ABSTRACT
Colon-specific mutual azo prodrugs of 5-aminosalicylic acid with essential amino acids were synthesized for the management of inflammatory bowel disease. The structures were confirmed by elemental and spectral analyses. 85-88% release of 5-aminosalicylic acid was achieved in rat fecal matter with half-lives ranging from 140 to 160 min, following first order kinetics. The prodrugs exhibited comparable ameliorating effect as that of sulfasalazine on trinitrobenzenesulfonic acid-induced experimental colitis in rats with a better safety profile.
Subject(s)
Aminosalicylic Acids/chemical synthesis , Aminosalicylic Acids/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Prodrugs/chemical synthesis , Prodrugs/therapeutic use , Animals , Arthritis/chemically induced , Arthritis/drug therapy , Colitis/chemically induced , Colitis/drug therapy , Colon/drug effects , Colon/pathology , Female , Inflammatory Bowel Diseases/chemically induced , Male , Peroxidase/metabolism , Rats , Rats, Wistar , Ulcer/drug therapy , Ulcer/pathologyABSTRACT
Mutual azo prodrug of 5-aminosalicylic acid with l-tryptophan was synthesized by coupling l-tryptophan with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-aminosalicylic acid, whereas in phosphate buffer (pH 7.4) 18% release was observed over a period of 7 h. In rat fecal matter, 87.9% of 5-aminosalicylic acid was released with a half-life of 143.6 min, following first order kinetics. The azo conjugate was evaluated for its ulcerogenic potential by Rainsford's cold stress method. The ameliorating effect of the azo conjugate and therapeutic efficacy of the carrier system was evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. The synthesized prodrug was found to be equally effective in mitigating the colitis in rats as that of sulfasalazine without the ulcerogenicity of 5-aminosalicylic acid.
Subject(s)
Azo Compounds/therapeutic use , Colitis/drug therapy , Colitis/pathology , Mesalamine/therapeutic use , Prodrugs/therapeutic use , Trinitrobenzenesulfonic Acid/pharmacology , Tryptophan/therapeutic use , Animals , Azo Compounds/chemical synthesis , Azo Compounds/chemistry , Body Weight/drug effects , Colitis/chemically induced , Kinetics , Mesalamine/chemistry , Molecular Structure , Organ Size/drug effects , Prodrugs/chemical synthesis , Prodrugs/chemistry , RatsABSTRACT
Mutual azo prodrug of 5-aminosalicylic acid with d-phenylalanine was synthesized by coupling D-phenylalanine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-aminosalicylic acid, whereas in phosphate buffer (pH 7.4) only 15% release was observed over a period of 7h. In rat fecal matter the release of 5-aminosalicylic acid was almost complete (85%), with a half-life of 160.1 min, following first order kinetics. The azo conjugate was evaluated for its ulcerogenic potential by Rainsford's cold stress method. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. The synthesized prodrug was found to be equally effective in mitigating the colitis in rats as that of sulfasalazine without the ulcerogenicity of 5-aminosalicylic acid.
Subject(s)
Chemistry, Pharmaceutical/methods , Drug Delivery Systems , Inflammatory Bowel Diseases/drug therapy , Mesalamine/chemical synthesis , Phenylalanine/chemical synthesis , Prodrugs/pharmacology , Animals , Colon/pathology , Drug Design , Hydrochloric Acid/chemistry , Kinetics , Mesalamine/pharmacology , Models, Chemical , Molecular Conformation , Phenylalanine/pharmacology , Rats , Sulfasalazine/chemistryABSTRACT
Mutual azo prodrug of 5-aminosalicylic acid with l-tyrosine was synthesized by coupling l-tyrosine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in rat fecal matter showed 87.18% release of 5-aminosalicylic acid with a half-life of 140.28min, following first order kinetics. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. Myeloperoxidase activity was determined by the method of Krawisz et al. The synthesized prodrug was found to produce comparable mitigating effect as that of sulfasalazine on colitis in rats.
