Colonic enzyme controlled

NO has a cytostatic effect by inhibiting ATP synthesis [99] via Kreb s cycle (aconitase inhibition, [100]), glycolysis (GADPH inhibition) and mitochondrial respiration (NAD ubiquinone oxydoreductase and succinate ubiquinone oxydoreductase inhibitions, [101]). Another pathway is the ornithine decarboxylase inhibition. This enzyme is implicated in polyamine production necessary to cell proliferation and its activity is inhibited by NO in human colon cancer cells HT-29 and Caco-2 [102]. Furthermore NO directly inactivates ribonucleotide reductase [103] of TA3 cancer cells (murine breast cancer cells) [104]. This enzyme controlling DNA synthesis catalyses desoxyribonucleotides synthesis, and its inhibition blocks cells in S phase. This inhibition is rapid and reversible in K562 and TA3 cells [105]. 

This time controlled release tablet with a designated lag time followed by a rapid release may provide an alternative to site-specific delivery of drugs with optimal absorption windows or colonic delivery of drugs that are sensitive to low pH or enzyme action for the treatment of localized conditions such as ulcerative colitis, Crohn s disease, and irritable bowel syndrome (IBS). Also, by controlling a predetermined lag time of drug from dosage form, the release behavior can be matched with the body s circadian rhythm pattern in chronotherapy. 

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