Perspectives in nonsteroidal anti-inflammatory agents

Among numerous nonsteroidal anti-imflammatory agents synthesized in the past few years, various analogs of indomethacin, phenylacetic acid and heteroarylacetic acid have reached the stage of clinical evaluation. Their biochemical mechanisms of action are exemplified by the broad activity profile of indomethacin which includes inhibition of mediators and enzymes, effects on cell membranes, and, most recently, inhibition of prostaglandin biosynthesis. The importance of pharmacodynamic properties to clinical efficacy was clearly demonstrated in some cases. Several candidates were eliminated because of their side-effects. A group of α-methylarylacetic acids showed a high degree of stereospecificity in their potency and metabolisms in vivo, as well as inhibition of prostaglandin synthetase and albumin binding in vitro. Extrinsic Cotton effect provides a sensitive technique in the study of interactions of these drugs with biopolymers. Competitive binding and antagonistic interactions between nonsteroidal drugs, particularly salicylate, were observed in vitro and in vivo. Progress in salicylate research was marked by the synthesis of flufenisal as a new derivative with enhanced potency and longer duration of action. Several fenamate analogs and new chemical types have shown promise in preliminary clinical trials. Various immunological approaches are under investigation for the treatment of rheumatoid arthritis. Newer concepts are still needed to achieve more effective control of arthritic disorders.     

Separation of non-steroidal anti-inflammatory agents using supercritical fluid chromatography.

Supercritical fluid chromatography (SFC) was investigated for the separation of non-steroidal anti-inflammatory agents (NSAIs). Three different stationary phases (SB-methyl-100, SB-biphenyl-30, and SB-cyanopropyl-50) were compared for the separation of the compounds. Baseline separation of a flufenamic acid, mefenamic acid, fenbufen and indomethacin mixture was achieved on the SB-biphenyl-30 column using a pressure gradient. A mixture containing flufenamic acid, mefenamic acid, acetylsalicylic acid, ketoprofen and fenbufen and another mixture containing ibuprofen, fenoprofen, naproxen, ketoprofen and tolmetin were well separated on the SB-cyanopropyl-50 column using pressure gradients. Typical analysis time for a mixture of NSAIs on the biphenyl or cyanopropyl column was approximately 20-25 min. Application of the method using the biphenyl column to the determination of NSAIs present in selected commercial dosage forms was demonstrated.     

Effect of the molecular mass of tremella polysaccharides on accelerated recovery from cyclophosphamide-induced leucopenia in rats

The body of tremella were decocted with water, and hydrolyzed with 0.1 mol/L hydrochloric acid for different times, giving tremella polysaccharides with six molecular mass values. The structures of all the tremella polysaccharides had non-reducing terminals of β-D-pyranglucuronide, the backbone was composed of (1 → 3)-linked β-D-manno-pyranoside, and the side chain composed of (1 → 6)-linked β-D-xylopyranoside was attached to the C(2) of the backbone mannopyranoside. Immunomodulatory effect studies indicated that tremella polysaccharides increased the counts of leukocytes in the peripheral blood which were significantly lowered by cyclophosphamide, and the lower the molecular mass of the tremella polysaccharide, the better this effect was.     

Thermoanalytical study of some anti-inflammatory analgesic agents

Thermogravimetry (TG), differential thermal analysis (DTA), differential scanning calorimetry (DSC) as well as X-ray diffraction powder (DRX) patterns and Fourier transformed infrared spectroscopy (FTIR) were used to study ketoprofen, ibuprofen, and naproxen. The chemical or physical properties of the studied compounds were established and when possible by X-ray powder diffractometry and/or infrared spectroscopy were used. In this investigation, quantum chemical approach was used to determine the molecular structures using Becke three-parameter hybrid method and the Lee–Yang–Par (LYP) correlation functional. The performed molecular calculations in this work were done using the Gaussian 03 routine. Theoretical calculations help in interpretations of FTIR spectra supplying structural and physicochemical parameters.     

Luminescence analysis of anti-inflammatory agents in blood or plasma following thin-layer chromatographic separation.

The luminescence properties of some anti-inflammatory agents and of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carbox-ylic acid, 6-chloro-9-[2-(2-methyl-5-pyridyl)ethyl]-1,2,3,4-tet-rahydrocarbazole-2-methanol.HCl, and (d,l)-6-chloro-alpha-methyl-carbazole-2-acetic acid have been examined at both ambient and cryogenic temperatures. Assays were developed for indomethacin, the tetrahydrocarbazoles, and the carbazole based upon solvent extraction from blood or plasma, thin-layer chromatographic separation of the drugs from interfering materials and phosphorimetry of the eluted materials. The solvent elution may be accomplished either by manual scraping and elution or by the use of a semiautomated elution apparatus. These two techniques were compared with respect to overall recovery and precision using both fluorometry and phosphorimetry.     

Effect of fruit extract on renal stone formation and kidney injury in rats

This study investigated the effect of oral administration of Cactus fruit extracts on calcium oxalate deposition, malondialdehyde (MDA) and superoxide dismutase (SOD) activity in rat model. About 42 rats were used for the study. The animals were divided into seven groups. Control group maintained on regular rat food and drinking water throughout the study period, whereas in other groups nephrolithiasis was induced by ethylene glycol. Rats in kidney stone group were sacrificed after 28 days and all remaining groups after 58 days. Treatment groups were treated with 1 and 100 mg/kg of aqueous and ethanolic extracts of Cactus fruit for 30 days. After treatment, SOD activity was increased and MDA was decreased significantly. CaOx depositions were decreased significantly, especially in ethanolic extract of Cactus fruit in high dose (100 mg/kg).     

Extractive spectrophotometric determination of some anti-inflammatory agents with methylene violet

A fairly sensitive spectrophotometric method for the determination of ibuprofen, ketoprofen, piroxicam, diclofenac sodium, mefenamic acid or enfenamic acid in bulk samples and pharmaceutical preparations is described, based on the formation of a chloroform-soluble, coloured ion-association complex between the drug and Methylene Violet at pH 7.6.     

Bioisosteric hybrids of two anti-inflammatory agents, rutaecarpine and piroxicam

Bioisosteric replacements were accomplished by building the structural elements of piroxicam, an anti-inflammatory drug, into the pentacyclic system of rutaecarpine, a quinazolinocarboline alkaloid, in order to modify activity and selectivity on COX-isoenzymes. The pentacyclic compounds were synthesized efficiently by employing 1-oxo-9,10,11,12-tetrahydro-4H-pyrido[1,2-b]1,2-benzothiazine 5,5-dioxide as a key intermediate, and prepared by alternative routes. Condensation of the tricyclic ketone with arylhydrazines and subsequent Fischer-indolization provided the first representatives of new heterocyclic ring systems 3 and 4.     

Aluminum ions accelerated the oxidative stress of copper-mediated melanin formation

A comparison between the effects of aluminum and cupric ions on the dopachrome (DC) conversion and the cooperation effect of the both ions in the DOPA oxidation to melanin pathway has been studied by UV-Vis spectrophotometric method. Both aluminum and cupric ions catalyze the DC conversion reaction, which is an important step in the melanin synthesis pathway. However, cupric ions catalyze the conversion of DC to yield 5,6-dihydroxyindole-2-carboxylic acid (DHICA) but the product of DC conversion catalyzed by aluminum is 5,6-dihydroxyindole (DHI). DOPA oxidation catalyzed by aluminum and cupric ions is studied in the presence of hydrogen peroxide. The results from our experiments provide evidence that aluminum can markedly increase the oxidative stress of copper-mediated the melanin formation and influence the properties of the melanin by means of changing the ratio of DHICA/DHI in the acidic environment (pH 5.5).     

Effect of air change rate on rubber accelerated ageing tests in hot air. Part 1. Preliminary study

Using a multi-cell ageing oven an NR compound was aged for 168 h at 70 °C in air with 3, 8, 10 and 15 air changes per hour. Ageing was evaluated by values of stress at 300% elongation (M 300), tensile strength (TS), elongation at break (EB) and hardness (IRHD). Simultaneously, a similar ageing treatment but in a normal oven at much lower air change rate was carried out. The statistical analysis of results showed that there are significant differences in M300 and TS after ageing among the various air-flows and also in M300 and EB between the results obtained in the normal oven and in the block oven at 3 air changes per hour. There were no significant differences among the cells in the oven nor (except in hardness test prices) in the material subjected to ageing, although it was prepared in several curing operations.     

Chemical degradation of crosslinked ethylene-propylene-diene rubber in an acidic environment. Part I. Effect on accelerated sulphur crosslinks

The time-dependent chemical degradation of accelerated sulphur cured ethylene propylene diene rubber containing 5-ethylidene-2-norbornene as diene in an acidic environment (20% Cr/H₂SO₄) was investigated. Two different rubbers with a similar ethylene to propylene ratio and diene content but with a significant difference in molar mass and level of long chain branching were used in the study. The molecular mechanisms of the chemical degradation occurring at the surface were determined using surface analysis (X-ray photoelectron spectroscopy and attenuated total reflectance Fourier transform infrared spectroscopy). The results reveal formation of several oxygenated species on the surface as a consequence of the acid attack. Furthermore, the crosslink sites of the exposed rubber samples are also found vulnerable to hydrolytic attack as evidenced by the decrease in crosslink density. The extent of surface degradation was strong enough to affect the bulk mechanical properties. Changes in mechanical properties were also monitored through determining retention in tensile strength, (%) elongation at break, modulus at 50% elongation, and change in micro-hardness. A negative correlation is also established between retention in modulus at 50% elongation and decrease in crosslink density. Scanning electron microscopy reveals the topographical damage at the surface due to the aqueous acid induced chemical degradation. The results indicate that the chemical degradation proceeds mainly via hydrolysis of crosslinks but upon prolonged exposure, the oxygenated species tend to combine with each other. The effect of molar mass and level of long chain branching also influences the chemical degradation.     

Synthesis and in silico investigation of thiazoles bearing pyrazoles derivatives as anti-inflammatory agents

Searching novel, safe and effective anti-inflammatory agents has remained an evolving research enquiry in the mainstream of inflammatory disorders. In the present investigation series of thiazoles bearing pyrazole as a possible pharmacophore were synthesized and assessed for their anti inflammatory activity using in vitro and in vivo methods. In order to decipher the possible anti-inflammatory mechanism of action of the synthesized compounds, cyclooxygenase I and II (COX-I and COX-II) inhibition assays were also carried out. The results obtained clearly focus the significance of compounds 5d, 5h and 5i as selective COX-II inhibitors. Moreover, compound 5h was also identified as a lead molecule for inhibition of the carrageenin induced rat paw edema in animal model studies. Molecular docking results revealed significant interactions of the test compounds with the active site of COX-II, which perhaps can be explored for design and development of novel COX-II selective anti-inflammatory agents.     

Metal complexes used as anti-inflammatory agents: Synthesis,characterization and anti-inflammatory action of VO(II)-complexes

The anti-inflammatory activity of the vanadium complexes has been studied using the carrageenan induced hind paw oedema method in albino rats (Wister strain). The coordination complexes of VO (II) with the Schiff base derived from 4-aminoacetophenone, 1-acetonaphthone and 4-methoxybenzaldehyde with 2-imino 4-thiobiuret; 3-acetoxypyridine with 2-amino 4-benzathiazol and 4-chloro aniline with salicylaldehyde have been synthesized and characterized by micro analytical data, FT-IR, electronic spectra and FAB-mass spectral studies. The Schiff base ligands behave as bidentated. The stoichiometry of the complexes is in 1:2 and 1:1 (M:L) ratio. The oxovanadium complexes in general show maximum inhibition percentage at about 1 h. After 1 h it goes on reducing and reaches a minimum at about 5 h. Complex-3 (91.17%) and Complex-5 (85.30%) are most potent in in vivo experiment and exhibited promising anti-inflammatory activity in 0.5 h.     

Effect of air change rate on rubber accelerated ageing tests in hot air. Part 2. Ageing of different compounds

Seven different compounds based on NR, SBR, NBR and EPDM were aged at 100 and 125°C, and 3, 6.5 and 10 changes of air per hour, and in a normal oven at much lower air change rate at 100 °C. Ageing was evaluated by tensile strength, elongation at break, stress at intermediate elongation and changes of IRHD after ageing. The statistical analysis of results shows that air change rate has a significant effect on ageing results.