Refined high-content imaging-based phenotypic drug screening in zebrafish xenografts.

Zebrafish xenotransplantation models are increasingly applied for phenotypic drug screening to identify small compounds for precision oncology. Larval zebrafish xenografts offer the opportunity to perform drug screens at high-throughput in a complex in vivo environment. However, the full potential of the larval zebrafish xenograft model has not yet been realized and several steps of the drug screening workflow still await automation to increase throughput. Here, we present a robust workflow for drug screening in zebrafish xenografts using high-content imaging. We established embedding methods for high-content imaging of xenografts in 96-well format over consecutive days. In addition, we provide strategies for automated imaging and analysis of zebrafish xenografts including automated tumor cell detection and tumor size analysis over time. We also compared commonly used injection sites and cell labeling dyes and show specific site requirements for tumor cells from different entities. We demonstrate that our setup allows us to investigate proliferation and response to small compounds in several zebrafish xenografts ranging from pediatric sarcomas and neuroblastoma to glioblastoma and leukemia. This fast and cost-efficient assay enables the quantification of anti-tumor efficacy of small compounds in large cohorts of a vertebrate model system in vivo. Our assay may aid in prioritizing compounds or compound combinations for further preclinical and clinical investigations.

Dynamic real-time subtraction of stray-light and background for multiphoton imaging.

We introduce a new approach to reduce uncorrelated background signals from fluorescence imaging data, using real-time subtraction of background light. This approach takes advantage of the short fluorescence lifetime of most popular fluorescent activity reporters, and the low duty-cycle of ultrafast lasers. By synchronizing excitation and recording, laser-induced multiphoton fluorescence can be discriminated from background light levels with each laser pulse. We demonstrate the ability of our method to - in real-time - remove image artifacts that in a conventional imaging setup lead to clipping of the signal. In other words, our method enables imaging under conditions that in a conventional setup would yield corrupted data from which no accurate information can be extracted. This is advantageous in experimental setups requiring additional light sources for applications such as optogenetic stimulation.

Optimizing pulse compressibility in completely all-fibered Ytterbium chirped pulse amplifiers for in vivo two photon laser scanning microscopy.

A simple and completely all-fiber Yb chirped pulse amplifier that uses a dispersion matched fiber stretcher and a spliced-on hollow core photonic bandgap fiber compressor is applied in nonlinear optical microscopy. This stretching-compression approach improves compressibility and helps to maximize the fluorescence signal in two-photon laser scanning microscopy as compared with approaches that use standard single mode fibers as stretcher. We also show that in femtosecond all-fiber systems, compensation of higher order dispersion terms is relevant even for pulses with relatively narrow bandwidths for applications relying on nonlinear optical effects. The completely all-fiber system was applied to image green fluorescent beads, a stained lily-of-the-valley root and rat-tail tendon. We also demonstrated in vivo imaging in zebrafish larvae, where we simultaneously measure second harmonic and fluorescence from two-photon excited red-fluorescent protein. Since the pulses are compressed in a fiber, this source is especially suited for upgrading existing laser scanning (confocal) microscopes with multiphoton imaging capabilities in space restricted settings or for incorporation in endoscope-based microscopy.

Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the Notch pathway.

Human oncogenes involved in the development of hematological malignancies have been widely used to model experimental leukemia. However, models of myeloid leukemia rarely reproduce the human disease in full, due to genetic complexity or to difficulties in targeting leukemia initiating cells. Here, we used a zebrafish genetic model to induce the expression of oncogenic RAS in endothelial cells, including the hemogenic endothelium of the dorsal aorta that generates hematopoietic cells, and observed the development of a myelo-erythroid proliferative disorder. In larvae, the phenotype is characterized by disruption of the vascular system and prominent expansion of the caudal hematopoietic tissue. In few surviving juveniles, increased number of immature hematopoietic cells and arrest of myeloid maturation was found in kidney marrow. Peripheral blood showed increased erythroblasts and myeloid progenitors. We found that the abnormal phenotype is associated with a downregulation of the Notch pathway, whereas overexpressing an activated form of Notch together with the oncogene prevents the expansion of the myelo-erythroid compartment. This study identifies the downregulation of the Notch pathway following an oncogenic event in the hemogenic endothelium as an important step in the pathogenesis of myelo-erythroid disorders and describes a number of potential effectors of this transformation.

Meta-analysis of genome-wide association studies for personality.

Personality can be thought of as a set of characteristics that influence people's thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in 10 discovery samples (17,375 adults) and five in silico replication samples (3294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data of ≈ 2.4M single-nucleotide polymorphisms (SNPs; directly typed and imputed using HapMap data) were available. In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P=2.8 × 10(-8) and 3.1 × 10(-8)) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P=4.9 × 10(-8)). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.

Life events and borderline personality features: the influence of gene-environment interaction and gene-environment correlation.

BACKGROUND: Traumatic life events are generally more common in patients with borderline personality disorder (BPD) than in non-patients or patients with other personality disorders. This study investigates whether exposure to life events moderates the genetic architecture of BPD features. As the presence of genotype-environment correlation (rGE) can lead to spurious findings of genotype-environment interaction (G × E), we also test whether BPD features increase the likelihood of exposure to life events. METHOD: The extent to which an individual is at risk to develop BPD was assessed with the Personality Assessment Inventory - Borderline features scale (PAI-BOR). Life events under study were a divorce/break-up, traffic accident, violent assault, sexual assault, robbery and job loss. Data were available for 5083 twins and 1285 non-twin siblings. Gene-environment interaction and correlation were assessed by using structural equation modelling (SEM) and the co-twin control design. RESULTS: There was evidence for both gene-environment interaction and correlation. Additive genetic influences on BPD features interacted with the exposure to sexual assault, with genetic variance being lower in exposed individuals. In individuals who had experienced a divorce/break-up, violent assault, sexual assault or job loss, environmental variance for BPD features was higher, leading to a lower heritability of BPD features in exposed individuals. Gene-environment correlation was present for some life events. The genes that influence BPD features thus also increased the likelihood of being exposed to certain life events. CONCLUSIONS: To our knowledge, this study is the first to test the joint effect of genetic and environmental influences and the exposure to life events on BPD features in the general population. Our results indicate the importance of both genetic vulnerability and life events.

The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data.

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

Genome-wide association scan for five major dimensions of personality.

Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome-wide association (GWA) scan of 3972 individuals from a genetically isolated population within Sardinia, Italy. On the basis of the analyses of 362 129 single-nucleotide polymorphisms we found several strong signals within or near genes previously implicated in psychiatric disorders. They include the association of neuroticism with SNAP25 (rs362584, P=5 x 10(-5)), extraversion with BDNF and two cadherin genes (CDH13 and CDH23; Ps<5 x 10(-5)), openness with CNTNAP2 (rs10251794, P=3 x 10(-5)), agreeableness with CLOCK (rs6832769, P=9 x 10(-6)) and conscientiousness with DYRK1A (rs2835731, P=3 x 10(-5)). Effect sizes were small (less than 1% of variance), and most failed to replicate in the follow-up independent samples (N up to 3903), though the association between agreeableness and CLOCK was supported in two of three replication samples (overall P=2 x 10(-5)). We infer that a large number of loci may influence personality traits and disorders, requiring larger sample sizes for the GWA approach to confidently identify associated genetic variants.

Heritability of borderline personality disorder features is similar across three countries.

BACKGROUND: Most of our knowledge about borderline personality disorder features has been obtained through the study of clinical samples. Although these studies are important in their own right, they are limited in their ability to address certain important epidemiological and aetiological questions such as the degree to which there is a genetic influence on the manifestation of borderline personality disorder features. Though family history studies of borderline personality disorder indicate genetic influences, there have been very few twin studies and the degree of genetic influence on borderline personality disorder remains unclear. METHOD: Data were drawn from twin samples from The Netherlands (n=3918), Belgium (n=904) and Australia (n=674). In total, data were available on 5496 twins between the ages of 18 and 86 years from 3644 families who participated in the study by completion of a mailed self-report questionnaire on borderline personality disorder features. RESULTS: In all countries, females scored higher than males and there was a general tendency for younger adults to endorse more borderline personality disorder features than older adults. Model-fitting results showed that additive genetic influences explain 42% of the variation in borderline personality disorder features in both men and women and that this heritability estimate is similar across The Netherlands, Belgium and Australia. Unique environmental influences explain the remaining 58% of the variance. CONCLUSION: Genetic factors play a role in individual differences in borderline personality disorder features in Western society.

A double-blind, randomized, placebo-controlled study of efficacy and tolerance of meloxicam treatment in patients with osteoarthritis of the knee.

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID), with a favourable ratio of inhibition of cyclooxygenase-2 (COX-2)/cyclooxygenase-1 (COX-1), giving the drug the potential to produce few gastric adverse effects. The aim of this study was to investigate the efficacy and safety of meloxicam in patients with osteoarthritis (OA) of the knee. Five hundred and thirteen patients were treated in a double-blind trial comparing once-daily meloxicam 7.5 mg, 15mg, 30mg, or placebo (140, 134, 102 and 137 patients, respectively). Outcome measures included scores on Visual Analogue Scales (VAS) for pain on movement (primary endpoint) and pain at rest in the target joint as well as global efficacy. Lesquesne's index of severity and paracetamol consumption were also measured. Global tolerability and the occurrence of adverse events were monitored. Both meloxicam 7.5 mg and 15 mg were significantly more effective than placebo with respect to pain on movement (p < 0.01 and p < 0.03, respectively). Both doses of meloxicam compared favourably with placebo with respect to pain of the target joint at rest, although only the 15 mg dose achieved statistical significance (p < 0.02). Global efficacy showed a significant difference for both doses of meloxicam (p < 0.05 and p < 0.002 for 7.5 mg and 15 mg doses, respectively). Once daily meloxicam 7.5 and 15 mg is effective and well tolerated in the short term symptomatic treatment of OA of the knee.

Meloxicam clinical data on a preferential cyclooxygenase-2 inhibitor.

Concomitant inhibition of both cyclooxygenase (COX) isoforms, COX-1 and COX-2, has been used to explain the therapeutic efficacy and gastrointestinal (GI) toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatic diseases. While COX-2 is induced during inflammatory responses, constitutively expressed COX-1 is cytoprotective in the GI tract. Newer inhibitors such as meloxicam, which have been shown to inhibit COX-2 preferentially in vitro, are expected to retain their efficacy while exhibiting decrease toxicity. Clinical trials have been performed with meloxicam to evaluate these parameters. Controlled trials showed that meloxicam is significantly more effective than the placebo for the treatment of both rheumatoid arthritis and osteoarthritis. In comparative studies with piroxicam, naproxen, and diclofenac, meloxicam was approximately as effective as the other drugs. Analysis of the safety profile of meloxicam indicated that the risk of GI adverse events, especially PUBs (perforation, ulceration, and bleeding) is significantly reduced with meloxicam compared with that of comparators. These data confirm that preferential COX-2 inhibitors such as meloxicam provide a significant advantage over standard NSAIDs in the treatment of rheumatic diseases.

A double-blind, randomized trial to compare meloxicam 15 mg with diclofenac 100 mg in the treatment of osteoarthritis of the knee.

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID), which, in animal tests, displays a high potency for anti-inflammatory and analgesic action. The aim of this study was to investigate the efficacy and tolerability of 15 mg meloxicam in comparison with 100 mg slow-release diclofenac in patients with osteoarthritis of the knee. Two hundred and fifty-eight patients were included in the intent-to-treat analysis; these were randomized into two groups to receive either 15 mg meloxicam (N = 128) or 100 mg diclofenac (N = 130) for a period of 6 weeks. The results with respect to efficacy showed a trend in favor of meloxicam regarding pain on movement, global efficacy and paracetamol consumption, although these differences did not reach statistical significance. The most frequently-occurring adverse events in both groups were of a gastrointestinal (GI) nature. However, there was a higher incidence (26 vs 16%) of GI adverse events in the diclofenac group compared with the meloxicam group. Both drugs were well tolerated when assessed by the patients on a visual analog scale (VAS). Thus, 15 mg meloxicam is an effective and well-tolerated therapy for osteoarthritis and compares favorably with diclofenac 100 mg, a well-established treatment for this indication.

Efficacy and safety of meloxicam in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and safety of meloxicam, a new acidic enolic nonsteroidal anti-inflammatory drug, at doses of 7.5 and 15 mg once daily in patients with rheumatoid arthritis (RA). METHODS: Meloxicam 15 and 7.5 mg daily was administered for 21 days in this double blind, randomized, placebo controlled study. 159 patients received meloxicam 7.5 mg, 162 received meloxicam 15 mg, and 147 received placebo. RESULTS: Meloxicam 15 mg once daily was significantly superior (p < 0.05) to placebo in 3 of the 4 primary endpoints (disease activity assessed by the investigator, disease activity assessed by the patient, and reduction of the number of tender/painful joints). No difference was observed regarding number of swollen joints. The difference between meloxicam 7.5 mg once daily and placebo reached statistical significance in 2 of the 4 primary endpoints, disease activity assessed by the patient and number of tender/painful joints. A statistically significant difference between meloxicam 1.5 mg and 7.5 mg was not observed for any primary endpoint. The rating of global tolerance by investigators and patients at the end of the study was similar in the 3 treatment groups, indicating that meloxicam and placebo were generally similarly well tolerated. However, there was a slightly higher incidence of gastrointestinal (GI) disturbances reported by patients receiving meloxicam 15 mg. GI adverse events were reported by 11, 11, and 16% of patients in the placebo, meloxicam 7.5 mg, and meloxicam 15 mg groups, respectively. None were serious. CONCLUSION: Meloxicam in daily doses of 7.5 and 15 mg is effective in treating the signs and symptoms of RA.

Development of an underwater weighing system for determining body composition.

A system was developed to reduce some of the difficulties associated with hydrostatic (underwater) weighing, specifically the need for complete exhalation and the subjective approximation of weighing scale measurements. The exhalation portion of the weighing protocol is particularly difficult for many disabled individuals and has contributed to the lack of available body composition information for this population. The components of our system include a computer system, load cell, spirometer, breathing tube, logic and signal conditioning circuitry specially constructed for this system, and a software package developed for this project. In a preliminary test, the body fat percentages of fourteen subjects (six males and eight females, ages 21-32 years) were determined both with the standard method and with our system. A correlation of r = 0.967 was found between the two methods, with our system's precision ranging from 1.0 to 1.3 body fat percentage points. The system could be used, for example, in developing a database for monitoring an individual's fitness or for making comparisons between groups (such as athlete to non-athlete).

Evaluation of the safety, tolerability, and efficacy of meloxicam tablets in patients with osteoarthritis.

This 12-week, open-label, multicenter study assessed the safety, tolerability, and efficacy of the tablet formulation of meloxicam 15 mg, a new, nonsteroidal antiinflammatory drug (NSAID), in patients with confirmed osteoarthritis (OA) of the hip or knee. Meloxicam differs from established NSAIDs in its preferential activity against cyclooxygenase type 2 compared with cyclooxygenase type 1. One hundred thirty-nine patients were given meloxicam tablets 15 mg once daily. Data were analyzed using an intent-to-treat analysis. Assessments of global tolerability at the end of the study showed meloxicam tablets to be well or very well tolerated by 83% of patients, with only 4% rating the tablets poorly. This finding was supported by the low incidence of adverse events. Only 11% of patients discontinued therapy due to gastrointestinal adverse events, and no serious gastrointestinal adverse events related to meloxicam 15-mg tablets occurred during treatment. Efficacy results showed significant improvement from baseline, with 41% of patients experiencing mild or no pain by the end of the study. In conclusion, the tablet formulation of meloxicam 15 mg is well tolerated and effective in patients with moderate-to-severe, clinical confirmed OA of the hip or knee.

A double-blind, three-week study to compare the efficacy and safety of meloxicam 7.5 mg and meloxicam 15 mg in patients with rheumatoid arthritis.

A multicentre, double-blind, randomized study was conducted in patients with rheumatoid arthritis (RA) in order to compare the efficacy and safety of two different doses of meloxicam, a new preferential cyclooxygenase-2 (COX-2) inhibitor. Four hundred and twenty-three patients were randomized to receive once-daily oral meloxicam 7.5 mg (n = 216) or meloxicam 15 mg (n = 207) for 3 weeks. The Ritchie joint index and pain in the morning were significantly improved versus baseline (P < 0.001) in both groups. There were no significant differences between the effects of each dose with respect to these measures nor with respect to final assessment of global efficacy by the patients. However, the 15 mg dose was associated with a significantly (P < 0.05) better effect on morning stiffness and grip strength. No differences between the doses were observed with regard to the other secondary efficacy parameter (pain at night, body weight and erythrocyte sedimentation rate). Both doses of meloxicam were well tolerated. There were no differences between the doses with respect to global tolerance as assessed by the patient and the patients, 'general condition'. In conclusion, meloxicam at a once-daily dose of either 7.5 or 15 mg is well tolerated and effective in the treatment of patients with RA.

A double-blind study to compare the efficacy and safety of meloxicam 15 mg with piroxicam 20 mg in patients with osteoarthritis of the hip.

Meloxicam 15 mg once daily (n = 128) was compared with piroxicam 20 mg (n = 127) in this 6 week, double-blind, parallel-group, randomized, multicentre study in out-patients with symptomatic osteoarthritis (OA) of the hip. Assessments of pain, global efficacy and global tolerance were made on a 10 cm horizontal visual analogue scale; severity of OA was evaluated by Lequesne's index. Efficacy results showed significant improvement compared with baseline, with no significant difference between meloxicam 15 mg and piroxicam 20 mg. The type and frequency of adverse events were comparable for the two drugs. The most frequent events reported were gastrointestinal (GI) disorders, occurring in 21 and 23% of meloxicam and piroxicam patients respectively. The global tolerance assessment by patients at the end of treatment favoured meloxicam. In conclusion, meloxicam at a dose of 15 mg/day is comparable in efficacy and safety to piroxicam 20 mg.

A six-month double-blind trial to compare the efficacy and safety of meloxicam 7.5 mg daily and naproxen 750 mg daily in patients with rheumatoid arthritis.

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID) which preferentially inhibits cyclooxygenase-2 over cyclooxygenase-1. A double-blind parallel-group trial compared meloxicam 7.5 mg once daily (n = 199) with naproxen 750 mg (n = 180) in rheumatoid arthritis. There was no significant difference between the groups regarding the primary efficacy variables (global efficacy assessment by patient and investigator, number of painful/tender and swollen joints) and eight of the ten secondary efficacy endpoints. Only the swollen joint severity index and the number of discontinuations due to lack of efficacy favoured naproxen 750 mg significantly over meloxicam 7.5 mg. Meloxicam was better tolerated in the gastrointestinal (GI) tract, with fewer GI adverse events in the meloxicam-treated group (30.3%) than in the naproxen-treated group (44.7%), where two patients developed ulcers. No ulcers were seen in meloxicam patients. Significantly more patients discontinued due to GI adverse events in the naproxen group. Additionally, there was a significant decrease in haemoglobin and a significant increase in serum creatinine and urea in the naproxen group compared with the meloxicam group. In conclusion, meloxicam 7.5 mg once daily is a promising treatment in rheumatoid arthritis, with efficacy comparable to naproxen 750 mg. Meloxicam has the advantage of a significantly lower incidence of GI and renal side effects.

Meloxicam in osteoarthritis: a 6-month, double-blind comparison with diclofenac sodium.

A multicentre, double-blind, randomized study was conducted in patients with osteoarthritis (OA) of the hip or knee in order to compare the efficacy and safety of the new cyclooxygenase-2 (COX-2) inhibitor, meloxicam, with diclofenac sodium, a conventional treatment for this condition. Three hundred and thirty-six patients were treated with oral meloxicam 7.5 mg once daily or diclofenac 100 mg slow release once daily for 6 months. There were no significant differences between the treatment groups with respect to overall pain, pain on movement, global efficacy or quality of life scores at the end of treatment, all of which showed good levels of improvement. Sixty-six patients were withdrawn after the start of the double-blind phase due to adverse events (n = 21, meloxicam; n = 31, diclofenac) or to lack of efficacy (seven in each group). The median of dose paracetamol taken concomitantly was statistically significantly lower in the meloxicam group than in the diclofenac group (185 vs 245 mg/day; P = 0.0123) with a comparable proportion of patients taking concomitant paracetamol therapy in both groups. Both drugs were well tolerated, although severe adverse events, treatment withdrawal and clinically significant laboratory abnormalities were more common with diclofenac than with meloxicam. Thus, meloxicam 7.5 mg is a safe and effective treatment for OA of the hip and knee which demonstrates a trend towards an improved safety profile compared with diclofenac.

Safety of meloxicam: a global analysis of clinical trials.

Meloxicam is a new preferential cyclooxygenase-2 (COX-2) inhibitor for the treatment of rheumatic disease. This paper presents a global safety analysis of data from meloxicam clinical studies, focusing on gastrointestinal (GI) adverse events. Meloxicam 7.5 and 15 mg (n = 893 and 3282) were compared with piroxicam 20 mg (n = 906), diclofenac 100 mg slow release (n = 324) and naproxen 750-1000 mg (n = 243). With respect to all GI adverse events, meloxicam 7.5 and 15 mg were significantly better than all comparators in a pooled analysis of double-blind studies in rheumatoid arthritis (RA) and osteoarthritis (OA). When examining non-serious GI events, severe GI events, discontinuous due to GI events, dyspepsia, abdominal pain and upper GI events, both meloxicam doses were significantly better than comparator non-steroidal anti-inflammatory drugs (NSAIDs) in most cases. Where statistical significance was not demonstrated, there was generally a trend in favour of meloxicam. With respect to upper GI perforations, ulcerations and bleedings, the most serious of NSAID-associated side-effects, meloxicam was better tolerated than the comparators, reaching statistical significance for piroxicam and naproxen. Meloxicam's improved GI safety profile is likely to be due to its preferential inhibition of inducible COX-2 relative to constitutive COX-1.