Mesalamine in the Treatment of Diverticular Disorders

Diverticular disease of the colon is a common condition worldwide, affecting up to 60% of

persons older than 60 years old in western countries(1). Colonic diverticula are classically

described as occurring at weak points in the colonic wall, thus creating pseudodiverticula

consisting of herniations of only the mucosal and submucosal layers. Both a lack of dietary

fiber and alteration in the connective tissue milieu have been implicated in the formation of

colonic diverticula(2). The clinical manifestations of colonic diverticular disease vary, and

many of the complications that arise can be attributed to the incomplete wall and vascular supply

of the diverticulum. Most patients with diverticular disease remain asymptomatic, though up to

20% may experience complications such as diverticulitis, significant gastrointestinal bleeding,

and chronic abdominal symptoms such as abdominal pain, altered bowel habits, and recurrent

passage of blood per rectum (symptomatic diverticular disease).

While the exact pathogenic factors leading to diverticulitis are uncertain, a number of

theories have been proposed. Obstruction of the diverticulum with inspissated stool and fecaliths

leading to bacterial overgrowth and tissue ischemia, and eventual inflammation, has long been

the mechanism suspected of causing acute diverticulitis. More recently, a low grade chronic

inflammation, secondary to an alteration in colonic microflora and similar to inflammatory

bowel disease has also been proposed(3). Research has shown that the inflammatory cascade in

diverticular disease can lead to an imbalance of cytokines and interleukins, which can also lead

to a local, mucosal inflammation similar to inflammatory bowel disease(4,5). Additional studies

have also found an increase in nitric oxide in patients with diverticulitis, which is important in

regulation of inflammation, and may be a factor in the inflammatory response seen in these

patients(6).

Mesalamine

Mesalamine is a derivative of sulfasalazine, a compound which has been used

successfully in the treatment of inflammatory bowel disease (IBD) for over 60 years.

Sulfasalazine is chemically composed of a sulfa-based component, sulfapyridine, linked via an

azo-bond to a 5-aminosalicylic acid moiety (5-ASA), as depicted in Figure 1. The 5-ASA

compound exerts the beneficial anti-inflammatory effects, and is the active drug(7). 5-ASA

alone is rapidly absorbed in the jejunum, and therefore is not an effective medication for the

treatment of distal small bowel and colonic diseases. Sulfasalazine is able to deliver 5-ASA to

the colon due to the azo-bond, which requires colonic bacteria for cleavage and release of 5-ASA

and sulfapyridine in the colon. Sulfapyridine was found to be the cause of a number of the side

effects which have been attributed to sulfasalazine, which led to the development 5-ASA

products which are able to deliver the drug directly to the colon without containing sulfapyridine.

Mesalamine is one such medication, and is now widely used as a substitute to sulfasalazine due

to its superior side effect profile. A number of preparations of mesalamine are currently

available which have been formulated to be released in the colon preferentially, either via

mechanisms which allow 5-ASA delivery only at colonic pH, or through the use of inert carriers

and coatings (See Table 1). All of these medications exert a topical anti-inflammatory effect

directly to the colonic mucosa.

While the exact mechanism of action of mesalamine is unclear, mechanisms such as

immunosuppression, altered cytokine synthesis and necrosis factor-κB (NF- κB) pathways, free

radical scavenging, and disruption of prostaglandin synthesis via interaction with the

lipooxygenase pathways have all been proposed (8). Some studies have shown an effect of 5-

ASA products on B- and T-cell clonal proliferation, (9-11), which in turn leads to a decreased

inflammatory response. Additionally, mesalamine likely exerts direct anti-inflammatory

properties via antioxidant effects (12). Mesalamine may also interrupt the synthesis of important

proinflammatory cytokines and leukotrienes through action on the lipoxygenase pathway, which

would lead to a decreased inflammatory response (13-17). 5-ASA products may also enhance

the expression of intestinal epithelial heat shock protein, which is thought to provide increased

cellular protection (18). Further studies have shown an inhibitory effect of mesalamine on

interleukin 1, interleukin 12, and tumor necrosis factor -alpha, and more recent reports have also

suggested that mesalamine may exhibit anti-inflammatory effects via the Peroxisome

Proliferator-Activated Receptor γ (PPAR- γ) (19,20). All of the known molecular interactions of

mesalamine are depicted in Figure 1; note the interactions with leukotrienes, NF- κB, and PPAR-

γ as described above. (Insert Figure 2 here)

5-ASA is composed of a salicylic acid component, and is chemically similar to aspirin.

While similar in structure, however, 5-ASA and aspirin differ significantly in pharmacology and

mode of action. While aspirin exerts effects on the cyclooxygenase (COX) enzymes, 5-ASA has

not been shown to effect the COX family of enzymes, and subsequently does not possess the

anti-thrombotic and anti-cancer effects of aspirin. It has been proposed, however, that

suppression of chronic low grade inflammation may protect against colorectal cancer (CRC), and

the use of mesalamine for prevention of CRC in patients with ulcerative colitis has been

suggested and is currently being investigated. While not mediated through COX2, in-vitro

studies have suggested the anti-cancer effect may be mediated via inhibition of β-catenin

pathway and interference with the endothelial growth factor receptor (EGFR)(21,21a). As most

of the patients affected with diverticular disease are also in the age group for colorectal cancer

risk, the use of mesalamine in these patients may in the future also prove to have a beneficial

anti-cancer effect as well.

Diverticular disease and Inflammatory bowel disease

The classic inflammatory process affecting patients with diverticulosis is diverticulitis, an

acute inflammatory process of an individual diverticulum. Acute inflammation, however, is non-

specific, and it is occasionally difficult to distinguish between bouts of diverticulitis and IBD.

Findings of acutely inflamed mucosa affecting patients with diverticular disease have been

described and have been termed "segmental colitis associated with diverticulitis" (SCAD)

(22,23). The inflammation noted closely resembles the acute mucosal changes seen in Crohn's

disease and ulcerative colitis, but only occurs in the segments of the colon affected by

diverticulosis, with the sigmoid colon being the most common area of presentation. Patients

commonly are older, with the average age of onset of 64, present with an initial episode of

hematochezia, and have normal levels of inflammatory biomarkers(24). Whether the finding of

SCAD represents a presentation of IBD or a separate entity is still unclear, though one study

found that of 25 patients with SCAD who underwent surgical resection, 23 did not develop

Crohn's disease after a 6 year follow-up (25). A recent systematic review of 218 patients has

also shown that SCAD is a distinct entity(24), though data showing an increase in TNF-α levels

in SCAD do suggest a potential common pathogenesis(26) . The use of anti-inflammatory

agents, such as mesalamine, has been suggested as a possible treatment option in patients with

SCAD due to these similarities.

Mesalamine and Treatment of Diverticular Disease

The potential similarities between diverticular inflammation and inflammatory bowel

diseases such as Crohn's disease and ulcerative colitis have led researchers to consider the use of

medications widely used in the treatment of IBD in the treatment of diverticular disease and

diverticulitis. An in-depth discussion of the traditional treatments of diverticulitis are beyond the

scope of this review, but mention will be made of the use of antibiotic treatments and surgical

interventions. Most patients diagnosed clinically with uncomplicated diverticulitis are treated

with bowel rest and antibiotic treatment. There are many effective antibiotic treatments

available, with the most common prescribed drugs for diverticulitis include quinolones and

metronidazole. Recent studies have also shown the use of oral rifaxamin, and non-absorbable

antibiotic, to be beneficial in the treatment of diverticular disease. Those patients with

complicated diverticulitis and recurrent disease are often considered for surgical resection of the

affected areas, when antibiotics are not successful or the disease is considered to be severe.

Diverticulitis

A number of researchers have investigated the use of mesalamine in diverticulitis. The

first study was performed by Tursi, et.al. in 1997 and followed 166 patients with symptomatic

large bowel diverticulitis(27). In this randomized, non-blinded study, all patients were treated

with conventional antibiotic therapy, followed by randomization into groups who received

mesalamine 400mg twice daily for 8 weeks or placebo. At four years of follow-up, there were

significantly fewer relapses and microhemorrhagic events in the group treated with mesalamine

(p<0.00005). Patients in the mesalamine group also had significantly less likelihood of having

diverticular bleeding and were more likely to be symptom free at 4 years.

This study was followed by a report on the use of the combination of rifaxamin and

mesalamine in the treatment of diverticulitis, which was performed with the effectiveness of

rifaxamin alone and rifaxamin plus mesalamine in the prevention of recurrent diverticulitis in

218 patients as the primary endpoint(28) . All patients enrolled had at least two documented

episodes of diverticulitis in the year prior to enrollment, and were randomized to receive either

rifaxamin alone (400mg twice daily) for 7 days, followed by a 7 day course each month for 12

months, or rifaxamin and mesalamine (800mg three times daily) together in an identical dosage

schedule. Patients were followed for one year, and assessed for recurrence of symptoms (upper

and/or lower abdominal pain, bloating, tenesmus, diarrhea, abdominal tenderness). A

significantly higher number of patients in the combined (rifaxamin + mesalamine) group were

asymptomatic at 3,6,9 and 12 months (85% vs. 49% at 12 months, p<0.0005). In addition, those

patients receiving combined therapy had a 2.75% rate of recurrent diverticulitis at 12 months, vs.

18% in the group that took rifaxamin alone.

Symptomatic uncomplicated diverticular disease

Two prospective randomized studies evaluated the improvement in symptoms in patients

with uncomplicated diverticular disease who received mesalamine. As many of the studies

regarding the topic of mesalamine in diverticular disease originate in Italy and are similar in

patient population and design, the definition of symptomatic uncomplicated diverticular disease

(SUDD) remains constant throughout the following studies. Symptomatic uncomplicated

diverticular disease is described as constipation, diarrhea, abdominal pain, rectal bleeding, or

mucous passage with stool, associated with diverticular disease of the colon in the absence of

acute inflammation.

One hundred and seventy patients with uncomplicated diverticular disease who received

either rifaxamin (at 200mg or 400mg twice daily) or mesalamine (at 400mg or 800mg twice

daily) for 10 days each month were followed by DiMario, et. al. for three months(29). A

statistically significant improvement in symptoms (as calculated by the global symptomatic

score, taking into account abdominal pain, tenesmus, bloating, diarrhea, and 6 other associated

symptoms) was seen in both mesalamine groups and the 400mg rifaxamin dose, with patients

receiving the higher dose of mesalamine having the most improvement. In a follow up study

published in 2007, Comparato and colleagues compared the use of rifaxamin and mesalamine

alone in symptomatic, uncomplicated diverticular disease and confirmed the effectiveness of

cyclic mesalamine in SUDD(30). Two hundred and sixty eight patients who exhibited two of ten

symptoms attributed to diverticulosis for at least two months were enrolled in the study and

followed for 12 months. In a treatment schedule similar to the study by DiMario, et al in 2005,

patients received either rifaxamin (200mg or 400mg BID) or mesalamine (400mg or 800mg

BID) for ten days each month. At 6 months, both treatment groups receiving mesalamine (and

those receiving rifaxamin 400mg BID) had improvement in tenesmus, bloating, diarrhea, well-

being, and bleeding. This finding, along with the finding of an improvement in lower abdominal

pain, persisted at 12 months.

The second study also compared treatment with mesalamine alone to mesalamine plus

rifaxamin for symptomatic diverticular disease(31). In a prospective, open fashion, 90 patients

were treated with rifaxamin and mesalamine (2.4 gram) for 10 days, followed by mesalamine

alone (1.6 grams) for 8 weeks. At completion, 77% of patients were asymptomatic, while 2

patients experienced an episode of acute diverticulitis. A significant improvement in total

symptom score was found when compared to pre-treatment assessments (p<0.001).

Interestingly, 2/90 patients were forced to discontinue mesalamine due to severe diarrhea, which

is a reported side effect of the drug.

The use of combined mesalamine and rifaxamin in symptomatic diverticular

disease, in conjunction with the probiotic Lactobacillus, was investigated in 2006 in a

prospective, randomized, non controlled study (32). This study evaluated 90 consecutive

patients with resolved uncomplicated diverticular disease for recurrence of symptoms within 12

months. All patients were treated with rifaxamin and mesalamine to achieve remission, after

which patients received either mesalamine 1.6 gram daily, probiotic (Lactobacillus casei 16

billion/day for 15 days per month) or both probiotic and mesalamine for 15 days per month.

Overall, 96% of patients treated with mesalamine and Lactobacillus for 12 months were

symptom free, vs. 77% of patients treated with mesalamine alone.

While the effectiveness of mesalamine in symptomatic diverticular disease has been

shown in a number of studies, the optimal dosing schedule has not been determined. In a study

evaluating daily vs. cyclic mesalamine, forty patients were enrolled after successful treatment of

recurrent symptomatic diverticular disease of the colon, which was described as recurrent

abdominal pain in patients with diverticulosis, and without evidence of inflammation

(diverticulitis)(33). At the completion of the 24 month follow up period, 70% (14/18) of the

patients receiving mesalamine at 1.6gram/day were symptom free, vs. 45% (9/16) in the group

treated for 10 days monthly.

Balsalazide

5-ASA begins to exert its topical effects at the level of the small bowel, and as noted above is

rapidly absorbed in the jejunum. As such, it is not commonly present in therapeutic levels in the

colon. To date, we are not aware of any studies investigating the use of sulfasalazine in the

treatment of diverticular disease, though other mesalamine preparations have been considered.

Balsalazide is a prodrug formulation consisting of a 5-ASA molecule bound to an inactive carrier

molecule (4-aminobenzoil-b-alanine). Colonic bacteria cleave the bond between the two

components of the drug, leading to the delivery of the active 5-ASA directly to the colon. In

2007, Tursi et. al., studied the use of balsalazide and probiotics in the prevention of recurrent

diverticulitis; 30 consecutive patients with evidence of uncomplicated diverticulitis were enrolled

in an unblinded fashion and followed for one year(34). One half of the patients received

balsalazide 2.25gram/daily and rifaxamin 800mg daily for 10 days, followed by balsalazide daily

and probiotic formulation VSL#3 for 15 days each month for 12 months (Group A). 15 patients

in received only the initial 10 day course of balsalazide and rifaxamin, plus 12 months of VSL#3

only for 15 days each month (group B). At the end of one year, 73% of group A patients were

asymptomatic vs. 60% in group B. One episode of recurrence occurred in group A, and two

patients recurred in group B (p<0.1, NS). Overall symptom scores at the completion of the study

were significantly better in group A, however. Although the data show a modest benefit of

balsalazide in diverticular disease, the low sample size and unblinded design are important

factors to take into account.

Future studies

A number of studies, as reviewed above, have been performed with the goal of evaluating

the effectiveness of mesalamine in the treatment of diverticular diseases, though most of these

studies have flaws which limit the validity and applicability of their findings. Recently, there

have been four large, randomized, double blinded, placebo controlled prospective studies

designed to evaluate mesalamine in the prevention of recurrent diverticulitis, all of which are

currently ongoing. Two concurrent studies on the use of MMX mesalamine in the prevention of

recurrent diverticulitis have completed enrollment, and the results are pending. In these studies,

patients were given either 1.2, 2.4, or 4.8 grams of MMX mesalamine daily for 2 years and

followed for acute diverticulitis. A third study, which has also completed clinical enrollment, has

compared the number of acute diverticulitis flares in patients with at least one episode of prior

diverticulitis who received either 1.6 grams/day of mesalamine (Asacol) for 10 days each month

or placebo for 24 months.

The durability of mesalamine in the long term treatment of SUDD has yet to be

determined. At a recent national meeting, data was presented in abstract form regarding the five

year effectiveness of mesalamine in maintaining symptom relief and preventing recurrence of

acute diverticulitis(35,36). In sixty seven patients with SUDD who received cyclic mesalamine

for five years, 4% were found to have at least one episode of diverticulitis, vs. 11% of population

controls(35). Similar long term symptomatic improvements were also noted in a separate study

of sixty seven patients performed by the same group (36). Lastly, a study of patients with

symptomatic diverticular disease randomized to receive mesalamine 3grams/day or placebo for

three months is currently ongoing. It is anticipated that the results of these studies will offer

reliable data and significant insight into the clinical effectiveness of mesalamine in acute and

chronic diverticular diseases

Mesalamine Side Effects

Mesalamine was seen to have a favorable side effect profile in all of the reported studies,

which is a finding that has been confirmed in the extensive literature available regarding the use

of mesalamine in IBD. Overall, the most common side effects of mesalamine include headache,

abdominal pain, and diarrhea. Fever and rash have also been reported (37). A number of large,

randomized studies assessing the effectiveness of mesalamine in the treatment of ulcerative

colitis (38-40) have been performed, and offer quality side effect data. In the Ascend I trial, 301

patients were assigned to 6 weeks of mesalamine, and a total of 4 (1%) were reported to have

serious side effects(38). The Ascend II trial reported an overall side effect profile of 39%, with

the most reported adverse events of headache (7.5%), abdominal pain (4.7%), diarrhea (3.7%),

and infection (3.7%)(39). Serious side effect rate was 1% (one episode each of pancreatitis,

cholecystitis, and pericarditis). A third study of 772 patients receiving mesalamine revealed an

overall side effect rate of 20%(40). The most common side effects were headache (3%), nausea

(2%), and nasopharyngitis (1.5%).

Approximately 10-15% of patients may develop diarrhea as a side effect of 5-ASA drugs.

While most commonly seen in preparations with nonabsorbable components (olsalazine and

balsalazide), patients receiving mesalamine may also experience bowel habit changes.

Acute interstitial nephritis has been described in a small number of patients receiving

mesalamine, occurring at a rate of 0.26/patient year, and routine monitoring of renal function in

patients receiving this drug is recommended(41). Pancreatitis is a rare but potentially serious

side effect of mesalamine which, if present, should preclude any further treatment with 5-ASA

compounds(42). Blood dyscrasias and hepatocellular injury have also been reported with the use

of mesalamine, though in small numbers and at a lower rate than sulfasalazine (43).

5-ASA is chemically similar to aspirin, and mesalamine manufacturers have determined

it to be contraindicated in patients with aspirin sensitivity. Most clinicians would also advise

against mesalamine therapy in this situation, though there have been reports of the successful use

of mesalamine in patients with aspirin hypersensitivity(44). The risks of a potential

hypersensitivity reaction outweigh the benefits of the use of mesalamine in diverticular disease

in this population, and until further data is available, we recommend it be avoided in these

patients.

Mesalamine has been classified as a pregnancy category B drug, and is generally

considered safe to use in expectant women. One large study which evaluated 146 women who

received mesalamine during pregnancy did not reveal any increase in major congenital

malformations, miscarriage rate, fetal distress, or rate of live births(45). Mesalamine is widely

used throughout pregnancy in patients with IBD, and, although unlikely to be needed in this age

group, should be considered safe in the treatment of diverticular disease.

Conclusion

Diverticulosis is a very common finding in many patients who consume a western diet.

Despite the prevalence of the disease, however, a majority of the patients with diverticulosis

remain asymptomatic and do not require treatment. Those patients who do develop

complications of diverticulosis commonly present with acute gastrointestinal bleeding, acute

diverticulitis, and symptoms consistent with the more recent diagnosis of symptomatic

uncomplicated diverticular disease.

The treatment of diverticulitis and SUDD has recently undergone a number of changes,

with the addition of non-absorbable antibiotics such as rifaxamin and probiotics to the treatment

algorithms. Mesalamine was initially considered as a treatment option for patients with

diverticular complications due to its known anti-inflammatory effects, and has shown some

promising results in the treatment of diverticulitis and SUDD. It is important to distinguish

between these two entities when evaluating the use of mesalamine in diverticular disease, as they

are pathogenetically somewhat different, and have different expected treatment outcomes.

Symptomatic diverticular disease occurs commonly in older patients with diverticulosis,

and is generally described as lower abdominal pain, with or without other associated abdominal

complaints such as bloating, changes in bowel habits, or rectal mucous, in the setting of

diverticulosis coli without evidence of acute inflammation(46). SUDD may present with

symptomatology similar to irritable bowel syndrome, and some authors have suggested that the

two diagnoses should be considered manifestations of the same disease(26,47). In two studies of

patients receiving mesalamine at 400 mg and 800mg twice daily for SUDD, global symptomatic

score was improved at 3 and 12 months, with the most benefit being achieved with the higher

dose of mesalamine(29,30). This finding was also confirmed in a short study of patients

receiving mesalamine at 1.6 grams/day(31). It should be noted that none of these studies

incorporated a control group, which creates difficulty in interpreting these results, as the baseline

symptomatic improvement rate in SUDD is not yet clear. Additionally, the short follow up

period of two of the studies (eight weeks and three months, respectively) may not have been

sufficient to determine long term effectiveness of mesalamine in affecting recurrence of

symptoms, though the results were seen to be reproduced at 12 months in a later study.

The combined use of mesalamine and probiotic in SUDD has also been studied, and

beneficial effects of both have been found(32). Patients receiving both treatments for one year

had less symptoms than patients receiving only mesalamine (96% vs. 77%). One potential

confounding factor of this study, however, is the inclusion of patients with prior complaints-68%

of patients had had symptomatic diverticular disease prior to enrollment, and it is unclear if these

patients were equally represented in each group. Many authors have suggested that an alteration

in the colonic microflora may be an important pathogenetic factor in the development of SUDD

and diverticulitis, and the restoration of colonic flora achieved with the use of probiotic may

explain the additional benefit seen in patients receiving both treatments in this study.

While the studies performed to date on the use of mesalamine in SUDD are varied in

dosing, duration, and design, the number of patients who remain free of symptoms after the

administration of mesalamine 1.6 daily appears to be consistent, with rates of 70%, 77%, and

77% being reported in studies with follow up periods ranging from 8 weeks to 2 years (31-33).

Mesalamine has shown benefit in the prevention of recurrent symptoms in SUDD, but

less data are available on the use of mesalamine in acute diverticulitis. We have identified only

two studies to date in which patients with acute inflammation of a diverticulum were given

mesalamine and prospectively followed, and one in which patients received balsalazide (27,28,

34). In the initial study performed, patients received mesalamine for only the initial 8 weeks

after treatment for diverticulitis, and the beneficial effect remained at 48 months(27). In the

largest study, the addition of mesalamine to treatment with rifaxamin for one year offered a

significant decrease in rate of recurrent diverticulitis (2.75% vs. 18%)(28). The rate of recurrent

diverticulitis in control patients in this study is consistent with previous studies, which have

reported a rate of a single, recurrent episode of diverticulitis of between 13 and 19% (48-50),

which supports the beneficial effect of mesalamine in this study.

The benefit of mesalamine in acute diverticulitis appears to be in the prevention of

recurrent disease once the acute inflammation has been treated. This finding leads to the

suggestion of a low level, chronic inflammatory condition in the pathogenesis of acute

diverticulitis, which is contrary to the traditional belief of acute diverticular obstruction leading

to inflammation in these patients. At this time, there is not enough data to suggest that

mesalamine offers benefit in the acute treatment of these patients, however, and it should be not

be considered as a primary treatment of acute diverticulitis.

To date, we are not aware of any data on the use of mesalamine in SCAD, though it is

generally thought to be a beneficial in decreasing colonic inflammation in these patients, and is

recommended by many authors as a treatment option (23,51).

The dose and timing of mesalamine used in these studies should also be noted, as doses

of 1.6-2.4 gram/day were used, which is on the lower end of the therapeutic dose traditionally

required in the treatment of IBD, and patients were given mesalamine in a cyclic pattern (7-15

days every month) in most of the studies. It is unclear why the dose requirements of 5-ASA may

be lower in the treatment of diverticular symptoms, though it may be related to the lower level of

chronic inflammation in these patients. This low level of inflammation, in comparison to IBD,

may also be the reason for the effectiveness of mesalamine on a cyclic dosing schedule.

Recently, a systematic review by Gatta, et al , has also investigated the issue of 5-ASA

and diverticular disease(52). Six randomized studies of 5-ASA and diverticular disease were

identified, three of which were performed on patients with diverticulitis, and three on patients

with SUDD(27,28,30,32-34). The authors concluded that 5-ASA likely has a role in the

treatment of diverticular disorders, but due to the heterogeneity of the studies available, further

randomized, controlled studies need are required.

In summary, mesalamine appears to be an effective treatment when used to decrease the

chronic symptoms of SUDD. Data on the use of mesalamine in acute diverticulitis are not as

strong, but the studies that are available do suggest a decrease in the rate of recurrent

diverticulitis in patients maintained on mesalamine. The optimal dose of mesalamine, however,

as well as the duration of treatment necessary to obtain a significant benefit, is not currently

known. Additionally, all of the studies available on the use of mesalamine in diverticular

diseases originate in Italy, which may limit the reproducibility of the findings, and this should be

considered when the data are applied to different patient populations. It is expected that further

studies, which are already ongoing, will add significant information to the discussion of

mesalamine in diverticular disease and offer answers to some of these important questions.

Given the available data and the beneficial side effect profile, we find it reasonable to consider a

trial of mesalamine in patients with suspected SUDD and resolved acute diverticulitis.

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Table 1- Preparations and Mechanisms of Action of 5-ASA Products

Preparation Drug Mechanism of Release Carrier/Coating

Apriso Mesalamine pH-controlled N/A

Asacol/Asacol HD Mesalamine PH-co N/A

Colazal Balsalazide Inert carrier 4-aminobenzoyl-b-alanine

Dipentum Olsalazine Azo-bond of two 5-ASA molecules

N/A

Lialda MMX Mesalamine

PH-controlled/matrix coating

Lipophilic/Hydrophilic Matrix

Pentasa Mesalamine Time release Ethylcellulose granules

Azulfidine Sulfasalazine Azo-bond Sulfapyridine

Table 2- Studies of 5-ASA in diverticular disease

Study Drug Design Co-treatment Duration Results Comments

Trespi, et. al.

1997 (27)

Mesalamine Randomized,prospective, controlled

None 48 months Significant improvement in symptomatic relapses, microhemorraghic phenomena and duration of abdominal pain

Mesalamine only given for initial 8 weeks of study

Tursi, et. al.

2002 (28)

Mesalamine Randomized, prospective , open

Rifaximin 12 months 85% remained asymptomatic in

All patients enrolled had >1 prior episode of

combined rifaximin+mesalamine group, vs. 49% in rifxamin alone group at 12 months; Decrease in rate of recurrent diverticulitis in combined group (2.75% vs. 18%)

diverticulitis

Brandimarte, Tursi

2004 (31)

Meslamine Prospective, open

Rifaximin 8 weeks 77% symptom free at 8 weeks

All patients received rifaximin+mesalamine initially, then alone for 8 weeks; short follow-up

Diverticultiis chronic?

nATURAL HISTORY or recurrent diverticultisi.

While these study did show a benefit of the use of mesalamine in the setting of , the results are somewhat limited by the short follow up period and the lack of evalaution for recurrent symptoms.

recA total of five studies were found that investigated the use of mesalamine in the treatment of SUDD. Importantly, data from these studies (Study, Study 3, Study 5, Study 6, Study 7) need to be interpreted in the context of symptomatic diverticular disease, rather than acute diverticulitis. It is unclear how these results may translate to patients with the acute diverticulitis, and the small number of patients included in the final evaluation of one of the studies (Study 5) may limit the reliability of the findings.

***43 references so far***

Tursi A. New physiopathological and therapeutic approaches to thediverticular disease of the colon. Exp Opin Pharmacother. 2007;8:299–307.

Dig Liver Dis. 2008 Sep;40(9):737-42. Epub 2008 Apr 2.

Effect of mesalazine on epithelial cell proliferation in colonic diverticular disease.

Tursi A, Brandimarte G, Elisei W, Giorgetti GM, Inchingolo CD, Aiello F.

Digestive Endoscopy Unit, Lorenzo Bonomo Hospital, Via Torino, 49, 70031 Andria, BA, Italy. antotursi@tiscali.it

Symptomatic diverticular disease is presumed to be a low grade inflammatory condition which may mimic inflammatory bowel disease, (Floch, Jclin Gastro 2006, ) 25. Narayan R, Floch MH. Microscopic colitis as part of the naturalhistory of diverticular disease [Abstract]. Am J Gastroenterol.2002;97(suppl):112.26. Tursi A, Brandimarte G, Elisei W, et al. Assessment and gradingof mucosal inflammation in colonic), and acute diverticulitis is known to represent a clear inflammatory condition. This finding has led to the consideration of mesalamine and 5-ASA preparations as potential treatments of acute diverticular disease.