Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis

Summary The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex^®) and rofecoxib (Vioxx^®). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic.     

Palladium‐mediated synthesis of novel nimesulide derivatives

Synthesis of a series of compounds structurally related to the anti‐inflammatory agent nimesulide has been accomplished via Pd‐catalyzed C? C bond forming reactions. Thus 4‐iodo derivative, prepared from nimesulide, participated in Sonogashira (copper‐free), Heck and Suzuki coupling reactions to afford the corresponding alkynyl, alkenyl and aryl substituted products. Some of the compounds synthesized were tested for anti‐inflammatory activities in vivo. Copyright © 2010 John Wiley & Sons, Ltd.     

Inclusion Complexation and Dissolution Properties of Nimesulide and Meloxicam–hydroxypropyl-β-cyclodextrin Binary Systems

The purpose of the work is physicochemical characterization of nimesulide (NI) and meloxicam (ME)–hydroxypropyl-β-cyclodextrin (HP-β-CD) binary systems both in solution and solid states and to improve the pharmaceutical properties of NI and ME via inclusion complexation with HP-β-CD. Binary systems of NI and ME with HP-β-CD have been characterized both in solution and solid state by different physicochemical methods. Three types of drug–HP-β-CD binary systems, namely physical mixtures (PM), kneaded systems (KS) and co evaporated systems (CS) in 1:1 and 1:2 molar ratios (1:1 and 1:2 M) were prepared. Phase solubility and ¹H-NMR spectroscopic studies in solution state revealed 1:1 M complexation of NI and ME with HP-β-CD. A partial inclusion of NI with HP-β-CD at both molar ratios of kneaded and co evaporated systems and a true inclusion of ME with HP-β-CD at both molar ratios of co evaporated systems in solid state was confirmed by differential scanning calorimetry (DSC), powder X-ray diffractometry (powder X-RD) and scanning electron microscopy (SEM) studies. Dissolution properties of NI and ME–HP-β-CD binary systems were superior when compared to corresponding pure drugs. The aqueous solubility and dissolution properties of NI and ME can be improved by inclusion complexation with HP-β-CD. Author for correspondence: E-mail: nbnaid2@E-mail.uky.edu     

A rapid LC‐MS/MS method for quantification of CSUOH0901, a novel antitumor agent,in rat plasma

CSUOH0901, a novel anticancer derivative of nimesulide, exhibits very promising anticancer activities in various cancer cell lines. In order to support further pharmacological and toxicological studies of this promising anticancer drug candidate, an LC‐MS/MS method was developed and validated in accordance with the US Food and Drug Administration guidelines. The drug molecules were extracted from plasma samples by protein precipitation and then analyzed with LC‐ESI‐MS/MS. An excellent analyte separation was achieved using a phenomenex C₁₈ column with a mobile phase of 90% methanol and 5 m m of ammonium formate. The validated linear dynamic range was between 0.5 and 100 ng/mL and the achieved correlation coefficient (r²) was >0.9996. The results of inter‐ and intra‐day precision and accuracy were satisfactory, that is, <12% for accuracy and within ±5% for precision at a low and high quality control concentrations, respectively. In addition, the analyte and internal standard (JCC76) were found to be stable under the storage conditions at ?20°C for about 2 months. Hence, the acquired results proved that the LC‐ESI‐MS/MS method developed is precise, accurate and selective for the quantification of CSUOH0901 in plasma, and can be used for pharmacokinetic studies. Copyright © 2014 John Wiley & Sons, Ltd.     

A Simple,Rapid, and Validated LC Method for the Estimation of Nimesulide in Human Serum and Its Application in Bioavailability Studies

Abstract

A new, simple, and rapid, sensitive reversed phase liquid chromatographic method was developed for the estimation of nimesulide in blood serum using a 60:40 mixture of acetonitrile and orthophosphoric acid (pH 3.0) as the mobile phase at 230 nm. The mobile phase and other chromatographic conditions were optimized to minimize interference from the serum matrix and at the same time provide sufficient sensitivity for the method to be adopted for in vivo studies of oral formulations of nimesulide. Acetonitrile was used to precipitate proteins from serum during sample preparation. Detector response was found to be linear in the region of 100–1000 ng/ml. The detection and quantitation limit, as per the error propagation theory, was found to be 50 ng/ml and 100 ng/ml, respectively. The linear equation obtained by the least square regression method was Area = 37.29 × Conc.(ng/ml)?1699.89 with a retention time of 3.97 ± 0.04 min. The results of the analysis were treated statistically, as per ICH guidelines for validation of analytical procedures, USP-2000. and by recovery studies. An internal standard was not employed in the method, as sample recoveries were in good agreement with their label claims. The results were found to be accurate, reproducible, and free from interference. The developed methods were further used for estimation of nimesulide for oral bioavailability of designed sustained release formulations of nimesulide.     

Solubility,Permeability, Anti-Inflammatory Action and In Vivo Pharmacokinetic Properties of Several Mechanochemically Obtained Pharmaceutical Solid Dispersions of Nimesulide

Nimesulide (NIM, N-(4-nitro-2-phenoxyphenyl)methanesulfonamide) is a relatively new nonsteroidal anti-inflammatory analgesic drug. It is practically insoluble in water (<0.02 mg/mL). This very poor aqueous solubility of the drug may lead to low bioavailability. The objective of the present study was to investigate the possibility of improving the solubility and the bioavailability of NIM via complexation with polysaccharide arabinogalactan (AG), disodium salt of glycyrrhizic acid (Na₂GA), hydroxypropyl-β-cyclodextrin (HP-β-CD) and MgCO₃. Solid dispersions (SD) have been prepared using a mechanochemical technique. The physical properties of nimesulide SD in solid state were characterized by differential scanning calorimetry and X-ray diffraction studies. The characteristics of the water solutions which form from the obtained solid dispersions were analyzed by reverse phase and gel permeation HPLC. It was shown that solubility increases for all complexes under investigation. These phenomena are obliged by complexation with auxiliary substances, which was shown by ¹H-NMR relaxation methods. The parallel artificial membrane permeability assay (PAMPA) was used for predicting passive intestinal absorption. Results showed that mechanochemically obtained complexes with polysaccharide AG, Na₂GA, and HP-β-CD enhanced permeation of NIM across an artificial membrane compared to that of the pure NIM. The complexes were examined for anti-inflammatory activity on a model of histamine edema. The substances were administered per os to CD-1 mice. As a result, it was found that all investigated complexes dose-dependently reduce the degree of inflammation. The best results were obtained for the complexes of NIM with Na₂GA and HP-β-CD. In noted case the inflammation can be diminished up to 2-fold at equal doses of NIM.     

平行催化氢波法测定非甾体抗炎药尼美舒利

尼美舒利;过二硫酸钾;催化氢波;平行催化氢波