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)

Research strongly indicates that increased expression of the isoenzyme cyclooxygenase-2 (COX-2) is responsible for elevated production of prostaglandins in inflamed joint tissues and is involved in the mediation of pain. In contrast, COX-1 is a constitutively produced isoenzyme that is involved in the synthesis of eicosanoids that have important homeostatic functions, for example, in the gastric mucosa and platelets. This new knowledge led to the development of drugs that are highly specific inhibitors of COX-2 while not inhibiting COX-1 at maximally efficacious dosages. The first COX-2 specific agent approved for clinical use in the United States was celecoxib. Large multicenter trials have shown that celecoxib at dosages of 100 mg BID and 200 mg BID is as effective as naproxen 500 mg BID in patients with osteoarthritis of the knee or hip. Another large multicenter trial also demonstrated that celecoxib 200 mg BTD and 400 mg BID is as effective as naproxen 500 mg BID in patients with rheumatoid arthritis (RA). A comparative trial showed that celecoxib 200 mg BID is as effective as diclofenac SR 75 mg BID in patients with RA. The potential of COX-2 specific inhibitors to provide antiinflammatory and analgesic efficacy equivalent to that of conventional nonsteroidal antiinflammatory drugs without the adverse gastrointestinal mucosal and platelet effects associated with nonspecific COX inhibitors promises to revolutionize the clinical care of arthritis patients.
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PMID:Antiinflammatory and analgesic efficacy of COX-2 specific inhibition: from investigational trials to clinical experience. 1103 98

Following the discovery of inducible COX-2 in arthritic joint fluid and immunocompetent cells a revolution in the field of antiinflammatory treatment was expected. The detection of a constitutive COX-2 in the kidney, in stomach and central nervous system destroyed this hypotheses. Further experiments in animal models were done to elucidate the role of the constitutive COX-2 in different physiological and pathophysiological states. In central nervous system was shown that the constitutive COX-2 is the predominant isoform of cyclooxygenases in brain and spinal cord and is highly regulated by different mediators. After experimental induction of peripheral inflammation a significant induction of COX-2 gene, protein expression and synthesis of prostaglandins in the spinal cord was detected. It was concluded that COX-2 is strongly involved in pain mediation processing in the spinal cord. The detection of COX-2 in the brain endothelial cells and its role in fever led to new insights of development and time course of temperature elevation. Probably, the use of selective COX-2 inhibitors decreases fever more effective than classical antipyretics. Furthermore, newer results show a role of COX-2 in differentiation and maturation processes in brain. These findings implicate new ways for the treatment of Alzheimer's disease and other degenerative brain disorders. Clinical and experimental results with selective COX-2 inhibitors show a better safety profile than non-selective COX inhibitors. The clinical use after drug registration will be decide on the further role of this new class of drugs in analgesic/antiinflammatory therapy and on new fields of clinical use.
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PMID:COX-2 in brain and spinal cord implications for therapeutic use. 1103 61

NSAIDs are widely used and beneficial for patients with inflammatory pain. However, NSAIDs cause significant adverse upper gastrointestinal effects, including increased mortality from serious ulcer complications. NSAIDs exert their anti-inflammatory effects by inhibiting the activity of the COX enzyme, which was recently shown to exist in two isoforms, a constitutive COX-1 and an inducible COX-2. The latter isoform is induced in inflammation, while the former is responsible for prostaglandin effects on platelet function and gastric mucosal defense. Two specific COX-2 inhibitors have recently been introduced into the market. The available data from clinical trials indicate that these new drugs have anti-inflammatory and analgesic effects similar to those of conventional NSAIDs, but reduced rates of adverse upper gastroduodenal effects, which are similar to those observed with placebo. This difference in rates of adverse effects might imply improved safety for patients requiring anti-inflammatory treatment. It has, however, to be kept in mind that specific COX-2 inhibitors lack cardiovascular protective effects. Considering the high consumption rate of NSAIDs to achieve pain relief in arthritis and other musculo-sceletal diseases, the reduced risk of gastrointestinal ulcers and ulcer complications may have a positive impact on population health and health economy.
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PMID:Selective inhibitors of COX-2--are they safe for the stomach? 1114 80

Although paracetamol potently reduces pain and fever, its mechanism of action has so far not been satisfactorily explained. It inhibits both COX-1 and COX-2 weakly in vitro, but reduces prostaglandin synthesis markedly in vivo. In mouse macrophage J774.2 cells, COX-2 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced COX-2. In the rat pleurisy model of inflammation, a second peak of COX-2 protein appears 48 hr after administration of the inflammatory stimulus, during the resolution phase of the inflammatory process. Inhibition of the activity of this late-appearing COX-2 with indomethacin or a selective COX-2 inhibitor, delays resolution and the inflammation is prolonged. Cultured lung fibroblasts also express COX-2 activity after stimulation with IL-1beta which is highly sensitive to inhibition with paracetamol. Thus, evidence is accumulating for the existence of a COX-2 variant or a new COX enzyme which can be inhibited with paracetamol.
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PMID:Paracetamol-inhibitable COX-2. 1119 35

NSAIDs are used throughout the World Health Organization three-step analgesic ladder, and are indicated for pain in all stages of malignancy. Side-effects are common with NSAIDs. Much has been written about NSAIDs and COX, since the discovery of COX-1 and COX-2 isoforms. How do you choose the appropriate NSAID? The choice of NSAID continues to be dependent upon associated gastroduodenal toxicity and the related risk factors of individual patients. Choosing the appropriate NSAID should minimize the likelihood of needing additional medications to manage adverse effects and symptoms caused by the NSAID therapy itself.
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PMID:Ibuprofen to rofecoxib: what does it all mean and what do I do now? 1146 2

Prostanoids sensitize sensory afferents during inflammation. However, their role in neuropathic pain is still unclear. We analyzed the actions of prostanoids, non-selective (indomethacin) or selective (celecoxib and NS-398) cyclooxygenase-2 (COX or COX-2) inhibitors, on the ectopic activity of dorsal root ganglia (DRG) and dorsal horn (DH) neurons in a model of neuropathic injury. Extracellular recordings of DRG and DH neurons and cardiovascular measurements were performed on anesthetized, paralyzed and artificially ventilated adult male Sprague-Dawley rats whose sciatic nerve had been transected. PGD(2), PGE(2), PGF(2alpha), carbaprostacyclin (cPGI(2); a stable prostacyclin analog), and carbocyclic thromboxane (cTXA(2)) were administered at cumulative doses (0.0001-5 mg/kg, i.p.) at 5 or 10 min intervals. Only cPGI(2) significantly increased the DRG and DH activity in a dose-dependent manner, with ED(50) values of 0.05 (0.01-0.96) and 0.69 (0.11-1.04) mg/kg, respectively. The other prostanoids did not significantly increase activity, although they reduced heart rate for up to 5 min following administration. Time course experiments with single doses of cPGI(2) (1 mg/kg, i.v.) increased DH discharge rate 3-17 min after injection. Indomethacin (3 mg/kg, s.c.), but not celecoxib or NS-398 (both at 6 mg/kg, s.c.), reduced both DRG and DH activity. Our results indicate that cPGI(2) excites DRG and DH neurons of neuropathic rats, and may suggest a role for IP prostanoid receptors in pain episodes associated with nerve injury. The inhibitory effect of indomethacin, but not celecoxib or NS-398, on ectopic activity may suggest that a tonic generation of PGI(2) by COX-1 could contribute to neuropathic pain.
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PMID:A stable prostacyclin analog enhances ectopic activity in rat sensory neurons following neuropathic injury. 1151 14

The non-steroidal anti-inflammatory drugs (NSAID) are most commonly used drugs in rheumatology. NSAID effectively reduce the pain and inflammation. However, the use of NSAIDs is associated with various gastrointestinal side effects. The discovery of the two COX isoforms, namely COX1 (constitutive) and COX2 (inducible) led to the search for specific COX2 inhibitors with better gastrointestinal safety. Beside the simply gastrointestinal safety the issue point to the still not resolved questions about coxibs effects on the constitutive COX2 function in brain, kidney and the reproductive tract, as well as vigilance in post-marketing surveillance.
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PMID:[Nonsteroidal antirheumatic agents--present status and perspectives]. 1155 13

Pain of multiple etiologies remains a substantial problem for many patients presenting in the clinical setting. Improved pain relief can be demonstrated, and adverse effects minimized, by multimodal analgesic combinations as the method to improve pain treatment. Substantial evidence supports combining analgesics for the management of pain and, in some instances, they have a heterogeneous pharmacologic sparing effect. Fixed-dose combination analgesics with demonstrated efficacy and safety are widely useful for pain management. However, work needs to continue to further explore which analgesics at which doses can be combined with a coanalgesic in a patient-specific manner to achieve additive, if not synergistic, multimodal pain relief with the fewest possible adverse consequences. Unsupervised consumption of over-the-counter drugs that contain acetaminophen, aspirin, or ibuprofen offers clinical challenges to both the patient and health care providers. Couple this often undisclosed over-the-counter medication consumption event with prescription medications, which many contain similar combination ingredients, and the potential for a therapeutic misadventure may precipitate. This article will address the safety and efficacy of acetaminophen, aspirin, and ibuprofen independently and in combination with currently available prescription dosage forms with a focus on pharmacology, pharmacotherapeutics, pharmacodynamics, and pharmacokinetics, including drug interactions at the CYP450 system. Patient-specific cautions are presented for opiate/opioid combinations, codeine, hydrocodone, oxycodone, and propoxyphene, and there is a discussion of COX I/COX II agents.
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PMID:Acetaminophen, aspirin, or Ibuprofen in combination analgesic products. 1170 82

Osteoid osteoma is a benign bone forming neoplasm that is characterized by its small size (less than 2 cm), self-limited growth, and the tendency to cause extensive reactive changes in the adjacent tissue. The lesion classically presents with severe pain at night that is dramatically relieved by NSAIDs. The tumor has been shown to express very high levels of prostaglandins, particularly PGE2 and PGI2. The high local levels of these prostaglandins are presumed to be the cause of the intense pain seen in patients with this lesion. One generally accepted form of treatment is the prolonged use of NSAIDs. Since the cyclooxygenases are thought to be the source of these prostaglandins, and the central target of NSAIDs, we evaluated the expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in osteoid osteoma tissues from patients following surgery. In the 12 specimens examined we found that the tumor osteoblasts had strong immunohistochemical staining for COX-2, while the staining in the surrounding host osteoblasts in the reactive bone was scant. Significant COX-1 staining was also detected in both tumor and host osteoblasts. For comparison we examined the COX expression in human fracture callus, fibrous dysplasia, osteoblastoma, osteofibrous dysplasia, and myositis ossificans. With the exception of fracture callus, very limited amounts of COX-2 could be detected in these tissues. Taken together, we conclude that the increased production of prostaglandins by osteoid osteomas implicates that COX-2 is one of the mediators of this condition. These findings suggest that the newly selective COX-2 inhibitors could be used to more safely treat osteoid osteomas.
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PMID:COX-1 and COX-2 expression in osteoid osteomas. 1600 74

Pain-induced functional impairment in the rat (PIFIR) is a model of inflammatory and arthritic pain similar to that of clinical gout. Nociception is induced by the intra-articular injection of uric acid into the right hind limb, inducing its dysfunction. Animals then receive analgesic drugs and the recovery of functionality over time is assessed as an expression of antinociception. We have examined the role of peripheral prostaglandins synthesized by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in inflammatory pain using the PIFIR model. Rofecoxib (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor) both produced dose-dependent effects. When the inhibitors were administered before uric acid, they showed similar potency, but the antinociceptive efficacy of SC-560 was lower than rofecoxib; the best antinociceptive effects were obtained with the dose of 100 microg/articulation of each inhibitor (pre-treatment). In post-treatment (inhibitors administered after the uric acid), rofecoxib showed the least antinociceptive effect and SC-560 was more potent than rofecoxib. The inhibition of both COX-1 and COX-2 produced a more profound analgesic effect than the inhibition of either COX-1 or COX-2 alone. The present data support the idea that both COX isoforms contribute to the development and maintenance of local inflammatory nociception. Thus, it could be expected that inhibition of both COX-1 and COX-2 is required for non-steroidal anti-inflammatory drugs (NSAID)-induced antinociception in the rat. These findings suggest that the therapeutic effects of NSAIDs may involve, at least in part, inhibition of COX-1 and COX-2.
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PMID:Involvement of peripheral cyclooxygenase-1 and cyclooxygenase-2 in inflammatory pain. 1190 7


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