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 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory and analgesic effects. Unfortunately, these drugs are not without toxicity, namely on the gastric mucosa, but also on the cardiovascular system. In this context, the marketing of the coxibs, a new series of NSAIDs that selectively inhibit COX-2, resulted in a large debate around their cardiovascular safety, because they may increase the incidence of myocardial infarction and stroke. The recent suspension of a large, randomised, controlled trial comparing celecoxib, naproxen and placebo in Alzheimer patients (the ADAPT trial) because of an apparent elevated cardiovascular risk in the naproxen group revived the debate on the cardiovascular safety of these drugs, but this time with special emphasis on the effect of traditional nonselective NSAIDs (tNSAIDs). In this paper that reviews and discusses the cardiovascular safety profile of tNSAIDs, essentially naproxen and ibuprofen in view of the most recent experimental and clinical data, the authors note that the published data are quite discordant and one cannot conclude that there is clear evidence to support a cardiovascular hazard from the administration of naproxen or non-naproxen NSAIDs unless additional information is provided. In addition, the results of retrospective case-control studies have to be interpreted very carefully because of the risk of confounding factors that are not always taken into account when subjects were classified either as cases or controls. Thus, in the absence of clear cut data, physicians will have to use traditional NSAIDs (or coxibs) in patients with a high cardiovascular risk on the basis of their common sense rather than on evidence-based medicine. For these patients, one should not forget that an inadequate long-term control of cardiovascular risk factors such as a hypertension, dyslipidaemia, diabetes, smoking and weight excess is more deleterious in terms of cardiovascular mortality than the administration of NSAIDs itself.
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PMID:Comparative cardiovascular safety of traditional nonsteroidal anti-inflammatory drugs. 1637 Sep 58

The totality of data--the vascular biology and dinical trial data available to date--support the following conclusions: if COX-2 inhibitors are to be used, they should be considered as 2nd- or 3rd-line agents. They should be used for brief periods of time among patients who are at low risk for cardiovascular events. It is worth pointing out that COX-2 inhibitors were designed initially for use in patients at risk for bleeding ulcers, to minimize gastrointestinal toxicity. Large healthcare databases show, however, that the largest growth of COX-2-inhibitor use has occurred among individuals at low risk for GI side effects. COX-2 inhibitors increase the risk for cardiovascular events. The risk differs, to some degree, across agents, and does appear to be dose related. The relationship between cardiovascular risk and duration of therapy is an important question that requires further consideration. Early risk, from the perspective of pathobiology, may differ from long-term risk. The mechanism of cardiovascular risk is multifactorial and relates to sites of COX-2 synthesis, expression within the vasculature, and related local consequences of an imbalance between thromboxane A2 and prostacyclin. Considered collectively, increased platelet aggregation, hypertension, endothelial cell dysfunction, impaired angiogenesis, and destabilization of the atherosclerotic plaque matrix are important contributors to the "prothrombotic environment." Randomized clinical trials are required to better understand the hazards among individuals at low and high risk for cardiovascular events.
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PMID:COX-2 inhibitors. 1639 24

Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to minimize gastrointestinal complications of traditional NSAIDs--adverse effects attributed to suppression of COX-1-derived PGE2 and prostacyclin (PGI2). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2-derived PGI2 removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a "balance" between COX-2-derived PGI2 and COX-1-derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.
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PMID:Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. 1639 96

Macula densa (MD) cells of the juxtaglomerular apparatus (JGA) synthesize type 1 nitric oxide synthase (NOS1) and type 2 cyclooxygenase (COX-2). Both nitric oxide (NO) and prostaglandins have been considered to mediate or modulate the control of renin secretion. Reactive oxygen species (ROS) produced locally by NADPH oxidase may influence NO bioavailability. We have tested the hypothesis that in hypertension elevated ROS levels may modify the expression of NOS1 and COX-2 in the JGA, thereby interacting with juxtaglomerular signaling. To this end, spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY) received the specific NADPH oxidase inhibitor, apocynin, during 3 wk. Renal functional and histochemical parameters, plasma renin activity (PRA), and as a measure of ROS activity, urinary isoprostane excretion (IP) were evaluated. Compared with WKY, IP levels in untreated SHR were 2.2-fold increased, and NOS1 immunoreactiviy (IR) of JGA 1.5-fold increased, whereas COX-2 IR was reduced to 35%, renin IR to 51%, and PRA to 7%. Apocynin treatment reduced IP levels in SHR to 52%, NOS1 IR to 69%, and renin IR to 62% of untreated SHR, whereas renin mRNA, COX-2 IR, glomerular filtration rate, PRA, and systolic blood pressure remained unchanged. WKY revealed no changes under apocynin treatment. These data show that NADPH oxidase is an important contributor to elevated levels of ROS in hypertension. Upregulation of MD NOS1 in SHR may have the potential of blunting the functional impact of ROS at the level of bioavailable NO. Downregulated COX-2 and renin levels in SHR are apparently unrelated to oxidative stress, since apocynin treatment had no effect on these parameters.
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PMID:Effect of apocynin treatment on renal expression of COX-2, NOS1, and renin in Wistar-Kyoto and spontaneously hypertensive rats. 1646 5

The COX-inhibiting nitric oxide donors (CINODs) are a new class of agents designed for the treatment of pain and inflammation. CINODs have a multi-pathway mechanism of action that involves COX inhibition and nitric oxide donation. The anti-inflammatory and analgesic effects of COX inhibition are reinforced through inhibition of caspase-1 regulated cytokine production, while nitric oxide donation provides multiorgan protection. Whereas both conventional nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2-selective NSAIDs are associated with a variety of adverse effects on the renal system, such as hypertension and edema, CINODs may offer an improved renal safety profile. These agents are devoid of hypertensive effects in animal models and their mechanism of action suggests that they may not cause edema. CINODs also have other renal-sparing effects, being better tolerated than NSAIDs in models of kidney failure. CINODs have been shown to prevent platelet activation in vitro and exhibit anti-thrombotic activity in vivo. In animal models of ischemia/reperfusion, CINODs treatment results in improved recovery of heart contractility and reduced left ventricular end-diastolic pressure, in contrast to the effects of aspirin. The combination of improved analgesia, reduced gastrointestinal toxicity and cardiorenal protection has been established in animal models, and early clinical results suggest a favourable gastrointestinal safety profile in humans. The potential for CINODs to provide cardiorenal protection in humans is currently being investigated.
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PMID:COX-inhibiting nitric oxide donors (CINODs): potential benefits on cardiovascular and renal function. 1661 Oct 49

Pyruvic acid, an intermediate metabolite of glucose, an effective scavenger of reactive oxygen species (ROS), inhibits tumor necrosis factor-alpha production and NF-kappaB signaling pathways, reduces circulating levels of HMGB1 (high mobility group B1), decreases COX-2 (cyclo-oxygenase-2), iNOS (inducible nitric oxide synthase), and IL-6 (interleukin-6) mRNA expression in liver, ileal mucosa, and colonic mucosa in animal models with endotoxemia. These studies suggest that pyruvate has potent anti-oxidant and anti-inflammatory actions. Insulin influences the production of pyruvate by its action on glucose metabolism and pyruvate is an insulin secretagogue. This suggests that in metabolic syndrome X, obesity, hypertension, diabetes mellitus, and cancer (where insulin resistance is common due to enhanced TNF-alpha production) pyruvate plays a role. This may have relevance to the use of glucose-insulin-potassium regimen in these clinical conditions, sepsis, and cancer.
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PMID:Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. 1664 87

The renal side effects of nonsteroidal anti-inflammatory drugs are very often and could be seen in 5% of patients who are treated with this drugs. These side effects could be separated in 5 clinical syndromes: 1. acute renal failure, 2. acute interstitial nephritis with nephrotic syndrome, 3. electrolyte and fluid disorders, 4. hypertension and 5. analgesic nephropathy. There are a lot data in the literature which suggest that selective COX-2 inhibitors (rofecoxib and celecoxib) produce the similar effects on the kidney as traditional nonsteroidal anti-inflammatory drugs (inhibitors of COX-1 and COX-2).
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PMID:[Nonsteroidal antirheumatics and the kidney]. 1668 32

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation. Nonselective NSAIDs inhibit both cyclooxygenase (COX)-1 and COX-2. Nephrotoxicity of nonselective NSAIDs has been well documented. The effects of selective COX-2 inhibitors on renal function and blood pressure are attracting increasing attention. In the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in the mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. Similar to nonselective NSAIDs, inhibition of COX-2 may cause edema and modest elevations in blood pressure in a minority of subjects. COX-2 inhibitors may also exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Occasional acute renal failure has also been reported. Caution should be taken when COX-2 inhibitors are prescribed, especially in high-risk patients (including elderly patients and patients with volume depletion).
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PMID:COX-2 and the kidney. 1678 27

Before the withdrawal of 2 COX-2 selective agents (COX-2s) from the market, many rheumatoid arthritis patients were using these products regularly, with disease-modifying antirheumatic agents. Clinical trials have shown benefit of COX-2s equivalent to nonselective nonsteroidal anti-inflammatory drugs (NS-NSAIDs) in rheumatoid arthritis. Better gastrointestinal (GI) safety has been demonstrated with COX-2s; numerical but not statistical benefit with concomitant use of cardiovascular (CV) doses of aspirin. COX-2 benefit may extend to lower GI blood loss against which proton pump inhibitors are not protective. COX-2s are associated with hypertension and edema of similar magnitude to NS-NSAIDs in predisposed individuals. Epidemiologic studies and clinical trials have confirmed the association of serious thromboembolic (CV) events and congestive heart failure with rofecoxib>25 mg daily, celecoxib, and NS-NSAIDs, although there is a paucity of long-term data. Important questions remain regarding relative GI and CV risks: is concomitant aspirin protective when coadministered with COX-2s? Does this abrogate their GI benefit? As identified many years ago with NS-NSAIDs, patients may respond to one and not another; COX-2s should be considered individually and not as a single "class." Patients deserve the opportunity to make a choice about the perceived benefit/risk assessment when using these therapies, with the collaboration of their physician.
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PMID:Expectations from patients with rheumatoid arthritis regarding COX-2s: cutting to the heart of the matter. 1678 30

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.
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PMID:Cyclooxygenase-2 inhibitors: a painful lesson. 1678 94


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