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Azo prodrugs of aminosalicylates viz: 5-aminosalicylic acid and 4-aminosalicylic acid were synthesised using phenols as colon- targeting carriers for management of inflammatory bowel disease. The structures were confirmed by spectral and elemental analysis. These azo- linked prodrugs showed increased hydrophilicity which prevented their absorption from the upper GIT thus delivering them intact to the colon. They were also seen to be stable in stomach and intestinal homogenates, showing minimal release. Activation of prodrugs was faster in cecal matter showing upto 96-98% release with prolonged half lives. Amongst the azo series; 5-A? and 4-Ares significantly attenuated the symptoms of colitis induced by TNBS but their overall efficacy was less than SLZ. Safety assessment revealed absence of any abnormalities in hepatic and pancreas morphology with significantly low ulcerogenic propensity.

Novel carrier-linked azo prodrugs of 4 and 5-aminosalicylic acids (4-ASA and 5-ASA respectively) using the same drugs as carriers in different permutations and combinations were designed for targeting colon affected with inflammatory bowel disease (IBD). Improved hydrophilic nature of the prodrugs assisted in minimizing their absorption in upper GIT and efficient delivery of the active drugs to colon as evidenced from their stability in aqueous buffers (pH 1.2 and 7.4) and upper GIT homogenates with 68-91% release on incubation with rat cecal matter. Amongst the series, 4A4AAZ (prodrug of 4-ASA with 4-ASA) at a dose of 53 mg/Kg was found to be the most promising candidate as it substantially alleviated the quantifying markers of colonic inflammation in TNBS-induced experimental colitis in Wistar rats. Moreover it displayed significantly lower GI toxicity (at ten times higher dose). 5-ASA- induced pancreatitis and sulfapyridine-induced adverse effects on liver that are characteristic of sulfasalazine were not observed with 4A4AAZ. It could be explored further as a potential candidate for IBD patients intolerant to pancreatitis induced by oral administration of 5-ASA.

Sterically hindered esters or esters of drugs with macromolecular carriers like dextran and cyclodextrin find wide applicability in colon-targeted delivery. We report here synthesis, in vitro release kinetics of macromolecular prodrug of 4-aminosalicylic acid (4-ASA) with -cyclodextrin and its extensive pharmacological evaluation in 2, 4, 6- trinitrobenzenesulphonic acid - induced colitis in rats. Formyl 4-ASA was conjugated with -cyclodextrin by CDI coupling followed by deprotection of the final product which was then characterized by IR, 1H-NMR and LC-MS. In vitro stability and release were studied in buffers (pH 1.2 and 7.4), stomach/small intestinal homogenates and rat cecal/fecal matters. The prodrug resisted pH-dependent hydrolysis. In stomach and small intestinal homogenates 20-23 release was observed (t1/2: 1278 and 1103 min respectively) while 68 and 92 release was furnished in rat cecal and fecal matters (t1/2: 341 and 245 min respectively). Mitigating effect of 4-ACyd on colitis was moderate when compared with sulfasalazine or 4/5-ASA administered rectally, but it was comparable to that of aminosalicylates administered orally, suggesting incomplete delivery of 4-ASA to colon due to partial hydrolysis of 4-ACyd in the upper GIT. The histological assessment of pancreas and liver of the prodrug-treated group showed no pathological changes indicating its better safety profile than that of sulfasalazine or oral 5-ASA. The prodrug brought about significant lowering in ulcer index compared to aminosalicylates suggesting significant improvement in gastro-protective effect than oral aminosalicylates.

Earlier colon was considered as a black-box, acting as a site for production and temporary storage of excreta and responsible for absorption of electrolytes and water. But, with the discovery of sulfasalazine as colon-specific prodrug, the promising and challenging issue of treating local pathologies was presented with colon as an organ of significance for target-specific delivery of drugs. The need and desirable attributes of colon-specific drug delivery systems have been well recognized, extensively explored and documented in the literature. The success of a colon-specific prodrug depends on its rational design and understanding the demands of the organ to be targeted and the delivery system to be developed. The present review mainly focuses on anatomy/physiology of colon, colonic microbiota, enzymatic set up of colon, pathophysiology of local diseases of colon, factors, obstacles and rationale for designing colon specific drug delivery system, various targets, potential drug candidates and novel colon-targeting carriers along with varied linkages that could be explored, merits and demerits of this design and recent trends in this field. Brief review of methodologies for characterization and in vitro/in vivo release studies is presented. The available animal models with quantifying parameters for evaluating colon-targeting potential and effectiveness of the colon-specific prodrugs for inflammatory bowel disease is also included in this review.

ABSTRACTFifty-six serum posaconazole trough levels were measured in 17 cardiothoracic transplant recipients. Initial levels were ≤0.5, 0.51 to 0.99, and ≥1 μg/ml for 47, 29, and 24% of patients, respectively. Median trough levels associated with therapeutic success were higher than those associated with failure (1.55 versus 0.34 μg/ml; P= 0.006). Patients with levels consistently >0.5 μg/ml were more likely to have successful outcome (P= 0.055). Age ≥65 years, oral administration, and absence of proton pump inhibitors were associated with higher levels of posaconazole (P= 0.006, 0.006, and 0.001, respectively).

Little is known about the incidence or significance of mold infections in the explanted lungs of lung transplant recipients.