However, the increased cardiovascular risk with celecoxib was observed only at doses ≥400 mg/day. The second analysis, which included observational rather than randomized studies, did not find an increased risk of cardiovascular

events with celecoxib at doses commonly used in clinical practice (approximately 200 mg/day) (48). A more recent network meta-analysis indicated that celecoxib is associated with an increased risk of myocardial infarction and of cardiovascular death compared with placebo; however, the low event rates in the included trials meant that the estimates of rate ratios were imprecise, with wide credibility intervals, and statistical Inhibitors,research,lifescience,medical significance was not reached (49). A large study involving 20,000 Inhibitors,research,lifescience,medical Tubacin cost patients with arthritis, either with or at risk of developing cardiovascular disease, is attempting to establish the true risk: benefit

profile of celecoxib compared with traditional NSAIDs [Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION); NCT00346216] (50). Recently, celecoxib has been withdrawn from use in familial adenomatous polyposis, in the USA and European markets, due to inadequate enrollment in follow-up clinical trials and concerns that any long-term benefits of treatment had not been shown to outweigh the increased risk of cardiovascular and GI side effects (33). Any further trials Inhibitors,research,lifescience,medical in this setting should therefore include careful follow-up of all patients, particularly if the 400 mg bid regimen is utilized, and interim toxicity and safety analyses should be integrated

into the study design. The combination of gefitinib and celecoxib used in this study was generally well tolerated. Inhibitors,research,lifescience,medical The most frequent AEs attributed to gefitinib were mild to moderate acne and diarrhea, while for celecoxib they were abdominal/upper abdominal pain, nausea, stomatitis, and diarrhea. These AEs were typical of each drug in terms of nature, incidence, and severity. Although only limited activity was reported in this study, Inhibitors,research,lifescience,medical there have been other previous studies that have investigated the use of gefitinib in GI tumors. The combination of gefitinib (250 mg/day) and celecoxib (400 mg bid) has been SB203580 p38 MAPK inhibitor evaluated in 15 chemonaïve patients with squamous-cell carcinoma (n=3) or adenocarcinoma (n=12) of the esophagus (51). Of the 14 patients who were evaluable for efficacy after Anacetrapib two months, three patients (21%) had stable disease and remained in follow-up after a mean of 5.5 months (one patient had been lost to follow-up). Gefitinib monotherapy (500 mg/day) has been evaluated in two phase II trials in patients with advanced esophageal cancer, with promising results. Response rates of 3% and 11% were reported, along with disease control rates of 31% and 37% (52,53). In both of these studies, the most common drug-related AEs were diarrhea [58% (52) and 59% (53)] and rash [47% (52) and 52% (53)]. Twenty-five (83%) of the 30 patients enrolled in the current study had colorectal cancer.