 was evaluated by the in-vivo ability to prevent cyclic flow reductions (CFRs) and ex-vivo inhibition of platelet adhesion/aggregation reflected by prolongation of Platelet Function Analyzer (PFA-100®) collagen /ADP closure time. The anti-hemostatic effect was assessed by template bleeding time. GPG-290 at doses of 25, 50 and 100 μg/kg abolished CFRs in 67%...
P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which... more P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicyl... more Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.
Cytosolic phospholipase A 2 (cPLA 2 ) mediates the release of arachidonic acid upon cell activati... more Cytosolic phospholipase A 2 (cPLA 2 ) mediates the release of arachidonic acid upon cell activation. Metabolites of arachidonic acid, the eicosanoids, are recognized as important modulators of platelet signaling. Inhibitors of the eicosanoid pathway (eg aspirin) reduce the ...
Introduction: Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder, which leads t... more Introduction: Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder, which leads to red blood cell sickling, hemolysis and vaso-occlusion. Acute systemic painful vaso-occlusive crisis (VOC) is the predominant pathophysiology requiring emergency medical care by SCD patients. 10-20% of SCD patients hospitalized with VOC tend to develop acute chest syndrome (ACS), a type of lung injury within next few days, suggesting a role for pulmonary vaso-occlusion in ACS. This epidemiology also provides a window for therapeutic intervention provided treatments to prevent vaso-occlusion are available. Earlier, we have shown that VOC involves entrapment of large neutrophil-platelet aggregates in lung arterioles of SCD mice, which is inhibited following intravenous administration of P-selectin function blocking antibody. Recently, a tandem-P-selectin-glycoprotein-ligand-immunoglobulin (TSGL-Ig) with two P-selectin binding sites in tandem, has been shown to prevent P-selectin-dependent...
Systemic changes occurring after donor brain death (BD) may intensify early inflammatory processe... more Systemic changes occurring after donor brain death (BD) may intensify early inflammatory processes in peripheral organs and accelerate acute allograft rejection after transplantation. Selectins are responsible for initial binding of circulating inflammatory cells to activated vascular endothelium. By competitive binding, a recombinant soluble selectin ligand (rPSGL-Ig) has been shown to inhibit their activity and to block the subsequent inflammatory cascade. In this study, the authors investigated both early and late effects of rPSGL-Ig in a chronic rejection rat renal allograft model. Six hours after induction of BD, kidneys from F344 donors were grafted into Lewis recipients. Kidneys from living donors (group 1) and normotensive BD-donors (group 2) served as controls. rPSGL-Ig was given intravenously (50 µ g) to the donor animal 3 h after BD. A 2nd dose was given to the host after transplantation (n = 8, group 3). All recipients were treated with low-dose cyclosporin A (1.5 mg/kg, 10 d). Urinary protein levels (24-h urine) were measured serially, followed by histological analysis of the kidneys 200 days after transplantation. The mRNA transcription of representative inflammatory molecules was examined in untreated and treated BD donors before transplantation (6 h after BD) and after 200 days. Proteinuria in animals in groups 1 and 2, but not in group 3, increased progressively after approximately 12 weeks. Histologically, grafts from rPSGL-Ig treated animals showed only minor changes at 200 days, whereas the changes of chronic rejection had developed in untreated controls. Cytokine and chemokine activity, both early and late, was up-regulated in control kidneys, but not in those from the treated group. These data suggest that administration of rPSGL-Ig inhibits early inflammatory processes associated with donor BD. In turn, resultant chronic allograft dysfunction is prevented. These findings may be of particular clinical interest.
SummaryUnder high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet recept... more SummaryUnder high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ibα, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIbα interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 µg/kg, n=6; 500 µg/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105±34 and 156±23 (p<0.05) min, respectively compared to the saline treated control group (32±6min, n=6). Patency of the injured vessel was sustained in 1/6 (100µg/kg) and 3/6 vessels (500 µg/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 µg/kg dose, but only at the 1 hr time point. Clopidogrel was studied in two dosing regimens representing either a clinical pretreatment regimen (PTR) of 4.3 mg/kg on day –2 followed by 1.1 mg/kg daily for2 days prior to the procedure or pre-procedural loading dose...
Host sensitization to major histocompatibility complex (MHC) antigens is among the most critical ... more Host sensitization to major histocompatibility complex (MHC) antigens is among the most critical of problems facing heart transplantation. Selectins are postulated to mediate the early adhesive events in the recruitment of leukocytes at the allograft site. We investigated the significance of selectin-P-selectin glycoprotein ligand-1 (PSGL-1)-mediated in vivo interactions in the immune cascade leading to rejection of cardiac allografts in skin presensitized rats. Infusion of a soluble recombinant form of PSGL-1 (rPSGL-Ig) during skin graft-mediated sensitization prevented Day 1.0 Ϯ 0.1 "accelerated" rejection in sensitized rat recipients, and prolonged cardiac allograft survival to Day 3.8 Ϯ 1.0 (p Ͻ 0.001). This therapy significantly depressed serum IgM levels and decreased intragraft expression of Th1 type cytokines (IL-2 and IFN-␥) as well as of IL-1 and MCP-1, as compared with controls, without affecting the initial number of infiltrating mononuclear cells (MNC). A profound decrease in graft-infiltrating MNC was recorded at 24 hours in rPSGL-Ig-treated rats. The expression of heme oxygenase-1 (HO-1), an inducible heat shock protein 32 that protects against oxidative cell/tissue injury, was found in approximately 14-fold higher levels in the rPSGL-Igtreated recipients as compared with controls. The HO-1 overexpression in rPSGL-Ig-treated hosts, primarily by infiltrating macrophages, was accompanied by virtual absence of myocardial infarcts and decreased frequency of TUNEL ϩ cells at the graft site. Moreover, down-regulation of HO-1 expression by zinc protoporphyrin, an HO-1 antagonist, decreased expression of antiapoptotic Bag-1 molecule in recipients conditioned with rPSGL-Ig. Thus, the blockade of selectin-PSGL-1 interactions depresses intracardiac allograft expression of Th1 type cytokines, and might inhibit the differentiation of Th1 type cells. In addition, it up-regulates HO-1 expression and protects against myocardial infarction and apoptosis. Hence, this study reports on a previously unrecognized role of selectin-PSGL-1-mediated interactions after in vivo alloantigenic challenge. (Lab Invest 2002, 82:61-70).
Background: Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus a... more Background: Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus and local thrombotic and inflammatory mechanisms. We hypothesized that inhibition of vein wall injury through reduction of thrombotic and inflammatory events with P-selectin inhibition and/or low-molecular-weight heparin (LMWH) occurs independently of thrombus resolution in a rat model of venous thrombosis. Methods: Male rats underwent inferior vena cava (IVC) stenosis (94.4% ؎ 0.5% reduction in IVC diameter) to induce thrombosis. Rats were treated from 2 days after thrombosis until they were killed 7 days later. Groups consisted of (1) PSI-697, a P-selectin inhibitor (30 mg/kg; oral gavage daily); (2) LMWH-Lovenox (LOV; enoxaparin) 3 mg/kg subcutaneously daily; (3) PSI-697 (30 mg/kg; oral gavage daily) plus LOV 3 mg/kg subcutaneously daily (PSI ؉ LOV); (4) and untreated controls. Evaluations included thrombus mass, vein wall tensiometry (stiffness [inverse of compliance]), intimal thickness scoring by light microscopy, vein wall inflammatory mediators by enzyme-linked immunosorbent assay, and vein wall inflammatory cells by histologic evaluation. Results: Thrombus mass was not reduced by any treatment. Animals treated with PSI-697 alone, LOV alone, or PSI ؉ LOV demonstrated significant decreases in vein wall stiffness when compared with controls. The vein wall stiffness of the PSI-697-treated groups was also significantly lower than in the LOV-only group. Animals treated with PSI-697 showed a significantly decreased intimal thickness score when compared with vehicle control IVCs. Vein wall intimal thickening was also significantly decreased in animals treated with PSI-697 vs LOV. The PSI-697 and PSI ؉ LOV groups manifested significant decreases in the immunoregulatory and inflammatory cytokine interleukin 13 as compared with controls and LOV. Vein wall monocyte chemotactic protein 1 levels were also significantly reduced in the PSI-697 and PSI ؉ LOV groups vs control. Only PSI-697 significantly decreased vein wall levels of platelet-derived growth factor . Both the LOV and PSI ؉ LOV groups had significant increases in vein wall monocytes and total inflammatory cells vs controls. Conclusions: These data suggest that both LMWH and PSI-697 inhibit vein wall injury independently of thrombus mass. P-selectin inhibition seemed superior to LMWH in measured parameters of injury and mediator inhibition. (J Vasc Surg 2006;44:625-32.) Clinical Relevance: Deep venous thrombosis (DVT) remains a serious health care problem in this country, affecting more than 250,000 patients annually. Chronic venous insufficiency, a major complication of DVT, promotes the impairment of venous outflow, loss of vein compliance, and valvular dysfunction. The current standard of care for both treatment and prophylaxis of DVT is low-molecular-weight heparin. However, this therapy confers a bleeding risk and does not protect against postthrombotic syndrome. In previous rat studies, using a recombinant P-selectin receptor antagonist (rPSGL-Ig) 2 days after thrombosis resulted in less vein wall fibrosis without a decrease in thrombus mass. Further studies in the rat model of DVT have shown that P-selectin inhibition also inhibits profibrotic cytokine production and vein wall collagen. This study evaluated the effects of P-selectin inhibition by using a novel oral agent (PSI-697) on the postthrombotic vein wall and compared this with the current standard of care.
Nouvelle glycoproteine ligand de P-selectine, qui comporte la sequence d'acides amines presen... more Nouvelle glycoproteine ligand de P-selectine, qui comporte la sequence d'acides amines presentee dans SEQ ID NO:2 ou par la sequence d'acides amines presentee dans SEQ ID NO:4. Des sequences d'ADN codant la proteine ligand de P-selectine sont egalement decrites, ainsi que des vecteurs, des cellules hotes et des procedes permettant de fabriquer ladite proteine ligand de P-selectine. Des compositions pharmaceutiques contenant cette proteine et des procedes de traitement d'etats inflammatoires caracterises par des adherences intercellulaires induites par la P-selectine et la E-selectine sont egalement decrites.
SummaryThe interaction between von Willebrand factor (VWF) and platelet glycoprotein Ibα (GPIbα) ... more SummaryThe interaction between von Willebrand factor (VWF) and platelet glycoprotein Ibα (GPIbα) is a critical step that allows platelet adhesion, activation and subsequent thrombus formation to the injured vessel wall under high-shear conditions. In this study, we sought to investigate 1) whether GPG-290, a recombinant human GPIbα chimeric protein, would prevent thrombosis in a canine model of coronary thrombosis by blocking VWFGPIbα interaction; and 2) whether desmopressin (DDAVP), a VWF release stimulant, could reduce the prolonged bleeding time caused by a 10x efficacious dose of GPG-290. The antithrombotic efficacy of GPG-290 was evaluated by the in-vivo ability to prevent cyclic flow reductions (CFRs) and ex-vivo inhibition of platelet adhesion/aggregation reflected by prolongation of Platelet Function Analyzer (PFA-100®) collagen /ADP closure time. The anti-hemostatic effect was assessed by template bleeding time. GPG-290 at doses of 25, 50 and 100 μg/kg abolished CFRs in 67%...
P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which... more P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicyl... more Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.
Cytosolic phospholipase A 2 (cPLA 2 ) mediates the release of arachidonic acid upon cell activati... more Cytosolic phospholipase A 2 (cPLA 2 ) mediates the release of arachidonic acid upon cell activation. Metabolites of arachidonic acid, the eicosanoids, are recognized as important modulators of platelet signaling. Inhibitors of the eicosanoid pathway (eg aspirin) reduce the ...
Introduction: Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder, which leads t... more Introduction: Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder, which leads to red blood cell sickling, hemolysis and vaso-occlusion. Acute systemic painful vaso-occlusive crisis (VOC) is the predominant pathophysiology requiring emergency medical care by SCD patients. 10-20% of SCD patients hospitalized with VOC tend to develop acute chest syndrome (ACS), a type of lung injury within next few days, suggesting a role for pulmonary vaso-occlusion in ACS. This epidemiology also provides a window for therapeutic intervention provided treatments to prevent vaso-occlusion are available. Earlier, we have shown that VOC involves entrapment of large neutrophil-platelet aggregates in lung arterioles of SCD mice, which is inhibited following intravenous administration of P-selectin function blocking antibody. Recently, a tandem-P-selectin-glycoprotein-ligand-immunoglobulin (TSGL-Ig) with two P-selectin binding sites in tandem, has been shown to prevent P-selectin-dependent...
Systemic changes occurring after donor brain death (BD) may intensify early inflammatory processe... more Systemic changes occurring after donor brain death (BD) may intensify early inflammatory processes in peripheral organs and accelerate acute allograft rejection after transplantation. Selectins are responsible for initial binding of circulating inflammatory cells to activated vascular endothelium. By competitive binding, a recombinant soluble selectin ligand (rPSGL-Ig) has been shown to inhibit their activity and to block the subsequent inflammatory cascade. In this study, the authors investigated both early and late effects of rPSGL-Ig in a chronic rejection rat renal allograft model. Six hours after induction of BD, kidneys from F344 donors were grafted into Lewis recipients. Kidneys from living donors (group 1) and normotensive BD-donors (group 2) served as controls. rPSGL-Ig was given intravenously (50 µ g) to the donor animal 3 h after BD. A 2nd dose was given to the host after transplantation (n = 8, group 3). All recipients were treated with low-dose cyclosporin A (1.5 mg/kg, 10 d). Urinary protein levels (24-h urine) were measured serially, followed by histological analysis of the kidneys 200 days after transplantation. The mRNA transcription of representative inflammatory molecules was examined in untreated and treated BD donors before transplantation (6 h after BD) and after 200 days. Proteinuria in animals in groups 1 and 2, but not in group 3, increased progressively after approximately 12 weeks. Histologically, grafts from rPSGL-Ig treated animals showed only minor changes at 200 days, whereas the changes of chronic rejection had developed in untreated controls. Cytokine and chemokine activity, both early and late, was up-regulated in control kidneys, but not in those from the treated group. These data suggest that administration of rPSGL-Ig inhibits early inflammatory processes associated with donor BD. In turn, resultant chronic allograft dysfunction is prevented. These findings may be of particular clinical interest.
SummaryUnder high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet recept... more SummaryUnder high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ibα, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIbα interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 µg/kg, n=6; 500 µg/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105±34 and 156±23 (p<0.05) min, respectively compared to the saline treated control group (32±6min, n=6). Patency of the injured vessel was sustained in 1/6 (100µg/kg) and 3/6 vessels (500 µg/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 µg/kg dose, but only at the 1 hr time point. Clopidogrel was studied in two dosing regimens representing either a clinical pretreatment regimen (PTR) of 4.3 mg/kg on day –2 followed by 1.1 mg/kg daily for2 days prior to the procedure or pre-procedural loading dose...
Host sensitization to major histocompatibility complex (MHC) antigens is among the most critical ... more Host sensitization to major histocompatibility complex (MHC) antigens is among the most critical of problems facing heart transplantation. Selectins are postulated to mediate the early adhesive events in the recruitment of leukocytes at the allograft site. We investigated the significance of selectin-P-selectin glycoprotein ligand-1 (PSGL-1)-mediated in vivo interactions in the immune cascade leading to rejection of cardiac allografts in skin presensitized rats. Infusion of a soluble recombinant form of PSGL-1 (rPSGL-Ig) during skin graft-mediated sensitization prevented Day 1.0 Ϯ 0.1 "accelerated" rejection in sensitized rat recipients, and prolonged cardiac allograft survival to Day 3.8 Ϯ 1.0 (p Ͻ 0.001). This therapy significantly depressed serum IgM levels and decreased intragraft expression of Th1 type cytokines (IL-2 and IFN-␥) as well as of IL-1 and MCP-1, as compared with controls, without affecting the initial number of infiltrating mononuclear cells (MNC). A profound decrease in graft-infiltrating MNC was recorded at 24 hours in rPSGL-Ig-treated rats. The expression of heme oxygenase-1 (HO-1), an inducible heat shock protein 32 that protects against oxidative cell/tissue injury, was found in approximately 14-fold higher levels in the rPSGL-Igtreated recipients as compared with controls. The HO-1 overexpression in rPSGL-Ig-treated hosts, primarily by infiltrating macrophages, was accompanied by virtual absence of myocardial infarcts and decreased frequency of TUNEL ϩ cells at the graft site. Moreover, down-regulation of HO-1 expression by zinc protoporphyrin, an HO-1 antagonist, decreased expression of antiapoptotic Bag-1 molecule in recipients conditioned with rPSGL-Ig. Thus, the blockade of selectin-PSGL-1 interactions depresses intracardiac allograft expression of Th1 type cytokines, and might inhibit the differentiation of Th1 type cells. In addition, it up-regulates HO-1 expression and protects against myocardial infarction and apoptosis. Hence, this study reports on a previously unrecognized role of selectin-PSGL-1-mediated interactions after in vivo alloantigenic challenge. (Lab Invest 2002, 82:61-70).
Background: Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus a... more Background: Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus and local thrombotic and inflammatory mechanisms. We hypothesized that inhibition of vein wall injury through reduction of thrombotic and inflammatory events with P-selectin inhibition and/or low-molecular-weight heparin (LMWH) occurs independently of thrombus resolution in a rat model of venous thrombosis. Methods: Male rats underwent inferior vena cava (IVC) stenosis (94.4% ؎ 0.5% reduction in IVC diameter) to induce thrombosis. Rats were treated from 2 days after thrombosis until they were killed 7 days later. Groups consisted of (1) PSI-697, a P-selectin inhibitor (30 mg/kg; oral gavage daily); (2) LMWH-Lovenox (LOV; enoxaparin) 3 mg/kg subcutaneously daily; (3) PSI-697 (30 mg/kg; oral gavage daily) plus LOV 3 mg/kg subcutaneously daily (PSI ؉ LOV); (4) and untreated controls. Evaluations included thrombus mass, vein wall tensiometry (stiffness [inverse of compliance]), intimal thickness scoring by light microscopy, vein wall inflammatory mediators by enzyme-linked immunosorbent assay, and vein wall inflammatory cells by histologic evaluation. Results: Thrombus mass was not reduced by any treatment. Animals treated with PSI-697 alone, LOV alone, or PSI ؉ LOV demonstrated significant decreases in vein wall stiffness when compared with controls. The vein wall stiffness of the PSI-697-treated groups was also significantly lower than in the LOV-only group. Animals treated with PSI-697 showed a significantly decreased intimal thickness score when compared with vehicle control IVCs. Vein wall intimal thickening was also significantly decreased in animals treated with PSI-697 vs LOV. The PSI-697 and PSI ؉ LOV groups manifested significant decreases in the immunoregulatory and inflammatory cytokine interleukin 13 as compared with controls and LOV. Vein wall monocyte chemotactic protein 1 levels were also significantly reduced in the PSI-697 and PSI ؉ LOV groups vs control. Only PSI-697 significantly decreased vein wall levels of platelet-derived growth factor . Both the LOV and PSI ؉ LOV groups had significant increases in vein wall monocytes and total inflammatory cells vs controls. Conclusions: These data suggest that both LMWH and PSI-697 inhibit vein wall injury independently of thrombus mass. P-selectin inhibition seemed superior to LMWH in measured parameters of injury and mediator inhibition. (J Vasc Surg 2006;44:625-32.) Clinical Relevance: Deep venous thrombosis (DVT) remains a serious health care problem in this country, affecting more than 250,000 patients annually. Chronic venous insufficiency, a major complication of DVT, promotes the impairment of venous outflow, loss of vein compliance, and valvular dysfunction. The current standard of care for both treatment and prophylaxis of DVT is low-molecular-weight heparin. However, this therapy confers a bleeding risk and does not protect against postthrombotic syndrome. In previous rat studies, using a recombinant P-selectin receptor antagonist (rPSGL-Ig) 2 days after thrombosis resulted in less vein wall fibrosis without a decrease in thrombus mass. Further studies in the rat model of DVT have shown that P-selectin inhibition also inhibits profibrotic cytokine production and vein wall collagen. This study evaluated the effects of P-selectin inhibition by using a novel oral agent (PSI-697) on the postthrombotic vein wall and compared this with the current standard of care.
Uploads
Papers by Gray Shaw