Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The novel cyclooxygenase- (COX)-2 inhibitor celecoxib is an effective treatment for the signs and symptoms of osteoarthritis and rheumatoid arthritis. Conventional treatment for these debilitating conditions routinely involves the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs), which are nonspecific inhibitors of COX-1 and COX-2. Numerous studies suggest that inhibition of renal prostaglandin synthesis by NSAIDs is deleterious to kidney function, particularly in high-risk patients. As celecoxib inhibits COX-2 and spares COX-1 at therapeutic doses, we hypothesized that it may offer an improved renal safety profile in patients at risk for NSAID-induced renal toxicity. This article represents a post hoc analysis of the renal safety of celecoxib, using the safety database generated during its clinical development program. This analysis includes data from more than 50 clinical studies involving more than 13,000 subjects. Most subjects were enrolled in randomized, controlled trials (of up to 12 weeks' duration); however, more than 5000 subjects received celecoxib for as long as 2 years in a long-term, open-label study at as much as twice the maximum recommended dosage. The overall incidence of renal adverse events after celecoxib was greater than that after placebo but similar to that after NSAIDs. The most common events reported after celecoxib, namely, peripheral edema (2.1%), hypertension (0.8%), and exacerbation of preexisting hypertension (0.6%), were not time- or dose-related. Peripheral edema was not associated with increased weight or blood pressure. Furthermore, there was no evidence of drug-drug interactions between celecoxib and concomitant angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium channel blockers, or diuretics. We conclude that celecoxib is well tolerated by patients who may be at risk for NSAID-induced renal toxicity, such as the elderly and those with hypertension or preexisting chronic heart disease.
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PMID:Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. 1131 63

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world, but their use is limited because of their propensity to cause gastrointestinal (GI) injury. All patients are at risk of GI injury but certain risk factors increase the likelihood of adverse GI effects. The most important include a history of ulcer or GI complications, increasing age, concomitant anticoagulation, concomitant corticosteroid use, and high-dose NSAIDs or multiple NSAIDs (including an NSAID plus low-dose aspirin). Concurrent illness (e.g., severe rheumatoid arthritis, heart disease) has also been reported to increase the risk of GI events. NSAID-associated GI side effects markedly increase health care costs, with up to 31% of cost of managing arthritis patients accounted for through the management of GI side effects. The COX-2 specific inhibitors (coxibs) were developed with the aim of maintaining anti-inflammatory efficacy but improving gastrointestinal safety in comparison to non-selective NSAIDs. The use of COX-2 specific inhibitors significantly decreases the rate of endoscopic ulcers as compared to traditional NSAIDs. Prospective GI outcomes studies also indicate that these agents decrease clinical GI events as compared to non-selective NSAIDs. The number of patients needed to treat to avert one clinical event in one year is approximately 40-100. The cost-effectiveness of coxibs increases (the cost per GI event averted decreases) in patients with high-risk clinical features because they have higher rates of GI hospitalizations and greater use of expensive prophylactic co-therapy.
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PMID:Gastrointestinal effects of NSAIDs and coxibs. 1260 55

To understand the potential role of cyclooxygenase (COX) in normal and inflammatory human diseases, we characterized the expression of COX-1 and COX-2 in biopsies of osteoarthritis, atherosclerosis, and cancer. Tissues were prepared for immunohistochemistry by standard methods, and representative cases assayed via Western blot and quantitative RT-PCR. COX-2 was not detected in normal human tissues with few exceptions. Moderate to marked COX-2 was observed in the macula densa (MD) and thick ascending limb (TAL) in human fetal kidneys, but was not detected in neonatal and adult MD and TALs. Low level, constitutive COX-2 was detected in colonic epithelium, peribronchial glands, and pancreatic ductal epithelium. Low to moderate COX-2 was detected basally in the cortex, hippocampus, hypothalamus, and spinal cord, and in reproductive tissues during ovulation, implantation and labor. No COX-2 was detected in the existing vasculature in normal tissues, and was also not expressed throughout the ductus arteriosus. COX-2 was markedly induced in human tissues of osteoarthritis, atherosclerosis and cancer. COX-2 was prominently expressed in the synovium, fibrocartilage of osteophytes, and in the blood vessels in the osteoarthritic (OA) knee joint. COX-2 was also prominently detected in the macrophages/foam cells in atherosclerotic plaques, and in the endothelium overlying and immediately adjacent to the fibrofatty lesion. Moderate- to intense COX-2 expression was consistently observed in the inflammatory cells, neoplastic lesions, and blood vessels in all epithelial-derived human cancers studied. In contrast, COX-1 was relatively ubiquitously observed in both normal and pathophysiological conditions. These data collectively imply COX-2 plays an important role in mediating a variety of inflammatory diseases, and imply COX-2 inhibitors may be effective in the prevention and/or treatment of OA, heart disease, and epithelial cancers.
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PMID:Cyclooxygenase-2 in human pathological disease. 1266 83

Both cholesterol and polyunsaturated fatty acid (PUFA) metabolism play an important role in retinal and brain development and function. Dietary intake of cholesterol is accompanied with higher risk of heart disease and was suggested to have a role in the pathogenesis of Alzheimer's disease, while dietary PUFAs were reported to act in an opposite way. The same phenomena could be seen in case of inflammation. These effects are mainly realized through gene expression changes. In the present study, the effects of dietary cholesterol and the combination of cholesterol and fish oil were analyzed on the modulation of fatty acid composition and gene expression in the brain and in the eye. At the transcription level, specific changes could be detected in both tissues among transcription factor genes coding for sterol regulatory element binding proteins, retinoid X receptors and peroxisome proliferator-activated receptors, and different fatty acid binding protein genes by using quantitative real-time PCR. In the eye, cholesterol diet attenuated the positive effects of fish oil on inflammatory gene expression as the combined diet resulted in increased RNAm level of phospholipase A-2, inducible nitric oxide synthase, TNF-alpha, COX-1, COX-2 and cytokine, ICAM-1. This induction was absent in the brain. Complex changes could be also recorded in the fatty acid composition of lipids extracted from eye and brain tissue due to the dietary intervention. One of the most interesting changes was the reduced level of docosahexaenoic acid by cholesterol in the eye. Our results on fatty acid composition and gene expression changes may open up new alleys in understanding the complex roles of cholesterol and PUFAs in normal and pathological visual and brain function.
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PMID:Cholesterol and cholesterol plus DHA diet-induced gene expression and fatty acid changes in mouse eye and brain. 1558 91

Aspirin protects against heart disease, while COX-2 Inhibitors appear to injure the heart. The studies by [this Issue of Cell Metabolism]) shed light on two distinct prostaglandin receptors contributing to these conflicting cardiovascular effects.
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PMID:Getting to the heart of COX-2 inhibition. 1615 2

Cancer is predicted to become the leading cause of death--surpassing heart disease--by the end of this decade. Colorectal cancer is a major health concern, with more than 1,000,000 new cases and 500,000 deaths expected worldwide per year. There is much evidence to suggest a link between the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) and the prevention of colorectal cancer (CRC). The consumption of NSAIDs is not problem free, and the number of deaths due to NSAIDs equals the number of deaths from AIDS or leukemia. Therefore, although chemoprevention of CRC is possible, drugs that have more acceptable side effect profiles than the currently available NSAIDs are required. Since up to 50% of polyps and 85% of colonic tumors in humans overexpress cyclooxygenase (COX-2), COX-2 inhibitors are an ideal drug candidate for CRC prevention or treatment.
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PMID:Cyclooxygenase-2 inhibition prevents colorectal cancer: from the bench to the bed side. 1621 Aug 75

Although heart failure is predominantly caused by cardiovascular conditions such as hypertension, coronary heart disease and valvular heart disease, it can also be an adverse reaction induced by drug therapy. In addition, some drugs have the propensity to adversely affect haemodynamic mechanisms in patients with an already existing heart condition. In this article, non-cardiac drugs known to be associated with the development or worsening of heart failure are reviewed. Moreover, drugs that may adversely affect the heart as a pump without causing symptoms or signs of heart failure are also included. The drugs discussed include anticancer agents such as anthracyclines, mitoxantrone, cyclophosphamide, fluorouracil, capecitabine and trastuzumab; immunomodulating drugs such as interferon-alpha-2, interleukin-2, infliximab and etanercept; antidiabetic drugs such as rosiglitazone, pioglitazone and troglitazone; antimigraine drugs such as ergotamine and methysergide; appetite suppressants such as fenfulramine, dexfenfluramine and phentermine; tricyclic antidepressants; antipsychotic drugs such as clozapine; antiparkinsonian drugs such as pergolide and cabergoline; glucocorticoids; and antifungal drugs such as itraconazole and amphotericin B. NSAIDs, including selective cyclo-oxygenase (COX)-2 inhibitors, are included as a result of their ability to cause heart disease, particularly in patients with an already existing cardiorenal dysfunction. Two drug groups are of particular concern. Anthracyclines and their derivatives may cause cardiomyopathy in a disturbingly high number of exposed individuals, who may develop symptoms of insidious onset several years after drug therapy. The risk seems to encompass all exposed individuals, but data suggest that children are particularly vulnerable. Thus, a high degree of awareness towards this particular problem is warranted in cancer survivors subjected to anthracycline-based chemotherapy. A second group of problematic drugs are the NSAIDs, including the selective COX-2 inhibitors. These drugs may cause renal dysfunction and elevated blood pressure, which in turn may precipitate heart failure in vulnerable individuals. Although NSAID-related cardiotoxicity is relatively rare and most commonly seen in elderly individuals with concomitant disease, the widespread long-term use of these drugs in risk groups is potentially hazardous. Pending comprehensive safety analyses, the use of NSAIDs in high-risk patients should be discouraged. In addition, there is an urgent need to resolve the safety issues related to the use of COX-2 inhibitors. As numerous drugs from various drug classes may precipitate or worsen heart failure, a detailed history of drug exposure in patients with signs or symptoms of heart failure is mandatory.
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PMID:Heart failure induced by non-cardiac drugs. 1680 50

Etoricoxib is a highly selective COX-2 inhibitor (coxib) approved in Europe for the treatment of osteoarthritis (OA), rheumatoid arthritis and acute gouty arthritis. Etoricoxib is an effective analgesic drug that has shown some improved efficacy versus traditional NSAIDs and it is the only coxib approved for the treatment of acute gouty arthritis. Moreover, recent studies evidence its efficacy in patients with ankylosing spondylitis. In the Etoricoxib Diclofenac Gastrointestinal Evaluation study performed in patients with OA, etoricoxib significantly reduced the rate of discontinuation by 50% due to gastrointestinal adverse events versus diclofenac. Comparable rates of thrombotic cardiovascular events were detected. Rates of discontinuation due to hypertension-related adverse effects were higher on etoricoxib than diclofenac. Similarly to other selective COX-2 inhibitors, etoricoxib is contraindicated in patients with ischaemic heart disease or stroke and it should be used with caution in patients with risk factors for heart disease. The European Medicines Agency has contraindicated the use of etoricoxib in patients with uncontrolled hypertension. Selective COX-2 inhibitors remain an appropriate choice in patients at low cardiovascular risk, but with increased risk of gastrointestinal complications.
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PMID:Clinical pharmacology of etoricoxib. 1692 42

Nonsteroidal antiinflammatory drugs (NSAIDs) have potentially important renal adverse effects. With regard to renal adverse effects there is no indication of significant differences between conventional NSAIDs and selective COX-2 inhibitors. Their nephrotoxicity has been well documented. Many of the renal abnormalities that are encountered as a result of NSAIDs use can be attributed to the inhibition of prostaglandins synthesis. The release of prostaglandins is particulary importent in high-risk patients, including patients with severe heart disease, liver disease, preexisting renal disease, elderly and patients with volume depletion. The common complication of NSAID use is retention of sodium and edema formation due to increased reabsorption of sodium and water in the loop of Henle and hyperkalemie due to diminished renin secretion. Nonsteroidal antiiflammatory drugs can induce two different forms of acute renal failure. Decreased prostaglandin synthesis can lead to reversible renal ischemia and hemodynamically-mediated acute renal failure. Second form of acute renal failure is acute interstitial nephritis. This type of interstitial nephritis is often accompanied by nephrotic syndrome due to minimal change disease. Nephrotic syndrome after NSAIDs treatments may be also associated with membranous nephropathy. Another complication of NSAIDs treatment is modest rise of systemic blood pressure in some hypertensive patients due to increase in renal and systemic vascular resistence. In patients consuming excessive amount of NSAIDs over a prolonged period of years papillary necrosis can occur. Exposure to large quantities of NSAIDs can probably induce in some patients chronic renal insufficiency.
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PMID:[Nonsteroidal antiinflammatory drugs and the kidney]. 1696 9

Non-steroidal anti-inflammatory agents (NSAIDs) and selective cyclooxygenase (COX-2) inhibitors (coxibs) are commonly used as analgesic and anti-inflammatory agents. Selective COX-2 inhibitors or coxibs were primarily developed as a response to the gastrointestinal toxicity of conventional NSAIDs but may have other side effects. Currently available data suggests definite prothrombotic risk with the coxibs, and the magnitude of risk may vary with individual agents. Based on available data, coxibs should be restricted to use as 2nd-line, possibly as 3rd-line, agents for carefully chosen patients and randomized trials versus placebo or an accepted comparator must be performed to define the overall safety profile in diverse patient populations. The recently announced Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen (PRECISION) trial will assess the relative cardiovascular safety of three of the most commonly used pain relievers in the treatment of arthritis patients, ibuprofen, naproxen and celecoxib. The study will enroll patients with osteoarthritis, the most common form of arthritis, who have known coronary heart disease or who have multiple risk factors for heart disease and also some patients with rheumatoid arthritis. Patients will be followed for an average of two years to track the occurrence of serious cardiovascular events, including death, heart attack and stroke. This study should provide some definitive evidence of the relative cardiovascular safety of the available anti-inflammatory agents but would be even more useful if it included an arm where patients were treated with analgesics such as acetaminophen and/or moderate strength narcotics.
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PMID:Does a coxib-associated thrombotic risk limit the clinical use of the compounds as analgesic anti-inflammatory drugs? Arguments in favor. 1700 15


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