Reference Non-steroidal Anti-inflammatory Drugs Research Articles

Synthesis and biological activity evaluation of new thiazolidinone-diclofenac hybrid molecules

A novel series of [2-(2,6-dichlorophenylamino)-phenyl]-acetic acid N`-3-(substituted)-4-thiazolidin-5-ylidenemethyl-hydrazide derivatives has been designed and synthesized. The structures of synthesized compounds were confirmed by their 1H NMR, 13C NMR and LCMS spectroscopic data. Target compounds were screened for their in vitro anticancer activity according to US NCI protocols, in vitro trypanocidal activity toward Trypanosoma brucei brucei (Tbb) and evaluated for anti-inflammatory activity on the carrageenan edema model in rats. Biological screening data led to identification of compounds 3.3 ([2-(2,6-dichloro-phenylamino)-phenyl]-acetic acid N`-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-hydrazide) and 3.7 ([2-(2,6-dichloro-phenylamino)-phenyl]-acetic acid N`-(4-oxo-2-thioxo-3-(3-trifluoromethylphenyl)thiazolidin-5-ylidenemethyl)-hydrazide) which demonstrated moderate antitumor activity on the non-small-cell lung cancer NCI-H522 and colon cancer HCT-116 cell lines. Several hit compounds (3.2, 3.4) exhibited the promising and significant inhibition growth of the parasites at micromolar concentrations (IC50 values of 4.8 and 7.06 μM, respectively). The synthesized compounds also demonstrated considerable anti-inflammatory effect comparable to the reference non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac sodium or ketorolac tromethamine.

In Vivo Anti-inflammatory Activity of Some Naturally Occurring O- and N-Prenyl Secondary Metabolites

A series of O- and N-prenyl secondary metabolites of insect, fungal, and plant origin have been evaluated for their topical anti-inflammatory activity using the Croton oil ear test in mice as a model of acute inflammation. Some of the tested compounds revealed an effect (ID50 = 0.31 divided by 0.56 micromol/cm2) comparable with that of the reference non-steroidal anti-inflammatory drug indomethacin (ID50 = 0.23 micromol/cm2).

Anti-inflammatory potential of curcumin and quercetin in rats

Flavonoids are group of compounds that have been shown to possess potent anti-inflammatory effects in both cellular and animal models of inflammation. In the current study, the single and combined effects of the two flavonoids, curcumin and quercetin, against carrageenan-induced acute inflammation in rats were evaluated with emphasis on the role of oxidative stress, anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α). Curcumin (50 mg/kg), quercetin (50 mg/kg) and a combination of both were orally administered for 14 days before carrageenan injection in rats and compared with the reference nonsteroidal anti-inflammatory drug, indomethacin (10 mg/kg). The percentage increase in paw thickness was calculated. Frozen hind paws were used for the estimation of lipid peroxides (malondialdehyde, MDA), nitric oxide (NO), reduced glutathione (GSH), TNF-α level and HO-1 messenger RNA (mRNA) expression. Formalin-fixed hind paws were used for histopathological examination. Results showed that both curcumin and quercetin caused reduction in carrageenin-induced edema and lymphocytes infiltration along with the decrease is being even higher in case of their combination. Additionally, both flavonoids reduced MDA and NO formation, and restored GSH contents in the paw. Furthermore, both flavonoids increased HO-1 mRNA expression and decreased the elevated TNF-α level. Results showed that both flavonoids moderately lowered inflammation, while their combination was more effective. Accordingly, this study suggests that the reduction in oxidative stress and modulation of HO-1 mRNA expression and TNF-α release by curcumin and quercetin may contribute to the synergistic anti-inflammatory effects of these two flavonoids upon combination.

Synthesis of New Mannich Bases of Arylpyridazinones as Analgesic and Anti-inflammatory Agents

A series of 2-[[4-(substituted-phenyl/ benzyl)-1-piperazinyllmethyl]-6-(4-methoxyphenyl)-3(2H)pyridazinone derivatives was prepared and examined for analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and 1H-NMR spectra and elementary analysis. Among the compounds prepared, 2-[[4-(4-fluorophenyl)-1-piperazinyl]methyl]-6-(4-methoxyphenyl)-3(2H)pyridazinone IVe was found to be a most promising analgesic and anti-inflammatory agent. Compound IVe showed more potent analgesic activity than acetylsalicyclic acid in the phenylbenzoquinone-induced writhing test. Also IVe showed anti-inflammatory activity comparable to that of the standard compound indometacin against the carrageenan-induced paw edema. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed a gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. On the basis of the available data, the structure-activity relationship of the series of 2-[[4-(substituted-phenyl/benzyl)-1-piperazinyl]methyl]-6-(4-methoxyphenyl)-3(2H) pyridazinones is also discussed.

Synthesis and Analgesic and Anti-inflammatory Activity of Ethyl (6-Substituted-3(2H)-pyridazinone-2-yl)acetate Derivatives

A number of 6-substituted-3(2H)-pyridazinones and the corresponding methyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives carrying the arylpiperazinyl structure present in potent antinociceptive agents reported in the literature were synthesized. As part of a programme a series of diverse arylpiperazine derivatives of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate were prepared and tested for their in vivo analgesic and anti-inflammatory activity by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference non-steroidal anti-inflammatory drugs (NSAIDs). On the basis of available data, the structure-activity relationship in the series of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives was also discussed. When compared to parent 6-substituted-3(2H)-pyridazinones, the new ester derivatives, for example ethyl (6-4-[(2-fluoro)phenyl]piperazine-3(2H)-pyridazinone-2-yl)acetate exhibited better analgesic and anti-inflammatory activity and a lower ulcerogenic effect.

Synthesis and Analgesic and Anti-inflammatory Activity of 6-Phenyl/(4-methylphenyl)-3(2H)-pyridazinon-2-propionamide Derivatives

For reducing gastrointestinal toxicity associated with non-steroidal anti-inflammatory drugs (NSAIDs) a variety of 6-phenyl/(4-methylphenyl)-3(2H)-pyridazinon-2-propionamide were synthesized. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. All the new compounds were tested in vivo for their analgesic and anti-inflammatory activities. The analgesic activity of the test compounds was determined by phenylbenzoquinone-induced writhing assay and the anti-inflammatory activity was evaluated by the carrageenan-induced rat paw edema model. 6-Phenyl-3(2H)-pyridazinon-2-yl-[4-(4-fluorophenyl)piperazinyl] propanamide IVa-3 was the most active one among the synthesized compounds. Also this compound exhibited most potent anti-inflammatory activity. Acetylsalicylic acid and indometacin were used as reference drugs. Adverse effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with the reference NSAIDs.

The influence of irradiation on the potential chondroprotective effect of aqueous extract of propolis in rats

Purpose: Cartilage degradation usually results as a consequence of inflammatory processes in the joints. To study this phenomenon experimentally, adjuvant-induced arthritis (AIA) was used as a model of chronic inflammation under the influence of irradiation. The potential chondroprotective effect of 13% aqueous extract of propolis (AEP) in arthritic rats was investigated.Materials and methods: The influence of whole body irradiation on the arthritic inflammatory response was investigated by subjecting rats to a Gamma source before the induction of arthritis. 13% AEP was injected intraperitoneally in a dose of 5 ml/kg and diclofenac was used as reference non-steroidal anti-inflammatory drug (NSAID) in a dose of 3 mg/kg. The chosen parameters for cartilage integrity were glycosaminoglycan (GAG), hydroxyproline contents in cartilage and cartilage oligomeric matrix protein (COMP) in serum. The serum levels of tumour necrosis factor-alpha (TNF-α), nitric oxide (NO) and the oxidative stress biomarkers such as blood glutathione (GSH) and plasma malondialdehyde (MDA) levels.Results: Induction of arthritis led to a reduction in GAG and hydroxyproline content of femoral cartilage and a corresponding rise in COMP in serum. Previous exposure to irradiation resulted in a milder reduction of GAG and hydroxyproline and a lesser rise in COMP. Treatment of arthritic irradiated and non-irradiated rats with 13% AEP markedly prevented the breakdown of cartilage in a much more effective manner than diclofenac. Both AEP and diclofenac were equipotent in reducing the level of TNF-α and were able to normalize NO and the oxidative stress biomarkers in non-irradiated and irradiated arthritic rats.Conclusion: The ability of propolis to protect cartilage degradation could therefore prove of value in the treatment of chronic arthritic diseases, offering an advantage over some NSAID, particularly those with a potential detrimental effect on cartilage integrity.

The Cyclooxygenase-Inhibiting Nitric Oxide Donator (CINOD) Compound NCX 429 Exhibits Reduced Gastrointestinal Toxicity as Compared with Naproxen in Arthritic and Aspirin-Treated Rats

Purpose: The efficacy of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) for the treatment of inflammation and pain is well recognized. Nonetheless, their long-term use poses challenges due to gastrointestinal (GI) and cardiovascular safety concerns. All NSAIDs, even COX-2 inhibitors, induce GI damage in susceptible patients, such as aspirin (ASA) users. In the constant quest for NSAIDs with improved tolerability, an approach using nitric oxide (NO) has been made. Cyclooxygenase-Inhibiting Nitric Oxide Donators (CINODs) are anti-inflammatory compounds designed to concomitantly inhibit cyclooxygenase (COX) and donate NO, with the aim of mitigating the side effects derived from COX inhibition. We studied the anti-inflammatory activity and GI tolerability of NCX 429, and reference NSAIDs naproxen and celecoxib, in rats with arthritis or pre-treated with ASA. Methods: Rats displaying Freund's complete adjuvant (FCA)-induced arthritis were orally treated for 14 days (twice daily, starting day 7 after arthritis induction) with vehicle, NCX 429 (16 mg/kg), naproxen (10 mg/kg) or celecoxib (10 mg/kg). Paw volume was measured by plethysmography. At sacrifice (day 21), stomach and intestine were excised and examined for damage (expressed as the sum of the length in mm of all lesions). In a separate setting, ASA (30 mg/kg) was administered to fasted rats 30 min before gavage with vehicle, NCX 429 (49 or 98 mg/kg), naproxen (30 mg/kg) or celecoxib (20 mg/kg). Gastric damage was measured 4 hours after drug treatment. Results: NCX 429, naproxen and celecoxib, all similarly and significantly reduced paw edema in arthritic rats. NCX 429 displayed significantly reduced gastric and intestinal damage (1.4±0.7 and 1.0±1.0 mm, respectively) than equimolar naproxen (6.2±1.8 and 8.4±3.5mm, respectively, p<0.01), and not differently from celecoxib. In fasted rats, ASA administration caused gastric mucosal damage (4.1±1.2mm, p<0.05 vs. control), which was reduced by NCX 429 (2.2±1.2mm at the maximal dose tested) but conversely exacerbated by naproxen and celecoxib (15.3±4.4 and 10.2±3.3mm, respectively, p<0.05). Conclusion: The CINOD NCX 429 shows effective anti-inflammatory activity in arthritic rats similarly to reference NSAIDs, naproxen and celecoxib. NCX 429 features a GI sparing profile over naproxen. Moreover, oppositely to naproxen and celecoxib, NCX 429 reduces ASA-induced gastric lesions, supporting the NO donating approach aimed at potentially mitigating gastric damage. This experimental evidence, needing clinical validation, would suggest a potential for CINODs in the treatment of inflammatory pathologies, especially individuals at risk for GI damage. Disclosure: Drs Bastia, Monopoli, Bolla, Viappiani - Empoyee: Company NicOx Drs Coruzzi, Guaita, Morini, Wallace - Consultant: Company NicOx. This study has been supported by a grant from NicOx SA to Drs Coruzzi and Wallace.

Thioctic acid protects against carrageenan‐induced acute inflammation in rats by reduction in oxidative stress, downregulation of COX‐2 mRNA and enhancement of IL‐10 mRNA

Free radicals are highly reactive species which played an important role in the pathogenesis of acute inflammation. In this study, the protective role of the known antioxidant, thioctic acid, in carrageenan-induced acute inflammation in rats was assessed and was compared to the reference non-steroidal anti-inflammatory drug (NSAID) indomethacin. In addition, the roles of oxidative stress, nitric oxide (NO), inducible cyclooxygenase isoform (COX-2) and interleukin (IL)-10 mRNA expressions in thioctic acid-induced effects were also investigated. Inflammation was induced by injection of 0.1 ml of 1.5% carrageenan into the plantar side of right hind paws of the rats. Thioctic acid (50, 100 or 200 mg/kg), indomethacin (10 mg/kg), DMSO and saline were injected i.p. 2 h before carrageenan injection. The percentage increase in paw weight was calculated. Frozen hind paw were used for estimation of lipid peroxides (MDA), NO, GSH, COX-2 and IL-10 mRNA expression. Formalin fixed hind paw were used for histopathological examination. Thioctic acid (200 mg/kg) reduced both paw edema formation and lymphocytes infiltration more significant than indomethacin itself: Both thioctic acid and indomethacin reduced paw MDA and NO formation. In addition, both agents restored the depleted GSH contents in the paw. Thioctic acid decreased the elevated COX-2 mRNA while indomethacin, failed. Furthermore, thioctic acid increased IL-10 mRNA expression while indomethacin decreased its expression. Thioctic acid exhibited a potent anti-inflammatory effect on carrageenan-induced inflammation compared to the NSAID indomethacin. The mechanisms of thioctic induced protection were proved to be due to reduction of NO, MDA, COX-2 mRNA and induction of GSH, IL-10 mRNA.

Synthesis and analgesic and anti-inflammatory activities 6-substituted-3(2 H)-pyridazinone-2-acetyl-2-( p-substituted/nonsubstituted benzal)hydrazone derivatives

In this study new 6-substituted-3(2 H)-pyridazinone-2-acetyl-2-( p-substituted benzal)hydrazone V derivatives were synthesized as analgesic and anti-inflammatory agents. The structures of compounds were elucidated by spectral and elemental analysis. Compounds Va, Vb and Vc were exhibited more potent analgesic activity than ASA. Also these derivatives demonstrated anti-inflammatory activity as well as standard compound indomethacin. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs). On the basis of available data, the structure–activity relationship of V derivatives was also discussed.

Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase‐2

This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t(1/2) << 1 min), whilst COX-2 binding was slowly reversible (t(1/2) = 25 min). In vivo, robenacoxib inhibited PGE2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID50 0.3 mg/kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg/kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg/kg but not at 2-30 mg/kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID50 0.40-0.48 mg/kg), LPS-induced fever (ID50 1.1 mg/kg) and Randall-Selitto pain (10 mg/kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng/mL in vitro). After intravenous dosing, clearance was 2.4 mL/min/kg and volume of distribution at steady-state was 306 mL/kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE2 or 6-keto PGF(1alpha) concentrations in the stomach and ileum at 30 mg/kg. Robenacoxib also had no relevant effects on kidney function at 30 mg/kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs.

WITHDRAWN: Non-aspirin, non-steroidal anti-inflammatory drugs for treating osteoarthritis of the knee.

Reason for withdrawal from publication Review has been withdrawn until an update can be undertaken to reflect the current evidence. To view the published versions of this article, please click the 'Other versions' tab.

Guest Editorial: Vioxx Scandal and Ineffective Nsaids in Osteoarthritis – Implications for Physical Therapy?

Adverse events of long-term medication with nonsteroidal anti-inflammatory drugs (NSAIDs) and their subgroup of cyclo-oxygenase-2 inhibitors (coxibs) has recently received much attention in the media due to the Vioxx scandal. Consequently, coxibs like Vioxx have been withdrawn and another coxib, Prexige, has been withheld from the market. 1 The whole group of coxibs are now under special observation by drug agencies in both Europe and the US. In contrast to the virtually non-existent side-effects of physical therapy, NSAID side-effects cause an estimated number of 2000 deaths annually in Great Britain alone. 2 The traditional NSAIDs like naproxen, diclofenac and ibuprofen cause gastrointestinal sideeffects in about 30% of patients. The newer coxibs are more expensive and are associated with less gastrointestinal side-effects, but an increased risk of adverse cardiovascular events and renal failure for long-term users. Do these events have any relevance for physical therapists? Yes, definitely. By chance we had the fortune to participate in the periphery of this fascinating debate, simply because we wanted to compare physical therapy modalities with the reference NSAIDs treatment for osteoarthritis. Much to our surprise, updated data from systematic reviews and metaanalyses of NSAIDs were not available, either in the Cochrane Library or in other EBM-resources. How does one explain that the last Cochrane updates in 2004 had literature searches ending in 1994 for hip, and in 1996 for knee, osteoarthritis? These Cochrane reviews consisted only of 3 and 2 (respectively), randomised placebo-controlled trials, and none of these included coxibs. Still, all major guidelines recommend NSAIDs for osteoarthritis. So for us, the only possi

Glaucopines A and B, New Cyathane Diterpenes from the Fruiting Bodies ofSarcodon glaucopus

Glaucopine A (1) and B (2), two new cyathane diterpenes, have been isolated from the mushroom Sarcodon glaucopus: their structures have been determined on the basis of spectral data. Their topical anti-inflammatory activity was evaluated using the Croton oil ear test in mice: compounds 1 and 2 (1 micromol/cm2) provoked edema reduction (62 % and 55 %, respectively) similar to that induced by the reference non-steroidal anti-inflammatory drug, indomethacin (0.3 micromol/cm2, 61 % edema reduction).

Synthesis and analgesic and antiinflammatory activity of methyl 6-substituted-3(2h)-pyridazinone-2-ylacetate derivatives.

A series of methyl 6-substituted-3(2H)-pyridazinone-2-ylacetates 9 were synthesized and their analgesic and anti-inflammatory effects were evaluated in the phenylbenzoquinone-induced writhing test (PBQ test) and carrageenan-induced paw edema method, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. Methyl 6-(4-(4-fluorophenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9e was found to be more active than acetylsalicylic acid (ASA). Methyl 6-(4-(2-ethoxyphenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9c has shown an anti-inflammatory activity as compared to the standard compound indometacin at the carrageenan-induced paw edema method.A significant dependence of the anti-inflammatory effect on the substituents has been observed. The pharmacological study of these compounds confirms that modification of the chemical group at the position 6 of the 3(2H)-pyridazinone system influences analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and (1)H-NMR spectra and elemental analysis.

Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones

Sixteen 1-(2-naphthyloxyacetyl)-4-substituted-3-thiosemicarbazide, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-oxadiazole, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-thiadiazole and 5-(2-naphthyloxymethyl)-4-substituted-1,2,4-triazole-3-thione derivatives have been prepared and evaluated as orally active anti-inflammatory agents with reduced side-effects. The structures of the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin and phenylbutazone. In carrageenan-induced foot pad edema assay, 2-(2-naphthyloxymethyl)-5-methylamino-1,3,4-oxadiazole, 5-(2-naphthyloxymethyl)-4-methyl-1,2,4-triazole-3-thione and 5-(2-naphthyloxymethyl)-4-ethyl-1,2,4-triazole-3-thione showed an interesting anti-inflammatory activity. In the air-pouch test, 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives reduced total number of leukocytes of the exudate that indicates excellent inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, liver and stomach and none of the compounds showed significant side effects compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs).

Topical anti-inflammatory activity of Salvia officinalis L. leaves: the relevance of ursolic acid

Salvia officinalis L. leaves, obtained from four plant populations of different origin, were investigated for their topical anti-inflammatory properties. The n-hexane and the chloroform extracts dose-dependently inhibited the Croton oil-induced ear oedema in mice, the chloroform extracts being the most active. By contrast, the methanol extracts showed a very low effect and the essential oil was inactive. Chemical and pharmacological investigation of the most potent chloroform extract, issued from an autochthonous sage population grown in the submediterranean climatic region of Slovenia, revealed ursolic acid as the main component involved in its anti-inflammatory activity. The anti-inflammatory effect of ursolic acid (ID 50=0.14 μMoles/cm 2) was two fold more potent than that of indomethacin (ID 50=0.26 μMoles/cm 2), which was used as a reference non-steroidal anti-inflammatory drug (NSAID). The content of ursolic acid in sage and sage-based remedies for the topical treatment of inflammatory diseases is proposed as a parameter for quality control purposes.

Non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the knee.

To determine whether there is a difference in the relative efficacy of individual non-steroidal anti-inflammatory drugs (NSAIDs) when used in the management of osteoarthritis (OA) of the knee. We searched Medline (1966-1995) and Bids Embase (Jan-Dec, 1980-1995). The searches were limited to publications in the English language, and were last perfomed in November 1996. We used modified Cochrane Collaboration search strategy to identify all randomised controlled trials. The MeSH heading osteoarthritis was combined with the generic names of the 17 non-aspirin NSAIDs licensed in the UK for the management of OA in general practice. The search of Embase used the term "osteoarthritis" if present in the abstract, title or keywords, and was combined with the generic names of the 17 non-aspirin NSAIDs, only if they were mentioned in the title, abstract or keywords. All double blind, randomised controlled trials, in the English language, comparing the efficacy of two non-aspirin NSAIDs in the management of osteoarthritis of the knee, were selected. Only trials with subjects aged 16 years and over, with clinical and/or radiological confirmation of the diagnosis of OA knee were included. Studies which compared one "trial" NSAID with one "reference" NSAID were included provided they were non-aspirin NSAIDs available in the UK and were licensed for the treatment of OA by general practitioners. Trials which were placebo-controlled and which also involved the comparison of two NSAIDs were also included. The methodological design of each study was scored according to a pre-determined system. The three main outcome measures of pain, physical function and patient global assessment were chosen based on the core set agreed upon by OMERACT (Outcome Measures in Rheumatology Clinical Trials). These were used to determine the power of each trial. The equivalency of NSAID doses was calculated using the percentage of the recommended maximum daily dose. Sample size estimates for the detection of clinically relevant changes in outcome measures used in the assessment of OA knee were used for power calculations. These calculations were performed to determine whether the trials were of a sufficient size to detect clinically relevant differences which were statistically significant. The calculations incorporate estimates of standard deviation, and minimum, median and maximum differences (delta) between drugs which are deemed to be clinically important. The number of "withdrawals due to lack of efficacy" was also selected as an outcome measure for this review. The Peto odds ratio and 95% confidence intervals were calculated where possible. The results of studies which compared the same trial and reference NSAIDs were combined where possible. Of the 1151 trials identified by the search strategy, 22 involved knee osteoarthritis only. Sixteen of these trials fulfilled the inclusion criteria and were entered in the review. Eight NSAIDs were represented in these trials. Etodolac was represented in 11 trials. The reference NSAID in these trials was piroxicam (n=3), naproxen(n=3), diclofenac (n=3), indomethacin (n=1), and, nabumetone (n=1). The reported methodological design of the trials was poor, with a median score of 3 (out of a maximum of 8). The results of the trials comparing the same trial and reference NSAIDs were pooled for the outcome "withdrawal due to lack of efficacy". For the comparison, etodolac vesus piroxicam, the odds ratio favoured etodolac i.e. patients receiving etodolac were less likely to withdraw due to lack of efficacy. The dose of etodolac used in each of these three studies, however, was greater than the corresponding dose of piroxicam (based on percentage maximum daily dose). The significance of these results is therefore questionable. For the comparisons etodolac versus diclofenac, and etodolac versus naproxen, there were no clear differences betw

Selective inhibition of cyclooxygenase 2

Cyclooxygenase (COX), a key enzyme in the formation of prostanoids, is known to exist in two isoforms: an inducible enzyme (COX 2) and a constitutive form (COX 1). Both enzymes are inhibited by non-steroidal anti-inflammatory drugs (NSAID), but only marginal selectivity has thus far been reported. In this study, we report on a novel selective inhibitor of COX 2, CGP 28238 (6-(2,4-dinuorophenoxy)-5-methyl-sulfonylamino-1-indanone). Human washed platelets were used as a source of COX 1. For IL-1 stimulated rat mesangial cells we demonstrated the almost exclusive presence of COX 2 in western blot and mRNA analysis. Therefore these two model systems were chosen for selectivity testing. With an ic 50 value of 15 nM, CGP 28238 blocked COX 2 activity in a similar concentration range to that of other potent NSAID such as indomethacin and diclofenac ( ic 50 = 1.17-8.9 nM). However, in contrast to these reference NSAIDs, CGP 28238 was at least 1000-fold less potent in inhibiting COX 1. Using other cell systems reported to express COX 1 or COX 2, we obtained a similar selectivity for COX 2. Thus, on the basis of our findings, CGP 28238 is a novel, highly potent and selective inhibitor of COX 2 and may be a lead compound for a new generation of potent anti-inflammatory drugs with an improved side-effect profile.

Etodolac: Effect on prostaglandin concentrations in gastric mucosa of rats

Etodolac is a structurally novel compound exhibiting potent analgesic and anti-inflammatory activity in laboratory animals and man, with excellent G.I. tolerance. Like other nonsteroidal anti-inflammatory drugs (NSAIDs) etodolac inhibits prostaglandin (PG) biosynthesis. In view of the cytoprotective role of PGE 2, we have investigated in normal rats the effect of etodolac on the gastric mucosal concentration of PGE 2, as well as of 6-keto-PGF 1α, the stable metabolite of prostacyclin; naproxen and piroxicam served as reference NSAIDs. The orally effective anti-inflammatory doses in the chronic arthritic rat model (3 mg/kg for etodolac and naproxen; 0.5 mg/kg for piroxicam), and their arbitrarily selected multiples of 10 were used. Rats were killed at 1, 2, 6 and 24 hr after single doses and the PG concentrations were measured by RIA. With the low dose, 2 and 6 hr after dosing, etodolac diminished the PGE 2 concentration by 20–25% (vs control) while naproxen and piroxicam caused a fall of 53–65%; the difference between etodolac and the untreated control group is not statistically significant but the difference between etodolac and both piroxicam and naproxen is significant (p < 0.001). At the high doses, the lowering in PGE 2 was similar after all three drugs, i.e. about 70% at 1 and 2 hr; 50% at 6 hr, and 20–50% at 24 hr after dosing. Except for the consistently smaller reduction of concentrations after etodolac, the effects on 6-keto-PGF 1α concentration followed a similar pattern but the differences are not significant. The lack of the G.I. irritation of etodolac in rats and man at therapeutically effective doses may be attributed to the benefits of the relatively short-lived and slight decrease in gastric mucosal PGE 2 concentrations found in this study.