TREATMENT OF
INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease
mainly refers to ulcerative colitis and Crohn’s disease. Ulcerative colitis is charac-terized by a
relapsing inflammatory condition involving the mucosa of variable lengths of
the colon resulting in bleeding, urgency, diarrhea, and tenesmus. The
endo-scopic and radiographic appearance may demonstrate multiple diffuse
erosions or ulcerations. Biopsy reveals distorted crypt abscesses and
diminished goblet cells. When involvement is limited to the rectum, it is
termed ulcerative proctitis. Crohn’s disease may involve the gut from esophagus
to anus; however, the small bowel or colon or both are the major areas of
involvement. Inflammation is transmural. If the colon is predomi-nantly
involved, the symptoms and presentation are quite similar to those of
ulcerative colitis. Small bowel involvement may result in large-volume
bloodless diar-rhea or obstruction. Normal areas of gut may be found between
areas of inflamed mucosa. Fistulas, strictures, and abscess formation are
fairly common in Crohn’s disease.
The present primary mode of
therapy for these dis-eases involves the use 5-amino-salicylate (5-ASA)
products. Often patients require additional medications, including
corticosteroids, to help induce remission and various immune modulators, such
as azathioprine, 6-mercaptopurine or methotrexate, to maintain remis-sion. In
Crohn’s disease certain antibiotics, such as metronidazole and ciprofloxacin,
and infliximab (Remi-cade), an
anti–tumor necrosis factor- (TNF ) antibody,
also have been used.
Sulfasalazine (Azulfidine) was first introduced in 1940
as a treatment for rheumatoid arthritis. It was found that a number of patients
with coexistent inflammatory bowel disease showed improvement of their GI
symp-toms, and the drug has subsequently been used for the treatment of
patients with inflammatory bowel disease.
Sulfasalazine is composed of
sulfapyridine and 5-ASA molecules linked by an azo bond. Sulfapyridine has no
effect on the inflammatory bowel disease, and in-stillation of this agent into
the colon does not heal colonic mucosa. It is, however, responsible for most of
sulfasalazine’s side effects, including sulfa allergic reac-tions. 5-ASA, the
active metabolite, may inhibit the syn-thesis of mediators of inflammation.
Following oral
administration, 30% of the sul-fasalazine is absorbed from the small intestine.
Because most of the compound that is absorbed is later excreted into the bowel,
75 to 85% of the administered oral dose eventually reaches the colon intact.
Bacteria in the colon then split the azo linkage, liberating sulfapyridine and
5-ASA. The sulfapyridine is absorbed, acetylated, hydroxylated, and conjugated
to glucuronic acid in the liver. The major portion of the sulfapyridine
molecule and its metabolites are excreted in the urine. The 5-ASA remains in
the colon, eventually reaching high fe-cal levels.
Sulfasalazine treatment
results in an 85% remission rate in mild to moderate ulcerative colitis.
Termination of therapy leads to an 80% relapse within the next year. In Crohn’s
disease, sulfasalazine acts primarily on in-volved colonic mucosa, although
remission of ileal dis-ease also has been reported. The National Cooperative
Crohn’s Disease Study found sulfasalazine to be better in the treatment of
colonic disease, while corticosteroids were judged better in the treatment of
small bowel dis-ease. Since sulfasalazine does not prevent relapse of Crohn’s
disease once remission is achieved, mainte-nance therapy is not
characteristically used.
Nausea, vomiting, and
headaches, the most common side effects, are related to the blood level of
sulfapyri-dine. If the dose is reduced, symptoms frequently im-prove. Fever,
rash, aplastic anemia, and autoimmune hemolysis are hypersensitivity reactions
to the medica-tion. These occur less commonly and are not dose re-lated.
Sulfasalazine should not be used in patients with hypersensitivity
agranulocytosis or aplastic anemia.
Since sulfasalazine inhibits
the absorption of folic acid, patients may become folate deficient during
long-term therapy. Sulfasalazine decreases the bioavailability of digoxin.
Cholestyramine reduces the metabolism of sulfasalazine. Sulfasalazine causes a
reversible decrease in sperm counts. Sulfasalazine is safe in pregnancy.
To avoid the side effects of
sulfapyridine, various preparations to target 5-ASA directly to sites of
disease have been formulated. Also known as mesalamine, 5-ASA has been formulated
in oral forms (Pentasa, Asacol). Pentasa is a time-release
capsule that releases the drug
throughout the GI tract. Asacol is a pH-dependent–release preparation that
delivers drug to the distal small bowel and colon. The response of ulcerative
colitis to this formulation appears to be identical to that seen with
sulfasalazine. Mesalamine can also be admin-istered as a suppository (Canasa) or enema (Rowasa) for distal colonic disease.
Olsalazine sodium (Dipentum) links two 5-ASA molecules with
an azo linkage. Following cleavage of the azo linkage in the colon, two 5-ASA
molecules are released. Olsalazine is approved for maintenance of re-mission of
ulcerative colitis, but a commonly reported side effect is a paradoxical
increase in diarrhea. The U. S. Food and Drug Administration (FDA) has
ap-proved balsalazide disodium (Colazal)
as a treatment of mild to moderately active ulcerative colitis. Balsalazide
disodium is delivered intact
to the colon, where it is cleaved by bacterial azoreduction to release
equimolar quantities of mesalamine, the therapeutically active portion of the
molecule, and 4-aminobenzoyl- -alanine; the latter compound is only minimally
absorbed and is largely inert.
TNF-α is an inflammatory
cytokine thought to have a contributory role in producing chronic inflammation
in various diseases, including Crohn’s disease and rheuma-toid arthritis .
Infliximab (Remicade) is a
mouse–human chimeric monoclonal neutralizing
anti-body to human TNF-α and is considered a biological drug. Specific
indications are for the reduction of signs and symptoms in patients with
moderately to severely active Crohn’s disease who have had an inadequate
re-sponse to conventional therapies (single infusion) and for reduction of the
number of draining enterocuta-neous fistulas in patients with fistulizing
Crohn’s disease (three-infusion regimen). Responses occur within 2 weeks of an
infusion, and significant clinical responses were reported in 50 to 80% of
patients in initial trials with infliximab. This antibody is being studied as
main-tenance therapy for Crohn’s disease and to determine the best induction
regimen to achieve remission.
The most common side effects,
which are related to the intravenous infusion itself, include rash, low blood
pressure, chills, and chest pain. These symptoms are generally temporary and
often respond to a decrease in infusion rate. In addition, some patients
develop anti-bodies, which have been associated in rare cases with symptoms
similar to those of patients with systemic lu-pus erythematosus. These symptoms
were also tempo-rary. Another side effect is increased risk of infections.
Fatal cases of tuberculosis have been reported follow-ing infliximab therapy.
Another potential side effect is an increased risk of lymphoma. Its occurrence
remains controversial.
Recently, budesonide (Entecort EC) has been approved for the
treatment of mildly to moderately active Crohn’s disease involving the ileum
and/or ascending colon. Budesonide is a synthetic corticosteroid having a
potent glucocorticoid and weak mineralocorticoid ac-tivity. In standard in
vitro and animal models, budes-onide has an approximately 200-fold higher
affinity for the glucocorticoid receptor and a 1000-fold higher top-ical
antiinflammatory potency than cortisol. While budesonide is well absorbed from
the GI tract, its oral bioavailability is low (about 10%), primarily because of
extensive first-pass metabolism in the liver. Two ma-jor metabolites (16
-hydroxyprednisolone and 6 - hydroxybudesonide) are formed via the cytochrome
P450 3A enzyme. In vitro studies on the binding of the two primary metabolites
to the corticosteroid receptor indicate that their affinity for the receptor is
less than 1% of that of the parent compound. It is hoped that use of this drug
will avoid the long-term adverse reactions seen with systemically active
corticosteroids.
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