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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The disturbance of microcirculation following cerebral ischemia leads to an enlargement of cerebral infarct volume. Endogenous thrombin may play a role in this disturbance of microcirculation following cerebral ischemia. Therefore, the inhibition of thrombin may improve neurodegeneration and the accumulation of cerebral edema following cerebral ischemia in gerbils. The effects of thrombin inhibitor (argatroban) on cerebral ischemia were investigated in comparison with thromboxane A2 synthase inhibitor (ozagrel) and cyclooxygenase inhibitor (aspirin) following bilateral common carotid artery occlusion and reperfusion (CCA:O/R) in male Mongolian gerbils. This study consisted of three experiments: (1) morbidity and survival ratio (n=40 for each), (2) histopathology (n=12 for each), and (3) mean arterial blood pressure, local cerebral blood flow (CBF), and cerebral specific gravity (n=8 for each). Argatroban treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex and hippocampus and cerebral edema in cortex compared with aspirin and saline, in concert with the fast recovery of local CBF without reactive hyperemia following bilateral CCA:O/R. Ozagrel treatment also improved those factors compared with saline, in concert with the fast recovery of local CBF with reactive hyperemia. Aspirin treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex. Thrombin inhibition with argatroban decreases neurodegeneration and cerebral edema following bilateral CCA:O/R in gerbils.
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PMID:Thrombin inhibition attenuates neurodegeneration and cerebral edema formation following transient forebrain ischemia. 1138 20

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.
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PMID:Ifetroban sodium: an effective TxA2/PGH2 receptor antagonist. 1148 65

Despite undisputed clinical benefit of platelet inhibitors in an acute interventional setting, chronic antiplatelet treatment with aspirin and clopidogrel have shown a moderate reduction of approximately 18% in the prevention of myocardial infarction and stroke. More recent data on the effect of combining the two compounds leading to an irreversible blockade of cyclooxygenase as well as the adenosine diphosphate receptor showed increased protection from cardiac events in patients with unstable angina and no significant protection from stroke. This improvement did come with the price of a significant increase in major bleeding, requiring hospitalization or transfusion. Furthermore, the most potent inhibition of platelet aggregation by blocking the binding of fibrinogen to activated platelets did not further improve the clinical outcome. All major clinical investigations of the effect of chronic administration have been recently terminated owing to an overall increased mortality rate for the entire class of drugs of orally active fibrinogen receptor antagonists. This poses the question of whether measuring platelet aggregation in vitro and ex vivo can serve as an adequate surrogate parameter to select antithrombotic therapy, particularly in the chronic setting. When evaluating the importance of other endogenous antithrombotic defense systems, the test for inhibition of platelet aggregation must fail. The importance of the endogenous defense systems is easily demonstrated by in vivo studies of thrombus formation in smaller vessels. The rapid and well-balanced interaction of local prothrombotic as well as antithrombotic factors is key in keeping the process confined. By carefully shifting this balance with antiplatelet therapy in combination with therapy to amplify the endogenous antithrombotic defense systems, a far more pronounced overall antithrombotic therapeutic effect can be demonstrated. By employing more complex antithrombotic tests performed in vivo, this balance can be studied. These studies confirm the importance of the ratio of two independent antithrombotic treatments when given together, which was not reflected in in vitro tests but was found to correlate with clinical outcome data. The attention in selecting antithrombotic treatment is to be shifted from approaches only directed toward the inhibition of platelets to an antithrombotic treatment, which includes amplification of the local therapeutic effects often mediated through the vessel wall.
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PMID:How to get from antiplatelet to antithrombotic treatment. 1170 83

Aspirin and the nonsteroidal anti-inflammatory drugs (NSAIDs) have been commercially available for decades, and their ability to reduce pain and inflammation are well known. The ability of these agents to cause adverse effects are also known, and the search for newer NSAIDs with less side effects accelerated after the two isoforms of cyclooxygenase (COX) (COX-1 and COX-2) were discovered. The selective COX-2 inhibitors seem to have equivalent efficacy, but potentially less gastrointestinal adverse effects than the traditional NSAIDs. Recent concern that the selective COX-2 inhibitors could increase cardiovascular events requires more investigation. In the meantime, aspirin continues to receive attention as a potential primary cardiovascular agent because of its antiplatelet effects and past and current clinical trials. Several trials have demonstrated that low-dose aspirin may significantly reduce the risk of myocardial infarction and other cardiovascular events. However, the benefits of aspirin need to be weighed against its primary side effect in these situations (hemorrhagic stroke). Patients at low risk for future cardiovascular events are probably not good candidates for this therapy; however, those individuals with a high risk of a future cardiovascular event may qualify for this therapy. Aspirin has also demonstrated a potential ability to reduce the risk of deep venous thrombosis and pulmonary embolism. A recent large trial of low-dose aspirin after major surgery revealed that this agent could also have some activity in the venous component of the human body. Aspirin may also have some applicability for reducing side effects of oral estrogens in men with advanced prostate cancer. Thus, it seems as if aspirin, NSAIDS, and even the selective COX-2 inhibitors may have therapeutic potential far beyond reducing pain and general inflammation. These overall observations and effects provided some of the impetus to investigate their potential ability to reduce the risk and possibly progression of a number of cancers. A few already available over-the-counter products and prescriptions seem to be receiving attention as possible anticancer agents.
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PMID:An introduction to aspirin, NSAIDs, and COX-2 inhibitors for the primary prevention of cardiovascular events and cancer and their potential preventive role in bladder carcinogenesis: part I. 1176 81

Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 are expressed in vascular smooth muscle cells stimulated with interleukin-1beta (IL-1beta), resulting in the production of nitric oxide (NO) and prostaglandins (PGs) such as PGI2. The iNOS and COX-2 proteins and their mRNA expressions in cultured vascular smooth muscle cells isolated from 6-7 week-old stroke-prone spontaneously hypertensive rats (SHRSP) were compared with those in the cells isolated from age-matched normotensive Wistar Kyoto rats (WKY). The IL-1beta-induced NO production and iNOS expression in vascular smooth muscle cells of SHRSP were significantly lower than those in cells of WKY. Similarly, PGI2 production and COX-2 expression were significantly lower in vascular smooth muscle cells of SHRSP than WKY, whereas there was no difference in the COX-1 expression. There were no significant differences in iNOS and COX-2 mRNA expressions between the two strains, suggesting that these protein expression may be reduced at the post-transcriptional level in cells of SHRSP. These results further suggest that the reduction of iNOS and COX-2 expressions in vascular smooth muscle cells may have relevance to the pathophysiology in SHRSP.
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PMID:Reduced expressions of inducible nitric oxide synthase and cyclooxygenase-2 in vascular smooth muscle cells of stroke-prone spontaneously hypertensive rats. 1185 30

Reduction of plasma low density lipoprotein (LDL) levels is associated with a reduced risk of myocardial infarction, stroke, and death. Some of this clinical benefit may be derived from an improvement in endothelium-dependent vasodilation. In the present study, we examined the effects of LDL reduction on cyclooxygenase (COX) activity and prostacyclin (PGI2) production. Human umbilical vein endothelial cells exposed to reduced concentrations of LDL demonstrated increased PGI2 production in a dose-dependent manner (from 0.75+/-0.2 to 2.6+/-0.2 ng/mL, P<0.0001). This alteration in PGI2 production did not result from LDL-induced changes in PGI2 synthase expression. However, selective inhibition of COX-2, but not COX-1, blocked PGI2 production under low cholesterol conditions. Addition of exogenous cholesterol induces dose-dependent reductions in endothelial COX-2 expression as measured by reverse transcription-polymerase chain reaction and by Western blotting. Pretreatment of cells with actinomycin D, a transcription inhibitor, reduced COX-2-derived PGI2 production by 45.9% (from 0.55+/-0.09 to 0.25+/-0.08 ng/mL). Taken together, these observations indicate that endothelial PGI2 production is regulated by cholesterol at the transcriptional level and that cholesterol-sensitive transcriptional pathways that regulate COX-2 expression are present in vascular tissue.
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PMID:Cyclooxygenase-2-dependent prostacyclin formation is regulated by low density lipoprotein cholesterol in vitro. 1206 8

Cyclooxygenases catalyze the first committed step in the formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is expressed in brain selectively in neurons of hippocampus, cerebral cortex, amygdala, and hypothalamus. Prostaglandins function in many processes in the CNS, including fever induction, nociception, and learning and memory, and are upregulated in paradigms of excitotoxic brain injury such as stroke and epilepsy. To address the varied functions of COX-2 and its prostaglandin products in brain, we have developed a transgenic mouse model in which COX-2 is selectively overexpressed in neurons of the CNS. COX-2 transgenic mice demonstrate elevated levels of all prostaglandins and thromboxane, albeit with a predominant induction of PGE(2) over other prostaglandins, followed by more modest inductions of PGI(2), and relatively smaller increases in PGF(2alpha),PGD(2), and TxB(2). We also examined whether increased neuronal production of prostaglandins would affect fever induction in response to the bacterial endotoxin lipopolysaccharide. COX-2 induction in brain endothelium has been previously determined to play an important role in fever induction, and we tested whether neuronal expression of COX-2 in hypothalamus also contributed to the febrile response. We found that in mice expressing transgenic COX-2 in anterior hypothalamus, the febrile response was significantly potentiated in transgenic as compared to non-transgenic mice, with an accelerated onset of fever by 1 2 hours after LPS administration, suggesting a role for neuronally derived COX-2 in the fever response.
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PMID:Neuronal overexpression of COX-2 results in dominant production of PGE2 and altered fever response. 1266 73

Free fatty acids (FFAs) are elevated in the brain following both ischemic and traumatic injury. Phospholipase activation, with the subsequent release of FFAs from membrane phospholipids, is the likely mechanism. In addition to phospholipases A1, B, C, and D, there are at least 19 groups of PLA2, including multiple cytosolic, calcium independent, and secretory isoforms. Phospholipase activity can be regulated by calcium, by phosphorylation, and by agonists binding to G-protein-coupled receptors. These enzymes normally function in the physiological remodeling of cellular membranes, whereby FFAs are removed by phospholipase activity and then reacylated with a different FFA. However, reductions in the cell's ability to maintain normal metabolic function and the resultant fall in ATP levels can cause the failure of reacylation of membrane phospholipids. Alterations to membrane phospholipids would be expected to compromise many cellular functions, including the ability to accumulate excitotoxic amino acids. This review presents evidence for a central role of phospholipases and their products in the etiology of damage following injury to the brain. Phospholipase expression and activity is increased in animal models of cerebral ischemia and trauma. FFA release from the in vivo rat brain is reduced following the application of selective phospholipase inhibitors, and this inhibition also decreases the severity of cortical damage following forebrain ischemia, focal (middle cerebral artery occlusion) ischemia, and cerebral trauma. Mice with knockouts of PLA2 have decreased infarct volumes. Human data demonstrate a correlation between the elevation of CSF FFAs and worsened outcome following stroke, traumatic brain injury, and subarachnoid hemorrhage. The released FFAs, especially arachidonic and docosahexaenoic acids, together with the production of lysophospholipids, can initiate a chain of events which may be responsible for the development of neuronal damage. Inhibitors of both cyclooxygenase and lipoxygenase pathways have been shown to reduce cerebral deficits following ischemia and trauma. These results suggest therapeutic strategies to reduce morbidity following cerebral injury using selective inhibitors of phospholipases, cyclooxygenases, and lipoxygenases, underlining the need for further investigation of their role in the development of cerebral damage.
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PMID:The role of phospholipases, cyclooxygenases, and lipoxygenases in cerebral ischemic/traumatic injuries. 1451 63

Inflammation is a key component of host defence responses to peripheral inflammation and injury, but it is now also recognized as a major contributor to diverse, acute and chronic central nervous system (CNS) disorders. Expression of inflammatory mediators including complement, adhesion molecules, cyclooxygenase enzymes and their products and cytokines is increased in experimental and clinical neurodegenerative disease, and intervention studies in experimental animals suggest that several of these factors contribute directly to neuronal injury. Most notably, specific cytokines, such as interleukin-1 (IL-1), have been implicated heavily in acute neurodegeneration, such as stroke and head injury. In spite of their diverse presentation, common inflammatory mechanisms may contribute to many neurodegenerative disorders and in some (e.g. multiple sclerosis) inflammatory modulators are in clinical use. Inflammation may have beneficial as well as detrimental actions in the CNS, particularly in repair and recovery. Nevertheless, several anti-inflammatory targets have been identified as putative treatments for CNS disorders, initially in acute conditions, but which may also be appropriate to chronic neurodegenerative conditions.
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PMID:Inflammation in central nervous system injury. 1456 25

Arachidonic acid metabolism plays an important role in acute ischemic syndromes affecting the coronary or cerebrovascular territory, as reflected by biochemical measurements of eicosanoid biosynthesis and the results of inhibitor trials in these settings. Two cyclooxygenase (COX)-isozymes have been characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, preferential coupling to upstream and downstream enzymes, and susceptibility to inhibition by the extremely heterogeneous class of COX-inhibitors. Although the role of platelet COX-1 in acute coronary syndromes and ischemic stroke is firmly established through approximately 20 years of thromboxane metabolite measurements and aspirin trials, the role of COX-2 expression and inhibition in atherothrombosis is substantially uncertain, because the enzyme was first characterized in 1991 and selective COX-2 inhibitors became commercially available only in 1998. In this review, we discuss the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque "vulnerability," and the clinical consequences of COX-2 inhibition. Recent studies from our group suggest that variable expression of upstream and downstream enzymes in the prostanoid biosynthetic cascade may represent important determinants of the functional consequences of COX-2 expression and inhibition in different clinical settings.
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PMID:Cyclooxygenase-2 expression and inhibition in atherothrombosis. 1459 54


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