PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.

COM

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5-ASAs in the Treatment of

Inflammatory Bowel Disease
BRIAN BOSWORTH, MD

ELLEN J. SCHERL MD

Assistant Professor of Medicine

Weill Cornell Medical College
Anne and Ken Estabrook Clinical Scholar
in Gastroenterology
Weill Cornell Medical College
Assistant Attending Physician
NewYork-Presbyterian Hospital
New York, New York

Director, Jill Roberts Center

for Inflammatory Bowel Disease
Associate Professor of Clinical Medicine
Weill Cornell Medical College
Associate Attending Physician
NewYork-Presbyterian Hospital
New York, New York

lthough the dogma of dividing the

major auto-inflammatory maladies

of the gastrointestinal tract into

2 distinct entitiesulcerative colitis (UC)

and Crohns disease (CD)has persisted
for decades, a more nuanced view

presents inflammatory bowel disease

(IBD) as a spectrum of chronic and

recurring diseases of the intestines.

This review will address the concept

of a targeted, personalized approach

to IBD treatment, with a focus on
5-aminosalicylates (5-ASAs).

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Epidemiologic data on IBD are fractionated into the

pigeon holes of separate diagnoses, with an incidence
of 7 to 9 per 100,000 and a prevalence of 200 to 250 per
100,000 for UC; the incidence and prevalence of CD is 6 to
8 per 100,000 and 130 to 200 per 100,000, respectively.1-3
Although there are patients who fall more clearly into one
category than another, the concept of indeterminate colitis
(IC) is poorly defined and therapeutic guidelines are lacking.
Thus IC might represent part of an immunologic continuum,
rather than a well-defined clinical subset of UC and CD.4,5

G A S T R O E N T E R O L O G Y & E N D O S C O P Y N E W S J U LY 2 0 1 1

Challenging Traditional IBD Classifications

of IBD, and will be a bridge linking clinical immunophenotypes with genotypes.12,13 While new genes continue
to highlight host microbial interactions, serologic markers indicate dysregulated antibodyantigen immune
responses.14,15
Differentiation between types of IBD becomes important in stratifying therapeutic strategies. Poor therapeutic response is an indication for surgery in approximately
30% of patients with UC and 50% to 70% of patients with
CD. Patients with refractory left-sided colitis or IC may
benefit from serologic testing, in addition to documentation of clubbing and oral aphthae.13 In these patients,
if the markers are more consistent with a molecular pattern of CD, physicians may consider anti-tumor necrosis factor (TNF) therapy as an option rather than total
colectomy.
Serologic profiling already has proven helpful in
patient stratification. Although controversial, high levels of perinuclear antineutrophil cytoplasmic antibodies
(pANCA) have consistently correlated with postoperative
pouchitis.16 Additionally, anti-CBir1, an antibody to flagellin of the polyflagellated organisms, is associated with
an increased incidence of chronic pouchitis in patients
who have high pANCA levels, and with acute pouchitis in
those with low pANCA levels.17 Expression of antiSaccharomyces cerevisiae antibody (both immunoglobulin
[Ig] subtypes A and G) correlates with a younger age of
onset and more aggressive fibrostenotic disease.18,19 Also,
antibodies against the CD-related bacterial sequence I2,
Escherichia coli outer membrane porin C, and CBir1 flagellin identify a unique subset of immunologically vulnerable patients with complicated/aggressive CD.20,21
Serologic diagnostic and biomarker testing provides
a molecular snapshot of patients with IBD. New markers and prospective trials are required to correlate immunologic, molecular, and clinical patterns of IBD and will
advance the risk assessment of patients, the selection
of prevention-oriented therapies, and the science of IBD.

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The Montreal classification has been used to characterize the phenotype of classically defined CD into
inflammatory, penetrating (or fistulizing), and fibrostenotic.6 However, Crohns colitis has not been well defined
in the literature and may be difficult to classify,7 for example, the patient who presents with diarrhea and pancolitis with minimal bleeding, the patient with left-sided colitis and a cecal patch, or the patient on therapy for colitis
now with an endoscopic distribution of disease demarcated by skip areas.
The many forms of UC (eg, ulcerative proctitis, leftsided colitis, universal colitis) may be a series of diseases
rather than a single class. Just as rectal cancer is treated
in a different fashion than more proximal colonic adenocarcinomas, UC may be a pathologic state with many etiologies. Serologic markers may help to provide a window
for observing an abnormal antibodyantigen response
and thus could potentially help identify patients at risk
for rapid progression of disease who may benefit from
early intervention.8 Molecular diagnostics, such as antibody serologic and biomarkers, hold the promise of
enhancing the understanding of IBD subtypes and stratifying patients on the basis of immunophenotypes.
A broad differential diagnosis is increasingly recognized as important in distinguishing active inflammation
from other conditions (eg, medication-induced pseudorefractory IBD [including infections, eg, Clostridium difficile, cytomegalovirus], irritable bowel syndrome, celiac
disease, lactose and/or fructose intolerance, dietary
indiscretion, bile acid diarrhea, obstructive stricturing or
fistulizing CD requiring surgery) and in stratifying optimal therapeutic response to biologic agents and immunosuppressives.9 In select patients with moderately to
severely active IBD, early intervention with effective therapy is associated with significant improvement in mucosal healing and reduction in the progression of disease.10,11
However, these latter approaches using biologic therapy in a top-down fashion (as DHaens argues in his
revolutionary Lancet paper10) and possibly in combination with immunomodulators (as illustrated in the SONIC
[Study of Biologic and Immunomodulator Naive Patients
in Crohns Disease] trial9) are reserved for those patients
in whom systemic corticosteroids are either being considered or being used. Corticosteroids have a myriad of
adverse effects, including acne, hyperglycemia, avascular necrosis of the femoral neck, cataracts, among others.
There is proven benefit for using 5-ASAs in patients with
mild to moderate UC, although their role in CD is more
controversial.

Molecular Classification of IBD

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

The majority of patients with IBD have moderate disease. Approximately, three-fourths of patients have
active UC22 and two-thirds of patients with CD have moderate to severe disease that requires alternatives to treatment with mesalamine therapies.23 The treatment goals
for patients with IBD are universalto induce remission
as quickly as possible, maintain remission as long as possible, facilitate mucosal healing, improve quality of life,
minimize toxicity, and minimize cost.
For patients with UC, oral and rectal 5-ASA agents,
corticosteroids (administered orally or intravenously),
immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP]), and infliximab are used to induce
remission. Cyclosporine has been used to induce remission as well, with faster time to symptom relief, but there
is an increased burden on patients and providers for
monitoring. Laharie et al recently presented the findings
of a study comparing cyclosporine and infliximab that
showed equivalent efficacy for short-term remission and

IBD nomenclature does not accurately reflect the

complexity of the clinical phenotype. Although the role
of serum antibody markers remains controversial, using
a combination of markers enhances accuracy and specificity in classifying IBD-related aberrant immunophenotypes. The emerging role of molecular diagnostics is
vital in characterizing the immunologic heterogeneity

Treatment of IBD Subtypes

l ri

Al

avoidance of colectomy.24 For maintenance of remission

of UC, 5-ASAs and 6-MP/AZA or infliximab may be used.
Additionally, infliximab is approved for the reduction of
signs and symptoms, induction of clinical remission and
mucosal healing, and elimination of corticosteroid use in
patients with moderately to severely active UC who have
had an inadequate response to conventional therapies.25
For patients with CD, steroids are still recommended
as possible first-line agents. There are no good controlled
trials evaluating antibiotics (eg, metronidazole, ciprofloxacin [alone, or in combination], rifaximin). Immunomodulators (eg, 6-MP, AZA, methotrexate [MTX]), anti-TNF
drugs (eg, infliximab, adalimumab, certolizumab), and
natalizumab are used to induce remission. For maintenance of remission, immunomodulators and biologics can be used.26-31 There are limited data for 5-ASAs in
both the induction and maintenance of remission in CD.
Probiotics and novel antibiotics (eg, rifaximin) have
the potential to revolutionize the treatment of patients
with IBD.32 For example, anti-inflammatory interleukin
(IL)-10 levels have been associated with Bifidobacterium infantis.33 However, a greater understanding of gut
microecology and further clinical trials are needed.

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5-ASAS: MECHANISM

OF

ACTION

!#

;*#

Figure 1. Disease distribution of

ulcerative colitis at presentation to
the physicians office.
Based on reference 43

PPARs are members of the nuclear receptor superfamily.

They are activated by fatty acids and are involved in the
complex interplay of metabolic and nutritional signals
leading to transcriptional responses. They are expressed
in high levels in the colonic epithelium and their ligands
are involved in regulation of inflammation. A randomized
placebo controlled clinical trial of rosiglitazone (a PPAR-
ligand) demonstrated efficacy in treating mild to moderate UC.42 However, despite these numerous experimental studies, the true basic mechanism of action of 5-ASA
remains unknown.
Because 5-ASAs work topically within the lumen of the
gastrointestinal tract, achieving maximal concentration
of the agent at the site of active disease is tantamount.
The specific goals of 5-ASA therapy are to quickly induce
complete remission, to facilitate mucosal healing, and to
minimize steroid use and toxicity. Often overlooked is the
distribution of UC; more than 50% of patients have leftsided disease (Figure 1).43
In 1942, 5-ASA was combined with an antibiotic sulfapyridine in a molecule named sulphasalazine. Thirty-five
years later, Azad Khan et al44 demonstrated that 5-ASA
was the therapeutically active moiety of this drug with
proven anti-inflammatory effects in IBD. Both mesalamine (free, unconjugated 5-ASA) and mesalamine prodrugs (azo-bonded 5-ASA) have similar modes of action.
Sulfasalazine, the archetypal azo-bonded 5-ASA designer
drug, is engineered to release free 5-ASA in the colon,
protecting it from proximal absorption. However, intolerance and hypersensitivity to the sulfapyridine moiety limit the dose of sulfasalazine, and have led to the

5-ASA acts locally in the colon and is absorbed by

colonic epithelial cells.34-36 The effectiveness of the compound is related to its mucosal concentration,37 and systemic dosages remain low after oral sulphasalazine and
rectal 5-ASA administration.38 The putative anti-inflammatory actions of 5-ASA include modulation of inflammatory cytokine production, decreased transcriptional
activity of nuclear factor-kappa B (NF-B) by modulating RelA/p65 phosphorylation, and inhibition of the biosynthesis of prostaglandins and leukotrienes.39
One proposed mechanism of action of 5-ASA is the
inhibition of the cyclooxygenase (COX) and 5-lipoxygenase pathways of arachidonic acid metabolism, resulting
in a decrease in pro-inflammatory prostaglandins and
leukotrienes.40 The role of the COX pathway and prostaglandin biosynthesis in IBD remains to be elucidated.
Attention has shifted from the arachidonic acid cascade
to NF-B. The discovery of the role of nucleotide-binding oligomerization domain 2 in the activation of NF-B
emphasizes the importance of NF-B in the inflammatory
signaling cascade and its interaction with luminal bacterial antigens and genetic susceptibility. In vitro studies demonstrate that sulfasalazine inhibits NF-B, which
provides evidence in support of the direct biologic efficacy of 5-ASA.
Clinicians should question whether the site of 5-ASA
release is a determinant in optimizing and individualizing therapy. Two therapeutic strategies expose opposing
views: one is that all 5-ASA preparations are equivalent;
the other is that subtle differences in the mode of 5-ASA
delivery translate into differences in clinical efficacy.
Recently, it has been postulated that 5-ASA leads
to peroxisome proliferatoractivated receptor-gamma
(PPAR-) transcription and protein expression.41 The

$

G A S T R O E N T E R O L O G Y & E N D O S C O P Y N E W S J U LY 2 0 1 1

pH-independent
ethylcelluloseencapsulated
mesalamine

pH-independent
azo-bonded
5-ASA

Figure 2. Oral aminosalicylate delivery

in the small and large intestine.
5-ASA, 5-aminosalicylic acid

development of new 5-ASAcontaining analogs. The

newer topical and oral 5-ASA agents are delivered to different anatomic sites, ideally corresponding to the distribution of active disease (Figure 2; Figure 3). Although
these agents are less toxic than sulfapyridine, allergies to
mesalamine have been reported. Interstitial nephritis has
been reported with the 5-ASA moiety alone45; although
rare, the potential for this adverse event (AE) mandates
periodic renal function monitoring. One potential untoward reaction to 5-ASA is intolerance to the drug, presenting as bloody diarrhea mimicking the underlying IBD
itself. In cases of severe refractory UC, it is advisable to
consider discontinuing the 5-ASA along with initiation of
salvage therapy in hopes of preventing colectomy.
OF

UC

Until the introduction of balsalazide, all of the newer

5-ASA agents had been shown to induce and maintain
remission of UC nearly as well as sulfasalazine and usually
as well as one another. Recently, novel dual-delivery systems (delayed- and extended-release formulations) allow
for effective dose de-escalation, with lower doses of active
5-ASA delivered to the site of active colitis (Table).46-48
In the first head-to-head trial comparing an equimolar dose of balsalazide (6.75 g) with pH-dependent mesalamine (2.4 g), balsalazide showed superior efficacy in
patients with new-onset left-sided UC (62% vs 37%) and
shorter time to response (10 vs 25 days) compared with
pH-dependent mesalamine. Also, response rates were
higher with balsalazide compared with pH-dependent
mesalamine in patients with right-sided UC, although the
difference was less significant compared with patients with
left-sided disease.49,50 A stratification study confirms that
among patients with new-onset left-sided UC, more than
60% of those treated with balsalazide were in remission
at 1 month compared with 40% of those treated with pHdependent mesalamine. Additionally, patients with rightsided UC who were treated with balsalazide had less rectal bleeding, better sigmoidoscopic-evident healing, and

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

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pH-dependent
acrylate-coated
mesalamine

TREATMENT

improved stool frequency.

Levine et al51 conducted a randomized, double-blind
study comparing 2 doses of balsalazide (6.75 and 2.25
g) and mesalamine (2.4 g) in patients with active, mild to
moderate UC. At week 8, rates of remission were similar for
all 3 treatment groups, as were safety profiles. The primary
difference between balsalazide (6.75 g) and mesalamine
appeared to be the time to symptom resolution (10 vs 25
days, respectively). Kornbluth et al52 compared the colonic
mucosal concentration of 5-ASA in patients treated with a
mean of 6.75 g per day of balsalazide with those treated
with a mean of 3.74 g per day of pH 7dependent mesalamine and demonstrated that patients who received balsalazide had significantly higher mean mucosal concentrations
of 5-ASA than patients who received mesalamine.
Because of the predominance of left-sided disease, the
combination of oral and topical aminosalicylates is critical in inducing and maintaining remission.53,54 Safdi et al53
elegantly demonstrated that although topical mesalamine
was more effective than oral in patients with left-sided UC,
the combination of 2.4 g of oral mesalamine and mesalamine enemas produced earlier and more complete cessation of rectal bleeding. For maintenance of remission,
DAlbasio et al54 found that a combination of 1.6 g of oral
mesalamine with twice weekly mesalamine enemas produced higher rates of remission compared with oral therapy alone (61% vs 31%, respectively). Topical mesalamine
(enemas and suppositories) used as infrequently as twice
per week was effective in maintaining remission in patients
with distal colitis.
Biddle et al55 established that 75% of patients (9 of
12) randomized to receive mesalamine enemas remained
in remission at 1 year compared with 85% of patients (11
of 13) on placebo who had relapsed by week 16. Similarly,
mesalamine suppositories were associated with long-term
remission in patients with ulcerative proctitis56; at 12 and 24
months, 86% and 89% of patients on placebo had relapsed
compared with 32% and 46% of patients treated with mesalamine suppositories, respectively. A meta-analysis established that in patients with left-sided UC and ulcerative
proctitis, topical mesalamine showed greater efficacy and
fewer side effects than oral therapies and topical steroids.57
Additionally, Campieri et al58 demonstrated that mesalamine suppositories were effective in inducing remission in
patients with ulcerative proctitis (distal colitis up to 20 cm).
In that study, 74% of patients who received mesalamine
suppositories (1.5 g) achieved clinical remission at week 4
compared with 39% of patients who received placebo.
The pH-sensitive 5-ASAs were evaluated in a placebocontrolled trial in patients with mild to moderate UC.59
Complete remission was achieved in 24% of patients on
mesalamine 4.8 g, 9% of patients on mesalamine 1.6 g, and
5% of patients on placebo. Partial response was noted in
50% of patients in the high dose mesalamine group compared with 18% in the low-dose group and 13% in the placebo group. The ASCEND II trial found 4.8 g of delayedrelease mesalamine to be superior to 2.4 g in patients with
moderate UC, with response rates of 72% and 59%, respectively; remission rates were similar in both groups at 24%.60

6.75

5-ASA
SASP Carrier

Daily Dose, g

4-ABA Carrier

5
4

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ASCEND I and II were the first head-to-headalthough

nonplacebo-controlledcomparisons of 2.4 versus 4.8 g
of Asacol in patients with mild to moderate UC. In ASCEND
III, the response rate at 6 weeks was 70% for patients taking
4.8 g of Asacol (6 tablets, 800 mg each) compared with
66% for those taking 2.4 g of Asacol (6 tablets, 400 mg
each).61 This study met its primary end point of non-inferiority of the 2 doses. Subset analyses showed efficacy with
the higher dose in those patients requiring steroids or multiple UC medications.
Another pH-dependent formulation of 5-ASAmultimatrix (MMX) mesalaminetaken once or twice daily has
been shown to be well tolerated and to induce remission in
patients with mild and moderate UC. The formulation is a
1.2-g tablet and has been evaluated for twice-daily (1, 1.2-g
tablet, bid; 2.4 g/d) and once-daily (4, 1.2-g tablets, once
daily; 4.8 g/d) administration. Lichtenstein et al showed
that after 8 weeks of treatment, rates of clinical and endoscopic remission were significantly higher for patients taking MMX mesalamine compared with patients taking placebo (34.1% and 29.2% for 2.4 g/d and 4.8 g/d, respectively,
vs 12.9% for placebo; P<0.01).62,63 Increasing the dose to
4.8 g per day for an additional 8 weeks resulted in clinical and endoscopic remission and symptom resolution for
nearly 60% of patients in a median time of 15 days.64 In a
separate study by Kamm et al, once- or twice-daily MMX
mesalamine resulted in maintenance of clinical and endoscopic remission.65
A granulated pH 6releasing formulation of 5-ASA with
a polymer matrix core has been approved by the FDA for
the maintenance of remission at 1.5 g per day. Lichtenstein
et al66 demonstrated maintenance of remission in nearly
79% of patients who switched from different 5-ASA formulations compared with almost 60% who maintained remission on placebo.
A European dose-ranging study that evaluated this pH
6releasing formulation of 5-ASA in patients with mildly to
moderately active UC yielded remission rates of 66% for
patients taking 3 g per day, 50% for those taking 1.5 g per
day, and 55% for those taking 4.5 g per day.46 Although
there was no placebo arm in the study, clinical remission
rates in all 3 treatment groups were high. With the exception of endoscopic improvement, which was better in the 3
g per day group than in the 1.5 g per day group, no significant differences among the 3 groups were observed. These
findings suggest that the novel delivery mechanism of this
mesalamine may lead to release of the drug at the site of
active disease.
In another study, 2 dosing strategies of mesalamine
granulesa 3-g dose given once daily and a 1-g dose
given 3 times per daywere shown to be similarly safe and
effective for inducing clinical and endoscopic remission in
patients with mildly to moderately active UC.47
A recent meta-analysis confirmed the benefit of 5-ASA
for inducing and maintaining remission in UC.67 The optimal
dose appeared to be 2.4 g per day with no apparent benefit from increasing the dose. Similarly, the optimum dose
to prevent relapse was 2.0 g to 2.4g per day. These recommended doses are expressed in mesalamine or equivalent.

2.4

2
1

Mesalamine

Sulfasalazine

Balsalazide

Equivalents

Figure 3. Drug doses needed to

provide equal amount of 5-ASA.

4-ABA, 4-aminobenzoyl-B-alanine; 5-ASA, 5-aminosalicylic acid;

SASP, sulfasalazine

TREATMENT

OF

CD

Compared with UC, the role of 5-ASA therapy in maintenance of remission of CD is not well defined.
The results of ACCENT I (A Crohns disease Clinical
trial Evaluating infliximab in a New Long term Treatment
regimen), which established the efficacy of infliximab for
maintenance therapy in CD, challenge the lack of effectiveness of maintenance strategies previously established by the multicenter National Cooperative Crohns
Disease Study and European Cooperative Crohns Disease Study.68-70 These trials did not demonstrate a statistically significant benefit of sulfasalazine in the maintenance of remission of CD. Notably, only 20% to 30% of
patients with CD have colonic disease alone, and most
sulfasalazine is released in the colon. Subsequent smaller
trials confirmed the lack of efficacy of sulfasalazine. All of
these studies were flawed, in that they analyzed different
disease sites (ileal, ileocolonic, colonic), different groups
of patients (medical vs surgical), and different doses of
medication.
With the introduction of mesalamine, higher doses of
active 5-ASA have shown increased efficacy for both the
induction and maintenance of remission in patients with
CD.71 A meta-analysis of 10 randomized controlled trials evaluating mesalamine maintenance therapy in 1,371
patients with CD showed no statistically significant difference in relapse rates between treatment and placebo;
however, mesalamine treatment was associated with significantly lower relapse rates in patients with limited ileal
disease of long duration.72
A recent meta-analysis yielded 6 randomized placebocontrolled trials and suggests that 5-ASAs may be more
effective than placebo with a number needed to treat of
11.73 Although the evidence was of low quality, and there

G A S T R O E N T E R O L O G Y & E N D O S C O P Y N E W S J U LY 2 0 1 1

Table. Mechanisms of Release and Indications of 5-ASAContaining Drugs

Mechanism

Advantage

Indication

Diffusion-dependent

Time-released, moisturedependent ethylcelluloseencapsulated mesalamine

travels in solution and
allows free 5ASA mesalamine to diffuse out of
the ethylcellulose beads
and begin releasing in the
upper intestines and continue throughout the small
and large intestines.

Independent of pH or
bacteria; mucosal delivery
of mesalamine is less
affected by rapid intestinal
transit time (ie, diarrhea).

Free 5-ASA (mesalamine)

is indicated in patients
with proximal disease
activity, severe
diarrhea, strictures
(1-mm ethylcellulose
microspheres offer
advantages), pouchitis
(the constant moisturedependent release may
provide advantages),
and postoperative
anastomosis.

The pH-dependent mesalamine preparations are

coated with an acrylate
resin and are released at
variable pH levels between
6.0 and 7.0 in the distal
ileum and colon. (The pH
in the ileum and ascending
colon is 7.0.)

Free 5-ASA (mesalamine)

dosage can be maximized
to 4.8 to 6 g daily, equivalent to a triple dose of sulfasalazine (12 g) with significantly less toxicity.

A pH-dependent delivery
system is indicated in
ileocolonic disease.

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Mesalamine controlledrelease
(Pentasa, Shire)

pH-dependent

Mesalamine delayedrelease (pH 7.0)

(Asacol, Warner
Chilcott)

MMX mesalamine
(pH 7.0) (Lialda, Shire)
Mesalamine delayedrelease (pH>6.0)
(Eudragit-L, Degussa
Rohm)

Mesalamine delayedand extended-release

(polymer core of slowrelease mesalamine;
pH 6.0) (Apriso, Salix)

Colonic
floradependent,
azo-bonded

Sulfasalazine
(Azulfidine, Pfizer)

Sulfasalazine delayedrelease (Azulfidine

EN-Tabs, Pfizer)
Balsalazide disodium
(Colazal, Salix)
Olsalazine sodium
(Dipentum, Pfizer)

Topical/rectal
formulations

Mesalamine
suppositories
(Canasa, Axcan Pharma)

Lialda is a 1.2-g tablet that

is a high-dose delayedrelease pH-dependent
mesalamine formulation. Once-daily dosage
is between 2.4 and 4.8 g
(2-4 tablets).

Apriso once-daily 1.5-g

granulated delayed- and
extended-release mesalamine (4, 0.375-g capsules)
travels in solution.

There are currently 3

variations of colonicreleasing, azo-bonded
5-ASA: olsalazine
consists of 2 molecules
of 5-ASA linked to each
other; balsalazide links
an inert polymer of
4-aminobenzoyl-B-alanine
to 5-ASA; sulfasalazine
consists of 5-ASA bonded
to sulfapyridine.

In these azo-bonded
Indicated for patients with
5-ASA forms, the molecule universal and distal colitis.
reaches the colon primarily
intact, and the azo bond is
cleaved by colonic bacterial azoreductase, thereby
releasing free, unconjugated 5-ASA (mesalamine).

Rectal preparations
include 5-ASA suspensions
(4-g mesalamine enema
and 500-mg mesalamine
suppositories) instilled
directly into the rectum.

Advantages of topical
preparations include direct
exposure to diseased
mucosa.

A high-dose, 1.1-g
balsalazide tablet allows
for lower pill burden and
twice-daily dosing.

Indicated for patients

with left-sided colitis and
proctitis.

Mesalamine enema
(Rowasa, Alaven)

5-ASA, 5-aminosalicylic acid; MMX, multimatrix

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

was not a sufficient number of trials to recommend or

advise against 5-ASA use in preventing relapse, further
trials might be helpful.

16. Fleshner PR, Vasiliauskas EA, Kam LY, et al. High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before
colectomy predicts the development of chronic pouchitis after ileal pouch
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Optimization of Oral 5-ASAs

17. Fleshner P, Ippoliti A, Dubinsky M, et al. Both preoperative perinuclear antineutrophil cytoplasmic antibody and anti-CBir1 expression in ulcerative
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Although there are no studies evaluating combinations

of oral 5-ASA drugs, combination therapy can be considered in patients who fail to respond to mesalamine monotherapy or 5-ASA pro-drug monotherapy. 5-ASA nonresponders may benefit from a combination of pH-dependent polymer-coated mesalamine, moisture-dependent
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AUTHOR DISCLOSURESDr. Bosworth serves as a consultant to Salix Pharmaceuticals and Shire. Dr. Scherl has received grant and research support from Abbott Laboratories, Axcan Pharma, Centocor Ortho Biotech Inc., Cerimon Pharmaceuticals, Inc., Elan, Millennium
Pharmaceuticals, Inc., Osiris Therapeutics, Inc., Prometheus Laboratories, Salix Pharmaceuticals, and UCB. She has served as a consultant or advisory board member for Abbott Laboratories, AstraZeneca, Axcan Pharma, Berlex Laboratories, Centocor Ortho Biotech
Inc., Cerimon Pharmaceuticals, PDL BioPharma, Inc., Procter & Gamble, Prometheus Laboratories, Questcor Pharmaceuticals, Inc., Salix
Pharmaceuticals, Shire, Sigma-Tau Pharmaceuticals, Inc., Solvay, TAP Pharmaceuticals, and UCB. She has served on the speakers bureau
for Abbott Laboratories, Axcan Pharma, Centocor Ortho Biotech Inc., Prometheus Laboratories, Questcor Pharmaceuticals, Inc., Salix
Pharmaceuticals, Shire, and Solvay. She has received honoraria from Abbott Laboratories, AstraZeneca, Axcan Pharma, Centocor Ortho
Biotech Inc., Procter & Gamble, PDL BioPharma, Inc., Prometheus Laboratories, Salix Pharmaceuticals, Shire, Sigma-Tau Pharmaceuticals,
Inc., Solvay, TAP Pharmaceuticals, and UCB. She has received other financial or material support from Abbott Laboratories, Centocor
Ortho Biotech Inc., PDL BioPharma, Inc., Prometheus Laboratories, Salix Pharmaceuticals, and UCB.

DISCLAIMERThis review is designed to be a summary of information and represents the opinions of the author. Although detailed, the
review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and
the absence of typographical errors is not guaranteed. Copyright 2011, McMahon Publishing, 545 West 45th Street, 8th Floor, New York,
NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form.

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