Firstline Pharmacotherapy

The founding member of the 5-aminosalicylate drugs, 5-ASA's, was sulfasalazine, a chemical combination of sulfapyridine and 5-ASA. These agents (eg. mesalazine and olsalazine) are first-line therapy for the treatment of patients with mild to moderate UC and CD, and as a maintenance therapy to prevent disease relapse in UC. For disease in the distal bowel, multiple delayed- and sustained-release formulations, as well as pro-drugs such as olsalazine, have been designed to release the majority of an oral dose directly in the distal ileum/colon, thus preventing topical exposure in the proximal small intestine. The most recently introduced pro-drug, balsalazide (1) contains azo bonds that are cleaved by colonic bacterial azo-reductases and release the active 5-ASA, mesalazine, locally. For rectal disease, rectal foams are also administered. The mechanism by which the 5-ASA's exert their anti-inflammatory activity appears to be, in part, by inhibiting the activation of NF-kB (5).

Mild disease can be treated with 5-ASA's, but many patients eventually require corticosteroids to control symptoms. Glucocorticoids (eg. prednisolone) are some of the most effective therapies for inducing clinical remission in patients with active CD and UC when used for short periods of treatment. However, adverse effects (incl. obesity, osteoporosis, hypertension and adrenal suppression) as well as the fact that chronic dosing invariably culminates in development of clinically-challenging, steroid-refractory disease, limits their use. Moreover, significant numbers of patients are unable to discontinue glucocorticoid therapy without disease exacerbation. Budesonide (2) is a second-generation corticosteroid and is available as a controlled-release oral formulation for distal CD and as an enema for topical treatment in UC. Budesonide has an extensive first-pass metabolism and lower systemic bioavailability (-11%), enabling it to achieve similar efficacy to prednisolone, but with significantly fewer glucocorticoid-related side effects. Given the higher receptor affinity of budesonide and that as a CYP3A4 substrate, plasma levels can be substantially elevated in the presence of CYP3A4 inhibitors (eg. ketoconazole), the outcomes of long-term safety studies are awaited to confirm budesonide's safety profile compared with other corticosteroid therapies. Budesonide is a good illustration of how engineering features into a molecule can limit the potential for systemic side effects.

Further attempts have been made to chemically-modify these agents to increase their efficacy or reduce adverse events associated with their use. Specifically, an NO donor-containing derivative of prednisolone, NCX-1015 (3), has been shown to have superior efficacy, compared to the parent molecule in the mouse TNBS colitis model (6). Similarly, an NO-releasing form of mesalazine, NCX-456 (4), has superior efficacy to the parent molecule in the rat TNBS colitis model (7). Notwithstanding these recent developments, there appears to be limited scope to extend existing approaches to overcome their limitations. Thus, this article will focus on emerging mechanisms for which there is rationale for activity in IBD.

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