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)

Blockade of prostaglandin (PG) production by COX inhibitors is the treatment of choice for inflammatory pain but is also prone to severe side effects. Identification of signaling elements downstream of COX inhibition, particularly of PG receptor subtypes responsible for pain sensitization (hyperalgesia), provides a strategy for better-tolerated analgesics. Here, we have identified PGE2 receptors of the EP2 receptor subtype as key signaling elements in spinal inflammatory hyperalgesia. Mice deficient in EP2 receptors (EP2-/- mice) completely lack spinal PGE2-evoked hyperalgesia. After a peripheral inflammatory stimulus, EP2-/- mice exhibit only short-lasting peripheral hyperalgesia but lack a second sustained hyperalgesic phase of spinal origin. Electrophysiological recordings identify diminished synaptic inhibition of excitatory dorsal horn neurons as the dominant source of EP2 receptor-dependent hyperalgesia. Our results thus demonstrate that inflammatory hyperalgesia can be treated by targeting of a single PG receptor subtype and provide a rational basis for new analgesic strategies going beyond COX inhibition.
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PMID:Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. 1571 70

1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitrates
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PMID:Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo. 1585 32

The mechanism by which COX inhibitors exert their analgesic effect is well established. However, data show no direct correlation between drug concentrations in plasma and the analgesic or adverse effects in chronic inflammatory conditions. This represents a major problem in the development of COX inhibitors, since it is difficult to predict the appropriate dosing regimen for the treatment of chronic inflammatory pain, based upon information from pre-clinical studies and eventually early clinical studies. The factors that determine response in inflammatory pain must be understood in order to make predictions about the time course of the analgesic effect. In this review the determinants of drug response and their variability will be discussed: physicochemical properties, pharmacokinetics (PK), pathophysiology and disease progression. From a mechanistic point of view, endogenous mediators of inflammation might be used as a biomarker for the analgesic effect and safety assessment. Such a biomarker can be an intermediate step between drug exposure and response. In addition, its concentration-effect relationship could be characterized by pharmacokinetic-pharmacodynamic (PK/PD) modelling. Indeed, recent investigations have shown that COX-2 inhibition, as determined by modelling of prostaglandin E2 (PGE2) levels in the whole blood assay in vitro can be used as a marker to predict drug effects (analgesia) in humans. A model-derived parameter, IC80, (total and unbound) was found to correlate directly with the analgesic plasma concentration of different COX inhibitors varying in enzyme selectivity. These findings indicate that PGE2 and thromboxane B2 inhibition can be used to predict and select efficacious doses in humans.
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PMID:Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors. 1585 83

Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used medications worldwide to inhibiting COX activity for the treatment of pain and inflammation. Their nephrotoxicity has been well documented. With the development and clinical implementation of new COX-2 inhibitors, the safety, including the effects on renal function and blood pressure, is 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 mediation of renin release, regulation of sodium excretion and maintenance of renal blood flow. Similar to conventional 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 and patients with volume depletion). Recently, agents with combined lipooxygenase/COX inhibition and agents that combine NSAIDs with a nitric oxide (NO) donor have been reported to reduce adverse renal effects.
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PMID:Renal effects of non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors. 1589 76

Non-selective NSAIDs enhance the risk of serious ulcer complications (bleeding, perforation, obstruction), hospitalization and death about 3-10-fold. The gastrointestinal side effects of NSAIDs have a considerable economical burden, since they are responsible for 5-10 billion dollars in hospitalization charges and lost work time. NSAIDs cause gastrointestinal damage by both topical and systemic effects. COX-1-mediated inhibition of prostaglandin synthesis is probably the most relevant mechanism, but NSAIDs can cause gastrointestinal injury also by COX-independent pathways. COX-2-selective inhibitors (Coxibs) such as celecoxib, rofecoxib or valdecoxib have been developed to achieve an equal relief of pain and inflammation as classical NSAIDs but without their risk of gastrointestinal side effects. Within the first three months, celecoxib became the fastest selling drug in history. The gastrointestinal safety of classical NSAIDs and Coxibs has been compared in a variety of endoscopic investigations, meta-analyses and outcome studies. In conclusion, these studies have clearly shown, that Coxibs are associated with significantly less dyspeptic symptoms, erosions, ulcers and ulcer complications. In contrast, Coxibs seem to delay gastric ulcer healing to the same extent as traditional NSAIDs. Besides their effects on the upper gastrointestinal tract, NSAIDs can cause small intestinal inflammation, ulcers of the small and large intestine, ileal dysfunction, intestinal strictures, colitis and NSAID enteropathy. In addition, NSAIDs increase the risk of lower gastrointestinal complications including bleeding, perforation and obstruction. Current data suggest, that Coxibs are associated with a significantly lower risk of serious lower GI events than traditional NSAIDs. It is now under debate, who should receive COX-2-selective inhibitors instead of classical NSAIDs, since Coxibs are much more expensive. Data from cost-effectiveness studies suggest, that Coxibs should currently be used only in patients with high risks of GI complications.
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PMID:Impact of COX-2 inhibitors in common clinical practice a gastroenterologist's perspective. 1597 40

Hyperalgesia from an incisional pain is evoked by noxious stimuli (mechanical and cold). The present study was aimed to examine the effect of licofelone, a dual inhibitor of cyclooxygenases (COX-1/COX-2) and 5-lipoxygenase (5-LOX) against mechanical hyperalgesia and cold allodynia in the rat model of incisional pain. Mechanical hyperalgesia and cold allodynia was assessed employing Randall and Sellitto analgesymeter and cold water maintained at 10 degrees C, respectively. Zileuton (25-100 mg/kg, po), a 5-LOX inhibitor, indomethacin (1-30 mg/kg, po), a non-selective COX inhibitor, and licofelone (10-100 mg/kg, po) a dual inhibitor, significantly reversed the mechanical hyperalgesia and also caused an increase in cold allodynia threshold with different pharmacologic profile. The rank order of potency based on ED50 values in both the paradigms was found to be licofelone > indomethacin > zileuton. The results of the present study are indicative of the role of leukotrienes along with prostaglandins in the rat model of incisional pain (a paradigm of postoperative pain). The results suggested that dual inhibition approach of simultaneous inhibition of COX and LOX pathways might prove beneficial in combating hyperalgesia of postoperative pain.
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PMID:Effect of licofelone against mechanical hyperalgesia and cold allodynia in the rat model of incisional pain. 1598 22

Despite the diverse chemical structure of aspirin-like drugs, the antinociceptive effect of NSAIDs is mainly due to their common property of inhibiting cyclooxygenases involved in the formation of prostaglandins. Prostaglandins are potent hyperalgesic mediators which modulate multiple sites along the nociceptive pathway and enhance both transduction (peripheral sensitizing effect) and transmission (central sensitizing effect) of nociceptive information. Inhibition of the formation of prostaglandins at peripheral and central sites by NSAIDs thus leads to the normalisation of the increased pain threshold associated with inflammation. The contribution of peripheral and central mechanisms to the overall antinociceptive action of NSAIDs depends on several factors including the location of the targets of drug action, the site of drug delivery and the uptake and distribution to the site of action. The present work reviews the data on the regulation and location of cyclooxygenases at central and peripheral sites of the nociceptive pathway and focuses on the role of COX in the generation and maintenance of pain hypersensitivity. Experimental and clinical evidences are used to evaluate the significance of the peripheral and central antihyperalgesic effects of NSAIDs.
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PMID:COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. 1599 52

Cyclooxygenase-2 (COX-2) is up-regulated in stromal and inflammatory cells. The inducible COX-2 isoform is expressed during inflammation, in some cancers, and in brain tissue after global and focal ischemia. Tissue acidosis is a dominant factor in inflammation, and contributes to pain and hyperalgesia. Recently, compelling epidemiological and clinical evidence has documented the COX-independent effects of some COX-2 inhibitors (i.e., celecoxib, valdecoxib, and rofecoxib); among these effects are carbonic anhydrase (CA) inhibition. Carbonic anhydrases are zinc metalloenzymes expressed in various cell types, including those of the kidney, where they act as general acid-base catalysts. The kidneys are also known to express the highest concentration of COX-2 messenger ribonucleic acid. Celecoxib, like the prototypic CA inhibitor acetazolamide, is structurally characterized by an unsubstituted sulfonamide moiety. In the present study, we report that celecoxib exhibits the characteristics of a potent CA inhibitor, showing inhibitory human carbonic anhydrase II (hCAII) activity in the nanomolar range. Valdecoxib was relatively less potent. Rofecoxib, which lacks the unsubstituted sulfonamide moiety characteristic of CA inhibitors, showed no significant hCAII inhibitory activity. The current study corroborates our earlier report of structure-activity relationships as predictors of such metabolic events as hyperchloremia, acidosis, and changes in calcium and phosphate disposition; and clinical manifestations associated with CA inhibition reported with celecoxib. These data showing inhibition of hCAII by the unsubstituted sulfonamides celecoxib and valdecoxib, but not by rofecoxib, may have important implications for the elucidation of the mechanisms of action as well as the side effects associated with COX-2 inhibitors.
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PMID:The cyclooxygenase-2 inhibitor celecoxib is a potent inhibitor of human carbonic anhydrase II. 1613 2

Clinical and experimental studies have shown that renal and cardiovascular effects of most selective COX-2 inhibitors (rofecoxib, celecoxib) are similar to other traditional NSAIDs (dual COX inhibitors). In these study the effect of nimesulide--preferential COX-2 inhibitor, administration on 24-hour blood pressure profile was investigated in 40 adult individuals on antihypertensive therapy with pain states caused by osteoartritis. Nimesulide was administered orally, twice a day at the conventional dose of 0.1 g for five days. In the next (or previous) 5 days the same patients were administered with ketoprofen at the dose of 0.05 g three times a day. On the last day of the NSAID administration period, 24-hour blood pressure monitoring was performed. Our results indicate no difference between nimesulide and ketoprofen effects on mean blood pressure values during antihypertensive therapy.
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PMID:Effect of nimesulide-a preferential COX-2 inhibitor on arterial blood pressure, compared to ketoprofen. 1614 90

In a very short time, COX-2 enzyme inhibitors have gone from the darlings to the pariahs of the pharmaceutical industry. These drugs were developed based on the hypothesis whereby selective inhibition of the COX enzyme would lead to reduction in pain and inflammation without associated gastrointestinal and bleeding risks. However, in September 2004, rofecoxib was voluntarily removed from the market for increased cardiovascular risk and in April 2005, valdecoxib was also withdrawn, at least in part, due to excess cardiovascular risk. Celecoxib was the first COX-2 inhibitor introduced and the only remaining one on the US market. There is consequently a justified concern that cardiovascular toxicity is a class effect of all COX-2 inhibitors. This article systematically reviews the evidence surrounding COX-2 inhibitors and cardiovascular risk. Although the evidence suggests a fairly consistent cardiovascular risk with rofecoxib, the evidence for cardiovascular risk with celecoxib is more equivocal. Although isolated studies have suggested some cardiovascular risk for celecoxib, the totality of the evidence suggests that any risk is likely to be small and comparable to traditional NSAIDs. The cardiovascular risks of COX-2 inhibitors appear heterogeneous, influenced not only by the drug class, but also individual drug, dosage and patient characteristics. Specific modifying factors of the cardiovascular risk of COX-2 inhibitors including dose, concomitant drugs, individual cardiac and genetic risk profiles, will require further study.
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PMID:Celecoxib and cardiovascular risks. 1637 Sep 48


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