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)

The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-inflammatory drugs with fewer side effects than existing non-steroidal anti-inflammatory drugs (NSAIDs). We have now identified 6-[(2,4-difluorophenyl)-thio]-5-methanesulfonamido-1-indanone++ + (20) (L-745,337) as a potent, selective, and orally active COX-2 inhibitor. The structure-activity relationships in this series have been extensively studied. Ortho- and para-substituted 6-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave compounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 20 has an efficacy profile that is superior or comparable to that of the nonselective COX inhibitor indomethacin in animal models of inflammation, pain, and fever and appears to be nonulcerogenic within the dosage ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, compound 20 is more potent in the rat paw edema assay, has a longer t1/2 in squirrel monkeys, and seems less ulcergenic than 2 in rats.
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PMID:Cyclooxygenase-2 inhibitors. Synthesis and pharmacological activities of 5-methanesulfonamido-1-indanone derivatives. 852 3

Inducible cyclooxygenase-2 (COX-2), but not constitutive COX-1, can be upregulated in rheumatoid synovial tissue by interleukin-1 beta and phorbol esters and is inhibited by dexamethasone. This supports the role of COX-2 in acute inflammation in arthritis. Selective inhibition of COX-2 by non-steroidal anti-inflammatory drugs (NSAIDs) has been proposed as an approach to reduce their associated side effects while maintaining efficacy. The improved safety profile of selective COX-2 inhibitors will allow more widespread and sustained use than is currently possible with standard NSAIDs. In rheumatoid arthritis they may be used as effective symptomatic relief, in combination with disease modifying therapy at an early stage of disease. In osteoarthritis, and, more particularly, soft tissue rheumatism, pain contributes to the development of chronic disease, therefore the main benefit of selective COX-2 inhibition will be to provide safe, effective pain relief to maintain mobility and reduce disability.
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PMID:Clinical implications of selective cyclooxygenase-2 inhibition. 862 78

A multicentre, double-blind, randomized study was conducted in patients with rheumatoid arthritis (RA) in order to compare the efficacy and safety of two different doses of meloxicam, a new preferential cyclooxygenase-2 (COX-2) inhibitor. Four hundred and twenty-three patients were randomized to receive once-daily oral meloxicam 7.5 mg (n = 216) or meloxicam 15 mg (n = 207) for 3 weeks. The Ritchie joint index and pain in the morning were significantly improved versus baseline (P < 0.001) in both groups. There were no significant differences between the effects of each dose with respect to these measures nor with respect to final assessment of global efficacy by the patients. However, the 15 mg dose was associated with a significantly (P < 0.05) better effect on morning stiffness and grip strength. No differences between the doses were observed with regard to the other secondary efficacy parameter (pain at night, body weight and erythrocyte sedimentation rate). Both doses of meloxicam were well tolerated. There were no differences between the doses with respect to global tolerance as assessed by the patient and the patients, 'general condition'. In conclusion, meloxicam at a once-daily dose of either 7.5 or 15 mg is well tolerated and effective in the treatment of patients with RA.
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PMID:A double-blind, three-week study to compare the efficacy and safety of meloxicam 7.5 mg and meloxicam 15 mg in patients with rheumatoid arthritis. 863 Jun 31

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID), which has a higher activity against cyclooxygenase-2 (COX-2) than against cyclooxygenase-1 (COX-1), with potentially high anti-inflammatory and analgesic action. This study was designed to assess the long-term safety and efficacy of meloxicam 15 mg daily. Three hundred and fifty-seven patients (aged 19-84 yr, mean 56 yr) with rheumatoid arthritis (RA) received meloxicam 15 mg orally once daily, for up to 18 months. Sixty-six per cent of patients remained on therapy for 18 months. Mean global efficacy, assessed by each patient on a visual analogue scale (0 cm = excellent, 10 cm = useless), was 3.32 +/- 3.1 cm at the last study visit (all patients included) and 2.33 +/- 2.25 cm after 18 months. Health status, general condition, morning stiffness, grip strength of right hand, Ritchie joint index, pain in the morning and pain at night all improved significantly. Efficacy was maintained through the study. Only 11.4% of patients discontinued prematurely due to lack of efficacy. Mean global tolerance was good. Twenty-eight per cent of patients experienced gastrointestinal (GI) adverse events, 21% musculoskeletal system disorders, 18% skin disorders and 15% respiratory disorders. Only 13.7% of patients discontinued due to adverse events. Severe GI effects, such as perforation, ulcer and bleeding, occurred in only three patients (0.8%). Withdrawals due to GI adverse events occurred in 3.9% of patients. Meloxicam 15 mg once daily was effective and compared favourably with standard NSAIDs regarding tolerance when administered to patients with RA over an 18 month period.
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PMID:A long-term study to evaluate the safety and efficacy of meloxicam therapy in patients with rheumatoid arthritis. 863 Jun 33

A multicentre, double-blind, randomized study was conducted in patients with osteoarthritis (OA) of the hip or knee in order to compare the efficacy and safety of the new cyclooxygenase-2 (COX-2) inhibitor, meloxicam, with diclofenac sodium, a conventional treatment for this condition. Three hundred and thirty-six patients were treated with oral meloxicam 7.5 mg once daily or diclofenac 100 mg slow release once daily for 6 months. There were no significant differences between the treatment groups with respect to overall pain, pain on movement, global efficacy or quality of life scores at the end of treatment, all of which showed good levels of improvement. Sixty-six patients were withdrawn after the start of the double-blind phase due to adverse events (n = 21, meloxicam; n = 31, diclofenac) or to lack of efficacy (seven in each group). The median of dose paracetamol taken concomitantly was statistically significantly lower in the meloxicam group than in the diclofenac group (185 vs 245 mg/day; P = 0.0123) with a comparable proportion of patients taking concomitant paracetamol therapy in both groups. Both drugs were well tolerated, although severe adverse events, treatment withdrawal and clinically significant laboratory abnormalities were more common with diclofenac than with meloxicam. Thus, meloxicam 7.5 mg is a safe and effective treatment for OA of the hip and knee which demonstrates a trend towards an improved safety profile compared with diclofenac.
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PMID:Meloxicam in osteoarthritis: a 6-month, double-blind comparison with diclofenac sodium. 863 Jun 35

Pre-administered NS-398 (0.1, 1 and 10 mg/kg p.o.), a selective cyclooxygenase-2 inhibitor without gastro-intestinal side-effects, dose-dependently reduced carrageenan evoked spinal c-Fos expression (16 +/- 4%, 32 +/- 3% and 56 +/- 5% reduction, respectively) at 3 h after intraplantar carrageenan. The effects of NS-398 on carrageenan induced peripheral oedema and spinal c-Fos expression were correlated, thus demonstrating the beneficial relief of inflammatory pain.
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PMID:Selective cyclooxygenase-2 inhibition reduces carrageenan oedema and associated spinal c-Fos expression in the rat. 873 41

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used as anti-inflammatory and analgesic agents in the elderly, as well as for their anti-thrombotic properties. In the future, NSAIDs may be more widely used in this sector of the population for the prevention of colon cancer. However, the elderly demonstrate a particularly high incidence of adverse reactions to this class of compounds. The factors responsible for this differential toxicity involve age-related pharmacokinetic, pharmacodynamic and physiological factors, as well as coincident disease states and polypharmacy. Selective inhibitors of cyclooxygenase-2 form a novel class of anti-inflammatory drugs that, in animal studies, exhibit significantly fewer adverse effects on the gastrointestinal tract than standard NSAIDs. If this proves to be the case in humans, these novel agents may be useful for the treatment of inflammation and pain as well as in colorectal cancer prevention, but they will not have utility as antithrombotic agents.
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PMID:Selective inhibitors of cyclooxygenase-2. Potential in elderly patients. 897 41

Chronic inflammatory conditions produce a state of hyperalgesia which is evident from a few hours to days after administration of an inflammatory stimulus. The molecular mechanisms involved in the initiation of hyperalgesia are not well understood and in this study we have investigated the role of prostaglandins in this process in the rat. Unilateral intraplantar injection of Freund's complete adjuvant produces an immediate localized swelling (oedema) with the development of altered pain responses in the ipsilateral paw such as a reduced threshold to noxious stimuli (hyperalgesia) and lowered thresholds such that normally innocuous stimuli produce a pain response (allodynia). We have monitored levels of cyclooxygenase messenger RNA and prostaglandins in lumbar spinal cord in parallel with these behavioural responses (oedema, hyperalgesia and allodynia) and identified a marked increase in cyclooxygenase-2 messenger RNA (3-fold), maximal at 2-4 h after Freund's complete adjuvant, followed by a significant increase in 6-keto prostaglandin F1alpha and prostaglandin E2 which is maximal by 8 h. Pretreatment of animals with the unselective cyclooxygenase inhibitor indomethacin attenuated oedema (approximately 40%) and allodynia (80-100%), but had no effect on the development of mechanical hyperalgesia. Pretreatment with the cyclooxygenase-2 selective inhibitors DuP 697, flosulide and SC58125 also attenuated allodynia (by 80-100%) but had no effect on the development of oedema or mechanical hyperalgesia. The marked increase in cyclooxygenase-2 messenger RNA in the lumbar spinal cord following intraplantar Freund's complete adjuvant suggests that the cyclooxygenase enzyme and its product may have a role in the adaptive response that occurs in the lumbar spinal cord during a peripheral inflammatory reaction. Pharmacological analysis reveals that prostaglandins are directly involved in the development of allodynia. However, these studies show that the development of mechanical hyperalgesia does not require the production of prostaglandins indicating that more than one pathway mediates the altered pain responses associated with a peripheral inflammatory lesion.
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PMID:The potential role of spinal cord cyclooxygenase-2 in the development of Freund's complete adjuvant-induced changes in hyperalgesia and allodynia. 915 62

Pain is the major symptom that leads patients to consult their physicians for the treatment of arthritis; therefore, effective pain control is an important goal in the management of this disorder. Pharmacologic therapy begins with simple analgesics and education. In many patients, simple analgesics do not adequately control moderate arthritis pain, and nonsteroidal antiinflammatory drugs (NSAID) are substituted for or added to the analgesic therapy. While NSAID are effective in controlling pain in mild to moderate osteoarthritis (OA), they are associated with significant toxicity (most frequently gastrointestinal) and may even cause complications that result in death. Patients who experience the pain associated with arthritis would therefore benefit from the antiinflammatory and analgesic actions of agents that are devoid of significant toxicities. Cyclooxygenase-2 (COX-2) inhibitors are being evaluated in clinical trials or are in development. These agents appear to inhibit only the COX-2 isoenzyme, which is produced largely during inflammation and is responsible for the biosynthesis of prostaglandins and other mediators of inflammation as well as sensitizers to pain. Because COX-2 inhibitors do not inhibit COX-1 isoenzyme activity at pharmacologic concentrations, they are devoid of many of the toxicities that are typical side effects of NSAID. Short term studies in dental pain, OA, and rheumatoid arthritis found that the COX-2 inhibitor celecoxib was an effective analgesic but did not cause gastroduodenal erosions. It has the potential to provide analgesia and antiinflammatory action in patients with arthritis without the side effects of NSAID. Further studies are required to substantiate these findings.
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PMID:Pain management in osteoarthritis: the role of COX-2 inhibitors. 924 47

PGs derived from cyclooxygenase-2 (COX-2), in particular PGE2, play important roles in the initiation of inflammation and pain. In the present study, we evaluated the role of COX-2-derived PGE2 in an animal model of established hyperalgesia. Inflammation and hyperalgesia were first induced by injection of carrageenan into rat footpads. Then we investigated the effects of subsequent therapeutic treatment with a selective COX inhibitor, with a nonsteroidal anti-inflammatory drug and with anti-PGE2 antibody. Test compounds were administered 1 to 3 hr after carrageenan challenge, and inhibition of pain (hyperalgesia, measured by withdrawal from a thermal stimulus), and changes in paw edema and PG levels were evaluated. The i.v. administration of a nonselective COX inhibitor, ketorolac, caused a rapid reduction in hyperalgesia in the inflamed footpad, returning it to near-normal values within 1 hr. Normal (control) paw response times were not affected. Therapeutic administration of ketorolac prevented most further swelling caused by carrageenan but did not reverse edema already present at the time of dosing. Administered p.o., a selective COX-2 inhibitor (SC-58635) was as efficacious as ketorolac in reducing inflammatory hyperalgesia. Footpad PG levels returned to base line or below within 5 min of dosing with ketorolac, which suggests rapid turnover of PG in the inflamed tissue. Therapeutic treatment with a monoclonal anti-PGE2 antibody also fully reversed the hyperalgesia response. These studies suggest that continuous production of PGE2 by the COX-2 enzyme is a critical element in sustaining the hyperalgesic response at sites of tissue inflammation.
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PMID:Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production. 939 78


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