Aminosalicylates

Campregher, Christoph; Gasché, Christoph

doi:10.1016/j.bpg.2011.10.013

Cited by 35 publications

(30 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To elucidate pathways interfered by PAK1, we stained multiple 5-ASA targets (27), including p65, PPARg, p-ERK, b-catenin, p-AKT, and p-mTOR (17) via IHC. Sequestration of p65 in the cytoplasm maintains NF-kB signaling in an inactive state, although its nuclear translocation is required for transcriptional activation.…”

Section: Resultsmentioning

confidence: 99%

PAK1 Promotes Intestinal Tumor Initiation

Dammann

Khare

Harpain

et al. 2015

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

p21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APC min or APC min /PAK1 À/À mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six-to 8-week-old PAK1 À/À and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APC min mice. IHC revealed that PAK1 deletion reduced p-AKT, b-catenin, and c-Myc expression in APC min adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked b-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.

show abstract

Section: Resultsmentioning

confidence: 99%

PAK1 Promotes Intestinal Tumor Initiation

Dammann

Khare

Harpain

et al. 2015

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…The precipitate thus obtained was filtered, washed several times with cold water; and dried in vacuum to obtain formyl-4-ASA (2). To the solution of formyl-4-ASA (1 mmol, 0.18 g) in dimethylformamide (5 ml), CDI (1.5 mmol, 0.25 g) was added slowly and reacted for 1 h at room temperature and -cyclodextrin (1 mmol, 1.6 g) in DMSO (10 ml) was then added drop-wise.…”

Section: Synthesis Of 4-asa--cyd Conjugatementioning

confidence: 99%

“…Literature reports that 5-ASA-induced recurrent pancreatitis is not observed in IBD patients, on subsequent treatment with 4-ASA enemas [2][3][4]. Left-sided UC is unresponsiveness to oral sulfasalazine, but *Address correspondence to this author at the Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune-411 038, Maharashtra, India; Tel: (+91-20) 25437237; 25436898; Fax: (+91-20) 25439383; E-mail: suneeladhaneshwar@rediffmail.com in a double-blind, placebo-controlled trial, 4-ASA enemas were shown to be safe and effective, providing clinical, sigmoidoscopic, and histologic improvement in 81% patients [5].…”

Section: Introductionmentioning

confidence: 95%

“…Apart from significant anti-tubercular activity, 4-aminosalicylic acid (4-ASA) has also shown promising effects in IBD, where it is thought to act via nuclear factorkappa B (NF-B) inhibition [2]. Literature reports that 5-ASA-induced recurrent pancreatitis is not observed in IBD patients, on subsequent treatment with 4-ASA enemas [2][3][4].…”

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Macromolecular Prodrug of 4-Aminosalicylic Acid for Targeted Delivery to Inflamed Colon

Vadnerkar¹,

Dhaneshwar²

2013

Current Drug Discovery Technologies

View full text Add to dashboard Cite

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 β-cyclodextrin and its extensive pharmacological evaluation in 2, 4, 6- trinitrobenzenesulphonic acid - induced colitis in rats. Formyl 4-ASA was conjugated with β-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-AβCyd 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-AβCyd 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.

show abstract

“…Meanwhile, several aminosalicylates (sulfasalazine, olsalazine, balsalazide and mesalazine) are available for use in IBDs, but in the USA more than 88% of patients receive 5-ASA [40,41]. The mechanism of action of 5-ASA in UC is complex and several effects have been observed [42]. It is believed that 5-ASA interacts with damaged epithelium and mediates its effect locally on the mucosa.…”

Section: Introductionmentioning

confidence: 99%

Risks of Inflammatory Bowel Disease Treatment with Glucocorticosteroids and Aminosalicylates

Curkovic

Egbring

Kullak‐Ublick

2013

Dig Dis

View full text Add to dashboard Cite

Background: Glucocorticosteroids and aminosalicylates, mainly mesalazine (5-ASA), are both standard therapeutics in the treatment of inflammatory bowel disease (IBD) patients. The glucocorticosteroids are highly effective in inducing remission in both ulcerative colitis and Crohn's disease, but their use is limited by the high incidence and the potentially serious nature of adverse events. In an attempt to limit systemic side effects, rapidly metabolized corticosteroids such as budesonide have been introduced. The safety profile of aminosalicylates differs between the formulations. Methods: We summarize the potentialrisks associated with glucocorticosteroid and aminosalicylate therapy in IBDs. Results: The numerous adverse events of glucocorticosteroids, particularly at high doses and prolonged treatment, include opportunistic infections, diabetes mellitus, hypertension, ocular effects (glaucoma and cataracts), psychiatric complications, hypothalamic-pituitary-adrenal axis suppression and increased fracture risk. Partially, these systemic adverse events occur with budesonide, which only has a low systemic exposure. The safety profile of 5-ASA is comparable to placebo and superior to the old aminosalicylate prodrug sulfasalazine, which had a significantly higher incidence of intolerance reactions including allergic rashes. Only in rare cases has nephrotoxicity such as interstitial nephritis been associated with 5-ASA. Conclusion: Considering the toxicity profile of conventional glucocorticosteroids, one primary goal of treatment in IBD should be corticosteroid-free remission. Therapy with budesonide may result in a better safety profile. 5-ASA treatment is usually well tolerated, but with regard to the rare nephrotoxic events, it is advisable to assess renal function before and during treatment with 5-ASA.

show abstract

Aminosalicylates

Cited by 35 publications

References 85 publications

PAK1 Promotes Intestinal Tumor Initiation

PAK1 Promotes Intestinal Tumor Initiation

Macromolecular Prodrug of 4-Aminosalicylic Acid for Targeted Delivery to Inflamed Colon

Risks of Inflammatory Bowel Disease Treatment with Glucocorticosteroids and Aminosalicylates

Contact Info

Product

Resources

About