The association between nonsteroidal anti-inflammatory drugs and skin cancer: Different responses in American and European populations.

OBJECTIVE: To conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer (SC) and its subclasses (basal cell carcinoma BCC; squamous cell carcinoma SCC; melanoma; nonmelanoma skin cancer NMSC) in general, American and European populations. METHODS: PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and ClinicalTrials.gov were searched up to 24 February 2019. Pooled effect sizes and 95% confidence intervals were used to estimate associations. RESULTS: Results based on 26 original studies including 223,619 cases and 1,398,507 controls showed both NSAIDs and nonselective Cyclooxygenase (COX) inhibitors to be statistically significantly associated with a reduced risk of SC, BCC, SCC and NMSC but not with melanoma. Conversely, no association was observed between selective Cyclooxygenase 2 (COX-2) inhibitors and SC or its subclasses. Further subgroup analysis showed that the results analyzed for American populations were almost the same as those for the general population. For European populations, neither NSAIDs nor its subtypes correlated significantly with susceptibility to SC or its subclasses. CONCLUSIONS: The use of NSAIDs might reduce the risk of SC, but many factors including study population, drug subtype, and disease subclass affect the significance of the association.

Solubility of lumiracoxib in supercritical carbon dioxide.

This study aims to use a static-based solubility method for measuring the solubility of lumiracoxib at a temperature of 308-338 K and pressure of 120-400 bar for the first time. The obtained solubility data for lumiracoxib is between 4.74 × 10-5 and 3.46 × 10-4 (mole fraction) for the studied ranges of pressure and temperature. The solubility values reveal that the lumiracoxib experiences a crossover pressure of about 160 bar. Moreover, the measured solubility data of these two drugs are correlated with density-based semi-empirical correlations namely Bartle et al., Mendez-Santiago-Teja, Kumar and Johnstone, Chrastil and modified Chrastil models with an average absolute relative deviation of 10.7%, 9.5%, 9.8%, 7.8%, and 8.7% respectively for lumiracoxib. According to these findings, it is obvious that all of the examined models are rather accurate and there is no superiority between these models for both examined drugs although the Chrastil model is slightly better in the overall view.

Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.

Lumiracoxib is a substrate-selective inhibitor of endocannabinoid oxygenation by cyclooxygenase-2 (COX-2). We assayed a series of lumiracoxib derivatives to identify the structural determinants of substrate-selective inhibition. The hydrogen-bonding potential of the substituents at the ortho positions of the aniline ring dictated the potency and substrate selectivity of the inhibitors. The presence of a 5'-methyl group on the phenylacetic acid ring increased the potency of molecules with a single ortho substituent. Des-fluorolumiracoxib (2) was the most potent and selective inhibitor of endocannabinoid oxygenation. The positioning of critical substituents in the binding site was identified from a 2.35Å crystal structure of lumiracoxib bound to COX-2.

Determination of lumiracoxib by a validated stability-indicating MEKC method and identification of its degradation products by LC-ESI-MS studies.

A stability-indicating MEKC method was developed and validated for the analysis of lumiracoxib (LMC) in pharmaceutical formulations using nimesulide as the internal standard (IS). Optimal conditions for the separation of LMC and degradation products were investigated. The method employed 50 mM borate buffer and 50 mM anionic detergent SDS solution at pH 9.0. MEKC method was performed on a fused-silica capillary (50 µm id; effective length, 40 cm) maintained at 30°C. The applied voltage was 20 kV and photodiode array (PDA) detector was set at 208 nm. The method was validated in accordance with the International Conference on Harmonisation requirements. The stability-indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using PDA detection. The degradation products formed under stressed conditions were investigated by LC-ESI-MS and the two degraded products were identified. MEKC method was linear over the concentration range of 5-150 µg/mL (r(2) =0.9999) of LMC. The method was precise, accurate, with LOD and LOQ of 1.34 and 4.48 µg/mL, respectively. The robustness was proved by a fractional factorial design evaluation. The proposed MEKC method was successfully applied for the quantitative analysis of LMC in tablets to support the quality control.

A validated UHPLC-MS/MS method for simultaneous determination of lumiracoxib and its hydroxylation and acyl glucuronidation metabolites in rat plasma: Application to a pharmacokinetic study.

Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor. The aim of this study was to develop a simple and sensitive ultra-high performance liquid chromatography tandem mass spectrometric method (UHPLC-MS/MS) for the simultaneous determination of lumiracoxib and its circulating metabolites 4'-Hydroxyl-lumiracoxib and lumiracoxib-acyl-glucuronide in rat plasma. The analytes and diclofenac (internal standard, IS) were extracted using acetonitrile containing 0.2 % formic acid. Chromatographic separation was executed on ACQUITY BEH C18 column (2.1 × 50 mm, 1.7 µm) with water containing 0.2 % formic acid and acetonitrile as mobile phase. Mass detection was achieved in positive multiple reactions monitoring (MRM) mode, with precursor-to-product transitions at m/z 294.1 > 248.1, m/z 310.1 > 264.1, m/z 470.1 > 276.1 and m/z 296.0 > 250.0 for lumiracoxib, 4'-hydroxyl-lumiracoxib, lumiracoxib-acyl-glucuronide and for IS, respectively. The developed LC-MS/MS method was validated based on the guidance of U.S. Food and Drug Administration. The linearity was evident (r > 0.995) over the concentration ranges of 1-1000 ng/mL for lumiracoxib, 1-500 ng/mL for 4'-hydroxyl-lumiracoxib and 1-200 ng/mL for lumiracoxib-acyl-glucuronide, respectively. The precision (RSD) did not exceed 8.23 % and accuracy (RE) ranged from -7.85 % to 9.50 %. The extraction recovery was more than 80.54 %. All the analytes were demonstrated to be stable under the tested storage and processing conditions. The validated LC-MS/MS method has been successfully applied to the pharmacokinetic study of lumiracoxib and its metabolites in the rats after orally administered with lumiracoxib.

Bioactivation of lumiracoxib in human liver microsomes: Formation of GSH- and amino adducts through acyl glucuronide.

Lumiracoxib is a selective cyclooxygenase-2 inhibitor, which has been reported to cause rare but severe liver injury. Considering that lumiracoxib has a carboxylic group in the molecule, glucuronidation to form acylglucuronide would be one of the possible mechanisms of lumiracoxib-induced liver injury. The aim of this study was to identify the metabolites of lumiracoxib that were formed via acyl-glucuronidation in human liver microsomes using glutathione (GSH) and N-acetyl-lysine (NAL) as trapping agents by liquid chromatography combined with high resolution mass spectrometry. The structures of the detected metabolites were identified by their accurate masses, fragment ions, and retention times. Under the current conditions, eight lumiracoxib associated metabolites were identified. With the presence of UDPGA, lumiracoxib was biotransformed into lumiracoxib-1-O-acylglucuronide (M1) and 4'-hydroxyl-lumiracoxib-1-O-acylglucuronide (M2), both of which were reactive and prone to react with GSH to form drug-S-acyl-GSH adducts (M3 and M4) through transacylation. In addition to reaction with GSH, the formed 1-O-acylglucuronides were chemically unstable (T1/2 = 1.5 h in phosphate buffer) and rearranged to 2-, 3-, and/or 4-isomers, which further underwent ring-opening to form aldehyde derivatives and then reacted with NAL to yield Schiff base derivatives (M5-M8). The present study provides a clear bioactivation profile of lumiracoxib through acyl glucuronidation, which would be one of the mechanisms attributed to liver injury caused by lumiracoxib.

Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.

Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.

Structure-toxicity relationship and structure-activity relationship study of 2-phenylaminophenylacetic acid derived compounds.

2-Phenylaminophenylacetic acid is a widely-exploited chemical scaffold whereby notable NSAIDs such as diclofenac and lumiracoxib were derived. Yet, their clinical usage has been associated with toxicities in the liver. While some studies have attributed toxicities to the bioactivation of both drugs to reactive intermediates, the structural predisposition for toxicity, as well as relationship between this toxicity and COX inhibitory activity has not been elucidated. In this study, we aimed to address their intricate link by synthesizing compounds that possess the 2-phenylaminophenylacetic acid backbone with varying alkyl and halogen substituents at three positions critical to the COX inhibitory pharmacophore. These compounds were subjected to cytotoxicity testing on two liver cell lines of contrasting metabolic competencies. We observed higher toxicity in the more metabolically competent cell line, supporting the role of bioactivation as a prerequisite for toxicity. We have also shown that structural changes on the chemical scaffold exerted pronounced effect on liver cytotoxicity. The most lipophilic and brominated compound (24) was identified as the most cytotoxic of all the compounds. A concurrent determination of their pharmacological activity using COX inhibition assays allowed us to derive a safety profile, which showed that selectivity towards COX-2 negatively affected activity and toxicity.

Efficacy of etoricoxib, celecoxib, lumiracoxib, non-selective NSAIDs, and acetaminophen in osteoarthritis: a mixed treatment comparison.

OBJECTIVE: To compare the efficacy of etoricoxib, lumiracoxib, celecoxib, non-selective (ns) NSAIDs and acetaminophen in the treatment of osteoarthritis (OA) METHODS: Randomized placebo controlled trials investigating the effects of acetaminophen 4000mg, diclofenac 150mg, naproxen 1000mg, ibuprofen 2400mg, celecoxib 100-400mg, lumiracoxib 100-400mg, and etoricoxib 30-60mg with treatment duration of at least two weeks were identified with a systematic literature search. The endpoints of interest were pain, physical function and patient global assessment of disease status (PGADS). Pain and physical function reported on different scales (VAS or LIKERT) were translated into effect sizes (ES). An ES 0.2 - 0.5 was defined as a "small" treatment effect, whereas ES of 0.5 - 0.8 and > 0.8 were defined as "moderate" and "large", respectively. A negative effect indicated superior effects of the treatment group compared to the control group. Results of all trials were analyzed simultaneously with a Bayesian mixed treatment comparison. RESULTS: There is a >95% probability that etoricoxib (30 or 60mg) shows the greatest improvement in pain and physical function of all interventions compared. ESs of etoricoxib 30mg relative to placebo, celecoxib 200mg, ibuprofen 2400mg, and diclofenac 150mg were -0.66 (95% Credible Interval -0.83; -0.49), -0.32 (-0.50; -0.14), -0.25 (-0.53; 0.03), and -0.17 (-0.41; 0.08), respectively. Regarding physical functioning, ESs of etoricoxib 30mg relative to placebo, celecoxib 200mg, ibuprofen 2400mg, and diclofenac 150mg were -0.61 (-0.76; -0.46), -0.27 (-0.43; -0.10), -0.20 (-0.47; 0.07), and -0.09 (- 0.33; 0.14) respectively. The greatest improvements in PGADS were expected with either etoricoxib or diclofenac. CONCLUSION: The current study estimated the efficacy of acetaminophen, nsNSAIDs, and COX-2 selective NSAIDs in OA and found that etoricoxib 30 mg is likely to result in the greatest improvements in pain and physical function. Differences in PGADS between interventions were smaller.

Preemptive versus postoperative lumiracoxib for analgesia in ambulatory arthroscopic knee surgery.

We compared the efficacy and safety of preemptive vs postoperative dosing of lumiracoxib 400 mg in patients undergoing minor ambulatory arthroscopic knee surgery. Eligible patients were randomized to preemptive lumiracoxib, postoperative lumiracoxib, and placebo. The main efficacy parameter was pain intensity (PI) (0-100 mm visual analog scale) in the target knee upon movement, 2 hours after surgery. Other efficacy variables included PI in the target knee at rest and upon movement at 1, 3, 4, and 24 hours, time to first rescue medication intake. In the lumiracoxib preemptive and postoperative groups, the estimated treatment difference compared to placebo for primary endpoint was -4.0 (95% CI: -9, -1; p = 0.007) and -3.5 (95% CI: -8.5, 0; p = 0.052), respectively. There was no statistical significant difference between two active treatment groups (p = 0.602). Both preemptive and postoperative lumiracoxib resulted in significantly lower PI scores at rest and after movement at all time-points and no statistically significant difference was observed between the active treatments. Time to rescue medication intake was comparable for both active treatments. The proportion of adverse events was similar among all groups. We conclude that the efficacy of lumiracoxib 400 mg is not affected by the timing of administration (preemptive or postoperative).

Efficacy and tolerability of lumiracoxib, a highly selective cyclo-oxygenase-2 (COX2) inhibitor, in the management of pain and osteoarthritis.

Lumiracoxib is a COX2 inhibitor that is highly selective, is more effective than placebo on pain in osteoarthritis (OA), with similar analgesic and anti-inflammatory effects as non-selective NSAIDs and the selective COX2 inhibitor celecoxib, has a lower incidence of upper gastrointestinal (GI) side effects in patients not taking aspirin, and a similar incidence of cardiovascular (CV) side effects compared to naproxen or ibuprofen. In the context of earlier guidelines and taking into account the GI and CV safety results of the TARGET study, lumiracoxib had secured European Medicines Agency (EMEA) approval with as indication symptomatic treatment of OA as well as short-term management of acute pain associated with primary dysmenorrhea and following orthopedic or dental surgery. In the complex clinical context of efficiency and safety of selective and non-selective COX inhibitors, its prescription and use should be based on the risk and safety profile of the patient. In addition, there is further need for long-term GI and CV safety studies and general post-marketing safety on its use in daily practice. Meanwhile, at the time of submission of this manuscript, the EMEA has withdrawn lumiracoxib throughout Europe because of the risk of serious side effects affecting the liver.

Lumiracoxib: the evidence of its clinical impact on the treatment of osteoarthritis.

INTRODUCTION: The symptoms of osteoarthritis (OA) include joint pain, stiffness, and a reduced ability to perform normal daily activities, which result in decreased quality of life. There is currently no known cure or means of preventing the progression of joint damage due to OA. Therefore, treatment focuses on the control of symptoms, including the use of various agents [including nonselective and selective nonsteroidal antiinflammatory drugs (NSAIDs)] to provide pain relief and reduce inflammation. Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor for the treatment of OA. AIMS: To review the evidence for the treatment of OA with lumiracoxib. EVIDENCE REVIEW: There is evidence that lumiracoxib reduces the pain and stiffness associated with OA, and is as effective as nonselective NSAIDs, and the COX-2 inhibitor celecoxib. There is some evidence that lumiracoxib treatment results in a lower incidence of upper gastrointestinal (GI) ulcer complications compared with nonselective NSAIDs. However, evidence suggests that there is no GI benefit in patients receiving concomitant aspirin medication. With the exception of GI ulcers, the evidence indicates that lumiracoxib has a tolerability profile similar to nonselective NSAIDs: low risk of cardiovascular (CV) events and a low incidence of edema. Changes in liver function occur in some patients, largely at doses >100 mg. The cost effectiveness of lumiracoxib compared with nonselective NSAIDs remains to be determined. CLINICAL VALUE: Lumiracoxib is an alternative treatment option for OA which provides effective pain relief without the GI complications associated with nonselective NSAIDs, and with a low risk of CV events. Lumiracoxib is contraindicated in patients with current, previous, or at risk of, hepatic impairment.

Mechanisms of lumiracoxib on antitumor in human lung cancer cells / 中国药理学通报

Aim To investigate the possible mechanism of antitumor in human lung cancer cell lines A549 and NCI-H460 induced by lumiracoxib.Methods The expression of COX-2 was detected by Western blot and the levels of PGE2 and cAMP was determined by radioimmunoassay (RIA).Results COX-2 protein was highly expressed in A549 and NCI-H460 cells.After treatment with 15~240 ?mol?L-1 LUM for 24 hrs,LUM significantly decreased the level of COX-2 in A549 cells,but not in NCI-H460 cells.Compared with the control,the PGE2 production was reduced and the level of cAMP was increased after the treatment with 15,30,60,120,240 ?mol?L-1 of LUM,respectively.Conclusion The effect of Lumiracoxib on antitumor is in COX-2-dependent or-independent manner. The antitumor effect of LUM may be related to inhibiting the COX-2 activities by decreasing its secretion,up-regulating the level of cAMP,and down-regulating the level of PGE2.