thromboxane-a2 and Stroke

To evaluate the efficacy of aspirin for the treatment and prevention of ischemic stroke and identify the minimum dose proven to be effective for each indication.. PubMed and MEDLINE searches (up to January 2010) were performed to identify primary literature, using search terms including aspirin, stroke prevention, acute ischemic stroke, acetylsalicylic acid, atrial fibrillation, myocardial infarction, and carotid endarterectomy. Additionally, reference citations from publications identified were reviewed.. Articles published in English were evaluated and relevant primary literature evaluating the efficacy of aspirin in the prevention of stroke was included in this review.. Antiplatelet therapy is the benchmark for the prevention of ischemic stroke. Aspirin has been proven to prevent ischemic stroke in a variety of settings. Despite the frequency at which aspirin continues to be prescribed in patients at risk of ischemic stroke, there remains confusion in clinical practice as to what minimum dose is required in various at-risk patients. A thorough review of the primary literature suggests that low-dose (50-81 mg daily) aspirin is insufficient for some indications. Acute ischemic stroke treatment requires 160-325 mg, while atrial fibrillation and carotid arterial disease require daily doses of 325 and 81-325 mg, respectively.. Available evidence suggests that aspirin dosing must be individualized according to indication. Recommendations provided by national guidelines at times recommend lower doses of aspirin than have been proven effective. Higher doses are indicated for stroke prevention in atrial fibrillation (325 mg) and acute ischemic stroke patients (160-325 mg). Aspirin has not yet been proven effective for primary prevention of strokes in men, and a minimum dose for these patients cannot be determined from the available data.

Topics: Aspirin; Atherosclerosis; Carotid Artery Diseases; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Ischemia; Myocardial Infarction; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Stroke; Thromboxane A2

Historically, anti-inflammatory drugs had their origins in the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., this enabled these compounds to be synthesized and from this, acetyl-salicylic acid or Aspirin was developed. Likewise, the chemical advances of the 19th-20th centuries lead to development of the non-steroidal anti-inflammatory drugs (NSAIDs), most of which were initially organic acids, but later non-acidic compounds were discovered. There were two periods of NSAID drug discovery post-World War 2, the period up to the 1970's which was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in the drug-discovery process. Those drugs developed up to the 1980-late 90's were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities in laboratory animal models. Some were successfully developed that showed low incidence of gastro-intestinal (GI) side effects (the principal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GI reactions being detected and screened out in animal assays. In the 1990's an important discovery was made from elegant molecular and cellular biological studies that there are two cyclo-oxygenase (COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2)]; COX-1 that produces PGs and TxA2 that regulate gastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990's for the discovery and development of drugs to selectively control COX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor in development of adverse reactions, including those in the GI tract. At the turn of this century, there was enormous commercial development following the introduction of two new highly selective COX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) which were claimed to have low GI side effects. While found to have fulfilled these aims in part, an alarming turn of events took place in the late 2004 period when rofecox

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; Digestive System Diseases; Disease Models, Animal; Drug Delivery Systems; Drug Design; Fever; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Inflammation; Isoenzymes; Neoplasms; Neurodegenerative Diseases; Pain; Prostaglandins; Signal Transduction; Stroke; Thromboxane A2

Cyclooxygenase (COX) enzymes catalyse the biotransformation of arachidonic acid to prostaglandins which subserve important functions in cardiovascular homeostasis. Prostacyclin (PGI2) and prostaglandin (PG)E2, dominant products of COX activityin macro- and microvascular endothelial cells, respectively, in vitro, modulate the interaction of blood cells with the vasculature and contribute to the regulation of blood pressure. COXs are the target for inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs--which include those selective for COX-2) and for aspirin. Modulation of the interaction between COX products of the vasculature and platelets underlies both the cardioprotection afforded by aspirin and the cardiovascular hazard which characterises specific inhibitors of COX-2.

Topics: Animals; Cyclooxygenase 2 Inhibitors; Eicosanoids; Endothelium, Vascular; Epoprostenol; Gastrointestinal Hemorrhage; Heart Diseases; Humans; Isomerases; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Stroke; Thromboxane A2

Topics: Arteriosclerosis; Aspirin; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Gastrointestinal Hemorrhage; Humans; Male; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk; Stroke; Thrombosis; Thromboxane A2

This review presents a comprehensive discussion on the chemistry, pharmacokinetics, and pharmacodynamics of ifetroban sodium, a new thomboxane A2/prostaglandin H2 receptor antagonist. Thromboxane A2 is an arachidonic acid product, formed by the enzyme cyclooxygenase. In contrast to other cyclooxygenase products, thromboxane A2 has been shown to be involved in vascular contraction and has been implicated in platelet activation. In general, results of clinical studies and animal experiments indicate that hypertension is associated with hyperaggregability of platelets and increased thomboxane A2 levels in blood, urine, and tissues. The precursors to thromboxane A2, prostaglandin G2, and prostaglandin H2, also bind and activate the same receptors. Thus, a receptor antagonist was thought to be an improved strategy for reversing the actions of thromboxane A2/prostaglandin H2, rather than a thromboxane synthesis inhibitor. This review describes new methods for the synthesis and analysis of ifetroban, its tissue distribution, and its actions in a variety of animal models and disease states. We describe studies on the mechanisms of how ifetroban relaxes experimentally contracted isolated vascular tissue, and on the effects of ifetroban on myocardial ischemia, hypertension, stroke, thrombosis, and its effects on platelets. These experiments were conducted on several animal models, including dog, ferret, and rat, as well as on humans. Clinical studies are also described. These investigations show that ifetroban sodium is effective at reversing the effects of thromboxane A2- and prostaglandin H2-mediated processes.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Humans; Hypertension; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Ischemia; Oxazoles; Platelet Aggregation Inhibitors; Prostaglandin H2; Prostaglandins H; Randomized Controlled Trials as Topic; Receptors, Prostaglandin; Receptors, Thromboxane; Stroke; Thrombosis; Thromboxane A2

To compare the results of computer estimation of atherosclerotic plaque with biochemical data and ascertain any relationship with the occurrence of stroke.. The study involved 20 atherosclerotic plaques causing 70-99% stenosis of internal carotid arteries (ICA). Ultrasonographic examination (USG) images of plaques were analyzed using a computer program. A histogram was obtained for each plaque and a gray scale median (GSM) was determined for each histogram in order to measure the echogenicity of an examined plaque. Then the plaques, collected during endarterectomy, were examined with regard to the concentration of prostaglandins E2 (PGE2), thromboxane A2 (TXA2), and 8 - epi-prostaglandin F2α. This data was compared with GSM and the occurrence of stroke.. The statistical analysis showed significant correlations between low GSM and the occurrence of strokes. Out of 10 plaques with GSM<35, 6 (60.0%) were associated with a stroke. In contrast, out of 10 plaques with GSM>35, only 1 (10.0%) had a stroke. In addition, there were significant differences in the plaque content of PGE 2, (P<0.05) and (TXA2, P<0.011) between groups.. High levels of PGE2 and TXA2, correlated with the low GSM values, may be the features of unstable plaques and that may be associated with a risk for stroke.

Topics: Aged; Biomarkers; Carotid Artery, Internal; Carotid Stenosis; Dinoprost; Female; Humans; Logistic Models; Male; Middle Aged; Pilot Projects; Plaque, Atherosclerotic; Prostaglandins E; Risk Factors; Stroke; Thromboxane A2; Ultrasonography, Doppler, Duplex

Eicosanoids may play a role in ischemic stroke. However, the associations of variants in cyclooxygenase (COX) pathway genes and interaction among these variants with carotid plaque vulnerability are not fully understood. In present study, twelve variants in COX pathway genes were examined using matrix-assisted laser desorption ionization time-of-flight mass spectrometry method in 396 patients with ischemic stroke and 291 controls. Platelet aggregation, platelet-leukocyte aggregates, and urine 11-dehydrothromboxane B2 (11-dTxB2) were also measured. According to the results of carotid high-resolution B-mode ultrasound, the patients were stratified into the following groups [i.e., non-carotid plaque and carotid plaque. The carotid plaque was further classified into subgroups of echolucent plaque (ELP) and echogenic plaque (EGP)]. Additionally, gene-gene interactions were analyzed to assess whether there was any interactive role for assessed variants in affecting carotid plaque vulnerability, platelet activation and 11-dTxB2 levels. There were no significant differences in the frequencies of genotypes of the twelve variants between patients and controls. Among 396 patients, 294 cases (74.2%) had carotid plaques (106 had ELP, 188 had EGP). Frequency of PTGS2 rs20417CC, TXAS1 rs2267679TT, TXAS1 rs41708TT, PTGIS rs5602CC, and TXA2R rs1131882TT genotype was significantly higher in patients with plaque compared with patients without plaque, or in patients with ELP compared with patients with EGP. 11-dTxB2 levels, platelet aggregation and platelet-leukocyte aggregates were significantly higher in patients with ELP compared with patients without plaque or with EGP. Multivariate logistic regression analysis revealed that PTGS2 rs20417CC, TXA2R rs1131882TT, and high-risk interaction among variants in PTGS2 rs20417, TXA2R rs1131882 and TXAS1 rs41708 were independently associated with the risk of ELP after adjusting for confounding variables. The variants in COX pathway genes and the high-risk interactions among variants in PTGS2 rs20417, TXA2R rs1131882 and TXAS1 rs41708 were associated with high 11-dTxB2 and platelet activation, and independently associated with the risk of carotid plaque vulnerability. These variants might be potential markers for plaque instability.

Topics: Aged; Aged, 80 and over; Brain Ischemia; Carotid Arteries; Case-Control Studies; Cyclooxygenase 2; Female; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Platelet Activation; Polymorphism, Single Nucleotide; Receptors, Thromboxane A2, Prostaglandin H2; Stroke; Thromboxane A2; Thromboxane-A Synthase

Thromboxane A2 (TXA2) can induce the platelet aggregation and lead to thrombosis. This will cause the low-reflow phenomenon after ischemic stroke and aggravate the damage of brain issues. Therefore, it is potential to develop the drugs inhibiting TXA2 pathway to treat cerebral ischemia.. This study aims to prove the protective effect of N2 (4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoic acid) on focal cerebral ischemia and reperfusion injury through platelet aggregation inhibition.. Middle cerebral artery occlusion/reperfusion (MCAO/R) is used as the animal model. Neurological deficit score, Morris water maze, postural reflex test, Limb-use asymmetry test, infarct volume, and water content were performed to evaluate the protective effect of N2 in MCAO/R rats. 9, 11-dieoxy-11α, 9α-methanoepoxyprostaglandin F2α (U46619) or adenosine diphosphate (ADP) was used as the inducer of platelet aggregation.. N2 can improve the motor function, learning and memory ability in MCAO/R rats while reducing the infarct volume. N2 can inhibit TXA2 formation but promote PGI2, and can inhibit platelet aggregation induced by U46619 and ADP. Further, N2 inhibits thrombosis with a minor adverse effect of bleeding than Clopidogrel. In conclusion, N2 can produce the protective effect on MCAO/R brain injury through inhibiting TXA2 formation, platelet aggregation and thrombosis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Animals; Arteriovenous Shunt, Surgical; Blood Coagulation; Brain; Brain Ischemia; Edema; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Imidazoles; Male; Maze Learning; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Stroke; Thrombosis; Thromboxane A2; Vanillic Acid

Thromboxane A2 (TXA2) promotes ischemic stroke injury and has strong effects in vascular contraction and vascular endothelial cell dysfunction. Agents that reduce TXA2 production have potential for ameliorating neural injury in ischemic stroke. Thromboxane synthetase (TXS) is essential for TXA2 production, and TXS inhibitors have been developed as drugs for the prevention and treatment of stroke. However, ozagrel, a typical TXS inhibitor currently in clinical use, must be delivered via intravenous injection (I.V.). N2, 4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoate, is a potential thromboxane synthetase (TXS) inhibitor, which is being developed as an orally available formulation. The aim of this study was to investigate the effects of N2 on focal cerebral ischemia-reperfusion injury and related mechanisms. Neurological deficits, a Y-maze test and infarct volume were measured to evaluate the effects of N2 post-treatment on middle cerebral artery occlusion (MCAO)-induced ischemia/reperfusion (I/R) injury in rats. Furthermore, the influence of N2 on U46619-induced rat aorta contraction was investigated ex vivo. Moreover, we investigated the protective effects of N2 on rat brain microvessel endothelial cells (RBMECs) in hypoxia/deoxygenating (H/R) induced by Na2S2O4 in vitro. Cell viability and TXA2 biosynthesis were measured by 3-(4, 5-dimethylthiazol-2-yl)- 195 2, 5-diphenyltetrazolium bromide (MTT) and enzyme-linked immunosorbent assay (ELISA) assays, respectively. The results showed that N2 treatment effectively improves performance in neurological deficit and the Y-maze test and reduces the infarct volume in I/R rats. U46619-induced rat aorta contraction was inhibited by N2 ex vivo. Furthermore, N2 incubation improved the morphology of RBMECs, increased cell viability, and suppressed TXA2 production by inhibiting TXS during H/R damage. In summary, this study demonstrated that N2 was neural protective in focal cerebral I/R injury, which might be associated with the effects of N2 on endothelium protection and vascular contraction inhibition. In depth, the mechanisms underlying this phenomenon might be the influence of N2 on TXA2 production targeting TXS.

Topics: Animals; Brain Ischemia; Imidazoles; In Vitro Techniques; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; Thromboxane A2; Vanillic Acid

We tested the hypothesis that the phytoestrogen genistein protects the brain against ischemic stroke by improving the circulatory function in terms of reduced production of thromboxane A2 and leukocyte-platelet aggregates, and of preserved vascular reactivity. Ischemia-reperfusion (90 min-3 days, intraluminal filament) was induced in male Wistar rats, and functional score and cerebral infarct volume were the end points examined. Genistein (10mg/kg/day) or vehicle (β-cyclodextrin) was administered at 30 min after ischemia or sham-operation. Production of thromboxane A2 and leukocyte-platelet aggregates, as well as reactivity of carotid artery to U-46619 (thromboxane A2 analogue) and to platelet releasate was measured. At 3 days post-ischemia, both improvement in the functional examination and reduction in the total infarct volume were shown in the ischemic genistein-treated group. Genistein significantly reverted both the increased thromboxane A2 concentration and the increased leukocyte-platelet aggregates production found in samples from the ischemic vehicle-treated group. Both U-46619 and platelet releasate elicited contractions of the carotid artery, which were significantly lower in the ischemic vehicle-treated group. Genistein significantly restored both the decreased U-46619- and the decreased platelet releasate-elicited contractile responses. In conclusion, genistein protects the brain against an ischemia-reperfusion challenge, at least in part, by its beneficial effects on the circulatory function.

Topics: Animals; Brain Ischemia; Genistein; Male; Neuroprotective Agents; Phytoestrogens; Platelet Aggregation; Rats; Rats, Wistar; Stroke; Thromboxane A2

The pharmacological target of aspirin is the inhibition of cyclooxygenase-1 (COX1) and thromboxane-A2 (TX) synthesis. Very few data are available on TX assessment in patients with stroke. We studied platelet TX synthesis, COX1-independent platelet reactivity, the influence of platelet-erythrocyte interactions and the potential association between platelet responses and the severity of stroke, evaluated with a clinical score (NIHSS).. We examined 157 aspirin-treated patients with acute stroke or TIA, 128 aspirin-free and 15 aspirin-treated healthy subjects (HS). Collagen-induced TX, platelet recruitment in whole blood and platelets ± erythrocytes (haematocrit 40%) were assessed in patients on daily-aspirin within three days from onset. Arachidonic-acid-, ADP-, thrombin-receptor activating peptide TRAP-, and collagen-induced aggregation were also evaluated.. Partial TX inhibition (<95% inhibition vs aspirin-free controls) was observed in 13% of patients. This was associated with marked increases in COX1-dependent responses (arachidonic-acid- and collagen-induced aggregation and platelet recruitment; P<0.0001) but not with differences in ADP- or TRAP-induced aggregation. Partial TX inhibition was independently associated with severe stroke (NIHSS ≥ 12) at both admission (P<0.05) and discharge (P<0.05). Among patients with fully blocked TX, those with elevated COX1-independent platelet reactivity (mean+2SD of aspirin-treated HS) were most likely to suffer severe stroke (P<0.05). Platelet-erythrocyte interactions enhanced platelet reactivity in these patients by COX1-dependent and -independent mechanisms (P<0.0001).. TX inhibition by aspirin varied across patients. Partial TX inhibition and COX1-independent platelet hyperfunction were associated with more-severe stroke.

Topics: Acute Disease; Aged; Aspirin; Case-Control Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Female; Humans; Ischemic Attack, Transient; Male; Platelet Aggregation; Stroke; Thromboxane A2

Acetylsalicylic acid (ASA) is effective in preventing strokes, heart attacks and vascular-related events associated with cardiovascular disease (CVD). Notwithstanding, many patients suffer recurrent events while on ASA therapy. During the past decade, a number of investigators have suggested that these patients are unresponsive to ASA or are 'ASA-resistant'. In the past, this view was met with wide skepticism. Although there is mounting evidence that ASA resistance is a real phenomenon, an understanding of its biological basis and how to measure it is still unclear. The complexity of the problem is discussed below in an attempt to stimulate clinicians and CVD researchers to give serious thought to the ASA resistance problem. It is anticipated that a better understanding of ASA resistance will help us to appreciate its relative importance and its implications in the clinical setting.

Topics: Acetylation; Acetyltransferases; Arachidonic Acid; Aspirin; Drug Resistance; Fibrinolytic Agents; Humans; Myocardial Infarction; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Stroke; Thromboxane A2

Compliance with antiplatelet therapy is essential for the efficiency of secondary prevention of ischemic stroke. The objective of this study was to evaluate adherence to aspirin treatment in patients with ischemic stroke.. We studied outpatients of 5 neurological ambulatory centers in an urban city, Valencia, all with a history of ischemic stroke who had received aspirin for at least 6 months. A personal interview was carried out in all cases, during which the patients were questioned about adherence to treatment. Platelet thromboxane A2 synthesis was assessed in a single laboratory for the biochemical determination in all patients.. A total of 73 patients (mean age 67) were studied, with a mean duration of aspirin therapy of 25.4 months (range 6-144 months). Sixty-six patients (90.4%) were included in laboratory tests. All showed inhibition of thromboxane A2 synthesis, consistent with adherence to treatment.. Aspirin compliance was found to be excellent. All the patients who presented themselves for laboratory tests were taking aspirin. Even if the patients who failed to show up for laboratory testing are regarded as noncompliants, at least 90% of all patients were compliants--in agreement with the findings of the recent literature. Personal interview plus biochemical determination of platelet thromboxane A2 synthesis seem adequate for assessing adherence to aspirin.

Topics: Adult; Aged; Ambulatory Care; Aspirin; Brain Ischemia; Female; Follow-Up Studies; Health Care Surveys; Humans; Male; Middle Aged; Patient Compliance; Platelet Aggregation Inhibitors; Stroke; Thromboxane A2

In vitro studies have suggested that losartan interacts with the thromboxane (TxA2)/ prostaglandin H2 (PGH2) receptor in human platelets, reducing TxA2-dependent platelet activation. The aim of this study was to evaluate the effect of different angiotensin II type 1 receptor antagonists in stroke-prone spontaneously hypertensive rats (SHRSP). The level of platelet activation was assessed by determining P-selectin expression in platelets by flow cytometry. The ex vivo adhesion of platelets was also analyzed. The number of platelets that expressed P-selectin in SPSHR was significantly increased (% P-selectin expression: WKY 4 +/- 0, 4%; SHRSP 15.5 +/- 0, 8% [n = 8], p < 0.05). In SHRSP receiving losartan (20 mg/kg body weight per day) the percentage of platelets expressing P-selectin fell to levels close to that observed in WKY. The number of platelets from SHRSP treated with valsartan and candesartan (20 mg/kg body weight per day for 14 days) that expressed P-selectin was not significantly different from those from untreated SPRHR. Only losartan treatment reduced ex vivo platelet adhesion to a synthetic surface. The antiplatelet effect of losartan does not appear to be related to the level of blood pressure reduction. In ex vivo experiments, losartan significantly reduced the binding of the radiolabeled TxA2 agonist U46619 to platelets obtained from SHRSP in a dose-dependent manner. Treatment with losartan reduced the number of activated platelets in SHRSP independently of its blood pressure effects. TxA2-receptor blockade is proposed as a mechanism by which losartan can prevent platelet activation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Platelets; Blood Pressure; Humans; Hypertension; Losartan; P-Selectin; Platelet Activation; Platelet Adhesiveness; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Tetrazoles; Thromboxane A2; Valine; Valsartan