5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) is classically subdivided into ulcerative colitis (UC) and Crohn's disease (CD). Patients with IBD have increased risk for colorectal cancer. Because the pathogenesis of colorectal carcinoma has not been entirely defined yet and there is no ideal treatment for colon cancer, cancer prevention has become increasingly important in patients with IBD. The two adopted methods to prevent the development of colon cancer in clinical practice include the prophylactic colectomy and colonoscopic surveillance. But patients and physicians seldom accept colectomy as a routine preventive method and most patients do not undergo appropriate colonoscopic surveillance. Chemoprevention refers to the use of natural or synthetic chemical agents to reverse, suppress, or to delay the process of carcinogenesis. Chemoprevention is a particularly useful method in the management of patients at high risk for the development of specific cancers based on inborn genetic susceptibility, the presence of cancer-associated disease, or other known risk factors. Prevention of colorectal cancer by administration of chemopreventive agents is one of the most promising options for IBD patients who are at increased risks of the disease. The chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against intestinal tumors has been well established. But with reports that NSAIDs aggravated the symptoms of colitis, their sustained use for the purpose of cancer Chemoprevention has been relatively contraindicated in IBD patients. Another hopeful candidate Chemoprevention drug for IBD patients is 5-aminosalicylic acid (5-ASA), which is well tolerated by most patients and has limited systemic adverse effects, and no gastrointestinal toxicity. 5-ASA lacks the well-known side effects of longterm NSAIDs use. Retrospective correlative studies have suggested that the long-term use of 5-ASA in IBD patients may significantly reduce the risk of development of colorectal cancer. According to the literature, this agent might well satisfy clinical expectations with respect to a safe and effective chemopreventive agent.     

Indications for 5-aminosalicylate in inflammatory bowel disease： IS the body of evidence complete？

INTRODUCTION In the late 1970s, elegant studies revealed that 5-aminosalicylate is the active moiety of sulphasalazine in patients suffering from ulcerative colitis (UC) and Crohn’s disease (CD)[1,2]. Since then, 5-aminosalicylate has become the gold standard first line therapy for patients with UC, although its use in CD remains controversial. After 25 years, discussion of monocomponent 5-aminosalicylate with regard to its efficacy in comparison with sulphasalazine[3,4], drug profile…     

Treatment of inflammatory bowel disease： A review of medical therapy

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor （TNF） alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non- systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine （6-MP） and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn＇s disease, and infliximab is also approved for the treatment of UC.     

Drug therapy for ulcerative colitis

Ulcerative colitis (UC) is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is not the only choice for UC treatment and medical management should be as a comprehensive whole.Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-aminosalicylic acid (5-ASA), which is the topical anti-inflammatory ingredient. Pentasa is more commonly used in treating Crohn‘s ileitis because Pentasa capsules release more 5-ASA into the small intestine than Asacol tablets. Pentasa can also be used for treating mild to moderate UC. Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis. The sulfafree 5-ASA agents (Asacol, Pentasa, Dipentum and Rowasa) have fewer side effects than sulfa-containing Azulfidine. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds,systemic (oral) corticosteroids should be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.)are potent and fast-acting drugs for treating UC, Crohn‘s ileitis and ileocolitis. Systemic corticosteroids are not effective in maintaining remission in patients with UC.Serious side effects can result from prolonged corticosteroid treatment. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved. In patients with corticosteroid-dependent or unresponsive to corticosteroid treatment, surgery or immunomodulator is considered. Immunomodulators used for treating severe UC include azathioprine/6-MP,methotrexate, and cyclosporine. Integrated traditional Chinese and Western medicine is safe and effective in maintaining remission in patients with UC.     

Ileal pouch surgery for ulcerative colitis

Ulcerative colitis （UC） is a relapsing and remitting disease characterised by chronic mucosal and submucosal inflammation of the colon and rectum. Treatment may vary depending upon the extent and severity of inflammation. Broadly speaking medical treatments aim to induce and then maintain remission. Surgery is indicated for inflammatory disease that is refractory to medical treatment or in cases of neoplastic transformation. Approximately 25% of patients with UC ultimately require colectomy. Ileal pouch-anal anastomosis （IPAA） has become the standard of care for patients with ulcerative colitis who ultimately require colectomy. This review will examine indications for IPAA, patient selection, technical aspects of surgery, management of complications and long term outcome following this procedure.     

Direct invasion to the colon by hepatocellular carcinoma： Report of two cases

Although hepatocellular carcinoma （HCC） is a common tumor, direct invasion of the gastrointestinal tract by HCC is uncommon. Recently, we encountered two cases of HCC with direct invasion to the colon. The first patient was a 79-year-old man who underwent transarterial chemo-embolization （TACE） for HCC 1.5 years prior to admission to our hospital. Computed tomography （CT） showed a 7.5-cm liver tumor directly invading the transverse colon. Partial resection of the liver and transverse colon was performed. The patient survived 6 mo after surgery, but died of recurrent HCC. The second patient was a 69-year-old man who underwent TACE and ablation for HCC 2 years and 7 months prior to being admitted to our hospital for melena and abdominal distension. CT revealed a 6-cm liver tumor with direct invasion to the colon. The patient underwent partial resection of the liver and right hemicolectomy. The patient recovered from the surgery. But, unfortunately, he died of liver failure due to liver cirrhosis one month later. Although the prognosis of HCC that has invaded the colon is generally poor due to the advanced stage of the disease, surgical resection may be a favorable treatment option in patients with a good general condition.     

Duration of treatment with 5-aminosalicylic acid compounds

The development of 5-aminosalicylic acid (5-ASA) therapy as a life long treatment for ulcerative colitis is reviewed from its origins in the 1940s to the present day. The drug was designed to treat rheumatoid arthritis,but was found helpful in the management of nine patients with ulcerative colitis. This discovery preceded the emergence of the clinical trial as a tool for assessing a new drug's efficacy; as a result it lacked scientific rigour and was selective in its presentation of results. Nevertheless it identified the future cornerstone of therapy in ulcerative colitis. In 1962,the first double blind controlled trial of sulphasalazine was conducted on 40 patients. Outcome measures were subjective and included symptoms and an assessment of the rectal mucosa. In 1973,the first two papers on the role of sulphasalazine in maintenance of remission were published. Both used placebo controls and had a stratified design. Outcomes were measured using "an intention to treat" approach. The British study of 64 patients used both subjective and objective criteria to assess outcomes. Patients on placebo had a relapse rate four times patients on active treatment and this founded the basis for a life long approach to therapy with 5-ASA compounds in ulcerative colitis. However,in 1985,a small "on demand" study of 32 patients suggested this approach might be as effective as continuous treatment. Some support for this view came from an Italian study which showed no benefit to continued treatment for those in remission for two years or more. The central problem these studies identify is that of adherence to treatment in the long-term. Few studies have considered patients' attitudes to continuous therapy and it is an area that needs further investigation.     

Combined duplication of the colon and vermiform appendix in an adult patient

Combined duplication of the colon and vermiform appendix is one of the rare congenital anomalities of the alimentary tract. Only a few cases have been reported in the adult population. A 28-year-old man presented to the clinic with a mass in the right flank. Imaging showed only a hydronephrotic atrophic kidney. The final diagnosis was only available at exploration. Combined duplication of the tubular colon and vermiform appendix was confirmed histopathologically. The patient was treated with nephrectomy and complete resection of the duplicated colon and vermiform appendix. The patient recovered uneventfully, and has done well for the past year. This is believed to be one of the first reports of combined duplication of the tubular colon and vermiform appendix as a cause of hydronephrotic atrophic kidney in an adult patient.     

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant.However,despite the long use of tacrolimus in clinical practice,the best way to use this agent is still a matter of intense debate.The start of the genomic era has generated new research areas,such as pharmacogenetics,which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body.This variability seems to be correlated with the presence of genetic polymorphisms.Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus;also,unlike phenotypic tests,the genotype is a stable characteristic that needs to be determined only once for any given gene.However,prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication.At present,research has been able to reliably show that the CYP3A5 genotype,but not the CYP3A4 or ABCB1 ones,can modify the pharmacokinetics of tacrolimus.However,it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity.For these reasons,pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.     

Colon-specific drug delivery systems based on cyclodextrin prodrugs： In vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates

AIM: To investigate the release of cyclodextrin-5-amino-salicylic acid (CyD-5-ASA) in cecum and colon. METHODS: An anti-inflammatory drug 5-ASA was conjugated onto the hydroxyl groups of α-,β- and γ-cyclodextrins (CyDs) through an ester linkage, and the in vivo drug release behavior of these prodrugs in rat' s gastrointestinal tract after the oral administration was investigated. RESULTS: The 5-ASA concentration in the rat's stomach and small intestine after the oral administration of CyD-5-ASA conjugate was much lower than that after the oral administration of 5-ASA alone. The lower concentration was attributable to the passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specific in the cecum and colon. The oral administration of CyD-5-ASA resulted in lower plasma and urine concentration of 5-ASA than that of 5-ASA alone. CONCLUSION: CyD-5-ASA conjugates may be used as prodrugs for colon-specific drug delivery system.     

A new oral delivery system for 5-ASA: preliminary clinical findings for MMx

BACKGROUND: Multi-matrix (MMx), a new delivery system for mesalazine, seems to release 5-aminosalicyclic acid (5-ASA) preferentially in the sigmoid colon. This study had 2 objectives: (1) to evaluate the therapeutic response to MMx in patients with active left-sided disease and (2) to gain additional insights as to how the therapy would compare with topical 5-ASA. METHODS: Patients received either 1.2 g of 5-ASA MMx three times per day plus placebo enema or 4 g of 5-ASA enema plus placebo tablets for 8 weeks. The primary endpoint was clinical remission (clinical activity index < or =4) at 8 weeks. Secondary endpoints were endoscopic and histologic remissions. RESULTS: Seventy-nine patients were enrolled. Clinical remission rates at 4 and 8 weeks were 57.5% and 60.0% for patients treated with MMx and 68.4% and 50.0% for patients randomized to 5-ASA enemas, respectively (95% confidence interval for the difference at 8 weeks, -12 to +32). Endoscopic remission was achieved by 45.0% of patients on 5-ASA MMx and by 36.8% of those on enema, whereas 15.0% and 8% of patients, respectively, showed histologic remission. Compliance was 97.0% for oral and 87.5% for topical therapy. In the enema group, compliance was 88.0% for the patients in remission and 65.5% for those with active disease. CONCLUSIONS: Preliminary studies suggest that similar rates for induction of remission can be expected from 5-ASA enemas and MMx for patients with left-sided ulcerative colitis.     

Recent advances in the management of distal ulcerative colitis

The most frequent localization of ulcerative colitis (UC) is the distal colon. In treating patients with active distal UC, efficacy and targeting of the drug to the distal colon are key priorities. Oral and rectal 5-aminosalicylic acid (5-ASA) preparations represent the first line therapy of mild-to-moderate distal UC for both induction and maintenance treatment. It has been reported that many UC patients are not adherent to therapy and that non-compliant patients had a 5-fold risk of experiencing a relapse. These findings led to the introduction of once-daily oral regimens of 5-ASA as better therapeutic options in clinical practice due to improved adherence. New formulations of mesalazine, including the multi-matrix delivery system, and mesalazine granules, which allow once-daily administration, have been developed. They have been demonstrated to be efficacious in inducing and maintaining remission in mild-to-moderate distal UC in large clinical trials. However, existing data for distal UC are rather insufficient to make a comparison between new and classical 5-ASA formulations. It seems that the new formulations are at least as effective as classical oral 5-ASA formulations. Other treatment options, in the case that 5-ASA therapy is not effective, include systemic corticosteroids, thiopurines (azathioprine or 6-mercaptopurine), cyclosporine, infliximab and surgery. The combination of a prompt diagnostic work-up, a correct therapeutic approach and an appropriate follow-up schedule is important in the management of patients with distal UC. This approach can shorten the duration of symptoms, induce a prolonged remission, improve patient's quality of life, and optimize the use of health resources.     

Treatment of spondyloarthropathy with 5-aminosalicylic acid (mesalazine): an open trial

OBJECTIVE: Ankylosing spondylitis (AS) and spondyloarthropathy (SpA) are inflammatory diseases of unknown etiology. Various exogenous and endogenous (inherited) factors play a role in their development. Sulfasalazine (SSZ) is generally accepted as a disease modifying drug in the treatment of AS and SpA. Which part of SSZ, 5-acetylsalicylic acid (5-ASA, mesalazine) or sulfapyridine (SP), is the effective moiety is unknown. As the bowel, colon, and the ileum play an important role in the development of AS and SpA, it may be possible that 5-ASA is the effective moiety, with a similar mode of action as in the treatment of inflammatory bowel disease. To determine the efficacy of 5-ASA an open pilot study was done in 2 groups of patients with SpA. METHODS: Twenty patients with SpA, who were taking SSZ, were switched to 5-ASA (Pentasa), and 19 patients with active SpA were treated with 5-ASA without previous administration of SSZ. RESULTS: In the first group, 17 (85%) patients responded with respect to the physician global clinical assessment compared to the previous SSZ treatment period; whereas in the second patient group a statistically significant improvement was obtained in erythrocyte sedimentation rate. CONCLUSION: The results support our hypothesis that 5-ASA might be the active moiety of SSZ in the treatment of SpA.     

Aminosalicylates and steroids in the treatment ot chronic inflammatory bowel diseases--consensus paper of the Working Group for Chronic Inflammatory Bowel Diseases of the OGGH

5-aminosalicylates (5-ASA) and steroids constitute a cornerstone of medical therapy in patients with inflammatory bowel diseases (IBD). Whereas the efficacy of 5-ASA in Crohn's disease (CD) is equivocal, ulcerative colitis (UC) is the main indication for this drug. In UC, 5-ASA is effective in the treatment of mild to moderate acute disease and in maintenance of remission. Furthermore, 5-ASA topical therapy is an important treatment option in patients with mild to moderate proctitis and/or left-sided UC and shows additive efficacy to oral therapy. From retrospective data a chemo-preventative activity of long-term 5-ASA therapy in UC is delineated. Steroids are treatment of first choice for moderate to severe cases of CD and UC. Budesonide, a modified steroid with less side effects, plays a major role in the treatment of ileocolonic CD +/- involvement of the right colon and is used as treatment of choice in mild-to-moderate cases. In case of acute, severe disease conventional steroids are superior compared to budesonide and therefore budesonide should only be used after considerable improvement of disease activity. The necessity to apply steroids in a given patient represents a negative prognostic indicator for the course of disease and should incite the early introduction of immunosuppressive therapy in this case. Steroids are only effective as short term therapy of IBD and are to be avoided for maintenance treatment. In all cases of steroid therapy an osteoporosis prophylaxis with calcium and vitamin D is recommended. Topical steroid treatment is less effective in left-sided UC compared to 5-ASA.     

New oral salicylates in the therapy of chronic idiopathic inflammatory bowel disease

Sulfasalazine has been the mainstay of therapy for ulcerative colitis and Crohn's disease of the colon. More recently, it has become clear that 5-ASA is the active moiety of the compound and that the sulfapyridine component is responsible for most of the adverse responses to sulfasalazine. The modes of action of sulfasalazine and 5-ASA have not been determined despite active investigations. There has been great current emphasis on the development of delivery systems to allow maximum concentration of therapeutically active 5-ASA in the colon or other gastrointestinal mucosal locations. Olsalazine accomplishes this goal by creatively coupling two molecules of 5-ASA to each other by a diazo bond. Bacterial azoreductases uncouple the parent drug and deliver 5-ASA to the colonic mucosa. Several pharmaceutical manufacturers have devised variations in mesalamine (5-ASA) coatings designed to release in pH and time-related manners. Oral Rowasa, Claversal, and Asacol accomplish distal delivery with acrylic coating of tablets. Oral Pentasa seems unique in distributing 5-ASA throughout the small bowel as well as the colon by utilization of small ethylcellulose-coated microgranules. For this reason, Pentasa may be particularly useful in the treatment of small bowel Crohn's disease. There are no data to suggest that patients unresponsive to oral sulfasalazine will respond to 5-ASA in any form, although it is possible that better toleration of the 5-ASA formulations will allow more effective dosage levels to be delivered. There are also preliminary data supporting synergism between oral and topical rectal 5-ASA in certain patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of aminosalicylates in the treatment of ulcerative colitis

Aminosalicylates (5-ASA, sulfasalazine and mesalazine) play a central role in the treatment of ulcerative colitis (UC). For acute treatment of mild to moderate flares and in maintenance treatment, their efficacy has been established. Since ulcerative colitis is limited to the distal colon in two thirds of the patients, topical therapy also plays an important role. In mild/moderate active disease 5-ASA 4 g/d is as effective as oral corticosteroids. Ulcerative proctitis is treated with 2 x 500 mg or 1 x 1 g suppositories and proctosigmoiditis with 1 to 4 g enemas. Oral 5-ASA is also safe in maintenance treatment and is generally well tolerated. The risk of colorectal tumours is increased in patients with longstanding ulcerative colitis and epidemiological evidence indicates that chronic 5-ASA treatment reduces this risk. However, at present there is insufficient evidence to maintain patients on life-long 5-ASA maintenance treatment for this indication.     

Standard treatment of ulcerative colitis

Ulcerative colitis (UC) is an idiopathic, chronic inflammation of the colon which may present with a range of mild to severe symptoms. The disease may be localized to the rectum or can be more extensive and involve the left side of the colon or the whole colon. Treatment in UC is directed towards inducing and maintaining remission of symptoms and mucosal inflammation. The key parameters to be assessed for the most appropriate treatment are the severity and extent of the inflammation. Meta-analyses of published trials have shown that topical treatment with 5-aminosalicylic acid (5-ASA) is the treatment of choice in active distal mild-to-moderate UC. Oral aminosalicylates are effective in both distal and extensive mild-to-moderate disease, but in distal disease, the rates of remission are lower than those obtained with topical 5-ASA. New steroids, such as budesonide and beclomethasone dipropionate (BDP), administered as enemas, constitute an alternative to 5-ASA therapy. In some studies, these have been shown to be as effective as conventional steroids but with significantly lower inhibition of plasma cortisol levels. Patients with unresponsive disease or those with more severe presentation will require oral corticosteroids and sometimes intravenous therapy. Approximately 10% of patients with unresponsive UC have severe attacks requiring hospitalization. Patients with severe disease should be managed jointly by a medical and surgical team, and intensive intravenous treatment should be started with high-dose steroids. Early recognition of failure of therapy will allow the introduction of immunosuppressive therapy with intravenous cyclosporine. Patients who respond are shifted to oral cyclosporine associated with azathioprine/6-mercaptopurine, whereas those who fail will require proctocolectomy. Oral aminosalicylates are the first-line therapy in maintenance of remission. Topical 5-ASA may play a role in distal disease. Patients who are steroid dependent can be started on azathioprine or 6-mercaptopurine although it may take up to 3 months for the treatment to become effective. They may have reversible immediate side effects, such as pancreatitis or bone marrow suppression, which disappear upon discontinuation of therapy. Close monitoring of these hematologic and biochemical parameters will improve safety. The use of biologic therapy with infliximab in more severe disease has not been established.     

Does treatment schedule matter? Once daily versus divided doses of 5-ASAs

Sulfasalazine was the first 5-ASA used to treat ulcerative colitis (UC). Because of tolerability issues, it was administered in a three times a day schedule in order to try to minimize side effects. With the development of sulfa-free 5-ASA products, the controlled trials used historical clinical experience and in vitro pharmacokinetic studies to dose their therapies to perhaps be in the most favorable light possible. However, it became clear over the years that outside of the context of a clinical trial, t.i.d. or even q.i.d. dosing led to lower patient satisfaction and overall adherence. Research demonstrated that upwards of 40% of patients were not taking their maintenance 5-ASA, and many patients cited unintentional forgetfulness as the reason. It became clear that simplifying the regimen was paramount for acceptable outcomes. Early pilot data and then controlled trials demonstrated the efficacy and safety of twice daily 5-ASA for active and quiescent UC. Now several large controlled trials demonstrate the non-inferiority and increased patient adherence and satisfaction with once daily dosing. MMX mesalamine was the first 5-ASA to receive US FDA approval in a once daily regimen. Results from the PODIUM and QDIEM trials have demonstrated acceptable effectiveness rates with favorable side effect profiles. Adherence rates remain high in real-world settings when medication is given once daily and data now suggest that once daily may be more effective than more frequently. It thus appears that the majority of patients with UC, whether with active or quiescent disease, can be treated with once daily 5-ASA.     

Ulcerative colitis therapy: importance of delivery mechanisms

Since the initial observation that mesalamine or 5-aminosalicylate (5-ASA) has an anti-inflammatory effect on ulcerative colitis, investigators have been trying to improve on the delivery mechanisms of this compound. As it is believed that the anti-inflammatory effect of 5-ASAs is mediated topically, current formulations are designed to release 5-ASA in the small intestine and colon, or predominantly in the colon. A dose-response curve is seen with some preparations of mesalamine but not all. In general, 5-ASAs are effective in patients with ulcerative colitis and much less effective in Crohn's disease. Evidence demonstrates that 5-ASAs are effective for induction of remission and maintenance of remission. Preparations that deliver 5-ASA in a pH-dependent manner are most affected by variability in luminal pH, whereas those that depend on bacterial cleavage for release of the active 5-ASA are most affected by transit time. Most studies have not compared different preparations of mesalamine and examined differences in colonic delivery. Depending on the endpoint examined in the studies, efficacy of the various 5-ASA products appears similar at the most optimal doses. For a given patient, however, it may be necessary to experiment with more than one preparation if an initial trial results in a suboptimal response.