Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-steroidal anti-inflammatory drugs (NSAIDs) are the principal drug treatments for inflammation, pain and fever. They act primarily by inhibiting prostaglandin (PG) synthesis but this can cause adverse events (AEs). Since the discovery of two PG synthesising enzymes, COX-1 and COX-2, and the substantial evidence that sparing COX-1 is advantageous for gastric safety, great interest has focused on selective COX-2 inhibitors. Much of the impetus has come from the most recently developed compounds celecoxib and rofecoxib, which have shown spectacular sales growth. However, the older drugs etodolac, nimesulide and meloxicam, made before COX-2 was discovered, are also COX-1-sparing and have good GI safety and therapeutic activities. These five compounds show similarities and differences that are discussed in relation to aspects that include their uses, efficacy, actions and safety.
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PMID:COX-2 inhibitors compared and contrasted. 1182 22

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used as analgesics. Although the results of clinical studies indicate considerable disparity in the analgesic efficacy of NSAIDs, the pre-clinical models generally used for the study of nociception do not allow a clear distinction to be made between the analgesic properties of agents belonging to this family. As clinical pain is characterized by hyperalgesia, we evaluated the effects of NSAIDs with similar chemical structures but different selectivities for cyclo-oxygenase (COX)-1 and COX-2 in a new behavioural model of central hyperalgesia in rats. We assessed the effects of lornoxicam, piroxicam, and meloxicam on the reduction of hindpaw nociceptive thresholds to thermal stimulation produced by a 10% formaldehyde (formalin) injection into rat tail. Each drug was administered intraperitoneally (i.p.) at its ED(50)for the anti-inflammatory effect (namely the inhibition of carrageenan-induced hindpaw oedema). At this dose (1.3 mg kg(-1), 1.0 mg kg(-1), and 5.8 mg kg(-1), respectively), lornoxicam, piroxicam, and meloxicam produced the same anti-inflammatory effect, did not modify thermal nociceptive thresholds, and significantly reduced the hyperalgesia. However, only lornoxicam was fully effective for prevention of hyperalgesia. Our results indicate a dissociation between the anti-inflammatory and the anti-hyperalgesic activity of NSAIDs, where the latter seems to be more evident after the block of both COX-1 and COX-2. Finally, they suggest that our experimental model of thermal hindpaw hyperalgesia can be effectively utilized to assess the ability of different drugs to reduce central sensitization, and thus hyperalgesia.
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PMID:Effects of lornoxicam, piroxicam, and meloxicam in a model of thermal hindpaw hyperalgesia induced by formalin injection in rat tail. 1184 20

Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective inhibitors of cyclooxygenase (COX) isoforms COX-1 and COX-2. NSAIDs have analgesic and anti-inflammatory properties that are proven, and they are extensively used in the treatment of arthritis, pain, and headache. Despite their good efficacy, NSAIDs are associated with significant gastrointestinal (GI) toxicity, which appears to be related to the inhibition of the cytoprotective function of COX-1. Thus, selective COX-2 inhibitors, or coxibs, were designed to inhibit only the production of COX-2-dependent inflammatory prostaglandins, without any effect on COX-1 and its gastroprotective function. This article reviews important evidence on the GI safety of coxibs. Endoscopic studies demonstrated that coxibs, such as celecoxib and rofecoxib, induced significantly fewer ulcers than nonspecific NSAIDs. To analyze whether the incidence of clinical GI events is also lower with coxibs, 2 large controlled clinical trials, the Celecoxib Long-term Arthritis Safety Study (CLASS) and Vioxx Gastrointestinal Outcomes Research (VIGOR), evaluated the GI safety of celecoxib and rofecoxib, respectively. Based on evidence from the VIGOR trial, it was demonstrated that rofecoxib has already fulfilled the promise and significantly decreases the risk of clinically important and complicated GI events compared with a nonselective NSAID, naproxen. In contrast, the CLASS trial showed that the incidence of ulcer complications in patients treated with celecoxib was similar in patients treated with nonspecific NSAIDs.
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PMID:An evidence-based evaluation of the gastrointestinal safety of coxibs. 1190 55

Prostaglandins (PGs) and leukotrienes (LTs) are important proinflammatory mediators. They are both derived from arachidonic acid (AA). Cyclooxygenase (COX), the key enzyme in transforming AA into PGs, has two isoforms: COX-1 is constitutively expressed, and COX-2, is inducible. Lipoxygenase (5-LO) is the key enzyme for LT production. PGs and LTs have been intensively studied. Release of these molecules is associated with mucus secretion, redness, pain, fever and other inflammatory manifestations. Both PGs and LTs are involved in host defense against various pathogens. In addition to mediating inflammatory symptoms, PGs might suppress some innate immune factors, including nitric oxide (NO) production. PGs also suppress a TH1 response. LTs have pathologic potential, especially in asthma. LTs also have been found to have positive roles in host defense, either against virus or bacteria. Finally, PGs and LTs might regulate the production of each other, possibly at the level of substrate competition by their enzymes. Because they are clinically important molecules, a further understanding of the roles that PGs and LTs played in host defense will have great impact on therapeutic research.
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PMID:Distinct roles of eicosanoids in the immune response to viral encephalitis: or why you should take NSAIDS. 1195 35

The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 microl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.
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PMID:Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test. 1199 Dec 54

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used. These agents are associated with adverse renal effects caused by the reduction in synthesis of renal prostaglandins through inhibition of cyclooxygenase (COX). Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney in constitutive and inducible forms. It is assumed therefore that the COX-2-selective inhibitors, rofecoxib and celecoxib, would have an effect on renal function similar to that of nonselective NSAIDs. Several studies have evaluated this issue, although they have different study models and some have design flaws that limit their interpretation. Therefore, conclusions should be based on the pattern of observed effects rather than on individual data. These studies suggest that both celecoxib and rofecoxib can cause sodium retention and decrease glomerular filtration rate (GFR) to a similar extent as nonselective NSAIDs in patients at risk for adverse renal effects. Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered.
J Pain Symptom Manage 2002 Apr
PMID:Renal effects of cyclooxygyenase-2-selective inhibitors. 1199 45

Nonsteroidal anti-inflammatory drugs (NSAIDs) are substances other than steroids that inhibit a component of the inflammatory cascade. This article is dedicated to those substances which specifically inhibit cyclooxygenase. NSAIDs are used extensively in the veterinary field. This article discusses their pharmacologic mechanism of action, indications, and toxicity. The two isoforms of cyclooxygenase (COX-1 and COX-2) are reviewed along with the newer NSAID which are more effective and less toxic due to more specific COX-2 inhibition. Specific effects on soft tissue, bone, cartilage, and synovium are summarized. Pain modulation is extensively reviewed as well as the antiendotoxic and antithrombotic uses.
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PMID:Nonsteroidal anti-inflammatory drugs. 1206 80

Anti-inflammatory agents have been used for centuries, but only in the last few decades has medical science gained insight into the complex biologic roles of the primary mediators of inflammation, the eicosanoids and their derivatives. Detailed understanding of the prostaglandins and leukotrienes provides a framework for the treatment of pain, inflammation, and fever with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), but these agents have exacted a substantial side effect burden. The discovery of cyclooxygenase-2 (COX-2) has guided development of rationally designed therapeutic agents that have the benefits of older NSAIDs with reduced gastrointestinal toxicity. Elucidation of the structure of COX isoenzymes has been key in the development of coxibs, the COX-2-selective subset of NSAIDs. Methods to determine the degree of COX-2 selectivity have been refined and are indispensable for comparing the relative selectivity of these agents. This review summarizes some of the key aspects of COX biochemistry, structure, and function and the evolution of understanding the mechanism of action of COX-2-selective inhibitors. The clinical relevance of COX-1 compared with COX-2 inhibition is discussed to provide a framework upon which clinicians can better appreciate current and future therapeutic applications of coxibs.
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PMID:Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility. 1208 89

Aspirin and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory and analgesic effects. In addition, aspirin is documented to reduce cardiovascular events in selected populations, presumably because of inhibition of platelet aggregation. Yet these drugs are not without toxicity, particularly adverse effects on the gastric mucosa. The gastrointestinal toxicity of nonselective NSAIDs and aspirin derives from the inhibition of the cyclooxygenase (COX) enzyme, COX-1, which synthesizes gastroprotective prostaglandins, while the anti-inflammatory and pain-relieving effects are largely derived from inhibition of COX-2-derived prostaglandins. Available data indicate that the harmful gastric effects of nonselective NSAIDs are reduced by substitution of agents that only inhibit the COX-2 protein. The COX-2-selective inhibitors, however, have also been shown to inhibit the production of vascular prostacyclin, which has vasodilatory effects and inhibits platelet aggregation; unlike nonselective NSAIDs, they do not inhibit the production of thromboxane, an eicosanoid that promotes platelet aggregation. Whether these effects could potentially contribute to a prothrombotic environment is the subject of current, intensive debate. In the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, there was a higher incidence of cardiovascular thrombotic events in the rofecoxib- vs the naproxen-treated group: 1.67 vs 0.70 per 100 patient years. However, in a pooled analysis of rofecoxib studies, the risk of sustaining a thrombotic cardiovascular event was similar when comparing patients receiving rofecoxib with those receiving placebo, or when comparing patients receiving rofecoxib with those receiving nonnaproxen nonselective NSAIDs. These findings are likely to result, at least in part, from the antiplatelet action of naproxen, which has been shown to be potent and sustained during a typical dosing regimen (500 mg twice daily in VIGOR). In contrast, the other NSAID comparators effect weaker and/or nonsustained antiplatelet action. In the Celecoxib Long-term Arthritis Safety Study (CLASS) trial, there was no difference between celecoxib and the nonselective NSAIDs explored (which did not include naproxen) in cardiovascular event rates. Unlike those in VIGOR, patients in the CLASS trial were allowed to take low-dose aspirin. Thus, despite concerns raised by results of VIGOR, other existing data, including those pooled from existing placebo-controlled trials, do not support a clinically relevant prothrombotic effect of the COX-2 inhibitors. Additional placebo-controlled data, from patients at both high and low risk for cardiovascular events, are warranted to clarify the cardiovascular effects of this class of agents.
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PMID:Current perspective on the cardiovascular effects of coxibs. 1208 93

Postsurgical pain is often undertreated. Opioids are frequently used in perioperative analgesia, but concern about side effects can result in administration of an inadequate dose for pain relief. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used increasingly for postoperative analgesia. The use of balanced analgesia-a combination of opioids, NSAIDs, and local anesthesia utilizing agents from other classes (eg, ketamine, clonidine)-improves the efficacy of pain relief and decreases risk of side effects. While lacking some of the troublesome side effects of opioids, nonselective NSAIDs may cause bleeding as a result of their inhibitory effects on COX-1. For this reason, COX-2-selective inhibitors (coxibs) are attractive opioid-sparing analgesic options in the perioperative setting. Factors in addition to side effects such as time to onset of action, duration of action, maximum pain relief, use of rescue medication, and other factors relevant to a given pain model are important in determining overall analgesic efficacy. Clinical studies show that COX-2-selective inhibitors are effective for the treatment of preoperative and postoperative pain and reduce postsurgical requirements for opioids. This evidence supports a role for COX-2-derived prostaglandins as key mediators of nociceptive pain and peripheral sensitization (hyperalgesia). Pain management in the perioperative setting and the role of COX-2-selective inhibitors in acute and postoperative pain are reviewed here.
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PMID:Cyclooxygenase-2-selective inhibitors in the management of acute and perioperative pain. 1208 97


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