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There are many chronic diseases related with inflammation. The chronic inflammation can produce other problems as cancer. Therefore, it is necessary to design drugs with better anti-inflammatory activity than those in the clinic. Likewise, these could be used in chronic treatments with minimum adverse effects. The amide or ester functionality in combination with the insertion of a silyl alkyl moiety is able to improve some drug properties. In this context, the evaluation of a group of silicon containing ibuprofen derivatives (SCIDs) as antioxidants and anti-inflammatory agents is reported. Antioxidant activity was evaluated by the 2,2-Diphenyl-1-picrylhydrazyl (DPPH⨪), 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS•+) and the Fe(II) chelating ability methods. The anti-inflammatory activity was determined by using the carrageenan induced rat paw edema. The gastrotoxic profile of the SCIDs that displayed significant anti-inflammatory activity was determined by the indomethacin induced ulceration method. The SCIDs performed better than ibuprofen as chelating agents for Fe(II) and as scavengers for the free radicals DPPH• and ABTS•+. On the anti-inflammatory test, compound 4a inhibited the edema up to 87%, while 4d &10b achieved significant inflammation inhibition at a lower effective dose 50 (ED50) than ibuprofen´s. None of the SCIDs endowed with anti-inflammatory activity, showed significant gastrotoxic effects with respect to those displayed by ibuprofen. Based on the experimental results and aided by the theoretical docking approach, it was possible to rationalize how the SCIDs may bind to cyclooxygenase isoforms and helped to explain their reduced gastrotoxicity. The evaluated effects were improved in SCIDs with respect to ibuprofen.

The potential advantage of using combination therapy is that analgesia can be maximized while minimizing the incidence of adverse effects. In order to assess a possible synergistic antinociceptive interactions, the antinociceptive effects of ketorolac tromethamine, p.o., a nonsteroidal anti-inflammatory drug (NSAID), and tramadol hydrochloride, p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally ketorolac alone (0.18, 0.32, 0.56, 1.0, 1.78, 3.16, and 5.62 mg/kg), tramadol alone (3.16, 5.62, 10.0, 17.78, 31.62, 56.23, and 100.0 mg/kg), or 24 different combinations of ketorolac plus tramadol. Ten combinations exhibited various degrees of potentiation of antinociceptive effects (17.78 mg/kg tramadol with either 0.18, 0.32, or 0.56 mg/kg ketorolac; 10.0 mg/kg tramadol with either 0.18, 0.32, 0.56, or 1.8 mg/kg ketorolac; 5.6 mg/kg tramadol with either 0.32 or 0.56 mg/kg ketorolac; and 3.16 mg/kg tramadol with 0.32 mg/kg ketorolac), whereas the other 14 combinations showed additive antinociceptive effects. Three combinations of ketorolac+tramadol (1.0+17.78, 1.78+10, and 1.78+17.78, mg/kg respectively) produced the maximum antinociceptive effects, and two combinations (0.32+10.0 and 0.56+10.0 mg/kg, respectively) presented effects of high potentiation (P

It has been observed that caffeine improves antinociceptive efficacy of some non-steroidal antiinflammatory drugs (NSAIDs) in several experimental models, however, these effects have been questioned in humans. Controversy in clinical studies may be due to the use of different protocols as well as to high interindividual variability in patient response. In addition, the antinociceptive interaction of ibuprofen+caffeine has not been studied. To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ibuprofen, and caffeine administered either separately or in combinations were determined in a model of arthritic pain: "Pain-induced functional impairment in the rat (PIFIR model). The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine or acetylsalicylic acid alone. The animals were administered with 0.05 ml intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received either acetylsalicylic acid, morphine, ibuprofen or caffeine, or a combination ibuprofen+caffeine (18 combinations). We report here that caffeine (17.8 and 31.6 mg/kg) is able to potentiate the antinociceptive effect of ibuprofen. This investigation showed that six combinations presented effects of potentiation and twelve combinations only showed antinociceptive effects not different from that of ibuprofen alone. The maximum antinociceptive effect was 270.7+/-12.7 area units (au), produced by ibuprofen 100 mg/kg+caffeine 17.8 mg/kg; this effect was greater than the maximum produced by morphine 17.8 mg/kg (244.7+/-22.9 au) in these experimental conditions. The maximum potentiation was 197 % produced with the combination of ibuprofen 17.8 mg/kg+caffeine 17.8 mg/kg. These results suggest that the antinociceptive effect of ibuprofen was significantly potentiated by doses of caffeine that by themselves are ineffective in this model.

The role of nitric oxide (NO) in the antinociceptive effect of indomethacin was assessed in the pain-induced functional impairment model in the rat (PIFIR model), a model of inflammatory and chronic pain similar to that observed in clinical gout. Oral administration of indomethacin (5.6 mg/kg), a nonselective cyclooxygenase inhibitor, significantly decreased the nociceptive response elicited by uric acid injected into the knee joint of the right hind limb (2.0+/-3.0 and 149.7+/-18.0 area units [au], in the absence and the presence of indomethacin, respectively). This effect of indomethacin was reduced in nearly 50% by local pretreatment with the nonselective inhibitor of NO synthase, N G-L-nitro-arginine methyl ester (L-NAME) (72.9+/-10.7 vs. 149.7+/-18.0 au, P

It has been observed that some non-steroidal anti-inflammatory drugs (NSAIDs) may act through several mechanisms, in addition to central inhibition of prostaglandin synthesis. These other mechanisms include the L-arginine-nitric oxide (L-arginine-NO) pathway, as well as endogenous opiate and serotonergic mechanisms. Some of these mechanisms can explain the efficacy of NSAIDs in chronic pain conditions such as rheumatoid arthritis. The present study was designed to elucidate the involvement of the above pathways/mechanisms in the antinociceptive effect of S-(+)-ketoprofen at supraspinal and spinal levels. S-(+)-ketoprofen induced dose-dependent antinociception in the pain-induced functional impairment model in the rat. The antinociceptive effect of S-(+)-ketoprofen was not altered by i.t. or intracerebroventricula (i.c.v.) pre-treatment with L-arginine (29.6 microg/site) and L-nitro-arginine-monomethylester (L-NAME) (21.1 microg/site) and neither was the effect of S-(+)-ketoprofen modified by the opiate antagonist, naloxone (1 mg/kg, s.c.). In marked contrast, both i.c.v. administration of the 5-hydroxytryptamine (5-HT)(1)/5-HT(2)/5-HT(7) receptor antagonist, methiothepin (1.5 microg/site), and i.t. administration of the 5-HT(3)/5-HT(4) receptor antagonist, tropisetron (0.9 microg/site), significantly inhibited the S-(+)-ketoprofen-induced antinociceptive effect. These data suggest that the antinociceptive response to S-(+)-ketoprofen involves serotoninergic mechanisms via both supraspinal 5-HT(1)/5-HT(2)/5-HT(7) receptors and 5-HT(3) receptors located at spinal level. A role of the L-arginine-NO and opiate systems in S-(+)-ketoprofen-induced antinociception in the pain-induced functional impairment model in the rat model seems unlikely.

This work evaluates the antinociceptive and constipating effects of the combination of 3.2 mg/kg s.c. morphine with 177.8 mg/kg s.c. metamizol in acutely and chronically treated (once a day for 12 days) rats. On the 13th day, antinociceptive effects were assessed using a model of inflammatory nociception, pain-induced functional impairment model, and the charcoal meal test was used to evaluate the intestinal transit. Simultaneous administration of morphine with metamizol resulted in a markedly antinociceptive potentiation and an increasing of the duration of action after a single (298+/-7 vs. 139+/-36 units area (ua); P