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Salette Reis - One of the best experts on this subject based on the ideXlab platform.
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Acemetacin phosphatidylcholine interactions are determined by the drug ionization state
Physical Chemistry Chemical Physics, 2018Co-Authors: Catarina Pereiraleite, Cláudia Nunes, Débora Grahl, José Carlos Bozelli, Shirley Schreier, Iolanda M. Cuccovia, Christina S Kammalorger, Salette ReisAbstract:Gastrointestinal (GI) toxicity is a major drawback of the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAIDs topical actions on the protective phospholipid layers of the GI mucosa seem to be a central toxicity mechanism of these pharmaceuticals. This work describes the interactions of Acemetacin, a commercialized NSAID, with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers at pH 3.0, 5.0, and 7.4. This pH range was chosen to mimic the pH gradient found in the gastric mucosa, and to ultimately gain insights into the mechanisms underlying the Acemetacin-induced gastric toxicity. Various experimental techniques were combined to characterize the partitioning of Acemetacin in DMPC bilayers, and its effects on the phase transition behavior, as well as the structure and dynamics of DMPC bilayers. The Acemetacin-DMPC interactions were clearly pH-dependent. The neutral (protonated) form of Acemetacin had more affinity for the DMPC bilayer than the negatively charged form. Due to the higher affinity of neutral Acemetacin, the drug effects on the phase transition and the structure and dynamics of the DMPC bilayer were more pronounced at lower pH values. In general, Acemetacin decreased the temperature and the cooperativity of the lipid phase transition and induced changes in the packing and dynamics of the DMPC bilayer. These results support the hypothesis that Acemetacin-induced gastric toxicity may be related to its effects on the protective phospholipid layers of the mucosal barrier.
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Acemetacin–phosphatidylcholine interactions are determined by the drug ionization state
Physical chemistry chemical physics : PCCP, 2018Co-Authors: Catarina Pereira-leite, Cláudia Nunes, Débora Grahl, José Carlos Bozelli, Shirley Schreier, Christina S. Kamma-lorger, Iolanda M. Cuccovia, Salette ReisAbstract:Gastrointestinal (GI) toxicity is a major drawback of the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAIDs topical actions on the protective phospholipid layers of the GI mucosa seem to be a central toxicity mechanism of these pharmaceuticals. This work describes the interactions of Acemetacin, a commercialized NSAID, with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers at pH 3.0, 5.0, and 7.4. This pH range was chosen to mimic the pH gradient found in the gastric mucosa, and to ultimately gain insights into the mechanisms underlying the Acemetacin-induced gastric toxicity. Various experimental techniques were combined to characterize the partitioning of Acemetacin in DMPC bilayers, and its effects on the phase transition behavior, as well as the structure and dynamics of DMPC bilayers. The Acemetacin-DMPC interactions were clearly pH-dependent. The neutral (protonated) form of Acemetacin had more affinity for the DMPC bilayer than the negatively charged form. Due to the higher affinity of neutral Acemetacin, the drug effects on the phase transition and the structure and dynamics of the DMPC bilayer were more pronounced at lower pH values. In general, Acemetacin decreased the temperature and the cooperativity of the lipid phase transition and induced changes in the packing and dynamics of the DMPC bilayer. These results support the hypothesis that Acemetacin-induced gastric toxicity may be related to its effects on the protective phospholipid layers of the mucosal barrier.
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Hydrogen peroxide scavenging activity by non-steroidal anti-inflammatory drugs.
Life sciences, 2005Co-Authors: David Costa, José L. F. C. Lima, Salette Reis, Ana Gomes, Eduarda FernandesAbstract:Hydrogen peroxide (H2O2) has been shown to be formed during inflammatory processes and is implicated in its pathophysiology. Thus, a putative scavenging activity against this reactive oxygen species (ROS) by anti-inflammatory drugs may be of great therapeutical value. The present study was undertaken to evaluate the scavenging activity for H2O2 by several non-steroidal anti-inflammatory drugs (NSAIDs), namely indomethacin, Acemetacin, etodolac, tolmetin, ketorolac, oxaprozin, sulindac and its metabolites sulindac sulfide and sulindac sulfone. The H2O2 scavenging assay was performed by measuring H2O2-elicited lucigenin chemiluminescence using a microplate reader. The specificity of the method was confirmed by the use of catalase, which completely prevented the H2O2-induced lucigenin chemiluminescence. The endogenous antioxidants melatonin and reduced glutathione (GSH) were used as positive controls. The obtained results demonstrated that all the studied NSAIDs display H2O2 scavenging activity, although in different extents. The ranking order of potency found was sulindac sulfone > sulindac sulfide > GSH > sulindac > indomethacin > Acemetacin > etodolac > oxaprozin > ketorolac approximately melatonin > tolmetin.
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In vitro scavenging activity for reactive oxygen and nitrogen species by nonsteroidal anti-inflammatory indole, pyrrole, and oxazole derivative drugs.
Free radical biology & medicine, 2004Co-Authors: Eduarda Fernandes, David Costa, Sofia A. Toste, José L. F. C. Lima, Salette ReisAbstract:Abstract This study was undertaken to evaluate the scavenging activity for reactive oxygen species (ROS) and reactive nitrogen species (RNS) by several nonsteroidal anti-inflammatory drugs (NSAIDs), namely indole derivatives (indomethacin, Acemetacin, etodolac), pyrrole derivatives (tolmetin and ketorolac), and an oxazole derivative (oxaprozin). The inhibition of prostaglandin synthesis constitutes the primary mechanism of the anti-inflammatory action of these drugs. Nevertheless, it has been suggested that the anti-inflammatory activity of NSAIDs may be also partly due to their ability to scavenge ROS and RNS and to inhibit the respiratory burst of neutrophils triggered by various activator agents. Thus, the scavenging activity of these NSAIDs was evaluated against an array of ROS (O2 −, HO , HOCl, and ROO ) and RNS ( NO and ONOO−) using noncellular in vitro systems. The results obtained demonstrated that tolmetin, ketorolac, and oxaprozin were not active against O2 −, while Acemetacin, indomethacin, and etodolac exhibited concentration-dependent effects. Oxaprozin was also the least active scavenger for HO , among all the tested NSAIDs shown to be active. The scavenging effect for HOCl was not observed for any of the tested NSAIDs. The ROO was effectively scavenged by etodolac, with the other tested NSAIDs being much less active. NO and ONOO− were scavenged by all the tested NSAIDs. These effects may strongly contribute to the anti-inflammatory therapy benefits that may be attained with some of the studied NSAIDs.
Yue Hong-kun - One of the best experts on this subject based on the ideXlab platform.
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Preparation and stability test of Acemetacin sustained release tablets
Chinese New Drugs Journal, 2005Co-Authors: Yue Hong-kunAbstract:Objective:To investigate the preparation and stability of the Acemetacin sustained release tablets(Ac-SRT).Methods: Acemetacin sustained release tablets composed of a matrix material HPMC were prepared by the wet granulation.Several factors that affected the sustained release characteristics,such as the viscosity and amount of HPMC and the adhesive concentrations,were assessed.The stability test was performed according to the guideline in China Pharmacopoeia.Results: The viscosity of HPMC was found to be the sole factor that affected the sustained release.The rest of factors had no significant effects on the sustained release behavior of Ac-SRT.This Ac-SRT showed a good stability in a long-term stability test involved with light,moisture and heat.Conclusion: The stable Ac-SRT was attainable.
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STUDIES ON THE FACTORS AFFECTING Acemetacin RELEASE FROM SUSTAINED RELEASE TABLETS AND THE OPTIMIZATION OF FORMULATION
Journal of Hebei Medical University, 2005Co-Authors: Yue Hong-kunAbstract:ObjectiveTo prepare the Acemetacin sustained release tablets(Ac-SRT) and study the affecting factors.MethodsThe Acemetacin sustained release tablets were prepared by the wet granulation method,using HPMC as skeleton material.The effect of the viscosity and amount of HPMC and the concentration adhesive on the release of Ac sustained release tablets were observed.On the basis of pharmaceutical preformulation studies,the preparation technique and optimized formulation of Ac-SRT were designed.ResultsThe release behavior of the tablets follows the Higuchi equation.Amount of HPMC and the concentration of adhesive has no significant effects on the release of Ac-SRT,while the viscosity of HPMC affect the release of Ac-SRT to some degree.ConclusionCombining with other filters,a sustained release tablet(SRT) of once daily administration is prepared by using hydropropyl methylcellulose as the basic matrix material.
John L. Wallace - One of the best experts on this subject based on the ideXlab platform.
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lack of effects of Acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety
British Journal of Pharmacology, 2008Co-Authors: Mario I. Ortiz, W Mcknight, M Dicay, Aracely Evangelina Chavezpina, Linda Vong, R C O Zanardo, Gilberto Castanedahernandez, John L. WallaceAbstract:Background and purpose: Acemetacin is a non-steroidal anti-inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of Acemetacin. Experimental approach: The gastric and intestinal damaging effects of Acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B4 and thromboxane B2, on leukocyte-endothelial adherence in postcapillary mesenteric venules, and on gastric expression of tumour necrosis factor-a (TNF-a) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX-2 and NOS. Key results: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not Acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF-a. Pretreatment with L-nitro-arginine methyl ester or lumiracoxib increased the severity of indomethacin-induced gastric damage, but this was not the case with Acemetacin. Conclusions and implications: The increased gastric and intestinal tolerability of Acemetacin may be related to the lack of induction of leukocyte–endothelial adherence. This may be attributable to the reduced ability of Acemetacin to elevate leukotriene-B4 synthesis and TNF-a expression, compared to indomethacin, despite the fact that Acemetacin is rapidly
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Mechanisms underlying the anti-inflammatory activity and gastric safety of Acemetacin
British journal of pharmacology, 2007Co-Authors: Aracely Evangelina Chávez-piña, Gilberto Castañeda-hernández, W Mcknight, M Dicay, John L. WallaceAbstract:Background and purpose: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of Acemetacin are unclear. The anti-inflammatory effects of Acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of Acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of Acemetacin (to indomethacin) to its anti-inflammatory actions. Experimental approach: The zymosan airpouch model was used in rats. Indomethacin or Acemetacin (2.7–83.8 μmol kg−1) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E2 and leukotriene (LT) B4 levels in exudates, and whole blood thromboxane (TX) B2 synthesis were measured. Key results: Acemetacin was rapidly converted to indomethacin after its administration. Both Acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE2 and TXB2 synthesis. However, indomethacin induced more gastric damage than Acemetacin and elevated LTB4 production in the airpouch. Conclusions and implications: The similar effects of Acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of Acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB4 production. Such differences may contribute to the relative gastric safety of Acemetacin compared to indomethacin. British Journal of Pharmacology (2007) 152, 930–938; doi:10.1038/sj.bjp.0707451; published online 17 September 2007
Eduarda Fernandes - One of the best experts on this subject based on the ideXlab platform.
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Hydrogen peroxide scavenging activity by non-steroidal anti-inflammatory drugs.
Life sciences, 2005Co-Authors: David Costa, José L. F. C. Lima, Salette Reis, Ana Gomes, Eduarda FernandesAbstract:Hydrogen peroxide (H2O2) has been shown to be formed during inflammatory processes and is implicated in its pathophysiology. Thus, a putative scavenging activity against this reactive oxygen species (ROS) by anti-inflammatory drugs may be of great therapeutical value. The present study was undertaken to evaluate the scavenging activity for H2O2 by several non-steroidal anti-inflammatory drugs (NSAIDs), namely indomethacin, Acemetacin, etodolac, tolmetin, ketorolac, oxaprozin, sulindac and its metabolites sulindac sulfide and sulindac sulfone. The H2O2 scavenging assay was performed by measuring H2O2-elicited lucigenin chemiluminescence using a microplate reader. The specificity of the method was confirmed by the use of catalase, which completely prevented the H2O2-induced lucigenin chemiluminescence. The endogenous antioxidants melatonin and reduced glutathione (GSH) were used as positive controls. The obtained results demonstrated that all the studied NSAIDs display H2O2 scavenging activity, although in different extents. The ranking order of potency found was sulindac sulfone > sulindac sulfide > GSH > sulindac > indomethacin > Acemetacin > etodolac > oxaprozin > ketorolac approximately melatonin > tolmetin.
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In vitro scavenging activity for reactive oxygen and nitrogen species by nonsteroidal anti-inflammatory indole, pyrrole, and oxazole derivative drugs.
Free radical biology & medicine, 2004Co-Authors: Eduarda Fernandes, David Costa, Sofia A. Toste, José L. F. C. Lima, Salette ReisAbstract:Abstract This study was undertaken to evaluate the scavenging activity for reactive oxygen species (ROS) and reactive nitrogen species (RNS) by several nonsteroidal anti-inflammatory drugs (NSAIDs), namely indole derivatives (indomethacin, Acemetacin, etodolac), pyrrole derivatives (tolmetin and ketorolac), and an oxazole derivative (oxaprozin). The inhibition of prostaglandin synthesis constitutes the primary mechanism of the anti-inflammatory action of these drugs. Nevertheless, it has been suggested that the anti-inflammatory activity of NSAIDs may be also partly due to their ability to scavenge ROS and RNS and to inhibit the respiratory burst of neutrophils triggered by various activator agents. Thus, the scavenging activity of these NSAIDs was evaluated against an array of ROS (O2 −, HO , HOCl, and ROO ) and RNS ( NO and ONOO−) using noncellular in vitro systems. The results obtained demonstrated that tolmetin, ketorolac, and oxaprozin were not active against O2 −, while Acemetacin, indomethacin, and etodolac exhibited concentration-dependent effects. Oxaprozin was also the least active scavenger for HO , among all the tested NSAIDs shown to be active. The scavenging effect for HOCl was not observed for any of the tested NSAIDs. The ROO was effectively scavenged by etodolac, with the other tested NSAIDs being much less active. NO and ONOO− were scavenged by all the tested NSAIDs. These effects may strongly contribute to the anti-inflammatory therapy benefits that may be attained with some of the studied NSAIDs.
Gilberto Castañeda-hernández - One of the best experts on this subject based on the ideXlab platform.
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Evidence against the participation of a pharmacokinetic interaction in the protective effect of single-dose curcumin against gastrointestinal damage induced by indomethacin in rats.
Journal of integrative medicine, 2017Co-Authors: Liliana Zazueta-beltrán, Gilberto Castañeda-hernández, Aracely Evangelina Chávez-piña, Lorena Medina-aymerich, Nadia Estela Díaz-triste, Leticia Cruz-antonioAbstract:Abstract Objective To determine the role of a pharmacokinetic interaction in the protective effect of curcumin against the gastric damage induced by indomethacin administration as such or as its prodrug Acemetacin. Methods Wistar rats orally received single dose of indomethacin (30 mg/kg) with and without curcumin (30 mg/kg); gastric injury was evaluated by determining the total damaged area. Additional groups of rats received an oral single dose of indomethacin (30 mg/kg) or its prodrug Acemetacin (34.86 mg/kg) in the presence or absence of curcumin (30 mg/kg). Indomethacin and Acemetacin concentrations in plasma from blood draws were determined by high-performance liquid chromatography. Plasma concentration-against-time curves were constructed, and bioavailability parameters, maximal concentration (Cmax) and area under the curve to the last sampling time (AUC0-t) were estimated. Results Concomitant administration of indomethacin and curcumin resulted in a significantly reduced gastric damage compared to indomethacin alone. However, co-administration of curcumin did not produce any significant alteration in the bioavailability parameters of indomethacin and Acemetacin after administration of either the active compound or the prodrug. Conclusion Curcumin exhibits a protective effect against indomethacin-induced gastric damage, but does not produce a reduction of the bioavailability of this nonsteroidal anti-inflammatory drug, indomethacin. Data thus suggest that a pharmacokinetic mechanism of action is not involved in curcumin gastroprotection.
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Acemetacin ANTINOCICEPTIVE MECHANISM IS NOT RELATED TO NO OR K + CHANNEL PATHWAYS.
Methods and findings in experimental and clinical pharmacology, 2010Co-Authors: Gil-flores M, Gilberto Castañeda-hernández, Mario I. Ortiz, Aracely Evangelina Chávez-piñaAbstract:SUMMARY Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of acute gout and inflammation. However, its use is limited due to side effects. Acemetacin is a prodrug of indomethacin that exhibits better gastric tolerability in preclinical and clinical trials. The aim of this study was to examine if the systemic administration of Acemetacin involved the sequential participation of nitric oxide (NO) or K + channel pathways to confer its antinociceptive effect, as compared to indomethacin. The antinociceptive effect of both drugs was studied with the formalin test. Equimolar doses of Acemetacin or indomethacin were administered orally. The intraplantar administration of either L-NAME, glibenclamide, apamin or charybdotoxin plus indomethacin or Acemetacin was studied using the formalin test and the anti-inflammatory and antihyperalgesic effects were measured. The antinociceptive effect of Acemetacin or indomethacin was not significantly different when pretreatment with L-NAME, glibenclamide, apamin or charybdotoxin was done. The antihyperalgesic and antiinflammatory effects were also similar for both indomethacin and Acemetacin. Our results suggest that the antinociceptive effect of indomethacin or Acemetacin is not mediated by NO or K + channel activation.
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Pharmacokinetics of Acemetacin and its active metabolite indomethacin in rats during acute hepatic damage and liver regeneration
Annals of hepatology, 2009Co-Authors: Aracely Evangelina Chávez-piña, Liliana Favari, Gilberto Castañeda-hernándezAbstract:Background and aim: The pharmacokinetics of Acemetacin, a non-steroidal anti-inflammatory drug which is biotransformed to indomethacin by hepatic first-pass effect, was examined during the necrotic and regeneration phases resulting from acute hepatitis induced by carbon tetrachloride (CCl 4 ). Material and methods: Acute hepatitis was induced by oral CCl 4 administration to male Wistar rats. On days 0, 1 and 3 after the insult, liver histological analysis was performed, biochemical markers of liver damage and regeneration were measured, and the pharmacokinetics of oral Acemetacin and of its active metabolite, indomethacin, were determined. Results: One day after CCl 4 administration, liver necrosis was apparent and there was an increase in the circulating levels of indicators of liver damage and regeneration with regard to control conditions. Acemetacin bioavailability was increased, although not in a statistically significant manner. On the other hand, indomethacin bioavailability was significantly reduced. By day 3, histological analysis revealed liver recovery, although not complete, while biochemical indicators of hepatic damage had reverted either totally or partially. Markers of liver regeneration were still increased. Bioavailability Acemetacin and indomethacin was comparable to control values. In conclusion: Indomethacin bioavailability after oral administration of its precursor, Acemetacin, is significantly reduced by acute hepatitis produced by CCl 4 . Pharmacokinetic alterations, as liver damage, are reversible, but do not require complete liver regeneration to return to basal conditions.
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Mechanisms underlying the anti-inflammatory activity and gastric safety of Acemetacin
British journal of pharmacology, 2007Co-Authors: Aracely Evangelina Chávez-piña, Gilberto Castañeda-hernández, W Mcknight, M Dicay, John L. WallaceAbstract:Background and purpose: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of Acemetacin are unclear. The anti-inflammatory effects of Acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of Acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of Acemetacin (to indomethacin) to its anti-inflammatory actions. Experimental approach: The zymosan airpouch model was used in rats. Indomethacin or Acemetacin (2.7–83.8 μmol kg−1) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E2 and leukotriene (LT) B4 levels in exudates, and whole blood thromboxane (TX) B2 synthesis were measured. Key results: Acemetacin was rapidly converted to indomethacin after its administration. Both Acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE2 and TXB2 synthesis. However, indomethacin induced more gastric damage than Acemetacin and elevated LTB4 production in the airpouch. Conclusions and implications: The similar effects of Acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of Acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB4 production. Such differences may contribute to the relative gastric safety of Acemetacin compared to indomethacin. British Journal of Pharmacology (2007) 152, 930–938; doi:10.1038/sj.bjp.0707451; published online 17 September 2007
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Evaluation of the interaction between Acemetacin and opioids on the hargreaves model of thermal hyperalgesia.
Pharmacology biochemistry and behavior, 2007Co-Authors: Mario I. Ortiz, Nury Pérez-hernández, Eduardo Fernández-martínez, Héctor A. Ponce-monter, Arturo Macías, Eduardo Rangel-flores, Gilberto Castañeda-hernándezAbstract:It has been shown that the association of opioids analgesic agents with non-steroidal anti-inflammatory drugs (NSAIDs) can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the goal of the present study was to examine the possible pharmacological interaction between Acemetacin and two opioids in the Hargreaves model of thermal hyperalgesia in the mouse. Acemetacin, codeine, nalbuphine or fixed-dose ratios Acemetacin-codeine and Acemetacin-nalbuphine combinations were administrated systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. All treatments produced a dose-dependent antihyperalgesic effect. ED40 values were estimated for all the treatments and an isobologram was constructed. The derived theoretical ED40 for the Acemetacin-codeine and Acemetacin-nalbuphine combinations were 55.9+/-4.9 mg/kg and 40.3+/-3.8 mg/kg, respectively, being significantly higher than the actually observed experimental ED40, 14.5+/-1.7 mg/kg and 12.7+/-2.2 mg/kg, respectively. These results correspond to synergistic interactions between Acemetacin and opioids on the Hargreaves model of thermal hyperalgesia. Highest doses of the individual drugs or the combinations did not affect motor coordination in the balancing test on a rota-rod. Data suggest that low doses of the Acemetacin-opioids combination can interact synergistically at systemic level and therefore this drugs association may represent a therapeutic advantage for the clinical treatment of inflammatory pain.