Sulfasalazine, balsalazide, and olsalazine work as a prodrug and use a similar mechanism to carry the active moiety, 5-ASA, to the colon. As mentioned above, sulfasalazine consists of 5-ASA and sulfapyridine joined together by a diazo-bond. Sulfasalazine is 40 % 5-ASA, and about 80–90 % reaches the colon, where it is broken down to 5-ASA and sulfapyridine by the azoreductase of the colonic microbiota [23]. The bioavailability of the 5-ASA moiety that is released ranges from 11 to 33 %. Balsalazide instead uses 4-aminobenzoyl-β-alanine as a carrier to reach the colon [25]; 4-aminobenzoyl-β-alanine and 5-ASA are joined by a diazo-bond (Fig. 6.2b). Balsalazide is 35 % 5-ASA, and nearly the entire dose reaches the colon, where the diazo-bond is uncleaved to release 5-ASA. The bioavailability for balsalazide ranges from 12 to 35 % [26]. Olsalazine is a polymer of two molecules of 5-ASA joined together by a diazo-bond, and it contains about 89 % of 5-ASA [27, 28] (Fig. 6.2c). Approximately 98 % reaches the colon, where it releases two molecules of 5-ASA. The bioavailability of the 5-ASA moiety that is released is about 14–31 %. These three products are all delivered to the colon as an intact form (~about 90–99 %) and are degraded by the bacterial azoreductase to release 5-ASA. Azoreductase is an intracellular enzyme possessed mainly by a wide range of colonic bacteria, which rapidly uncleaves the diazo-bond. Concurrent use of antibiotics that affect the colonic microbiota can decrease the metabolism of these three agents, as can shortened colonic transit time, such as diarrhea, medication, and colectomy. Some studies suggest that during active inflammatory bowel disease, the bioavailability of the bacterial enzymes including azoreductase are compromised, which may interfere with its clinical efficacy [29].

pH-dependent formulations utilize the gradient of pH in the gastrointestinal tract to deliver the active agent into aimed part of the intestine. The pH in the stomach is approximately 2. The pH in the upper small bowel is about 5–6, and in the lower parts of the small bowel including the terminal ileum, it reaches 6–7. Throughout the colon, the pH is maintained close to neutral between 7 and 8 [30]. Asacol^® utilizes an acrylic-based resin (Eudragit-S) coating that is soluble at a pH of >7, thus delivering 5-ASA in the terminal ileum and entire colon [31]. Asacol^® was recently replaced by Delzicol^®, which is a bioequivalent product that does not contain dibutyl phthalate (DBP), a solvent with potential adverse effect on fetal reproductive system [32, 33]. Lialda^® is a Multi-Matrix System (MMX^®) mesalamine (marketed as Lialda^® in the USA and Mezavant^® in the European Union) that is designed to deliver 5-ASA throughout the entire colon as a high-strength once-daily dosing tablet [34, 35]. The mechanism of the MMX^® delivery system is a double matrix consisting of a lipophilic matrix dispersed within a hydrophilic matrix [36]. 5-ASA is incorporated into microparticles in the lipophilic matrix, contained within the hydrophilic matrix. This double matrices is then covered by a pH-dependent polymer film that delays the release of 5-ASA until the film dissolves when exposed to a pH of >7.0 in the terminal ileum to colon. When the hydrophilic matrix is exposed to the intestinal fluids, it swells and creates a viscous gel mass, theoretically resulting in slow dispersion of 5-ASA. The hydrophilic matrix adheres to the colonic mucosa, which also contributes to targeted drug delivery to the colon. Apriso^® utilizes a patented delivery system called Intellicor^TM delayed- and extended-release delivery system that provides coverage throughout the colon [37]. It disintegrates at pH 6.0 in the distal jejunum where the 5-ASA begins to be released. This formulation combines delayed and sustained release and allows the5-ASA to travel through the jejunum to the colon. It provides the convenience of once-daily dosing like the MMX^® mesalamines.

Pentasa^® is currently the only available microsphere formulation of mesalamine [38, 39]. It encapsulates 5-ASA in ethyl cellulose-coated microgranules that gradually starts to release 5-ASA beginning in the duodenum. The release of 5-ASA from the microgranules is not affected by the bowel acidity and occurs in any enteral pH conditions. Thus, the release continues throughout the jejunum, the ileum, and the colon as well as the rectum.

The risk of renal dysfunction may be increased in patients receiving known nephrotoxic agents, such as NSAIDs. Coadministration of azathioprine or mercaptopurine with mesalamine products may result in an increase in blood 6-thioguanine nucleotide concentrations which may lead to leucopenia [67].

The 5-ASA formulations (sulfasalazine, olsalazine, balsalazide, and mesalamine) have long been foundational treatments for mild to moderate UC. Guidelines suggest that combination of oral and topical therapies induces remission in mild to moderately active distal colitis patients and may effectively maintain remission [71–73]. As described above, the therapeutic effect of mesalamine in UC depends on the ability of the active drug to reach the sites of inflammation for topical (not systemic) anti-inflammatory activity. The currently available oral mesalamine preparations each utilize a slightly different method to increase efficient delivery of the active ingredient to small and/or large intestine. These methods include incorporation of mesalamine into a prodrug through covalent azo-bond, incorporation of unmodified mesalamine into a pH-sensitive acrylic coating or moisture-sensitive ethyl cellulose microspheres, and a newer formulation that utilizes both a pH-sensitive acrylic layer and a coating of lipophilic/hydrophilic excipients [19, 39, 74, 75]. All formulations are equally as effective, though the use of sulfasalazine is limited in its use mainly due to patient intolerance [76].

Dating back to the 1950–1960s, several studies demonstrated that sulfasalazine was superior to placebo for the treatment of active UC. In these initial studies, sulfasalazine was used at a dose of 4–6 g daily and was effective in 60–80 % of patients as compared to 30–40 % of the patients treated with placebo [21, 77, 78]. The response was also dose dependent.

Two randomized double-blinded studies demonstrated that balsalazide 6.75 g/day was as effective as sulfasalazine 3 g/day, but with a favorable safety profile [75, 79]. Balsalazide was shown to be superior to mesalamine in a double-blinded randomized trial for active UC. Patients on balsalazide 6.75 g/day showed superior 12-week clinical remission rate as compared to mesalamine 2.4 g/day (62 % vs. 37 %, p = 0.02), and it appears that the effect of balsalazide was more rapidly achieved [80]. Several other studies demonstrated similar efficacy between balsalazide and mesalamine [64]. In a double-blinded placebo-controlled trial, olsalazine 2 g/day was superior to placebo in achieving a clinical and endoscopic response [27]. Several studies have shown comparable efficacy between olsalazine 1.5–2 g/day and sulfasalazine 3 g/day for mildly to moderately active UC [81–83].

Asacol^® was shown to be superior to placebo at a dose of 1.6 or 2.4 g/day in achieving remission at 6 weeks (43 % and 49 % vs. 23 % of placebo, p = 0.03, and 0.003, respectively) [84]. Schroeder et al. showed superior rates of remission with Asacol^® 4.8 g/day compared to placebo (24 % vs. 5 %, p = 0.047) [5]. The rates of clinical response were more significant in patients with left-sided colitis (75 % vs. 21 %, p = 0.0001). Pentasa^® was more effective than placebo at 2 or 4 g/day in achieving clinical and endoscopic remission at 8 weeks [85]. A double-blind trial between Pentasa^® and sulfasalazine showed that Pentasa^® at a dose 2.4 g/day was superior to sulfasalazine 2 g/day in achieving symptomatic and endoscopic improvement at 4 weeks [86].

In a dose-finding study of Apriso^®, Kruis et al. demonstrated that doses of 1.5 g, 3 g, or 4.5 g daily were equally as effective for active UC [87]. There were no significant differences in remission rates, time to response, endoscopic improvement, or histological improvement. In another study, 3 g once-daily dosing was as effective as 1 g three times daily, suggesting that once-daily dosing of Apriso^® is efficacious [88]. Lialda^®, a once-daily mesalamine product, was tested in a randomized clinical trial of 2.4 g, 4.8 g, and placebo for 8 weeks [35]. Remission rates with both doses of Lialda^® were significantly superior to placebo, but not different from each other.

More recently, the interest of mesalamine therapy has focused on optimized dosing and once-daily formulations.

The ASCEND (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) trials aimed to investigate the dose–response effect of mesalamine (Asacol^®) in the induction of remission in UC. The ASCEND I trial randomized 301 patients with mildly to moderately active UC to receive either 2.4 g/day or 4.8 g/day of Asacol^® [89]. At week 6, similar proportion of patients experienced improvement in each group (51 % vs. 56 %, p = ns). The difference was not significant; however, when results were stratified according to the disease severity, patients with moderate disease had a more substantial response to the 4.8 g/day dose compared to those with mild disease. Based on these results, the ASCEND II trial focused on moderately active UC and confirmed that 4.8 g/day of Asacol^® led to a greater treatment response than 2.4 g/day (72 % vs. 59 %, p = 0.036) [90]. In the ASCEND III trial, 772 patients with moderately active UC were randomized to receive 2.4 g/day or 4.8 g/day doses of Asacol^®, and there was no difference between the two groups in terms of overall improvement (complete remission and partial response), but significantly more patients who received 4.8 g/day compared to 2.4 g/day achieved clinical remission at week 3 (p = 0.02) and week 6 (p = 0.04) [74]. Furthermore, subgroup analysis showed that patients with difficult-to-treat disease, such as those previously treated with steroids, oral mesalamine, rectal therapies, or those taking multiple UC medications, responded better to higher doses than to lower doses.

Studies have shown that only about half of the patients are adherent to multidose therapy [91, 92], and in clinical practice, poor adherence often leads to recurrence of disease [93]. Once-daily oral formulations may improve the adherence by decreasing the pill burden and, in fact, are a preferred choice by patients [94, 95]. Lialda^® utilizes the MMX^® system providing a slow and gradual release of mesalamine throughout the colon that permits once-daily administration [19]. Lichtenstein et al. performed a randomized, double-blind, parallel-group, placebo-controlled multicenter study in patients with mildly to moderately active UC comparing the effect of Lialda^® 2.4 g/day given twice daily, 4.8 g/day given once daily, and placebo [96]. Similar proportion of patients achieved clinical remission with 2.4 g/day twice daily or 4.8 g/day once daily (34.1 % and 29.2 % vs. 12.9 % of placebo, p < 0.001 and p = 0.009, respectively). In another double-blind, placebo-controlled, multicenter trial, the effect of Lialda^® 2.4 g once daily and 4.8 g once daily was compared to placebo and a delayed-release mesalamine (Asacol^®) 2.4 g daily given three times daily [35]. At week 8, more patients achieved clinical and endoscopic remission in the Lialda^® groups compared to placebo (40.5 % and 41.2 % vs. 22.1 %, vs. placebo; p = 0.01 and p = 0.007, respectively). No significant difference in clinical remission rates between patients receiving Asacol^® and placebo was seen (33.7 % vs. 22.1 %, p = 0.089); however, it was unclear whether there was a statistical difference between Lialda^® and Asacol^®. Furthermore, a subsequent study combining the patients that achieved clinical and endoscopic remission in the abovementioned 2 studies evaluated the efficacy of Lialda^® 2.4 g daily dosed once or twice daily as maintenance therapy [97]. At 12 months, similar proportion of patients was in clinical and endoscopic remission with once-daily and twice-daily regimen (64.4 % vs. 68.5 %, p = ns). Another once-daily mesalamine preparation (Salofalk^®) that is available in Europe was evaluated in a dose-ranging trial and also proved to be efficacious in inducing remission in mildly to moderately active UC [98]. In a randomized, investigator-blinded study, controlled-release mesalamine (Pentasa^®) was shown to be more effective when given in once-daily regimen [98]. At 12 months, 73.8 % of patients receiving Pentasa^® 2 g once daily maintained remission compared to 63.6 % of patients receiving 1 g twice daily (p = 0.024). The study also demonstrated that compliance was better with once-daily regimen.