Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of Inlammator dimseas, but sg t side effects such as g oi l erosion and renal damage lmit their use. NSAIDs Inhibit the enzyme cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to p (PGs) and thromboxane. Two forms of COX have been identlfled-COX-1, which is constitutively expressed in most tissues and organs, and the Inducible enzyme, COX-2, whih has been localized primarily to ilmmatory cells and tsues. In an animal model of acute inflammation (Injection ofcarrageenan into the footpad), edema was produced that was associated with marked accumulation of COX-2 mRNA and thromboxane. A selective inhibitor of COX-2 (SC-58125) inhibited edema at the inmatory site and was analgesic but had no effect on PG production In the stomach and did not cause gastric toxicity. These data suggest that selective inhibition of COX-2 may produce superior an mmatory drugs with substantial safety advantages over existing NSAIDs. bone density, fluid and electrolyte imbalance, and "Cushinglike" symptoms. These untoward effects limit glucocorticoid use in chronic inflammatory disorders such as rheumatoid arthritis (13).Studies were designed to evaluate the role ofCOX-2 in vivo at the site of inflammation. We report that in a model of inflammation useful in the characterization of NSAIDs, the carrageenan-injected rat paw, COX-2 was expressed locally in response to the proinflammatory stimulus and that the induction of COX-2 mRNA coincided with the synthesis of proinflammatory PGs and the development of edema and hyperalgesia. COX-1 mRNA was detectable in the normal rat paw, but its expression did not change following the onset of the inflammatory reaction. Furthermore, a selective inhibitor of COX-2 {SC-58125: 1-[(4-methylsulfonyl)phenyll-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole} blocked edema and hyperalgesia in vivo following an inflammatory insult, without causing gastric mucosal damage.

Background: Osteosarcoma, a primary malignant bone tumor derived from mesenchymal tissue, is the most common type of pleomorphic tumor that occurs in children and adolescents. The aim of this study was to compare the efficacy and safety of high-dose methotrexate (M), doxorubicin (D), cisplatin (C), and ifosfamide (I) in the management of osteosarcoma. Methods: Electronic databases including PubMed, Cochrane Library, and Embase database were searched for studies published from when the databases were established to July 13, 2019. The network meta-analysis was performed using software R 3.3.2 and STATA version 41.0 after demographic and outcome data extraction. The ranks based on probabilities of interventions for each outcome were performed. In addition, the consistency of direct and indirect evidence was assessed by node splitting. Results: The network meta-analysis results revealed that MDCI had a significant lower hazard risk of overall survival [MDCI vs MDC: HR = 0.74, 95% CrI (0.23, 0.87); MDCI vs DC: HR = 0.60, 95% CrI (0.16, 0.92)]. In addition, MDCI had a clearly longer progression-free survival time than that of DC [MDCI: HR = 0.88, 95% CrI (0.46, 0.98)]. No significant difference was detected in MDC and DC in OS, PFS, and AEs. The probabilities of rank plot showed that MDCI ranked first in OS (73.12%) and PFS (52.43%). DC was the best treatment in safety, ranked first (75.43%). Conclusions: MDCI showed its superiority among all chemotherapeutic agents in relation to efficacy and safety, followed by MDC. In addition, MDCI was associated with an increased risk of AEs. According to our analysis, DC was less effective but safer for MDC and MDCI.

Receptor theory predicts that fixed-proportion mixtures of a competitive, reversible agonist (e.g., fentanyl) and antagonist (e.g., naltrexone) at a common receptor [e.g., mu-opioid receptors (MORs)] will result in antagonist proportion-dependent decreases in apparent efficacy of the agonist/antagonist mixtures and downward shifts in mixture dose-effect functions. The present study tested this hypothesis by evaluating behavioral effects of fixed-proportion fentanyl/naltrexone mixtures in a warm-water tail-withdrawal procedure in rhesus monkeys ( = 4). Fentanyl (0.001-0.056 mg/kg) alone, naltrexone (0.032-1.0 mg/kg, i.m.) alone, and fixed-proportion mixtures of fentanyl/naltrexone (1:0.025, 1:0.074, and 1:0.22) were administered in a cumulative-dosing procedure, and the proportions were based on published fentanyl and naltrexone values at MOR in monkey brain. Fentanyl alone produced dose-dependent antinociception at both 50 and 54°C thermal intensities. Up to the largest dose tested, naltrexone alone did not alter nociception. Consistent with receptor theory predictions, naltrexone produced a proportion-dependent decrease in the effectiveness of fentanyl/naltrexone mixtures to produce antinociception. The maximum effects of fentanyl, naltrexone, and each mixture were also used to generate an efficacy-effect scale for antinociception at each temperature, and this scale was evaluated for its utility in quantifying 1) efficacy requirements for antinociception at 50 and 54°C and 2) relative efficacy of six MOR agonists that vary in their efficacies to produce agonist-stimuated GTPS binding in vitro (from lowest to highest efficacy: 17-cyclopropylmethyl-3,14-dihyroxy-4,5-epoxy-6-[(3'-isoquinolyl)acetamindo]morphine, nalbuphine, buprenorphine, oxycodone, morphine, and methadone). These results suggest that fixed-proportion agonist/antagonist mixtures may offer a useful strategy to manipulate apparent drug efficacy for basic research or therapeutic purposes.