A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective chemopreventive agents for colorectal neoplasia. Polymorphisms in NSAID targets or metabolizing enzymes may affect NSAID efficacy or toxicity. We conducted a literature review to summarize current evidence of gene-drug interactions between NSAID use and polymorphisms in COX1, COX2, ODC, UGT1A6 and CYP2C9 on risk of colorectal neoplasia by searching OVID and PubMed. Of 134 relevant search results, thirteen investigated an interaction. One study reported a significant interaction between NSAID use and the COX1 Pro17Leu polymorphism (P=0.03) whereby the risk reduction associated with NSAID use among homozygous wild-type genotypes was not observed among NSAID users with variant alleles. Recent pharmacodynamic data support the potential for gene-drug interactions for COX1 Pro17Leu. Statistically significant interactions have also been reported for ODC (315G>A), UGT1A6 (Thr181Ala+Arg184Ser or Arg184Ser alone), and CYP2C9 (*2/*3). No statistically significant interactions have been reported for polymorphisms in COX2; however, an interaction with COX2 -765G>C approached significance (P=0.07) in one study. Among seven remaining studies, reported interactions were not statistically significant for COX1, COX2 and ODC gene polymorphisms. Most studies were of limited sample size. Definitions of NSAID use differed substantially between studies. The literature on NSAID-gene interactions to date is limited. Reliable detection of gene-NSAID interactions will require greater sample sizes, consistent definitions of NSAID use and evaluation of clinical trial subjects of chemoprevention studies

Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia

Abstract: Chronic inflammation is one of the main features of cancer cachexia. Experimental and clinical studies showed that cyclooxygenase-2 inhibitors, such as celecoxib, may be beneficial in counteracting major symptoms of this devastating syndrome. We carried out a prospective phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib (300 mg/day for 4 months) on key variables of cachexia (lean body mass, resting energy expenditure, serum levels of proinflammatory cytokines, and fatigue) in patients with advanced cancer at different sites. A sample of 24 patients was enrolled from January to December 2008 and all were deemed assessable. A significant increase of lean body mass and a significant decrease of TNF-alpha were observed. Moreover, an improvement of grip strength, quality of life, performance status, and Glasgow prognostic score was shown. There were no grade 3/4 toxicities. Patient compliance was very good; no patient had to reduce the celecoxib dosage nor interrupt treatment. Our results showed that the COX-2 selective inhibitor celecoxib is an effective single agent for the treatment of cancer cachexia. Although the treatment of cancer cachexia, a multifactorial syndrome, is more likely to yield success with a multitargeted approach; in the present study, we were able to show that a treatment, such as celecoxib, addressing a single target, albeit very important as chronic inflammation, could have positive effects. Therefore, phase III clinical trials are warranted to test the efficacy and safety of celecoxib

The effect of orbital decompression surgery on refraction and intraocular pressure in patients with thyroid orbitopathy

Purpose: To investigate the effect of orbital decompression surgery in thyroid orbitopathy (TO) on both refractive status and intraocular pressure (IOP). Patients and methods: A prospective, multicentre, consecutive audit of patients undergoing thyroid decompression surgery. Indications for surgery included cosmetically unacceptable proptosis or corneal exposure. Exclusion criteria included the following: previous orbital surgery, glaucoma, corneal disease, steroid use in the preceding 12 months, or an acute optic neuropathy. Automated refraction, keratometry, pachymetry, Hertel exophthalmometry, and IOP were recorded at 1 month pre- and 3 months postoperatively. IOP using the Tono-Pen (mean of three readings) was measured in the primary, upgaze, and downgaze positions. Results: Data were collected from 52 orbits of 33 patients (East Grinstead, New York, and Adelaide). There was no significant difference between pre- and postoperative data for sphere, cylinder, or central corneal thickness (CCT). The mean spherical equivalent was −0.43±1.49 D pre-operatively and −0.28±1.52 D postoperatively. The steepest meridian of corneal curvature was 93.1 degrees pre- and 94.2 degrees postoperatively, with no significant difference. Mean IOP significantly decreased when measuring by Goldmann applanation tonometry (GAT) (2.28 mm Hg, * P=0.001) and Tono-Pen (3.06 mm Hg, * P=<0.0001). IOP measured in upgaze was significantly greater than that in the primary position. Regression analysis between change in IOP and either Hertel exophthalmometry or the number of orbital walls decompressed was non-significant (*Student's t-test). Conclusion: Patients with TO undergoing orbital decompression had, on average, with-the-rule astigmatism not affected by orbital decompression surgery. IOP was significantly reduced by decompression surgery although no relationship between IOP and the degree of decompression was observed.JH Norris, JJ Ross, M Kazim, D Selva, and R Malhotr