Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostacyclin (PGI2) is released by vascular endothelial cells and serves as a potent vasodilator, inhibitor of platelet aggregation (anti-thrombotic), and moderator of vascular smooth muscle cell proliferation-migration-differentiation (anti-atherosclerotic). These actions are mediated via a seven transmembrane-spanning G-protein coupled receptor (GPCR), known as the human prostacyclin receptor or hIP. Animal studies using prostacyclin receptor knock-out (IP-/-) mice have revealed increased propensities towards thrombosis, intimal hyperplasia, atherosclerosis, restenosis, as well as reperfusion injury. Of further importance has been the world-wide withdrawal of selective COX-2 inhibitors, due to their discriminating suppression of COX-2-derived PGI2 and its cardioprotective effects, leading to increased cardiovascular events, including myocardial infarction and thrombotic stroke. Over the last decade, mutagenesis studies of the IP receptor, in conjunction with in vitro functional assays and molecular modeling, have provided critical insights into the molecular mechanisms of both agonist binding and receptor activation. Most recently, the discovery of naturally-occurring and dysfunctional mutations within the hIP has provided additional insights into the proposed cardioprotective role of prostacyclin. The aim of this review is to summarize the most recent findings regarding hIP receptor structure-function that have developed through the study of both synthetic and naturally-occurring mutations.
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PMID:Human prostacyclin receptor structure and function from naturally-occurring and synthetic mutations. 1716 37

Several studies suggest that cyclooxygenase (COX)-2 plays a pivotal role in the progression of ischaemic brain damage. In the present study, we investigated the effects of selective inhibition of COX-2 with nimesulide (12 mg/kg) and selective inhibition of COX-1 with valeryl salicylate (VAS, 12-120 mg/kg) on prostaglandin E(2) (PGE(2)) levels, myeloperoxidase (MPO) activity, Evans blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischaemia in the rat. Post-ischaemic treatment with nimesulide markedly reduced the increase in PGE(2) levels in the ischaemic cerebral cortex 24 h after stroke and diminished infarct size by 48% with respect to vehicle-treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood-brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischaemic episode. These studies provide the first experimental evidence that COX-2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischaemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischaemia, confirming a wide therapeutic window of COX-2 inhibitors in experimental stroke. On the contrary, selective inhibition of COX-1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX-2 activity, but not COX-1 activity, contributes to the progression of focal ischaemic brain injury, and that the beneficial effects observed with non-selective COX inhibitors are probably associated to COX-2 rather than to COX-1 inhibition.
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PMID:Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats. 1717 64

The arachidonic acid-specific cytosolic phospholipase A(2) alpha (cPLA(2)alpha) has been implicated in the generation of neurological injuries. cPLA(2)alpha-dependent neurological injury has been postulated to be mediated through inflammatory and eicosanoid pathways. We determined if cPLA(2)alpha amplifies the injury of a non-inflammatory, excitotoxic stimulus by modifying a well-described toxicity assay to measure the toxicity of N-methyl-d-aspartate (NMDA) in the CA1 region of organotypic, mouse hippocampal cultures. Hippocampal cultures from wild-type and cPLA(2)alpha knockout mice were exposed to 5, 7.5 or 10 microm NMDA for 1 h. Toxicity was measured 23 h later. Cultures derived from cPLA(2)alpha(-/-) mice and cultures treated with the selective inhibitor AACOCF(3) were significantly protected from NMDA toxicity, as compared with wild-type cultures. To determine if cPLA(2)alpha-dependent toxicity is cyclooxygenase (COX)-2 dependent, COX-2 and PGE(2) levels were measured 7 and 25 h after NMDA treatment. NMDA treatment failed to induce COX-2 protein or increase PGE(2) in the culture media in either genotype at either time. In contrast, phorbol 12-myristate 13-acetate and ionophore treatment caused robust induction of COX-2 and PGE(2) in both genotypes. We conclude that cPLA(2)alpha may have a hitherto unrecognized direct effect on excitatory neurotoxicity, suggesting that cPLA(2)alpha inhibition is a therapeutic candidate for treatment of the early, excitotoxic injury observed in stroke.
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PMID:Cytosolic phospholipase A alpha modulates NMDA neurotoxicity in mouse hippocampal cultures. 1722 87

Selective cyclooxygenase (COX)-2 inhibitors have been associated with an increased risk of thromboembolic cardiovascular (CV) events. Prior studies have found that rofecoxib has a destabilizing effect on blood pressure; however, whether this translates to an increased risk of thromboembolic CV events is unknown. The objective of this study was to evaluate risk of thromboembolic CV events among hypertensive and nonhypertensive patients treated with rofecoxib or celecoxib, nonselective nonsteroidal anti-inflammatory drugs (ns-NSAIDs), or no NSAIDs (nonusers). This was a retrospective cohort study of 31,743 adult arthritis patients enrolled in a Blue Cross/Blue Shield health insurance plan in the northeastern United States. The main outcome measure was incident acute myocardial infarction and stroke. A clinically significant channeling effect was observed where selective COX-2 inhibitor users had a more severe CV risk profile. Among normotensive patients, the hazard ratio (HR) of CV events for ns-NSAIDs, rofecoxib, or celecoxib versus nonusers was 0.91 (95% confidence interval, 0.68-1.21), 1.05 (0.61-1.80), and 1.19 (0.86-1.66), respectively. Among hypertensive patients, the risk of CV events for ns-NSAIDs users was not significantly different versus nonusers (HR=1.21; 0.88-1.67). However, rofecoxib was associated with a significant 2-fold increase in CV risk versus nonusers of NSAIDs (HR=2.16; 1.51-3.09), whereas celecoxib was not (HR=1.18; 0.89-1.57). These data support the hypothesis that elevated CV risk is not a drug class effect of selective COX-2 inhibitors. That this effect was specific to hypertensive patients indicates that blood pressure destabilization is likely an important contributing mechanism.
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PMID:Thromboembolic cardiovascular risk among arthritis patients using cyclooxygenase-2-selective inhibitor or nonselective cyclooxygenase inhibitor nonsteroidal anti-inflammatory drugs. 1730 69

During the past 2 years, a great deal of evaluation has been conducted on the cardiovascular (CV) effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors. This review focuses on the effects of the NSAIDs and COX-2 inhibitors on blood pressure and CV events. Clinical trial databases for NSAIDs and COX-2 inhibitors have shown varying levels of destabilization of blood pressure control in treated hypertensive patients as well as variable incident rates of the development of arrhythmias, congestive heart failure, myocardial infarction, and stroke. Nonselective and COX-2 selective NSAIDs can be used carefully in arthritis patients with hypertension and stable CV disorders (excluding congestive heart failure and moderate to severe kidney dysfunction) when the individual clinical benefit of anti-inflammatory therapy outweighs the CV and gastrointestinal risk.
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PMID:Cardiovascular risk, hypertension, and NSAIDs. 1743 65

A novel group of O2-acetoxymethyl-protected diazeniumdiolate-based non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) were synthesized by esterifying the carboxylate group of aspirin, ibuprofen, or indomethacin with O2-acetoxymethyl 1-[N-(2-hydroxyethyl)-N-methylamino]diazeniumdiolate. The resulting nitric oxide (*NO)-releasing prodrugs (7-9) did not exhibit in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50s>100 microM). In contrast, prodrugs 7 and 8 significantly decreased carrageenan-induced rat paw edema showing enhanced in vivo anti-inflammatory activities (ID50's=552 and 174 micromol/kg, respectively) relative to those of the parent NSAIDs aspirin (ID50=714 micromol/kg) and ibuprofen (ID50=326 micromol/kg). The rate of porcine liver esterase-mediated *NO release from prodrugs 7-9 (2 mol of *NO/mol of test compound in 0.6-6.5 min) was substantially higher compared to that observed without enzymatic catalysis (about 1 mol of *NO/mol of test compound in 40-48 h). These incubation studies suggest that both *NO and the parent NSAID would be released upon in vivo activation (hydrolysis) by esterases. Data acquired in an in vivo ulcer index (UI) assay showed that NONO-aspirin (UI=0.8), NONO-indomethacin (UI=1.3), and particularly NONO-ibuprofen (UI=0) were significantly less ulcerogenic compared to the parent drugs aspirin (UI=57), ibuprofen (UI=46) or indomethacin (UI=34) at equimolar doses. The release of aspirin and *NO from the NONO-aspirin (7) prodrug constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction.
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PMID:O2-acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs): synthesis, nitric oxide release, and biological evaluation studies. 1750 88

NSAIDs are a widely used class of analgesic and anti-inflammatory drugs that act by inhibiting the cyclo-oxygenase (COX) enzyme. However, because of their nonspecificity of action, use of these agents as long-term therapy for chronic pain in diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA) is often discouraged. Among NSAIDs, COX-2 inhibitors are promising candidates for long-term therapy of chronic diseases, particularly in the elderly, because of their reduced incidence of gastrointestinal adverse effects. However, in recent times these agents have also been shown to cause adverse effects such as cardiovascular effects (myocardial infarction, stroke and hypertension) and renal effects (decreased renal blood flow/glomerular filtration rate), which in 2004 led to the withdrawal of rofecoxib and in 2005 the withdrawal of valdecoxib from the US market. Importantly, these adverse effects can be effectively reduced by achieving site specific/targeted delivery through new formulation approaches. These formulations not only restrict the drug supply to specific organs but also reduce the dose required. As a result, use of new delivery systems such as nanoparticles, microparticles, microemulsions and nanogels has gained widespread applicability in the management of chronic disease, especially in the elderly, and particularly when there is a need to decrease dose-dependent adverse effects (as is the case with COX-2 inhibitors). This article reviews various new approaches to the delivery of COX-2 inhibitors and highlights issues related to the development of delivery systems for these agents for RA, OA, cancer (familial adenomatous polyposis, prostate, breast and non-small cell lung cancer), ocular diseases (such as diabetic retinopathy) and inflammatory diseases of the skin, with emphasis on their potential for use in the elderly. Emphasis is also placed on the preparation of these particulate systems, their release profile and behaviour in biological systems.
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PMID:New dosage formulations for targeted delivery of cyclo-oxygenase-2 inhibitors: focus on use in the elderly. 1757 10

1. Cerebral vessels express oestrogen receptors (ER) in both the smooth muscle and endothelial cell layers of cerebral blood vessels. Levels of ERalpha are higher in female rats chronically exposed to oestrogen, either endogenous or exogenous. 2. Chronic exposure to oestrogen, either endogenous (normally cycling females) or exogenous (ovariectomized with oestrogen replacement), results in cerebral arteries that are more dilated than arteries from ovariectomized counterparts when studied in vitro. This effect is primarily mediated by an increase in the production of vasodilator factors, including nitric oxide (NO) and prostacylin. In contrast, oestrogen appears to suppress the production of endothelial-derived hyperpolarizing factor. Oestrogen treatment increases cerebrovascular levels of endothelial nitric oxide synthase (eNOS), cyclo-oxygenase (COX)-1 and prostacyclin synthase. In addition, via activation of the phosphatidylinositol 3-kinase/Akt pathway, both acute and chronic oestrogen exposure increases eNOS phosphorylation, increasing NO production. 3. Oestrogen receptors have also been localized to cerebrovascular mitochondria and exposure to oestrogen increases the efficiency of energy production while simultaneously reducing mitochondrial production of reactive oxygen species. Oestrogen increases the production of mitochondrial proteins encoded by both mitochondrial and nuclear DNA, including cytochrome c, subunits I and IV of complex IV and Mn-superoxide dismutase. Oestrogen treatment increases the activity of citrate synthase and complex IV and decreases mitochondrial production of H(2)O(2). 4. Oestrogen also has potent anti-inflammatory effects in the cerebral circulation that may have important implications for the incidence and severity of cerebrovascular disease. Administration of lipopolysaccharide or interleukin-1beta to ovariectomized female rats induces cerebrovascular COX-2 and inducible nitric oxide synthase (iNOS) protein expression and increases prostaglandin E(2) expression. Levels of COX-2 and iNOS expression vary with the stage of the oestrous cycle, and the cerebrovascular inflammatory response is suppressed in ovariectomized animals treated with oestrogen. Interleukin-1beta induction of COX-2 protein is prevented by treatment with a nuclear factor (NF)-kappaB inhibitor, and oestrogen treatment reduces cerebrovascular NF-kappaB activity. 5. Cerebrovascular dysfunction and pathology contribute to the pathogenesis of stroke, brain trauma, oedema and dementias, such as Alzheimer's disease. A better understanding of the action of oestrogen on cerebrovascular function holds promise for the development of new therapeutic entities that could be useful in preventing or treating a wide variety of cerebrovascular diseases.
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PMID:Cerebrovascular effects of oestrogen: multiplicity of action. 1760 May 62

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 rofecoxib was withdrawn worldwide because of serious cardiovascular events and other coxibs were subsequently suspected to have this adverse reaction, although to a varying degree. Major efforts are currently underway to discover why cardiovascular reactions took place with coxibs, identify safer coxibs, as well as elucidate the roles of COX-2 and COX-1 in cardiovascular diseases and stroke in the hope that there may be some basis for developing newer agents (e.g. nitric oxide-donating NSAIDs) to control these conditions. The discovery of the COX isoforms led to establishing their importance in many non-arthritic or non-pain states where there is an inflammatory component to pathogenesis, including cancer, Alzheimer's and other neurodegenerative diseases. The applications of NSAIDs and the coxibs in the prevention and treatment of these conditions as well as aspirin and other analogues in the prevention of thrombo-embolic diseases now constitute one of the major therapeutic developments of the this century. Moreover, new anti-inflammatory drugs are being discovered and developed based on their effects on signal transduction and as anti-cytokine agents and these drugs are now being heralded as the new therapies to control those diseases where cytokines and other nonprostaglandin components of chronic inflammatory and neurodegenerative diseases are manifest. To a lesser extent safer application of corticosteroids and the applications of novel drug delivery systems for use with these drugs as well as with NSAIDs also represent newer technological developments of the 21st century. What started out as drugs to control inflammation, pain and fever in the last two centuries now has exploded to reveal an enormous range and type of anti-inflammatory agents and discovery of new therapeutic targets to treat a whole range of conditions that were never hitherto envisaged.
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PMID:Anti-inflammatory drugs in the 21st century. 1761 44

This data were previously presented in February 2007 at the American Society of Clinical Oncology's Prostate Cancer Symposium in Orlando, FL, USA. COX-2 inhibition has shown promise in treating prostate cancer, but concerns exist regarding the risk profile associated with this class of drugs. This study analyzes the cardiovascular and cerebral vascular morbidity associated with high doses of the COX-2 inhibitor, celecoxib, in patients with metastatic hormone-refractory prostate cancer (mHRPC). We retrospectively reviewed 67 patients with mHRPC who were treated at our institution between 1999 and 2005. All charts were reviewed for cardiac risk factors and the clinical course whilst on therapy and post-treatment was analyzed. This study included 34 patients who were on protocols that involved celecoxib 400 mg b.i.d.. Treatment ranged from 21 to 355 days, with a median of 118.5 days. There were three myocardial infarctions (MIs)--two in the study group and one in the control group. One patient had a MI while on treatment, but he had a significant cardiac disease history. There were also two cerebral vascular accidents (CVAs) in each group, although none in any patient who was on-study. Although this is a small study, these findings, in the context of other published data, suggest that some patients with advanced malignancies may still benefit from therapies involving COX-2 inhibitors without clinically significant increase in risk for MI or CVA.
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PMID:A retrospective analysis of cardiovascular morbidity in metastatic hormone-refractory prostate cancer patients on high doses of the selective COX-2 inhibitor celecoxib. 1766 25


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