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Статті в журналах з теми "Anti-thrombotic Molecules"
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Péč, Martin Jozef, Jakub Benko, Jakub Jurica, Monika Péčová, Marek Samec, Tatiana Hurtová, Tomáš Bolek, et al. "The Anti-Thrombotic Effects of PCSK9 Inhibitors." Pharmaceuticals 16, no. 9 (August 22, 2023): 1197. http://dx.doi.org/10.3390/ph16091197.
Повний текст джерелаАнотація:
Atherosclerosis is the primary process that underlies cardiovascular disease. The connection between LDL cholesterol and the formation of atherosclerotic plaques is established by solid evidence. PCSK9 inhibitors have proven to be a valuable and practical resource for lowering the LDL cholesterol of many patients in recent years. Their inhibitory effect on atherosclerosis progression seems to be driven not just by lipid metabolism modification but also by LDL-independent mechanisms. We review the effect of PCSK9 inhibitors on various mechanisms involving platelet activation, inflammation, endothelial dysfunction, and the resultant clot formation. The main effectors of PCSK9 activation of platelets are CD36 receptors, lipoprotein(a), oxidised LDL particles, tissue factor, and factor VIII. Many more molecules are under investigation, and this area of research is growing rapidly.
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De Meyer, Simon. "ADAMTS13, an Anti-thrombotic Protein: Evidence Outside of Thrombotic Thrombocytopenic Purpura." Blood 134, Supplement_1 (November 13, 2019): SCI—41—SCI—41. http://dx.doi.org/10.1182/blood-2019-121114.
Повний текст джерелаАнотація:
von Willebrand factor (VWF) is a large multimeric plasma glycoprotein that plays a crucial role in hemostasis and thrombosis. VWF recruits platelets at sites of vascular injury by acting as a molecular bridge between circulating platelets and the site of injured or activated blood vessels. Biosynthesis of VWF is restricted to endothelial cells and megakaryocytes. Endothelial VWF is constitutively secreted into plasma and subendothelium, or is stored as "ultra-large" (UL)-VWF multimers in endothelial Weibel-Palade bodies. VWF produced in megakaryocytes is packaged as UL-VWF in the a-granules of platelets. VWF stored in endothelial and platelet storage organelles is secreted in a regulated process in response to stimulation by secretagogues. Absence or dysfunction of VWF results in bleeding symptoms, as observed in patients with von Willebrand disease. An abnormally high activity of VWF can lead to thrombotic events. Interestingly, the activity of VWF is determined by the size of its multimers and UL-VWF can spontaneously form platelet aggregates. An important regulator of VWF size is the metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which digests large thrombogenic VWF molecules into smaller, less reactive multimers via cleavage of the Y1605-M1606 bond in the VWF A2 domain. ADAMTS13 is mainly synthesized in the liver by hepatic stellate cells, but other sites of synthesis, including renal podocytes, tubular epithelial cell, platelets and endothelial cells, have also been described. ADAMTS13 is released as an active enzyme into the circulation with no physiological inhibitors. Reduced or absent ADAMTS13 activity causes the microangiopathic disorder thrombotic thrombocytopenic purpura (TTP), characterized by VWF and platelet-rich microthrombi that cause multiple organ failure and even death when left untreated. Besides its clear role in the pathophysiology of TTP, the anti-thrombotic and even anti-inflammatory properties of ADAMTS13 have also become apparent in various other thrombotic conditions. High VWF levels and low ADAMTS13 levels are associated with increased risk or even worse outcome of cardiovascular disease, including ischemic stroke and myocardial infarction. Preclinical studies in mouse models showed the beneficial effect of ADAMTS13 in both cerebral and myocardial ischemia/ reperfusion injury by decreasing both thrombosis and inflammation. In addition, ADAMTS13 was shown to also exert a direct thrombolytic effect on VWF-rich thrombi. In a mouse model of ischemic stroke, this thrombolytic activity resulted in efficient lysis of intracranial thrombi that were resistant to standard treatment with tissue plasminogen activator. Hence, ADAMTS13, as a therapeutic agent, could become an interesting avenue, not only to manage TTP, but also to treat other thrombotic complications. Disclosures De Meyer: Fonds voor Wetenschappelijk Onderzoek: Research Funding; KU Leuven: Employment, Research Funding; Ablynx: Consultancy, Research Funding; Cerenovus: Membership on an entity's Board of Directors or advisory committees; WhiteSwell: Consultancy.
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Fuentes, Eduardo, and Iván Palomo. "Extracellular ATP metabolism on vascular endothelial cells: A pathway with pro-thrombotic and anti-thrombotic molecules." Vascular Pharmacology 75 (December 2015): 1–6. http://dx.doi.org/10.1016/j.vph.2015.05.002.
Повний текст джерела
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Muro, S., and V. Muzykantov. "Targeting of Antioxidant and Anti-Thrombotic Drugs to Endothelial Cell Adhesion Molecules." Current Pharmaceutical Design 11, no. 18 (July 1, 2005): 2383–401. http://dx.doi.org/10.2174/1381612054367274.
Повний текст джерела
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Zaki, Magdi E. A., Sami A. Al-Hussain, Vijay H. Masand, Manoj K. Sabnani, and Abdul Samad. "Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity." International Journal of Molecular Sciences 22, no. 15 (August 3, 2021): 8352. http://dx.doi.org/10.3390/ijms22158352.
Повний текст джерелаАнотація:
Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R2tr = 0.831, Q2LMO = 0.828, R2ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds.
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Shiels, Katie, Alexandros Tsoupras, Ronan Lordan, Constantina Nasopoulou, Ioannis Zabetakis, Patrick Murray, and Sushanta Kumar Saha. "Bioactive Lipids of Marine Microalga Chlorococcum sp. SABC 012504 with Anti-Inflammatory and Anti-Thrombotic Activities." Marine Drugs 19, no. 1 (January 10, 2021): 28. http://dx.doi.org/10.3390/md19010028.
Повний текст джерелаАнотація:
Microalgae are at the start of the food chain, and many are known producers of a significant amount of lipids with essential fatty acids. However, the bioactivity of microalgal lipids for anti-inflammatory and antithrombotic activities have rarely been investigated. Therefore, for a sustainable source of the above bioactive lipids, the present study was undertaken. The total lipids of microalga Chlorococcum sp., isolated from the Irish coast, were fractionated into neutral-, glyco-, and phospho-lipids, and were tested in vitro for their anti-inflammatory and antithrombotic activities. All tested lipid fractions showed strong anti-platelet-activating factor (PAF) and antithrombin activities in human platelets (half maximal inhibitory concentration (IC50) values ranging ~25–200 μg of lipid) with the highest activities in glyco- and phospho-lipid fractions. The structural analysis of the bioactive lipid fraction-2 revealed the presence of specific sulfoquinovosyl diacylglycerols (SQDG) bioactive molecules and the HexCer-t36:2 (t18:1/18:1 and 18:2/18:0) cerebrosides with a phytosphingosine (4-hydrosphinganine) base, while fraction-3 contained bioactive phosphatidylcholine (PC) and phosphatidylethanolamine (PE) molecules. These novel bioactive lipids of Chlorococcum sp. with putative health benefits may indicate that marine microalgae can be a sustainable alternative source for bioactive lipids production for food supplements and nutraceutical applications. However, further studies are required towards the commercial technology pathways development and biosafety analysis for the use of the microalga.
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Shiels, Katie, Alexandros Tsoupras, Ronan Lordan, Constantina Nasopoulou, Ioannis Zabetakis, Patrick Murray, and Sushanta Kumar Saha. "Bioactive Lipids of Marine Microalga Chlorococcum sp. SABC 012504 with Anti-Inflammatory and Anti-thrombotic Activities." Marine Drugs 19, no. 1 (January 10, 2021): 28. http://dx.doi.org/10.3390/md19010028.
Повний текст джерелаАнотація:
Microalgae are at the start of the food chain, and many are known producers of a significant amount of lipids with essential fatty acids. However, the bioactivity of microalgal lipids for anti-inflammatory and antithrombotic activities have rarely been investigated. Therefore, for a sustainable source of the above bioactive lipids, the present study was undertaken. The total lipids of microalga Chlorococcum sp., isolated from the Irish coast, were fractionated into neutral-, glyco-, and phospho-lipids, and were tested in vitro for their anti-inflammatory and antithrombotic activities. All tested lipid fractions showed strong anti-platelet-activating factor (PAF) and antithrombin activities in human platelets (half maximal inhibitory concentration (IC50) values ranging ~25–200 μg of lipid) with the highest activities in glyco- and phospho-lipid fractions. The structural analysis of the bioactive lipid fraction-2 revealed the presence of specific sulfoquinovosyl diacylglycerols (SQDG) bioactive molecules and the HexCer-t36:2 (t18:1/18:1 and 18:2/18:0) cerebrosides with a phytosphingosine (4-hydrosphinganine) base, while fraction-3 contained bioactive phosphatidylcholine (PC) and phosphatidylethanolamine (PE) molecules. These novel bioactive lipids of Chlorococcum sp. with putative health benefits may indicate that marine microalgae can be a sustainable alternative source for bioactive lipids production for food supplements and nutraceutical applications. However, further studies are required towards the commercial technology pathways development and biosafety analysis for the use of the microalga.
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Clemetson, Jeannine, and Kenneth Clemetson. "Platelet GPIb complex as a target for anti-thrombotic drug development." Thrombosis and Haemostasis 99, no. 03 (2008): 473–79. http://dx.doi.org/10.1160/th07-12-0718.
Повний текст джерелаАнотація:
SummarySpecific inhibition of platelet function is a major target of antithrombotic drug research. Platelet receptors are both accessible and specific but have multiple functions often linked to a wide range of ligands. GPIb complex is best known as a major platelet receptor for vonWillebrand factor essential for platelet adhesion under high shear conditions found in arteries and in thrombosis. Recent animal studies have supported inhibition of GPIb as a good candidate for anti-thrombotic drug development with several classes of proteins showing important specific effects and the required discrimination between roles in haemo- stasis and thrombosis is important to protect against bleeding complications.These include antibodies, several classes of snake venom proteins, mutant thrombin molecules and peptides affecting subunit interactions.However,due to the nature of its receptor- ligand interactions involving large protein-protein interfaces, the possibility of developing classic pharmaceutical inhibitors for long term (and perhaps oral) treatment is still unclear, and additional information about structural interactions and signalling mechanisms is essential.
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Bălașa, Adrian Florian, Cristina Chircov, and Alexandru Mihai Grumezescu. "Marine Biocompounds for Neuroprotection—A Review." Marine Drugs 18, no. 6 (May 31, 2020): 290. http://dx.doi.org/10.3390/md18060290.
Повний текст джерелаАнотація:
While terrestrial organisms are the primary source of natural products, recent years have witnessed a considerable shift towards marine-sourced biocompounds. They have achieved a great scientific interest due to the plethora of compounds with structural and chemical properties generally not found in terrestrial products, exhibiting significant bioactivity ten times higher than terrestrial-sourced molecules. In addition to the antioxidant, anti-thrombotic, anti-coagulant, anti-inflammatory, anti-proliferative, anti-hypertensive, anti-diabetic, and cardio-protection properties, marine-sourced biocompounds have been investigated for their neuroprotective potential. Thus, this review aims to describe the recent findings regarding the neuroprotective effects of the significant marine-sourced biocompounds.
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Lopez, Jose J., Mohammed El Haouari, Isaac Jardin, Nieves Alonso, Sergio Regodon, Raquel Diez-Bello, Pedro C. Redondo, and Juan A. Rosado. "Flavonoids and Platelet-Derived Thrombotic Disorders." Current Medicinal Chemistry 26, no. 39 (January 3, 2019): 7035–47. http://dx.doi.org/10.2174/0929867325666180417170218.
Повний текст джерелаАнотація:
: Thrombotic disorders are characterized by an increase in the probability of the formation of unnecessary thrombi that might be due to the activation of the coagulation cascade or the circulating platelets. Platelets or thrombocytes play an essential role in hemostasis but abnormal platelet function leads to the development of a number of cardiovascular complications, including thrombotic disorders. Under pathological conditions, platelets are associated with the development of different thrombotic disorders, including atherosclerosis, arterial thrombosis and stroke, deep venous thrombosis and pulmonary embolism; therefore, platelets are the target of a number of anti-thrombotic strategies. Flavonoids, a large group of polyphenols ubiquitously expressed in fruits and vegetables that have attracted considerable attention because of their benefits in human health, including the reduction of the risk of cardiovascular disease. Flavonoids have been reported to reduce platelet activity by attenuating agonist-induced GPIIb/IIIa receptor activation, mobilization of intracellular free Ca2+, granule exocytosis, as well as activation of different signaling molecules such as mitogen- activated protein kinases or phospholipases. This review summarizes the current studies concerning the modulation of platelet activation by flavonoids, giving especial attention to those events associated to thrombotic disorders.
Дисертації з теми "Anti-thrombotic Molecules"
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Khalaf, Ali. "Design, synthesis and biological evaluation of new platelet aggregation inhibitors and novel methodologies for the preparation of CF₂R containing molecules." Phd thesis, Université Rennes 1, 2013. http://tel.archives-ouvertes.fr/tel-00861475.
Повний текст джерелаАнотація:
The first part of the thesis deals with the synthesis and biological evaluation of new platelets aggregation inhibitors, based on 12-HETE, 13-HODE and their analogues. In the second part we are interested in novel methodologies for the preparation of CF₂-containing molecules : First, a flexible strategy for the synthesis of gem-difluoro-bisarylic derivatives and heteroaromatic analogues was designed based on the easy synthesis and the reactivity of gem-difluoro propargylic intermediates, which by Diels-Alder cycloaddition and 1,3-dipolar cycloadditions afforded respectively the bisarylic and mixed arylic heteroarylic scaffolds. In addition, two small libraries were constructed around a bisarylic scaffold as representative examples. Second, we were interested in the synthesis of optically active functionalized molecules containing a gem-difluoro group, using asymmetric organocatalysis protocols. After preparation of the gem-difluoro enals, from their difluoropropargylic precursors, asymmetric organocalytic Diels-Alder cycloaddition and 1,4-conjugated additions were successfully performed.
Книги з теми "Anti-thrombotic Molecules"
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Medjeral-Thomas, Nicholas, Anna Richards, and Matthew C. Pickering. Molecular basis of complement-mediated renal disease. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0333.
Повний текст джерелаАнотація:
Abnormal regulation of complement is intimately associated with C3 glomerulopathy and atypical haemolytic uraemic syndrome. Atypical haemolytic uraemic syndrome is characterized by renal thrombotic microangiopathy due to an inability to regulate complement activation along the renal endothelium. The development of thrombosis is critically dependent on the ability to activate C5. Eculizumab, a monoclonal anti-C5 antibody, is an effective therapy for this condition. C3 glomerulopathy refers to glomerular lesions characterized by accumulation of C3 in the absence of immunoglobulin. The prototypic example is dense deposit disease. This condition is associated with impaired regulation of the alternative pathway in plasma. In other subtypes of C3 glomerulopathy, familial studies have identified mutations within the complement factor H-related protein family. Polymorphic variation within this protein family also influences susceptibility to IgA nephropathy. The mechanism underlying these associations remains unknown and is the subject of ongoing research efforts.
Тези доповідей конференцій з теми "Anti-thrombotic Molecules"
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Sas, G. "DEFECTS IN SERINE PROTEASE INHIBITORS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643714.
Повний текст джерелаАнотація:
Several serine protease inhibitorsof plasma inhibit the activated coagulation enzymes but only antithrombin III(AT-III)and heparin cofactor II (HC-II) are implicated in the pathogenesisof the familial thrombosis. Since thefirst publication (1965) many thrombophilic families with reduced AT-III synthesis have been investigated. These studies have proved that the disorder is associated with a high risk forvenous thrombosis and the inheritanceis autosomal dominant. The AT-III activity in the plasma of the affected patients is about 50% of the normalvalue.In recent years the heterogeneity of the inherited AT-III deficiency has been verified. The various AT-III abnormalities are not mere interestingrarities but they provide naturally occurring models for the solution of theoretical problems such as the function of AT-III molecule, the physiological significance of heparin, etc. Furthermore, the clinical manifestationof the particular variants greatly differs from symptomless abnormality tosevere thrombotic cases.In the majority of cases, reduced functional activity is accompanied with a parallel decrease of antigen concentration of AT-III. This is the characteristic feature of the quantitative or Type I ("classical")AT-III deficiency. By means of crossed immunoelectrophoresis, electro-focussing and recombinant DNA techniques the heterogeneity of this group has been established. In one subgroup (Type la) AT-III molecules are normal as regards their biochemical characteristics. In Type lb, subnormal AT-IIIquantity is accompanied with decreased heparin affinity. Differentiation of these subgroups has practical consequences: therapeutic concentrations of heparin apparently does not decrease AT-III level in the plasma of patients with Type lb AT-III deficiency.The other main form is the qualitative deficiency of AT-III (Type II) which is characterised by reduced functional activity at normal antigen concentration. In general, two populations of AT-III molecules can be detected in the blood of these patients: a normal and an abnormal one. Up till now at least 24 different abnormalities were found and designatedwith toponymes. These disorders can be classified with relatively simple laboratory methods such as functional anti-IIaXaFirstDepartment of Medicine, Postgraduate Medical University, Budapest, Hungary.arin cofactor activity, crossed immunoelectrophoresiswith and without heparin, heparin-affinity chromatography. Type na is characterised by profound structural changes of the molecule,variably: reflected in reduced inactivation of F Ha and F Xa, abnormal heparin-AT-III reaction and aberrant immunochemical structure Seven different abnormalities fall into this group (Budapest I, Tokyo, MalmÖ, Chicago, Milano, Trento and Northwick Park). The last three abnormalities are very similar.In Type lib an isolated defect of protease inactivation can be detected and an isolated disturbance of the active centre ofthe molecule is assumed.Until now 6 apparently different variants belonging to this group have been described. (Aalborg, Vicenza, Denver, Hvidovre, Charleville, Milano 2.) Type lie abnormality is characterised by an isolated defect of the heparin-AT-III reaction. In these cases a disturbance of the heparin binding site(s) is assumed. Eleven families with this type of abnormality have been recorded (Ann Arbor, Basel, Paris 1 and 2, Toyama* Tours, Padova I and 2, Algers, Fontainebleu and Budapest 2). This subgroup is heterogeneous in respect ofheparin affinity: in the majority of cases the abnormal AT-III molecules have no heparin affinity at all while in rare cases (such as Basel, Budapest 2) they have reduced affinity.TheType lie AT-III deficiency has several distinctive features compared with the other subtypesJClinically, the thromboembolic complications are rare: in 4 families thrombosis has notoccurred at all. Only one member in each of 4 other families had thrombosis. In 3 families homozygous patients suffered severe thrombosis in young age and/or in unusual localisations (intraarterial, intracardiac, etc.) butthe other heterozygous members were free of thrombotic symptoms. No increased intravascular coagulation could be detected in Type lie heterozygous cases incontrast to the "classical" AT-III deficiency.These observations suggest a different mechanism and clinical manifestation of the deficiency of progressiveserine protease inactivation and of heparin cofactor activity. In case of progressive inactivation, reduction of 50% of the activity predisposes mainly to venous thrombosis as a consequence of the hypercoagulability of theblood. The isolated reduction of heparin cofactor activity seems to bringabout thrombosis in any part of the vascular system, but only if this reduction is as severe as that of the coagulant factors in case of coagulopathies.In accordance with this finding, rare cases of HCII deficiency give rise to thrombosis in both the arteries and the veins. Heparin cofactor activities may play an important role in the antithrombotic mechanism along theendothelial surface of the whole vascular system.
2
Johnston, R. V., M. Orr, A. Rumley, J. McLachalan, and C. D. Forbes. "A STUDY OF THE ANTI-THROMBOTIC POTENTIAL OF LOW MOLECULAR WEIGHT HEPARIN LHN-1 (NOVO) IN NORMAL VOLUNTEERS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643225.
Повний текст джерелаАнотація:
Studies of low molecular weight heparin have shown a molecular sized dependency of the anti-coagulant activity. We studied the effects of a low molecular weight heparin LHN-1 (Novo) with a mean molecular weight of 5-7000 daltons on the coagulation mechanism and platelet function of normal volunteers. The heparin was given for 5 days on a once daily dose of 2500, 5000 or 7500 anti-Xa units to 3 groups of volunteers and in a twice daily regime of 2500 and 5000 anti-Xa units in 2 further groups of volunteers. After subcutaneous injection LHN-1 produced a significant (p<0.01) increase in anti-Xa activity which peaked between 3-4 hours after subcutaneous injection on both once and twice daily regime. On once daily regime there was no significant measure able anti-Xa activity 24 hours after the last injection. There was a small but significant increase in both KCCT and thrombin time (p<0.01) following injection, which was also dose related. Bleeding time did not change and there was no effect on platelet function. There was a significant (p<0.01) increase in fibrinolysis as measured by the fibrin plate method. There were no bleeding problems. These findings would suggest that LHN-1 merits further clinical evaluation to confirm its anti-thrombotic and profibrinolytic potential.
3
Hobblen, P. M. J., G. MT Vogel, and D. G. Meuleman. "PHARMACOKINETIC BEHAVIOUR OF ANTITHROMBOTIC AND BLEEDING ENHANCING EFFECTS OF VARIOUS HEPARIN(OID)S IN RATS: THEIR RELATION WITH INTERACTIONS WITH FACTORS IIa AND Xa." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644172.
Повний текст джерелаАнотація:
The effects on thrombus formation and bleeding of various heparin(oid)s were studied at several time-intervals: in addition, the αXa-, αiia-, and thrombin generation inhibitory (IIaGI)-activities were measured amidolytically in plasma from these animals. The following substances were studied: heparin (HEP), the fraction of heparin with high affinity for ATIII (HA-HEP), a low molecular weight fraction of heparin (LMW-HEP), nitrous acid degraded heparin (NAD-HEP), FragrainR (FRA), Org 10172 and the fraction of Org 10172 with high affinity for ATIII (HA-10172). The substances were given in a dose of 800 αXa U/kg i.v. in the thrombosis model and in the double dose (1600 αXa U/kg i.v.) in the bleeding model because of the lower intrinsic effect on bleeding. The initial magnitude and the duration of the anti-thrombotic and bleeding enhancing effects of these substances are summarized in the table together with the half-lives of the αXa-, αia- and IIaGI-activities. NE: not estimated due to too low alla-activities.The following conclusions could be drawn concerning the duration of the effects: 1. in contrast with HEP most lower molecular weight substances showed different time courses of the anti-thrombotic and the bleeding enhancing effect 2. the duration of the antithrombotic effect of Org 10172 and HA-10172 is considerably longer than that of the other substances 3. the duration of the bleeding enhancing effect of Org 10172, HA-10172, NAD-HEP and FragminR is shorter than that of HEP, HA-HEP and LMW-HEP. Additional conclusions could be drawn by inspecting the time response curves and taking the magnitude of the effects into account: 4. Org 10172 and its high affinity fraction have a better benefit/risk ratio in comparison with the other substances, which even increases in time 5. the time-response curves of the anti-thrombotic effects seem to be associated with those of the aXa-activities and 6. the time-response curves of the bleeding enhancing effects seem to be related to those of thrombin inactivation.
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Turple, A. G. G., M. N. Levin, J. Hirish, C. J. Carter, R. M. Jay, P. J. Powers, M. Andrew, H. N. Magnani, R. D. Hull, and M. Gent. "A DOUBLE BLIND RANDOMIZED TRIAL OF ORG 10172 LOW MOLECULAR WEIGHT HEPARINOID IN THE PREVENTION OF DEEP VEIN THROMBOSIS IN PATIENTS WITH THROMBOTIC STROKE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643239.
Повний текст джерелаАнотація:
The optimal method of venous thrombosis prophylaxis in patients with stroke is uncertain. ORG 10172 is a low molecular weight heparinoid consisting principally of heparan and dermatan sulphates. In animal studies, ORG 10172 is as effective as unfractionated heparin in preventing venous thrombosis but produces less bleeding. There have been a limited number of descriptive studies on its use in humans, but to date randomized efficacy trials of ORG 10172 in the prevention of venous thrombosis have not been reported. A double blind randomized trial was carried out to compare ORG 10172 with placebo in the prevention of deep vein thrombosis in patients with thrombotic stroke. Seventy-five patients were randomized to receive ORG 10172 (50 patients) in a loading dose of 1,000 anti-Xa units intravenously followed by 750 anti-Xa units subcutaneously 12 hourly or placebo (25 patients). Prophylaxis was commenced within 7 days of stroke onset, continued for 14 days or until discharge from hospital, if earlier. Venous thrombosis surveillance was carried out with 125-1 fibrinogen leg scanning and impedance plethysmography. Venous thrombosis was confirmed by venography which occurred in 2 of 50 (4%) in the ORG 10172 group and 7 of 25 (28%) in the placebo group (p=0.005). The corresponding rates for proximal vein thrombosis were 0% and 16%, respectively (p=0.01). There was one major haemorrhage in the treated group and one minor haemorrhage in the placebo group. The anti-factor Xa levels (units/ml; mean ± SE) gradually rose from 0.18 ± 0.001 and 0.06 ± 0.01 six and 12 hours after injection on the first day to 0.24 ± 0.02 and 0.12 ± 0.01 after 11 days treatment. The results of this study indicate that ORG 10172 heparinoid is effective prophylaxis against deep vein thrombosis in patients with acute thrombotic stroke.
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Van de Water, A., R. Xhonneux, and F. De Clerck. "ANTI-THROMBOTIC EFFECT IN CANINE CORONARY ARTERIES OF A COMBINED TXA2 synthetase/TXA2-prostaglandin ENDOPEROXIDE RECEPTOR INHIBITOR (R 68070)." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643463.
Повний текст джерелаАнотація:
The effects of R 68070 an oxime-alkane carboxylic acid derivative combining specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/prostaglandin endoperoxide receptor blockade in one molecule, on thrombus formation in a coronary artery following electrically-induced endothelial injury and on its myocardial repercussions were examined in dogs. In an open-chest model in anaesthetized dogs, a stainless steel electrode was inserted into the left anterior descending coronary artery (LAD) distally (+ 1 cm) from an electromagnetic flow probe. ECG and heart rate were derived from limb leads. Serum TXB2 levels were measured by RIA on venous spontaneously coagulated blood (1 h, 37°C). Endothelial cell injury in the LAD coronary artery was induced by the application of an anodal current of 300 μA during 30 min; after an additional 60 min observation period, the thrombus wet weight was determined.In comparison with solvent treatment (n = 8), R 68070 (1.25 mg/kg I.V. 10 min before electrical stimulation, n = 7), significantly reduced the thrombus mass (solvent : 43 mg; R 68070 : 18 mg median value, p < 0.05), the incidence of ECG changes indicative for myocardial ischemia (fibrillation : solvent 1/8; R 68070 0/7; arrhythmias : solvent 3/8; R 68070 2/7; ST changes : solvent 7/8; R 68070 1/7, p < 0.05) and the decrease in coronary blood flow after electrical stimulation (solvent : from 13 to 6.5 ml/min; R 68070 : from 13 to 11 ml/min median values, p < 0.05). Serum TXB2 levels were reduced by 92 % at 100 min after the injection of the active compound (median value, n = 7).Heart rate and coronary blood flow measured before the induction of the endothelial injury were not modified by R 68070.The present study thus demostrates that R 68070 exerts a potent anti-thrombotic effect in canine coronary arteries. The relative contributions to this effect of TXA2 synthetase inhibition and of TXA2/prostaglandin endoperoxide receptor blockade exerted by the compound are being investigated.
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Hach-Wunderle, V., R. Walter-Fincke, H. K. Beck, and I. Scharrer. "FAMILY STUDIES OF PATIENTS WITH RECURRENT VENOUS THROMBOSES AND INHERITED DISORDERS OF BLOOD COAGULATION OR FIBRINOLYSIS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643045.
Повний текст джерелаАнотація:
Several defects of the coagulation and/or fibrinolytic system have been found to be associated with venous thromboembolism. In young patients with recurrent thromboses or a positive family history, an inherited disorder should be excluded535 young patients with venous thromboses, phlebitis and/or pulmonary embolism were investigated from 1980 until 1986. The first thrombotic event had occurred at an age of less than 45 years.An inborn disorder of the blood coagulation or fibrinolytic system was found in 18 families. Most of them (n=13/18) had a positive family history. In all families either thromboses had occurred in at least one member (n=12/18) and/or the defect could be detected in one of them (n=12/18)Most often we found a deficiency of antithfombin III (n=6). A deficiency of protein C (type I) was detected in 3 and a deficiency of protein S in 5 families. In one patient a combined deficiency of anti thrombin III, protein C and protein S was found. Extensive family studies revealed a deficiency of antithrombin III in the grandmother of the patient, who suffered from arterial thrombosis. A deficiency of plasminogen and an abnormal plasminogen molecule were detected in 2 other families. Defective release of t-PA could be demonstrated in 3 members of one investigated family up to nowSeme family members with either defects of protein C, protein S or plasminogen as well as a defective release of t-PA lack thrombotic events. Furthermore thromboses of mesenteric veins occurred in 2 of 6 patients with anti thrombin III deficiency and in 1 of 5 patients with protein S deficiency. Superficial vein thromboses were mainly found in patients with protein C- or protein S-deficiency
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Van Reempts, J., B. Van Deuren, M. Borqers, and F. De Clerck. "R 68 070, A COMBINED TXA2-SYNTHETASE/TXA2-PROSTAGLANDIN ENDOPEROXIDE RECEPTOR INHIBITOR. REDUCES CEREBRAL INFARCT SIZE AFTER PHOTOCHEMICALLY INITIATED THROMBOSIS IN SPONTANEOUSLY HYPERTENSIVE RATS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643470.
Повний текст джерелаАнотація:
The effects of R 68 070, an oxime-alkane carboxylic acid derivative combining specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/prostaglandin endoperoxide receptor blockade in one molecule, were investigated in a model of photochemically induced stroke in spontaneously hypertensive rats.Each experimental group was compared with an untreated control group. All animals were anesthetized with halothane in N20/02 and artificially ventilated. After incision of the scalp and stereotaxic positioning of a fibre optic light source, halothane was discontinued. When physiological variables reached normal values, a focal cortical infarction was produced by injection of 10 mg.kg-1 rose bengal and 20 min irradiation of the brain through the intact skull. Four hours later the brains were perfusion fixed and damaged areas measured on consecutive histologic sections. Infarct size was calculated by numerical integration.R 68 070 (40 mg.kg-1 p.o.,-3 h) significantly reduced the cerebral infarct size to 2.32 mm3 compared with 5.78 mm3 in controls (median values; n = 5; p < 0.05). At 2.5 mg.kg-1 the lesion was reduced from 11.75 mm3 in the control group to 7.82 mm3 in the treated group (n = 5; p = 0.095). Serum TXB2 levels were reduced by > 80 %.Production of damage in this model is based upon photodynamic generation of singlet molecular oxygen, resulting in peroxidative endothelial cell injury and subsequent platelet thrombus formation. Protection with R 68 070 can be explained by the anti-thrombotic effect of the compound. The relative contribution to this protective effect of synthetase and receptor blockade by R 68 070 are being investigated.
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Wester, J., F. W. J. Van Mensvoort, D. G. Meuleman, H. ten Cate, C. P. Henny, and J. W. ten Cate. "EFFECTS OF ORG 10172, A NOVEL LMW HEPARINOID ON PRIMARY HAEMOSTASIS IN RATS AND HUMANS. A MORPHOLOGICAL STUDY." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643238.
Повний текст джерелаАнотація:
Org 10172 is a novel low molecular weight heparinoid isolated from animal mucosa with a higher anti-thrombotic/bleeding risk ratio than standard heparin. The effects of Org 10172 and heparin on primary haemostasis in rats and humans have been studied by light and electron microscopy (LM&EM).In rat ears bleeding wounds were inflicted. The wound areas were excised 5, 15 or 30 min. after bleeding induction, and processed for LM and EM. Org 10172 and heparin have been administered in doses of 300 or 600 anti-Xa U/kg i.v., 5 or 1 min. prior to bleeding induction. Bleeding wounds of drug treated animals have been compared with those of placebo animals. Heparin inhibited degranulation as well as fibrin deposition and groups of not aggregated, sometimes even discoidal platelets could be found after heparin treatment. Org 10172 inhibited degranulation to some extent but less than heparin and Org 10172 hardly inhibited fibrin deposition.In six human volunteers SimplateR bleeding time wounds were excised by punch biopsy, 20 min. after bleeding induction and processed for LM and EM. Org 10172 was administered as single bolus injection of either 3200 or 6400 anti-Xa U i.v., 10 min. prior to bleeding induction. Heparin was given in a dosis of 10.000 anti-Xa U i.v. All biopsies from post-drug bleeding time wounds were compared with biopsies taken from pre-drug bleeding time wounds in the same volunteer. As in the rat studies, heparin inhibited degranulation and fibrin deposition whereas after Org 10172 treatment these effects were hardly detectable. In general the effects of both drugs on haemostasis in the human volunteer study were less distinct than in the rat study. This may be attributed to the lower dose levels used.In conclusion, primary haemostasis after Org 10172 treatment is somewhat retarded, but essentially normal, whereas haemostasis after heparin treatment is more severely disturbed.
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KUROSO, K., S. IKEMATSU, M. HADA, M. FUJIMAKI, and K. FUKUTAKE. "DEVELOPMENT OF A NEW ASSAY METHOD FOR THE DETECTION OF DD/E COMPLEX." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643130.
Повний текст джерелаАнотація:
A new assay method for the detection of DD/E complex derived from crosslinked fibrin is developed. This assay is performed on a microtitre plate using capture/tag antibody technique, in which the monoclonal antibody against D dimer fragment (DD-3B6, MAbCO) is coated and anti-E fragment polyclonal F(ab)’2 conjugated with horse radish peroxidase is for a tag-anti body. Antigen dilution curve is drawn in the range of 0.01-1.0 pg/ml of purified DD/E complex. DD/E complex can be measured specifically and other high molecular weight derivatives from crosslinked fibrin show a little crossreaction, though fibrinogen and fibrinogen degradation products show no crossreactivities on this assay. D dimer fragment dissociated from DD/E complex after further plasmin digestion is less reactive in this assay, while this type of D dimer can be detected by DIMERTEST-EIA (MAbCO). These data suggest that an early stage of plasmin digestion of crosslinked fibrin can be detected by this method. A trace amount of DD/E complex curculating in plasma from a small thrombus is possibly detected, because this assay gives an excellent high sensitivity with the detection limit of 0.01 jug/ ml. Normal value of plasma DD/E complex (n=50) indicates below 0.12 pg/ml as 90 percentile. Patients with DIC (n=24) show high levels of DD/E complex between 0.6 and 40 g/ml. These elevated levels of DD/E complex may suggest consequently the existence of the plasmic digestion of crosslinked fibrin in the cases with DIC. In summary, it is concluded that the development of this assay will add one technique to discriminate between fibrinolysis and fibrinogenolysis and this assay is useful for the quantitative detection of DD/E complex produced in an early stage of fibrinolysis seen in various thrombotic disorders, and for the evaluation of the efficacy of thrombolytic therapy.
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De Clerck, F., R. Van de Wiele, B. Xhonneux, L. Van Gorp, Y. Somers, W. Loots, J. Beetens, J. Van Wauwe, E. Freyne, and P. A. J. Janssen. "PLATELET TXA2 SYNTHETASE INHIBITION AND TXA2/PROSTAGLANDIN ENDOPEROXIDE RECEPTOR BLOCKADE COMBINED IN ONE MOLECULE (R 68070)." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643465.
Повний текст джерелаАнотація:
F 68070, an oxime-alkane carboxylic acid derivative (Janssen Pharmaceutica), is a potent inhibitor of thromboxane A2 (TXA2) synthetase activity (IC50 in vitro against thrombin-stimulated human platelets in plasma : R 68070 : 2.9 x 10-8 M; CGS 13080 : 6 x 10-8 M; OKY-1581 : 8.2 x 10-8 M; dazmegrel : 2.6 x 10-8 M; dazoxiben : 2.3 x 10-8 M).The compound specifically inhibits platelet TXA2 synthetase activity (14C-arachidonic acid metabolism by washed human platelets) without effect on the cyclo-oxygenase, lipoxygenase (platelets, RBL cells) or prostacyclin synthetase activities (rat aortic rings).The inhibitory effect of R 68070 against human platelet TXA2 synthetase activity increases upon prolongation of the contact time (ICsg at 0.5 min of contact : 5.2 x 10-7 M; at 5 min : 8.3 x 10-8 M; at 30 min : 2.5 x 10-8 M) and is reversed by washing of the platelets.In vivo, the compound has a comparatively strong inhibitory effect on platelet TXA2 synthetase activity after oral administration to rats (ED50 - 2 h : R 68070 0.013 mg/kg; CGS-13080 : 0.8 mg/kg; OKY-1581 : 0.61 mg/kg; dazmegrel : 1 mg/kg; dazoxiben : 4.1 mg/kg) and a protracted duration of action in rats and dogs (inhibition 8 h after 1.25 mg/kg orally > 80 %).In vitro, R 68070 inhibits the aggregation of human platelets in plasma stimulated with collagen (IC50 : 4 x 10-6 M), but also with U 46619 (IC50 : 3.8 x 10-6 M) without affecting the primary aggregation reaction elicited by ADP, 5-HT or adrenaline. The compound thus also produces platelet TXA2/prostaglandin endoperoxide receptor blockade.In rats and in dogs R 68070 (1.25 mg/kg I.V.) potently prevents thrombus formation in carotid and coronary arteries damaged by electrical stimulation.The combination of platelet TXA2 synthetase inhibition with TXA2/prostaglandin endoperoxide blockade in one molecule thus might offer an improved anti-thrombotic effectiveness.