sulindac and Inflammatory-Bowel-Diseases

To reduce the morbidity and mortality from colorectal cancer (CRC), current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients at risk for CRC. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with a sporadic or genetic risk of CRC. It will also discuss therapeutic end points under evaluation in current efforts to develop drugs for treating CRC risk factors.

Topics: Adenomatous Polyposis Coli; Antineoplastic Agents; Chemoprevention; Clinical Trials as Topic; Colonoscopy; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Eflornithine; Genetic Predisposition to Disease; Humans; Inflammatory Bowel Diseases; Neoplasm Recurrence, Local; Sulindac

OSI Pharmaceuticals is developing OSI-461, a potent analog of exisulind, for the potential treatment of cancer and inflammatory bowel disease. In August 2001, OSI-461 entered phase II trials involving patients with chronic lymphocytic leukemia. In July 2002, the company embarked on a pilot phase II study evaluating OSI-461 for the treatment of Crohn's disease. By October 2002, Cell Pathways had selected hormone-refractory prostate cancer as the lead cancer indication for clinical development of OSI-461.

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drugs, Investigational; Humans; Inflammatory Bowel Diseases; Neoplasms; Phosphodiesterase Inhibitors; Sulindac

Discovery of an isoform of Cyclo-oxygenase (COX) 1, the inducible COX-2, has made it possible to avoid some side effects of non-specific COX inhibitors. The COX-2 gene is over-expressed in reflux oesophagitis, Barrett's oesophagus, gastric and colon cancer, familial adenomatous polyposis, pancreatic cancer, hepatocellular carcinoma, hepatotoxicity, cirrhosis, and inflammatory bowel disease, and specific COX-2 inhibitors have been tried experimentally and clinically and found effective.. A Medline search was performed of English-language experimental studies and controlled clinical trials from January 1980 to January 2002, and relevant citations were noted.. Review of available literature shows that sulindac and COX-2 inhibitors are effective in preventing as well as regressing familial adenomatous polyposis. However, they have not been shown to prevent cancer in these patients. Studies evaluating NSAIDs and COX-2 inhibitors in carcinogen-induced and genetically manipulated animal models of various cancers have been promising especially in conditions such as Barrett's oesophagus, oesophageal and hepatocellular carcinoma and pancreatic cancer. COX-2 inhibitors may be of value in the treatment of reflux oesophagitis, pancreatitis and hepatitis, although carefully planned randomized controlled clinical trials demonstrating their efficacy need to be conducted. At present NSAIDs and COX-2 inhibitors cannot be recommended for average-risk individuals or for those with sporadic colorectal neoplasia (or other forms of cancers) as chemo-preventive agents.. COX-2 inhibitors may open up a new therapeutic era in which these drugs can be used for chemo-prophylaxis. However, COX-2 selective inhibitors retain renal adverse effects of the non-selective inhibitors and the concern regarding the pro-thrombotic potential of COX-2 inhibitors will limit their value as chemo-preventive agents.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Barrett Esophagus; Clinical Trials as Topic; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Gastrointestinal Neoplasms; Humans; Inflammatory Bowel Diseases; Isoenzymes; Kidney Diseases; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Sulindac

The aim of this study was to investigate the potential of prodrugs of some non-steroidal anti-inflammatory drugs (NSAIDs) as colon targeted delivery systems for treatment of inflammatory bowel diseases. Naproxen, sulindac and flurbiprofen (Fbp) were used. The carboxylic group of those drugs was conjugated onto the amino group of l-aspartic acid or the hydroxyl group of alpha- or beta-cyclodextrin (CyD). Prodrugs hydrolysis in buffers of pH range 1.2-7.2 and in rat gastrointestinal tract homogenates and the effect of oral pretreatment of rats with clindamycin on the hydrolysis of the prodrugs was examined. Additionally, the effect of oral administration of Fbp-beta-CyD prodrug on the experimentally induced colitis in rats was evaluated. The in vivo inflammatory response was assessed macroscopically, histologically and by measurement of reduced glutathione (GSH) levels in colon tissues. No significant hydrolysis of the proposed seven prodrugs in buffers having pH range of 1.2-7.2 was observed over 72h. Negligible % of drug released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs was detected in rat stomach contents, intestinal tissues and intestinal contents homogenates. On the other hand, Fbp-alpha-CyD and Fbp-beta-CyD prodrugs released about 60% Fbp within 4h in rat colon homogenate. Oral pretreatment of rats with clindamycin significantly reduced % Fbp released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs. Oral administration of Fbp-beta-CyD to rats after induction of colitis significantly attenuated the severity of the colonic injury and reduced the score of the macroscopic and microscopic damage. Additionally, there was a significant increase in the level of GSH. The present study provided an evidence that Fbp-beta-CyD prodrug may be beneficial in treatment of inflammatory bowel disease.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartic Acid; Buffers; Chromatography, High Pressure Liquid; Colon; Cyclodextrins; Drug Carriers; Drug Delivery Systems; Flurbiprofen; Gastrointestinal Transit; Hydrogen-Ion Concentration; Hydrolysis; In Vitro Techniques; Inflammatory Bowel Diseases; Male; Naproxen; Prodrugs; Rats; Sulindac