Search

Introduction: Non-steroidal anti-inflammatory drugs (NSAID) are the most commonly used drugs for the treatment of pain, inflammation and fever. Although they are effective for a huge number of users, their analgesic properties are not sufficient for several patients and the occurrence of side effects still constitutes a big challenge during long term therapy. Areas covered: This review gives an overview about the first and second generations of NSAIDs (COX1/2 non-selective, COX-2 selective), and their main side effects which gave still an urgent need for safer drugs and for the establishment of novel treatment strategies (improved safety, tolerability, patient convenience). The current developments of a possible third generation NSAID class comprise changes in the formulation of already approved drugs, combination therapies, dual cyclooxygenase-lipoxygenase inhibitors, NO- and H 2 S-releasing NSAIDs, prostaglandin synthase inhibitors and EP receptor modulators, respectively. Literature search has been done with PubMed NCBI. Expert opinion: Currently, there is no newly developed drug that is superior to the already approved selective and non-selective NSAIDs. Several novel approaches show promising analgesic efficacy but side effects are still an important problem. Solutions might be constituted by combination therapies allowing administration of lower drug doses or by individualized therapies targeting molecules apart from COX, respectively.

AMP-activated kinase (AMPK) is a cellular energy sensor, which is activated in stages of increased adenosine triphosphate (ATP) consumption. Its activation has been associated with a number of beneficial effects such as decrease of inflammatory processes and inhibition of disease progression of diabetes and obesity. A recent study suggested that salicylate, the active metabolite of the non-steroidal anti-inflammatory drug (NSAID) acetyl-salicylic acid (aspirin), is able to activate AMPK pharmacologically. This observation raised the question whether or not other NSAIDs might also act as AMPK activators and whether this action might contribute to their cyclooxygenase (COX)-independent anti-inflammatory properties. In this study, we investigated mouse and human neuronal cells and liver tissue of mice after treatment with various NSAIDs. Our results showed that the non-selective acidic NSAIDs ibuprofen and diclofenac induced AMPK activation similar to aspirin while the COX-2 selective drug etoricoxib and the non-opioid analgesic paracetamol, both drugs have no acidic structure, failed to activate AMPK. In conclusion, our results revealed that AMPK can be activated by specific non-steroidal anti-inflammatory drugs such as salicylic acid, ibuprofen or diclofenac possibly depending on the acidic structure of the drugs. AMPK might therefore contribute to their antinociceptive and anti-inflammatory properties., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In this study, we investigated the effects of prolonged administration of the selective COX-2 inhibitors celecoxib and rofecoxib and the non-selective NSAID naproxen on the initiation and progression of atherosclerosis. ApoE(-/-) mice, as well as corresponding wild-type mice, were fed either a normal chow or a high fat Western diet with or without addition of the respective drugs over a period of 16 weeks. Thereafter, aortic lesion size, plasma lipid levels, and COX-2 expression in the plaques were determined. The results showed that neither the COX-2 selective inhibitors nor naproxen had a significant impact on the initiation and progression of atherosclerosis in diet-fed ApoE(-/-) mice, although both celecoxib and rofecoxib showed a tendency to reduce plaque size. This slight effect may be due to selective inhibition of COX-2 activity because the COX-2 expression was not altered in the plaque. Plasma lipid levels were also not significantly influenced by these drugs. Interestingly, in ApoE(-/-) mice that have been fed with normal chow, we found an increased incidence of plaque formation after treatment with celecoxib and rofecoxib, indicating that coxibs may promote the initiation of atherosclerosis. This effect was probably masked in diet-fed mice by the more pronounced effects of the high cholesterol diet. In conclusion, the reduction in diet-induced plaque size in animals fed a high fat diet and the promotion of atherosclerosis in mice on a normal diet indicate a dual role of the coxibs. In advanced stages of atherosclerosis, they may exert antithrombotic properties due to their COX-2 inhibiting activity, whereas in very early stages they may favor the initiation of atherogenesis. However, because these results were only observed in ApoE(-/-) and not in wild-type animals, coxibs may increase the risk of thrombosis in patients with a predisposition for thrombotic complications.

R-flurbiprofen, a non cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID), has been found to inhibit tumor growth in various animal models. In vitro experiments have shown that this effect is based on the induction of a cell cycle block and apoptosis. Cell cycle inhibition has been explained by activation of the c-Jun-N-terminal kinase (JNK) and downregulation of cyclin D1 expression. However, the molecular mechanism leading to apoptosis is unknown. Here, we show that treatment of the human colon carcinoma cell line HCT116 with different concentrations of R-flurbiprofen leads to an accumulation of p53 protein which is accompanied by an increase in phosphorylated p53 at serine 15. Mutation of serine 15 to alanine by site directed mutagenesis and overexpression of the mutated p53 gene in HCT116 cells, revealed that these cells are significantly less sensitive to apoptosis induced by R-flurbiprofen than pcDNA control cells, as measured by PARP-cleavage and flow cytometry. By contrast, no difference was detected between HCT116p53ser15ala cells and HCT116 pcDNA cells with respect to induction of a cell cycle block after R-flurbiprofen treatment. Moreover, in nude mice HCT116p53ser15ala overexpressing xenografts were significantly less sensitive to R-flurbiprofen than HCT116 pcDNA control xenografts. In conclusion, we were able to show that induction of apoptosis in HCT116 cells after R-flurbiprofen treatment is at least partly dependent on the tumor suppressor gene p53 and that mutation of p53 at serine 15 impairs the apoptotic potency of R-flurbiprofen.

Rofecoxib is a selective cyclooxygenase (COX)-2 inhibitor approved for the treatment of pain and inflammation in rheumatoid and osteoarthritis. Daily doses between 12.5 and 50 mg were found to reduce pain and inflammation, however, without a clear dose-effect relationship. Interestingly, rofecoxib treatment is associated with an unexpected incidence of renal adverse events compared with other COX inhibitors. Here, the effects of rofecoxib on the transcription factors nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) were analyzed to find out whether transcriptional changes might explain the lack of clear dose dependency and the occurrence of renal side effects. In vitro, rofecoxib dose dependently inhibited DNA binding capacity of NF-kappaB at doses of 10 to 100 microM, whereas the binding activity of AP-1 was considerably increased at 100 microM. In vivo, the anti-inflammatory effect of rofecoxib was equal at 1 and 10 mg/kg, whereas 50 mg/kg caused a significant further reduction of a zymosan-induced paw edema. This was associated with a clear decrease of inducible nitric oxide synthase (iNOS) protein expression in the spinal cord at this dose. At 1 and 10 mg/kg, however, iNOS was increased but COX-2 was decreased. Thus, the expression of proinflammatory proteins was similarly inconsistent as transcription factor regulation. In conclusion, the opposite effects of rofecoxib on AP-1 and NF-kappaB may explain the lack of clear dose dependency with rofecoxib in clinical studies or animal experiments. The effects on AP-1 may possibly affect renal sodium transport because certain renal sodium channels are regulated through AP-1. Transcription factor regulation might therefore influence both wanted and unwanted effects of rofecoxib.