5-Aminosalicylic acid azo-linked to procainamide acts as an anti-colitic mutual prodrug via additive inhibition of nuclear factor kappaB (original) (raw)
Related papers
2004
The protective and anti-inflammatory effects of azo and azo-linked polymeric prodrugs of 5-aminosalicylic acid (5-ASA) on acetic acid induced colitis in rats were investigated. Three azo prodrugs; 4,4'-dihydroxy-azobenzene-3-carboxilic acid (azo compound I), 4-hydroxy-azobenzene-3,4’dicarboxilic acid (azo compound II), 4,4'-dihydroxy-3'-formyl-azobenzene-3-carboxylic acid (azo compound III) and their polyethylene glycol (PEG 6000) derivatives were synthesized. Rats were pretreated orally (1 hour prior to induction of colitis) with sulfasalazin (300 mg/kg), azo compounds I, II, III and polyethylene glycol conjugates of azo compounds II and III in doses which had the same amount of 5-ASA as sulfasalazin contains. The colonic damage was examined 24 hours later and characterized by gross microscopic injury and colonic edema. Among prodrugs only azo compound III (215 mg/kg) produced a significant (p<0.01) protective effect against colonic injury comparable with sulfasalazi...
Inflammatory Bowel Diseases, 2008
Background: The impact of the antiinflammatory agent 5-aminosalicylic acid (5-ASA) on the risk for colitis-associated colorectal cancer remains controversial. The chemopreventive activity of 5-ASA was evaluated in the Swiss Webster model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated neoplasia.Methods: Mice were injected with AOM (7.4 mg/kg i.p.) and randomized to receive either vehicle or 5-ASA (75, 150, and 225 mg/kg) for the remainder of the study. DSS treatment began at 9 weeks of age and continued for 3 cycles. At the time of sacrifice (18 weeks of age), the entire colon and rectum were processed for histopathologic examination.Results: An inverse trend was observed between dose and multiplicity of colonic dysplasias in all drug-treated groups (P = 0.03), with animals receiving 75 mg/kg 5-ASA exhibiting 56% of the number of dysplasias of the AOM/DSS controls (mean ± SEM: 7.6 ± 1.4 and 13.6 ± 2.7, respectively). Administration of 75 mg/kg 5-ASA decreased both the mean multiplicity of flat dysplasias (1.8 ± 0.4 for drug-treated versus 5.6 ± 1.2 for AOM/DSS control) and the burden of polypoid dysplasias (tumor burden: 6.7 ± 2.7 for drug-treated versus 14.9 ± 3.9 units for AOM/DSS controls) significantly (P = 0.002 and 0.04, respectively). Inflammation was least severe in the 75 mg/kg group, which exhibited the fewest number of colorectal tumors.Conclusions: These data suggest that low-dose 5-ASA may be efficacious in preventing colitis-associated dysplasias and provide strong support for optimizing this therapy for the prevention of colonic neoplasms in patients with ulcerative colitis.(Inflamm Bowel Dis 2008)
A colon-specific prodrug of metoclopramide ameliorates colitis in an experimental rat model
Drug Design, Development and Therapy, 2018
Background: We examined whether metoclopramide (MCP), a modulator of dopamine and serotonin receptors, alleviated colitis and had synergistic effects when coadministered with 5-aminosalicylic acid (5-ASA) in an experimental model of colitis. Methods: MCP azo-linked to 5-ASA (5-[4-chloro-2-{2-(diethylamino)ethylcarbamoyl}-1-methoxyphenyl]azosalicylic acid, MCP-azo-ASA) was synthesized, where 5-ASA was used as a colon-targeting carrier and an anti-colitic agent, and the ability of MCP-azo-ASA to target the colon in vitro and in vivo was evaluated. Results: Our results indicate that MCP-azo-ASA was cleaved to MCP and 5-ASA in the cecal contents, but not in the contents of the small intestine. Oral gavage with equimolar concentrations of MCP-azo-ASA and sulfasalazine (SSZ, a colon-specific prodrug of 5-ASA widely used clinically) demonstrated that the two prodrugs delivered comparable amounts of 5-ASA to the cecum. MCP was barely detected in the blood after oral gavage with MCP-azo-ASA. In a rat model of 2,4-dinitrobenzene sulfonic acid hydrate (DNBS)-induced colitis, MCP-azo-ASA alleviated colonic damage in a dose-dependent manner. Moreover, MCP-azo-ASA reduced the concentrations of inflammatory mediators in the inflamed colon. At low equimolar doses, MCP-azo-ASA, but not SSZ, resulted in significant anti-colitic effects, which indicates that MCP has anti-colitic activity. MCP-azo-ASA had anti-colitic effects equal to those of SSZ at high equimolar doses. Conclusion: Thus, our results indicate that MCP-azo-ASA is a colon-specific prodrug of MCP. Targeted delivery of MCP to the colon ameliorated DNBS-induced colitis in rats, and we did not observe any synergistic effects of MCP after co-delivery with 5-ASA.
AAPS PharmSciTech, 2015
Colonic drug delivery is intended not only for local treatment in inflammatory bowel disease (IBD) but also for systemic delivery of therapeutics. Intestinal myeloperoxidase (MPO) determination could be used to estimate the average level of inflammation in colon as well as to determine the efficacy of drugs to be used in the treatment of inflammatory bowel diseases or study the specificity of dosage forms to be used for colonic targeting of anti-inflammatory drugs. Colonic prodrug sulfasalazine (SASP) gets metabolized to give 5-aminosalicylic acid (5-ASA), which is the active portion of SASP. However, when given orally, 5-ASA is absorbed in upper part of gastrointestinal tract (GIT) and not made available in colon. In the present study, colon-targeted delivery of 5-ASA was achieved by formulating tablets with two natural polymers namely guar gum and pectin using compression coating method. Colonic specificity of 5-ASA tablets (prepared using guar gum and pectin as polymers) was evaluated in vitro using simulated fluids mimicking in vivo environment as well as in vivo method using chemically (2,4,6trinitrobenzenesulfonic acid and acetic acid)-induced colitis rat model. Both colon-specific formulations of 5-ASA (guar gum and pectin) were observed to be more effective in reducing inflammation in chemically induced colitis rat models when compared to colon-specific prodrug sulfasalazine as well as conventional 5-ASA administered orally.
2006
Mutual azo prodrug of 5-aminosalicylic acid with histidine, was synthesized by coupling L-histidine with salicylic acid, for targeted drug delivery to the inflamed gut tissue, in inflammatory bowel disease. 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 14% release was observed over a period of 6h. In rat fecal matter, the release of 5-aminosalicylic acid was almost complete (85.6%), with a half life of 163 min, following zero 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 trinitrobenzenesulphonic 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, and adverse effects of sulfasalazine. Prodrug approach is one of the important approaches for The present work reports the synthesis, physico-chemical characterization, in vitro kinetic studies, and
Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery
Digestive Diseases and Sciences, 1994
In an attempt to obtain site-specific delivery of 5-ASA in the intestinal tract, we have determined the extent of absorption and metabolism of a number of novel 5-ASA derivatives, namely, (N-L-glutamyl)-amino-2-salicylic acid (1), (N-L-aspartyl)-amino-2salicylic-acid (2), 5-aminosalicyl-L-proline-L-leucine (3), and 5-(N-L-glutamyl)aminosalicyl-L-proline-L-leucine (4), which are selectively cleaved by intestinal brush border aminopeptidase A and carboxypeptidases. These novel prodrugs, 5-ASA, and sulfasalazine were administered to adult Fisher rats (N = 30) and to animals that had undergone prior colostomy (N = 30). Urine and feces were collected at timed intervals for 48 hr and the metabolites, 5-ASA, and N-acetyl-5-ASA were measured by highperformance liquid chromatography. The absorption and metabolism of all compounds were essentially identical in colostomized and normal animals. 5-ASA exhibited a rapid proximal intestinal absorption as evidenced by the high cumulative urinary excretion (>65%) and low fecal excretion. Sulfasalazine, as expected, exhibited a lower urinary recovery (<35%) and higher fecal excretion of 5-ASA and its metabolite. The novel glutamate and aspartate derivatives (1 and 2) behaved similarly to sulfasalazine, while administration of the proline-leucine derivative (3) resulted in urinary and fecal recovery values intermediate with respect to those observed with 5-ASA and sulfasalazine. 5-(N-L-Glutamyl)-aminosalicyl-L-proline-L-leucine yielded the highest fecal recovery of 5-ASA and its N-acetyl derivative, indicating a more efficient delivery to the distal bowel. Amino acid derivatives of 5-ASA appear to be potentially useful prodrugs for the site-specific delivery of 5-ASA to different regions of the intestinal tract.
Review article: mode of action and delivery of 5-aminosalicylic acid – new evidence
Alimentary Pharmacology and Therapeutics, 2006
The effectiveness of sulfasalazine depends on the splitting of the diazo bond in the molecule by the action of bacteria in the large bowel, releasing the pharmacologically active moiety, 5-aminosalicylic acid. The development of pH-dependent, delayed-release formulations of 5-aminosalicylic acid abolished the toxicity associated with the sulfapyridine part of sulfasalazine. 5-aminosalicylic acid is now believed to act by activating a class of nuclear receptors involved in the control of inflammation, cell proliferation, apoptosis and metabolic function, the c form of peroxisome proliferator-activated receptors. These receptors are expressed at particularly high levels in colon epithelial cells, where their expression appears to be at least in part stimulated by gut bacteria. Other drugs known to act via peroxisome proliferator-activated receptor-c, such as rosiglitazone and the selective peroxisome proliferator-activated receptor-c ligand GW1929, can be displaced from their binding sites on the peroxisome proliferator-activated receptor-c molecule by 5-aminosalicylic acid at concentrations of 5-aminosalicylic acid that correspond with the concentrations found in the lumen of ulcerative colitis patients taking oral mesalazine. Genetically engineered heterozygous knockout mice (peroxisome proliferator-activated receptor-cAE) are particularly susceptible to colonic inflammation, and inflammation is more severe in these mice, in response to chemicals that induce experimental colonic ulcers. In these experimental models, 5-aminosalicylic acid is ineffective in peroxisome proliferator-activated receptor-cAE mice. This new insight provides a mechanistic foundation for the possibility that long-term treatment with 5-aminosalicylic acid can reduce the risk of colorectal cancer in patients with ulcerative colitis.