Nimesulide

Nimesulide is a relatively COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties.Nimesulide is a selective COX-2 inhibitor used in a variety of inflammatory, pain and fever states. After healthy volunteers

Quantification and In Silico Toxicity Assessment of Nimesulide and its Related Substances.[Pubmed:28168284]

J Chromatogr Sci. 2017 May 1;55(5):508-517.

Availability of analytical method which is compatible with both Ultra high performance liquid chromatography (UHPLC) and Liquid chromatography mass spectrometry to identify and quantify the impurities in pharmaceutical products is an advantage for drug product development; such analytical method was developed for Nimesulide using a fused core column. Ammonium acetate and methanol were used as mobile phase in the gradient elution at a detection wavelength 230 nm. Quality-by-design principles helped in identifying the critical method development parameters and design space. Limit of detection and the limit of quantification are 0.025 and 0.075%, respectively. Precision of the method is <0.4% RSD and correlation coefficient is >0.999 for Nimesulide and all related substances. Accuracy of Nimesulide ranged from 99.3 to 100.4% at assay concentration. Application of this method in stability analysis has been demonstrated by analyzing stressed samples. The method was validated for specificity, linearity, accuracy, precision and robustness in compliance with International Conference on Harmonization (ICH) Q2(R1). This is the first reported UHPLC method for the estimation of Nimesulide and its related substances. According to ICH M7 guidelines, all impurities were assessed for genotoxicity, LD50, skin sensitization, irritation potential and carcinogenicity using Derek and TOPKAT software. Combined knowledge of analytical and toxicology assessment will help in developing safe and quality product.

1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential anticancer agents.[Pubmed:28011214]

Bioorg Med Chem Lett. 2017 Feb 1;27(3):518-523.

A new hybrid template has been designed by integrating the structural features of Nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of Nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of Nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 approximately 6-10muM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60-70% at 10muM) that was supported by the docking studies (PLP score 87-94) in silico.

Nimesulide inhibits pathogenic fungi: PGE2-dependent mechanisms.[Pubmed:27866353]

Folia Microbiol (Praha). 2017 Mar;62(2):169-174.

Certain non-steroidal anti-inflammatory drugs can inhibit fungal growth, fungal prostaglandin E2 production, and enzyme activation. This study aims to investigate the antifungal effect of Nimesulide against pathogenic filamentous fungi and yeast. The experiments detailed below were also designed to investigate whether the action is dependent on E2 fungal prostaglandins. Our data showed that Nimesulide exhibited potent antifungal activity, mainly against Trichophyton mentagrophytes (ATCC 9533) and Cryptococcus neoformans with MIC values of 2 and 62 mug/mL, respectively. This drug was also able to inhibit the growth of clinic isolates of filamentous fungi, such as Aspergillus fumigatus, and dermatophytes, such as T. rubrum, T. mentagrophytes, Epidermophyton floccosum, Microsporum canis, and M. gypseum, with MIC values ranging from 112 to 770 mug/mL. Our data also showed that the inhibition of fungal growth by Nimesulide was mediated by a mechanism dependent on PGE2, which led to the inhibition of essential fungal enzymes. Thus, we concluded that Nimesulide exerts a fungicidal effect against pathogenic filamentous fungi and yeast, involving the inhibition of fungal prostaglandins and fungal enzymes important to the fungal growth and colonization.

Nimesulide and 4'-Hydroxynimesulide as Bile Acid Transporters Inhibitors Are Contributory Factors for Drug-Induced Cholestasis.[Pubmed:28202577]

Drug Metab Dispos. 2017 May;45(5):441-448.

Nimesulide (NIM) is a classic nonsteroidal anti-inflammatory drug. However, some patients treated with NIM experienced cholestatic liver injury. For this reason, we investigated the potential mechanism underlying NIM-induced cholestasis by using in vivo and in vitro models. Oral administration of 100 mg/kg/day NIM to Wistar rats for 5 days increased the levels of plasma total bile acids, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase by 1.49-, 1.31-, 1.60-, and 1.29-fold, respectively. In sandwich-cultured rat hepatocytes, NIM and 4'-hydroxyNimesulide (M1) reduced the biliary excretion index of d8-taurocholic acid (d8-TCA) and 5 (and 6)-carboxy-2',7'-dichlorofluorescein in a concentration-dependent manner, indicating the inhibition of the efflux transporters bile salt export pump and multidrug resistance-associated protein 2, respectively. In suspended rat hepatocytes, NIM and M1 inhibited the uptake transporters of d8-TCA for Na(+)-taurocholate cotransporting polypeptide at IC50 values of 21.3 and 25.0 muM, respectively, and for organic anion-transporting proteins at IC50 values of 45.6 and 39.4 muM, respectively. By contrast, nitro-reduced NIM and the further acetylated metabolite did not inhibit or only marginally inhibited these transporters at the maximum soluble concentrations. Inhibitory effects of NIM and M1 on human bile acid transporters were also confirmed using sandwich-cultured human hepatocytes. These data suggest that the inhibition of bile acid transporters by NIM and M1 is one of the biologic mechanisms of NIM-induced cholestasis.

Nimesulide is a selective COX-2 inhibitor, with IC50s of 70 nM-70 μM in a time-dependent manner, but it shows no effect on COX-1 (IC50 >100 μM). Nimesulide has potent anti-inflammatory, analgesic and antipyretic properties.

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