ascorbic-acid and rofecoxib

Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Ascorbic Acid; Celecoxib; Chemoprevention; Clinical Trials as Topic; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2 Inhibitors; Drug Therapy, Combination; Eflornithine; Humans; Lactones; Pyrazoles; Sulfonamides; Sulfones; Sulindac; Vitamins

Reflux-induced injury and oxidative stress result in esophageal inflammation and the potential for progression to intestinal metaplasia and adenocarcinoma. Proton-pump inhibitors represent the standard medical approach, but anti-inflammatories and antioxidants offer novel therapeutic possibilities.. Six weeks after an esophagojejunostomy reflux procedure, female Wistar rats (n = 100) were randomized to receive either an antioxidant (vitamin C, 8 mg or 28 mg/day), a cyclooxygenase-2 (COX-2) inhibitor (rofecoxib, 1 mg/day), or no therapy. After sacrifice 16 weeks later, esophageal injury was scored using pathologic and image analysis scoring.. Esophagitis was present in all 63 animals completing the study and was severe in 27 (43%). No animal developed metaplasia or tumor. The extent of inflammation and esophageal ulceration were not significantly different between experimental groups.. In this model of reflux injury, antioxidants and COX-2 inhibitors failed to ameliorate the severe inflammation induced. Further experimental designs should evaluate these novel approaches in less severe experimental models.

Topics: Animals; Antioxidants; Ascorbic Acid; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Esophagitis, Peptic; Esophagus; Female; Jejunum; Lactones; Random Allocation; Rats; Rats, Wistar; Sulfones

Reflux-induced injury and oxidative stress result in esophageal inflammation and the potential for progression to intestinal metaplasia and adenocarcinoma. Proton-pump inhibitors represent the standard medical approach, but anti-inflammatories and antioxidants offer novel therapeutic possibilities.. Six weeks after an esophagojejunostomy reflux procedure, female Wistar rats (n = 100) were randomized to receive either an antioxidant (vitamin C, 8 mg or 28 mg/day), a cyclooxygenase-2 (COX-2) inhibitor (rofecoxib, 1 mg/day), or no therapy. After sacrifice 16 weeks later, esophageal injury was scored using pathologic and image analysis scoring.. Esophagitis was present in all 63 animals completing the study and severe in 27 (43%). No animal developed metaplasia or tumor. The extent of inflammation and esophageal ulceration were not significantly different between experimental groups.. In this model of reflux injury, antioxidants and COX-2 inhibitors failed to ameliorate the severe inflammation induced. Further experimental designs should evaluate these novel approaches in less severe experimental models.

Topics: Animals; Antioxidants; Ascorbic Acid; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Esophagitis, Peptic; Esophagus; Female; Inflammation; Jejunum; Lactones; Models, Animal; Random Allocation; Rats; Rats, Wistar; Sulfones; Ulcer

Chronic stress precipitates many neuropsychiatric disorders and alters the various oxidative stress parameters in brain. Cyclooxygenase (COX) is reported to play an important role in pathogenesis of various neurodegenerative disorders including stroke and seizures. In the present study, we examined the effect of naproxen (non-selective COX-inhibitor having much potency towards COX-I isoform) or rofecoxib (a selective COX-2 inhibitor) in subchronic immobilization stress. Mice were subjected to immobilized stress for 6 h daily for a period of seven days. Naproxen (7 mg/kg, i.p.) or rofecoxib (2 mg/kg, i.p.) was administered daily for 7 days before challenging them to immobilization stress. Behavioral analysis revealed the hyperlocomotor activity and increased anxiety response. Subchronic stress decreased percent retention of memory and also caused hyperalgesia in mice. Biochemical analysis revealed that chronic immobilization stress significantly increased lipid peroxidation and nitrite levels and decreased the reduced glutathione and adrenal ascorbic acid levels. Chronic treatment with naproxen or rofecoxib significantly attenuated the immobilization stress-induced behavioral and biochemical alterations. These results suggested that the use of COX-inhibitors (naproxen or rofecoxib) could be a useful neuroprotective strategy in the treatment of stress.

Topics: Adrenal Glands; Analysis of Variance; Animals; Anxiety; Ascorbic Acid; Behavior, Animal; Biomarkers; Brain; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Administration Schedule; Glutathione; Hot Temperature; Hyperalgesia; Injections, Intraperitoneal; Lactones; Lipid Peroxidation; Male; Maze Learning; Mice; Motor Activity; Naproxen; Nitrites; Protective Agents; Restraint, Physical; Stress, Psychological; Sulfones