Identification of potential inhibitory analogs of metastasis tumor antigens (MTAs) using bioactive compounds: revealing therapeutic option to prevent malignancy.

The deeper understanding of metastasis phenomenon and detection of drug targets could be a potential approach to minimize cancer mortality. In this study, attempts were taken to unmask novel therapeutics to prevent metastasis and cancer progression. Initially, we explored the physiochemical, structural and functional insights of three metastasis tumor antigens (MTAs) and evaluated some plant-based bioactive compounds as potent MTA inhibitors. From 50 plant metabolites screened, isoflavone, gingerol, citronellal and asiatic acid showed maximum binding affinity with all three MTA proteins. The ADME analysis detected no undesirable toxicity that could reduce the drug likeness properties of top plant metabolites. Moreover, molecular dynamics studies revealed that the complexes were stable and showed minimum fluctuation at molecular level. We further performed ligand-based virtual screening to identify similar drug molecules using a large collection of 376,342 compounds from DrugBank. The results suggested that several structural analogs (e.g., tramadol, nabumetone, DGLA and hydrocortisone) may act as agonist to block the MTA proteins and inhibit cancer progression at early stage. The study could be useful to develop effective medications against cancer metastasis in future. Due to encouraging results, we highly recommend further in vitro and in vivo trials for the experimental validation of the findings.

Toward Multitasking Pharmacological COX-Targeting Agents: Non-Steroidal Anti-Inflammatory Prodrugs with Antiproliferative Effects.

The antitumor activity of certain anti-inflammatory drugs is often attributed to an indirect effect based on the inhibition of COX enzymes. In the case of anti-inflammatory prodrugs, this property could be attributed to the parent molecules with mechanism other than COX inhibition, particularly through formulations capable of slowing down their metabolic conversion. In this work, a pilot docking study aimed at comparing the interaction of two prodrugs, nabumetone (NB) and its tricyclic analog 7-methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one (MC), and their common active metabolite 6-methoxy-2-naphthylacetic acid (MNA) with the COX binding site, was carried out. Cytotoxicity, cytofluorimetry, and protein expression assays on prodrugs were also performed to assess their potential as antiproliferative agents that could help hypothesize an effective use as anticancer therapeutics. Encouraging results suggest that the studied compounds could act not only as precursors of the anti-inflammatory metabolite, but also as direct antiproliferative agents.

Nabumetone induced photogenotoxicity mechanism mediated by ROS generation under environmental UV radiation in human keratinocytes (HaCaT) cell line.

Nabumetone (NB) is a non-steroidal anti-inflammatory drug (NSAID), prescribed for managing pain associated with acute/chronic rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders. Though some incidences of photosensitivity have been reported, there is limited information available on its phototoxicity potential. In this study, NB photodegraded in a time-dependant manner (0-4 h) under UVA (1.5 mW/cm2), UVB (0.6 mW/cm2) and natural sunlight as observed through UV-vis spectrophotometer and the results were further confirmed with Ultra High-Performance Liquid Chromatography (UHPLC). Photosensitized NB generated reactive oxygen species (ROS) as observed by lipid peroxidation, suggesting oxidative degradation of lipids in cell membrane, thereby resulting in cell damage. MTT and NRU (neutral red uptake) assays revealed that NB induced phototoxicity in concentration-dependent manner (0.5, 1, 5, 10 µg/ml) under UVA, UVB and sunlight exposure (30 min) in human keratinocytes cell line (HaCaT), with significant phototoxicity at the concentration of 5 µg/ml. Photosensitized NB generated intracellular ROS, disrupted mitochondrial and lysosomal membrane integrity, resulting in cell death. UV-induced genotoxicity by NB was confirmed through micronuclei generation, γ-H2AX induction and cyclobutane pyrimidine dimer formation. This is the first study which showed the phototoxicity and photogenotoxicity potential of NB in HaCaT cell line. We also observed that photosensitized NB upregulated inflammatory markers, such as COX-2 and TNFα. This study proposes that sunlight exposure should be avoided by patients using nabumetone and proper guidance should be provided by clinicians regarding photosensitivity of drugs for better safety and efficacy.

Effect of nabumetone on humoral immune responses in mice / Efeito da nabumetona nas respostas imunes humorais em camundongos

Nabumetone is used to reduce the pain and inflammation in rheumatoid arthritis. In the current study, immunomodulatory effect of Nabumetone is investigated in mice. The control group was administered normal saline orally as placebo. Nabumetone was administered orally via gavage in two treatment groups at 14mg/kg.b.w. doses and 28mg/kgb.w., respectively. Haemagglutination (HA) assay, Jerne hemolytic plaque and mice lethality assays were applied. In HA assay, the titer was significantly decreased in Nabumetone treatment groups (P< 0.001). In Jerne hemolytic plaque formation assay, there was a significant reduction (P< 0.001) in number of plaques in Nabumetone treated groups when compared with control. In mice lethality assay, there was a significant difference in mortality ratio of mice in control and Nabumetone treated groups (P< 0.001). Therefore, it is concluded that Nabumetone suppresses the humoral immune response in mice.(AU)

A nabumetona é usada na redução da dor e inflamação da artrite reumática. No presente estudo, o efeito imunomodulador é investigado em camundongos. O grupo de controle recebeu solução salina via oral como placebo. Nabumetona foi administrada oralmente via gavagem em dois grupos de tratamentos com doses de 14mg/kg.b.w. e 28mg/kgb.w., respectivamente. Foram realizados ensaios de hemaglutinação (HA), placa hemolítica de Jerne e letalidade dos camundongos. No ensaio HA, o grau foi significativamente menor nos grupos de tratamento com nabumetoma (P< 0.001). No ensaio de formação de placa hemolítica de Jerne houve redução significativa (P< 0.001) no número de placas em grupos tratados com nabumetoma comparado ao controle. No ensaio de letalidade dos camundongos houve diferença significativa no grau de mortalidade de camundongos no grupo de controle e grupos tratados com nabumetoma (P< 0.001). Portanto, conclui-se que a Nabumetoma suprime a resposta imune humoral em camundongos.(AU)

Production of nabumetone nanoparticles: Effect of molecular weight, concentration and nature of cellulose ether stabiliser.

The ability of a range of hydrophilic nonionic cellulose ethers (CEs) (namely methylhydroxethylcellulose, hydroxypropylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose) to prepare stable nabumetone nanoparticles (<1000nm, as measured by laser diffraction) using wet-bead milling has been investigated. Due to the limited range of CE molecular weights commercially available, the CEs were degraded using ultrasonication for varying lengths of time to yield CEs of lower molecular weight. Of the CEs tested, only hydroxyethylcellulose was found not to stabilise the production of nabumetone nanoparticles at any of the molecular weights tested, namely viscosity average molecular weights (Mv) in the range of 236-33kg/mol. All other CEs successfully stabilised nabumetone nanoparticles, with the lower molecular weight/viscosity polymers within a series being more likely to result in nanoparticle production than their higher molecular weight counterparts. Unfortunately due to the nature of the ultrasonication process, it was not possible to compare the size of nabumetone particles produced using polymers of identical Mv. There was, however, enough similarity in the Mv of the various polymers to draw the general conclusion that there was no strong correlation between the Mv of the various polymers and their ability to produce nanoparticles. For example hydroxypropylcellulose of 112.2kg/mol or less successfully produced nanoparticles while only ethylhydroxyethylcellulose and hydroxypropylmethyl polymers of 52 and 38.8kg/mol or less produced nanoparticles. These results suggest that polymer molecular weight is not the only determinant of nanoparticle production and that structure of the polymer is at least as important as its molecular weight. In particular the hydrophobic nature of the CE was thought to be an important factor in the production of nabumetone nanoparticles: the more hydrophobic the polymer, the stronger its interaction with nabumetone and the greater its ability to produce nanoparticles. In this context HPC was the most hydrophobic polymer and HEC the least hydrophobic.

The modulation of carbonyl reductase 1 by polyphenols.

Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the reduction of many xenobiotics, including important drugs (e.g. anthracyclines, nabumetone, bupropion, dolasetron) and harmful carbonyls and quinones. Moreover, it participates in the metabolism of a number of endogenous compounds and it may play a role in certain pathologies. Plant polyphenols are not only present in many human food sources, but are also a component of many popular dietary supplements and herbal medicines. Many studies reviewed herein have demonstrated the potency of certain flavonoids, stilbenes and curcuminoids in the inhibition of the activity of CBR1. Interactions of these polyphenols with transcriptional factors, which regulate CBR1 expression, have also been reported in several studies. As CBR1 plays an important role in drug metabolism as well as in the protection of the organism against potentially harmful carbonyls, the modulation of its expression/activity may have significant pharmacological and/or toxicological consequences. Some polyphenols (e.g. luteolin, apigenin and curcumin) have been shown to be very potent CBR1 inhibitors. The inhibition of CBR1 seems useful regarding the increased efficacy of anthracycline therapy, but it may cause the worse detoxification of reactive carbonyls. Nevertheless, all known information about the interactions of polyphenols with CBR1 have only been based on the results of in vitro studies. With respect to the high importance of CBR1 and the frequent consumption of polyphenols, in vivo studies would be very helpful for the evaluation of risks/benefits of polyphenol interactions with CBR1.

Discovery of nonsteroidal anti-inflammatory drug and anticancer drug enhancing reprogramming and induced pluripotent stem cell generation.

Recent breakthroughs in creating induced pluripotent stem cells (iPSCs) provide alternative means to obtain embryonic stem-like cells without destroying embryos by introducing four reprogramming factors (Oct3/4, Sox2, and Klf4/c-Myc or Nanog/Lin28) into somatic cells. iPSCs are versatile tools for investigating early developmental processes and could become sources of tissues or cells for regenerative therapies. Here, for the first time, we describe a strategy to analyze genomics datasets of mouse embryonic fibroblasts (MEFs) and embryonic stem cells to identify genes constituting barriers to iPSC reprogramming. We further show that computational chemical biology combined with genomics analysis can be used to identify small molecules regulating reprogramming. Specific downregulation by small interfering RNAs (siRNAs) of several key MEF-specific genes encoding proteins with catalytic or regulatory functions, including WISP1, PRRX1, HMGA2, NFIX, PRKG2, COX2, and TGFß3, greatly increased reprogramming efficiency. Based on this rationale, we screened only 17 small molecules in reprogramming assays and discovered that the nonsteroidal anti-inflammatory drug Nabumetone and the anticancer drug 4-hydroxytamoxifen can generate iPSCs without Sox2. Nabumetone could also produce iPSCs in the absence of c-Myc or Sox2 without compromising self-renewal and pluripotency of derived iPSCs. In summary, we report a new concept of combining genomics and computational chemical biology to identify new drugs useful for iPSC generation. This hypothesis-driven approach provides an alternative to shot-gun screening and accelerates understanding of molecular mechanisms underlying iPSC induction.

Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV study in Korean patients.

BACKGROUND: S-adenosylmethionine (SAMe) has antiinflammatory and analgesic effects and has been reported to ameliorate the pain and dysfunction of osteoarthritis (OA). The metabolism of SAMe can be affected by geographic or ethnic factors. However, its efficacy and tolerability versus NSAIDs have not been reported in an Asian population. OBJECTIVE: This study compared the efficacy and tolerability of SAMe 1200 mg/d and nabumetone 1000 mg/d in Korean patients with knee OA. METHODS: This study was an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV clinical trial. Eligible patients were aged >18 years and had knee OA according to the clinical and radiologic criteria of the American College of Rheumatology, with a symptom duration of > or =3 months and with a baseline pain rating of >40 mm on a visual analog scale (VAS) or a pain rating on the VAS that was increased by >10 mm or 20% during the washout period compared with the screening visit. After a washout period of 2 weeks, patients with OA were randomly assigned to receive SAMe 1200 mg/d (400 mg TID) or nabumetone 1000 mg once a day in the evening for 8 weeks. The primary end point was the patient's assessment of pain intensity using a VAS at week 8, and the secondary end points were functional class, patient's global assessment of disease status, physician's global assessment of response to therapy, and the Western Ontario and McMaster Universities (WOMAC) index. Adverse events were assessed based on spontaneous reports by patients during interviews and by laboratory tests. RESULTS: One hundred thirty-four patients, all Asians, were randomly allocated to 1 of 2 treatment groups: 67 patients (56 women, 11 men; mean [SD] age, 63.9 [8.2] years) received SAMe 400 mg TID, and 67 patients (60 women, 7 men; mean age, 62.1 [8.4] years) received nabumetone 1000 mg once daily for 8 weeks. An analysis of changes in pain intensity between weeks 0 and 8 found that both SAMe and nabumetone effectively reduced pain intensity from baseline in each group (mean [SD] change: SAMe, -13.0 [20.8] mm, P < 0.001; nabumetone, -15.7 [20.9] mm, P < 0.001), and the degree of decrease in pain intensity was not significantly different between groups. Secondary end points showed significant improvements from baseline to 8 weeks in both groups. The patient's global assessment of disease status, physician's global assessment of response to therapy, and WOMAC index scores were not significantly different between the groups. Use of acetaminophen as rescue medication did not differ significantly between the groups during weeks 0 to 4 (SAMe, 88.5% [54/61]; nabumetone, 81.3% [52/64]) or weeks 4 to 8 (SAMe, 79.5% [35/44]; nabumetone, 68.5% [37/54]). No significant differences were observed between the treatments in the proportions of patients with all adverse events (SAMe, 35.8% [24/67]; nabumetone, 31.3% [21/67]), drugrelated clinical or laboratory-determined adverse events (SAMe, 22.4% [15/67]; nabumetone, 25.4% [17/67]), or discontinuations due to any adverse events (SAMe, 13.4% [9/67]; nabumetone, 10.4% [7/67]). CONCLUSION: This study found no significant differences in pain relief or tolerability between treatment with SAMe or nabumetone over 8 weeks in Korean patients with knee OA.

Effect of a nonprotein bioactive agent on the reduction of cyclooxygenase-2 and tumor necrosis factor-alpha in human intervertebral disc cells in vitro.

OBJECT: Neurotropin is a nonprotein extract from the inflamed skin of rabbits inoculated with vaccinia virus. In the present study the authors sought to clarify the focal antiinflammatory effects of Neurotropin in intervertebral disc cells, and these effects were compared with those induced by the selective cyclooxygenase (COX)-2 inhibitor 6-methoxy-2-naphthylacetic acid (nabumetone). METHODS: Six human intervertebral disc specimens were harvested during spinal surgery for lumbar disc herniation. Cells were stimulated with 500 pg/ml of interleukin (IL)-1beta in the presence of various concentrations of Neurotropin (0, 10(-5), 10(-4), and 10(-3) Neurotropin Units/ml) or 50 microg/ml of nabumetone for 3 hours. The mRNA was extracted for polymerase chain reaction (PCR), and real-time PCR was used to quantify the mRNA levels of COX- 2, tumor necrosis factor (TNF)-alpha, and phospholipase A2. Cyclooxygenase-2, TNFalpha, and prostaglandin E2 (PGE2) protein concentrations were each determined by enzyme-linked immunosorbent assay. RESULTS: Neurotropin was found to significantly suppress the expression of COX-2 and TNFalpha at mRNA levels as well as the concentration of COX-2 at protein levels in a dose-dependent manner. Nabumetone was found to significantly increase COX-2 at mRNA levels but directly suppress the concentration of PGE2 in culture medium. CONCLUSIONS: Results in this study suggest that Neurotropin has an analgesic effect through the suppression of COX-2 and TNFalpha in a focal area, and nabumetone shows this same effect through the suppression of PGE2 production. Thus, Neurotropin could decrease pain by blocking the central pain pathway or increasing focal antiinflammatory effects.

Solubilisation of drugs in micellar solutions of diblock copolymers of ethylene oxide and styrene oxide.

The solubilisation of two poorly soluble drugs, furosemide and nabumetone, in micellar solutions of diblock copolymers of ethylene oxide and styrene oxide has been studied at 25 and 37 degrees C and solubilisation capacities compared with published values for griseofulvin and docetaxel. Solubilisation in the micelle core, corrected for the different proportions of poly(styrene oxide) in the copolymers, was similar for all four drugs. The highest solubilisation capacities were found for a copolymer with worm-like micelles.

Effect of polymer molecular weight on the production of drug nanoparticles.

Stable, polymer-coated nanoparticles of two hydrophobic drugs, namely nabumetone and halofantrine, have been prepared by a wet-bead milling process performed in the presence of a stabilizing homopolymer, either hydroxypropylmethylcellulose (HPMC) or polyvinylpyrrolidone (PVP), of differing molecular weights and concentrations. Although nabumetone nanoparticles could only be produced when HPMC was used as stabilizing polymer, halofantrine nanoparticles could be prepared using either HPMC or PVP. Stable nanoparticles of nabumetone could be produced using a HPMC solution of viscosity average molecular weight, M(v), of 5 kg/mol over an approximate four fold polymer concentration range (0.63-2.5% w/w) when a drug loading of 20% w/w was used. Increasing the molecular weight of HPMC up to a limiting M(v) of 89 kg/mol did not result in the formation of nanoparticles at any of the polymer concentrations examined. The amount of polymer absorbed onto the nanoparticles was determined by measuring the depletion of polymer from solution based on either an ultra-violet (PVP) or optical rotatory dispersion (ORD) (HPMC) assay. The slightly lower concentration of HMPC found to be present on the surface of the halofantrine nanoparticles compared with the nabumetone nanoparticles suggested a differing affinity of the polymer for the surface of the two drugs.

Comparison of different stationary phases for bioanalytical studies of biologically active compounds.

In this study, the chromatographic behaviour of four mixtures of compounds was tested on columns possessing various surface properties. Cocaine, dimefluron, nabumetone, and tramadol were chosen as the test compounds. Cocaine is a tropane alkaloid, which is relatively often abused as a drug. This is why many papers have already been written about its determination in human biological samples. Dimefluron, a derivative of benzo[c]fluorene, is a new perspective drug being investigated for its potential antineoplastic effects. Nabumetone is a non-steroidal anti-inflammatory prodrug used for treatment of inflammatory and degenerative rheumatic diseases. Tramadol, derived from an opioid structure is used as an anodyne for treatment of severe pain. As a medicament it is usually determined either in biological samples or in pharmaceuticals. The above-mentioned model drugs were separated using chromatographic columns with C18, C8, palmitamidopropyl, and pentafluorophenylpropyl chains. The best conditions for separation of the individual compounds and their metabolites were chosen on the basis of resolution, retention times, and peak symmetry.

Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease.

BACKGROUND & AIMS: It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS: First, patients with quiescent Crohn's disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS: Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS: NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.

Cyclo-oxygenase 2 inhibitor, nabumetone, inhibits proliferation in chronic myeloid leukemia cell lines.

The anti-tumor effect of cyclo-oxygenase (COX) inhibitors has been documented in several studies. COX2 inhibitors have attracted more attention because of the fewer side-effects and the more prominent anti-tumor effects. However, experience with these drugs in hematological malignancies is limited. In our study, a potent COX2 inhibitor, nabumetone (NBT), was investigated for its anti-proliferative and apoptotic effects in K-562 and Meg-01 chronic myeloid leukemia blastic cell lines as a single agent or in combination with adriamycin (ADR) and interferon alpha (IFN-a). In these cell lines, a dose-dependent inhibition of proliferation was observed with NBT. We observed no significant apoptotic effect of NBT. However, NBT potentiated the apoptotic effect of ADR in the K-562 cell line. Bcl-2 expression was reduced by NBT (11% vs. 2%). The combination of NBT with IFN did not have any significant effect on the K-562 cell line. We suggest that NBT inhibits proliferation and potentiates the apoptotic effect of ADR in chronic myeloid leukemia cell lines.

The nonsteroidal anti-inflammatory drug, nabumetone, differentially inhibits beta-catenin signaling in the MIN mouse and azoxymethane-treated rat models of colon carcinogenesis.

The mechanisms through which beta-catenin signaling is inhibited during colorectal cancer chemoprevention by nonsteroidal anti-inflammatory agents is incompletely understood. We report that nabumetone decreased uninvolved intestinal mucosal beta-catenin levels in the MIN mouse with a concomitant increase in glycogen synthase kinase (GSK)-3beta levels, an enzyme that targets beta-catenin for destruction. However, in the azoxymethane-treated rat, where beta-catenin is frequently rendered GSK-3beta-insensitive, nabumetone failed to alter beta-catenin levels but did decrease beta-catenin nuclear localization and transcriptional activity as gauged by cyclin D1. In conclusion, we demonstrate that the differential mechanisms for beta-catenin suppression may be determined, at least partly, by GSK-3beta.

Regulation of metalloproteinases and NF-kappaB activation in rabbit synovial fibroblasts via E prostaglandins and Erk: contrasting effects of nabumetone and 6MNA.

1 Nabumetone is a prodrug that is converted in vivo into 6-methoxy-2-naphthylacetic acid (6MNA), a cyclooxygenase inhibitor with anti-inflammatory properties. We tested the effects of nabumetone and 6MNA on the inflammatory responses of synovial fibroblasts (SFs). 2 Brief exposures to 6MNA (50-150 microm) had no effect on IL-1beta/TNF-alpha (each 20 ng ml(-1))-stimulated Erk activation. Longer exposures depleted prostaglandin E1 (PGE1) as much as 70%, and stimulated Erk as much as 300%. Nabumetone (150 microm) inhibited Erk activation by 60-80%. 6MNA (50-150 microm) stimulated (approximately 200%) and nabumetone (150 microm) inhibited (approximately 50%) matrix metalloproteinase (MMP)-1, but not MMP-13 secretion from SFs. 3 6MNA stimulation of MMP-1 secretion was inhibited approximately 30% by PGE1 (1 microm) and approximately 80% by the Erk pathway inhibitor UO126 (10 microm), confirming that PGE depletion and Erk activation mediate MMP-1 secretion by 6MNA. 4 Consistent with its role as an Erk inhibitor, nabumetone (150 microm) abrogated 6MNA enhancement of MMP-1 secretion. 5 UO126 (10 microm) and nabumetone (150 microm) inhibited (approximately 70 and 40%, respectively), but 6MNA (150 microm) enhanced (approximately 40%), NF-kappaB activation. 6 Our data indicate that 6MNA shares with other COX inhibitors several proinflammatory effects on synovial fibroblasts. In contrast, nabumetone demonstrates anti-inflammatory and potentially arthroprotective effects that have not been previously appreciated.

Risk factors of adverse drug reaction from non-steroidal anti-inflammatory drugs in Shanghai patients with arthropathy.

AIM: The study was to screen the possible risk factors of adverse drug reaction (ADR) induced by non-steroidal anti-inflammatory drugs (NSAIDs) in Shanghai patients with arthropathy. METHODS: The subjects were randomly selected from a database of outpatients with arthropathy from 9 main hospitals in Shanghai. A door to door retrospective epidemiological survey was used to collect demographic information about the patients, both individual and familial. This included data on their medical histories, lifestyle and dietary habits, history of smoking and alcohol consumption, history of drug therapy, quality of life (QOL) prior to NSAIDs intake, history of NSAIDs therapy and its ADR events, etc. Descriptive statistical methods and univariate analysis were also used to identify possible risk factors for ADRs induced by NSAIDs. RESULTS: Of the 1002 patients surveyed, the average length of NSAIDs intake was 2 years. ADR incidence from different NSAIDs was high, in a range from 46.7 %-66.2 %. In general, the candidate risk factors for ADRs were different for each NSAID. Each of the candidate risk factors were defined and studied in order to evaluate its role in the determination of ADRs from NSAIDs. "Family history of ADRs caused by NSAIDs" was found to be a significant risk factor for the four commonly used NSAIDs: meloxicam, diclofenac, nimesulide, and nabumetone. CONCLUSION: A retrospective epidemiological survey was useful in detecting the risk factors for ADRs caused by NSAIDs. The study found that different NSAIDs might have different risk factors and that there is no single risk factor universally applicable to all NSAIDs.