The purpose of this study was to review the published evidence on the clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to assess the cardiovascular risk (CVR) of cyclooxygenase-2 inhibitors (coxibs), excluding aspirin, by means of a meta-analytic procedure. A search was conducted on MEDLINE and EMBASE databases between October 1999 and June 2018. Cohort and case-control studies showing CVR as relative risk (RR), odds ratio, hazard ratio, or incidence rate ratio associated with NSAIDs versus no treatment were selected. We estimated the pooled RR and the 95% confidence interval (CI) for all NSAIDs as a whole and individually. Eighty-seven studies met the inclusion criteria. Overall, NSAIDs were found to be associated with a statistically significantly increased CVR (RR, 1.24 [95%CI, 1.19-1.28]). The risk was slightly higher for coxibs (RR, 1.22 [95%CI, 1.17-1.28]) as compared with nonselective NSAIDs (RR, 1.18 [95%CI, 1.12-1.24]). Data analysis by drug disclosed that rofecoxib (RR, 1.39 [95%CI, 1.31-1.47]), followed by diclofenac (RR, 1.34 [95%CI, 1.26-1.42]) and etoricoxib (RR, 1.27 [95%CI, 1.12-1.43]) were the NSAIDs associated with the highest CVR. Analysis by type of event showed that the highest risk corresponded to vascular events for both coxibs (RR, 2.18 [95%CI, 1.72-2.78]) and nonselective NSAIDs (RR, 2.46 [95%CI, 2.00-3.02]). The meta-analysis results suggest that the use of the marketed coxibs celecoxib and etoricoxib would be related to a statistically significant CVR increase. Etoricoxib CVR could be higher than that for celecoxib. This increment would be similar to classical NSAID CVR.

In order to find more natural lead-compounds as inhibitors for Cyclooxygenase-2, the essential structural features for human cyclooxygenase-2 inhibitors and 3D-Quantitative structure activity relationship (3D-QSAR) model were carried out based on dataset from three confirmatory bioassays using Phase program. Six point pharmacophore (AAHRRR) of COX-2 selective inhibitors was generated from training set of 52 compounds. The 3D-QSAR model was selected as having favourable statistic measures (R2 = 0.93, Q2ext = 0.81) for the training set and test set respectively. This model was developed using the best pharmacophore hypothesis that helped to reveal the essential features responsible for the anti-inflammatory activity. As a result, this pharmacophore hypothesis has aided in the identification of new four natural lead compounds from UNPD database (UNPD100208, UNPD168234, UNPD91145, UNPD57376) that can be used as potential anti-inflammatory agents or as a core structure to develop other more selective molecules. This result was confirmed by molecular docking, which showed that these four natural lead-compounds adopt the same orientation as Rofecoxib in the COX-2 active site. On the other hand, a molecular dynamic simulation (MDS) was applied and repeated on the top ranking complex 5KIR-UNPD100208 and compared with the results of MDS of 5KIR-Rofecoxib. The results from MDS revealed a good stability of the compound UNPD100208 in the active site based on several parameters such as RMSD, RMSF and potential energy, which can nominate it as a natural anti-inflammatory lead-compound candidate.

Significant body of evidence suggests that abnormal kynurenic acid (KYNA) level is involved in the pathophysiology of central nervous system disorders. In the brain, KYNA is synthesized from kynurenine (KYN) by kynurenine aminotransferases (KATs), predominantly by KAT II isoenzyme. Blockage of ionotropic glutamate (GLU) receptors is a main cellular effect of KYNA. High KYNA levels have been linked with psychotic symptoms and cognitive dysfunction in animals and humans. As immunological imbalance and impaired glutamatergic neurotransmission are one of the crucial processes in neurological pathologies, we aimed to analyze the effect of anti-inflammatory agents, inhibitors of cyclooxygenase-2 (COX-2): celecoxib, niflumic acid, and parecoxib, on KYNA synthesis and KAT II activity in rat brain in vitro. The influence of COX-2 inhibitors was examined in rat brain cortical slices and on isolated KAT II enzyme. Niflumic acid and parecoxib decreased in a dose-dependent manner KYNA production and KAT II activity in rat brain cortex in vitro, whereas celecoxib was ineffective. Molecular docking results suggested that niflumic acid and parecoxib interact with an active site of KAT II. In conclusion, niflumic acid and parecoxib are dual COX-2 and KAT II inhibitors.

Nonsteroidal anti-inflammatory drugs (NSAIDs) include traditional (tNSAIDs), such as ibuprofen, naproxen, and diclofenac, as well as selective cyclooxygenase-2 inhibitors (COXIBs), principally celecoxib. COXIBs were developed to decrease gastrointestinal side effects. Recently, the US Food and Drug Administration strengthened its warning about the risks of non-aspirin NSAIDs on myocardial infarction and stroke. The Cyclooxygenase 2 and Non-Steroidal Anti-Inflammatory Drug Trialist collaboration conducted a comprehensive worldwide meta-analysis using individual patient data exploring the risks of various COXIBs and NSAIDs on cardiovascular disease (CVD). Recently, the results of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial were published that tested risks of COXIBs and NSAIDs on CVD. Generally, data from meta-analyses of trials not designed a priori to test hypotheses are less reliable than large-scale randomized trials to test small to moderate benefits or harm. When the sample size is large, randomization provides control of confounding not possible to achieve in any observational study. Further, observational studies, and especially claims data, have inherent confounding by indication larger than the effects being sought. Nonetheless, trials must be of sufficient size and duration and achieve high compliance and follow-up to avoid bias and confounding. In this regard, PRECISION has high rates of nonadherence and losses to follow-up that may have introduced bias and confounding. At present, therefore, it may be most prudent for clinicians to remain uncertain about benefits and risks of these drugs and make individual clinical judgments for each of their patients.

Vitacoxib is a new drug candidate for treatment of inflammation, pain and fever as selective cyclooxygenase-2 inhibitors. In the current study, the mice sperm abnormality, mammalian erythrocyte micronucleus and in vivo chromosome aberration, and teratogenicity in SD rats were evaluated. Vitacoxib did not cause an increase in the frequency of structural chromosome aberrations, nor did it produce an increase in the number of micro nucleated polychromatic erythrocytes at dose of 1250-5000 mg/kg body weight (BW). There were no toxicological signs observed in teratogenicity test in female SD rats at dose of 200-5000 mg/kg BW. Based on these results of these studies, vitacoxib does not appear to be observed mutagenicity and teratogenicity.

Novel valdecoxib-based cyclooxygenase-2 inhibitors were synthesized in one step via 1,3-dipolar cycloaddition of nitrile oxides with a series of eleven aryl alkynes, six of them described for the first time. Application of Ru(ii)-catalysis leads preferably to the formation of the 3,4-diaryl-substituted isoxazoles, while under thermal heating with base the 3,5-diaryl substitution pattern is favoured. The new the 3,4-diaryl-substituted isoxazoles possessing a small substituent (H and Me) displayed high COX-2 inhibition affinity (IC50 = 0.042-0.073 μM) and excellent selectivity (COX-2 SI > 2000). In contrast, the 3,5-diaryl substituted compounds displayed almost no COX activity. The introduction of a 4-fluorophenyl substituent resulted in retained high COX-2 affinity, making these compounds together with the feasible one step reaction promising candidates for the development of fluorine-18 labelled radiotracers.