Relevant bibliographies by topics / Thromboxanes – Antagonistes

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  1. Journal articles
  2. Dissertations / Theses
  3. Book chapters
  4. Conference papers

Academic literature on the topic 'Thromboxanes – Antagonistes'

Author: Grafiati
Published: 4 June 2021
Last updated: 11 February 2022

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Journal articles on the topic "Thromboxanes – Antagonistes"

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Hall, Steven E. "Thromboxane A2 receptor antagonists." Medicinal Research Reviews 11, no. 5 (September 1991): 503–79. http://dx.doi.org/10.1002/med.2610110504.

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Gresele, P. "Thromboxane-synthase and thromboxane A2 antagonistic drugs." Thrombosis Research 65 (January 1992): S19. http://dx.doi.org/10.1016/0049-3848(92)90352-b.

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Klar, U., J. Kuhnke, A. Pletsch, H. Rehwinkel, and R. Schreyer. "Novel prostanoid thromboxane A2 antagonists." Bioorganic & Medicinal Chemistry Letters 5, no. 12 (June 1995): 1219–24. http://dx.doi.org/10.1016/0960-894x(95)00199-4.

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TERAO, Shinji. "Thromboxane A2 synthetase inhibitors and thromboxane A2 receptor antagonists." Journal of Synthetic Organic Chemistry, Japan 45, no. 1 (1987): 2–13. http://dx.doi.org/10.5059/yukigoseikyokaishi.45.2.

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Wardle, E. N. "Phospholipid derived mediators and glomerulonephritis." Mediators of Inflammation 2, no. 2 (1993): 99–102. http://dx.doi.org/10.1155/s0962935193000134.

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The contributions made by the various eicosanoids, PAF, the HETES and the lipoxins to the pathophysiology of glomerulonephritis is reviewed. A case can be made for clinical trials of PAF, leukotriene and thromboxane antagonists. Combined thromboxane synthetase and thromboxane receptor antagonism would seem to be the more efficacious approach for the various disease entities.
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Grandoch, Maria, Christof Börgermann, Paschal Oude Weernink, Yvonne Mahlke, Benjamin Schwindenhammer, Artur-Aron Weber, Jens Fischer, Karl Jakobs, Carsten Sand, and Martina Schmidt. "8-pCPT-conjugated cyclic AMP analogs exert thromboxane receptor antagonistic properties." Thrombosis and Haemostasis 103, no. 03 (2010): 662–76. http://dx.doi.org/10.1160/th09-06-0341.

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SummaryMembrane-permeable 8-(4-chlorophenylthio)-2'-O-methyl cyclic AMP (8-pCPT-2'-O-Me-cAMP) has been shown to specifically activate cAMP-regulated Epac proteins, without direct effects on protein kinase A and protein kinase G. During isometric tension measurements in thoracic aortic rings from Wistar rats, we observed that 8-pCPT-2'-O-Me-cAMP selectively induced a rightward shift of the concentration response curve for the thromboxane mimetic U46619, without altering the contractile response to noradrenaline. We hypothesised that 8-pCPT-2'-O-Me-cAMP and similar compounds may function as direct thromboxane receptor antagonists. Indeed, in addition to 8-pCPT-2'-OMe-cAMP, also 8-pCPT-cAMP, 8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-CPT-cAMPS) and 8-CPT-adenosine, but not 8-Bromo-2'-O-Me-cAMP, induced rightward shifts of the contractile response to U46619. Likewise, 8-pCPT-2'-O- Me-cAMP and Rp-8-CPT-cAMPS, but not 8-Bromo-2'-O-Me-cAMP, specifically reduced U46619-induced aggregation of human platelets. In addition, 8-pCPT-2'-O-Me-cAMP and Rp-8-CPT-cAMPS completely reversed U46619-induced reduction of intercellular adhesion molecule-1 expression and migration of human coronary artery endothelial cells. Most important, the cAMP analogs that reduced the contractile response to U46619 also concentration-dependently inhibited binding of the thromboxane receptor radioligand [5,6-3H]SQ29548 to human platelets. We conclude that 8-pCPT-conjugated cAMP analogs exert competitive thromboxane receptor antagonistic properties.
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HALL, S. E. "ChemInform Abstract: Thromboxane A2 Receptor Antagonists." ChemInform 22, no. 48 (August 22, 2010): no. http://dx.doi.org/10.1002/chin.199148316.

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Patrono, Carlo. "Thromboxane synthesis inhibitors and receptor antagonists." Thrombosis Research 57 (January 1990): 15–23. http://dx.doi.org/10.1016/0049-3848(90)90387-r.

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Vermylen, Jos, and Hans Deckmyn. "Thromboxane synthase inhibitors and receptor antagonists." Cardiovascular Drugs and Therapy 6, no. 1 (February 1992): 29–33. http://dx.doi.org/10.1007/bf00050914.

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Dickinson, Roger P., Kevin N. Dack, John Steele, and Michael S. Tute. "Thromboxane modulating agents. 2. Thromboxane receptor antagonists derived from the thromboxane synthase inhibitor dazmegrel." Bioorganic & Medicinal Chemistry Letters 6, no. 14 (July 1996): 1691–96. http://dx.doi.org/10.1016/0960-894x(96)00299-5.

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Dissertations / Theses on the topic "Thromboxanes – Antagonistes"

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Sbai, Brahim. "Les antagonistes des récepteurs du thromboxane A2." Bordeaux 2, 1995. http://www.theses.fr/1995BOR2P006.

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Perrin, Véronique. "Synthèse et caractérisation pharmacologique de nouveaux antagonistes potentiels des récepteurs du thromboxane A2." Lyon 1, 1996. http://www.theses.fr/1996LYO10314.

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Le thromboxane a#2 est un puissant constricteur des muscles lisses vasculaires et respiratoires ainsi qu'un agent de l'agregation plaquettaire. Il est implique dans des pathologies respiratoires, cardiovasculaires et renales. Compte tenu de l'etude des caracteristiques communes a de nombreux antagonistes connus, notre but etait de preparer des antagonistes des recepteurs du thromboxane a#2 possedant une structure 2-azanorbornane et ayant une fonction sulfone sur l'atome d'azote, ainsi que la chaine superieure, plus ou moins modifiee, des prostaglandines. Les differentes molecules obtenues ont ensuite ete soumises a des tests pharmacologiques in vivo sur les recepteurs vasculaires chez le rat conscient et in vitro sur les recepteurs plaquettaires chez le cobaye ; alors que les tests in vitro se sont averes en majorite negatifs, les tests in vivo ont permis de mettre en evidence une activite antagoniste sur les recepteurs vasculaires
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Traversa, Christel. "Synthèse et étude de nouveaux antagonistes potentiels du thromboxane A2 à partir d'aza-7-norbornadiènes." Lyon 1, 1994. http://www.theses.fr/1994LYO10305.

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Le thromboxane a#2 est un puissant agent constructeur des muscles lisses et un agregant plaquettaire implique dans l'hypertension arterielle, l'infarctus du myocarde, l'asthme et des maladies renales. Nous basant sur des caracteristiques communes a un grand nombre d'antagonistes connus, nous avons synthetise des molecules presentant comme structure de base un squelette 7-azanorbornane et la chaine superieure, complete ou non, des prostaglandines. Le squelette est obtenu par une reaction de diels-alder thermique entre le pyrrole 1-carboxylate de tertiobutyle et l'acetylene dicarboxylate de methyle. Le cycloadduit obtenu a pu etre transforme en aldehyde-ester sature selon deux voies. La premiere, apres l'hydrure de lithium et d'aluminium ; cependant, l'aldehyde est obtenu en melange d'isomeres. La seconde voie donne, par saponification, hydrogenation puis reduction selective de l'acide, un isomere pur. Cet aldehyde nous a alors permis, par reaction de wittig, d'introduire la chaine superieure de prostaglandines a six atomes de carbone. La chaine complete a pu etre obtenue par homologation de l'aldehyde puis condensation de wittig. Apres modification du substituant de l'azote, les molecules obtenues ont ete biologiquement testees soit in vitro sur des plaquettes de cobaye, soit in vivo sur des rats conscients. D'autres etudes ont ete menees en parallele pour eliminer la fonction ester restante sur le cycle de base et pour introduire une seconde fonction azotee dans la molecule. Ces dernieres voies n'ont pu encore aboutir
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Lacan, Fabrice. "Acides (2-(arylsulfonylimino)-2,3-dihydrothiazolyl)phenoxyacétiques antagonistes des récepteurs du thromboxana A2 : synthèse, étude structurale et pharmacologique." Bordeaux 2, 1997. http://www.theses.fr/1997BOR2B001.

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Riveron, Véronique. "Synthèse et étude de nouveaux antagonistes potentiels du thromboxane A2 et de la prostaglandine H2 faisant intervenir un squelette 2-azanorbornane." Lyon 1, 1993. http://www.theses.fr/1993LYO10293.

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Le thromboxane a2 est un puissant agent constricteur des muscles lisses et un agregant des plaquettes sanguines. Il intervient dans des pathologies cardiovasculaires et respiratoires. Au vu de la litterature, notre but etait d'obtenir des antagonistes des recepteurs du thromboxane a2 ayant un squelette 2-azanorbornane et incluant une fonction sulfonee sur l'azote, ainsi que la chaine alpha des prostaglandines (6 ou 7 atomes de carbone). La molecule finale comportant la chaine 5-hexenoique, a ete testee sur les recepteurs vasculaires chez le rat conscient normo-tendu, par observation des reponses du u 46619, agoniste connu des memes recepteurs: il s'est avere presenter une activite partielle et fugace a la dose de 50 mg/kg
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Fourcade, Olivier. "Rôle et mécanisme d'action de la sPLA2 de type ILA : hydrolyse après ectosytase et synthèse d'acide lysophatidique : inhibition de l'agrégation plaquettaire par le propofol : hydrolyse des phospholipides de nutritions parentérales." Toulouse 3, 2002. http://www.theses.fr/2002TOU30117.

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Harrold, Marc W. "Part 1, synthesis of trimetoquinol analogs as potential thromboxane A2 receptor antagonists ; Part 2, synthesis of permanently charged and permanently uncharged dopamine antagonists /." The Ohio State University, 1987. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487584612165271.

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Convard, Thierry. "Mise au point et validation d'un protocole général de modélisation moléculaire : application aux antagonistes du récepteur du thromboxane A2." Bordeaux 2, 1998. http://www.theses.fr/1998BOR2B003.

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Markovich, Kimberly M. "Part 1. Synthesis of fluorinated catecholamine derivatives as potential adrenergic stimulants and thromboxane A? antagonists ; Part 2. Synthesis of hydrazinium analogs of dopamine agonists and antagonists /." The Ohio State University, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487687485808709.

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Miljak, Marijan [Verfasser], and Christian [Akademischer Betreuer] Gratzke. "Effekte von Thromboxan-Rezeptor-Antagonisten auf die glattmuskuläre Kontraktion in der humanen Prostata / Marijan Miljak ; Betreuer: Christian Gratzke." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1126968226/34.

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Book chapters on the topic "Thromboxanes – Antagonistes"

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Davì, Giovanni, Francesca Santilli, and Natale Vazzana. "Thromboxane Receptors Antagonists and/or Synthase Inhibitors." In Antiplatelet Agents, 261–86. Berlin, Heidelberg: Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-29423-5_11.

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Marshall, Kay, Kate Lane, and Judith Senior. "Growth Inhibitory Effects of Thromboxane Antagonists on Breast Cancer Cell Lines: A Preliminary Study." In Advances in Experimental Medicine and Biology, 455–60. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4615-5325-0_61.

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Malo, P. E., M. A. Wasserman, and R. R. Osborn. "Evidence for a Thromboxane Antagonist in Selected In Vitro and In Vivo Systems." In Drugs Affecting Leukotrienes and Other Eicosanoid Pathways, 249–63. Boston, MA: Springer US, 1985. http://dx.doi.org/10.1007/978-1-4684-7841-9_20.

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Pill, J., J. Metz, K. Stegmeier, and F. Hartig. "Effects of Daltroban, a Thromboxane (TX) A2 Receptor Antagonist, on Lipid Metabolism and Atherosclerosis." In Prostaglandins in the Cardiovascular System, 107–13. Basel: Birkhäuser Basel, 1992. http://dx.doi.org/10.1007/978-3-0348-7262-1_16.

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Darius, Harald, Jutta Michael-Hepp, and Jürgen Meyer. "Receptor Binding Properties of the New and Specific Thromboxane Receptor Antagonist Bay U 3405." In Prostaglandins in the Cardiovascular System, 157–61. Basel: Birkhäuser Basel, 1992. http://dx.doi.org/10.1007/978-3-0348-7262-1_21.

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Abbas, Farhat, Zayheda Amin, Robert M. Burk, Achim H. P. Krauss, Kay Marshall, Judith Senior, and David F. Woodward. "A Comparative Study of Thromboxane (TP) Receptor Mimetics and Antagonists on Isolated Human Umbilical Artery and Myometrium." In Advances in Experimental Medicine and Biology, 219–30. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4899-1813-0_33.

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Meek, A. C., R. A. Harper, I. F. Lane, and C. N. McCollum. "The Evaluation of a New Specific Thromboxane A2 Antagonist on Radiolabelled Platelet Disposition in Prosthetic Grafts." In Clinical Application of Radiolabelled Platelets, 167–72. Dordrecht: Springer Netherlands, 1990. http://dx.doi.org/10.1007/978-94-009-0581-8_13.

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Simonet, Serge, Jean-Jacques Descombes, Marie-Odile Vallez, Thierry Dubuffet, Gilbert Lavielle, and Tony J. Verbeuren. "S 18886, a New Thromboxane (TP)-Receptor Antagonist Is the Active Isomer of S 18204 in All Species, Except in the Guinea-Pig." In Advances in Experimental Medicine and Biology, 173–76. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4899-1810-9_35.

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Dulin, Brian R., and Steven R. Steinhubl. "Thromboxane Antagonists." In Platelets in Cardiovascular Disease, 37–63. PUBLISHED BY IMPERIAL COLLEGE PRESS AND DISTRIBUTED BY WORLD SCIENTIFIC PUBLISHING CO., 2008. http://dx.doi.org/10.1142/9781860948527_0002.

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Le Breton, Guy C., Chang T. Lim, Chitra M. Vaidya, and Duane L. Venton. "[45] Thromboxane A2/prostaglandin H2 receptor antagonists." In Arachidonate Related Lipid Mediators, 406–14. Elsevier, 1990. http://dx.doi.org/10.1016/0076-6879(90)87047-7.

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Conference papers on the topic "Thromboxanes – Antagonistes"

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McCollum, C. N., R. A. Harper, I. F. Lane, and A. C. Meek. "A SPECIFIC THROMBOXANE A2 ANTAGONIST, GR32191, REDUCES PLATELET DEPOSITION IN PTFE GRAFTS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643753.

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Platelet inhibitory therapy improves patency in arterial grafts but when aspirin is given over 20% of patients discontinue therapy. We evaluated a specific Thromboxane A2 antagonist (GR32191 - Glaxo Group Research) on graft platelet uptake and pseudo-intimal hyperplasia in a canine model.Thirty greyhounds were randomised to orally administered placebo, GR32191 25mg, or aspirin150mg (ASA) plus dipyridamole 50mg (DPM) 12 hourly, commencing 48 hours prior to implantation of a 6cm length of 6mm-PTFE in the femoral artery. Autologous 111In-platelete were infused on the fifth postoperative day and platelet uptake measured by probe and ratemeter with the daily rise in graft radioactivity over reference expressed as Thrombogenicity Index (TI). Drugs were continued to 8 weeks when 111In-platelets were again infused and graft uptake measured on the excised graft and expressed as a ratio to blood. Percentage luminal stenosis was measured by grid microscopy.GR32191 significantly reduced luminal stenosis and graft platelet uptake compared to placebo and although TI appeared lower with both platelet inhibitory regimens this did not achieve statistical significance (p<0.1>0.05). Thromboxane A2 antagonists reducethrombus formation on artificial surfaces andbeing specific may have less undesirable effects.
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Stratton, L., and E. Hornby. "INHIBITION OF HUMAN PLATELET AGGREGATION BY THE THROMBOXANE MIMETIC, U46619." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644540.

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Recent publications suggest that high concentrations (10-100μM) of the stable analogues of PGH2, U46619 and U44069 stimulate adenylate cyclase (Avdonin et al.. 1985) and cause an elevation in cAMP in intact platelets (Best et al., 1979). The effect of high concentrations of U46619 on responses to ADP [1.0-30μM] and vasopressin [1-10nM] was investigated in human platelet rich plasma preincubated with the thromboxane antagonist, GR32191, [10μM] (Lumley et al., this meeting) and aspirin [0.1mM]. Concentration-effect curves to ADP were not affected by preincubation with O.lmM U46619 in the presence of GR32191 [10μM]. Under the same conditions, aggregation to vasopressin was inhibited. U46619 at 30μM had no effect on the vasopressin concentration-effect curve, but at 0.1mM, it resulted in an eight-fold rightwards shift and also reduced the maximum response by 30%. This was equivalent to the inhibition of vasopressin-induced aggregation achieved with prostacyclin at a concentration of 1nM in the same experiments. At 0.3mM, U46619 caused total inhibition of aggregation to vasopressin, equivalent to that seen with prostacyclin at 3nM. The failure of U44619 to inhibit ADP-induced aggregation may reflect inhibition of adenylate cyclase by ADP (Cusack et al. 1982). Aggregation induced by vasopressin is independent of inhibition of adenylate cyclase (Thomas et al.. 1983) and under these conditions, U46619 may induce increases in cAMP which exert an inhibitory action on platelet function. These results indicate that experiments using U44619 as an aggregating agent should be interpreted with caution. The high concentrations of U46619 required to induce aggregation in the presence of thromboxane antagonists may also cause stimulation of adenylate cyclase, thereby making an additional contribution to the inhibition observed. Avdonin P.V. et al.f Thromb. Res., 40, 101-112, 1985.Best L.C. et al.. Biochim, Biophys. Acta, 583. 344-351, 1979.Thomas M.E. et al.. Thromb. Res., 32, 557-566, 1983.Cusack et al.. Br. J. Pharmac., 76, 221-227, 1982.
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McCabe, P. J., L. E. Stratton, E. J. Hornby, and M. Foster. "INHIBITION OF GUINEA-PIG PLATELET FUNCTION IN VIVO AND EX VIVO USING THE THROMBOXANE A2 ANTAGONISTS, AH23848 AND GR32191." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643468.

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The thromboxane A2 antagonist, GR32191 (Lumley et al., this meeting) was tested as an inhibitor of platelet aggregation in the guinea-pig and compared with another Tx-antagonist, AH23848 (Brittain et al, 1985). Guinea-pigs were dosed with AH23848 or GR32191 at 0.01-1.0mg/kg. At intervals, blood was taken and PRP was prepared for ex vivo aggregation studies. Collagen concentrations causing half maximal aggregation (IC50) were calculated for test and vehicle-dosed groups. Inhibition was expressed as a concentration ratio (IC50 test/IC50 vehicle). For in vivo studies, 111In-labelled platelets (12μCi, 200μl) were injected into anaesthetised guinea-pigs and 24 hrs later oral doses of AH23848 or GR32191 (0.01-1.0mg/kg) or indomethacin (5mg/kg) were given. After one hour, blood was taken for platelet and radioactivity counting. The carotid artery was exposed under anaesthesia and a current of 2mA was applied for 60 sec. After 90 min, 1cm of the damaged and contralateral carotid vessels were removed for gamma-counting. Inhibition of accumulation of platelets on the injured artery was measured by comparison with the undamaged contralateral artery. Numbers of platelets deposited were calculated from the radioactivity of each section of artery and the radioactivity and platelet count in the blood. Oral doses of AH23848 or GR32191 inhibited ex vivo platelet aggregation induced by collagen. Maximum inhibition occurred one hour after dosing, and was still present at 6 hours for AH23848 (l.Omg/kg) and GR32191 (0.3mg/kg). GR32191 and AH23848 were active in vivo causing inhibition of platelet deposition at doses of 0.01-lmg/kg. The maximum inhibition of deposition was 58% for AH23848 (0.1mg/kg) and 63% for GR32191 (0.1mg/kg), with 50% inhibition at 0.02mg/kg for both. Indomethacin (5mg/kg p.o.) caused maximum inhibition of 58% at 5mg/kg p.o. suggesting that this represents the total thromboxane involvement in platelet deposition. GR32191 and AH23848 are thromboxane A2 antagonists with antithrombotic activity after oral dosing to guinea-pigs.Brittain R.T. et al Circulation, 72, 1208-1218, 1985.
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Johnson, G. J., P. C. Dunlop, M. J. Rabiet, L. A. Leis, and AH L. From. "THE DIHYDROPYRIDINE CALCIUM CHANNEL AGONIST, BAY K 8644, AND THE ANTAGONIST, NIFEDIPINE, INHIBIT U46619-INDUCED HUMAN PLATELET ACTIVATION BY COMPETITIVE BINDING TO THE THROMBOXANE A22/PGH2 RECEPTOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643756.

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The dihydropyridine (DP) Ca2+ channel antagonist, nifedipine (NF), inhibits platelet aggregation .in vitro and ex vivo by an undefined mechanism. Inhibition of Ca2+ influx via Ca2+ channels is a postulated mechanism, but voltage-dependent Ca2+ channels have not been demonstrated in platelets. We previously observed that NF blocked thromboxane A2 (TXA2)-induced platelet aggregation and secretion. In order to further evaluate the mechanism of DP inhibition of platelet activation, we studied the effects of NF and BAY K 8644, (BAY), a DP with opposite (agonist) effects on muscle cells, on human platelet aggregation and secretion induced by the TXA2 mimic, U46619. We also observed the effects of DP on biochemical consequences of platelet activation: cytoplasmic ionized Ca2+ ([Ca2+]i) by fura-2 fluorescence; phosphorylation of 40,000 Dalton protein (40KP) substrate of protein kinase C by SDS-PAGE and [32p] counting; TXA2 formation by RIA of TXB2. 1μM BAY and 10μM NF inhibited the 2nd wave of platelet aggregation and secretion induced by ADP or epinephrine and blocked aggregation and secretion induced by U46619. A Schild plot gave a slope of -1 indicating competitive inhibition of U46619 by BAY (K1[=0.7μM).BAY and NF also blocked U46619-induced phosphorylation of 40KP, rise in [Ca2+]i and TXB2 formation. The (+)-(R) enantiomer of BAY (BAY+) was responsible for BAY inhibition. BAY, BAY(+), and the R enantiomer of another DP, 202-791, all functioned as competitive antagonists of [3H]-U4661 9 binding (K1[ for BAY=2.8 μM-comparable to known receptor antagonists, 13-azaprostanoic acid and BM 13.177; K1 for BAY(+)=0.69μM). Neither BAY nor NF inhibited[3H]-yohimbine binding to α adrenergic receptors.NF, BAY, BAY(+) and BAY(-) in nM concentrations slightly stimulated platelet aggregation,secretion and biochemical events induced by U46619 similar to their effects on muscle. Therefore, DP's do not inhibit platelet activation by blocking voltage-dependent Ca2+ channels. The mechanism of DP inhibition of TXA2-induced platelet activation is stereoselective, competitive binding to the TXA2/PGH2 receptor. DP's may exert similar effects on TXA2-induced vascular smooth muscle contraction.
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Oura, Y., N. Sakiyama, R. Ueshima, M. Higuchi, E. Kakishitha, and K. Nagai. "Effect of Platelet Activating Factor(PAF) on the collagen induced platelet aggregation in whole blood." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643481.

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Studies of platelet aggregation are generally performed in p1ate1et-rich plasma(PRP) by the transmittance method. Recently, impedance aggregometry has been introduced which shows the platelet aggregability in whole blood. We compared the impedance aggregometry in whole blood with the transmittance method in PRP, with regard to collagen induced platelet aggregation. The aggregation rate in whole blood increased with increasing concentration of collagen, but remained unchanged in PRP. The factors which influence the platelet aggregation rate in whole blood were studied. CV-3988, that is the specific antagonist of PAF, acetylsalicylic acid (ASA) and phosphocreatine / creatine phosphokinase (CP/CPK) were used in order to evaluate the contribution of PAF, thromboxane and ADP in whole blood. CV-3988 dose-dependently inhibited platelet aggregation induced by collagen in whole blood, but did not inhibit the aggregation in PRP. ASA(10mM) inhibited the aggregation in whole blood incompletely too, but completely in PRP. And the inhibition of CP/CPK(CP/CPK : 1.5mM/50U/ml) was very weak in whole blood compared to that of other antagonists. The inhibitory effect of CV-3988 was investigated on the collagen induced platelet aggregation in whole blood which was pretreated with ASA ( 1 OmM ) and CP/CPK (1.5mM/50U/ml), resulting in a collagen induced aggregation in whole blood that was not completely inhibited. We conclude that there are some other different factors, which influence platelet aggregation in whole blood, in addition to thromboxane, ADP and PAF.
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Lumley, P., E. W. Collington, P. Hallett, E. J. Hornby, p. PA Humphrey, C. J. Wallis, D. Jack, and R. T. Brittain. "THE EFFECTS OF GR32191, A NEW THROMBOXANE RECEPTOR BLOCKING DRUG,ON PLATELETS AND VASCULAR SMOOTH MUSCLE IN VITRO." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643754.

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The effect of a new thromboxane receptor blocking drug GR32191 ([1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1"-biphenyl)-4-yl]methoxy] -3-hydroxy-2-(l-piperidinyl)cyclopentyl]-4-heptenoic acid,hydrochloride) has been examined upon platelets and vascular smooth muscle. In human platelet-rich plasma (PRP), aggregation to thromboxane(Tx) A2, PGH2, arachidonic acid, collagen andU-46619 was antagonised by GR32191 (IC50 range 2-36 nM).Primary aggregation (PRP treated with aspirin 10 pM) to ADP, 5-HT and adrenaline were unaffected by concentrations of GR32191 up to 10 pM. In human PRP, U-46619-induced aggregation and 5-HT release were antagonised by GR32191(10-100 nM). In contrast, in theabsence of aspirin, ADP-induced 5-HT release,but not aggregation, was antagonised by the compound implicating a role for TXA2 in the release process. In human PRP GR32191 (up to 30μM) did not itself induce aggregation or, in the presence of EGTA (4 mM), induce detectable shape change. Up to 10 μM GR32191 was without effect upon the inhibitory activity of PGI2 or PGD2 and at 1μMhad no significant inhibitory activity upon fatty acid cyclooxygenase, thromboxane synthase, prostacyclin synthase, 12-lipoxygenase orphosphodiesterase. The effect of GR32191was quantified further in human platelets suspended in whole blood or physiological salt solution. Aggregation to U-46619 was antagonised byGR32191 with a pA2 (slope of the Schild regression) of 8.2 (1.3) in whole blood and 8.8 (1.3) in resuspended platelets. The compound competitively and specifically antagonised the contractions of strips of human isolatedpulmonary blood vessels and rat and guinea-pig aortic strips produced by U-46619 with pA2 (slope) values of 8.2 (1.1), 7.9 (0.9) and 8.7(0.9) respectively. In contrast contractions induced by KC1 and 5-HT (rat) orKC1and histamine (guinea-pig) were unaffectedbyconcentrations of GR32191 up to 30 μM.Thus GR32191 is a potent and specific thromboxane receptor blocking drug on platelets and vascular smooth muscle in vitro. It is orally active and long lasting in man (Thomas, M et al.,this meeting).
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7

Van Diest, M. J., T. J. Verbeuren, and A. G. Herman. "RELAXATIONS INDUCED BY LIPOXYGENASE METABOLITES OF ARACHI-DONIC ACID IN SPLENIC ARTERIES OF THE DOG." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643796.

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The lipoxygenase metabolites of arachidonic acid, 15 hydroperoxyeicosatetraenoic acid (15HPETE) and its hydroxy derivative (15HETE) evoke contractions in a variety of isolated blood vessels. We recently were able to show that thromboxane A2 (TXA2)-receptor antagonists BM13177 and BM13505 suppress the contractions induced by lipoxygenase metabolites in canine splenic arteries, and that these compounds also inhibit the contractile effects of PGF2α and of the TXA2-mimetic U46619. We also reported that 15HETE and 15HPETE cause relaxations of isolated dog arteries when the tissues are contracted with prostaglandin F2α (PGF2α) or with U46619 and suggested that lipoxygenase metabolites may act as endogenous antagonists towards prostaglandin receptors. The present study was designed to investigate the effects of lipoxygenase metabolites of arachidonic acid in isolated splenic arteries in which the tone is raised by various agonists.Segments of canine splenic arteries with or without endothelium were placed in organ chambers filled with Krebs-Ringer solution at 37°C for isometric tension recording. Responses to 15HPETE were obtained in segments which were contracted with serotonin, K+, PGF2α or noradrenaline (the latter with or without BM13505); concentrations causing comparable levels of contraction were selected. HPETE evoked relaxations in segments with and without endothelium, during the contractions evoked by K+, PGF2α and noradrenaline (with or without BM13505). At higher concentrations, 15HPETE caused relaxations only during contractions induced by PGF2α and noradrenaline with BM13505. Our results suggest that 15HPETE can cause relaxations by two different mechanisms :(1) 15HPETE may act as an antagonist to PGF2α, which causes its contraction via the TXA2-receptor and,(2) in presence of BM13505, it suppresses the contractions to noradrenaline via an endothelium independent mechanism.
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8

Van Nueten, J. M., W. J. Janssens, and F. De Clerck. "VASOCONSTRICTION IN RESPONSE TO HUMAN PLATELET-VESSEL WALL INTERACTIONS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644598.

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Human blood platelets, stimulated with thrombin, induced contractions of isolated basilar artery segments of the dog. These platelet-mediated vascular contractions were inhibited in a concentration-dependent way by flunarizine, a Ca2+-entry blocker, selective for vascular tissues. This inhibition increased gradually as a function of time after contact with flunarizine to reach its maximum after 60-90 min. Biochemical and pharmacological analyses, using the 5-HT2-serotonergic antagonist ritanserin, the thromboxane A2/prostaglandin endo-peroxide antagonist BM 13.177 and the fatty acid cyclo-oxygenase inhibitor suprofen, showed that 5-hydroxytryptamine and prostanoids (thromboxane A2, prostaglandine endoperoxides) were the main mediators involved. They further suggested amplification between 5-hydroxytryptamine and prostanoids at the vascular level.(1) Incubation period; (2) Inhibition of platelet-mediated vascular contractions.This study demonstrates that 5-hydroxytryptamine, acting in concert with thromboxane A2 and/or prostaglandine-endoper-oxides, is responsible for the vasoconstrictor effects of aggregating platelets. It further indicates that influx of calcium ions is involved in these vasoconstrictor responses.
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9

Patscheke, H., K. Stegmeier, W. Hornberger, Ch Staiger, and G. Neugebauer. "INHIBITION OF PLATELET ACTIVATION BY THE NOVEL THROMBOXANE RECEPTOR ANTAGONIST BM 13.505." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643469.

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The effects of BM 13.505 (4-[2-(4-Chlorobenzenesulfonylami-no)ethyl]-benzene acetic acid = BM) on human washed platelets and platelet-rich plasma (PRP) were studied in vitro and after oral application in 10 male volunteers ex vivo/in vitro. BM inhibited the shape change, aggregation and (1H)serotonin release when the platelets were activated by agents that stimulate via the thromboxane Az/prostaglandin H2 (TXA2/PGH2) receptor. Such agonists were collagen, methyl mercury chloride (methyl-Hg), arachidonic acid and the PGH2 analogue U 46,619. BM was 9 times more potent an inhibitor than sulotroban (= BM 13.177). The slope of the Schild plot for U 46,619-induced shape change was close to unity, which is consistent with competitive antagonism. The pA2 -value in PRP was 6.5. BM did not inhibit the primary platelet activation induced by ADP, PAF or serotonin in aspirin-treated platelets, indicating that the inhibition by BM was specific for the platelet TXA2/PGH2 receptor. BM also suppressed platelet activation by PGH2 which accumulated when the platelets were stimulated by collagen, methyl-Hg or arachidonic acid in the presence of the thromboxane synthase inhibitor dazoxiben. At concentrations beyond about 600 times the apparent KD (200 μM in PRP and 10 μM in washed platelets), BM induced a transient shape change. This effect was inhibited by sulotroban and might indicate a slight intrinsic activity of BM. BM 10 μM exerted no effect on the formation of 14C-labelled TXB2, PGE2, PGD2, PGF2α , HHT and 12-HETE from 14C-labelled arachidonic in washed platelet suspensions, irrespective of whether exogenous or endogenous (by methyl-Hg mobilized) arachidonic acid was metabolized. Volunteers who received 7 oral doses of 400 mg in 12 hour intervals reached peak plasma concentrations between 9.5 and 45 pM 1 hour after dosage. The bleeding time was prolonged by 90 %. Platelet activation by collagen, methyl-Hg and U 46,619 was inhibited for at least 9 hours after a single dose. No objective and subjective side effects were observed in any of the subjects. Thus, BM 13.505 is a specific, we11-tolerated and long-acting TXA2/PGH2 receptor antagonist. (Supported by the DFG, Grant Pa-263).
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10

Brace, L. D., J. Fareed, and D. Hoppensteadt. "EFFECTS OF THROMBOXANE PATHWAY ANTAGONISTS ON HEPARIN-INDUCED PLATELET AGGREGATION (H-IPA) AND TESTING FOR HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643383.

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We have reported that heparin and heparin fractions can induce platelet aggregation (PA) in a substantial number of normal healthy drug-free donors. H-IPA was shown to depend upon the molecular weight and concentration of the heparin preparation used, but its mechanism remains unknown. Therefore, we performed experiments with antagonists of the thromboxane pathway to determine whether arachidonic acid metabolites contribute to H-IPA. When indomethacin or 13-azaprostanoic (a thromboxane receptor anatagonist) was added to the PRP of donors whose platelets had been shown to aggregate in response to heparin, H-IPA was completely inhibited: heparin (bovine or porcine) caused 75% PA, while pretreatment with indomethacin or 13-APA reduced the response to 6%. Similarly, if the same donors ingested 650 mg aspirin 3 hours prior to phlebotomy, the PA response to heparin was reduced to approx. 10%. These results demonstrate that at least part of the mechanism of H-IPA is mediated through thromboxane generation. However, the mechanism by which'heparin stimulates thromboxane production in platelets remains unknown.In some patients, heparin is known to induce an immune response that causes severe thrombocytopenia (HIT) and is associated with arterial and venous thrombosis. Fratantoni, et al. (Blood 45:395-401, 1975) have introduced a PA method for the diagnosis of HIT. We have used a modification of this method to show that the PA observed when heparin is added to a mixture of normal donor PRP and HIT patient’s serum or plasma can be inhibited by antagonists of the thromboxane pathway. When normal donor PRP was pretreated with indomethacin or 13-APA and then mixed with serum from a HIT patient (290 uL PRP:160 uL serum), the PA response to heparin was reduced from 75% to 10% or less. Similarly, if the PRP donors ingested 650 mg aspirin prior to phlebotomy, PA in the HIT test was reduced from 75% to 10% or less. Thus, the interaction of heparin with the antibody and platelets causes thromboxane generation and leads to PA. Cyclo-oxygenase specific antiplatelet drugs and inhibitors of thromboxane generation may be useful in the clinical management of HIT and H-IPA.
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