Recent Patents on Inflammation & Allergy Drug Discovery 2009, 3, 65-72
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Current Strategies for the Treatment of Ulcerative Colitis Praveen K. Yadav and Zhanju Liu* Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China Received: September 1, 2008; Accepted: October 23, 2008; Revised: November 5, 2008
Abstract: Ulcerative colitis (UC) is a chronic, relapsing and debilitating idiopathic inflammation of the gastrointestinal tract. Dysregulation of the mucosal immune response toward commensal bacterial flora together with genetic and environmental factors plays an important role in the pathogenesis. Refractory UC refers to disease that does not respond to or responds poorly to the many drugs used to treat the disease. The aim of medical treatment is to induce and maintain clinical remission. The most commonly used drugs, including mesalazine, azathioprine, 6-mercaptopurine, cyclosporine, and more recently anti-tumor necrosis factor (TNF) monoclonal antibody (e.g., infliximab), are chosen to suppress the immune system in intestinal mucosa. Additionally, colectomy may be required if medical treatments are unsuccessful or if complications develop. Some of the recent patent related to the field also discuss in this review article.
Keywords: Azathioprine, Crohn’s disease, inflammatory bowel disease, 6-mercaptopurine, methotrexate, tumor necrosis factor, ulcerative colitis. INTRODUCTION Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, relapsing and debilitating idiopathic inflammation of the gastrointestinal tract [1, 2]. UC is defined as continuous idiopathic inflammation of the colonic or rectal mucosa, and characterized by crypt abscesses and ulceration of the colon, which rarely extend beyond the muscularis layer. IBD shows a bimodal peak of appearance of the disease, typically, one in the population aged 15-25 years and another peak later in life around 60 years of age. The incidence of UC is approximately 10-20 per 100,000 per year with a reported prevalence of 100-200 per 100,000 [3-5]. Compared with UC in Western countries, UC in China has some differences in clinical characteristics. Therefore, a further populationbased epidemiological study is required to determine the prevalence and incidence rates of UC in China [6]. It is known that UC is associated with an increased risk of colorectal cancer. The incidence of colorectal cancer is estimated to be 2% in people who have had UC for 10 years, approaches 8% after 20 years and 18% after 30 years of having the disease [7]. Although the exact etiologies remain elusive, there is compelling evidence suggesting the implication of environmental risk factors, including commensal bacteria [8, 9], genetic predisposition [10-14], and disturbance of the immune reaction [15-17]. Both diseases are a response to environmental triggers (infection, drugs, or other agents) in genetically susceptible individuals. Smoking increases the risk of CD, but decreases the risk of UC through unknown mechanisms. Evidences have suggested that the commensal intestinal flora trigger an immune reaction in patients with a multifactorial genetic predisposition (perhaps involving abnormal epithelial barriers and mucosal immune defenses) *Address correspondence to this author at the Department of Gastroenterology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou 450014, China; Tel: +86-371-63939084; Fax: +86-371-63934118; E-mail:
[email protected] 1872-213X/09 $100.00+.00
[8, 9]. The broad areas examined are epidemiology, the gut/environmental interface, the inflammatory process, and genetics of each disease. Epidemiological studies have considered diet, drug, vaccination history, seasonal variation, water supply, and social circumstances. The gut/environmental interface includes work on luminal bacteria, biofilms, the epithelial glycocalyx and mucus, epithelial barrier function, epithelial remodelling, and immune/epithelial interactions. Genetics have adopted a candidate gene approach, genome wide screening through microsatellite markers and, most recently, studies on functional gene expression. The inflammatory process has been examined through cell signaling pathways, cytokine profiles, eicosanoid and other inflammatory mediators, lymphocyte trafficking, cell surface molecules, interactions between stromal and immune cells, and neuroimmune communication. In UC, the inflamed tissue is heavily infiltrated with inflammatory cells, mainly T lymphocytes. These cells are activated and secrete large amount of cytokines under inflammatory conditions, which in turn play a primary role in the pathogenesis of the diseases [18-21]. UC is a chronic disorder with periods of flares and remission. Because there is no known medical cure for UC, the therapeutic armamentarium is aimed at reducing the signs and symptoms associated with the disorder as well as the induction and maintenance of remission. Refractory UC refers to disease that does not respond to or responds poorly to the many drugs used to treat the disease. Patients who depend upon steroids to control their symptoms are usually referred to as having refractory disease. Most patients are treated with drugs that suppress the immune system. The most commonly used drugs are 5-aminosalicylate (5-ASA), azathioprine (AZA) and 6-mercaptopurine (6-MP), and more recently anti-TNF monoclonal antibody (e.g., infliximab). Lehr et al. disclose the use of Benzenesulfonyl-1h-indole derivatives as an effective therapeutic treatment in immunemediated diseases, e.g. intestinal disorders, such as autoimmune and inflammatory diseases or conditions specifically human IBD [22]. © 2009 Bentham Science Publishers Ltd.
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The other treatments for UC require intense research. Current research is finally addressing this probiotics. Social, environmental and dietary changes are associated with the changes of disease spectrum in a country. UC has become a commonly seen disease in China, probably due to extensive consumption of Western foods in recent years. Complementary therapies are increasing in popularity, and many of them are being gradually incorporated into the practice of modern medicine. Herbal remedies, which were the mainstay of drug treatment in Western medicine before synthetic single ingredient drugs were introduced and took over, and are still the mainstay of other medical systems. Homeopathic remedies continue to be a popular treatment option for people who don't like taking modern medicines. Recent advances in understanding the immune-mediated mechanisms underlying the pathophysiology of UC identified a variety of novel targets. The monoclonal antibodies that either recognize epitopes on immune-competent cells, or neutralize proinflammatory cytokine or chemokines represent the major class of new biological therapies for UC that selectively target components of inflammatory cascade. These agents include monoclonal antibodies against proinflammatory cytokines (TNF) and chemokines (IP-10), cell adhesion molecules (4, 47), T (CD25, CD4, CD3) and B (CD20) cells [23]. Additionally, colectomy (surgical removal of the colon) may be required if medical treatments are unsuccessful or if complications develop. Patients who can no longer tolerate the constant battle against the disease may also prefer to have their colon removed. 1. 5-ASA AGENTS: REDUCING INFLAMMATION The 5-ASA in oral formulations needs to be protected from being absorbed in the upper gastrointestinal tract so that it can be delivered to the lower gastrointestinal tract where it has been shown to be highly effective for the treatment of UC [24]. Currently, oral 5-ASA derivatives have been considered to be initial monotherapy in mild to moderate disease of UC [25]. There are numerous preparations and dosing regimens available, such as sulfasalazine, mesalazine, olsalazine and balsazazide, which are the most commonly prescribed antiinflammatory drugs in IBD. The precise mechanism of action of 5-ASA is not known, but is likely due to a local antiinflammatory effect from the luminal site in the diseased parts of gut [26]. When free 5-ASA is administered orally, it is nearly completely systemically absorbed from the proximal small intestine and then extensively metabolized to N-acetyl-5ASA in intestinal epithelial cells and the liver; it is then excreted in the urine [27]. 5-ASA has been shown to have a topical mechanism of action in the treatment of UC [28]. Therefore, strategies to "protect" orally administered 5-ASA from absorption until it reaches the colon have been developed. These strategies include the use of prodrugs; delayed-release formulations; controlled-release formulations; and, more recently, sophisticated formulations that combine both delayed-release and sustained-release mechanisms. Absorption of 5-ASA is followed by extensive metabolism to the major inactive N-acetyl-5-aminosalicylate (Nacetyl-5-ASA) by the N-acetyl-transferase 1 enzyme in
Yadav and Liu
intestinal epithelial cells and the liver. Oral or rectal administration of 5-ASA the released active agent is taken up by intestinal epithelial cells in the small and large bowel. Absorbed 5-ASA and intestinally inactivated N-Ac-5-ASA are partly secreted back into the intestinal lumen [29, 30]. Evidences have shown that 5-ASA could affect on eicosanoid metabolism and inhibit prostanglandin production in intestinal mucosa. It may interfere with the production of arachidonic acid by affecting the thromboxane and lipoxygenase synthesis pathway, function as “scavengers” of free oxygen radicals and inhibitors of reactive oxygen metabolite production. Moreover, 5-ASA may play a role in regulating mucosal lymphocyte and macrophage activities and inhibiting proinflammatory cytokine production such as IL-1 and IL-2. Sulfasalazine has an established role in the treatment of UC, being effective in controlling mild-to-moderate disease and in maintaining the remission in approximately 70% of patients. The recommended dose for sulfasalazine is 4 g/d in active UC, although some work suggests increased efficacy at 6 g/d. The side-effects are dose dependent, and many patients do not tolerate higher doses of sulfasalazine. Currently, mesalazine (5-ASA), the therapeutically active moiety of sulphasalazine, is a first-line drug for the treatment of patients with IBD [25], since lower frequencies of side effects appear. Mesalazine has a topical effect, which means that the drug may significantly concentrate into the intestinal mucosa only during its absorptive process. Thus, if it is absorbed by inflamed mucosa it may concentrate in the inflamed tissue, but if the drug is absorbed by normal mucosa it is almost completely lost for its therapeutic use. Thus, the goal of treatment is not only to achieve an optimal dosage, but especially to take the drug where it needs [31]. The delayed and sustained formulations have a dose response between 1.5 g/d and 4.8 g/d. Previous data demonstrated that balsalazide had a faster onset of action at 6.75 g/d over 12 weeks and improved tolerance compared to a pH-release mesalazine formulation of Asacol 2-4 g/d in patients with active UC [32]. Post hoc analysis also suggested that patients with left-sided disease might have responded better to basalazide. The dose is 2-6.75g in active UC and also for maintainance of remission in UC. Olsalazine may increase small bowel secretion and thus limit the upward dosing of azo-compound in active disease because of increasing loosening of stools at doses greater than 2 g/d (similar to basalazide at 6 g/d). Recently, mesalazine with MMX Multi Matrix System (MMX) technology was developed. Many patients with UC respond to mesalamine therapy within 8 weeks. Those not achieving remission after 8 weeks are often treated with steroids or other immunosuppressive therapies. The effect of 8 weeks' high-dose MMX mesalamine extension therapy in patients with active, mild-to-moderate UC who had previously failed to achieve complete remission in 2 phase III, double-blind, placebo-controlled studies of MMX mesalamine (SPD476-301 and -302) can achieve clinical and endoscopic remission following a further 8 weeks' treatment with high-dose MMX mesalamine therapy, thereby avoiding step-up therapy [33]. This high-strength formulation of 5ASA (1.2 g/tablet) utilizes MMX technology has a pHdependent gastro-resistant coating which delays the release
Treatment of Ulcerative Colitis
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of mesalamine to the colon, and a multimatrix system comprising lipophilic and hydrophilic matrices, normally in the terminal ileum and the cecum. MMX mesalamine tablets are 100% 5-ASA. After the gastroresistant pH-dependent polymer film disintegrates at or above pH 7.0 in the terminal ileum and the cecum, and the 5-ASA is released from the lipophilic and hydrophilic matrices, the bioavailability of mesalamine ranges from 21%-22 % [34]. MMX mesalazine tablets are administered orally 1 or 2 times daily 2.4 g to 4.8g per day has been shown to be effective, safe and tolerant in the maintenance of remission of UC [35]. Topical 5-ASA administration is higher effective for the management of mild-to-moderate distal UC. The suppository preparations reach the upper rectum, and the enema formulations reach the splenic flexure and distal transverse colon. The dose of 5-ASA enema varies from 1 to 4 g/d, but there is no proven benefit of topical doses greater than 1 g/d. Rectal formulations are superior to oral administration for the treatment of distal colitis with remission rates of 76% versus 46% for oral 5-ASA. Clinical data have also indicated that sulfasalazine and the newer 5-ASA formulation are effective to the maintenance of remission of UC. When the active disease is controlled, the dose required to maintain remission is the same as that used to induce remission. It is recommended that 2-4g/d of sulfasalazine and 0.75-4.8 g/d of the newer 5ASA formulations are necessary to maintain the remission. Importantly, 75% patients maintain long-term remission if continuous 5-ASA administration. Sulfasalazine and the newer 5-ASA formulations are well-tolerated for mild-tomoderate UC, and have a dose-effect in the maintenance of remission in UC. Unfortunately, dose-related side effects are seen in as many as 20% of patients, and dose-reduction to 2 g daily for sulfasalazine (or more likely switching to a nonsulfa containing mesalamine) may be necessary in those patients. As many as 30% of patients taking sulfasalazine report side effects that correlate closely with the amount of sulfapyridine moiety and the individual’s acetylator status (i.e. how fast sulfasalazine is metabolized) [36]. Generally, adverse effects include common and dose-dependent reactions such as headache, nausea, vomiting, and diarrhea; idiosyncratic symptoms such as rashes and itching; rare manifestations such as toxic hepatitis, pancreatitis, leukopenia, haemolytic anemia, and agranulocytosis; and extremely rare side effects such as neurotoxicity, pulmonary fibrosis and fetal hyperbilirubinemia. Nephrotoxic reactions reported in animal studies are dose-dependent, and nephrotoxicity has been reported repeatedly in patients taking sulfasalazine and 5-ASA [37]. Combination oral and topical 5-ASA therapy is better than either therapy alone. A fundamental principle of 5-ASA therapy is delivery of the drug to the site of disease. Therefore, a number of topical therapies have been developed and studied; in fact, remission of distal UC can be maintained with topical treatment alone. Daily (500 mg) and every-other-day (1000 mg) administration of mesalamine suppositories was more effective than placebo in maintaining remission in patients with mild-tomoderate ulcerative proctitis at 1 and 2 years [38]. Several studies, including a meta-analysis published in 2000, confirmed the efficacy of 5-ASA in an enema formulation in both inducing and maintaining remission in left-sided UC
(defined as distal to the splenic flexure) [39, 40]. The addition of topical 5-ASA to oral therapy increases mucosal levels of mesalamine by 3-fold in the descending colon and over 20-fold in the rectum. Moreover, it has been demonstrated repeatedly that the combination of 5-ASA in oral and enema formulations is superior to either therapy alone in inducing and maintaining remission of extensive colitis [39-41]. 2. IMMUNOSUPPRESSANT: INHIBITING ACTIVITY OF THE IMMUNE SYSTEM AZA AND 6-MP The immune modulating thiopurines 6-MP and its prodrug AZA have proven efficacy in active IBD and in the maintenance of an induced clinical remission. Purine analogues AZA and 6-MP are chemically related immunomodulators, AZA is nonenzymatically converted to 6-MP [42]. AZA and its metabolite 6-MP are purine base analogs which inhibit biosynthesis and incorporation of purine nucleotides in cells during mitosis. AZA and 6-MP have been used to treat refractory UC for many years. These drugs lessen symptoms in 60%-70% of patients and also help to maintain remission and decrease the need for steroids. Both drugs may require three to six months to produce their maximal effect. AZA and 6-MP are used for long-term treatment in steroiddependent cases or for patients who do not respond to 5ASA or corticosteroids. Optimal dosage for AZA is around 2.5 mg/kg body weight and induction of remission by these drugs may take 6-7 months. Intramuscularly applied methotrexate (MTX) is the second choice, while its efficacy starts earlier than that of AZA. Studies assessing oral lowdose MTX treatment are lacking. The risk of malignancy using immunosuppressive drugs as AZA is low and furthermore, especially AZA and 6-MP can be used rather safely during pregnancy. When initiating therapy with either AZA or 6-MP, measurement of complete blood count with differential is advocated at least every other week as long as doses of medications are being adjusted. The immunosuppressive properties of AZA/6-MP are mediated by the intracellular metabolism of 6-MP into its active metabolites, 6-thioguanine nucleotides (6TGN) and 6methylmercaptopurine (6-MMP). Preliminary studies have suggested that the red blood cell concentration of 6TGN (RBC 6TGN) is a potential guide to therapy. The aims of the study were to evaluate the RBC 6TGN concentrations in adult patients with CD under long-term AZA/6-MP therapy and to correlate it with response to treatment and hematological parameters [43]. Because of high relapse rate, it has been recently proposed to start with AZA or 6-MP as maintenance therapy for virtually all patients responding to cyclosporine. Prednisone tapering begins after 10-15 days and, after the patients are off-steroids, cyclosporine is stopped over the next month and the patient is maintained on AZA or 6-MP. CYCLOSPORINE Cyclosporine (CyA) is a powerful immunosuppressant drug usually used in patients who have undergone organ transplantation. It is an effective rescue therapy in steroidrefractory UC and may avoid immediate colectomy. However, CyA increases the risk of side effects and of CyA-
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related mortality [44, 45], it has not been adopted as rescue therapy for patients with failed steroid treatment in Sweden and most Danish centers. The individual response to CyA is poorly predictable. Clinical trials have shown that CyA is very effective in hospitalized patients with refractory UC when given intravenously. However, its role for the maintenance therapy is limited. The dose is 2 mg/kg/d (i.v. infusion) for all patients. Patients, who are making only a partial improvement with intensive intravenous regimen, may be the candidates for additional treatment with intravenous CyA. Lightiger et al. [46] evaluated the efficacy of intravenous CyA 4 mg/kg/day in severe attacks resistant to steroid treatment in a place a placebo-controlled trial with very few side effects. CyA retention enemas are safe and may be useful in the treatment of severe refractory distal UC. The use of CyA requires referral centers and expert gastroenterologists and surgeons are available to monitor these patients. Whole blood levels should be maintained between 150-300 ng/ml, evaluated by HPLC assay. It is important to determine blood concentrations of cholesterol and magnesium before starting treatment, because they may have seizures. Minor side-effects occur in 31%-51%, including tremor, paraesthesiae, malaise, headache, abnormal liver function, gingival hyperplasia, and hirsutism. Major complications are reported in 0-17%, including renal impairment, infections, and neurotoxicity. The risk of seizures is increased in patients with a low cholesterol (8) were randomly assigned to intravenous infliximab (5 mg/kg) or placebo. Twenty-nine percent of infliximab users had colectomy by 3 months after randomization, compared with 67% of placebo recipients (P = 0.017). In an early randomized study of infliximab for moderate UC, 43 patients who did not respond to oral corticosteroids were randomly assigned to infliximab (two doses: week 0 and week 2) or placebo [66]. Patients were evaluated at week 6
for remission based on a UC symptom index score of 2 or lower and a Baron score of 0 by sigmoidoscopy. At week 6, 39% of patients who received infliximab were in remission, compared with 30% of placebo recipients. Another small, randomized, controlled trial by Ochsenkuhn and colleagues [65] assessed the efficacy of infliximab for treatment of moderate active UC in patients who were not already receiving corticosteroids and azathioprine. Six of 13 patients were randomly assigned to one dose of infliximab (5 mg/kg), and seven were assigned prednisone (1.5 mg/kg/d). Clinical response (a decrease in True- love and Witts score of at least 5 points from baseline and a total score
