Journal articles on the topic 'In vitro antithrombotic properties'
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1
Vasconcelos, Ariana, Isabela Sucupira, Alessandra Guedes, Ismael Queiroz, Flavia Frattani, Roberto Fonseca, and Vitor Pomin. "Anticoagulant and Antithrombotic Properties of Three Structurally Correlated Sea Urchin Sulfated Glycans and Their Low-Molecular-Weight Derivatives." Marine Drugs 16, no. 9 (August 30, 2018): 304. http://dx.doi.org/10.3390/md16090304.
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The anticoagulant and antithrombotic properties of three structurally correlated sea urchin-derived 3-linked sulfated α-glycans and their low molecular-weight derivatives were screened comparatively through various in vitro and in vivo methods. These methods include activated partial thromboplastin time, the inhibitory activity of antithrombin over thrombin and factor Xa, venous antithrombosis, the inhibition of platelet aggregation, the activation of factor XII, and bleeding. While the 2-sulfated fucan from Strongylocentrotus franciscanus was observed to be poorly active in most assays, the 4-sulfated fucan from Lytechinus variegatus, the 2-sulfated galactan from Echinometra lucunter and their derivatives showed multiple effects. All marine compounds showed no capacity to activate factor XII and similar low bleeding tendencies regardless of the dose concentrations used to achieve the highest antithrombotic effect observed. The 2-sulfated galactan showed the best combination of results. Our work improves the background about the structure-function relationship of the marine sulfated glycans in anticoagulation and antithrombosis. Besides confirming the negative effect of the 2-sulfated fucose and the positive effect of the 2-sulfated galactose on anticoagulation in vitro, our results also demonstrate the importance of this set of structural requirements on antithrombosis in vivo, and further support the involvement of high-molecular weight and 4-sulfated fucose in both activities.
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Tsoupras, Alexandros, Ronan Lordan, Katie Shiels, Sushanta Saha, Constantina Nasopoulou, and Ioannis Zabetakis. "In Vitro Antithrombotic Properties of Salmon (Salmo salar) Phospholipids in a Novel Food-Grade Extract." Marine Drugs 17, no. 1 (January 18, 2019): 62. http://dx.doi.org/10.3390/md17010062.
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Marine and salmon polar lipids (PLs) extracted by conventional extractions with non-food-grade solvents (CE-salmon-PLs) possess antithrombotic bioactivities against platelet-activating factor (PAF) and thrombin. Similar effects of food-grade-extracted (FGE) marine PLs have not yet been reported. In this study, food-grade solvents were used to extract PLs from Irish organic farmed salmon (Salmo salar) fillets (FGE-salmon-PLs), while their antithrombotic bioactivities were assessed in human platelets induced by platelet aggregation agonists (PAF/thrombin). FGE-salmon-PLs were further separated by thin layer chromatography (TLC) into lipid subclasses, and the antithrombotic bioactivities of each subclass were also assessed. LC-MS was utilized to elucidate the structure-activity relationships. FGE-salmon-PLs strongly inhibited PAF-induced platelet aggregation, while their relevant anti-thrombin effects were at least three times more potent than the previously reported activities of CE-salmon-PLs. TLC-derived lipid fractions corresponding to phosphatidylcholines (PC) and phosphatidylethanolamines (PE) were the most bioactive lipid subclasses obtained, especially against thrombin. Their LC-MS analysis elucidated that they are diacyl- or alkyl-acyl- PC and PE moieties baring ω3 polyunsaturated fatty acids (PUFA) at their sn-2 position, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). Our results concerning the potent antithrombotic effects of FGE-salmon-PLs against both PAF and thrombin pathways strongly suggest that such food-grade extracts are putative candidates for the development of novel cardioprotective supplements and nutraceuticals.
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Merton, R. E., and D. P. Thomas. "Experimental Studies on the Relative Efficacy of Dermatan Sulphate and Heparin as Antithrombotic Agents." Thrombosis and Haemostasis 58, no. 03 (1987): 839–42. http://dx.doi.org/10.1055/s-0038-1646001.
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SummaryIn this study, the anticoagulant and antithrombotic properties of unfractionated heparin (UFH) and dermatan sulphate (DS) were compared. The ability of UFH and DS to impair thrombin generation in vitro and in ex vivo plasma samples was also studied. DS has minimal anticoagulant activity by conventional assays but impairs thrombin generation both in vitro and in ex vivo plasma samples. However, thrombin generation could not be suppressed below about 35% of control values at all doses of DS studied. While this was sufficient to impair experimental venous thrombosis during 10 minutes’ stasis, DS was ineffective in preventing thrombosis following 20 minutes’ stasis in doses up to 1.25 mg/kg. In contrast, 1 μg/ml of UFH completely suppressed thrombin generation in vitro, and 150 μg/kg prevented throm- bogenesis over a period of 20 minutes’ stasis. Neither drug prolonged the bleeding time (BT) at effective antithrombotic doses, but 2.5 mg/kg UFH significantly increased the BT, whereas DS did not. While DS has antithrombotic activity, it is less effective than UFH in inhibiting thrombin generation, and as an antithrombotic agent.
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Lordan, Ronan, Eoin O’Keeffe, Darren Dowling, Michael Mullally, Hannah Heffernan, Alexandros Tsoupras, and Ioannis Zabetakis. "The in vitro antithrombotic properties of ale, lager, and stout beers." Food Bioscience 28 (April 2019): 83–88. http://dx.doi.org/10.1016/j.fbio.2019.01.012.
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Nestele, Jeremy A., Anne-Katrin Rohlfing, Valerie Dicenta, Alexander Bild, Daniela Eißler, Frederic Emschermann, Marcel Kremser, et al. "Characterization of GPVI- or GPVI-CD39-Coated Nanoparticles and Their Impact on In Vitro Thrombus Formation." International Journal of Molecular Sciences 23, no. 1 (December 21, 2021): 11. http://dx.doi.org/10.3390/ijms23010011.
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Traditional antithrombotic agents commonly share a therapy-limiting side effect, as they increase the overall systemic bleeding risk. A novel approach for targeted antithrombotic therapy is nanoparticles. In other therapeutic fields, nanoparticles have enabled site-specific delivery with low levels of toxicity and side effects. Here, we paired nanotechnology with an established dimeric glycoprotein VI-Fc (GPVI-Fc) and a GPVI-CD39 fusion protein, thereby combining site-specific delivery and new antithrombotic drugs. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, NP-BSA, NP-GPVI and NP-GPVI-CD39 were characterized through electron microscopy, atomic force measurements and flow cytometry. Light transmission aggregometry enabled analysis of platelet aggregation. Thrombus formation was observed through flow chamber experiments. NP-GPVI and NP-GPVI-CD39 displayed a characteristic surface coating pattern. Fluorescence properties were identical amongst all samples. NP-GPVI and NP-GPVI-CD39 significantly impaired platelet aggregation. Thrombus formation was significantly impaired by NP-GPVI and was particularly impaired by NP-GPVI-CD39. The receptor-coated nanoparticles NP-GPVI and the bifunctional molecule NP-GPVI-CD39 demonstrated significant inhibition of in vitro thrombus formation. Consequently, the nanoparticle-mediated antithrombotic effect of GPVI-Fc, as well as GPVI-CD39, and an additive impact of CD39 was confirmed. In conclusion, NP-GPVI and NP-GPVI-CD39 may serve as a promising foundation for a novel therapeutic approach regarding targeted antithrombotic therapy.
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Chung, Amy, Frederick A. Ofosu, and Morris A. Blajchman. "The Antithrombotic Properties of Human Prothrombin Fragment 1.2 in Mice." Thrombosis and Haemostasis 63, no. 03 (1990): 413–16. http://dx.doi.org/10.1055/s-0038-1645057.
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SummaryWe have investigated the antithrombotic properties of prothrombin fragment 1.2 (F1.2) in this study. To do this, we established the minimum concentration of human placental tissue factor or human a-thrombin that was lethal in mice within 5 min after intravenous injection. Prothrombin F1.2 protected the mice from the lethal effect of tissue factor or α-thrombin in a dose dependent manner, with 500 μg (14 nmoles) of prothrombin F1.2 per mouse being the minimum amount required to protect all mice from the lethal effect of either thrombogenic stimulus. The minimum dose of heparin which protected mice from the lethal effect of thrombin or tissue factor was 6 units or ∼3.3 nmoles. The observation that prothrombin F1.2 has antithrombotic properties suggests prothrombin F1.2 can modulate coagulation in vivo, as it has previously been shown to do in vitro.
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Schwarz, Richard P., Jean-Claude P. Becker, R. Lynn Brooks, Marcie J. Hursting, James L. Joffrion, Gary D. Knappenberger, Timothy P. Kogan, Patricia W. Kogan, and Anthony A. McKinney. "State-of-the-Art Review: The Preclinical and Clinical Pharmacology of Novastan (Argatroban): A Small-Molecule, Direct Thrombin Inhibitor." Clinical and Applied Thrombosis/Hemostasis 3, no. 1 (January 1997): 1–15. http://dx.doi.org/10.1177/107602969700300101.
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Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have been focused on direct thrombin inhibitors, also known as site-directed thrombin inhibitors. The intravenous agent Novastan (argatroban) is a small-molecule, reversible, direct thrombin inhibitor that is selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant ef fects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose-response, and rapid restoration of the hemostatic systems to normal upon termination of intravenous infusion. Argatroban is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. It is in advanced clinical development in North America, South America, and Western Europe for several clinical indications, including (1) adjunctive therapy to thrombolytic agents in the treatment of acute myocardial infarction and (2) antithrombotic therapy for patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome. Key Words: Molecular properties—Novastan (argatroban)—Pharmacology—Thrombin inhibitor.
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Boulaftali, Yacine, Frédéric Adam, Laurence Venisse, Véronique Ollivier, Benjamin Richard, Sabrina Taieb, Denis Monard, et al. "Anticoagulant and antithrombotic properties of platelet protease nexin-1." Blood 115, no. 1 (January 7, 2010): 97–106. http://dx.doi.org/10.1182/blood-2009-04-217240.
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AbstractProtease nexin–1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma but is expressed by platelets. Here, we studied platelet PN-1 in resting and activated conditions and its function in thrombosis. Studies on human platelets from healthy donors and from patients with a Gray platelet syndrome demonstrate that PN-1 is present both at the platelet surface and in α-granules. The role of PN-1 was investigated in vitro using human platelets incubated with a blocking antibody and using platelets from PN-1–deficient mice. Both approaches indicate that platelet PN-1 is active on thrombin and urokinase-type plasminogen activator. Blockade and deficiency of platelet PN-1 result in accelerated and increased tissue factor-induced thrombin generation as indicated by calibrated automated thrombography. Moreover, platelets from PN-1–deficient mice respond to subthreshold doses of thrombin, as assessed by P-selectin expression and platelet aggregation. Thrombus formation, induced ex vivo by collagen in blood flow conditions and in vivo by FeCl3-induced injury, is significantly increased in PN-1–deficient mice, demonstrating the antithrombotic properties of platelet PN-1. Platelet PN-1 is thus a key player in the thrombotic process, whose negative regulatory role has been, up to now, markedly underestimated.
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Sie, P., D. Dupouy, C. Caranobe, M. Petitou, and B. Boneu. "Antithrombotic properties of a dermatan sulfate hexadecasaccharide fractionated by affinity for heparin cofactor II." Blood 81, no. 7 (April 1, 1993): 1771–77. http://dx.doi.org/10.1182/blood.v81.7.1771.1771.
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Abstract The relationship between the antithrombotic activity of dermatan sulfate (DS) in vivo and its catalytic effect on the inhibition of thrombin by heparin cofactor II (HC II) in vitro was investigated. DS was depolymerized by Smith degradation and the fragments obtained were separated by gel filtration. The fragment of minimal size with full catalytic activity was a hexadecasaccharide, which was further fractionated by affinity for immobilized HC II. Only a small proportion by weight (6.7%) was recovered in the high-affinity fraction, which had about 10 times more catalytic activity than the unfractionated oligosaccharide; the change in activity was primarily caused by the removal of inert materials, recovered in the low-affinity fraction. 1H- NMR spectra indicated strengthening of the signal given by Ido A (2S04) in the high-affinity fraction compared with that of the low-affinity fraction. The anticoagulant activity of the high-affinity fraction was exclusively HC II-dependent. The antithrombotic potency was evaluated in rabbits using the Wessler-thromboplastin model. Half-maximal prevention of thrombosis was obtained after injection of 250 micrograms/kg DS, of 500 micrograms/kg hexadecasaccharide, or of 60 micrograms/kg of its high-affinity fraction. The low-affinity fraction was ineffective at the highest dose tested (1,200 micrograms/kg) and did not potentiate the effect of the high-affinity fraction. These results show that the antithrombotic effect of DS is essentially dependent on HC II binding and activation and that HC II is therefore a suitable target for antithrombotic drugs.
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Sie, P., D. Dupouy, C. Caranobe, M. Petitou, and B. Boneu. "Antithrombotic properties of a dermatan sulfate hexadecasaccharide fractionated by affinity for heparin cofactor II." Blood 81, no. 7 (April 1, 1993): 1771–77. http://dx.doi.org/10.1182/blood.v81.7.1771.bloodjournal8171771.
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The relationship between the antithrombotic activity of dermatan sulfate (DS) in vivo and its catalytic effect on the inhibition of thrombin by heparin cofactor II (HC II) in vitro was investigated. DS was depolymerized by Smith degradation and the fragments obtained were separated by gel filtration. The fragment of minimal size with full catalytic activity was a hexadecasaccharide, which was further fractionated by affinity for immobilized HC II. Only a small proportion by weight (6.7%) was recovered in the high-affinity fraction, which had about 10 times more catalytic activity than the unfractionated oligosaccharide; the change in activity was primarily caused by the removal of inert materials, recovered in the low-affinity fraction. 1H- NMR spectra indicated strengthening of the signal given by Ido A (2S04) in the high-affinity fraction compared with that of the low-affinity fraction. The anticoagulant activity of the high-affinity fraction was exclusively HC II-dependent. The antithrombotic potency was evaluated in rabbits using the Wessler-thromboplastin model. Half-maximal prevention of thrombosis was obtained after injection of 250 micrograms/kg DS, of 500 micrograms/kg hexadecasaccharide, or of 60 micrograms/kg of its high-affinity fraction. The low-affinity fraction was ineffective at the highest dose tested (1,200 micrograms/kg) and did not potentiate the effect of the high-affinity fraction. These results show that the antithrombotic effect of DS is essentially dependent on HC II binding and activation and that HC II is therefore a suitable target for antithrombotic drugs.
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Zhang, Yafang, Cheng Ma, Linfeng He, Li Liao, Chaocheng Guo, Cheng Wang, Lihong Gong, et al. "Tetramethylpyrazine Protects Endothelial Injury and Antithrombosis via Antioxidant and Antiapoptosis in HUVECs and Zebrafish." Oxidative Medicine and Cellular Longevity 2022 (July 18, 2022): 1–14. http://dx.doi.org/10.1155/2022/2232365.
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Chuanxiong Rhizoma, the dried rhizome of Ligusticum chuanxiong Hort., is a commonly used drug for promoting blood circulation and dissipating congestion. Tetramethylpyrazine (TMP), the main active ingredient of Ligusticum chuanxiong, has significant antioxidant, anti-inflammatory, and vascular protective effects. However, the protective properties and underlying mechanisms of TMP against endothelial injury-induced insufficient angiogenesis and thrombosis have not been elucidated. Therefore, we aimed to explore the protective effects of TMP on endothelial injury and its antithrombotic effects and study the mechanism. In vitro experiments showed that TMP could alleviate hydrogen peroxide– (H2O2–) induced endothelial injury of human umbilical vein endothelial cells (HUVECs) and the protective mechanism might be related to the regulation of MAPK signaling pathway, and its antioxidative and antiapoptotic effects. In vivo experiments showed that TMP restored PTK787-induced damage to intersegmental vessels (ISVs) in Tg(fli-1: EGFP)y1 transgenic (Flik) zebrafish larvae. Similarly, adrenalin hydrochloride– (AH–) induced reactive oxygen species (ROS) production and thrombosis in AB strain zebrafish were inhibited by TMP. RT-qPCR assay proved that TMP could inhibit the expression of fga, fgb, fgg, f7, and von Willebrand factor (vWF) mRNA to exert an antithrombotic effect. Our findings suggest that TMP can contribute to endothelial injury protection and antithrombosis by modulating MAPK signaling and attenuating oxidative stress and antiapoptosis.
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Lordan, Ronan, Eoin O’Keeffe, Alexandros Tsoupras, and Ioannis Zabetakis. "Total, Neutral, and Polar Lipids of Brewing Ingredients, By-Products and Beer: Evaluation of Antithrombotic Activities." Foods 8, no. 5 (May 20, 2019): 171. http://dx.doi.org/10.3390/foods8050171.
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The in vitro antithrombotic properties of polar lipid constituents of malted grain (MG), pelleted hops (PH), brewer’s spent grain (BSG), spent hops (SH), wort, and bottled beer from the same production line were assessed in human platelets. The total lipids (TL) were extracted according to the Bligh and Dyer method and further separated into the total neutral lipids (TNL) and total polar lipids (TPL) extracts by counter-current distribution. The TL, TNL, and TPL extracts of all samples were assessed for their ability to inhibit platelet-activating factor (PAF) and thrombin-induced human platelet aggregation. The raw materials, by-products, wort, and beer lipid extracts all exhibited antithrombotic properties against PAF and thrombin. However, the beer TPL exhibited the lowest IC50 values against PAF-induced (7.8 ± 3.9 µg) and thrombin-induced (4.3 ± 3.0 µg) platelet aggregation indicating that these polar lipids were the most antithrombotic. The lipid extracts tended to be more bioactive against the thrombin pathway. The fatty acid content of all the TPL extracts were assessed using GC-MS. The fatty acid composition of the most bioactive TPL extracts, the wort and the beer, shared similar fatty acid profiles. Indeed, it was noted that fermentation seems to play a role in increasing the antithrombotic properties of polar lipids against PAF and thrombin by moderately altering the polar lipid fatty acid composition. Furthermore, the use of brewing by-products as a source of functional cardioprotective lipids warrants further investigation and valorisation.
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Tsantila, Nektaria, Haralabos C. Karantonis, Despina N. Perrea, Stamatios E. Theocharis, Dimitrios G. Iliopoulos, Smaragdi Antonopoulou, and Constantinos A. Demopoulos. "Antithrombotic and Antiatherosclerotic Properties of Olive Oil and Olive Pomace Polar Extracts in Rabbits." Mediators of Inflammation 2007 (2007): 1–11. http://dx.doi.org/10.1155/2007/36204.
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Olive oil polar lipid (OOPL) extract has been reported to inhibit atherosclerosis development on rabbits. Olive pomace polar lipid (PPL) extract inhibits PAF activity in vitro and the most potent antagonist has been identified as a glycerylether-sn-2-acetyl glycolipid with common structural characteristics with the respective potent antagonist of OOPL. The aim of this study was to investigate the effect of PPL on early atherosclerosis development on rabbits and to compare it with the antiatherosclerotic effect of OOPL. OOPL and PPL inhibition potency, towards both PAF action and PAF binding, was tested in vitro on washed rabbit platelets. Consequently, rabbits were divided into three groups (A, B, and C). All groups were fed atherogenic diet for 22 days. Atherogenic diets in groups B and C were enriched with OOPL and PPL, respectively. At the end of the experimental time, rabbits were euthanized and aortic samples were examined histopathologically. OOPL and PPL inhibited PAF-induced aggregation, as well as specific PAF binding, with PPL being more potent. Free and bound PAF levels and PAF-AH activity were significantly elevated at the end of the experimental time. Plasma total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides levels were also found increased. Groups B and C exhibited significantly increased values of EC50compared to group A. Histopathological examination revealed that the development of early atherosclerosis lesions in groups B and C were significantly inhibited compared to group A. Significant differences were noted in the early atherosclerosis lesions between groups B and C, thus indicating that PPL exhibit its anti-atherosclerotic activity by blocking PAF receptor. Specific PAF antagonists with similar in vitro and in vivo bioactivity to those that have been previously reported in OOPL exist in PPL.
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Antonopoulou, S., M. Detopoulou, E. Fragopoulou, T. Nomikos, M. Kontogianni, F. Petsini, and M. Choleva. "Antithrombotic properties of differently fed farmed gilthead sea bream: In vitro and in vivo studies." Atherosclerosis 331 (August 2021): e249-e250. http://dx.doi.org/10.1016/j.atherosclerosis.2021.06.763.
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Azzam, K., M. Cissé-Thiam, and L. Drouet. "The Antithrombotic Effect of Aurin Tricarboxylic Acid in the Guinea Pig Is not Solely due to Its Interaction with the von Willebrand Factor-GPIb Axis." Thrombosis and Haemostasis 75, no. 01 (1996): 203–10. http://dx.doi.org/10.1055/s-0038-1650243.
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SummaryCommercial aurin tricarboxylic acid (ATA) has been reported to interfere specifically with von Willebrand factor-glycoprotein lb (vWF-GPIb) axis. This study was designed to explore the antithrombotic effects of AT A by examining its effects on guinea pig platelet function in vitro, in vivo and ex vivo. In vitro, addition of various concentrations of ATA to platelet-rich guinea pig plasma totally inhibited ristocetin-induced platelet aggregation, as expected. Unexpectedly, however, ATA similarly inhibited the aggregation induced by ADP, PAF, collagen, I-BOP (a thromboxane A2/prostaglandin H2 analogue) and arachidonic acid.In vivo, the antithrombotic action of ATA was assessed in a model of acute platelet-dependent guinea pig mesenteric artery thrombosis triggered by laser-induced intimal injury. As the thrombotic response of arteries to such injury is a spontaneous cyclic recurrent process, 5 arteries in each animal were consecutively studied for 15 min each after i.v. bolus injection of 5, 7.5 or 10 mg/kg of ATA, which reduced the number of recurrent thrombi per artery in a dose-dependent manner. The highest dose of 10 mg/kg induced maximal inhibition of thrombus formation (72%, p <0.001) 5 min after injection.Ex vivo, platelet aggregation was assessed in blood samples taken before and after i.v. bolus injection of 10 or 15 mg/kg ATA. Ten mg/kg significantly inhibited collagen-induced aggregation, and 15 mg/kg, the aggregation induced by ristocetin, ADP, PAF, collagen, I-BOP and arachidonic acid.The results of the in vivo studies confirmed that ATA is an effective antithrombotic agent. In the in vitro and ex vivo studies, ristocetin-induced platelet aggregation confirmed that ATA interacts with the vWF-GPIb axis, and suggests that the final common pathway of the aggregation induced by other agents tested consists of fibrinogen binding to the platelet GPIIb/IIIa receptor. We conclude that ATA interferes with vWF binding to GPIb, that it may interact with fibrinogen binding to GPIIb/IIIa, and that it might possess potent antithrombotic properties in platelet-mediated thrombosis.
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Fareed, Jawed, D. Hoppensteadt, W. Haque, J. Diakur, W. Jeske, M. Florian-Kujawski, J. Maddineni, F. Baltasar, B. Neville, and J. M. Walenga. "Biochemical and Pharmacologic Profiling of a Novel Dual Acting Antithrombin Agent with Antiprotease and Antiplatelet Actions. Hematologic Implications." Blood 106, no. 11 (November 16, 2005): 1876. http://dx.doi.org/10.1182/blood.v106.11.1876.1876.
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Abstract Background: The pathogenesis of thrombosis involves both cellular and humoral processes. Most antithrombotic drugs exhibit either anti-protease or anti-platelet effects. A combination of anti-protease and anti-platelet drugs provides better efficacy in the management of thrombotic disorders. A series of synthetic low molecular weight serine protease inhibitors with varying anti-platelet effects (Medicure Inc.) are being assessed for antithrombotic properties. Materials and Methods: This investigation reports on a compound with low antithrombin/high anti-platelet activity MC 45301 (A) and a compound with high antithrombin/low anti-platelet activity MC 45308 (B) activity in in-vitro and in-vivo settings used to profile antithrombotic drugs. Results: A exhibited strong anti-platelet actions as measured using ADP as an agonist (IC50=1.1 g/ml), whereas B had a higher IC50 (9.4 g/ml). In the antithrombin titration assay A (>100 μg/ml) showed a relatively higher IC50 than B (45 μg/ml). In the global anticoagulant assays, A exhibited somewhat weaker effects than B. In the Xa generation assay, both compounds exhibited similar effects. However, in the thrombin generation assays B exhibited stronger effects. In whole blood assays both compounds produced anticoagulant and anti-platelet effects. Intravenous administration of these compounds to rabbits over a dose range of 50–500 g/kg produced strong dose dependent antithrombotic actions. In comparison to direct antithrombin agents such as argatroban, at a comparable dose, B produced identical antithrombotic actions, which were disproportional to the systemic anticoagulant effects. A produced modest antithrombotic actions with minimal ex vivo clotting effects. This data is highly suggestive that compounds with dual targets are able to produce stronger antithrombotic actions relative to monotherapeutic agents. Additional studies in arterial thrombosis may provide newer insights into the antithrombotic actions of compounds with dual sites of action. Moreover, these agents may be more effective in thrombotic conditions where both platelets and the coagulation system are involved.
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Fontayne, Alexandre, Muriel Meiring, Seb Lamprecht, Jan Roodt, Eddy Demarsin, Philippe Barbeaux, and Hans Deckmyn. "The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons." Thrombosis and Haemostasis 100, no. 10 (2008): 670–77. http://dx.doi.org/10.1160/th08-02-0073.
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SummaryThe Fab-fragment of 6B4, a murine monoclonal antibody targeting the human platelet glycoprotein (GP) Ibα and blocking the binding of von Willebrand factor (VWF), is a powerful antithrombotic. In baboons, this was without side effects such as bleeding or thrombocytopenia. Recently, we developed a fully recombinant and humanized version of 6B4-Fab-fragment, h6B4-Fab, which maintains its inhibitory capacities in vitro and ex vivo after injection in baboons. We here investigated the antithrombotic properties, the effect on bleeding time and blood loss and initial pharmacokinetics of h6B4-Fab in baboons. The antithrombotic effect of h6B4-Fab on acute platelet-mediated thrombosis was studied in baboons where thrombus formation is induced at an injured and stenosed site of the femoral artery, allowing for cyclic flow reductions (CFRs) which are measured on an extracorporeal femoral arteriovenous shunt. Injection of 0.5 mg/kg h6B4-Fab significantly reduced the CFRs by 80%, whereas two extra injections, resulting in cumulative doses of 1.5 and 2.5 mg/kg, completely inhibited the CFRs. Platelet receptor occupancy, plasma concentrations and effects ex vivo were consistent with what was previously observed. Finally, minimal effects on bleeding time and blood loss, no spontaneous bleeding and no thrombocytopenia were observed. We therefore conclude that h6B4-Fab maintains the antithrombotic capacities of the murine 6B4-Fab, without causing side effects and therefore can be used for further development.
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Nasopoulou, Constantina, Konstantina Lytoudi, and Ioannis Zabetakis. "Evaluation of Olive Pomace in the Production of Novel Broilers With Enhanced In Vitro Antithrombotic Properties." European Journal of Lipid Science and Technology 120, no. 4 (February 19, 2018): 1700290. http://dx.doi.org/10.1002/ejlt.201700290.
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Lin, Peichun, Suhua Chen, Min Liao, and Weimin Wang. "Physicochemical Characterization of Fucoidans from Sargassum henslowianum C.Agardh and Their Antithrombotic Activity In Vitro." Marine Drugs 20, no. 5 (April 28, 2022): 300. http://dx.doi.org/10.3390/md20050300.
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Sargassum fucoidan is a kind of sulfated heteropolysaccharide with a variety of biological activities. The aim of this study was to investigate the extraction, purification, physicochemical characterization and in vitro antithrombotic activity of fucoidan from Sargassum henslowianum C.Agardh. Hot-water-assisted ultrasound was used to extract fucoidan (F). Fucoidan was purified by DEAE cellulose 52 (F1), Vc-H2O2 (FD1) and Superdex 75 gel (FDS1). The physical and chemical properties of fucoidans were analyzed by chemical composition, monosaccharide composition, average molecular weight (Mw) and FTIR. The sulfate contents of F, F1, FD1 and FDS1 were 11.45%, 16.35% and 17.52%, 9.66%, respectively; the Mw was 5.677 × 105, 4.393 × 105, 2.176 × 104 and 6.166 × 103, respectively. The results of monosaccharide composition showed that the four fucoidans contained l-fucose, d-galactose, l-mannose, d-xylose, l-rhamnose and d-glucose, but the mass fraction ratio was different. The results of FTIR showed that fucoidan contained characteristic peaks of sugar and sulfate. In vitro, F1, FD1 and FDS1 could alleviate HUVEC damage induced by adrenaline (Adr). F1, FD1 and FDS1 decreased vWF and TF and increased the ratio of t-PA/PAI-1 in Adr-induced HUVEC.
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Morphis, Gregory, Aggeliki Kyriazopoulou, Constantina Nasopoulou, Eleni Sioriki, Constantinos Demopoulos, and Ioannis Zabetakis. "Assessment of the in Vitro Antithrombotic Properties of Sardine (Sardina pilchardus) Fillet Lipids and Cod Liver Oil." Fishes 1, no. 1 (September 28, 2015): 1–15. http://dx.doi.org/10.3390/fishes1010001.
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Herbert, J. M., J. P. Hérault, A. Bernat, R. G. M. van Amsterdam, J. C. Lormeau, M. Petitou, C. van Boeckel, P. Hoffmann, and D. G. Meuleman. "Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide." Blood 91, no. 11 (June 1, 1998): 4197–205. http://dx.doi.org/10.1182/blood.v91.11.4197.
Full textAbstract:
Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.
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Herbert, J. M., J. P. Hérault, A. Bernat, R. G. M. van Amsterdam, J. C. Lormeau, M. Petitou, C. van Boeckel, P. Hoffmann, and D. G. Meuleman. "Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide." Blood 91, no. 11 (June 1, 1998): 4197–205. http://dx.doi.org/10.1182/blood.v91.11.4197.411k09_4197_4205.
Full textAbstract:
SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.
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Brel, A. K., N. V. Atapina, Yu N. Budaeva, S. V. Lisina, S. S. Tsaruk, D. V. Kurkin, and I. N. Tyurenkov. "SYNTHESIS, ANTIAGGREGATION AND ANTITROMBOTIC ACTIVITIES OF NEW DERIVATIVES OF HYDROXYBENZOIC ACIDS WITH TAURIC FRAGMENT." Pharmacy & Pharmacology 9, no. 3 (August 19, 2021): 222–34. http://dx.doi.org/10.19163/2307-9266-2021-9-3-222-234.
Full textAbstract:
A high prevalence of thrombotic disorders, insufficient effectiveness or safety of antithrombotic therapy is an urgent problem of modern healthcare. The main means of preventing thrombosis is acetylsalicylic acid. Despite its long history, aspirin attracts researchers in the fields of medicinal chemistry, biology, and medicine. The development of new antiplatelet agents, including chemical modification of the acetylsalicylic acid molecule, remains relevant. Modification of the acetylsalicylic acid molecule using amino acids and obtaining their salt forms makes it possible to maintain antiplatelet or antithrombotic properties, as well as to impart additional pharmacodynamic effects. In modern science, a lot of attention is paid to the sulfur-containing amino acid taurine. An analysis of modern scientific literature revealed the protective effect of taurine in diabetes mellitus and cardiovascular diseases, liver dysfunction, gastrointestinal tract, and kidney diseases.The aim of the article is to study synthesis of new compounds, determination of their physical characteristics and assessment of their antiplatelet and antithrombotic activities in vitro and in vivo.Materials and methods. To confirm the structure of the synthesized new derivatives of hydroxybenzoic acids with a taurine fragment by the acelation method, thin layer chromatography and NMR spectra were used. In vitro studies were carried out on the model of ADP-induced platelet aggregation according to the Born G. methods modified by V.A. Gabbasov. In vivo, the studies were carried out on the model of arterial thrombosis induced by the application of iron chloride in the following groups of animals: intact, with experimental diabetes mellitus and three-year-olds; the rate of bleeding from the tail vein was also evaluated.Results. New compounds – derivatives of ortho-, meta- and para-hydroxybenzoic acids with a taurine residue – were synthesized. A procedure for the preparation of N-hydroxybenzoyl taurine compounds and their salt forms have been described; their spectral characteristics and melting points have been determined. The synthesized compounds are superior to acetylsalicylic acid in solubility and are not inferior to it in antiplatelet and antithrombotic activities. The results of the in vitro antiplatelet activity assessment in a wide concentration range from 10-4M to 10-8M, are presented. It has been revealed that the dipotassium salt of N-(2-hydroxybenzoyl)taurine exhibits a less antiplatelet activity than the dipotassium salt of N-(3-hydroxybenzoyl)taurine. The most pronounced antiplatelet activity is exhibited by the compound N-(4-hydroxybenzoyl)taurine. In in vivo experiments on the model of arterial thrombosis in 3-year-olds or animals with experimental diabetes mellitus, carotid artery thrombosis occurred faster than in young or intact animals. A single preliminary oral administration of the test compounds prolonged the time of the thrombus formation, which makes it possible to conclude that they have an antithrombotic effect. In this study, the dipotassium salt of N-(3-hydroxybenzoyl)taurine exhibits a more pronounced activity than that of acetylsalicylic acid.Conclusion. Against the background of the modeled pathologies, the studied drugs showed the expected antithrombotic activity, in terms of the severity not inferior to that found in acetylsalicylic acid.
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Irfan, Muhammad, Tae-Hyung Kwon, Dong-Ha Lee, Seung-Bok Hong, Jae-Wook Oh, Sung-Dae Kim, and Man Hee Rhee. "Antiplatelet and Antithrombotic Effects of Epimedium koreanum Nakai." Evidence-Based Complementary and Alternative Medicine 2021 (April 16, 2021): 1–11. http://dx.doi.org/10.1155/2021/7071987.
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Background and Objective. Epimedium koreanum Nakai is a medicinal plant known for its health beneficial effects on impotence, arrhythmia, oxidation, aging, osteoporosis, and cardiovascular diseases. However, there is no report available that shows its effects on platelet functions. Here, we elucidated antiplatelet and antithrombotic effects of ethyl acetate fraction of E. koreanum. Methodology. We analyzed the antiplatelet properties using standard in vitro and in vivo techniques, such as light transmission aggregometry, scanning electron microscopy, intracellular calcium mobilization measurement, dense granule secretion, and flow cytometry to assess integrin αIIbβ3 activation, clot retraction, and Western blot, on washed platelets. The antithrombotic effects of E. koreanum were assessed by arteriovenous- (AV-) shunt model in rats, and its effects on hemostasis were analyzed by tail bleeding assay in mice. Key Results. E. koreanum inhibited platelet aggregation in agonist-stimulated human and rat washed platelets, and it also reduced calcium mobilization, ATP secretion, and TXB2 formation. Fibrinogen binding, fibronectin adhesion, and clot retraction by attenuated integrin αIIbβ3-mediated inside-out and outside-in signaling were also decreased. Reduced phosphorylation of extracellular signal-regulated kinases (ERK), Akt, PLCγ2, and Src was observed. Moreover, the fraction inhibited thrombosis. HPLC results revealed that the fraction predominantly contained icariin. Conclusion and Implications. E. koreanum inhibited platelet aggregation and thrombus formation by attenuating calcium mobilization, ATP secretion, TXB2 formation, and integrin αIIbβ3 activation. Therefore, it may be considered as a potential candidate to treat and prevent platelet-related cardiovascular disorders.
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Pavan, Rajendra, Sapna Jain, Shraddha, and Ajay Kumar. "Properties and Therapeutic Application of Bromelain: A Review." Biotechnology Research International 2012 (December 10, 2012): 1–6. http://dx.doi.org/10.1155/2012/976203.
Full textAbstract:
Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple. Fruit bromelain and stem bromelainare prepared differently and they contain different enzymatic composition. “Bromelain” refers usually to the “stem bromelain.” Bromelain is a mixture of different thiol endopeptidases and other components like phosphatase, glucosidase, peroxidase, cellulase, escharase, and several protease inhibitors. In vitro and in vivo studies demonstrate that bromelain exhibits various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities. Bromelain is considerably absorbable in the body without losing its proteolytic activity and without producing any major side effects. Bromelain accounts for many therapeutic benefits like the treatment of angina pectoris, bronchitis, sinusitis, surgical trauma, and thrombophlebitis, debridement of wounds, and enhanced absorption of drugs, particularly antibiotics. It also relieves osteoarthritis, diarrhea, and various cardiovascular disorders. Bromelain also possesses some anticancerous activities and promotes apoptotic cell death. This paper reviews the important properties and therapeutic applications of bromelain, along with the possible mode of action.
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Renda, Giulia, Bianca Rocca, Roberto Crocchiolo, Raimondo De Cristofaro, and Raffaele Landolfi. "Effect of fibrinogen concentration and platelet count on the inhibitory effect of abciximab and tirofiban." Thrombosis and Haemostasis 89, no. 02 (2003): 348–54. http://dx.doi.org/10.1055/s-0037-1613452.
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SummaryGlycoprotein (Gp) IIb/IIIa blockers are powerful antithrombotic agents, but display a wide variability of their effect using weight-adjusted dosing. We investigated whether some hemostatic variables affected in vitro platelet inhibition exerted by the antibody abciximab and the peptidomimetic tirofiban. High fibrinogen concentrations reduced platelet inhibition by tirofiban, assessed in whole blood (r = –0.85, n = 10, p <0.01) and in platelet rich plasma (r = –0.89, n = 10, p <0.01) through PFA 100 and Born’s aggregometry assay, respectively. Both drugs were unaffected by von Willebrand factor levels, while platelet count was inversely related to their inhibitory effect (tirofiban: r = –0.9, n = 7, p <0.01; abciximab: r = –0.81, n = 9, p <0.01). Analysis of GpIIb-IIIa blockade showed that receptor occupancy at a fixed abciximab dose was inversely related to platelet counts. These experimental data were in agreement with the classical model of receptor saturation by a tight binding inhibitor.A role for fibrinogen and/or platelet count in influencing the antithrombotic properties of platelet GpIIb-IIIa antagonists can be hypothesized.
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Mohd Nor, Nurul Huda, Fauziah Othman, Eusni Rahayu Mohd Tohit, and Sabariah Md Noor. "Medicinal Herbals with Antiplatelet Properties Benefit in Coronary Atherothrombotic Diseases." Thrombosis 2016 (March 14, 2016): 1–7. http://dx.doi.org/10.1155/2016/5952910.
Full textAbstract:
Coronary atherothrombotic diseases such as coronary artery disease, peripheral vascular disease, cerebrovascular disease, and heart failure are the serious concerns of the thrombus formed in blood vessels. Anticoagulant and antiplatelet drugs are the cornerstones of the management of these diseases. To prevent the recurrence of these diseases, double antiplatelet drugs such as aspirin and clopidogrel has been the standard management in most hospitals. However, aspirin resistance and clopidogrel inefficient effects due to noncompliance with double drugs regimen can cause a sinister effect on patients. Medicinal plants serve as a greater resource for new medication and their potential currently became a topic of interest to the researchers all over the world. Traditionally, certain herbs have been used as a treatment for heart diseases but have been investigated for their antiplatelet properties. This current review explained few traditional antithrombotic herbals and their antiplatelet properties in vitro and in vivo and this is to be deeply discussed in further research.
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Ofosu, F. A., G. J. Modi, M. A. Blajchman, M. R. Buchanan, and E. A. Johnson. "Increased sulphation improves the anticoagulant activities of heparan sulphate and dermatan sulphate." Biochemical Journal 248, no. 3 (December 15, 1987): 889–96. http://dx.doi.org/10.1042/bj2480889.
Full textAbstract:
Heparan sulphate and dermatan sulphate have both antithrombotic and anticoagulant properties. These are, however, significantly weaker than those of a comparable amount of standard pig mucosal heparin. Antithrombotic and anticoagulant effects of glycosaminoglycans depend on their ability to catalyse the inhibition of thrombin and/or to inhibit the activation of prothrombin. Since heparan sulphate and dermatan sulphate are less sulphated than unfractionated heparin, we investigated whether the decreased sulphation contributes to the lower antithrombotic and anticoagulant activities compared with standard heparin. To do this, we compared the anticoagulant activities of heparan sulphate and dermatan sulphate with those of their derivatives resulphated in vitro. The ratio of sulphate to carboxylate in these resulphated heparan sulphate and dermatan sulphate derivatives was approximately twice that of the parent compounds and similar to that of standard heparin. Anticoagulant effects were assessed by determining (a) the catalytic effects of each glycosaminoglycan on the inhibition of thrombin added to plasma, and (b) the ability of each glycosaminoglycan to inhibit the activation of 125I-prothrombin in plasma. The least sulphated glycosaminoglycans were least able to catalyse the inhibition of thrombin added to plasma and to inhibit the activation of prothrombin. Furthermore, increasing the degree of sulphation improved the catalytic effects of glycosaminoglycans on the inhibition of thrombin by heparin cofactor II in plasma. The degree of sulphation therefore appears to be an important functional property that contributes significantly to the anticoagulant effects of the two glycosaminoglycans.
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Bhargavi Ram, Thimmiah, Chien Chien Belinda Tang, Siaw Fui Kiew, Sie Yon Lau, Gobi Gobi, Jeevanandam Jaison, and Michael K. Danquah. "Nanoformulation of Peptides for Pharmaceutical Applications: In Vitro and In Vivo Perspectives." Applied Sciences 12, no. 24 (December 13, 2022): 12777. http://dx.doi.org/10.3390/app122412777.
Full textAbstract:
Peptides are short sequences of proteins consisting of two or more amino acids that are linked by peptide bonds. Peptide-based designs and drug deliveries can offer several advantages, such as antioxidant, antimicrobial, antihypertensive activities, along with immunomodulatory and antithrombotic properties, with hormone or drug-like potential. Peptide-based therapeutic formulations are used as drug candidates for the treatment of various diseases. However, there are several concerns associated with the efficacy of peptides in pharmaceutical design and delivery, including rapid degradation, limited solubility, and poor permeability. The nanoformulation of peptides has been identified as a promising approach for improving the stability of peptides and providing metabolic stability and bioavailability. This article provides an overview of the advances in the development of peptides for drug design and formulation applications. It discusses various peptide nanoformulation approaches as well as recent developments in the in vitro and in vivo analyses of nanoformulated peptides for pharmaceutical applications.
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MANSO, M. A., C. ESCUDERO, M. ALIJO, and R. LÓPEZ-FANDIÑO. "Platelet Aggregation Inhibitory Activity of Bovine, Ovine, and Caprine κ-Casein Macropeptides and Their Tryptic Hydrolysates." Journal of Food Protection 65, no. 12 (December 1, 2002): 1992–96. http://dx.doi.org/10.4315/0362-028x-65.12.1992.
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κ-Casein macropeptide (CMP) is one of the components of whey and is obtained as a by-product in cheesemaking. There has been increasing interest in research to find new uses of cheese industry by-products in order to improve their value and promote their use. Human platelet aggregation inhibitory activities of bovine, ovine, and caprine CMPs and their tryptic hydrolysates were studied. CMPs from the three species exhibited in vitro antithrombotic properties similar to the activity of the γ-fibrinogen 400–411 peptide. Inhibitory activities increased following hydrolysis with trypsin. Active sequences were identified among the tryptic peptides by reversed-phase high-performance liquid chromatography with on-line mass spectrometry.
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Hernáez, Álvaro, Sara Jaramillo, Aránzazu García-Borrego, Juan Antonio Espejo-Calvo, María-Isabel Covas, Gemma Blanchart, Rafael de la Torre, et al. "From Green Technology to Functional Olive Oils: Assessing the Best Combination of Olive Tree-Related Extracts with Complementary Bioactivities." Antioxidants 10, no. 2 (January 30, 2021): 202. http://dx.doi.org/10.3390/antiox10020202.
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Our aim was to assess the combination of olive tree-related extracts with the most favorable profile of in vitro bioactive properties. We tested the antioxidant (increment of low-density lipoprotein resistance against oxidation), vasoactive (promotion of nitric oxide release and decrease of endothelin-1 production in human umbilical vein endothelial cells), anti-inflammatory (decrease of the endothelial production of vascular cell adhesion molecule-1), and antithrombotic (reduction of the endothelial release of plasminogen activator inhibitor-1) capacities of six phenolic extracts and three triterpenic acid solutions (Ps and Ts, respectively). We tested extracts alone and in combination, at nutritional (Ps: 0.05–0.5 μmol/L; Ts: 0.001–0.1 μmol/L) and nutraceutical doses (Ps: 1–10 μmol/L; Ts: 0.25–10 μmol/L). The combination of Ps rich in 3,4-dihydroxyphenylglycol (76%, P2), hydroxytyrosol (95%, P3), and oleuropein (70%, P4) (final nutritional concentration: 0.15 μmol/L; final nutraceutical concentration: 3 μmol/L) was the best in order to prepare functional products and nutraceuticals with cardioprotective properties, despite the fact that the isolated extract with the greatest in vitro properties was P5 (75% oleocanthal), suggesting a potential synergistic effect among different olive components.
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Winzely, Maximilian, Annukka Jouppila, Georg Ramer, Laurin Lux, Bernhard Lendl, Karina Barreiro, Riitta Lassila, and Gernot Friedbacher. "AFM investigation of APAC (antiplatelet and anticoagulant heparin proteoglycan)." Analytical and Bioanalytical Chemistry 414, no. 2 (November 13, 2021): 1029–38. http://dx.doi.org/10.1007/s00216-021-03765-y.
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Abstract Antiplatelet and anticoagulant drugs are classified antithrombotic agents with the purpose to reduce blood clot formation. For a successful treatment of many known complex cardiovascular diseases driven by platelet and/or coagulation activity, the need of more than one antithrombotic agent is inevitable. However, combining drugs with different mechanisms of action enhances risk of bleeding. Dual anticoagulant and antiplatelet (APAC), a novel semisynthetic antithrombotic molecule, provides both anticoagulant and antiplatelet properties in preclinical studies. APAC is entering clinical studies with this new exciting approach to manage cardiovascular diseases. For a better understanding of the biological function of APAC, comprehensive knowledge of its structure is essential. In this study, atomic force microscopy (AFM) was used to characterize APAC according to its structure and to investigate the molecular interaction of APAC with von Willebrand factor (VWF), since specific binding of APAC to VWF could reduce platelet accumulation at vascular injury sites. By the optimization of drop-casting experiments, we were able to determine the volume of an individual APAC molecule at around 600 nm3, and confirm that APAC forms multimers, especially dimers and trimers under the experimental conditions. By studying the drop-casting behavior of APAC and VWF individually, we depictured their interaction by using an indirect approach. Moreover, in vitro and in vivo conducted experiments in pigs supported the AFM results further. Finally, the successful adsorption of APAC to a flat gold surface was confirmed by using photothermal-induced resonance, whereby attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) served as a reference method. Graphical abstract
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Cirillo, Rocco, Annalisa Lippi, Alessandro Subissi, Giancarlo Agnelli, and Marco Criscuoli. "Experimental Pharmacology of Hirunorm: a Novel Synthetic Peptide Thrombin Inhibitor." Thrombosis and Haemostasis 76, no. 03 (1996): 384–92. http://dx.doi.org/10.1055/s-0038-1650588.
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SummaryEnhanced thrombin activity has been associated with coronary thrombosis and with acute and long-term complications following coronary balloon angioplasty. Blocking thrombin activity with specific inhibitors is proposed as a promising antithrombotic therapy. We describe the anticoagulant and antithrombotic properties of hirunorm, a novel synthetic 26-aminoacid peptide thrombin inhibitor, in comparison with r-hirudin and hirulog-1. Hirunorm was equipotent to hirulog-1 and 1/30 as potent as r-hirudin in blocking a-thrombin amidolytic activity (IC50 = 10 ± 2,15 ± 1 and 0.3 ± 0.1 nM, respectively), but it did not affect trypsin, plasmin and t-PA activities at 10 μM. All the compounds inhibited clot-bound thrombin to clots prepared by thrombin hydrolysis of purified fibrinogen in buffer. Hirunorm and hirulog-1 showed similar species-dependent potency in doubling basal in vitro clotting times of human, rat and rabbit plasma (EC200 varied 70 to 200 nM for TT, 0.7 to 16 μM for aPTT and 0.8 to 17 μM for PT), while r-hirudin was always at least three times more active. When assayed by HPLC or by bioassay of the intact peptide, hirunorm was stable against a-thrombin and plasma hydrolases, but it was catabolized by rat liver and kidney enzymes. Venous thrombosis was produced in anaesthetized rats by vena cava ligation following a procoagulant serum injection. Intravenous and subcutaneous hirunorm inhibited venous thrombosis at doses (≤0.3 mg/kg) two-three times higher than those of r-hirudin. Hirulog-1 was as active as hirunorm only after i. v. infusion. Arterial thrombosis was obtained in the anaesthetized rat by chemical (FeCl2) stimulation of a common carotid and i.v. infused hirunorm (1-3 mg/kg/30 min) inhibited it dose-dependently; r-hirudin was partly active only at 3 mg/kg, but hirulog-1 was inactive at either dose. Full antithrombotic doses of hirunorm did not affect the bleeding time as measured from punctured mesenteric vessels, in anaesthetized rats. In conclusion, hirunorm is a potent peptide thrombin inhibitor endowed with antithrombotic activity in models of venous and arterial thrombosis.
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Cao, Sujian, Xiaoxi He, Ling Qin, Meijia He, Yajing Yang, Zhichun Liu, and Wenjun Mao. "Anticoagulant and Antithrombotic Properties in Vitro and in Vivo of a Novel Sulfated Polysaccharide from Marine Green Alga Monostroma nitidum." Marine Drugs 17, no. 4 (April 25, 2019): 247. http://dx.doi.org/10.3390/md17040247.
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Sulfated polysaccharides from marine algae have high potential as promising candidates for marine drug development. In this study, a homogeneous sulfated polysaccharide from the marine green alga Monostroma nitidum, designated MS-1, was isolated using water extraction and anion-exchange and size-exclusion chromatography. Results of chemical and spectroscopic analyses showed that MS-1 mainly consisted of →3)-α-l-Rhap-(1→ and →2)-α-l-Rhap-(1→ residues, with additional branches consisting of 4-linked β-d-xylose, 4-/6-linked d-glucose, terminal β-d-glucuronic acid, and 3-/2-linked α-l-rhamnose. Sulfate ester groups substituted mainly at C-2/C-4 of →3)-α-l-Rhap-(1→ and C-4 of →2)-α-l-Rhap-(1→ residues, slightly at C-2 of terminal β-d-glucuronic residues. MS-1 exhibited strong anticoagulant activity in vitro and in vivo as evaluated by the activated partial thromboplastin time and thrombin time assays, and significantly decreased platelet aggregation. The anticoagulant activity mechanism of MS-1 was mainly attributed to strong potentiation thrombin by heparin cofactor-II, and it also hastened thrombin and coagulation factor Xa inhibitions by potentiating antithrombin-III. MS-1 possessed markedly thrombolytic activity evaluated by plasminogen activator inhibitior-1, fibrin degradation products, and D-dimer levels using rats plasma, and recanalization rate by FeCl3-induced carotid artery thrombosis in mice. MS-1 exhibited strong antithrombotic activity in vitro and in vivo evaluated by the wet weighs and lengths of thrombus, and thrombus occlusion time by electrically-induced carotid artery thrombosis in rats. These results suggested that MS-1 could be a promising marine drug for prevention and therapy of thromboembolic disease.
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Violi, Francesco, Daniele Pastori, Pasquale Pignatelli, and Roberto Carnevale. "Nutrition, Thrombosis, and Cardiovascular Disease." Circulation Research 126, no. 10 (May 8, 2020): 1415–42. http://dx.doi.org/10.1161/circresaha.120.315892.
Full textAbstract:
Previous studies reported an inverse association between healthy dietary patterns (such as Mediterranean diet) and the incidence of cardiovascular events. As the mechanism accounting for cardiovascular disease is prevalently due to the atherothrombosis, where a pivotal role is played by platelet activation, it would be arguable that diets with protective effects against cardiovascular disease exert an anti-atherothrombotic effect via inhibition of platelet activation. There are several and sparse typologies of studies, which investigated if single nutrients by diets recognized as having cardiovascular protection may exert an antithrombotic effect. The most investigated nutrients are key components of the Mediterranean diets such as fruits and vegetables, fish, olive oil, and wine; other diets with protective effects include nuts and cocoa. Here we summarize experimental and human interventional studies which investigated the antithrombotic effects of such nutrients in experimental models of thrombosis or analyzed biomarkers of clotting, platelet, and fibrinolysis activation in human; furthermore in vitro studies explored the underlying mechanism at level of several cell lines such as platelets or endothelial cells. In this context, we analyzed if nutrients affect simultaneously or separately clotting, platelet, and fibrinolysis pathways giving special attention to the relationship between oxidative stress and thrombosis as most nutrients are believed to possess antioxidant properties.
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Suzuki, Koji, and Masahiro Terasawa. "Biological Activities of Rhamnan Sulfate Extract from the Green Algae Monostroma nitidum (Hitoegusa)." Marine Drugs 18, no. 4 (April 24, 2020): 228. http://dx.doi.org/10.3390/md18040228.
Full textAbstract:
Monostroma nitidum is a green single-cell layered algae that grows on the southwest coast of Japan. It is often used for salad ingredients, boiled tsukudani, soups, etc., due to its health benefits. M. nitidum is composed of many cell aggregates, and the various substances that fill the intercellular space are dietary fibers, vitamins, and minerals. Rhamnan sulfate (RS), a sulfated polysaccharide, is main the component of the fiber extracted from M. nitidum. Recently, some biological properties of RS have been demonstrated by in vitro and in vivo studies that probably protect human subjects from viruses and ameliorate vascular dysfunction caused by metabolic disorders, especially lifestyle-related diseases. In this review, we focus on the antithrombotic effects of RS and introduce its antiviral and other biological activities.
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Mason, Emily, Lamia L’Hocine, Allaoua Achouri, Mélanie Pitre, and Salwa Karboune. "Health Promoting Bioactive Properties of Novel Hairless Canary Seed Flour after In Vitro Gastrointestinal Digestion." Foods 9, no. 7 (July 14, 2020): 932. http://dx.doi.org/10.3390/foods9070932.
Full textAbstract:
The bioactive properties and health-promoting effects of two novel yellow (C09052, C05041) and two brown (Calvi, Bastia) hairless canary seed (Phalaris canariensis L.) cultivars were investigated in comparison to two common cereal grains (wheat and oat). The cereal flours were digested using the standardized INFOGEST in vitro human gastrointestinal digestion model. The three-kilo dalton molecular weight cutoff (3 kDa MWCO) permeate of the generated digestates was assessed in vitro for their antioxidant, chelating, antihypertensive and antidiabetic activities. The results showed no significant differences in studied bioactivities between yellow and brown canary seed cultivars, except for antioxidant activity by the DPPH and chelating Fe2+ assays, where brown cultivars had higher activities. Canary seeds had superior or equivalent antioxidant activity than those from oat and wheat. The anti-hypertensive activity (Angiotensin-converting enzyme (ACE) inhibition) in yellow canary seed cultivars was significantly higher than that of oat and wheat, particularly for C09052 and Calvi varieties. Peptides exhibiting the highest antihypertensive activity from the permeate of the C09052 canary seed variety were further fractionated and identified by mass spectrometry. Forty-six peptides were identified belonging to 18 proteins from the Pooideae subfamily. Fourteen of the parent proteins were homologous to barley proteins. Peptides were analyzed in silico to determine potential bioactivity based on their amino acid composition. All 46 peptides had potential anti-hypertensive and anti-diabetic activities and 20 had potential antioxidant activity, thereby validating the in vitro assay data. Canary seed peptides also exhibited potential antiamnestic, antithrombotic, immunostimulating, opioid and neuro-activity, demonstrating important potential for health promoting effects, particularly against cardiovascular disease.
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Spasov, Alexander A., Aida F. Kucheryavenko, Ksenia A. Gaidukova, Maxim V. Chernikov, and Olga N. Zhukovskaya. "ANTITROMBOTIC ACTIVITY OF A NEW BENZIMIDAZOLE DERIVATIVE WITH A SPATIALLY DIFFICULT PHENOLIC SUBSTITUTE IN ITS STRUCTURE." Pharmacy & Pharmacology 8, no. 2 (October 14, 2020): 78–85. http://dx.doi.org/10.19163/2307-9266-2020-8-2-78-85.
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The aim of the study was to investigate antithrombogenic properties of compound RU-1144 with previously identified pronounced antiplatelet and antioxidant activities. The thrombosis induced by Ferric chloride (FeCl3) was carried out in rats’ carotid artery, in comparison with the known antiaggregant drugs - acetylsalicylic acid (ASA) and clopidogrel, as well as with the antioxidant preparation - ethylmethylhydroxypyridine succinate (EMHPS).Materials and methods. The antithrombotic activity of compound RU-1144 was studied on the model of the rats with carotid artery thrombosis, induced by the application of 50% ferric chloride (FeCl3), and the Global Thrombosis Test model (the Görög Thrombosis Test). The evaluation of this type of activity was carried out by prolonging the time of a blood clot formation. The studies of the compound RU-1144 effect on the bleeding time parameter were performed in mice. Acetylsalicylic acid, clopidogrel and EMHPS were used as reference drugs.Results. The antithrombotic effect of the RU-1144 substance revealed in the model of arterial thrombosis induced by the application of ferric chloride (FeCl3), exceeded that of both acetylsalicylic acid and clopidogrel by 3.5 times and that of EMHPS by 2.9 times. In the model of the in vitro Global Thrombosis Test (the Görög Thrombosis Test), compound RU-1144 reduced the thrombogenic potential of the blood equally with acetylsalicylic acid and clopidogrel. The assessment of “the bleeding time”, caused by the RU-1144 substance, showed that the prolongation of bleeding was twice as less pronounced than that caused by ASA and clopidogrel.Conclusion. The performed studies demonstrated a pronounced antithrombotic activity of compound RU-1144, which exceeded that of acetylsalicylic acid, clopidogrel and EMHPS, while the ability to prolong the bleeding time was reliably lower than that of reference drugs.Abbreviations: EMHPS-ethylmethylhydroxypyridine succinate; ASA - acetylsalicylic acid.
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Kumar, Sandeep, Rewati Raman, Satyendra Rathore, Reenesh Jaiswal, and Suruchi Prasad. "Study the Effects of Standardized Dolichos biflorus Seed Extract and Standardized Pterocarpus marsupium Bark Extract in Blood Coagulation." International Journal of Medical & Pharmaceutical Sciences 12, no. 07 (2022): 01–04. http://dx.doi.org/10.31782/ijmps.2022.12701.
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In this study, the antithrombotic activity [antiplatelet, activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) assays] of standardized Dolichos biflorus seed extract (DBSE) and standardized Pterocarpus marsupium bark extract (PMBE) was determined. The study investigated the anticoagulant activities in vitro by performing activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) assays. Antiplatelet aggregation activity of the extract was examined using adenosine diphosphate (ADP), collagen, and thrombin as agonists, and the inhibitions of factor Xa and thrombin were also investigated. Bleeding and clotting times in mice were used to determine its anticoagulant activities in vivo. This study is the first to show that DBSE and PMBE possess anticoagulant properties, most likely as a result of its capacity to block thrombin activity. DBSE and PMBE could be thrombin inhibitors with anticoagulant therapeutic properties. However, when compared to positive control medications like heparin, argatroban, and dabigatran etexilate, DBSE’s and PMBE’s anticoagulant action is lesser.
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Fan, Mei, Fei Zhao, Shanshan Peng, Qianfei Dai, Yuan Liu, Sheng Yin, and Zongkui Zhang. "Biocompatibility of Zinc Matrix Biodegradable Composites Reinforced by Graphene Nanosheets." Materials 15, no. 18 (September 19, 2022): 6481. http://dx.doi.org/10.3390/ma15186481.
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As a new type of biodegradable implant material, zinc matrix composites have excellent potential in the application of biodegradable implants because of their better corrosion resistance than magnesium matrix materials. Our previous studies have shown that graphene nanosheet reinforced zinc matrix composites (Zn-GNS) prepared by spark plasma sintering (SPS) have good mechanical properties and suitable degradation rate. However, the biocompatibility of zinc matrix composites is still a problem of concern. The cytocompatibility and blood compatibility of pure zinc and Zn-GNS composites in vitro were studied. The results showed that Zn-GNS composites had acceptable toxicity to MG-63 human osteosarcoma cells. In addition, the hemolysis rate of pure zinc and its composites were less than 3%, which has no adverse effect on adhered platelets, and has good antithrombotic and antiadhesion platelets properties. In conclusion, the addition of GNS did not adversely affect the biocompatibility of Zn-GNS composites, which indicated that Zn-GNS composites are a promising candidate for bone implantation.
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Chen, Jing, Zhuo Wang, Xuejing Jia, Rui Li, Jianping Chen, Xiaofei Liu, Bingbing Song, Saiyi Zhong, and Yi Qi. "Anticoagulant and Fibrinolytic Properties of Two Heparinoid Compounds Prepared from Shrimp Waste." Foods 12, no. 1 (December 23, 2022): 66. http://dx.doi.org/10.3390/foods12010066.
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Heparinoid, a type of compound that has structures similar to heparin, has been found in marine organisms such as shrimp head. This shrimp waste products were used to prepare, characterize, and evaluate the antithrombotic effect of heparinoid. Two heparinoid compounds were obtained from shrimp head, and the main fraction F1 was →4)-GlcA-(1→3)-GalNAc-(1→ with Ara, while the minor fraction F2 composed mainly of the backbone as →4)-β-D-GlcA (or IdoA)-(1→4)-β-D-GlcN (or GlcNAc)-(1→. Both F1 and F2 could extend activated partial thromboplastin time and thrombin time concentration-dependently, and F2 has stronger activity than F1 at the same concentration. The potential anticoagulant mechanism of F1 and F2 may relate to their combination with more antithrombin III, which binds to and potentiates the action of antithrombin as well as inhibiting coagulation factors Xa and IIa, preventing blood clot formation. Furthermore, heparinoid F1 and F2 were found to have high fibrinolytic capability in vitro and in vivo via activating the self-fibrinolytic system. In conclusion, heparinoids (F1 and F2) derived from shrimp head wastes could be used as candidate compounds to prevent thrombosis while posing a lower hemorrhagic risk.
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Pala, L., and C. M. Rotella. "The Role of DPP4 Activity in Cardiovascular Districts: In Vivo and In Vitro Evidence." Journal of Diabetes Research 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/590456.
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The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, since these drugs not only improve glycemia with minimal risk of hypoglycemia, but also have other extraglycemic beneficial effects. These agents, which are effective in improving glucose control, could also have positive effects on the incidence of cardiovascular events. The aim of this review is to summarize the present literature about the role of dipeptidyl peptidase 4 (DPP4) in cardiovascular districts, not only strictly correlated to its effect on glucagon-like peptide-1 (GLP-1) circulating levels, but also to what is known about possible cardiovascular actions. Actually, DPP4 is known to be present in many cells and tissues and its effects go beyond purely metabolic aspects. Almost always the inhibition of DPP4 activity is associated with improved cardiovascular profile, but it has shown to possess antithrombotic properties and these different effects could be connected with a site and/or species specificity of DPP4. Certainly, DPP4 seems to exert many functions, both directly and indirectly, on cardiovascular districts, opening new possibilities of prevention and treatment of complications at this level, not only in patients affected by diabetes mellitus.
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Wang, Jing-Shang, Ye Huang, Shuping Zhang, Hui-Jun Yin, Lei Zhang, Yan-Hong Zhang, Ye-Wen Song, and Dan-Dan Li. "A Protective Role of Paeoniflorin in Fluctuant Hyperglycemia-Induced Vascular Endothelial Injuries through Antioxidative and Anti-Inflammatory Effects and Reduction of PKCβ1." Oxidative Medicine and Cellular Longevity 2019 (April 10, 2019): 1–11. http://dx.doi.org/10.1155/2019/5647219.
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Hyperglycemia fluctuation is associated with diabetes mellitus (DM) complications when compared to persistent hyperglycemia. Previous studies have shown that paeoniflorin (PF), through its antiapoptosis, anti-inflammation, and antithrombotic properties, effectively protects against cardiovascular and cerebrovascular disease. However, the mechanism underlying the protection from PF against vascular injuries induced by hyperglycemia fluctuations remains poorly understood. Herein, we investigated the potential protective role of PF on human umbilical vein endothelial cells (HUVECs) subjected to intermittent glucose levels in vitro and in DM rats with fluctuating hyperglycemia in vivo. A remarkable increased apoptosis associated with elevated inflammation, increased oxidative stress, and high protein level of PKCβ1 was induced in HUVECs by intermittently changing glucose for 8 days, and PF recovered those detrimental changes. LY333531, a potent PKCβ1 inhibitor, and metformin manifested similar effects. Additionally, in DM rats with fluctuating hyperglycemia, PF protected against vascular damage as what has been observed in vitro. Taken together, PF attenuates the vascular injury induced by fluctuant hyperglycemia through oxidative stress inhibition, inflammatory reaction reduction, and PKCβ1 protein level repression, suggesting its perspective clinical usage.
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Otręba, Michał, Leon Kośmider, and Anna Rzepecka-Stojko. "Polyphenols’ Cardioprotective Potential: Review of Rat Fibroblasts as Well as Rat and Human Cardiomyocyte Cell Lines Research." Molecules 26, no. 4 (February 3, 2021): 774. http://dx.doi.org/10.3390/molecules26040774.
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According to the World Health Organization, cardiovascular diseases are responsible for 31% of global deaths. A reduction in mortality can be achieved by promoting a healthy lifestyle, developing prevention strategies, and developing new therapies. Polyphenols are present in food and drinks such as tea, cocoa, fruits, berries, and vegetables. These compounds have strong antioxidative properties, which might have a cardioprotective effect. The aim of this paper is to examine the potential of polyphenols in cardioprotective use based on in vitro human and rat cardiomyocytes as well as fibroblast research. Based on the papers discussed in this review, polyphenols have the potential for cardioprotective use due to their multilevel points of action which include, among others, anti-inflammatory, antioxidant, antithrombotic, and vasodilatory. Polyphenols may have potential use in new and effective preventions or therapies for cardiovascular diseases, yet more clinical studies are needed.
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Liu, Huan, Xuening Yang, John Andersen, Yipeng Wang, Fuyuki Tokumasu, José Ribeiro, Dongying Ma, et al. "A novel family of RGD-containing disintegrins (Tablysin-15) from the salivary gland of the horsefly Tabanus yao targets αIIbβ3 or αVβ3 and inhibits platelet aggregation and angiogenesis." Thrombosis and Haemostasis 105, no. 06 (2011): 1032–45. http://dx.doi.org/10.1160/th11-01-0029.
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SummaryA novel family of RGD-containing molecules (Tablysin-15) has been molecularly characterised from the salivary gland of the haematophagous horsefly Tabanus yao. Tablysin-15 does not share primary sequence homology to any disintegrin discovered so far, and displays an RGD motif in the N-terminus of the molecule. It is also distinct from disintegrins from Viperidae since its mature form is not released from a metalloproteinase precursor. Tablysin-15 exhibits high affinity binding for platelet αIIbβ3 and endothelial cell αVβ3 integrins, but not for α5β1 or α2β1. Accordingly, it blocks endothelial cell adhesion to vitronectin (IC50 ~1 nM) and marginally to fibronectin (IC50 ~1 μM), but not to collagen. It also inhibits fibroblast growth factor (FGF)-induced endothelial cell proliferation, and attenuates tube formation in vitro. In platelets, Tablysin-15 inhibits aggregation induced by collagen, ADP and convulxin, and prevents static platelet adhesion to immobilised fibrinogen. In addition, solid-phase assays and flow cytometry demonstrates that αIIbβ3 binds to Tablysin-15. Moreover, immobilised Tablysin-15 supports platelet adhesion by a mechanism which was blocked by anti-integrin αIIbβ3 monoclonal antibody (e.g. abciximab) or by EDTA. Furthermore, Tablysin-15 dose-dependently attenuates thrombus formation to collagen under flow. Consistent with these findings, Tablysin-15 displays antithrombotic properties in vivo suggesting that it is a useful tool to block αIIbβ3, or as a prototype to develop antithrombotics. The RGD motif in the unique sequence of Tablysin-15 represents a novel template for studying the structure-function relationship of the disintegrin family of inhibitors.
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Jeong, Soon S., Marinus J. Broekman, Timothy A. Mitsky, Ridong Chen, and Aaron J. Marcus. "Antithrombotic Activity of a Novel Engineered Human Apyrase. Enzymatic Profile, Ex Vivo and In Vivo Properties." Blood 104, no. 11 (November 16, 2004): 530. http://dx.doi.org/10.1182/blood.v104.11.530.530.
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Abstract Recent emphasis has been on ADP as a mediator of thrombotic events characterized by excessive platelet reactivity. In contrast, neither ATP nor AMP induces platelet activation. Thus, (enzymatic) removal of ADP from the milieu of activated platelets constitutes a novel antithrombotic strategy. Apyrases constitute a group of enzymes catalyzing metabolism of ATP to ADP, and ADP to AMP. Therefore, we cloned a human apyrase isozyme with 35% sequence identity to CD39 (NTPDase1) from a human genome cDNA library and enhanced its ADPase activity by protein engineering. The novel engineered apyrase, named APT102 was transfected into and secreted from HEK293 cell lines. It was purified from conditioned medium using anion exchange chromatography, size exclusion chromatography and affinity chromatography, and enzymatically characterized. APT102 was highly soluble and stable. It exhibited a 2.5-fold increase in ADPase activity relative to its ATPase activity, when compared to the parent compound, with catalytic efficiencies (Vmax/Km) of 0.135 and 0.164 respectively. APT102 strongly inhibited platelet reactivity in vitro when added to citrated and heparinized human platelet-rich plasma upon stimulation with ADP or collagen. ATP is released upon tissue damage and could potentially lead to formation of prothrombotic levels of ADP following its metabolism by apyrases. We demonstrated that with APT102, aggregation was efficiently inhibited and reversed by the enzyme. This occurred even when human platelets were initially stimulated with 10 μM ADP simultaneously with up to 100 μM ATP, followed within 5 min with another dose of 300 μM ATP. Following tail vein infusion of APT102 to male Sprague-Dawley rats (~300 g) at 0.75 mg/kg body weight, platelet aggregation ex vivo in PRP in response to ADP and collagen was strongly inhibited. The pharmacokinetics of APT102 were determined by enzyme activity assays with either ADP or ATP as substrate, as analyzed by our radio-TLC procedure. The data indicate that APT102 has a fast onset of action and a prolonged duration of action. This will be advantageous clinically since a bolus injection will suffice without a requirement for continuous infusion. The pharmacodynamics of APT102 were determined using ex vivo platelet aggregation to ADP, and showed identical properties. In keeping with the demonstrated lack in mice of a direct anti-platelet effect of soluble apyrase, the rat tail bleeding time was minimally prolonged in parallel experiments. Thus, APT102 strongly inhibits the recruitment of platelets into an evolving occlusive thrombus, but it is anticipated to be safer than currently employed antithrombotics since they all have a narrow therapeutic window between therapeutic effectiveness and undesirable side effects. In separate experiments involving experimental stroke, male Wistar rats were randomly infused via the tail vein with either saline or 0.75 mg APT102 per kg body weight prior to being subjected to temporary middle cerebral artery occlusion. Brain infarct volumes were determined 24 h following stroke induction. Treatment with APT102 resulted in a 40% reduction in brain infarct volume. We conclude that APT102 will represent a new therapeutic modality for platelet-driven thrombotic disorders, which appears to be safe and effective.
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Gerotziafas, Grigorios T., Galea Vasso, Jeanine M. Walenga, Evi Kalodiki, Mourad Chaari, Hatmi Mohamed, Jawed Fareed, and Elalamy Ismail. "Thrombin Generation Assessment in Platelet Rich Plasma Offers Additional Criteria for Low Molecular Weight Heparin Antithrombotic Fingerprint Characterization." Blood 114, no. 22 (November 20, 2009): 4177. http://dx.doi.org/10.1182/blood.v114.22.4177.4177.
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Abstract Abstract 4177 Introduction National and international organizations recognize that low molecular weight heparins (LMWHs) are distinct entities and that they should not be used interchangeably in clinical practice. Physicochemical properties, such as molecular weight anti-Xa/anti-IIa ratios, are used by health authorities to establish LMWHs differentiation. LMWHs are multitargeted drugs in which small differences in physicochemical properties may lead to significantly different inhibition of blood coagulation. In the present in vitro study we have investigated if thrombin generation assay, reflecting the overall coagulation process, is a suitable tool for the LMWH variability evalution. Materials and methods LMWHs (bemiparin, enoxaparin, nadroparin, dalteparin and tinzaparin) and unfractionated heparin (UFH) were added in vitro in normal citrated platelet rich plasma from 10 healthy individuals, at clinically relevant concentrations (ranging from 0.2 to 1 anti-Xa IU/ml). Thrombin generation was studied with Thrombogram-Thrombinoscope® assay using diluted thromboplastin (Innovin®, 1/1000 final dilution, Siemens France). The concentrations doubling the lag-time, the time to Peak, the IC50 for Peak, the endogenous thrombin potential (ETP) and the mean rate index of propagation phase (MRI) were determined for each compound. Results LMWHs compared on their anti-Xa activity basis showed variable inhibitory effect on thrombin generation. At equivalent anti-Xa concentrations tinzaparin was significantly more potent than the other LMWHs, being almost similar to UFH profile. Enoxaparin, nadroparin and dalteparin showed a similar inhibitory activity. Bemiparin had the lesser pronounced inhibitory effect on thrombin generation. The impact of anti-Xa and anti-IIa activities on each phase of thrombin generation process is different. Thrombogram chronometric parameters are mainly influenced by the anti-IIa activity. Similarly, ETP inhibition depends more on anti-IIa rather than anti-Xa activity. The MRI of the propagation phase is more sensitive to the anti-Xa activity of LMWHs. Conclusion Thrombin generation assessment in platelet rich plasma allows to evaluate the anticoagulant fingerprint of LMWHs and to differentiate them on global and functional criteria. Each LMWH has a particular inhibitory impact on each phase of thrombin generation process. These functional criteria need to be standardized and probably required for a better characterization of LMWHs heterogeneity by health authorities. They could be used also to evaluate bioequivalence of generic and original LMWHs. Disclosures: No relevant conflicts of interest to declare.
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Alame, Ghina, Pierre H. Mangin, Monique Freund, Nadia Riehl, Stéphanie Magnenat, Maurice Petitou, Béatrice Hechler, and Christian Gachet. "EP217609, a neutralisable dual-action FIIa/FXa anticoagulant, with antithrombotic effects in arterial thrombosis." Thrombosis and Haemostasis 113, no. 02 (March 2015): 385–95. http://dx.doi.org/10.1160/th14-05-0399.
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SummaryEP217609 is a new synthetic parenteral dual-action anticoagulant combining a direct thrombin inhibitor (α-NAPAP analog), an indirect factor Xa inhibitor (fondaparinux analog) and a biotin moiety allowing its neutralisation. EP217609 exhibited similar in vitro anticoagulant properties as its parent compounds. On the basis of dose-response curves, we identified low and moderate doses of EP217609 resulting in similar ex vivo prolongation of the APTT as α-NAPAP analog and comparable ex vivo anti-FXa activity as fondaparinux. The effects of EP217609 were compared to those of its parent compounds used alone or in combination in two models of experimental thrombosis induced by FeCl3 injury of the carotid artery or mechanical injury of atherosclerotic plaques in ApoE-deficient mice. When administered at low doses increasing the APTT by only 1.1 fold, EP217609 significantly reduced the thrombus area in both models as compared to α-NAPAP analog or fondaparinux alone, but not to the combination of these drugs. In contrast, at higher doses increasing the APTT 1.5 times, EP217609 was not superior to either parent compound. Low doses of EP217609 did not prolong the tail bleeding time or increase the volume of blood loss, although a tendency towards an increased blood loss was observed in five out of 12 mice. Finally, the effects of EP217609 could be neutralised in vivo by injection of avidin. The pharmacological profile of EP217609, its performance in arterial thrombosis models and its possible neutralisation make it an interesting molecule and a potential candidate as an antithrombotic drug.
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Kogushi, Motoji, Daniela Dastros-Pitei, Marcus Flather, Deepak L. Bhatt, and Victor L. Serebruany. "The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease." Thrombosis and Haemostasis 102, no. 07 (2009): 111–19. http://dx.doi.org/10.1160/th08-12-0805.
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SummaryE5555 is a potent protease-activated receptor (PAR-1) antagonist targeting the G-coupled receptor and modulating thrombinplatelet-endothelial interactions. The drug is currently being tested in phase II trials in patients with coronary artery disease (CAD) and has potential antithrombotic and anti-inflammatory benefits.We investigated the in-vitro effects of E5555 on platelet function beyond PAR-1 blockade in healthy volunteers and CAD patients treated with aspirin (ASA) with or without clopidogrel. Conventional aggregation induced by 5 µM ADP, 1 µg/ml collagen, 10 µM TRAP, whole blood aggregation with 1 µg/ml collagen, and expression of 14 intact, and TRAP-stimulated receptors by flow cytometry were utilised to assess platelet activity after preincubation with escalating concentrations of E5555 (20 ng/ml, 50 ng/ml, and 100 ng/ml) in healthy volunteers, CAD patients treated with ASA, and CAD patients treated with ASA and clopidogrel combination (n=10, for each group). E5555 inhibited a number of platelet biomarkers. Platelet inhibition was usually moderate, present already at 20 ng/ml, and was not seemingly dose-dependent without TRAP stimulation. E5555 caused 10–15% inhibition of ADP- and collagen-induced platelet aggregation in plasma, but not in whole blood.TRAP-induced aggregation was inhibited almost completely. PECAM-1, GP IIb/IIIa antigen, and activity with PAC-1, GPIb, thrombospondin, vitronectin receptor expression, and formation of platelet-monocyte aggregates were also significantly reduced by E5555.TRAP stimulation caused dose-dependent effects between 20 and 50 ng/ml E5555 doses. P-selectin, LAMP-1, LAMP, and CD40-ligand were not affected by E5555. In conclusion, E5555 in vitro moderately but significantly inhibits platelet activity beyond PAR-1 blockade. Antiplatelet potency of ASA alone, and the combination of ASA and clopidogrel may be enhanced by E5555 providing rationale for their synergistic use. Selective blockade of platelet receptors suggests unique antiplatelet properties of E5555 as a potential addition to current antithrombotic regimens.
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Polak, Dawid, Marcin Talar, Nina Wolska, Dagmara W. Wojkowska, Kamil Karolczak, Karol Kramkowski, Tomasz A. Bonda, Cezary Watala, and Tomasz Przygodzki. "Adenosine Receptor Agonist HE-NECA Enhances Antithrombotic Activities of Cangrelor and Prasugrel in vivo by Decreasing of Fibrinogen Density in Thrombus." International Journal of Molecular Sciences 22, no. 6 (March 17, 2021): 3074. http://dx.doi.org/10.3390/ijms22063074.
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Blood platelets’ adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y12 could serve as components of dual anti-platelet therapy. We have found that a selective A2A agonist 2-hexynyl-5’-N-ethylcarboxamidoadenosine (HE-NECA) improved the anti-thrombotic properties of either cangrelor or prasugrel in the model of ferric chloride-induced experimental thrombosis in mice. Importantly, HE-NECA was effective not only when applied in bolus as other AR agonists in the up-to-date published studies, but also when given chronically. In vitro thrombus formation under flow conditions revealed that HE-NECA enhanced the ability of P2Y12 inhibitors to decrease fibrinogen content in thrombi, possibly resulting in their lower stability. Adenosine receptor agonists possess a certain hypotensive effect and an ability to increase the blood–brain barrier permeability. Therefore, the effects of anti-thrombotic doses of HE-NECA on blood pressure and the blood–brain barrier permeability in mice were tested. HE-NECA applied in bolus caused a significant hypotension in mice, but the effect was much lower when the substance was given in doses corresponding to that obtained by chronic administration. At the same time, no significant effect of HE-NECA was observed on the blood–brain barrier. We conclude that chronic administration of the A2A agonist can be considered a potential component of a dual antithrombotic therapy. However, due to the hypotensive effect of the substances, dosage and administration must be elaborated to minimize the side-effects. The total number of animals used in the experiments was 146.