Overview of 5-ASA in Therapy of Inflammatory Bowel Disease

There are two forms of 5-aminosalicylic acid (5-ASA) drug delivery. First, a pro-drug form in which 5-ASA, the active principal, is attached to a c.arrier molecule and released in the intestine by bacterial cleavage. An example of this is sulfasalazine, originally developed in the 1940s and found to be effective, cheap, but limited by side effects due to the sulfapyridine component. The second drug delivery system depends on an enteric coating for delayed pH-dependent release or for a timed-released mechanism. 5-ASA inhibits 5-lipoxygenase, modulates leukocyte function and inhibits soluble mediator release, and is an effective scavenger action of free oxygen radicals, the relative importance of which is unknown. The multiplicity of action is probably its strength because drugs that have only one of these actions are relatively ineffective in inflammatory bowel disease. 5-ASA compounds are effective in treating mild to moderate acute ulcerative colitis and in maintaining remission, and are equivalent to sulfasalazine in this regard. 5-ASA used topically in enema or suppository form is highly efficient in both acute disease and in maintaining remission. 5-ASA is also effective in active Crohn’s disease, but not as effective as in maintenance therapy compared with ulcerative colitis. The pro-drugs tend to have more side effects. Slow release compounds are well tolerated with few side effects, allowing increases to effective dosage. In patients intolerant of sulfasalazine, switching to a 5-ASA preparation usually results in tolerance and therapeutic benefit, with an occasional allergic reaction to the 5-ASA molecule limiting its use.

oped in the ea rly 1940s ( 1) as an anti-inflammatory, antibiotic fo r use in rheumatoid arthritis, then thought to have an infec ti ous etiology.5-aminosalicylic ac id (5-ASA ) is the active principal of SAS.5-ASA is ava il able in carrier-mediated fo rm.Here, the prodrug is delivered to the large intestine, where bacterial action brea ks an azo bond (2) and releases the active principal.For SAS, the relea e is of the active principal, 5-ASA, and inacti ve sulphapyridine (3 ,4 ).For olsalazine (Dipentum; Pharmac ia), splitting the azo bond releases two molecules of 5-ASA.O ther pro-drugs, balsalazide and ipsalazide, are not available in Canada (5) .Enteric-coated, low-release, pHdependent fo rms of 5-ASA are available in North America: Asacol (Procter and Gamble), Salofalk (Axcan), Rowasa (Solvay Pharmaceutical ; Georgia) (Table 1) .These preparations avoid excessive upper intestinal absorption and theoretical renal damage (6).Sa lofa lk and Rowasa are released in the distal ileum, Asacol in the right colon (7) .Another preparation, Pentasa (N ordic ), is a for mulation of 5-ASA granules covered with ethyl ce llulose.This allows slow release starting in the prox imal small bowe l (8).
factor, interleukin-!, intestinal mast cell and basophil-stimulated histamine release.It is an effective scavenger of free oxygen radicals (10).The relative importance of these actions is not known.
5-ASA is metabolized to one end product only in humans, N-acetyl-5-ASA (1 1), and is independent of acetylation phenotype (12).This probably occurs by bacterial action in the colonic lumen as well as in the mucosa!cell (13) and the hepatocyte (14).N-acety l-5-ASA is believed to have no biological action (15) and i excreted by the kidneys.Factors affecting oral 5-ASA disposition include food intake, omeprazole, luminal pH, intestinal transit time, colon flora and antibiotics.Crohn's disease alters 5-ASA absorption and is reversed towards normal after effective treatment (16).There are few available

TABLE l
studies of intestinal pH in patients with inflammatory bowel disease (IBO).However, using serum, urine and stoo l measurements, increasing proportions of nonmetabolized 5-ASA reach the colon from the slow release (Pentasa) through the enteric-coated (Salofalk, Asacol) to the pro-drugs (olsalazine, SAS).Topical formulations of 5-ASA are available as enemas, suppositories and foams.
The pro-drug SAS is associated with an approximate 30% incidence of side effects, predominantly related to the sulphapyridine component (17).Desensitization is helpful for some, but not for hypersensitivity reactions such as agranulocytosis, hemolysis or aplastic anemia.Other rare side effects include male infertility and folate deficiency.S ide effects associated with 5-ASA tend to be dose-related and infrequent in number; headache, nausea, epigastric

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Company Coat in distress and diarrhea are common ( 18).Rare complications of 5-ASA include acute pancreatitis (19), pcrica rditis (20), myocarditis (21 ), thrombocytopenia (22) and renal tubular damage (23).Rarely, both drugs may exacerbate the IBO (24,25) .5-ASA is recommended for the treat• ment of patients with mild to moderate I RD.The type of 5-ASA used depends on the type of disease (Crohn's disease or ulcerative colitis), and the site and extent of disease.Oral 5-ASA drugs, including the pro-drugs, are probably equally effective when universal ulcerative colitis is present.Suppositories are the treatment of choice for distal disease of 20 cm or less; enemas are used when there is 20 to 40 cm of disease.Enemas are particularly effective in universal colitis, together with an oral 5-ASA, when rectal symptoms predominate.5-ASA is particularly u eful in Crohn's disease with colonic involvement with or without limited ilea!disease.Pentasa is probably the theoretical drug of choice in more proximal small bowel disease because of its mechanism, but this remains to be shown by clinical trial.5-ASA appears to induce remission more slow ly than corticosteroids and is more expensive.However, patient tolerability, especially for the topical formulations, is high and there is less toxicity.(34 ).There are many studies showing equal efficacy in maintaining remi sion between AS and another pro-drug, Oipentum (35), a well as between SA and entericcoated 5-ASA (36).Meta-analyse have shown that 5-ASA is equivalent to SAS in mild to moderate acute ulcerative colitis and in maintenance therapy (37,38).Similarly, the u e of topical 5-ASA in ulcerative colitis is very effective for enemas: 85 to 90% using 4 g at nighttime for four to 12 weeks (39,40); for suppositories, similar efficacy was 4. van Hees PAM, Bakker JH, van Tongeren JHM.Effect of sulphapyridine, 5-aminosalicylic acid and placebo in patients with idiopathic proctitis: a study to determine the active therapeutic moiety of sulphasalazine.Gut 1980;21:632-5.
Studies of two novel sulfa •alazine noted using either 500 mg twice or three times a day for six weeks ( 41,4 2).For maintenance therapy, l g at nighttime for enemas, and 0.5 g every second night for suppos itories are effective treatment .Recent meta-analysi of topical 5-A A in ulcerative colitis confirms significant benefits over placebo for both active disease and maintenance therapy (43).5-A A is effective in active Crohn' disease.There i a 32% therapeutic gain when A , 3 g/day, is compared with placebo over a four-month period (44).This wa later confirmed in the National Cooperative Crohn's Disease Study where a subgroup with colitis responded better (45).In a recent study, a 25% therapeutic gain with Pentasa versus placebo was seen in 310 patients randomized to various doses over a 16week period (46).There was no difference between placebo, 1 g or 2 g recipients in this study.In maintenance therapy, Pentasa is beneficial, compared with placebo in a subgroup of patients who had relap ed within three months prior to enrolment ( 4 7).Other studie have hown no effect when either Pentasa (48) or SAS (49) wa compared with placebo.However, in a large group of patients treated with SAS followed for up to two years, there was a therapeutic gain of 25% (50), and in another study of 12 months' duration, patient randomized to Claversal (SmithKline Beecham) experienced a 24% therapeutic gain over those randomized to placebo (51).Patients with Crohn's disease had remission rates on placebo varying from 35 to 54%, com-pare<l with 60% on SAS and 78% on Claversal over 12 months.These findings were confirmed in a recenr metaanalysis which found that maintenance therapy with 5-ASA or SA reduces the likelihood of clinical relapse at one year (52).
5-ASA i a well tolerated medication with few side effects, allowing increase in effective dosage.It is recommended that 4 g 5-ASA be given orally for active IBD, with increases as necessary.It is uncertain whether continuous active treatment should be advised for maintenance therapy, ie, 4 g/day or the standard 2 g/day.Different preparations can be u ed to target the ite of disease, and when given orally, appear to be equally as effective in maintaining remi sion as SAS.However SAS is much cheaper, and when tolerated, is effective therapy.5-ASA given to SAS-intolerant patients is of therapeutic benefit in most with the caveat of occa ional allergic reaction to 5-ASA.

ASA in IBD therapy
CAN J 0ASTROENTEROL VOL 8 No 6 NOVEMBER 1994 5-