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Dans cette etude, l'A., sur la base de la structure bipolaire du masal (= proverbe), montre que dans le livre de Job il y a exactement une telle structure qui correspond bien, comme instrument de communication esthetique, a son... more
Dans cette etude, l'A., sur la base de la structure bipolaire du masal (= proverbe), montre que dans le livre de Job il y a exactement une telle structure qui correspond bien, comme instrument de communication esthetique, a son contenu. Job et Dieu sont les deux poles d'une grande question, presentee dans deux perspectives diverses, celle de l'omme "jete" dans l'existence et celle d'un Dieu qui represente la reponse theologique. Mais le livre de Job ne donne aucune reponse finale: avec sa presentation bipolaire, l'A. met ainsi le lecteur lui-meme devant un interrogatif a repondre.
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Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers.
Over the last few years our understanding of the role of platelets has evolved. While originally considered to be solely involved in thrombus formation recent studies suggest that they play an important role in the innate immune system.... more
Over the last few years our understanding of the role of platelets has evolved. While originally considered to be solely involved in thrombus formation recent studies suggest that they play an important role in the innate immune system. As the most numerous particles in the blood platelets are the first responders to any breaches in the vasculature where they bind to the damaged vessel and aggregate to seal the leak. They also become activated and secrete the contents of their granules, which contain anti-microbial peptides, which acts to sterilise the wound and to recruit other immune cells. As a result thrombocytopenia is a common response to infection by many different organisms [1, 2].
ABSTRACT The fibrinogen receptor on platelets is glycoprotein (GP) IIb/IIIa, also known as αIIbβ3. This receptor can bind to immobilized fibrinogen in its resting state. Binding to soluble fibrinogen, however, requires activation of the... more
ABSTRACT The fibrinogen receptor on platelets is glycoprotein (GP) IIb/IIIa, also known as αIIbβ3. This receptor can bind to immobilized fibrinogen in its resting state. Binding to soluble fibrinogen, however, requires activation of the receptor. This can occur due to inside-out signaling in response to a platelet agonist such as ADP, or directly by agents such as manganese. The interaction between GPIIb/IIIa and fibrinogen is essential in the formation of platelet aggregates (1,2).
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Low‐dose aspirin (75 mg or 81 mg) is considered to be the lowest effective dose for cardiovascular protection; however, the use of enteric preparations has created a source of variability in bioavailability. As part of regulatory... more
Low‐dose aspirin (75 mg or 81 mg) is considered to be the lowest effective dose for cardiovascular protection; however, the use of enteric preparations has created a source of variability in bioavailability. As part of regulatory requirements, we carried out bioequivalence tests for two 75 mg enteric‐coated aspirin preparations (Caprin and Protek) using Nu‐Seals 75 mg aspirin as the comparator. The primary endpoint was serum thromboxane levels after 14 days of treatment. Protek failed to meet bioequivalence, as it was significantly less effective than Nu‐Seals. In contrast, Caprin was not bioequivalent with Nu‐Seals but as it was more effective it was granted approval. However, 75 mg plain aspirin was found to be more effective than Nu‐Seals at inhibiting serum thromboxane production. Thus, there is significant variation in the ability of low‐dose aspirin preparations to inhibit serum thromboxane production.
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It is clear that COVID-19 is more than a pneumonia and is associated with a coagulopathy and multi-organ failure. While the use of anti-coagulants does reduce the incidence of pulmonary emboli, it does not help with survival. This... more
It is clear that COVID-19 is more than a pneumonia and is associated with a coagulopathy and multi-organ failure. While the use of anti-coagulants does reduce the incidence of pulmonary emboli, it does not help with survival. This suggests that the coagulopathy is more likely to be platelet-driven rather than thrombin-driven. There is significant evidence to suggest that SARS-CoV-2 virions directly interact with platelets to trigger activation leading to thrombocytopenia and thrombosis. I propose a model of multiple interactions between SARS-CoV-2 and platelets that has many similarities to that with Staphylococcus aureus and Dengue virus. As platelet activation and thrombosis are major factors in poor prognosis, therapeutics that target the platelet-SARS-CoV-2 interaction have potential in treating COVID-19 and other virus infections.
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Dept of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2 Coppinger JA, O Connor RI, Cagney G, Cox D & Maguire PB. Recent evidence suggests that certain cytokines secreted by activated platelets can promote the... more
Dept of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2 Coppinger JA, O Connor RI, Cagney G, Cox D & Maguire PB. Recent evidence suggests that certain cytokines secreted by activated platelets can promote the development of atherosclerosis and thrombosis e.g the platelet specific cytokine platelet factor 4 (PF4) facilitates macrophage differentiation during inflammation and has shown to be incorporated into atherosclerotic plaques. In this study, we examined the release of several cytokines and other secretory markers from platelets stimulated by three different agonists in the presence and abscene of the anti-platelet drug aspirin. Using antibody array technology we detected the presence of 22 cytokines in the platelet releasate. High levels of abundant platelet cytokines RANTES, PDGF and EGF were seen throughout the arrays for all releasate fractions. The interleukin family were generally underrepresented with the exception of interleukin 8 and GRO. Several i...
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S. epidermidis is normally present on the surface of the skin, however in a hospital setting, it is responsible for many infections involving implanted medical devices resulting in potentially fatal complications such as infective... more
S. epidermidis is normally present on the surface of the skin, however in a hospital setting, it is responsible for many infections involving implanted medical devices resulting in potentially fatal complications such as infective endocarditis and septicemia. S. epidermidis has previously been shown to induce platelet aggregation (Ohshima et al. Microbiol Immunol 1991) through an unknown mechanism. The surface protein SdrG (serine-aspartate repeat G protein) is important in the initial colonization of the device, as it binds fibrinogen, which is one of the first proteins to coat foreign devices. We thus postulated that this SdrG fibrinogen complex may mediate the S. epidermidis interaction with platelets. In order to investigate the specific effects of SdrG on platelets, we expressed SdrG in Lactococcus lactis which does not activate platelets. L. lactis SdrG was able to support platelet adhesion in the absence of fibrinogen, and to a greater extent in the presence of fibrinogen sug...
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C-reactive protein (CRP) is a well established marker for inflammation, and a good predictor of coronary heart disease. It is also known to interact with the platelet FcγRIIa and to enhance the inhibition of platelet aggregation by... more
C-reactive protein (CRP) is a well established marker for inflammation, and a good predictor of coronary heart disease. It is also known to interact with the platelet FcγRIIa and to enhance the inhibition of platelet aggregation by aspirin by an unknown mechanism. CRP has also recently been demonstrated to compete for PAC-1 binding in collagen stimulated platelets, suggesting that CRP interacts with GPIIb/IIIa. In order to study the mechanism of interaction with platelets directly, we carried out platelet adhesion assays. We coated plates with recombinant CRP which was in the native pentameric form as confirmed by size exclusion chromatography. Platelets adhered to immobilized CRP and to immobilized fibrinogen to a similar extent. Adhesion to CRP and fibrinogen was inhibited by GPIIb/IIIa antagonists but not by antibody to the FcγRIIa (IV.3). Platelet adhesion to CRP was increased 5-fold when platelets were treated with 1 mM MnCl2. Adhesion of MnCl2 treated platelets was also inhibi...
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Infective endocarditis (IE) is characterized by thrombus formation on a cardiac valve that can embolize to a distant site. Staphylococcus aureus is the most frequent causative organism of IE. Previously we showed that fibrinogen binding... more
Infective endocarditis (IE) is characterized by thrombus formation on a cardiac valve that can embolize to a distant site. Staphylococcus aureus is the most frequent causative organism of IE. Previously we showed that fibrinogen binding to the S. aureus surface protein Clumping Factor A (ClfA) plays an essential role in mediating platelet aggregation. In this study we investigate the role of ClfA in mediating thrombus formation under pathological shear conditions. Bacteria were coated onto flow chamber glass cover slips overnight at room temperature. Platelets in whole blood were stained with a lipophilic dye. Experiments were recorded in real time and visualized using fluorescence and bright-field microscopy. Platelets failed to interact with immobilized S. aureus at a shear rate of <500s−1 but rapidly formed a thrombus at shear rates greater than 800s−1. Deletion of the ClfA gene from the parent S. aureus strain (Newman) resulted in no thrombus formation at any shear rate. Plat...
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Background/Aims: The purpose of this study was to develop a neural network (NN) pharmacodynamic (PD) model that correlates the inhibition of ex vivo platelet aggregation by orbofiban, an oral GPIIb/IIIa antagonist, with the administered... more
Background/Aims: The purpose of this study was to develop a neural network (NN) pharmacodynamic (PD) model that correlates the inhibition of ex vivo platelet aggregation by orbofiban, an oral GPIIb/IIIa antagonist, with the administered dose and patient characteristics.Methods: Data were obtained from a Phase-II dose-finding study in patients presenting with acute coronary syndromes. A back-propagation NN was designed to predict
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Serotonin (5-HT) induces platelet aggregation by activating its 5-HT2A receptor. Platelet uptake is mediated by the 5-HT transporter (5-HTT). A common 5-HTT promoter (5-HTTLPR) splice variant results in long (L) and short (S) alleles.... more
Serotonin (5-HT) induces platelet aggregation by activating its 5-HT2A receptor. Platelet uptake is mediated by the 5-HT transporter (5-HTT). A common 5-HTT promoter (5-HTTLPR) splice variant results in long (L) and short (S) alleles. 5-HTTLPR genotype has been associated with increased platelet activation and risk of MI. Variation within HTR2A gene (C1354T) that encodes the 5-HT2A receptor has also been associated with enhanced platelet aggregation. We hypothesised that 5-HTT and/or HTR2A variation may influence platelet response to aspirin in patients with stable CAD. Patients (n=144) with stable cardiovascular disease taking aspirin were genotyped for the 5-HTTLPR and HTR2A variants. Platelet inhibition was assessed by serum thromboxane and arachidonic acid-induced platelet aggregation assay. 5-HTT genotype (LL vs *S) was a significant determinant of serum TX level (8.9±2.6ng/ml vs 6.0±1.6ng/ml respectively; p<0.02) and 5-HTT LL genotype predicted an incomplete aspirin respons...
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ABSTRACT Drug delivery to the central nervous system (CNS) remains a challenge due to the difficulty in facilitating drug transport across the blood-brain barrier (BBB). Various types of nanoparticle (NPs) have been investigated and shown... more
ABSTRACT Drug delivery to the central nervous system (CNS) remains a challenge due to the difficulty in facilitating drug transport across the blood-brain barrier (BBB). Various types of nanoparticle (NPs) have been investigated and shown to enhance drug delivery and targeting to various cells and tissues including the CNS [1]. The aim of this study was to investigate the potential of NPs of poly-lactide-co-glycolide (PLGA) modified with the cell penetrating peptide, octa-arginine (R8) to enhance drug delivery to the CNS. NPs containing coumarin-6 or loperamide were prepared using an emulsion solvent evaporation method [2] and were conjugated with R8 at increasing concentration of 2.5, 5 and 10μM. NPs formulated had an average size of 198 to 356nm. Both size and Zeta potential increased when R8 was conjugated to NP surface. NPs were incubated with MDCK cell monolayers, an in vitro BBB model, over 4 hours. R8-PLGA NPs showed enhanced cellular uptake and permeability across the monolayers compared to PLGA NPs as measured by flow cytometry, fluorimetry and confocal microscopy. When administered intranasally to an in vivo mouse model, delivery of loperamide to the brain was observed for the R8-PLGA NPS, as demonstrated by the increase in latency of the mice to jump or lick a hind paw when placed on the hot plate. The data from this study supports R8-PLGA NP as a potential drug delivery carrier to the brain.
ABSTRACT Both platelets and neutrophils play major roles in the pathology of ischaemic heart disease. Platelets are involved in the development of an occlusive thrombus, while neutrophils are implicated in the oxidative damage of... more
ABSTRACT Both platelets and neutrophils play major roles in the pathology of ischaemic heart disease. Platelets are involved in the development of an occlusive thrombus, while neutrophils are implicated in the oxidative damage of reperfusion injury. In both cases, integrins play key roles in these pathological processes: in the case of platelets, the fibrinogen receptor glycoprotein (GP) IIb/IIIa; and in the case of neutrophils the β2 integrins and αLRI β3 . In recent years, a number of potent GPIIb/IIIa antagonists have gone into clinical trials. The most advanced of these are monoclonal antibodies and peptide analogues of RGDS. These have shown benefit in preventing reocclusion after thrombolysis and percutaneous transluminal coronary angioplasty (PTCA), as well as in the treatment of unstable angina. A number of non-peptide intravenous and oral preparations are in early clinical trials. At present, there are no suitable antagonists for the β2 integrins, and these will be an interesting target for future drug discovery.
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Research Interests: Epidemiology, Drug interactions, Cardiovascular disease, Prevention, Platelet, and 15 moreHumans, Platelet aggregation, Platelets, Animals, Drug Resistance, Aspirin, Clinical Sciences, Prevalence, Acute Coronary Syndrome, Public health systems and services research, Cardiovascular Diseases, Primary Prevention, Platelet Aggregation Inhibitors, Cardiovascular medicine and haematology, and Pharmacology and pharmaceutical sciences
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Research Interests: Membrane Proteins, Molecular Microbiology, Western blotting, Biological Sciences, Molecular, and 9 moreHumans, Platelet aggregation, Staphylococcus aureus, Recombinant Proteins, Protein Binding, Lactococcus lactis, Staphylococcal protein A, Platelet Aggregation Inhibitors, and Medical and Health Sciences
The discovery of the pathogen-recognition receptors such as Toll-like receptors on platelets has led to the emergence of the idea of platelets as important components of the host response to infection. Escherichia coli -mediated sepsis is... more
The discovery of the pathogen-recognition receptors such as Toll-like receptors on platelets has led to the emergence of the idea of platelets as important components of the host response to infection. Escherichia coli -mediated sepsis is a serious illness characterised by the occurrence of thrombocytopenia. While there has been a wealth of research on Gram-positive bacteria-induced platelet activation, little is known about the mechanisms associated with Gram-negative bacteria. Here we endeavour to determine the mechanisms by which Gram-negative E. coli induce platelet aggregation. Induction of platelet aggregation with E. coli strain O157:H7 was tested using platelet-rich plasma (PRP), washed platelets and serum depleted of complement factors. Platelet inhibitors (to αII b β3 , GPIbα and FcγRIIa) were used. Platelet thromboxane synthesis was analysed after E. coli stimulation. Cell binding assays were used to assess the ability of E. coli to support platelet adhesion. Trypsinisation was used to observe the effects of cleaving E. coli surface proteins. E. coli-induced aggregation in PRP was donor-dependent. E. coli O157:H7 induced aggregation with a lagtime of 6.9±1.3 minutes in an integrin αII b β3 and FcγRIIa-dependent manner. Furthermore, this interaction was enhanced by the presence of complement and dependent on thromboxane synthesis. These results show E. coli to be a potent inducer of platelet aggregation. This article is protected by copyright. All rights reserved.
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Long-term treatment with oral glycoprotein (GP)IIb/IIIa antagonists has failed to produce significant clinical benefit. We have examined the pharmacology of xemilofiban in the evaluation of oral xemilofiban in controlling thrombotic... more
Long-term treatment with oral glycoprotein (GP)IIb/IIIa antagonists has failed to produce significant clinical benefit. We have examined the pharmacology of xemilofiban in the evaluation of oral xemilofiban in controlling thrombotic events (EXCITE) trial. The EXCITE trial was a multicenter study of xemilofiban in 7232 patients undergoing percutaneous coronary intervention. Thirty-two patients randomized to xemilofiban (10 or 20 mg three times daily) or placebo were followed for up to 6 months. GPIIb/IIIa receptor number and occupancy were quantified using two monoclonal antibodies mAb1 and mAb2. mAb1 was used to quantify receptor number. mAb2 recognizes an epitope that is lost due to a ligand-induced conformational change in GPIIb/IIIa and is a marker of receptor occupancy. Platelet aggregation was performed by light transmission. In vitro, the active metabolite of xemilofiban (SC-54701) inhibited mAb2 binding (IC(50) of 0.5 +/- 0.1 x 10(-8) M) but not mAb1. In vivo, long-term therapy with xemilofiban did not alter GPIIb/IIIa receptor number. mAb2 binding was inhibited throughout the treatment period and recovered slowly after drug withdrawal. Maximum inhibition of ADP-induced aggregation occurred at 4 to 7 h after the first dose of study medication. However, inhibition of platelet aggregation was low (between 24 and 45%) before dosing on days 60 and 180. There was no significant rebound increase in platelet aggregation after drug withdrawal. Long-term xemilofiban therapy does not alter platelet GPIIb/IIIa receptor number. Inhibition of platelet aggregation was poor at the end of each dosing interval and this may explain the failure of xemilofiban to alter clinical events.
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Solid-phase peptide synthesis is the archetypal example of combinatorial chemistry. Advances in amino acid synthesis allow unprecedented structural diversity using automated synthesis. In this chapter we briefly introduce the history and... more
Solid-phase peptide synthesis is the archetypal example of combinatorial chemistry. Advances in amino acid synthesis allow unprecedented structural diversity using automated synthesis. In this chapter we briefly introduce the history and advances in peptide synthesis and include strategies for peptidomimetic development. We highlight examples of the use of peptides in drug development, including pharmacophore extrapolation, substrate/ligand mimicry, and post-genomics target protein identification. We also describe methods for virtual combinatorial peptide construction, using databases of commercially available, non-natural amino acids, as well as strategies for high throughput virtual screening and de novo design of inhibitors. Finally, we offer suggestions for using peptide diversity for lead compound identification and optimisation, as well as a number of pitfalls in both peptide synthesis and virtual screening that need to be avoided. In this chapter we explore the effect solid p...
Solid-phase peptide synthesis is the archetypal example of combinatorial chemistry. Advances in amino acid synthesis allow unprecedented structural diversity using automated synthesis. In this chapter we briefly introduce the history and... more
Solid-phase peptide synthesis is the archetypal example of combinatorial chemistry. Advances in amino acid synthesis allow unprecedented structural diversity using automated synthesis. In this chapter we briefly introduce the history and advances in peptide synthesis and include strategies for peptidomimetic development. We highlight examples of the use of peptides in drug development, including pharmacophore extrapolation, substrate/ligand mimicry, and post-genomics target protein identification. We also describe methods for virtual combinatorial peptide construction, using databases of commercially available, non-natural amino acids, as well as strategies for high throughput virtual screening and de novo design of inhibitors. Finally, we offer suggestions for using peptide diversity for lead compound identification and optimisation, as well as a number of pitfalls in both peptide synthesis and virtual screening that need to be avoided.
Drug delivery to the central nervous system (CNS) remains a challenge due to the difficulty in facilitating drug transport across the blood-brain barrier (BBB). Various types of nanoparticle (NPs) have been investigated and shown to... more
Drug delivery to the central nervous system (CNS) remains a challenge due to the difficulty in facilitating drug transport across the blood-brain barrier (BBB). Various types of nanoparticle (NPs) have been investigated and shown to enhance drug delivery and targeting to various cells and tissues including the CNS [1]. The aim of this study was to investigate the potential of NPs of poly-lactide-co-glycolide (PLGA) modified with the cell penetrating peptide, octa-arginine (R8) to enhance drug delivery to the CNS. NPs containing coumarin-6 or loperamide were prepared using an emulsion solvent evaporation method [2] and were conjugated with R8 at increasing concentration of 2.5, 5 and 10μM. NPs formulated had an average size of 198 to 356nm. Both size and Zeta potential increased when R8 was conjugated to NP surface. NPs were incubated with MDCK cell monolayers, an in vitro BBB model, over 4 hours. R8-PLGA NPs showed enhanced cellular uptake and permeability across the monolayers comp...
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Due to their role in processes central to cancer and autoimmune disease I-domain integrins are an attractive drug target. Both antibodies and small molecule antagonists have been discovered and tested in the clinic. Much of the effort has... more
Due to their role in processes central to cancer and autoimmune disease I-domain integrins are an attractive drug target. Both antibodies and small molecule antagonists have been discovered and tested in the clinic. Much of the effort has focused on αLβ2 antagonists. Maybe the most successful was the monoclonal antibody efalizumab, which was approved for the treatment of psoriasis but subsequently withdrawn from the market due to the occurrence of a serious adverse effect (progressive multifocal leukoencephalopathy). Other monoclonal antibodies were tested for the treatment of reperfusion injury, post-myocardial infarction, but failed to progress due to lack of efficacy. New potent small molecule inhibitors of αv integrins are promising reagents for treating fibrotic disease. Small molecule inhibitors targeting collagen-binding integrins have been discovered and future work will focus on identifying molecules selectively targeting each of the collagen receptors and identifying appro...
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Long-term treatment with oral glycoprotein (GP)IIb/IIIa antagonists has failed to produce significant clinical benefit. We have examined the pharmacology of xemilofiban in the evaluation of oral xemilofiban in controlling thrombotic... more
Long-term treatment with oral glycoprotein (GP)IIb/IIIa antagonists has failed to produce significant clinical benefit. We have examined the pharmacology of xemilofiban in the evaluation of oral xemilofiban in controlling thrombotic events (EXCITE) trial. The EXCITE trial was a multicenter study of xemilofiban in 7232 patients undergoing percutaneous coronary intervention. Thirty-two patients randomized to xemilofiban (10 or 20 mg three times daily) or placebo were followed for up to 6 months. GPIIb/IIIa receptor number and occupancy were quantified using two monoclonal antibodies mAb1 and mAb2. mAb1 was used to quantify receptor number. mAb2 recognizes an epitope that is lost due to a ligand-induced conformational change in GPIIb/IIIa and is a marker of receptor occupancy. Platelet aggregation was performed by light transmission. In vitro, the active metabolite of xemilofiban (SC-54701) inhibited mAb2 binding (IC(50) of 0.5 +/- 0.1 x 10(-8) M) but not mAb1. In vivo, long-term thera...
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Pentamidine was previously shown to act on glycoprotein (GP) IIb/IIIa (Cox et al., Thromb Haemost 1992; 68: 731). In this paper we study the effect of pentamidine on other RGD-dependent receptors. In a cell adhesion assay, pentamidine was... more
Pentamidine was previously shown to act on glycoprotein (GP) IIb/IIIa (Cox et al., Thromb Haemost 1992; 68: 731). In this paper we study the effect of pentamidine on other RGD-dependent receptors. In a cell adhesion assay, pentamidine was 500 times more potent than RGDS at inhibiting platelet adhesion to fibrinogen. While RGDS inhibited platelet adhesion to fibronectin, endothelial cell adhesion to vitronectin or fibronectin, 293 cell adhesion to vitronectin, IMR 32 cell adhesion to fibronectin and C32 cell adhesion to vitronectin; pentamidine failed to inhibit these interactions at doses as high as 1 mM. Resting platelets fixed in the presence of 1 mM RGDS had increased binding of fibrinogen, i.e., RGDS activated GPIIb/IIIa, while pentamidine at 100 microM had no effect. Similarly, RGDS induced the binding of an anti-LIBS monoclonal antibody, while pentamidine had no effect. Pentamidine partially, but significantly, inhibited lysosome and alpha-granule release induced by the thromb...
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Platelets aggregate in response to an adhesin and the platelet aggregation-associated protein (PAAP) expressed on the cell surfaces of certain strains of Streptococcus sanguis. We sought to identify the corresponding PAAP receptor and... more
Platelets aggregate in response to an adhesin and the platelet aggregation-associated protein (PAAP) expressed on the cell surfaces of certain strains of Streptococcus sanguis. We sought to identify the corresponding PAAP receptor and accessory adhesin binding sites on platelets. Since the adhesion(s) of S. sanguis for platelets has not been characterized, an anti-idiotype (anti-id) murine monoclonal antibody (MAb2) strategy was developed. First, MAb1s that distinguished the adhesin and PAAP antigens on the surface of S. sanguis I 133-79 were selected. Fab fragments of MAb1.2 (immunoglobulin G2b [IgG2b]; 70 pmol) reacted with 5 x 10(7) cells of S. sanguis to completely inhibit the aggregation of human platelets in plasma. Under similar conditions, MAb1.1 (IgG1) inhibited the adhesion of S. sanguis cells to platelets by a maximum of 34%, with a comparatively small effect on platelet aggregation. Together, these two MAb1s inhibited S. sanguis-platelet adhesion by 63%. In Western immun...
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In this paper we show that the non-peptide anti-parasite agent pentamidine is a broad spectrum anti-platelet agent with an IC50 of 1.1 microM in ADP-induced platelet aggregation in human platelet rich plasma (PRP). It had similar activity... more
In this paper we show that the non-peptide anti-parasite agent pentamidine is a broad spectrum anti-platelet agent with an IC50 of 1.1 microM in ADP-induced platelet aggregation in human platelet rich plasma (PRP). It had similar activity when collagen, arachidonic acid, platelet activating factor, thrombin and epinephrine were used. It had no effect on platelet intracellular cAMP levels. It inhibited 125I-fibrinogen, 125I-fibronectin and 125I-von Willebrand factor binding to ADP-activated fixed platelets with IC50 values of 160, 160 and 60 nM respectively. Pentamidine showed a high degree of species selectivity with slightly less activity in monkey and dog PRP and little activity in guinea pig, rabbit, rat and mouse PRP compared with human. This was similar to the other RGD analogues tested. This species specificity was shown to be dependent on the species of platelets and independent of the species of fibrinogen. Thus, pentamidine is a potent non-peptide inhibitor of fibrinogen bi...