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Lina Badimon - One of the best experts on this subject based on the ideXlab platform.
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a thromboxane a2 Prostaglandin H2 receptor antagonist s18886 shows high antithrombotic efficacy in an experimental model of stent induced thrombosis
Thrombosis and Haemostasis, 2007Co-Authors: Gemma Vilahur, Laura Casani, Lina BadimonAbstract:Acute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A2/Prostaglandin H2 receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s.Antithrombotic effects were assessed as 111In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD ≤48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated animals, respectively (P
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A thromboxane A2/Prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis
Thrombosis and haemostasis, 2007Co-Authors: Gemma Vilahur, Laura Casani, Lina BadimonAbstract:Acute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A2/Prostaglandin H2 receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s.Antithrombotic effects were assessed as 111In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD ≤48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated animals, respectively (P
Gemma Vilahur - One of the best experts on this subject based on the ideXlab platform.
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a thromboxane a2 Prostaglandin H2 receptor antagonist s18886 shows high antithrombotic efficacy in an experimental model of stent induced thrombosis
Thrombosis and Haemostasis, 2007Co-Authors: Gemma Vilahur, Laura Casani, Lina BadimonAbstract:Acute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A2/Prostaglandin H2 receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s.Antithrombotic effects were assessed as 111In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD ≤48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated animals, respectively (P
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A thromboxane A2/Prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis
Thrombosis and haemostasis, 2007Co-Authors: Gemma Vilahur, Laura Casani, Lina BadimonAbstract:Acute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A2/Prostaglandin H2 receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s.Antithrombotic effects were assessed as 111In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD ≤48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated animals, respectively (P
Patrick J Loll - One of the best experts on this subject based on the ideXlab platform.
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2.0 angstroms structure of Prostaglandin H2 synthase-1 reconstituted with a manganese porphyrin cofactor.
Acta crystallographica. Section D Biological crystallography, 2006Co-Authors: Kushol Gupta, Barry S Selinsky, Patrick J LollAbstract:Prostaglandin H2 synthase (EC 1.14.99.1) is a clinically important drug target that catalyzes two key steps in the biosynthesis of the eicosanoid hormones. The enzyme contains spatially distinct cyclooxygenase and peroxidase active sites, both of which require a heme cofactor. Substitution of ferric heme by Mn(III) protoporphyrin IX greatly diminishes the peroxidase activity, but has little effect on the cyclooxygenase activity. Here, the 2.0 angstroms resolution crystal structure of the Mn(III) form of ovine Prostaglandin H2 synthase-1 is described (R = 21.8%, R(free) = 23.7%). Substitution of Mn(III) for Fe(III) causes no structural perturbations in the protein. However, the out-of-plane displacement of the manganese ion with respect to the porphyrin is greater than that of the iron by approximately 0.2 angstroms. This perturbation may help to explain the altered catalytic properties of the manganese enzyme.
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2.0 Å structure of Prostaglandin H2 synthase-1 reconstituted with a manganese porphyrin cofactor
Acta Crystallographica Section D Biological Crystallography, 2006Co-Authors: Kushol Gupta, Barry S Selinsky, Patrick J LollAbstract:Prostaglandin H2 synthase (EC 1.14.99.1) is a clinically important drug target that catalyzes two key steps in the biosynthesis of the eicosanoid hormones. The enzyme contains spatially distinct cyclooxygenase and peroxidase active sites, both of which require a heme cofactor. Substitution of ferric heme by MnIII protoporphyrin IX greatly diminishes the peroxidase activity, but has little effect on the cyclooxygenase activity. Here, the 2.0 A resolution crystal structure of the MnIII form of ovine Prostaglandin H2 synthase-1 is described (R = 21.8%, Rfree = 23.7%). Substitution of MnIII for FeIII causes no structural perturbations in the protein. However, the out-of-plane displacement of the manganese ion with respect to the porphyrin is greater than that of the iron by approximately 0.2 A. This perturbation may help to explain the altered catalytic properties of the manganese enzyme.
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The 2.0 A resolution crystal structure of Prostaglandin H2 synthase-1: structural insights into an unusual peroxidase.
Journal of Molecular Biology, 2004Co-Authors: Kushol Gupta, Barry S Selinsky, Carl J. Kaub, Amy K Katz, Patrick J LollAbstract:Prostaglandin H2 synthase (EC 1.14.99.1) is an integral membrane enzyme containing a cyclooxygenase site, which is the target for the non-steroidal anti-inflammatory drugs, and a spatially distinct peroxidase site. Previous crystallographic studies of this clinically important drug target have been hindered by low resolution. We present here the 2.0 Aresolution X-ray crystal structure of ovine Prostaglandin H2 synthase-1 in complex with a-methyl-4-biphenylacetic acid, a defluorinated analog of the non- steroidal anti-inflammatory drug flurbiprofen. Detergent molecules are seen to bind to the protein's membrane-binding domain, and their positions suggest the depth to which this domain is likely to penetrate into the lipid bilayer. The relation of the enzyme's proximal heme ligand His388 to the heme iron is atypical for a peroxidase; the iron- histidine bond is unusually long and a substantial tilt angle is observed between the heme and imidazole planes. A molecule of glycerol, used as a cryo- protectant during diffraction experiments, is seen to bind in the peroxidase site, offering the first view of any ligand in this active site. Insights gained from glycerol binding may prove useful in the design of a peroxidase-specific ligand. q 2003 Elsevier Ltd. All rights reserved.
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structural analysis of nsaid binding by Prostaglandin H2 synthase time dependent and time independent inhibitors elicit identical enzyme conformations
Biochemistry, 2001Co-Authors: Barry S Selinsky, Kushol Gupta, Caroline T Sharkey, Patrick J LollAbstract:Nonsteroidal antiinflammatory drugs (NSAIDs) block prostanoid biosynthesis by inhibiting Prostaglandin H2 synthase (EC 1.14.99.1). NSAIDs are either rapidly reversible competitive inhibitors or slow tight-binding inhibitors of this enzyme. These different modes of inhibition correlate with clinically important differences in isoform selectivity. Hypotheses have been advanced to explain the different inhibition kinetics, but no structural data have been available to test them. We present here crystal structures of Prostaglandin H2 synthase-1 in complex with the inhibitors ibuprofen, methyl flurbiprofen, flurbiprofen, and alclofenac at resolutions ranging from 2.6 to 2.75 A. These structures allow direct comparison of enzyme complexes with reversible competitive inhibitors (ibuprofen and methyl flurbiprofen) and slow tight-binding inhibitors (alclofenac and flurbiprofen). The four inhibitors bind to the same site and adopt similar conformations. In all four complexes, the enzyme structure is essentially unc...
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synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the Prostaglandin H2 synthase cyclooxygenase active site
Biochemistry, 1996Co-Authors: Patrick J Loll, D Picot, O Ekabo, R M GaravitoAbstract:The cyclooxygenase activity of the membrane protein Prostaglandin H2 synthase isoform 1 (PGHS-1) is the target of the nonsteroidal antiinflammatory drugs (NSAIDs). The X-ray crystal structures of PGHS-1 in complex with the NSAIDs flurbiprofen and bromoaspirin have been determined previously [Picot, D., et al. (1994) Nature 367, 243−249; Loll, P. J., et al. (1995) Nat. Struct. Biol. 2, 637−643]. We report here the preparation and characterization of novel potent iodinated analogs of the NSAIDs indomethacin and suprofen, as well as the refined X-ray crystal structures of their complexes with PGHS-1. The PGHS−iodosuprofen complex structure has been refined at 3.5 A to an R-value of 0.189 and shows the suprofen analog to share a common mode of binding with flurbiprofen. The PGHS−iodoindomethacin complex structure has been refined at 4.5 A to an R-value of 0.254. The low resolution of the iodoindomethacin complex structure precludes detailed modeling of drug−enzyme interactions, but the electron-dense iodine a...
Perry V. Halushka - One of the best experts on this subject based on the ideXlab platform.
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increased platelet thromboxane a2 Prostaglandin H2 receptors in patients with pregnancy induced hypertension
Thrombosis Research, 1993Co-Authors: N. Liel, I. Nathan, T. Yermiyahu, Z. Zolotov, J.r. Lieberman, A. Dvilansky, Perry V. HalushkaAbstract:Pregnancy induced hypertension (PIH) is associated with a variety of disturbances in the hemostatic system including alterations in platelet function, thrombocytopenia (1), and an increase in platelet turnover (2,3). The density of platelet Thromboxane A2 (TXA2)/Prostaglandin H2 (PGH2) receptors was determined in patients with PIH and normal pregnant women, using [125I]-PTA-OH, a TXA2/PGH2 receptor antagonist. The number of platelet TXA2/PGH2 receptors significantly increased (p<0.008) from 1734±370 sites/platelet (n=8) in normal pregnant women to 3703±846 sites/platelet (n=9) in patients with severe PIH. The sensitivity of platelets to the TXA2 mimetic U46619 was significantly (p<0.0005) increased in platelets obtained from severe PIH patients (EC50=150±10nM, n=3) compared to controls (EC50=290±60nM, n=5). These results indicate that an increased number of TXA2/PGH2 receptors as well as increased sensitivity to TXA2/PGH2 mimetics occurs in PIH. Collectively, these results provide further support for the notion that TXA2 and its receptor may play an important role in the pathophysiology of PIH.
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Increased platelet thromboxane A2/Prostaglandin H2 receptors in patients with pregnancy induced hypertension
Thrombosis Research, 1993Co-Authors: N. Liel, I. Nathan, T. Yermiyahu, Z. Zolotov, J.r. Lieberman, A. Dvilansky, Perry V. HalushkaAbstract:Pregnancy induced hypertension (PIH) is associated with a variety of disturbances in the hemostatic system including alterations in platelet function, thrombocytopenia (1), and an increase in platelet turnover (2,3). The density of platelet Thromboxane A2 (TXA2)/Prostaglandin H2 (PGH2) receptors was determined in patients with PIH and normal pregnant women, using [125I]-PTA-OH, a TXA2/PGH2 receptor antagonist. The number of platelet TXA2/PGH2 receptors significantly increased (p
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Thromboxane A2/ Prostaglandin H2 receptors in streptozotocin-induced diabetes: Effects of insulin therapy in the rat
Prostaglandins, 1993Co-Authors: Thomas A. Morinelli, Masao Naka, G. E. Tempel, Ayad A. Jaffa, R.h. Silva, W. Folger, Perry V. HalushkaAbstract:Thromboxane A2 (TXA2) and Prostaglandin H2 (PGH2) are potent vasoactive and proaggregatory agents whose synthesis has been shown to be elevated in diabetes mellitus. In the present study the effects of streptozotocin (STZ)-induced uncontrolled diabetes (Severe) and insulin-treated STZ diabetes (Moderate) on TXA2/PGH2 receptor density and affinity in platelets, glomerular membranes and aortic membranes were determined using [125I]-BOP, a TXA2/PGH2 receptor agonist. The affinity and density of platelet TXA2/PGH2 receptors in Control, Moderate and Severe groups and glomerular membranes were not significantly different. However, daily insulin therapy caused significant changes in both TXA2/PGH2 receptor affinity and density of aortic membranes: Kd (nM) = 0.67 ± 0.09, (n=5), for Control; 0.27 ± 0.05∗, (n=6), Moderate; and 0.74 ± 0.16, (n=5), Severe; Bmax (fmoles/mg protein) = 38.6 ± 3.1, Control; 20.2 ± 4.2∗, Moderate; and 37.1 ± 4.1, Severe: (∗p
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Androgen regulation of thromboxane A2/Prostaglandin H2 receptor expression in human erythroleukemia cells.
The American journal of physiology, 1993Co-Authors: K Matsuda, R S Mathur, E Duzic, Perry V. HalushkaAbstract:Thromboxane A2 (TxA2), a platelet aggregator and vasoconstrictor, has been implicated as a potential mediator of cardiovascular diseases. Abuse of androgenic steroids has been associated with thrombotic cardiovascular diseases. Human erythroleukemia (HEL) cells, a megakaryocyte-like cell line, express functional TxA2/Prostaglandin H2 (PGH2) receptors with characteristics similar to those seen in platelets. This study characterized testosterone regulation of HEL cell TxA2/PGH2 receptors. TxA2/PGH2 receptor affinity (Kd) and density (Bmax) were determined via equilibrium binding experiments using the radiolabeled TxA2 mimetic (1S-[1 alpha,2 beta(5Z),3 alpha(1E,3R*),4 alpha])-7-(3-[3-hydroxy-4-(4'- iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]heptan-2-yl)-5-he ptenoic acid (125I-labeled BOP). Testosterone (200 nM) but not estradiol increased Bmax from 108 +/- 9 fmol/mg protein to 157 +/- 9 fmol/mg protein (n = 7 experiments; P < 0.01) without any significant change in Kd. Testosterone had no significant effect on alpha 2-adrenergic receptor density. The maximum increase in intracellular free calcium induced by the TxA2 agonists I-BOP or U-46619 was significantly (P < 0.005) greater in testosterone-treated cells compared with controls. Hydroxyflutamide (1 microM), an androgen-receptor antagonist, completely blocked the effect of testosterone (P < 0.01). Dihydrotestosterone, the active metabolite of testosterone, also increased Bmax in a concentration-dependent manner and was more potent than testosterone. The effect of testosterone to increase Bmax was significantly (P < 0.01) inhibited by coincubation with cycloheximide (0.1 microgram/ml) or actinomycin D (10 ng/ml). These results indicate that androgenic steroids regulate the expression of functional TxA2/PGH2 receptors in HEL cells. These findings may have relevance to cardiovascular disease.
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Radioiododestannylation. Convenient synthesis of a high affinity thromboxane A2/Prostaglandin H2 receptor antagonist
Journal of Labelled Compounds and Radiopharmaceuticals, 1991Co-Authors: Dale E. Mais, Perry V. Halushka, Masao Naka, Thomas A. Morinelli, John E. Oatis, Nobuyuki HamanakaAbstract:Radioiodination of methyl-7-[(2R, 2S, 3S, 5R)-6,6-dimethyl-3-(4-trimethylstannylbenzenesulfonylamino) bicyclo[3.1.1]hept-2-yl]-5(Z)-heptenoate with [125I] Na using a modification of the chloramine-T method in organic solvent is simple with high yields and site specific. The product, following hydrolysis of the ester, 7-[(2R, 2S, 3S, 5R)-6,6-dimethyl-3-(4-[125I]-iodobenzenesulfonylamino) bicyclo[3.1.1]hept-2-yl]-5(Z)-heptenoic acid ([125I]-ISAP), was purified by HPLC. The high specific activity and specific binding will make the ligand a useful tool for the characterization of thromboxane A2/Prostaglandin H2 receptors.
Laura Casani - One of the best experts on this subject based on the ideXlab platform.
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a thromboxane a2 Prostaglandin H2 receptor antagonist s18886 shows high antithrombotic efficacy in an experimental model of stent induced thrombosis
Thrombosis and Haemostasis, 2007Co-Authors: Gemma Vilahur, Laura Casani, Lina BadimonAbstract:Acute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A2/Prostaglandin H2 receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s.Antithrombotic effects were assessed as 111In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD ≤48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated animals, respectively (P
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A thromboxane A2/Prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis
Thrombosis and haemostasis, 2007Co-Authors: Gemma Vilahur, Laura Casani, Lina BadimonAbstract:Acute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A2/Prostaglandin H2 receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s.Antithrombotic effects were assessed as 111In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD ≤48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated animals, respectively (P
