Treatment

Treatment Options

Medical treatment using 5-ASA compounds to reduce colon inflammation is the mainstay of therapy for ulcerative colitis (UC). The objectives of treatment are:

• Symptomatic relief
• Relapse prevention
• Minimization of complications
• Prevention of extraintestinal manifestations

Newer 5-ASA releasing drugs are equally as effective as sulfasalazine, with significantly reduced adverse effect profiles. The exact mechanism of action for mesalamine-derivative compounds in vivo is unknown. Recent studies indicate that multiple therapeutic mechanisms contribute to their efficacy, including:

• Inhibition of arachidonic acid metabolism
• Decreased free radical formation by oxygen radical scavenging
• Reduced IL-1 and plasma cell immunoglobulin production
• Inhibition of peripheral and intestinal lymphocyte activation
• Inhibition of NFKB activation, mitogen-activated protein kinase and TNF-a production

A variety of mesalamine preparations have been developed to improve drug delivery and reduce adverse effects, including enema, suppository, and oral and oral delayed-release formulations.

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Sulfasalazine

Sulfasalazine, discovered in Sweden in the 1940s, was the first known and prototypical mesalamine derivative used to treat UC and other bowel diseases. Its efficacy for inducing remission in UC was first demonstrated in 1962.2 The sulfasalazine molecule has little therapeutic action itself; rather it serves as a prodrug to deliver 5-ASA to the colon. 5-ASA has broad-spectrum effects on the immune system, which may account for its anti-inflammatory action.

Sulfasalazine tablets are indicated in the treatment of mild to moderate UC, as adjunctive therapy in severe UC, and for the prolongation of the remission period between acute attacks of UC.3

The predominant metabolic route for the sulfasalazine/5-ASA compounds is acetylation in which an acetyl molecule, added via enzyme reaction, produces acetyl sulfapyridine. The rate of acetylation is genetically determined. Toxicity and adverse effects are two to three times more common in slow acetylators than fast acetylators.3

Up to 30% of patients report adverse effects with sulfasalazine-derived 5-ASA products and approximately 15% discontinue medication. The most common dose-related side effects are anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia.3,4

Recognition that sulfapyridine is associated with dose-related adverse events from sulfasalazine led the development of sulfa-free oral mesalamine products. 4 Four of these sulfa-free mesalamine compounds are commercially available in the United States:

• COLAZAL® (balsalazide disodium) Capsules 750 mg (prodrug azo bond targeted delivery)
• Asacol® 5 (mesalamine) 400 mg tablets (delayed release)
• Dipentum® 6 (olsalazine) 250 mg capsules (prodrug azo bond targeted delivery)
• Pentasa® 7 (mesalamine) 250 mg capsules (controlled release)

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COLAZAL® (balsalazide disodium)

COLAZAL is indicated for the treatment of mildly to moderately active UC and delivers 2.4 g of free 5-ASA directly to the colon. For the treatment of active UC, the usual dose in adults is three 750 mg capsules to be taken 3 times per day for a total daily dose of 6.75 g for duration of 8 weeks. Some patients require treatment for up to 12 weeks. It enters the colon intact where bacterial azoreduction cleaves it to release equimolar quantities of mesalamine and 4-aminobenzoyl-β-alanine (4-ABA). The 4-ABA carrier moiety is largely inert and only minimally absorbed. Less than 1% of balsalazide is recovered in urine. The safety and effectiveness of COLAZAL beyond 12 weeks of treatment has not been established.8

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Asacol® (mesalamine)

Asacol tablets are indicated for the treatment of mildly to moderately active UC and for the maintenance of remission of UC. For the treatment of mildly to moderately active disease, the usual dose in adults is two 400 mg tablets to be taken three times a day for a total daily dose of 2.4 g for a duration of 6 weeks. For maintenance of remission of UC, the recommended dosage in adults is 1.6 grams daily, in divided doses. Treatment duration in the prospective, well-controlled trial was 6 months. Asacol tablets contain a core of 400 mg of mesalamine coated with a pH-sensitive acrylic polymer called Eudragit®-S, which delays release of mesalamine until the tablet reaches an environment ≥ pH 7. The coating, which typically dissolves in the terminal ileum or colon, delivers 1.2g - 1.6 g of mesalamine to the colon with approximately 28% systemic absorption.9

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Dipentum® (olsalazine sodium)

Dipentum is indicated for maintenance of remission of UC in patients intolerant to sulfasalazine. It is not indicated for the treatment of active UC. Dipentum capsules contain 250 mg of olsalazine sodium, a prodrug consisting of two molecules of mesalamine joined by a diazo bond that is cleaved by bacterial action in the colon. The usual dosage is two 250 mg capsules twice a day for a total daily dose of 1.0 g. Less than 1% of olsalazine is recovered in urine.10

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Pentasa® (mesalamine)

Pentasa is indicated for the induction of remission and for the treatment of patients with mildly to moderately active UC. A controlled-release formulation of mesalamine, each capsule of Pentasa contains 250 mg of mesalamine and is released throughout the gastrointestinal tract. The recommended dosage is 4 capsules taken 4 times per day for a daily dose of 4 g, which provides 1.6 g of free mesalamine to the colon. Approximately 20% - 30% of Pentasa is absorbed. Treatment duration is up to 8 weeks.11

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Lialda™ (mesalamine)

Lialda is indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis (UC). Safety and effectiveness of Lialda beyond 8 weeks have not been established. The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is two or four 1.2g tablets to be taken once daily with food for a total dose of 2.4g or 4.8g.

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References

1. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347(6):417-429.
2. Svartz N. Sulfasalazine: II. Some notes on the discovery and development of salazopyrin. Am J Gastroenterol. 1988;83:497-503.
3. Azulfidine Product Information. Pharmacia, Inc. Montvale NJ. In: Physicians' Desk Reference, Medical Economics Data Production Company; 2000.
4. Ishaq S, Green JR. Tolerability of Aminosalicylates in inflammatory bowel disease. BioDrugs. 2001;15(5):339-349.
5. Asacol® is a registered trademark of Procter & Gamble Pharmaceuticals.
6. Dipentum® is a registered trademark of Celltech Group.
7. Pentasa® is a registered trademark of Shire Pharmaceuticals.
8. COLAZAL Product Information. Salix Pharmaceuticals, Inc. Raleigh, NC; August 2002.
9. Asacol Product Information. Proctor & Gamble Pharmaceuticals. Cincinnati, OH; April 2000. [Available at: http://www.asacol.com.] Accessed 9/2/02.
10. Dipentum Product Information. Pfizer. [Available at: http://www.dipentum.com/pfizer/main.jsp ]
11. Pentasa Product Information. Roberts Pharmaceutical Corp. Montvale NJ. In: Physicians' Desk Reference, Medical Economics Data Production Company; 2000.

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