Therapeutic Effects Of Nonsteroidal Anti-inflammatory Drugs Research Articles

Use of aceclofenac for the treatment of chronic pain in rheumatology

The high anti-inflammatory activity and pronounced analgesic effect of nonsteroidal anti-inflammatory drugs ((NSAIDs) allow successful treatment for pain syndrome associated with many diseases, primarily rheumatic diseases. NSAIDs are the main agents used to relieve pain in osteoarthritis, lower back pain, and periarticular soft tissue diseases. They are also an essential component of combination pharmacotherapy for chronic arthritis. The therapeutic effect of NSAIDs is determined by the suppressed activity of the cyclooxygenase (COX) isoenzymes COX- 1 and COX-2. The widely use of NSAIDs in clinical practice is considerably limited by the risk of adverse reactions (ARs) in the gastrointestinal tract (GIT), which are characteristic for this class of drugs. Medications that are able to selectively inhibit the activity of COX-2 while maintaining that of COX-1 less rarely cause ARs in GIT. This selective effect is produced by aceclofenac. A number of clinical trials have demonstrated the high efficacy of this drug in treating various locomotor diseases. The drug has been also noted to be well tolerated: the risk for aceclofenac- induced ARs in GIT is substantially lower than that due to the use of the majority of other NSAIDs.

The comparative efficacy and safety of topical non-steroidal anti-inflammatory drugs for the treatment of anterior chamber inflammation after cataract surgery: a systematic review and network meta-analysis.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of anti-inflammatory drugs that are used in ophthalmologic surgery. These drugs do not have a steroid structure, but can inhibit surgery-induced miosis, anterior chamber inflammation, and cystoid macular edema (CME). However, the application of NSAIDs remains controversial. Therefore, we performed a meta-analysis to assess the efficacy and safety of NSAIDs for the treatment of anterior chamber inflammation after cataract surgery. Relevant articles were identified from the PubMed, Embase, and Cochrane databases up to October 2016. The therapeutic effect of NSAIDs on anterior chamber inflammation was evaluated. The important outcomes of overall anterior chamber inflammation, freedom from ocular pain, and treatment-related/serious ocular adverse events were analyzed by using a random-effects network meta-analysis. The quality of evidence was assessed via the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. A total of 19 trials assessing 7,234 patients were included in our meta-analysis. Diclofenac was the most likely to improve anterior chamber inflammation after cataract surgery, followed by nepafenac, ketorolac, bromfenac, and flurbiprofen. Nepafenac was most likely to improve postoperative ocular pain relief, followed by bromfenac and ketorolac. Our analysis of treatment-related/serious ocular adverse events revealed that piroxicam was most likely to have the fewest related adverse events, but the robustness of this finding was low. Diclofenac was another near-ideal drug, followed by nepafenac, bromfenac, and ketorolac. NSAIDs are effective drugs compared to placebos for the relief of anterior chamber inflammation. Furthermore, diclofenac, nepafenac, ketorolac, and bromfenac demonstrated relatively greater significant effects than those of other NSAIDs.

Sodium salicylate acts through direct inhibition of phosphoinositide 3-kinase-like kinases to modulate topoisomerase-mediated DNA damage responses

Chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs) exhibit diverse pharmacological and biological activities mainly through their inhibitory effect on cyclooxygenase (COX). However, COX-independent mechanisms involving kinase inhibition have been proposed to explain certain therapeutic effects of NSAIDs. Here, we explored the potential relationship between chemopreventive NSAIDs and DNA damage responses induced by treatment with topoisomerase-targeting drugs. (1) Sodium salicylate, a non-COX-selective NSAID, was shown to reduce DNA damage-induced RPA and p53 phosphorylation. (2) The formation of enzyme cleavable complexes by topoisomerase-targeting drugs was not affected in the presence of sodium salicylate. (3) The attenuating effect of NSAIDs on the DNA damage responses is COX-2-independent, since COX-2-selective inhibitors failed to inhibit DNA damage-induced phosphorylation of replication protein A (RPA) and p53. (4) This COX-2-independent attenuating effect was mediated through interference of neither nuclear factor kappa B nor extracellular signal-regulated kinase pathways. (5) The activation of ataxia telangiectasia mutated (ATM) kinase and DNA-dependent protein kinase (DNA-PK), two key signal transducers upstream of RPA and p53, was found to be significantly reduced with sodium salicylate treatment. (6) Most importantly, sodium salicylate and other NSAIDs directly inhibited kinase activity of ATM and DNA-PK. The extent of inhibition on the kinase activity also correlated with the degree of attenuation on the DNA damage responses. (7) Unexpectedly, sodium salicylate showed a p53-independent protection effect on topoisomerase-mediated cell killing. Together, our study provides evidence that NSAIDs exhibit a novel COX-independent modulating activity of NSAIDs on the DNA damage responses and it is through inhibition of phosphoinositide 3-kinase-like kinases.

Involvement of peripheral cyclooxygenase-1 and cyclooxygenase-2 in inflammatory pain.

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.

A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database

Background: Two isoforms of cyclooxygenase (COX) have been identified, both of them inhibited by traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-2 has been associated with the therapeutic effects of NSAIDs, whereas inhibition of COX-1 is believed to be the cause of the adverse gastrointestinal effects associated with NSAID therapy. When administered at therapeutic doses, new COX-2—specific inhibitors inhibit only the COX-2 isoform. Objective: This study sought to compare renal safety signals between the COX-2—specific inhibitors rofecoxib and celecoxib, based on spontaneous reports of adverse drug reactions (ADRs) in the World Health Organization/Uppsala Monitoring Centre (WHO/UMC) safety database through the end of the second quarter 2000. Methods: Disproportionality in the association between a particular drug and renal-related ADR was evaluated using a bayesian confidence propagation neural network method in which a statistical parameter, the information component (IC) value, was calculated for each drug-ADR combination. In this method, an IC value significantly greater than 0 implies that the association of a drug-ADR pair is stronger than background; the higher the IC value, the more the combination stands out from the background. The ratio of actual to expected numbers of ADRs was also used to assess disproportionality. Results: As with traditional NSAIDs, both COX-2—specific inhibitors were associated with renal-related ADRs. However, the adverse renal impact of rofecoxib was significantly greater than that of celecoxib. IC values were significantly different for the following comparisons: water retention (1.97 rofecoxib vs 1.18 celecoxib; P < 0.01); abnormal renal function (2.38 vs 0.70; P < 0.01); renal failure (2.22 vs 1.09; P < 0.01); cardiac failure (2.39 vs 0.48; P < 0.01); and hypertension (2.15 vs 1.33; P < 0.01). In an additional analysis, celecoxib was shown to have a similar renal safety profile to that of diclofenac and ibuprofen. Conclusions: Based on spontaneous ADR reports in the WHO/UMC safety database at the end of the second quarter 2000, this analysis indicates that rofecoxib has significantly greater renal toxicity than celecoxib or traditional NSAIDs. This negative renal impact may have the potential to increase the risk for serious cardiac and/or cerebrovascular events.

Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis and prevent or revert the growth of premalignant colonic polyps. They inhibit cyclooxygenase (COX) but recent data indicate that this is not the only or even the most important mechanism of inhibition in colorectal tumor cells. We have used colonic carcinoma and adenoma cell lines to study the effects of the NSAID sulindac sulfide, its COX-inactive metabolite, sulindac sulfone, and the isoenzyme-specific inhibitors SC58125, SC236 and SC58560 on tumor cell growth in relation to COX-2 expression and prostaglandin production. To establish the role of COX-2 in NSAID action, we constructed clones expressing different levels of COX-2 from SW480 cells. All five compounds inhibited DNA synthesis and/or induced apoptosis, each with a characteristic pattern. ID(50)s were very similar in all the cell lines and were independent of COX expression, except for the COX-1 inhibitor SC58560, which was least effective in HT29/HI1, the cell line expressing the highest level of COX-1 (ID(50) 70 microM; in other cells lines the ID(50) was 15 microM). For all other compounds ID(50) concentrations varied less than two-fold: 25-40, 40-90 and 150 microM for SC236, sulindac sulfide and sulindac sulfone, respectively. SC58125 was the weakest inhibitor, never causing >50% cell loss. All compounds modulated expression of Bcl-2 and Bak and activated caspase 3. Overexpression of COX-2 in SW480 cells protected them against induction of apoptosis by sulindac sulfide. The effect was restricted to clones producing high levels of prostaglandin E(2). In summary, our data indicate that both COX-dependent and COX-independent mechanisms are involved in NSAID-induced growth in colorectal tumor cells. The concentrations necessary to inhibit growth were higher than serum concentrations that can be obtained in vivo, indicating that the therapeutic effect of NSAIDs cannot be explained by a direct effect of NSAIDs on the epithelial cells alone. For therapeutic purposes, compounds using different targets could be used to minimize side effects while optimizing therapeutic effect.

Evidence for Therapeutic Effects of NSAIDs in Alzheimer's Disease

Although epidemiological studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) can benefit patients with Alzheimer's disease (AD), there