424 results on '"Thromboxane Production"'
Search Results
2. Urinary Thromboxane Production in Diabetic and Non-Diabetic Patients of Acute Coronary Syndrome
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Ajit Singh, Tom Devasia, Deepak Uppunda, Gunajn Bonde, Sheetal Chauhan, Yeshwanth Rao Karkala, and Hashir Kareem
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Aging ,Percutaneous transluminal coronary angioplasty ,medicine.medical_specialty ,Acute coronary syndrome ,business.industry ,Urinary system ,medicine.disease ,Health Professions (miscellaneous) ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,General Biochemistry, Genetics and Molecular Biology ,Thromboxane Production ,Internal medicine ,Diabetes mellitus ,General Health Professions ,medicine ,Cardiology ,Dentistry (miscellaneous) ,business ,General Dentistry ,Non diabetic - Published
- 2020
3. Distribution of Cox-1 and Cox-2 in Normal and Inflamed Tissues
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Seibert, Karen, Zhang, Yan, Leahy, Kathleen, Hauser, Scott, Masferrer, Jaime, Isakson, Peter, Honn, Kenneth V., editor, Nigam, Santosh, editor, and Marnett, Lawrence J., editor
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- 1997
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4. Transfer of very low density lipoprotein-associated phospholipids to activated human platelets
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Salam Ibrahim, Anaël Djimet-Baboun, Valérie Pruneta-Deloche, Catherine Calzada, Michel Lagarde, and Gabriel Ponsin
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lipoprotein lipase ,thromboxane production ,high density lipoprotein ,tetrahydrolipstatin ,Biochemistry ,QD415-436 - Abstract
LDL-associated phospholipids (PLs) may be transferred into platelets. In this work, we characterized the role of VLDLs as PL donors. VLDL transferred radiolabeled PLs to platelets in a temperature- and concentration-dependent manner. LPL stimulated this process through its action on VLDL lipolysis, because it was abolished by tetrahydrolipstatin. LPL also stimulated the platelet production of thromboxane B2 (TXB2). Both LPL actions were inhibited in the presence of fatty acid-free albumin, suggesting that they were attributable to fatty acids generated during VLDL lipolysis. To study the relationship between PL transfers and platelet activation, we performed incubations in the presence of HDL, a physiological acceptor of PL released from VLDL. HDL antagonized the transfer of PL from VLDL to platelets but had no effect on the production of TXB2, suggesting that PL transfers were driven by platelet activation. Confirming this idea, thrombin stimulated both the production of TXB2 and the transfers of PL. In conclusion, VLDL can transfer PL to platelets. These transfers are stimulated by LPL and thrombin through their action on platelet activation. They might be enhanced in pathologies characterized by increased VLDL concentrations.
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- 2006
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5. Preserved Hemostasis During the Combined Use of Aprotinin and Aspirin in CABG Operations
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Tabuchi, N., van Oeveren, W., Eijsman, L., Roozendaal, K. J., Gu, Y. J., Wildevuur, Ch. R. H., Friedel, N., editor, Hetzer, R., editor, and Royston, D., editor
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- 1991
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6. Persistent long-term platelet activation and endothelial perturbation in women with Takotsubo syndrome
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Susanna Fiorelli, Benedetta Porro, Sonia Eligini, Nicola Cosentino, Simone Barbieri, Viviana Cavalca, José Pablo Werba, Patrizia Amadio, Alessandra Gorini, Silvia S. Barbieri, Alessandro Di Minno, Daniela Trabattoni, Elena Tremoli, Fabrizio Veglia, Mattia Giuliani, and Paolo Olivares
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0301 basic medicine ,Blood Platelets ,medicine.medical_specialty ,Time Factors ,Platelet Aggregation ,Thromboxane ,Thrombomodulin ,Prostacyclin ,RM1-950 ,Thromboxane Production ,03 medical and health sciences ,Thromboxane A2 ,0302 clinical medicine ,Takotsubo Cardiomyopathy ,Internal medicine ,medicine ,Humans ,Platelet ,Myocardial infarction ,Platelet activation ,Endothelial dysfunction ,Long-term follow-up ,Aged ,Pharmacology ,Aspirin ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Case-Control Studies ,Cardiology ,Citrulline ,Female ,Endothelium, Vascular ,Therapeutics. Pharmacology ,business ,Takotsubo syndrome ,Biomarkers ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Background Takotsubo (TTS) syndrome is an acute cardiac condition characterized by transient and reversible left ventricle dysfunction that mainly affects postmenopausal women. Catecholamine burst is the most accredited mechanism underpinning TTS onset and leading to endothelial dysfunction and platelet activation. Even if the use of low dose acetylsalycilic acid (ASA) in this clinical setting is based on both clinical presentation and unfavorable long-term prognosis, its efficacy has been recently challenged. Aim This study was designed to assess endothelial function, residual thromboxane formation and platelet aggregation in TTS women on low-dose ASA treatment at long-term follow-up. Methods Twenty-eight females with previously diagnosis of TTS syndrome were enrolled. Data were compared to those obtained from 23 coronary artery disease (CAD) women with a history of acute myocardial infarction, and 26 control subjects with no TTS or clinically evident CAD. Psychological and clinical profile were assessed in all study groups at the enrollment. Main metabolites involved in L-arginine/nitric oxide pathway, urinary prostacyclin, serum and urine thromboxane metabolites were measured by LC MS/MS methods. Thrombomodulin levels were quantified using an ELISA kit, and platelet aggregation, carried out on platelet rich-plasma, was induced by ADP or by epinephrine (EPI), norepinephrine (NORE) and TRAP-6, alone or in association with ADP and evaluated by Born’s method. Results In TTS women an endothelial derangement, characterized by reduced citrulline production and increased thrombomodulin concentration, with no perturbation in prostacyclin levels, was evidenced. In addition, despite ASA treatment, TTS displayed a higher residual thromboxane formation, in parallel with an enhanced platelet response to compared to CAD. Conclusions Our study highlighted the presence of endothelial perturbation in TTS patients even at long-term from the index event. The residual thromboxane production and platelet aggregation still leave open the question about the use of low dose ASA in this clinical setting.
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- 2021
7. Validating 123I-metaiodobenzylguanidine as a platelet marker for non-invasive imaging in rabbits
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Saihkay, Hom N.S., Rickards, Karen J., Page, Clive P., and Ballinger, James R.
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BLOOD platelet aggregation , *CHEMOTAXIS , *THROMBOXANES , *LABORATORY rabbits , *LEUCOCYTES , *INFLAMMATION , *RADIOACTIVITY , *PATHOLOGY - Abstract
Abstract: Introduction: Recent in vitro studies in our laboratory have demonstrated that platelets are necessary for leukocyte recruitment and airway remodelling in models of allergic airway inflammation, and also migrate to lung tissues in response to anti-IgE or relevant allergens in allergic asthma. Non-invasive imaging of platelet migration in vivo would provide a further insight into the roles of platelets in inflammatory diseases such as asthma, and metaiodobenzylguanidine (MIBG) was considered as a suitable platelet marker. Methods: The kinetics of MIBG uptake into rabbit platelets, the effect of MIBG on platelet function and the effect of platelet activation on MIBG uptake and retention were investigated. MIBG-labelled platelets were administered intravenously into rabbits and the time course of radioactivity in the lung and blood was monitored as a function of stimulation. Results: Following a 4h incubation of MIBG in rabbit PRP, a near maximal MIBG uptake (52.4±20.2%) in platelets occurred. This time point was chosen for subsequent in vitro studies. In vitro platelet function studies showed that MIBG has no effect on ADP or PAF-induced platelet aggregation, PAF-induced thromboxane production or fMLP-induced platelet chemotaxis. However, serotonin showed a significant effect on MIBG uptake and retention, but only at high concentrations. Stimulation of rabbit platelets with ADP and PAF caused a significant release of stored MIBG in vitro. Following i.v. administration of MIBG labelled platelets, the response to i.v. ADP and PAF stimulation was small but significant. Discussion: The release of MIBG from platelets in vivo, particularly following stimulation, leads to high background levels. Therefore, MIBG may have limited utility as a label for imaging platelets in vivo using PET. However, it may be a useful marker in detecting pathological conditions where platelet migration is involved. [ABSTRACT FROM AUTHOR]
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- 2011
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8. Defective acid hydrolase secretion inRUNX1haplodeficiency: Evidence for a global platelet secretory defect
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A. K. Rao and Mortimer Poncz
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Adult ,Blood Platelets ,Male ,0301 basic medicine ,Serotonin ,medicine.medical_specialty ,Hydrolases ,Haploinsufficiency ,030204 cardiovascular system & hematology ,Article ,Thromboxane Production ,03 medical and health sciences ,chemistry.chemical_compound ,Thromboxane A2 ,0302 clinical medicine ,Thrombin ,Internal medicine ,medicine ,Humans ,Secretion ,Platelet ,Phospholipids ,Genetics (clinical) ,Arachidonic Acid ,biology ,Platelet Count ,business.industry ,Secretory Vesicles ,Granule (cell biology) ,Thromboxanes ,Hematology ,General Medicine ,030104 developmental biology ,Endocrinology ,chemistry ,Case-Control Studies ,Child, Preschool ,Core Binding Factor Alpha 2 Subunit ,Mutation ,biology.protein ,Female ,Arachidonic acid ,Blood Platelet Disorders ,business ,Acid hydrolase ,medicine.drug - Abstract
Background RUNX1 haplodeficiency is associated with thrombocytopenia, platelet dysfunction and a predisposition to acute leukaemia. Platelets possess three distinct types of granules and secretory processes involving dense granules (DG), α-granules and vesicles or lysosomes containing acid hydrolases (AH). Dense granules and granule deficiencies have been reported in patients with RUNX1 mutations. Little is known regarding the secretion from AH-containing vesicles. Methods and results We studied two related patients with a RUNX1 mutation, easy bruising, and mild thrombocytopenia. Platelet aggregation and 14C serotonin in platelet-rich plasma (PRP) were impaired in response to ADP, epinephrine, collagen and arachidonic acid. Contents of DG (ATP, ADP), α-granules (β-thromboglobulin) and AH-containing vesicles (β-glucuronidase, β-hexosaminidase, α-mannosidase) were normal or minimally decreased. Dense granules secretion on stimulation of gel-filtered platelets with thrombin and divalent ionophore A23187 (4-12 μmol L−1) were diminished. β-thromboglobulin and AH secretion was impaired in response to thrombin or A23187. We studied thromboxane-related pathways. The incorporation of 14C -arachidonic acid into phospholipids and subsequent arachidonic acid release on thrombin activation was normal. Platelet thromboxane A2 production in whole blood serum and on thrombin stimulation of PRP was normal, suggesting that the defective secretion was not due to impaired thromboxane production. Conclusions These studies provide the first evidence in patients with a RUNX1 mutation for a defect in AH (lysosomal) secretion, and for a global defect in secretion involving all three types of platelet granules that is unrelated to a granule content deficiency. They highlight the pleiotropic effects and multiple platelet defects associated with RUNX1 mutations.
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- 2017
9. Antiplatelet, antioxidative, and anti-inflammatory effects of hydroquinone
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Mei-Chi Chang, Bei-En Chang, Li-Deh Lin, Ming-Shu Lee, Jiiang-Huei Jeng, Bor-Ru Lin, Yu-Hwa Pan, Yun-Chia Lian, and Sin-Yuet Yeung
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0301 basic medicine ,Blood Platelets ,Antioxidant ,Platelet Aggregation ,Physiology ,medicine.drug_class ,Thromboxane ,medicine.medical_treatment ,Clinical Biochemistry ,Anti-Inflammatory Agents ,Pharmacology ,Dinoprost ,Anti-inflammatory ,Antioxidants ,Dinoprostone ,Thromboxane Production ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Thromboxane A2 ,0302 clinical medicine ,medicine ,Animals ,Humans ,Platelet ,Platelet activation ,Cells, Cultured ,Dental Pulp ,Interleukin-8 ,Cell Biology ,Hydroquinones ,Thromboxane B2 ,030104 developmental biology ,chemistry ,Cyclooxygenase 2 ,030220 oncology & carcinogenesis ,Arachidonic acid ,Rabbits ,Inflammation Mediators ,Platelet Aggregation Inhibitors ,Signal Transduction - Abstract
Platelets play crucial roles in thrombosis and hemostasis through platelet activation and aggregation that are crucial in cardiovascular diseases. Hydroquinone (HQ) and its derivatives are present in many dermatological creams, paints, motor fuels, air, microorganisms, and plant products like wheat bread, fruit, coffee, and red wine. The effect of HQ on humans is not clear. In this study, we found that HQ (>25 μM) inhibited arachidonic acid (AA)-induced platelet aggregation. HQ suppressed AA-induced thromboxane B2 production of platelets. HQ (>10 μM) also attenuated ex vivo platelet-rich plasma aggregation. HQ prevented the interleukin (IL)-1β-induced 8-isoprostane, and PGE2 production, but not IL-8 production of pulp cells. These results indicate that HQ may have an antiplatelet effect via inhibition of thromboxane production. HQ has antioxidative and anti-inflammatory effects, and possible inhibition of COX. Exposure and consumption of HQ-containing products, food or drugs may have antiplatelet, antioxidative, and anti-inflammatory effects.
- Published
- 2018
10. High oxygen modifies vasodilator effect of cysteine via enhanced oxidative stress and thromboxane production in the rat mesenteric artery
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Hiroyuki Kinoshita, Emi Nakamura, Guo-Gang Feng, Hisaki Hayashi, Jiazheng Li, Motohiko Sato, Yoshitaka Yasuda, and Yoshihiro Fujiwara
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0301 basic medicine ,medicine.medical_specialty ,Physiology ,Clinical Biochemistry ,Glycine ,Vasodilation ,030204 cardiovascular system & hematology ,Thromboxane Production ,03 medical and health sciences ,chemistry.chemical_compound ,Thromboxane A2 ,0302 clinical medicine ,Superoxides ,Peroxynitrous Acid ,Physiology (medical) ,Internal medicine ,Glyburide ,medicine ,Animals ,Cysteine ,Rats, Wistar ,Mesenteric arteries ,Glycoproteins ,NADPH oxidase ,biology ,Superoxide ,Nitrotyrosine ,NADPH Oxidases ,Thromboxanes ,Mesenteric Arteries ,Rats ,Oxygen ,Thromboxane B2 ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Biochemistry ,Alkynes ,1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt ,biology.protein - Abstract
Whether high oxygen is harmful to the vascular function is unclear. The present study examined if high oxygen modifies vasodilator effect of cysteine via enhanced oxidative stress and thromboxane production. Rat mesenteric arteries with endothelium at 95 or 50 % oxygen were subjected to isometric force recordings, measurement of thromboxane B2 levels, determination of superoxide and peroxynitrite levels and evaluation of NADPH oxidase subunit protein expression, respectively. L-cysteine (0.01-3 mM) constricted or dilated arteries at 95 and 50 % oxygen, respectively. Thromboxane receptor antagonist SQ-29,548 (1 μM) abolished the constriction at 95 % oxygen. L-cysteine (3 mM) increased levels of thromboxane B2 in arteries upon 95 % oxygen application. L-cysteine relaxed arteries treated with superoxide inhibitor tiron (2 mM) or NADPH oxidase inhibitor gp91ds-tat (1 μM) irrespective of the oxygen concentration while ATP-sensitive K(+) channel inhibitor glibenclamide (1 μM) and cystathionine-γ-lyase (CSE) inhibitor DL-propargylglycine (10 mM) similarly abolished the relaxation. L-cysteine (3 mM) with 95 % oxygen augmented levels of superoxide as well as nitrotyrosine within the artery, concomitantly with enhanced membrane protein expression of NADPH oxidase subunit p47phox. The higher concentration of oxygen attenuates L-cysteine-induced vasodilation via superoxide production mediated by NADPH oxidase along with thromboxane A2 production, resulting in vasoconstriction. The increased levels of superoxide, as well as peroxynitrite, coexist with the impaired vasodilation related to ATP-sensitive K(+) channels and CSE. Higher oxygen with plasma cysteine may cause oxidative stress and vasoconstrictor prostanoid production in blood vessels.
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- 2016
11. Effect of acetylsalicylic acid on plasma thromboxane B and platelet aggregation in man.
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Nuotto, E., Gordin, A., Paasonen, M., Metsä-Ketelä, T., and Lamminsivu, U.
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The effect of acetylsalicylic acid (ASA) on plasma thromboxane A (TXA) and platelet aggregation was studied in 12 healthy, non-smoking, male students, in a double-blind, cross-over study, after single doses and 14-days on ASA 50, 100, 250 and 1000 mg/day. Platelet production of TXA was assessed by measuring the thromboxane B (TXB) content of clotted venous blood by RIA. Platelet aggregation induced by ADP and adrenaline was studied by the method of Born. All doses of ASA completely suppressed the production of TXB within 3 h, with the exception of the 50 mg dose, which effected only 61% suppression ( p<0.001). After administration for 14 days the suppression was complete, even including the lowest dose. At that time ASA had blocked the secondary phase of adrenaline-and ADP-induced platelet aggregation. It is concluded that the maximal antithromboxane and antiaggregatory effects, which last for at least 24 h, can be achieved by continuous daily administration of ASA 50 mg. [ABSTRACT FROM AUTHOR]
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- 1983
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12. Lack of Bioequivalence Among Low-dose, Enteric-coated Aspirin Preparations
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Dermot Cox and Desmond J. Fitzgerald
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Thromboxane ,030204 cardiovascular system & hematology ,Bioequivalence ,Pharmacology ,Thromboxane Production ,03 medical and health sciences ,Thromboxane A2 ,0302 clinical medicine ,Medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Aspirin ,Arachidonic Acid ,Dose-Response Relationship, Drug ,business.industry ,Enteric coating ,Effective dose (pharmacology) ,Peptide Fragments ,Bioavailability ,Dose–response relationship ,Therapeutic Equivalency ,Tablets, Enteric-Coated ,business ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Low-dose aspirin (75 mg or 81 mg) is considered to be the lowest effective dose for cardiovascular protection; however, the use of enteric preparations has created a source of variability in bioavailability. As part of regulatory requirements, we carried out bioequivalence tests for two 75 mg enteric-coated aspirin preparations (Caprin and Protek) using Nu-Seals 75 mg aspirin as the comparator. The primary endpoint was serum thromboxane levels after 14 days of treatment. Protek failed to meet bioequivalence, as it was significantly less effective than Nu-Seals. In contrast, Caprin was not bioequivalent with Nu-Seals but as it was more effective it was granted approval. However, 75 mg plain aspirin was found to be more effective than Nu-Seals at inhibiting serum thromboxane production. Thus, there is significant variation in the ability of low-dose aspirin preparations to inhibit serum thromboxane production.
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- 2017
13. Inherited Platelet Function Disorders
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A. Koneti Rao
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biology ,business.industry ,Hematology ,medicine.disease ,Platelet membrane glycoprotein ,Thromboxane Production ,Oncology ,Scott syndrome ,Recombinant factor VIIa ,Hemostasis ,Antifibrinolytic agent ,Immunology ,biology.protein ,Medicine ,Secretion ,Platelet ,business - Abstract
Inherited disorders of platelet function are characterized by highly variable mucocutaneous bleeding manifestations. The platelet dysfunction arises by diverse mechanisms, including abnormalities in platelet membrane glycoproteins, granules and their contents, platelet signaling and secretion mechanisms: thromboxane production pathways and in platelet procoagulant activities. Platelet aggregation and secretion studies using platelet-rich plasma currently form the primary basis for the diagnosis of an inherited platelet dysfunction. In most such patients, the molecular and genetic mechanisms are unknown. Management of these patients needs to be individualized; therapeutic options include platelet transfusions, 1-desamino-8d-arginine vasopressin (DDAVP), recombinant factor VIIa, and antifibrinolytic agents.
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- 2013
14. Iamin: A Human Growth Factor with Multiple Wound-Healing Properties
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Pickart, Loren and Sorenson, John R. J., editor
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- 1987
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15. Limitations in Measurement of Prostaglandins and Thromboxanes
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Kindahl, H., Granström, E., Boeynaems, J. M., editor, and Herman, A. G., editor
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- 1980
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16. Measurement of Thromboxane Production in Vivo: Metabolic and Analytical Aspects
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Granström, E., Westlund, P., Kumlin, M., Nordenström, A., Samuelsson, B., editor, Berti, F., editor, Folco, G. C., editor, and Velo, G. P., editor
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- 1985
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17. The Molecular, Biochemical and Human Pharmacology of Thromboxane A2 in Renal Disease
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FitzGerald, Garret A., Murray, Rosemary, Price, Patricia, Catella, Francesca, Dunn, Michael J., editor, Patrono, Carlo, editor, and Cinotti, Giulio A., editor
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- 1989
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18. Biosynthesis and Metabolism of Prostaglandins and Thromboxanes. Quantitative Determination in Biological Material
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Granström, E., Domschke, Wolfram, editor, Dammann, Hanns Gerd, editor, Peskar, B. M., editor, and Holtermüller, K. H., editor
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- 1988
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19. Cellular Interactions in Extracorporeal Circuitry
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Lawford, Patricia, Crawford, N., editor, and Taylor, D. E. M., editor
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- 1986
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20. Prostacyclin and Thromboxane Production from Macrophages of Amyloid Resistant and Sensitive Mice
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Leslie, Crystal A., Lazzarri, Antonio, Cathcart, Edgar S., Glenner, George G., editor, Osserman, Elliott F., editor, Benditt, Earl P., editor, Calkins, Evan, editor, Cohen, Alan S., editor, and Zucker-Franklin, Dorothea, editor
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- 1986
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21. Impact of Clozapine, N-Desmethylclozapine and Chlorpromazine on Thromboxane Production in Vitro
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Abigail J. Sheldrick, Luise Schmidt, Uta Ceglarek, Ulrich Sack, Katrin Bauer, Linda Kortz, Susen Becker, Joachim Thiery, Roland Mergl, Jeremias Schönherr, and Hubertus Himmerich
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Adult ,medicine.medical_specialty ,Chlorpromazine ,Thromboxane ,Stimulation ,Serotonergic ,Thromboxane Production ,Thromboxane A2 ,Young Adult ,chemistry.chemical_compound ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Clozapine ,Middle Aged ,Thromboxane B2 ,Endocrinology ,chemistry ,Female ,lipids (amino acids, peptides, and proteins) ,Antipsychotic Agents ,circulatory and respiratory physiology ,medicine.drug - Abstract
Thromboxane A2 (TxA2) and the activation of its receptor have been shown to modulate vasoconstriction and platelet aggregation as well as dopaminergic and serotonergic signalling. Dopaminergic and serotonergic systems play a crucial role in the pathophysiology of schizophrenia and these systems are the main targets of antipsychotics (APs). As the first antipsychotic (AP) chlorpromazine (CPZ) has already been shown to reduce TxA2, we hypothesized that the AP clozapine and its metabolite N-desmethylclozapine (NDMC) might also influence TxA2 production. We measured levels of thromboxane B2 (TxB2), the metabolite of the very unstable molecule TxA2, in unstimulated and stimulated blood samples of 10 healthy female subjects in a whole blood assay using toxic shock syndrome toxin-1 (TSST-1) and monoclonal antibody against surface antigen CD3 combined with protein CD40 (OKT3/CD40) as stimulants. Blood was supplemented with the APs CPZ, clozapine or NDMC in one of four different concentrations. Additionally, thromboxane levels were measured in blood without the addition of APs under different stimulation conditions. Under TSST-1 as well as OKT3/CD40 stimulation, mean TxB2 concentrations were significantly (p < 0.05) decreased by clozapine over all applied concentrations. NDMC led to a decrease in TxB2 levels under unstimulated conditions as well as under TSST-1 stimulation. CPZ reduced TxB2 production at low concentrations under unstimulated and TSST-1- stimulated conditions. Clozapine, NDMC and CPZ possibly act on neurotransmitter systems via modulation of TxA2 or TxB2 production. Additionally, known side effects of APs such as orthostatic hypotension may be a result of changes in the concentrations of TxA2 or TxB2.
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- 2012
22. Comparative effects of immediate‐release and extended‐release aspirin on basal and bradykinin‐stimulated excretion of thromboxane and prostacyclin metabolites
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Hui Nian, Rhonda H. Lee, Chang Yu, Jessica K. Devin, Claudia E. Ramirez, Jorge L. Gamboa, and Nancy J. Brown
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medicine.medical_specialty ,Thromboxane ,Metabolite ,Bradykinin ,Prostacyclin ,030204 cardiovascular system & hematology ,Excretion ,Thromboxane Production ,03 medical and health sciences ,Basal (phylogenetics) ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Aspirin ,prostacyclin ,Original Articles ,3. Good health ,Endocrinology ,Neurology ,chemistry ,Original Article ,bradykinin ,thromboxane ,medicine.drug - Abstract
A goal of aspirin therapy is to inhibit thromboxane production and platelet aggregation without inhibiting endothelial production of the vasodilator and anti‐thrombotic prostacyclin. This study tested the hypothesis that extended‐release aspirin (NHP‐554C) would have increased selectivity for inhibition of basal and simulated thromboxane formation compared to immediate‐release aspirin (ASA). Thirty‐six healthy subjects were randomized to NHP‐554C or ASA groups. Within each group, subjects were randomized to 5‐day treatment with 81 mg/d, 162.5 mg/d and placebo in a crossover design in which treatment periods were separated by 2‐week washout. On the fifth day of treatment, 81 mg/d and 162.5 mg/d ASA reduced basal urinary excretion of the stable thromboxane metabolite 11‐dehydro‐thromboxane B2 62.3% and 66.2% and basal excretion of the stable prostacyclin metabolite 2,3‐dinor‐6‐keto‐PGF1α 22.8% and 26.5%, respectively, compared to placebo. NHP‐554C 81 mg/d and 162.5 mg/d reduced 11‐dehydro‐thromboxane B2 53% (P = 0.03 vs. ASA 81 mg/d) and 67.9% and 2,3‐dinor‐6‐keto‐PGF1α 13.4% and 18.5%, respectively. NHP‐554C 81 mg/d did not significantly reduce basal excretion of the prostacyclin metabolite. Both doses of ASA and NHP significantly reduced excretion of both thromboxane and prostacyclin metabolites following intravenous bradykinin. During NHP‐554C 162.5 mg/d, but not during ASA, bradykinin significantly increased urinary 2,3‐dinor‐6‐keto‐PGF1α. Nevertheless, 11‐dehydro‐thromboxane B2 and 2,3‐dinor‐6‐keto‐PGF1α responses to bradykinin were statistically similar during ASA and NHP‐554C. In conclusion, at doses of 81 and 162.5 mg/d immediate‐ and extended‐release aspirin selectively decrease basal thromboxane production. Both forms of aspirin decrease bradykinin‐stimulated thromboxane and prostacyclin production, but some stimulated prostacyclin production remains during treatment with NHP‐554C.
- Published
- 2016
23. Inherited Platelet Disorders: Diagnosis and Management
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A. Koneti Rao and Natthapol Songdej
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Mutation ,biology ,business.industry ,Platelet disorder ,medicine.disease ,medicine.disease_cause ,Oculocutaneous albinism ,Thromboxane Production ,Membrane glycoproteins ,Recombinant factor VIIa ,Immunology ,medicine ,biology.protein ,Platelet ,Aminocaproic acid ,business ,medicine.drug - Abstract
Inherited disorders of platelets are characterized by highly variable mucocutaneous bleeding manifestations and excessive hemorrhage following surgical procedures or trauma. They include patients who have decreased platelet counts, abnormal platelet function or a combination of both, in general reflecting underlying abnormalities that culminate in defective platelet production and function. Over the last two decades there has been an impressive increase in the number of genetic abnormalities identified as leading to inherited thrombocytopenias. In some of these patients platelets have impaired function as well. Most patients with inherited platelet function have mild to moderate bleeding manifestations. In the vast majority of patients suspected to have an inherited platelet function defect the molecular and genetic mechanisms are unknown. The platelet dysfunction in these patients arises by diverse mechanisms, including abnormalities in membrane glycoproteins, granules and their contents, platelet signaling and secretion mechanisms, thromboxane production pathways and in platelet procoagulant activities. The platelet dysfunction may arise due to mutation in a transcription factor (e.g. RUNX1) leading to abnormalities in multiple mechanisms involved in platelet production as well as in function. In this chapter, clinical and laboratory aspects of Inherited disorders of platelets are discussed.
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- 2016
24. Inibição seletiva da ciclo-oxigenase-2: riscos e benefícios
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Reila Tainá Mendes, Regina Sordi, Daniel Fernandes, Fábio André dos Santos, Cassiano Pereira Stanczyk, and Michel Fleith Otuki
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medicine.medical_specialty ,Prostacyclin ,Inflammation ,Pharmacology ,Selective inhibition ,Thromboxane Production ,Gastrointestinal complications ,Rheumatology ,medicine ,Pain perception ,inibidores de ciclo-oxigenase 2 ,chemistry.chemical_classification ,biology ,business.industry ,farmacologia ,cardiovascular diseases ,Surgery ,Enzyme ,cyclooxygenase 2 inhibitors ,chemistry ,doenças cardiovasculares ,biology.protein ,Cyclooxygenase ,pharmacology ,medicine.symptom ,business ,medicine.drug - Abstract
Os anti-inflamatórios inibidores das ciclo-oxigenases (COX) representam a classe de fármacos mais comumente utilizada. A COX corresponde a uma classe de enzimas conservadas evolutivamente e tem duas isoformas principais: a COX-1 e a COX-2. Seus subprodutos têm papel fundamental na inflamação e na percepção da dor. Há uma grande discussão entre a inibição seletiva ou não da COX pelo fato de a mesma, além de participar dos eventos inflamatórios, ter papel fundamental na manutenção da homeostase do organismo. A inibição seletiva da COX-2 surgiu com o intuito de reduzir os efeitos deletérios gastrintestinais de uma inibição não seletiva; em contrapartida, a inibição exclusiva da COX-2 associou-se a sérios eventos cardiovasculares, por causar um desequilíbrio entre a produção de prostaciclina e tromboxano. O objetivo deste trabalho é revisar a literatura a esse respeito, apontando os prós e os contras da inibição seletiva ou não das enzimas ciclo-oxigenases. The cyclooxygenase (COX) inhibitors are the most common drugs used worldwide. COX corresponds to an evolutionarily conserved class of enzymes and has two main isoforms: COX-1, which is largely associated with physiological functions, and COX-2, which is largely associated with pathological functions. Their subproducts have an important role in inflammation and pain perception. The COX-2 selective inhibition was designed to minimize gastrointestinal complications of non-selective inhibition. However, this exclusive COX-2 inhibition was associated with serious cardiovascular events, for causing an imbalance between prostacyclin and thromboxane production. The objective of this study is to discuss the mechanisms underlying the cardiovascular effects, pointing out the advantages and disadvantages of the selective or nonselective COX inhibitors.
- Published
- 2012
25. Urinary 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin-F1α in healthy post-menopausal and pre-menopausal women receiving aspirin 100 mg
- Author
-
Zita Arieselia, Marcia Dewi Hartanto, Ali Baziad, Arini Setiawati, and Rianto Setiabudy
- Subjects
Aspirin ,medicine.medical_specialty ,business.industry ,Thromboxane ,Urinary system ,Prostacyclin ,Hematology ,Urine ,medicine.disease ,Menopause ,Thromboxane Production ,Endocrinology ,Internal medicine ,Antithrombotic ,medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
The prevalence of cardiovascular diseases in women increases sharply after menopause. In postmenopausal women, thromboxane production increases while prostacyclin decreases. Low dose aspirin reduces the production of both thromboxane and prostacyclin. The present study was an open-label clinical trial with two parallel groups of 15 premenopausal women and 15 postmenopausal women. Twenty-four hours urine was collected from each subject before and after aspirin 100 mg daily for 7 days. The concentration of thromboxane and prostacyclin was measured as their metabolites (11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin-F1α) in urine using enzyme immunoassay methods. This study showed that aspirin significantly reduced thromboxane in both groups with significantly larger percentage reduction in postmenopausal women compared to premenopausal women (73.32 vs. 61.13%, p = 0.021). This study also showed that aspirin reduced prostacyclin significantly in both groups, but the percentage reduction between the groups was not significantly different. The decrease in the ratio of 11-dTXB2/2,3-dinor-6-keto-PGF1α should be compared to assess aspirin efficacy as an antithrombotic. Calculation of the ratio of 11-dTXB2/2,3-dinor-6-keto-PGF1α before aspirin consumption was higher in postmenopausal women than in premenopausal women. The decrease in 11-dTXB2/2,3-dinor-6-keto-PGF1α ratio by aspirin was greater in postmenopausal women than in premenopausal women (1.91 vs. 0.17; p = 0.022). It was concluded that aspirin reduced thromboxane and prostacyclin significantly in each group with significant 11-dTXB2 percentage reduction between groups and non-significant 2,3-dinor-6-keto-PGF1α percentage reduction between groups, but reduced the 11-dTXB2/2,3-dinor-6-keto-PGF1α ratio much larger in postmenopausal women compared to that in premenopausal women.
- Published
- 2012
26. Simvastatin administration reduces thromboxane production in subjects taking aspirin: Links between aspirin resistance and thrombin generation
- Author
-
Roman Topór-Mądry, Zbigniew Siudak, Wiesława Tracz, Marta Leśniak, and Anetta Undas
- Subjects
Male ,Simvastatin ,medicine.medical_specialty ,Statin ,aspirin ,Thromboxane ,medicine.drug_class ,Drug Resistance ,statins ,Thromboxane Production ,Thromboxane A2 ,Thrombin ,Bleeding time ,Internal medicine ,medicine ,Humans ,Platelet ,Aspirin ,medicine.diagnostic_test ,business.industry ,cholesterol ,Middle Aged ,thrombin ,Endocrinology ,Cardiovascular Diseases ,Anesthesia ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,thromboxane ,medicine.drug - Abstract
Growing evidence indicates that statins may reduce thromboxane A(2) synthesis and thrombin generation. We investigated the relationships between thromboxane production, thrombin generation, and oxidative stress in patients receiving aspirin before and after statin administration.An open-label study was conducted in 112 men, aged 54.4 ± 7.3 years, at an increased cardiovascular risk receiving aspirin (75 mg/d). Prior to and following a 3-month simvastatin treatment (40 mg/d), we evaluated circulating thromboxane B(2) (TXB(2)), inflammatory markers, 8-isoprostane, and prothrombin fragment 1.2 (F1.2), a marker of thrombin generation, which was also measured in blood collected every 60s at the site of standardized skin incisions.Subjects (n=28) with pretreatment TXB(2) concentrations in the highest quartile ("aspirin-resistant patients") were more frequently current smokers and had elevated C-reactive protein (CRP), interleukin-6, 8-isoprostane, shorter bleeding time, and increased F1.2 production in a model of microvascular injury, when compared with the 3 remaining quartiles (all, p0.001). Simvastatin decreased serum TXB(2) in the whole group (by 20%, p=0.0008). Patients in the highest quartile of the baseline TXB(2) had still higher posttreatment TXB(2), CRP, interleukin-6, and F1.2 formation following injury (all, p0.001). Simvastatin-induced change in TXB(2) correlated with the magnitude of changes in maximum levels and the velocity of F1.2 formation (all p0.001) but not with changes in inflammatory markers or lipid profile.The study shows that statins significantly reduce platelet TXA(2) formation in patients taking low-dose aspirin and this effect is associated with attenuated thrombin formation in response to vascular injury.
- Published
- 2012
27. Pulmonary Arterial Responses to Reactive Oxygen Species Are Altered in Newborn Piglets With Chronic Hypoxia-Induced Pulmonary Hypertension
- Author
-
Yongmei Zhang, Candice D. Fike, Mark R. Kaplowitz, Judy L. Aschner, James C. Slaughter, and Sandra L. Pfister
- Subjects
medicine.medical_specialty ,Thromboxane ,Hypertension, Pulmonary ,Immunoblotting ,Indomethacin ,Sus scrofa ,Enzyme-Linked Immunosorbent Assay ,Prostacyclin ,Pulmonary Artery ,Statistics, Nonparametric ,Article ,Prostacyclin synthase ,Thromboxane Production ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Internal medicine ,medicine ,Animals ,Cyclooxygenase Inhibitors ,Dazoxiben ,Hypoxia ,biology ,Imidazoles ,medicine.disease ,Pulmonary hypertension ,Intramolecular Oxidoreductases ,Endocrinology ,Animals, Newborn ,chemistry ,Vasoconstriction ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Prostaglandins ,biology.protein ,Thromboxane-A Synthase ,Cyclooxygenase ,Thromboxane-A synthase ,Reactive Oxygen Species ,circulatory and respiratory physiology ,medicine.drug - Abstract
Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. ROS might mediate vascular responses, at least in part, by stimulating prostanoid production. Our goals were to determine whether the effect of ROS on vascular tone is altered in resistance pulmonary arteries (PRAs) of newborn piglets with chronic hypoxia-induced pulmonary hypertension and the role, if any, of prostanoids in ROS-mediated responses. In cannulated, pressurized PRA, ROS generated by xanthine (X) plus xanthine oxidase (XO) had minimal effect on vascular tone in control piglets but caused significant vasoconstriction in hypoxic piglets. Both cyclooxygenase inhibition with indomethacin and thromboxane synthase inhibition with dazoxiben significantly blunted constriction to X+XO in hypoxic PRA. X+XO increased prostacyclin production (70 ± 8%) by a greater degree than thromboxane production (50 ± 6%) in control PRA; this was not the case in hypoxic PRA where the increases in prostacyclin and thromboxane production were not statistically different (78 ± 13% versus 216 ± 93%, respectively). Thromboxane synthase expression was increased in PRA from hypoxic piglets, whereas prostacyclin synthase expression was similar in PRA from hypoxic and control piglets. Under conditions of chronic hypoxia, altered vascular responses to ROS may contribute to pulmonary hypertension by a mechanism that involves the prostanoid vasoconstrictor, thromboxane.
- Published
- 2011
28. Passive smoking increases platelet thromboxane
- Author
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Christian Pirich, Helmut Sinzinger, Bernhard A. Peskar, Yannis Stamatopoulos, Peter Schmid, H. Kritz, and Georgios Karanikas
- Subjects
medicine.medical_specialty ,Passive smoking ,Thromboxane ,business.industry ,Passive smoke ,medicine.disease_cause ,Malondialdehyde ,Thromboxane Production ,chemistry.chemical_compound ,Thromboxane A2 ,Endocrinology ,chemistry ,Anesthesia ,Internal medicine ,medicine ,Platelet ,Arachidonic acid ,Cardiology and Cardiovascular Medicine ,business - Abstract
Although active smoking is known to enhance platelet thromboxane production, no data on passive smoking are available yet. In an 18 m3 room, the influence of single and repeated exposure to passive smoke for 60 minutes was assessed in nonsmokers and smokers. Smokers and nonsmokers were matched for sex and age. All the evaluated parameters (plasma TXB2, serum TXB2, malondialdehyde, 11-dehydro-TXB2, conversion of exogenous arachidonic acid to hydroxy-5,8,10-heptadecatrienoic acid, and TXB2) were higher in smokers than nonsmokers at baseline conditions, immediately and 6 hours after passive exposure to cigarette smoke. Repeated exposure of nonsmokers rendered their platelets more activated, so they became closer to the behavior of smokers. Contributing to the development of hemostatic imbalance, these results indicate that passive smoking may enhance thromboxane A2 release from the platelets.
- Published
- 2011
29. Effects of Clopidogrel and Aspirin on Platelet Aggregation, Thromboxane Production, and Serotonin Secretion in Horses
- Author
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Denae N. LoBato, Soyoung Kwon, Benjamin M. Brainard, Mark G. Papich, Kira L. Epstein, and James N. Moore
- Subjects
Aspirin ,General Veterinary ,business.industry ,Laminitis ,Pharmacology ,Clopidogrel ,Serotonin secretion ,Thromboxane Production ,Thromboxane B2 ,chemistry.chemical_compound ,chemistry ,Anesthesia ,Medicine ,Platelet ,Platelet activation ,business ,medicine.drug - Abstract
Background: Critically ill horses are susceptible to thrombotic disease, which might be related to increased platelet reactivity and activation. Objectives: To compare the effect of oral clopidogrel and aspirin (ASA) on equine platelet function. Animals: Six healthy adult horses. Methods: Horses received clopidogrel (2 mg/kg PO q24h) or ASA (5 mg/kg PO q24h) for 5 days in a prospective randomized cross-over design. Platelet aggregation responses to adenosine diphosphate (ADP) and collagen via optical aggregometry, and platelet secretion of serotonin (5HT) and production of thromboxane B2 (TXB2) by ELISA were evaluated. In horses receiving clopidogrel, high-performance liquid chromatography analysis for clopidogrel and its carboxylic-acid metabolite SR 26334 was performed. Results: SR 26334 was identified in all clopidogrel-treated horses, although the parent compound was not detected. Clopidogrel resulted in decreases in ADP-induced platelet aggregation persisting for 120 hours after the final dose. ADP-induced platelet aggregation decreased from a baseline of 70.2 ± 14.7% to a minimum of 15.9 ± 7.7% 24 hours after the final dose (P < .001). Collagen-induced aggregation decreased from a baseline of 93 ± 9.5% to a minimum of 70.8 ± 16.9% 48 hours after the final dose (P < .001). ASA did not decrease platelet aggregation with either agonist. ASA decreased serum TXB2 from a baseline value of 1310 ± 1045 to 128 ± 64 pg/mL within 24 hours (P < .01). Conclusions and Clinical Importance: Clopidogrel effectively decreases ADP-induced platelet aggregation in horses, and could have therapeutic applications for equine diseases associated with platelet activation.
- Published
- 2010
30. Review Article: Blood platelets and their role in the genesis and sequelae of intestinal ischaemia
- Author
-
R.J. Evans
- Subjects
Disseminated intravascular coagulation ,Pathology ,medicine.medical_specialty ,business.industry ,Infarction ,General Medicine ,medicine.disease ,Thrombosis ,Review article ,Thromboxane Production ,Mechanism of action ,Immunology ,Medicine ,Platelet ,Platelet activation ,medicine.symptom ,business - Abstract
Summary Activation of platelets is the key step in the formation of macroscopic thrombi and emboli and in micro-thromboembolism associated with disseminated intravascular coagulation (DIC). Macroscopic thrombosis may compromise the blood supply of the gut. Strangulation or infarction of the gut, from whatever cause, commonly result in endotoxaemia, DIC and multiple organ failure. Equine platelets may be activated physiologically by a wide range of agonists. Information is now emerging about the receptor populations and intracellular signalling pathways of equine platelets. Less is known about platelet-vessel wall interactions in the horse or the mechanisms of platelet activation in endotoxaemia. Antiplatelet drugs have been disappointing in endotoxaemia, possibly because of the relative unimportance of thromboxane production in the activation of equine platelets. Dextran 70, however, is a useful treatment of thromboembolic colic and the mechanism of action is now beginning to be understood.
- Published
- 2010
31. The interaction of ibuprofen and diclofenac with aspirin in healthy volunteers
- Author
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H W H A Huntjens-Fleuren, M de Metz, E. J. Vollaard, and M P Schuijt
- Subjects
Adult ,Male ,Diclofenac ,Platelet Aggregation ,Analgesic ,Ibuprofen ,Pharmacology ,Thromboxane Production ,chemistry.chemical_compound ,Risk Factors ,medicine ,Humans ,Drug Interactions ,Platelet ,Antipyretic ,Aspirin ,Cross-Over Studies ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Middle Aged ,Research Papers ,Thromboxane B2 ,chemistry ,Delayed-Action Preparations ,Female ,business ,medicine.drug - Abstract
Background and purpose: Aspirin reduces the risk of myocardial infarction and stroke by inhibiting thromboxane production in platelets. This inhibition can be competitively antagonized by some non-steroidal anti-inflammatory drugs (NSAIDs). Experimental approach: By measuring thromboxane B2 production in healthy volunteers, we investigated whether ibuprofen (800 mg three times daily for 7 days) or diclofenac (50 mg three times daily for 7 days) taken concurrently with aspirin 80 mg (once daily for 7 days) influenced the inhibitory effect of aspirin. The effects were compared with aspirin 30 mg (once daily for 7 days), which is the lowest dose of aspirin with a proven thromboprophylactic effect. Key results: The median percentage inhibition of thromboxane B2 levels by 30 mg or 80 mg aspirin was 90.3% (range 83.1–96.0%) and 98.0% (range 96.8–99.2%) respectively. The inhibition by concurrent administration of slow release diclofenac and 80 mg aspirin was 98.1% (range 97.2–98.9%), indicating no interference between aspirin and diclofenac. The inhibition decreased significantly by concurrent administration of immediate release ibuprofen and 80 mg aspirin (86.6%; range 77.6–95.1%) to a level less than 30 mg aspirin. Conclusions and implications: As alternatives are easily available, NSAIDs such as diclofenac should be preferred to ibuprofen for combined use with aspirin.
- Published
- 2009
32. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides
- Author
-
Bengt Samuelsson, Jan T. Svensson, and Mats Hamberg
- Subjects
Blood Platelets ,Serotonin ,Platelet Aggregation ,Stereochemistry ,Thromboxane ,Medicine (miscellaneous) ,Arachidonic Acids ,Mass Spectrometry ,Thromboxane receptor ,Thromboxane Production ,chemistry.chemical_compound ,Thromboxane A2 ,Discovery and development of cyclooxygenase 2 inhibitors ,Humans ,Platelet ,Prostaglandin G2 ,Pyrans ,Multidisciplinary ,Nutrition and Dietetics ,biology ,Peroxides ,Thromboxane B2 ,chemistry ,Thromboxanes ,Prostaglandins ,biology.protein ,Arachidonic acid ,Thromboxane-A synthase ,Hydroxy Acids ,Prostaglandin H2 ,Research Article - Abstract
An unstable [t1/2 at 37 degrees = 32 +/- 2 (SD) sec] intermediate, thromboxane A2, was detected in the conversion of prostaglandin G2 into 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid (thromboxane B2) in platelets. The intermediate was trapped by addition of methanol, ethanol, or sodium azide to suspensions of washed human platelets incubated for 30 sec with arachidonic acid or prostaglandin G2. The structures of the resulting derivatives demonstrated that the intermediate possessed an oxane ring as in thromboxane B2 but lacked its hemiacetal hydroxyl group. Additional experiments using 18O2 or [2H8]arachidonic acid in the formation of thromboxane B2 and CH3O2H for the trapping of thromboxane A2, together with information on the t1/2 of the intermediate, indicated the presence of an oxetane structure in thromboxane A2. Incubation of arachidonic acid or prostaglandin G2 with washed platelets led to formation of an unstable factor that induced irreversible platelet aggregation and caused release of [14C]serotonin from platelets that had been incubated with [14C]serotonin. The properties and the mode of formation of this factor indicated that it was identical with thromboxane A2. Furthermore, evidence is presented that the more unstable and major component of rabbit aorta contracting substance (RCS) formed in platelets and guinea pig lung is also thromboxane A2.
- Published
- 2009
33. Policosanol: updating and perspectives
- Author
-
Giancarlo Cravotto, Simona Oliaro, Arianna Binello, and Franca Viola
- Subjects
Antioxidant ,Nutrition and Dietetics ,Chemistry ,medicine.medical_treatment ,Sugar cane ,Endocrinology, Diabetes and Metabolism ,Reductase ,Thromboxane Production ,Policosanol · High molecular weight alcohols · Clinical studies · Hypocholesterolaemic ,Decreased Platelet Aggregation ,Biochemistry ,medicine ,AMP Kinase ,Lower blood cholesterol ,Policosanol ,medicine.drug ,Food Science - Abstract
Different mixtures of higher aliphatic alcohols are on the market under the name “policosanol” claiming, without the support of independent data, the therapeutic efficacy and tolerability that former studies had demonstrated for the original policosanol. This name originally referred to a mixture of eight higher aliphatic primary alcohols obtained at the beginning of the 1990s from sugar-cane wax, and patented by Cuban researchers for its ability to lower blood cholesterol, and its antiplatelet and antioxidant properties. Analysis by GC-MS shows qualitative/quantitative differences in policosanol-like preparations from different plant sources and origins. The anticholesterolaemic activity and some desirable pleiotropic effects (decreased platelet aggregation, LDL oxidation, thromboxane production and foam-cell production) of the original policosanol have been confirmed by more than 50 clinical studies. However these results have recently been questioned by a few authors who have reported a modest or negligible activity of policosanol, whether from sugar cane or from other plant sources. A review of this important issue is therefore in order. Although the mechanism involved in the anticholesterolaemic effect has not been fully elucidated, there is clear evidence that policosanol induces AMP kinase phosphorylation and inhibits HMG-CoA reductase.
- Published
- 2008
34. UP-REGULATED THROMBOXANE PRODUCTION IN THE RAT LIVER WITH BILIARY OBSTRUCTION DOES NOT CONTRIBUTE TO PROMOTE HEPATIC INJURY
- Author
-
Satoru Kawai, Katsutaka Watanabe, Tomomi Kitagawa, Toru Kawai, Yukihiro Yokoyama, Masato Nagino, and Kiyotaka Kawai
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Metabolite ,medicine.medical_treatment ,Critical Care and Intensive Care Medicine ,Gastroenterology ,Gene Expression Regulation, Enzymologic ,Receptors, Thromboxane A2, Prostaglandin H2 ,Thromboxane Production ,Thromboxane A2 ,chemistry.chemical_compound ,In vivo ,Internal medicine ,medicine ,Animals ,Ozagrel ,Enzyme Inhibitors ,Hyaluronic Acid ,Rats, Wistar ,Receptor ,Saline ,Fibrous capsule of Glisson ,business.industry ,Liver Diseases ,Alanine Transaminase ,Bilirubin ,Bridged Bicyclo Compounds, Heterocyclic ,Rats ,Thromboxane B2 ,Hydrazines ,Endocrinology ,Liver ,chemistry ,Fatty Acids, Unsaturated ,Emergency Medicine ,Methacrylates ,lipids (amino acids, peptides, and proteins) ,Thromboxane-A Synthase ,business ,circulatory and respiratory physiology - Abstract
This study sought to determine whether in vivo inhibition of thromboxane A2 (TXA2) action contribute to attenuate hepatic damage after bile duct ligation (BDL). Male Wistar rats were assigned to sham operation or BDL. At the time of operation, infusion pump with saline, ozagrel natrium (TXA2 synthase inhibitor), or SQ29548 (TXA2 receptor antagonists) was implanted in the abdominal cavity. Plasma alanine aminotransferase, aspartate aminotransferase, hyaluronic acid, and total bilirubin levels were measured at 4 days after the operation. The levels of plasma TXB2, a stable metabolite of TXA2, were significantly increased after BDL. Gene expression of TXA2 synthase was also significantly upregulated in the liver. Nonetheless, either an inhibition of TXA2 synthesis by ozagrel natrium or a blockade of TXA2 receptor by SQ29548 has no effect in every measured parameter related to hepatic function. These results indicated that despite a highly increased production in the liver, TXA2 is not directly related to the hepatic injury in BDL rats.
- Published
- 2008
35. Aspirin Resistance in Children with Heart Disease at Risk for Thromboembolism: Prevalence and Possible Mechanisms
- Author
-
Lisa C. Heistein, David E Fixler, William A. Scott, Claudio Ramaciotti, Matthew S. Lemler, Janna M. Journeycake, and Thomas M. Zellers
- Subjects
Blood Platelets ,Heart Defects, Congenital ,Male ,medicine.medical_specialty ,Adolescent ,Heart disease ,Thromboxane ,Drug Resistance ,Gastroenterology ,Thromboxane Production ,chemistry.chemical_compound ,Risk Factors ,Thromboembolism ,Internal medicine ,Prevalence ,medicine ,Humans ,Platelet ,Platelet activation ,Child ,Retrospective Studies ,Aspirin ,Creatinine ,Dose-Response Relationship, Drug ,business.industry ,Infant ,Prognosis ,medicine.disease ,Texas ,Thromboxane B2 ,Epinephrine ,chemistry ,Child, Preschool ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Female ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,Follow-Up Studies ,medicine.drug - Abstract
Aspirin is used to prevent thromboembolism in children with heart disease without evidence supporting its efficacy. Studies in adults report a 5%-51% prevalence of aspirin resistance, yet the mechanisms involved are poorly understood. Our aims were to determine its prevalence in these children and to explore its possible mechanisms. One hundred twenty-three cardiac patients routinely receiving aspirin were prospectively enrolled. Platelet function was measured by Platelet Function Analyzer (PFA)-100 using epinephrine and adenosine diphosphate (ADP) agonists. Aspirin resistance was defined as failure to prolong the epinephrine closure time following aspirin administration. Urine levels of 11-dehydro-thromboxane B(2) (11-dTXB(2)) were measured to determine inhibition of the cyclo-oxygenase pathway. The prevalence of aspirin resistance was 26%. Median ADP closure time was shorter for aspirin-resistant (79.60-115 s) than for aspirin-sensitive (100.60-240 s) patients (p0.01). 11-dTXB(2) levels did not correlate with aspirin resistance. Aspirin-resistant patients had higher 11-dTXB(2) levels before (7297 vs. 4160 pg/mg creatinine; p0.01) and after (2153 vs. 1412 pg/mg; p = 0.03) aspirin, with a similar percentage decrease in thromboxane (70.5% vs. 66.1%; p = 0.43). Our findings suggest that resistance is not entirely due to lack of inhibition of platelet thromboxane production. Alternative sources of thromboxane and thromboxane-independent mechanisms, such as ADP-induced platelet activation, may contribute to aspirin resistance.
- Published
- 2007
36. Hydroxychavicol, a novel betel leaf component, inhibits platelet aggregation by suppression of cyclooxygenase, thromboxane production and calcium mobilization
- Author
-
Hsyueh Liang Wu, C. J. Kao, C. H. Chang, Jiiang-Huei Jeng, M. C. Chang, C. S. Lee, Biing-Jiun Uang, Yi-Ling Tsai, Bor-Ru Lin, Yi-Jane Chen, and C. Y. Tsai
- Subjects
Pharmacology ,biology ,Chemistry ,Thromboxane ,Thromboxane Production ,Thromboxane B2 ,chemistry.chemical_compound ,Eicosanoid ,Biochemistry ,biology.protein ,Platelet aggregation inhibitor ,Platelet ,Cyclooxygenase ,Ex vivo - Abstract
Background and purpose: Platelet hyperactivity is important in the pathogenesis of cardiovascular diseases. Betel leaf (PBL) is consumed by 200-600 million betel quid chewers in the world. Hydroxychavicol (HC), a betel leaf component, was tested for its antiplatelet effect. Experimental approach: We tested the effect of HC on platelet aggregation, thromboxane B2 (TXB2) and reactive oxygen species (ROS) production, cyclooxygenase (COX) activity, ex vivo platelet aggregation and mouse bleeding time and platelet plug formation in vivo. The pharmacokinetics of HC in rats was also assessed. Key results: HC inhibited arachidonic acid (AA) and collagen-induced platelet aggregation and TXB2 production. HC inhibited the thrombin-induced TXB2 production, but not platelet aggregation. SQ29548, suppressed collagen- and thrombin-induced TXB2 production, but not thrombin-induced platelet aggregation. HC also suppressed COX-1/COX-2 enzyme activity and the AA-induced ROS production and Ca2+ mobilization. HC further inhibited the ex vivo platelet aggregation of platelet-rich plasma (>100 nmole/mouse) and prolonged platelet plug formation (>300 nmole/mouse) in mesenteric microvessels, but showed little effect on bleeding time in mouse tail. Moreover, pharmacokinetics analysis found that more than 99% of HC was metabolized within 3 min of administration in Sprague-Dawley rats in vivo. Conclusions and implications: HC is a potent COX-1/COX-2 inhibitor, ROS scavenger and inhibits platelet calcium signaling, TXB2 production and aggregation. HC could be a potential therapeutic agent for prevention and treatment of atherosclerosis and other cardiovascular diseases through its anti-inflammatory and antiplatelet effects, without effects on haemostatic functions. British Journal of Pharmacology (2007) 152, 73–82; doi:10.1038/sj.bjp.0707367
- Published
- 2007
37. Eicosanoids in Inflammation: Biosynthesis, Pharmacology, and Therapeutic Frontiers
- Author
-
L. Gordon Letts, Subhash P. Khanapure, David S. Garvey, and David R. Janero
- Subjects
Inflammation ,Cyclooxygenase 2 Inhibitors ,biology ,Chemistry ,Thromboxane ,Lipoxygenase ,Anti-Inflammatory Agents ,Prostacyclin ,General Medicine ,Pharmacology ,Thromboxane Production ,Phospholipase A2 ,Eicosanoid ,Prostaglandin-Endoperoxide Synthases ,Drug Discovery ,biology.protein ,medicine ,Eicosanoids ,Humans ,Cyclooxygenase ,medicine.symptom ,Eicosanoid Production ,medicine.drug - Abstract
In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane and leukotrienes collectively termed eicosanoids. Eicosanoid production is considerably increased during inflammation. Both COX and LO pathways are of particular clinical relevance. The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications such as ulceration. In 1991, it was discovered that COX exists in two distinct isozymes, COX-1 and COX-2, of which COX-2 is primarily expressed at sites of inflammation and produces pro-inflammatory eicosanoids. For this reason, COX-2 selective inhibitors (COXIBs) have been developed recently as anti-inflammatory agents to minimize the risk of GI toxicity. Recently, some COX-2 selective inhibitors have shown adverse cardiovascular side effects, resulting in the withdrawal of rofecoxib and valdecoxib from the market. Selective inhibition of COX-2 without reducing COX-1-mediated thromboxane production could alter the balance between prostacyclin and thromboxane and promote a prothrombotic state, thereby explaining the observed COX- 2 cardiovascular risk. In this review, we describe mechanisms for the production of pro-inflammatory eicosanoid mediators contributing to inflammation and summarize promising options for the prevention of inflammatory mediator formation and the therapeutic inhibition of pain and inflammation.
- Published
- 2007
38. John R. Vane, « pharmacologue de l’endothélium vasculaire », 1927–2004
- Author
-
F. Chast
- Subjects
Pharmacology ,Aspirin ,biology ,business.industry ,Pharmaceutical Science ,Bradykinin ,Prostacyclin ,Vasodilation ,Inflammation ,Thromboxane Production ,chemistry.chemical_compound ,chemistry ,biology.protein ,Medicine ,Platelet aggregation inhibitor ,Cyclooxygenase ,medicine.symptom ,business ,medicine.drug - Abstract
The work of John Vane greatly contributed to the use of aspirin in cardiology. The impact of aspirin administration at low dose for the prevention of stroke or coronary attack results from its effect on enzymes regulating the production of prostaglandins. After understanding the mechanism of interaction between aspirin and the vascular endothelium, Vane proposed assigning a major physiological function to the vascular endothelium which then became a pharmacological target for new drugs. Using an ingenious "real time" biological assay of bloodstream hormones irrigating an isolated organ called the "blood-bathed organ cascade", John Vane developed a system for highly sensitive monitoring of several mediators like angiotensin, bradykinin and prostaglandins and discovered prostacyclin, a potent platelet aggregation inhibitor. Vane explained anti-inflammatory drugs effects (among which aspirin remains the leader) through their activity on cyclo-oxygenase and inhibition of prostacyclin and thromboxane production. Another cyclooxygenase isoform, so-called type 2, has been discovered in 1991. Thus, besides the constitutive COX-1, participating to stomach protection and renal artery vasodilatation, a COX-2 enzyme is existing, induced by inflammatory phenomenons and cytokines stimulation, allowing to design specific inhibitors "coxibs", playing an increasing but controversial role in the struggle against inflammation. He won Albert Lasker Prize in 1977 and Nobel Prize in medicine and physiology (shared with Sune Bergstrom and Bengt I. Samuelson) in 1982.
- Published
- 2006
39. Transfer of very low density lipoprotein-associated phospholipids to activated human platelets
- Author
-
Gabriel Ponsin, Valérie Pruneta-Deloche, Salam Ibrahim, Anaël Djimet-Baboun, Catherine Calzada, and Michel Lagarde
- Subjects
Blood Platelets ,medicine.medical_specialty ,Very low-density lipoprotein ,1,2-Dipalmitoylphosphatidylcholine ,QD415-436 ,Lipoproteins, VLDL ,digestive system ,Biochemistry ,Thromboxane Production ,Lactones ,chemistry.chemical_compound ,Endocrinology ,High-density lipoprotein ,tetrahydrolipstatin ,Internal medicine ,medicine ,Humans ,Lipolysis ,Platelet ,Platelet activation ,Enzyme Inhibitors ,Phospholipids ,Serum Albumin ,Orlistat ,Lipoprotein lipase ,Phosphatidylethanolamines ,Temperature ,Thrombin ,Phospholipid Ethers ,nutritional and metabolic diseases ,Cell Biology ,Platelet Activation ,Lipoproteins, LDL ,Thromboxane B2 ,Kinetics ,Lipoprotein Lipase ,chemistry ,high density lipoprotein ,thromboxane production ,lipids (amino acids, peptides, and proteins) ,Lipoproteins, HDL - Abstract
LDL-associated phospholipids (PLs) may be transferred into platelets. In this work, we characterized the role of VLDLs as PL donors. VLDL transferred radiolabeled PLs to platelets in a temperature- and concentration-dependent manner. LPL stimulated this process through its action on VLDL lipolysis, because it was abolished by tetrahydrolipstatin. LPL also stimulated the platelet production of thromboxane B2 (TXB2). Both LPL actions were inhibited in the presence of fatty acid-free albumin, suggesting that they were attributable to fatty acids generated during VLDL lipolysis. To study the relationship between PL transfers and platelet activation, we performed incubations in the presence of HDL, a physiological acceptor of PL released from VLDL. HDL antagonized the transfer of PL from VLDL to platelets but had no effect on the production of TXB2, suggesting that PL transfers were driven by platelet activation. Confirming this idea, thrombin stimulated both the production of TXB2 and the transfers of PL. In conclusion, VLDL can transfer PL to platelets. These transfers are stimulated by LPL and thrombin through their action on platelet activation. They might be enhanced in pathologies characterized by increased VLDL concentrations.
- Published
- 2006
40. Influence of vitamin E on the antiplatelet effect of acetylsalicylic acid in human blood
- Author
-
F. Sánchez de la Cuesta, J.A. González-Correa, A. Guerrero, J.P. De La Cruz, D. Ruiz-Villafranca, J. Muñoz-Marín, and M. M. Arrebola
- Subjects
Adult ,Blood Platelets ,Male ,Platelet Aggregation ,Thromboxane ,medicine.medical_treatment ,Prostacyclin ,Pharmacology ,Nitric Oxide ,Thromboxane Production ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Leukocytes ,medicine ,Humans ,Vitamin E ,Platelet ,Cells, Cultured ,Arachidonic Acid ,Aspirin ,Chemistry ,Drug Synergism ,Hematology ,General Medicine ,Middle Aged ,Epoprostenol ,Thromboxane B2 ,Biochemistry ,Prostaglandins ,Arachidonic acid ,Collagen ,alpha-Tocopherol ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
We analysed the in vitro interaction between acetylsalicylic acid and vitamin E on the principal antiplatelet sites of action of acetylsalicylic acid, i.e., platelet aggregation, prostanoid production in platelets and leukocytes, and nitric oxide synthesis. Aggregation was measured in whole blood and in platelet-rich plasma (PRP) with ADP, collagen or arachidonic acid as platelet inducers, and we measured the production of thromboxane B2, prostacyclin and nitric oxide. Vitamin E potentiated the antiplatelet effect of acetylsalicylic acid in both whole blood and PRP. In PRP induced with collagen the IC50 for acetylsalicylic acid alone was 339 � 11.26, and that of acetylsalicylic acid þ vitamin E was 0.89 � 0.09 (P < 0.05). Vitamin E did not enhance inhibition of platelet thromboxane production by acetylsalicylic acid. Vitamin E spared or even increased prostacyclin levels, and acetylsalicylic acid þ vitamin E diminished the inhibition of prostacyclin synthesis by acetylsalicylic acid (IC50 acetylsalicylic acid alone ¼ 1.81 � 0.15mM; IC50 acetylsalicylic acid þ vitamin E ¼ 12.92 � 1.10mM, P < 0.05). Vitamin E increased the effect of acetylsalicylic acid on neutrophil nitric oxide production 42-fold (P < 0.05). We conclude that vitamin E potentiates the antiplatelet effect of acetylsalicylic acid in vitro, and thus merits further research in ex vivo studies.
- Published
- 2005
41. The effect of ginger (Zingiber officinale) on platelet aggregation: a systematic literature review
- Author
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Marx, Wolfgang, McKavanagh, Daniel, McCarthy, Alexandra L., Bird, Robert, Ried, Karin, Chan, Alexandre, Isenring, Liz, Marx, Wolfgang, McKavanagh, Daniel, McCarthy, Alexandra L., Bird, Robert, Ried, Karin, Chan, Alexandre, and Isenring, Liz
- Abstract
BACKGROUND: The potential effect of ginger on platelet aggregation is a widely-cited concern both within the published literature and to clinicians; however, there has been no systematic appraisal of the evidence to date. METHODS: Using the PRISMA guidelines, we systematically reviewed the results of clinical and observational trials regarding the effect of ginger on platelet aggregation in adults compared to either placebo or baseline data. Studies included in this review stipulated the independent variable was a ginger preparation or isolated ginger compound, and used measures of platelet aggregation as the primary outcome. RESULTS: Ten studies were included, comprising eight clinical trials and two observational studies. Of the eight clinical trials, four reported that ginger reduced platelet aggregation, while the remaining four reported no effect. The two observational studies also reported mixed findings. DISCUSSION: Many of the studies appraised for this review had moderate risks of bias. Methodology varied considerably between studies, notably the timeframe studied, dose of ginger used, and the characteristics of subjects recruited (e.g. healthy vs. patients with chronic diseases). CONCLUSION: The evidence that ginger affects platelet aggregation and coagulation is equivocal and further study is needed to definitively address this question.
- Published
- 2015
42. In vitro testing of fresh and lyophilized reconstituted human and baboon platelets
- Author
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H. MacGregor, Gina Ragno, Marc R. Barnard, L. Summaria, Alan D. Michelson, and C. R. Valeri
- Subjects
Immunology ,Stimulation ,Hematology ,Pharmacology ,In vitro ,Thromboxane Production ,chemistry.chemical_compound ,Thromboxane A2 ,Adenosine diphosphate ,chemistry ,Biochemistry ,In vivo ,Immunology and Allergy ,Arachidonic acid ,Platelet - Abstract
BACKGROUND: Studies have been performed on human fresh, liquid-preserved, and cryopreserved platelets (PLTs) to assess PLT-adhesive surface receptors, PLT membrane procoagulant activity, PLT aggregation, and thromboxane production. Lyophilization has been developed as a method to preserve PLTs. This study was performed to evaluate these measurements on human and baboon fresh and lyophilized reconstituted PLTs. STUDY DESIGN AND METHODS: In both human and baboon fresh and lyophilized PLTs, aggregation response and PLT production of thromboxane A2 were measured after stimulation, and PLT surface markers P-selectin, glycoprotein (GP) Ib, GPIIb-IIIa, and factor (F) V were measured before and after stimulation. RESULTS: Fresh PLTs responded to the dual agonists arachidonic acid and adenosine diphosphate (ADP) to aggregate and produce thromboxane A2, and in both the PLT surface markers P-selectin and GPIIb-IIIa increased and GPIb decreased after stimulation. Neither human nor baboon lyophilized reconstituted PLTs aggregated to dual agonists, and neither produced thromboxane A2, increased PLT surface markers P-selectin or GPIIb-IIIa, or decreased PLT GPIb after stimulation. Nevertheless, after recalcification the lyophilized reconstituted PLTs accumulated FV to a significantly greater degree than fresh PLTs. CONCLUSIONS: Lyophilized reconstituted PLTs exhibited modification of the PLT membrane that interfered with aggregation and thromboxane production, prevented increases in PLT P-selectin and GPIIb-IIIa and decreases in GPIb after stimulation, and increased FV accumulation after recalcification. The in vitro data suggest that lyophilized PLTs may have reduced in vivo survival. In vivo studies are needed to determine the survival and function of lyophilized PLTs.
- Published
- 2004
43. What is the lowest dose of aspirin for maximum suppression of in vivo thromboxane production after a transient ischemic attack or ischemic stroke?
- Author
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Peter J. Koudstaal, Simon S.C. Li, Diederik W.J. Dippel, Fop van Kooten, Ajnira Mehicevic, Frank W.G. Leebeek, Huub H.D.M. van Vliet, Neurology, and Hematology
- Subjects
Adult ,Male ,Thromboxane ,Thromboxane Production ,Double-Blind Method ,In vivo ,Risk Factors ,Medicine ,Humans ,Platelet ,cardiovascular diseases ,Stroke ,Aged ,Aspirin ,biology ,Dose-Response Relationship, Drug ,business.industry ,Thromboxanes ,Middle Aged ,medicine.disease ,nervous system diseases ,Thromboxane B2 ,Dose–response relationship ,Treatment Outcome ,Neurology ,Ischemic Attack, Transient ,Anesthesia ,biology.protein ,Patient Compliance ,Female ,Neurology (clinical) ,Cyclooxygenase ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Background: There is still worldwide disagreement about the optimal lowest dose of aspirin to be used in patients after a transient ischemic attack (TIA) or nondisabling stroke. We measured the urinary 11-dehydro-thromboxane-B2 (uTXB2) excretion to compare the degree of suppression of in vivo platelet activation by various low doses of aspirin. Methods: 60 patients were randomly allocated to treatment with either 30, 50, 75 or 325 mg of aspirin. All patients received a 413-mg loading dose of carbasalate calcium (equivalent to 325 mg of aspirin) on day 0. The study population was stratified into a subgroup with acute ischemic stroke (AIS; n = 20; onset of symptoms Results: On day 28, mean uTXB2 levels were 241, 130, 217 and 187 pmol/mmol creatinine in the four treatment groups (ANOVA, p = 0.43). In the AIS subgroup, uTXB2 remained suppressed on days 5 and 11 in all except the patients with the lowest dose (mean uTXB2 on days 5 and 11: 475 and 392 pmol/mmol creatinine; log-transformed ANOVA, p = 0.05). Conclusion: In patients with a TIA or nondisabling stroke, a daily dose of 30 mg of aspirin provides sufficient suppression of thromboxane synthesis. No indication of a dose-effect relationship was found. However, whether such a low dose adequately suppresses thromboxane synthesis in patients with acute stroke is uncertain.
- Published
- 2004
44. Antiplatelet effects of KW-7, a new inhibitor of cyclic nucleotide phosphodiesterases
- Author
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Fang Rong Chang, Reen Yen Kuo, Chin Chung Wu, Yang Chang Wu, and Wei Ya Wang
- Subjects
Blood Platelets ,medicine.medical_specialty ,Phosphodiesterase Inhibitors ,Thromboxane ,Cyclase ,Thromboxane Production ,Cyclic nucleotide ,chemistry.chemical_compound ,3',5'-Cyclic-GMP Phosphodiesterases ,Internal medicine ,medicine ,Animals ,Phosphodiesterase inhibitor ,Protein kinase A ,Pharmacology ,Sheep ,Dose-Response Relationship, Drug ,biology ,Phosphodiesterase ,Isoquinolines ,Endocrinology ,chemistry ,3',5'-Cyclic-AMP Phosphodiesterases ,biology.protein ,Rabbits ,Thromboxane-A synthase ,Platelet Aggregation Inhibitors - Abstract
The antiplatelet effect of a new synthetic compound, 8,9-dimethoxyl-1-(4-methoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-2,3-dione (KW-7), was determined in rabbit platelets. KW-7 concentration-dependently prevented platelet aggregation caused by arachidonic acid, collagen, platelet-activating factor, and thrombin. KW-7 induced a substantial increase in cyclic AMP levels and a smaller increase in cyclic GMP levels in platelets. In platelet homogenates, KW-7 inhibited both cyclic AMP- and cyclic GMP-phosphodiesterase activities. The antiplatelet effect of KW-7 was reversed by SQ22536 (an inhibitor of adenylate cyclase) and H89 (an inhibitor of protein kinase A) but not by ODQ (an inhibitor of soluble guanylate cyclase). These data suggest that the antiplatelet effect of KW-7 is cyclic AMP-dependent, and is through inhibition of platelet phosphodiesterases. In addition, KW-7 inhibited arachidonic acid-stimulated thromboxane production; this effect was associated with an increase in prostaglandin D2 levels indicating KW-7 is also an inhibitor of thromboxane synthase. The dual inhibition of KW-7 on phosphodiesterase and thromboxane synthase might provide an attractive target in developing antiplatelet drugs.
- Published
- 2004
45. A Novel Role for CD36 in VLDL-Enhanced Platelet Activation
- Author
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Nicola A. Englyst, Trevor Baglin, Christopher D. Byrne, Timothy J. Aitman, and Janis M. Taube
- Subjects
CD36 Antigens ,Very low-density lipoprotein ,medicine.medical_specialty ,Platelet Aggregation ,Endocrinology, Diabetes and Metabolism ,CD36 ,In Vitro Techniques ,Lipoproteins, VLDL ,Thromboxane Production ,Thromboxane A2 ,chemistry.chemical_compound ,Insulin resistance ,Antigens, CD ,Reference Values ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Platelet ,Platelet activation ,Receptor ,Triglycerides ,biology ,Platelet Activation ,medicine.disease ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Collagen - Abstract
Type 2 diabetes is characterized by increased plasma triglyceride levels and a fourfold increase in ischemic heart disease, but the mechanism is unclear. CD36 is a receptor/transporter that binds fatty acids of lipoproteins. CD36 deficiency has been linked with insulin resistance. There is strong evidence of in vivo interaction between platelets and atherogenic lipoproteins suggesting that atherogenic triglyceride-rich lipoproteins, such as VLDL, that are increased in diabetic dyslipidemia are important in this process. This study demonstrates that VLDL binds to the platelet receptor CD36, enhances platelet thromboxane A2 production, and causes increased collagen-mediated platelet aggregation. VLDL enhanced collagen-induced platelet aggregation by 1) shortening the time taken for aggregation to begin (lag time) to 70% of control (P = 0.001); 2) increasing maximum aggregation to 170% of control (P = 0.008); and 3) increasing thromboxane production to 3,318% of control (P = 0.004), where control represents platelets stimulated with collagen (100%). A monoclonal antibody against CD36 attenuated VLDL-enhanced collagen-induced platelet aggregation by 1) inhibiting binding of VLDL to platelets by 75% (P = 0.041); 2) lengthening lag time to 190% (P < 0.001); and 3) decreasing thromboxane production to 8% of control (P < 0.001). In support of this finding, platelets from Cd36-deficient rats showed no increase in aggregation, thromboxane production, and VLDL binding in contrast to platelets from rats expressing CD36. These data suggest that platelet Cd36 has a key role in VLDL-induced collagen-mediated platelet aggregation, possibly contributing to atherothrombosis associated with increased VLDL levels.
- Published
- 2003
46. In vitroandex vivoeffects of the phosphodiesterase 4 inhibitor, rolipram, on thromboxane production in equine blood
- Author
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Karen Rickards, Fiona M. Cunningham, George Gettinby, Peter Lees, and Clive P. Page
- Subjects
Pharmacology ,medicine.medical_specialty ,General Veterinary ,Lipopolysaccharide ,Thromboxane ,Chemistry ,medicine.disease ,Thromboxane Production ,chemistry.chemical_compound ,Endocrinology ,In vivo ,Internal medicine ,medicine ,Platelet ,Ex vivo ,Rolipram ,Recurrent airway obstruction ,medicine.drug - Abstract
Phosphodiesterase 4 (PDE4) inhibitors have been shown to inhibit equine neutrophil function in vitro and may be of benefit in recurrent airway obstruction (RAO), an allergy-based respiratory disease characterized by inflammatory cell recruitment and activation within the lungs following exposure of susceptible horses to allergens in mouldy hay. The aim of this study was to evaluate the inhibitory effects of the PDE4 inhibitor, rolipram, in an in vitro assay of thromboxane (Tx) production. The assay was then used to monitor the activity of this compound in vivo in normal and RAO-affected horses. Rolipram and the structurally distinct PDE4 inhibitor, denbufylline, attenuated both lipopolysaccharide (LPS)-induced and unstimulated Tx production in blood from normal horses. Thromboxane production appeared to involve a calcium-dependent interaction between leucocytes and platelets (LPS-induced Tx production = 2.3 +/- 0.4, 4.5 +/- 1.1 and 20.8 +/- 3.6 ng/mL for platelets, leucocytes and blood, respectively) and rolipram-inhibited Tx production via an effect on leucocytes. Inhibition of ex vivo LPS induced Tx production was detected after intravenous administration of rolipram (5 microg/kg) to normal ponies. This dose did not significantly affect either lung function or neutrophil accumulation when administered to three horses with clinical signs of RAO. This study suggests that inhibition of Tx production in equine blood can be used to measure PDE4 activity. However, PDE4 inhibitors with improved therapeutic profiles are required for evaluation in RAO.
- Published
- 2003
47. Inhibitory Actions of Glucosamine on Platelet Functions
- Author
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Yuko Tsutsumi-Ishii, Kazuhisa Iwabuchi, Jian Hua, Shiori Suguro, Isao Nagaoka, and Koji Sakamoto
- Subjects
Thromboxane ,Chemistry ,Organic Chemistry ,Syk ,Pharmacology ,Biochemistry ,Calcium in biology ,Thromboxane Production ,chemistry.chemical_compound ,Glucosamine ,Platelet ,Platelet activation ,Platelet factor 4 - Abstract
Glucosamine, an amino monosaccharide naturally occurring in the connective and cartilage tissues, contributes to maintaining the strength, flexibility and elasticity of these tissues. In recent years, glucosamine has been widely used to treat osteoarthritis in humans, because glucosamine increases proteoglycan synthesis and prevents cartilage degradation. Recently, we have revealed that glucosamine suppresses neutrophil functions, thereby possibly exhibiting anti-inflammatory actions in arthritis. Alternatively, we have found that glucosamine improves the fluidity of blood (hemorheology) analyzed by microchannel array. Therefore, in this study, we evaluated the effects of glucosamine on the functions of platelets, which play an essential role in thrombosis. Glucosamine suppressed platelet aggregation in response to ADP-stimulation, but not collagen-and thrombin-stimulation. Furthermore, glucosamine inhibited the extracellular release of granular constituents (ATP and platelet factor 4), and the production of thromboxane from ADP-stimulated platelets. In addition, glucosamine significantly inhibited the mobilization of intracellular calcium and the phosphorylation of Syk associated with platelet activation. Together these observations suggest that glucosamine suppresses platelet aggregation via the inhibition of calcium mobilization, Syk phosphorylation, granular content release and thromboxane production. Thus, glucosamine may have preventive effects on thrombosis by its suppressive actions on platelet functions.
- Published
- 2003
48. Role of contaminating platelets in thromboxane synthesis in primary cultures of human umbilical vein endothelial cells
- Author
-
Sandra L. Pfister, Miranda J. Hughes, William B. Campbell, and Mark Rosolowsky
- Subjects
Blood Platelets ,Umbilical Veins ,Physiology ,Thromboxane ,Prostacyclin ,6-Ketoprostaglandin F1 alpha ,Biochemistry ,Umbilical vein ,Thromboxane Production ,Thromboxane A2 ,chemistry.chemical_compound ,medicine ,Humans ,Microscopy, Phase-Contrast ,Dazoxiben ,Platelet ,Calcimycin ,Cells, Cultured ,Pharmacology ,Confluency ,Arachidonic Acid ,biology ,Cell Biology ,Molecular biology ,chemistry ,biology.protein ,Endothelium, Vascular ,Cyclooxygenase ,medicine.drug - Abstract
Previous studies suggested that cultured human endothelial cells metabolize arachidonic acid to thromboxane A 2 . When primary cultures of human umbilical vein endothelial cells were incubated with 14 C -arachidonic acid and the 14 C -metabolites resolved by reverse phase high pressure liquid chromatography, radioactive products were observed that comigrated with 6-keto-prostaglandin F 1α and thromboxane B 2 , the degradation products of prostacyclin and thromboxane A 2 , respectively. Since platelets synthesize thromboxane A 2 , the present study examined the hypothesis that adherent platelets may contaminate the primary cultures of human umbilical vein endothelial cells and be responsible for thromboxane B 2 production. Confluent primary cultures or passaged cells were stimulated with histamine (10 −5 M). Incubation buffer was analyzed by specific radioimmunoassays for 6-keto-prostaglandin F 1α and thromboxane B 2 . The production of thromboxane B 2 decreased in the passaged cells (207±44 pg/ml versus 65±12 pg/ml; primary versus passaged cells). A moderate decrease in the yield of 6-keto-prostaglandin F 1α was measured in the passaged cells compared to the primary cultures (3159±356 pg/ml versus 1678±224 pg/ml, primary versus passaged cells). If the primary cultures were incubated with human platelet-rich plasma for 30 min prior to stimulation with histamine, the amount of thromboxane B 2 increased approximately 10-fold. In an additional experiment, sub-confluent primary cells were incubated with platelet-rich plasma for 30 min, washed to remove non-adherent platelets, and allowed to reach confluency. Confluent cells were then passaged and stimulated with histamine. The amount of thromboxane B 2 was not significantly different from that obtained with passaged cells that had not been incubated with platelet-rich plasma during the primary culture (83±15 pg/ml versus 65±12 pg/ml, respectively). If the cyclooxygenase inhibitor indomethacin was included in the incubations, the amounts of both thromboxane B 2 and 6-keto-prostaglandin F 1α decreased. In contrast, the thromboxane A 2 synthase inhibitor dazoxiben blocked thromboxane production and had no effect on the amount of 6-keto-prostaglandin F 1α . Light microscopy revealed the presence of adherent platelets in primary cultures with and without platelet-rich plasma but no platelets were observed in any group of passaged cells. Histofluorescence for platelet serotonin indicated the presence of platelets only in primary cultures of human umbilical vein endothelial cells or in cultures pre-incubated with platelet-rich plasma. These studies suggest that primary cultures of human umbilical vein endothelial cells contain adherent platelets that contribute to thromboxane synthesis.
- Published
- 2002
49. Modulation of Prostacyclin and Thromboxane Secretion by Cytotrophoblasts from Normal and Pre-eclamptic Human Pregnancies
- Author
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Z.Q. Ding, Janet Rowe, Michael J. Sinosich, B. Ng, and Eileen D. M. Gallery
- Subjects
Adult ,Lipopolysaccharides ,medicine.medical_specialty ,Cell Survival ,Pyridines ,Thromboxane ,Indomethacin ,Prostacyclin ,Thromboxane Production ,Thromboxane A2 ,chemistry.chemical_compound ,Pre-Eclampsia ,Pregnancy ,Internal medicine ,medicine ,Humans ,Calcimycin ,Cells, Cultured ,reproductive and urinary physiology ,Dose-Response Relationship, Drug ,biology ,Tumor Necrosis Factor-alpha ,Tranylcypromine ,Imidazoles ,Obstetrics and Gynecology ,Epoprostenol ,Trophoblasts ,Drug Combinations ,Endocrinology ,Reproductive Medicine ,Eicosanoid ,chemistry ,embryonic structures ,biology.protein ,Female ,Thromboxane-A synthase ,Cytotrophoblasts ,Interleukin-1 ,Developmental Biology ,medicine.drug - Abstract
We and others have previously observed an imbalance in cytotrophoblast secretion of the vasoactive prostanoids prostacyclin and thromboxane A(2) in pre-eclampsia. To examine the effects of potential modulators of this imbalance, cytotrophoblasts isolated from normal and pre-eclamptic pregnancies were incubated in the presence of lipopolysaccharide, the calcium ionophore A23187, tumour necrosis factor alpha, or interleukin 1beta, with or without the cyclo-oxygenase inhibitor, indomethacin. Further incubations included the drugs tranylcypromine, a prostacyclin synthetase inhibitor (0.1, 10 microM ), or the thromboxane synthetase inhibitor, pirmagrel (0.001, 1 microM ). Results showed that cytotrophoblasts from pre-eclamptic pregnancies had increased thromboxane production and significant stimulation of prostacyclin production by lipopolysaccharide and calcium ionophore. Lipopolysaccharide stimulated thromboxane production in normal cytotrophoblasts, while indomethacin almost completely inhibited production of both prostanoids. Tranylcypromine mildly inhibited prostacyclin production in normal cytotrophoblasts only, whereas pirmagrel strongly inhibited thromboxane production in a dose-related manner, with reciprocal increase in prostacyclin production occurring in cytotrophoblasts from pre-eclamptic pregnancies. This study confirmed that cytotrophoblasts from pre-eclamptic women had increased thromboxane production and showed that pirmagrel, at the relatively low dose of 0.001 microM, was able to normalize the imbalance of thromboxane and prostacylin production and may therefore warrant further investigation as a treatment for pre-eclampsia.
- Published
- 2002
50. The current and future landscape of urinary thromboxane testing to evaluate atherothrombotic risk
- Author
-
Alan H.B. Wu, Robert L. Jesse, John L. Jefferies, Jeffrey L. Boone, Peter A. McCullough, Jeffrey S. Berger, Alan S. Maisel, Sean-Xavier Neath, and Joseph P. McConnell
- Subjects
Blood Platelets ,medicine.medical_specialty ,Platelet Function Tests ,Thromboxane ,Urinary system ,Drug Resistance ,Disease ,Urinalysis ,Risk Assessment ,Thromboxane Production ,Fibrinolytic Agents ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,medicine ,Humans ,Dosing ,Precision Medicine ,Intensive care medicine ,Aspirin ,business.industry ,Patient Selection ,Thromboxanes ,Thrombosis ,General Medicine ,Endocrinology ,Treatment Outcome ,Aspirin therapy ,Biomarker (medicine) ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,medicine.drug - Abstract
Biomarker testing for efficacy of therapy is an accepted way for clinicians to individualize dosing to genetic and/or environmental factors that may be influencing a treatment regimen. Aspirin is used by nearly 43 million Americans on a regular basis to reduce risks associated with various atherothrombotic diseases. Despite its widespread use, many clinicians are unaware of the link between suboptimal response to aspirin therapy and increased risk for inferior clinical outcomes in several disease states, and biomarker testing for efficacy of aspirin therapy is not performed as routinely as efficacy testing in other therapeutic areas. This article reviews the clinical and laboratory aspects of determining whole-body thromboxane production, particularly as it pertains to efficacy assessment of aspirin responsiveness.
- Published
- 2014
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