INTRODUCTION:

In the last two decades, Irritable Bowel Syndrome (IBS) has gained considerable attention in the health-care field due to its increasingly high prevalence, sometimes debilitating effects and diverse symptom representation^.[1] IBS belongs to a group of chronic gastrointestinal (GI) diseases referred to as functional bowel disorders (FBD) as classified by the Rome foundation,[2]an international organization dedicated to research and education in the field of functional GI disorders. The World Health Organization (WHO) has given IBS its own classification in its 10th revision of the International Classification of Diseases (ICD-10), recognizing the significance of this syndrome^.[3] The first diagnostic evaluation of IBS was introduced with the Manning criteria in the 1970s, which utilized a 15-symptom questionnaire to differentiate between IBS and what were then referred to as organic abdominal diseases.[4]

Over the past decade, advances have been made in classifying various chronic disease states of FBD to create differential diagnosis criteria as well as exploring new treatments for a group of widespread disorders. Although a precise definition of IBS is still controversial on the basis of a functional or an organic disorder with symptoms that differentiate it from other FBD, current efforts underline that IBS requires attention from a health-care professional. The purpose of this clinical review is to provide health-care practitioners with an overview of IBS epidemiology, symptoms and diagnostic criteria, and current treatment approaches.

Inflammatory Bowel Disease (IBD) is the name of a group of illnesses, of which Ulcerative Colitis (UC) and Crohn’s Disease are the two main ones. In IBD, the intestines, which are also called the bowels or gut, become swollen and inflamed (red and sore). If you have IBD your doctor is likely to prescribe drugs to treat your condition. We do not yet know what causes IBD, so these drugs are not cures, but they can be very effective in treating your symptoms.

IBD is a chronic condition, which means that it is ongoing and usually lasts throughout your life. It can change unpredictably may have times of good health, called remission, when there are few or no symptoms, alternating with times when your symptoms are more active, called relapses or ‘flare-ups’. Drugs are first prescribed to reduce the inflammation in bowels to give you relief from symptoms and bring about remission. Once condition is under control, doctor usually continues to prescribe drugs to help maintain remission and prevent a relapse. This is called maintenance therapy.

Epidemiology

Assessment of the prevalence of IBS has been complicated by the clarity of assessment criteria to differentiate between various FBD and other chronic GI disorders. The last comprehensive review of the prevalence and epidemiology of IBS in North America, in which five population based prevalence studies were evaluated, was conducted in 2002.[5] An important factor in diagnosing IBS is the set of criteria utilized, such as the Rome criteria[6] and the Manning questionnaire. In some cases, the two evaluation tools were directly compared in the studies and provided a more diverse dataset, depending on how many scale criteria a person had to meet in order to be diagnosed with IBS. The range of prevalence was from 3–20%, with most studies between 10% and 15% (mean of all 13 studies was 11.6% with a standard deviation of 4.6%). Interestingly, there is a higher ratio of women who develop IBS compared to men (ratio of 2:1) although there were also differences observed among studies. Age-related onset of IBS symptoms occurred predominantly in patients younger than 45 years but prevalence rose again in the elderly. The subclassification of IBS as either IBS-D (IBS with predominant diarrhea) with 5.0–5.5%, IBS-C (IBS with predominant constipation) with 5.2–5.4% or IBS-M (IBS with alternating constipation and diarrhea, mixed IBS) with 5.2% was evaluated by two population-based studies.[7,8] Other factors that have a significant impact on the development of IBS are health status, comorbid conditions, [9]diet [10] and mental health.[11,12] Recent study findings in Korea,[13] Greece [14] Malaysia[15] Finland[16] and France [17] showed variations in prevalence of IBS and distribution of the subclassification. In the Korean study, approximately half of the patients diagnosed with IBS first experienced symptoms before the age of 40 years with approximately even distribution between women and men. Although prevalence of IBS was not reported, these researchers evaluated the subtype of IBS and found that more than half of IBS patients suffered from constipation-predominant IBS. A study with young Malaysian adults (mean age 22 _ 1.8 years) showed a prevalence rate of 15.8% with a female-to-male ratio of 1.7:1.15 Subclassification of IBS also resulted in approximately 75% of patients diagnosed with IBS-C, with much lower IBS-M type occurrence. This outcome is surprising in light of other studies conducted in Asian populations that frequently reported a lower prevalence rate of IBS. One reason for this discrepancy might involve diagnostic criteria because use of Manning and Rome I criteria frequently resulted in a lower rate of a positive IBS diagnosis.1 In a Finnish study, the various diagnostic criteria were compared and applied to an obtained dataset of patients diagnosed with IBS. The prevalence as evaluated by Manning and Rome I and II criteria varied from 5.1–16.2%. Use of the Manning criteria in this study resulted in a significantly higher prevalence rate than the Rome criteria. The reported age of IBS onset was evenly distributed throughout the study population, with a slightly higher prevalence in women than men. It appeared that diarrhea was predominantly observed in this population but no subclassification has been made. French researchers utilized the Rome I criteria to conclude that prevalence of IBS was 4.0% with a female-to-male ratio of 2.3:1 and equal distribution of IBS-D, IBS-C and IBS-M subclassification throughout the study population. Prevalence of IBS symptoms ranged from 3.2–4.3% between the different age groups; the lowest prevalence was in younger adults 18–24 years of age. In a recent study conducted in Greece, prevalence of IBS was 15.7% based on the Rome II diagnostic criteria. Constipation predominant IBS was the most common among IBS subtypes, followed by diarrhea-predominant IBS. More women than men were affected, with a ratio of 1.3:1 with reported onset of IBS symptoms. Other important comorbidity factors that contribute to development of IBS as a functional disorder are depression, anxiety and insomnia, which should be evaluated by health-care providers to derive the differential diagnosis. The most common psychiatric disorder associated with IBS is depression, with a prevalence of approximately 30% in IBS patients compared to only 18% in a control population. Anxiety is also commonly encountered as a comorbid condition in IBS, with 16% affected compared to controls at a rate of 6%. There also appears to be a correlation between anxiety and depressive disorders and the severity of IBS symptoms as increases in comorbidity have been found between these diagnoses and worsening of IBS symptoms. Findings regarding association of comorbid conditions including psychiatric disorders with IBS may be strengthened by tightly controlled symptom criteria (e.g. instead of using self-reported diagnosis) with sufficient patient numbers. The population studies demonstrate the diversity of IBS based on ethnicity, age and culture (e.g. diet, access to health-care providers) and the importance of evaluation criteria that impact choice of therapy. Diet, as part of a cultural factor, has been studied in relation to IBS treatment. Simple changes in diet may improve symptoms (most likely reductions in fat consumption that lead to bloating) for some patients, while symptoms actually worsen for others if the diet is rich in fiber, wheat or carbohydrates (specifically diarrhea-predominant IBS).As mentioned before, these studies were mainly conducted in small patient populations and larger clinical studies are required to confirm these findings.

Diagnosis of IBD in adult patients

The diagnosis of IBD requires a comprehensive physical examination and a review of the patient’s history. Various tests, including blood tests, stool examination, endoscopy, biopsies, and imaging studies help exclude other causes and confirm the diagnosis.

Symptoms

IBD is a chronic, intermittent disease. Symptoms range from mild to severe during relapses and may disappear or decrease during remissions. In general, symptoms depend on the segment of the intestinal tract involved.

Laboratory tests

1) Stool examination:

2) Blood examination:

— Complete blood count (CBC).

— Erythrocyte sedimentation rate, C-reactive protein and orosomucoid; levels correlate imperfectly with inflammation and disease activity.

— Electrolytes and albumin, ferritin (may indicate absorption or loss problems), calcium, magnesium, vitamin B12.

— Serum ferritin can be elevated in active IBD and may be in the normal range even in the face of severe iron deficiency. Transferrin saturation can also be assessed to evaluate anemia. The best test, if available, is soluble transferring receptor (sTfR) assay, although this is expensive (and also involves an acute phase protein).

3) Plain abdominal radiography:

4) Imaging and endoscopy

Treatment of IBD

Aminosalicylates

Aminosalicylates [18]can be used in combination with steroids to induce and maintain remission in patients with inflammatory bowel disease. The first-line therapy for mild to moderate UC generally involves mesalamine (5-aminosalicylic acid, or 5-ASA). The archetype for this class of medications is sulfasalazine, which consists of 5-ASA linked to sulfapyridine by an azo bond. Although this drug was originally developed as a treatment for rheumatoid arthritis, clinical trials serendipitously demonstrated a beneficial effect on the gastrointestinal symptoms of subjects with concomitant UC. Sulfasalazine is most effective at maintaining remission in UC. When it reaches the colon, the diazo bond is cleaved by bacterial azoreductase, liberating mesalamine and sulfapyridine. Sulfapyridine is absorbed and metabolized by hepatic acetylationor hydroxylation followed by glucuronidation. Given individually, either 5-ASA or sulfapyridine is absorbed in the upper gastrointestinal tract; the azo linkage in sulfasalazine prevents its absorption in the stomach and small intestine, and the individual components are not liberated for absorption until colonic bacteria cleave the bond. 5-ASA is the active therapeutic moiety; sulfapyridine contributes little to the therapeutic effect. Although mesalamine is a salicylate, its therapeutic effect does not appear to be related to cyclooxygenase inhibition; indeed, traditional nonsteroidal anti-inflammatory drugs may actually exacerbate IBD. Many potential sites of action have been demonstrated in vitro for either sulfasalazine or mesalamine, including inhibition of IL-1 and TNF-_ production, inhibition of the lipoxygenase pathway, the scavenging of free radicals and oxidants, and inhibition of NF-_B (nuclear factor kappa B), a transcription factor pivotal to the production of inflammatory mediators [19]. Although it is not active therapeutically, sulfapyridine causes many of the same side effects observed in patients taking sulfasalazine. To preserve the therapeutic effect of 5-ASA without the side effects of sulfapyridine, several second-generation 5-ASA compounds have been developed. They are divided into two groups: prodrugs and coated drugs. Prodrugs contain the same azo bond as sulfasalazine but replace the linked sulfapyridine with either another 5-ASA (olsalazine) or an inert compound (balsalazide). These compounds act at similar sites along the gastrointestinal tract as sulfasalazine. The alternative approaches employ either a delayed-release formulation or a pH-sensitive coating. Delayed-release mesalamine is released throughout the small intestine and colon, whereas pH-sensitive mesalamine is released in the terminal ileum and colon. The different distributions of these drugs following delivery have potential therapeutic implications. Oral sulfasalazine has been shown to be effective in patients with mild or moderately active UC, with response rates between 60 and 80% [20]. The usual dose is 4 g/day, which is divided into four separate doses taken with food; to avoid adverse effects, the dose is increased gradually from an initial dose of 500 mg twice a day. Doses as high as 6 g/day can be used, but these doses cause an increased incidence of side effects. For patients with severe colitis, sulfasalazine is of less certain value even though it is often used as an adjunct therapy to systemic glucocorticoids. Regardless of disease severity, this drug plays a useful role in preventing relapses once remission has been achieved. In general, newer 5-ASA preparations have similar therapeutic efficacies in UC with fewer side effects. Because they lack the dose-related side effects of sulfapyridine, the newer formulations can be used to provide higher doses of mesalamine, which leads to some improvement in disease control. To treat active diseases, olsalazine is typically administered at a dose of 800 mg three times a day, and balsalazide is generally administered at a 1-g dose given four times a day. The efficacy of 5-ASA preparations (e.g., sulfasalazine) in CD is less striking, with a modest benefit at best in controlled trials. Sulfasalazine has not been shown to be effective in maintaining remission and has been replaced by newer 5-ASA preparations. Some studies have reported that both olsalazine and balsalazide are more effective than a placebo in inducing remission in patients with CD (particularly colitis), although higher doses than those typically used in UC are required. The role of mesalamine in maintenance therapy for CD is controversial, and there is no clear benefit of continued 5-ASA therapy in patients who achieve medical remission [21]. Because they largely bypass the small intestine, prodrugs such as olsalazine and balsalazide do not have a significant effect in CD of the small intestine. Topical preparations of mesalamine suspended in a wax matrix suppository or in a suspension enema are effective in active proctitis and distal UC, respectively [64]. They appear to be superior to topical hydrocortisone in this setting, with response rates of 75 to 90%. Mesalamine enemas (4 g/60 ml) should be used at bedtime and retained for at least eight hours; the suppository (500 mg) should be used two to three times a day with the objective of retaining it for at least three hours. Responses to local therapy with mesalamine may occur within three to 21 days; however, the usual course of therapy is from three to six weeks. Once remission has occurred, lower doses are used for maintenance. Side effects of sulfasalazine occur in 10 to 45% of patients with UC and are primarily related to the sulfa moiety. Some side effects are dose-related, including headache, nausea, and fatigue. These reactions can be minimized by administering the medication with meals or by decreasing the dose. Allergic reactions include rash, fever, Stevens-Johnson syndrome, hepatitis, pneumonitis, hemolytic anemia, and bone marrow suppression. Sulfasalazine reversibly decreases the number and motility of sperm but does not impair female fertility. It also inhibits intestinal folate absorption; therefore, folate usually is given with sulfasalazine. The newer mesalamine formulations are generally well tolerated, and side effects are relatively infrequent and minor. Headache, dyspepsia, and skin rash are the most common side effects. Diarrhea appears to be particularly common with olsalazine (occurring in 10 to 20% of patients); this may be related to its ability to stimulate chloride and fluid secretion in the small intestine. Nephrotoxicity, although rare, is a more serious concern. Mesalamine has been associated with interstitial nephritis; while its pathogenic role is controversial, renal function should be monitored in all patients receiving these drugs. Both sulfasalazine and its metabolites cross the placenta but have not been shown to harm the fetus. Although they have not been studied as thoroughly, the newer formulations also appear to be safe during pregnancy [22].

Corticosteroids

The glucocorticoid properties of hydrocortisone and prednisolone are the mainstay of IBD treatment. The preferred steroid is prednisolone, administered orally, rectally or parenterally in emergency situations. Corticosteroids can be used either alone or in combination with a suitable mesalamine formulation to induce and maintain remission in inflammatory bowel disease. The incidence of adverse effects appears to increase when prednisolone doses are higher than 40 mg/day. An alternate-day regimen is helpful because it reduces adrenal suppression. Azathioprine, with its steroid sparing property, may be introduced together with a lower dose of steroids. The response to steroids in individual patients with IBD divides them into three general classes: steroid-responsive, steroid-dependent, and steroid-unresponsive. Steroid-responsive patients improve clinically, generally within one to two weeks, and remain in remission as the dose of steroids is tapered and discontinued. Steroid-dependent patients also respond to glucocorticoids but experience a relapse of symptoms as the steroid dose is tapered [23]. Steroid-unresponsive patients do not improve even with prolonged high doses of steroids. Approximately 40% of patients are steroid-responsive, 30 to 40% have only a partial response or become steroid dependent, and 15 to 20% of patients do not respond to steroid therapy. Steroids are sometimes used for prolonged periods to control symptoms in steroid dependent patients. However, failure to respond to steroids with prolonged remission (i.e., a disease relapse) should prompt consideration of alternative therapies, including immunosuppressants and infliximab. Steroids are not effective in maintaining remission in either UC or CD [24]; thus, their significant side effects have led to an increased emphasis on limiting the duration and cumulative dose of steroids in IBD. Initial doses for prednisone is between 40 to 60 mg per day; higher doses are rarely more effective [25]. The glucocorticoid dose is tapered over weeks to months. Even with this slow tapering, efforts should be made to minimize the duration of steroid therapy. In severely ill hospitalized patients, 100 mg of hydrocortisone administered intravenously every eight hours is a reasonable initial therapy. Intravenous therapy generally produces a rapid improvement of symptoms, with maximal benefits occurring when the corticosteroid has been administered for six to eight days. Once the patient’s symptoms have improved, prednisone is tapered by 5 to 10 mg per week, until the dosage reaches 15 to 20 mg per day. This dosage is then tapered by 2.5 to 5 mg per week until the drug is discontinued. The goal is to remove patients from corticosteroids within a relatively short period of time while maintaining disease remission. Concomitant use of 5-ASA agents can be helpful. Alternatively, long-term, alternate-day corticosteroid therapy can be used in patients with refractory CD, although it may be necessary to use dosages of 20 to 25 mg every other day [26]. Systemic corticosteroids have an extensive side effect profile. Acute side effects include acne and severe mood changes, which are particularly common in young patients. Adrenal insufficiency can be triggered by an intercurrent infection in patients who are receiving low doses of systemic corticosteroids or in patients who have been recently tapered off of corticosteroids. Visual changes can occur because of steroid-induced hyperglycemia. Early cataract formation is another possible side effect.

Aseptic joint necrosis, which is the most dreaded side effect, usually occurs in patients receiving long-term, high-dose corticosteroid therapy. The incidence of this complication is 4.3% [27]. Budesonide is an enteric-release form of a synthetic steroid that is used for ileocecal CD [28]. It is thought to deliver adequate steroid therapy to a specific portion of the inflamed gut while minimizing systemic side effects caused by extensive first-pass hepatic metabolism to inactive derivatives. Topical therapies (e.g., enemas and suppositories) are also effective in treating colitis that is limited to the left side of the colon. While the topical potency of budesonide is 200 times higher than that of hydrocortisone, its oral systemic bioavailability is only 10%. In some studies, budesonide was associated with a lower incidence of systemic side effects than prednisone, although the data also indicate that systemic steroids are more effective in patients with higher CD activity index scores. Budesonide (9 mg/day for 10 to 12 weeks) is effective in the acute management of mild-tomoderate exacerbations of CD, but its role in maintaining remission has not been fully determined [29].

A significant number of patients with IBD fail to respond adequately to glucocorticoids and are either steroid-resistant or steroid-dependent. The reasons for this failure are poorly understood but may involve complications such as fibrosis or strictures in CD, which do not respond to anti-inflammatory measures alone, local complications such as abscesses, in which case the use of steroids may lead to uncontrolled sepsis, and intercurrent infections with organisms such as cytomegalovirus and Clostridium difficile. Steroid failures may also be related to specific pharmacogenomic factors, such as up-regulation of the multidrug resistance (mdr) gene [30] or altered levels of corticosteroid-binding globulin. Corticosteroid enemas are beneficial in patients with ulcerative proctosigmoiditis. The foam preparations may facilitate retention and thus may be more effective than the liquid preparations. Both foam and liquid corticosteroid enemas are slightly less effective than 5-ASA enemas and are almost as expensive. Some systemic absorption occurs; adrenal suppression and other corticosteroid side effects rarely occur with long-term use. Glucocorticoid enemas are useful in patients whose disease is limited to the rectum (proctitis) and left colon. Hydrocortisone is available as a retention enema (100 mg/60 ml), and the usual dose is one 60-ml enema per night for two or three weeks. When optimally administered, the drug can reach up to or beyond the descending colon. Patients with a distal disease usually respond within three to seven days. Hydrocortisone also can be given once or twice daily as a 10% foam suspension that delivers 80 mg hydrocortisone per application; this formulation can be useful in patients with very short areas of distal proctitis and difficulty retaining fluids. Tixocortol pivolate and fluticasone propionate are among the newer corticosteroid analogs currently under investigation. These newer corticosteroids are more rapidly metabolized than traditional corticosteroids, and they offer the promise of efficacy with fewer systemic side effects. The packaging of these agents in a pH-sensitive coating (similar to that used for 5-ASA preparations) offers the possibility of drug delivery to the small intestine and right colon with few side effects.

Immunosuppressants

Several drugs initially developed for cancer chemotherapy or as immunosuppressive agents in organ transplants have been adapted for the treatment of IBD. Immunosuppressant drugs can be an invaluable adjunct therapy for the treatment of patients with intractable inflammatory bowel disease or complex, inoperable perianal disease. Although immunosuppressant agents have significant side effects, they are safer and better tolerated than long-term corticosteroid therapy. However, these agents should not be used in young patients who are candidates for surgery or in patients who are noncompliant and refuse to return for periodic monitoring. Before immunosuppressant therapy is initiated, side effects and other treatment alternatives should be discussed with the patient. At this stage, it is best to set a definable goal, such as closure of a fistula or tapering the patient off of corticosteroids, and a minimum three-month time frame should be set to reach that goal [32]. Since the early 1970s, azathioprine and mercaptopurine have been used to treat IBD. These drugs are superior to the placebo, but their full effects may not become apparent for as long as three months. Azathioprine and mercaptopurine are beneficial in 50 to 70% of patients with intractable perianal CD [31]. Less information is available about their effectiveness in treating UC, although they have been beneficial in patients with this disease. The cytotoxic thiopurine derivatives mercaptopurine (6-MP) and azathioprine are used to treat patients with severe IBD or those who are steroid-resistant or steroid-dependent . These thiopurine antimetabolites impair purine biosynthesis and inhibit cell proliferation. Both are prodrugs; azathioprine is converted to mercaptopurine, which is subsequently metabolized to 6-thioguanine nucleotides, which are the presumed active moiety. These drugs are generally used interchangeably with appropriate dose adjustments; typically, azathioprine is administered at a dose of 2 to 2.5 mg/kg and mercaptopurine is given at a dose of 1.5 mg/kg. Because of concerns of side effects, these drugs were used initially only in CD, which lacks a surgical curative option. They now are considered equally effective in both CD and UC. These drugs effectively maintain remission in both diseases; they may also prevent (or, more typically, delay) recurrence of CD after surgical resection. The decision to initiate immunosuppressive therapy depends on an accurate assessment of the risk to benefit ratio. For both azathioprine and mercaptopurine, the initial dosage is 50 mg per day. A therapeutic benefit usually occurs at dosages of 50 to 100 mg per day for mercaptopurine and 75 to 150 mg per day for azathioprine. Mild leukopenia suggests that the drug is effective and therefore more likely to benefit the patient. It is prudent to obtain a complete blood count every two weeks during the initial treatment phase in patients with active disease and every three months in patients on maintenance therapy [32]. Drug-induced pancreatitis occurs in 3 to 5% of the patients, invariably during the first six weeks of azathioprine or mercaptopurine therapy. Pancreatitis is a contraindication for continued use of these agents. One large, retrospective review failed to find a significant association between azathioprine and the development of lymphoma or leukemia. For more than 20 years, low-dose methotrexate therapy has been used in patients with intractable psoriasis and rheumatoid arthritis. Methotrexate was engineered to inhibit dihydrofolate reductase, thereby blocking DNA synthesis and causing cell death. First used in cancer treatment, methotrexate was subsequently recognized to have beneficial effects in autoimmune diseases such as rheumatoid arthritis and psoriasis. The anti-inflammatory effects of methotrexate may involve mechanisms in addition to its inhibition of dihydrofolate reductase. One study showed that this treatment was beneficial in 70% of patients with severe IBD. The response to methotrexate appeared to be more rapid than the response to mercaptopurine. Methotrexate is given weekly as an intramuscular injection of 15 to 25 mg. Side effects are rare and include leukopenia and hypersensitive interstitial pneumonitis. Hepatic fibrosis is the most severe potential side effect of long-term therapy. Patients with concomitant alcohol abuse and/or morbid obesity are more likely to develop hepatic fibrosis and therefore should not be treated with methotrexate. It is prudent to obtain a baseline chest radiograph and to monitor the patient’s complete blood count, liver function, and renal function every two weeks until the patient is receiving oral therapy and every one to three months thereafter. Before methotrexate therapy is initiated, the risks of treatment and the possible need for a liver biopsy should be discussed with the patient. A pretreatment liver biopsy is indicated in patients who have abnormal liver function tests and in those at a potentially increased risk for hepatic toxicity. Follow-up liver function tests are not a good predictor of toxicity. As with azathioprine-mercaptopurine, methotrexate is generally reserved for patients whose IBD is either steroid-resistant or steroid-dependent. In CD, it both induces and maintains remission, generally with a more rapid response than observed with mercaptopurine or azathioprine. Only limited studies have examined the role of methotrexate in UC. Treatment of IBD with methotrexate differs somewhat from its use in other autoimmune diseases. Most importantly, higher doses (e.g., 15 to 25 mg/week) are given parenterally. The increased efficacy with parenteral administration may reflect the unpredictable intestinal absorption at higher doses of methotrexate. For unknown reasons, the incidence of methotrexate induced hepatic fibrosis in patients with IBD is lower than that seen in patients with psoriasis [33].

Cyclosporine

The calcineurin inhibitor cyclosporine is a potent immunosuppressant drug used in organ transplantation. Since the mid-1980s, this drug has also been used to treat patients with IBD. At this time, cyclosporine is most useful in severely ill patients with UC who have not responded to corticosteroid therapy. In such patients, intravenously administered cyclosporine is highly effective for rapid disease control, and it may allow patients to avoid surgery. However, after one year, 70 to 80% of these patients may still require surgery. Thus, in many patients, the role of cyclosporine is to change a risky emergency operation into a less urgent procedure. Cyclosporine is effective in specific clinical settings in IBD, but the high frequency of significant adverse effects limits its use as a first-line medication. Cyclosporine is effective in severe UC that has failed to respond adequately to glucocorticoids therapy. Between 50 and 80% of these severely ill patients improve significantly (generally within 7 days) in response to intravenous cyclosporine (2 to 4 mg/kg daily), which sometimes allows them to avoid an emergent colectomy. Careful monitoring of cyclosporine levels is necessary to maintain a therapeutic level in whole blood between 300 and 400 ng/ml. Oral cyclosporine is less effective as a maintenance therapy in IBD, perhaps because of its limited intestinal absorption. In this setting, long-term therapy with a microemulsion formulation of cyclosporine with increased oral bioavailability may be more effective, but this has not been fully studied. Cyclosporine can be used to treat fistulous complications of CD. A significant, rapid response to intravenous cyclosporine has been observed; however, frequent relapses accompany oral cyclosporine therapy, and other medical strategies are required to maintain fistula closure. Thus, it is generally used to treat specific problems over a short term while providing a bridge to long term therapy. Cyclosporine is lipid-bound and thus is associated with an increased risk of seizures when it is administered to acutely ill, severely malnourished patients who have low serum cholesterol lipid levels. Oral maintenance with cyclosporine has, at best, limited benefit, and the relapse rate is high. The drug has a significant side effect profile that includes renal insufficiency and hypertension. Other immunomodulators that are also being evaluated in IBD include tacrolimus and MMF. Tacrolimus is similar to cyclosporine, but its oral form is better absorbed than oral cyclosporine. It is showing promise in small studies of severe CD. Less than half of patients, however, achieve long-term remission. MMF is being studied as an alternative for Crohn’s patients with fistulas who cannot tolerate azathioprine or mercaptopurine. It appears to be roughly equivalent in effectiveness and safety to other agents, although not as effective in maintaining remission. Very small studies have shown a 75% fistula closure rate with an average of eight months of treatment with MMF.

Monoclonal antibodies (biological)

Biological response modifiers are drugs that interfere with the inflammatory response. Of special interest for the treatment of Crohn’s disease and other diseases are drugs that target the inflammatory immune factor known as TNF-_. The administration of humanized monoclonal antibodies is an entirely new and potentially highly successful concept for treating IBD. The first such product, infliximab, is available for treating refractory CD. It acts by inhibiting the functional activity of TNF-. Following treatment, histological evaluation of colonic biopsies revealed a substantial reduction in detectable TNF-_. Treatment was also associated with a reduction of the commonly elevated serum inflammatory maker CRP. Infliximab is a chimeric immunoglobulin (25% mouse, 75% human) that binds to and neutralizes TNF-_, and it represents a new class of therapeutic agents for treating IBD [34]. Although many pro- and anti-inflammatory cytokines are generated in the inflamed gut in IBD, there is some rationale for targeting TNF-_ because it is one of the principal cytokines mediating the T􀀀1 immune response characteristic of CD. Infliximab (5 mg/kg infused intravenously at intervals of several weeks to months) decreases the frequency of acute flare-ups in approximately two-thirds of patients with moderate to severe CD and facilitates the closing of enterocutaneous fistulas associated with CD. Its long-term role in CD is evolving, but emerging evidence supports its efficacy in maintaining remission and in preventing recurrence of fistulas. Although infliximab was specifically designed to target TNF-_, it also may have more complex actions. Infliximab binds membrane-bound TNF-_ and may cause lysis of these cells by antibody-dependent or cell-mediated cytotoxicity. Thus, infliximab may deplete specific populations of subepithelial inflammatory cells. These effects, together with its mean terminal plasma half-life of eight to 10 days, may explain the prolonged clinical effects of infliximab. The use of inflixamab as a biological response modifier raises several important considerations. Both acute (fever, chills, urticaria, or even anaphylaxis) and subacute (serum sickness-like) reactions may develop after infliximab infusion. Anti-double-stranded DNA antibodies develop in 9% of patients, but a frank lupus-like syndrome occurs only rarely. Antibodies to infliximab can decrease its clinical efficacy; strategies to minimize the production of these antibodies (e.g., treatment with glucocorticoids or other immunosuppressives) may be critical to preserving infliximab efficacy for either recurrent or chronic therapy. Other proposed strategies to overcome the problem of antibody resistance include increasing the dose of infliximab or decreasing the interval between infusions. Infliximab therapy is associated with the increased incidence of respiratory infections; of particular concern in infliximab treatment is the potential reactivation of tuberculosis or other granulomatous infections with subsequent dissemination. It is recommended that candidates for infliximab therapy be tested for latent tuberculosis with purified protein derivatives, and patients who test positive should be treated prophylactically with isoniazid. However, anergy with a false-negative skin test has been noted in some patients with CD, and some experts routinely perform chest radiographs to look for active or latent pulmonary disease. Infliximab is also contraindicated in patients with severe congestive heart failure (New York Heart Association classes III and IV) and should be used cautiously in class I or II patients. As with the immunosuppressant drugs, there are concerns about the possible increased incidence of non-Hodgkin’s lymphoma, but a causal role has not been established. Finally, the significant cost of infliximab is an important consideration for some patients. Adalimumab is an anti-TNF agent similar to infliximab and decreases inflammation by blocking TNF-_. In contrast to infliximab, adalimumab is a fully humanized anti-TNF antibody (no mouse protein). Adalimumab is administered subcutaneously instead of intravenously, as in the case of infliximab. Adalimumab is comparable to infliximab in effectiveness and safety for inducing and maintaining remission in patients suffering from Crohn’s disease (CD). Adalimumab is also effective in healing anal fistulas in patients with CD. Adalimumab is well tolerated and has been shown to be effective for patients who cannot tolerate infliximab. The most common side effect is skin reactions at the site of injection, such as swelling, itching, or redness. Other common side effects include upper respiratory infections, sinusitis, and nausea. Rare cases of lymphoma and nervous system inflammation have been reported with the use of adalimumab. Symptoms of nervous system inflammation may include numbness and tingling, vision disturbances, and weakness in the legs. Some patients receiving adalimumab may rarely develop symptoms that mimic systemic lupus; these symptoms include skin rash, arthritis, chest pain, or shortness of breath. These lupus-like symptoms resolve after cessation of drug treatment. In a randomized, double-blind, placebo-controlled trial, adalimumab was more effective than the placebo in maintaining clinical remission for patients with moderate-to-severe CD through 56 weeks. In this study, adalimumab demonstrated sustained maintenance of clinical remission, improvements in quality of life, and reductions in hospitalization during long-term treatment for CD, with no new safety concerns identified. Certolizumab pegol is a monoclonal antibody directed against TNF-_. More precisely, it is a PE (polyethylene) gylated Fab’ fragment of a humanized TNF-inhibiting monoclonal antibody; this PE gylation increases the half-life of the drug by up to 14 days. In welldesigned Phase III clinical trials, certolizumab pegol was associated with significantly greater response rates compared to the placebo at weeks six and 26 of induction treatment. In patients who responded to the six-week induction, certolizumab pegol, administered as a monthly subcutaneous injection, was effective in maintaining CD treatment response and remission. Findings from studies of certolizumab pegol in refractory CD are currently underway.

Natural remedies for UC

IBD reduces the quality of life, and conventional therapies are not totally successful in preventing relapse or achieving remission. Many herbal remedies have been suggested to be effective in chronic inflammatory conditions; however, there is little clinical or pharmacological data to support these claims. Reactive oxygen metabolites are present in excess in the inflamed colonic mucosa (lining of the colon) and are likely to play a role in inflammation. Therapies that have antioxidant activity may be clinically useful. Herbal therapies are popular among patients with UC; however, they should complement, not replace, conventional care. We discuss some natural remedies used for UC below.

Probiotics

Probiotics are a mixture of putatively beneficial lyophilized bacteria that are given orally. Although probiotics are a promising alternative to more conventional therapies for inflammatory bowel disease, their role in treating IBD requires further evaluation. In one study, they diminished the occurrence of pouchitis, a common inflammatory condition that occurs in surgically created ileal reservoirs after total proctocolectomy for the treatment of UC. Probiotics reside in the gut and have been found to be effective in managing UC. Additionally, they help to control the number of potentially harmful bacteria, reduce inflammation, and improve the protective mucus lining of the gut. Probiotics are among the more popular remedies because they are without significant side effects and appear to be safe. In one study, people with mild-to-moderate active UC who were unresponsive to conventional treatment were examined. They were treated with probiotic supplements, which provided a total of 3,600 billion bacteria a day, for six weeks. At the end of the study, 18 people (53%) demonstrated remission on sigmoidoscopy, and eight people (24%) had a favorable response. Another study analyzed bacteria from the rectal biopsies of patients with active UC and healthy control subjects. There were significantly less bifidobacterium numbers in the UC biopsies, which suggested that these probiotic bacteria might have a protective role in UC. In a further study, 18 people with active UC were given a bifidobacterium supplement or a placebo for one month. Sigmoidoscopy, biopsy, and blood tests showed significant improvement in the probiotic group compared to the placebo group. The probiotic yeast Saccharomyces boulardii was found to be beneficial in the maintenance of CD.

Oral Aloe vera gel

Aloe vera gel has been demonstrated to have an anti-inflammatory effect. A double-blind, randomized trial examined the effectiveness and safety of Aloe vera gel for the treatment of mild-to-moderate active UC. Thirty patients were treated with 100 ml of oral Aloe vera gel, and 14 patients were treated with 100 ml of a placebo twice daily for four weeks. Clinical remission, improvement, and responses occurred in nine (30%), 11 (37%), and 14 (47%) patients treated with aloe vera, respectively, compared to one (7%), one (7%), and two (14%) patients, respectively, who received the placebo.

Boswellia

Boswellia is an herb that comes from a tree native to India. The active ingredient is the resin from the tree bark, which has been found to block chemical reactions involved in inflammation. It is used by people with UC, rheumatoid arthritis, and other inflammatory conditions. Unlike anti-inflammatory medications, boswellia does not appear to cause the gut irritation that occurs with many conventional pain relievers. A study of people with UC found that 82% of those who took 350 mg of boswellia extract three times daily experienced remission. Rare side effects of boswellia include diarrhea, nausea, and skin rash [34].ro

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Received on 25.03.2014 Modified on 20.04.2014

Res. J. Pharmacology & P’dynamics. 6(3): July- Sept. 2014; Page 153-161

Study	Plant	Results
Watt et al[35]	Althaea officinalis	Whole plant ethanol extract Antibacterial activity against E. coli
Yoshikawa et al[36]	Boswellia carterii	Mono- and triterpenes isolated from this oleogum resin ↓NO production in lipopolysaccharide-activated mouse peritoneal macrophages
Chevrier et al[37]	Boswellia carterii	Ethanol extract of oleogum resin Immunomodulatory properties
Camarda et al[38]	Boswellia carterii	Essential oil isolated from oleogum resin Antimicrobial activities against various microorganisms including fungi, Gram-positive and Gram-negative bacterial strains
Moghtader et al[39]	Boswellia carterii	Essential oil of seed Antioxidant properties
Shahsavari et al[40] Essential oil of seed Antioxidant properties	Bunium persicum	Antioxidant properties
Kumar et al[41]	Cassia fistula	Crude extract of fruit Significant antimicrobial activity
Francis et al[42]	Commiphora mukul	Terpenoids and guggulusteroids ↓Lipid peroxidation and
Saeed et al[43]	Commiphora mukul	The essential oil, chloroform extract and seven sesquiterpenoids compounds of oleogum resin Wide range of inhibitory activity against both Gram positive and Gram negative bacteria