Which 5-ASA?

I read Dr Travis’ therapy update (Gut 2002;51:548–9) with interest; the topic is timely in a market about to be challenged by new generic mesalazine brands. I note the choice of time dependent mesalazine (Pentasa) but, if mesalazine is to be relied upon exclusively, some evidence suggests Pentasa may not be the best choice. The recent study by Kruis and colleagues¹ in the maintenance of remission in ulcerative colitis (UC) found that with Pentasa 1.5 g/day, the six month remission rate was 56.8% compared with 77.5% with balsalazide 3 g twice daily (p=0.045).

The assertion that the advantages of the azo bond delivery to the distal colon can be matched by simply increasing the dose of pH dependent (Asacol) or time dependent release (Pentasa) has not been borne out by laboratory or clinical studies. Tissue level studies have indicated that double dose mesalazine is delivered to the kidney, not the colon.² A large clinical trial of Pentasa in mild to moderate active UC found remission rates of 29% for both 2 g/day and 4 g/day.³ This latter study highlights the lack of efficacy of mesalazine released by a time dependent delivery system in active UC. In contrast, three studies comparing balsalazide with mesalazine (pH dependent release),^4–6 containing a total of 426 patients, all found balsalazide to be superior in active UC, with rapid resolution of symptoms (median 10 days in one study⁴) and superior sigmoidoscopic scores (in all three studies). Plasma concentrations of 5-aminosalicylic acid (5-ASA) were 4.5-fold lower in patients treated with balsalazide than mesalazine (p=0.018).⁵ Patients with most to benefit are new patients with distal disease.⁶ The use of 5-ASA in the initial treatment of UC does not require mega doses, as Dr Travis suggests, indeed mega doses of mesalazine delivered by Asacol or Pentasa are ineffective, but it does require a reliable delivery system, such as the azo bond, and an inert carrier, as with balsalazide. The clinical implication of this efficacy in mild to moderate active UC is that the threshold for the use of steroids can be raised. Of interest in the North American trials of balsalazide versus mesalazine, 60 patients failing mesalazine therapy were treated after the trial with balsalazide open label, with 60% response (data on file, Shire Pharmaceuticals Ltd).

Advocates of sulphasalazine (SASP) and those wishing to use the least expensive treatment cite trials of SASP versus newer agents⁷ and conclude that SASP is the most cost effective; these trials are in patients with known UC and specifically exclude patients who are SASP intolerant. In two recently published studies,^8,9 patients with newly diagnosed or previously untreated UC were randomised to SASP or balsalazide; 34% were intolerant of SASP at the modest dose of 3 g daily compared with 5% for balsalazide 6.75 g daily. The number needed to treat to avoid SASP intolerance at this rate is only 3, and in new patients it seems particularly important to use well tolerated effective treatment firstline and avoid the loss of confidence that drug intolerance produces.

It seems a sad reflection on the pharmaceutical industry sponsored research that the most recent trial on UC treatment with 5-ASA quoted in the therapy update was from 1998. Large clinical trials of one 5-ASA brand against another are expensive and the advent of generic mesalazine preparations is unlikely to improve this situation. My interpretation of recently published evidence is that the mesalazine release mechanism is important for the efficacy, reliability of delivery, and safety of the oral preparations and that balsalazide is now the gold standard for other agents to be judged against.