Colonic N-acetylation of 5-aminosalicylic acid in inflammatory bowel disease

5-Aminosalicylic acid presently is believed to represent the therapeutically active moiety of the sulfasalazine molecule in the treatment of inflammatory bowel disease. The metabolism of this compound, however, has not been studied in detail. In this paper we provide evidence that 5-aminosalicylic acid is acetylated to N-acetyl-aminosalicylic acid in homogenates from colonic biopsy specimens (370 +/- 20 nmol/g wet wt or 2.9 +/- 0.9 nmol/mg.min, n = 10), whereas acetylation in fecal samples was only small (13.0 +/- 3.0 nmol/g). Mucosal N-acetylation was rapid, cofactor- and pH-dependent, and could be enriched in the cytosolic fraction. In contrast, fecal acetylation was slow and did not depend on the presence of acetyl-coenzyme A. There were neither significant differences of acetylation between patients and controls nor a significant correlation to the individual acetylation phenotype. From our results we believe that presystemic acetylation of 5-aminosalicylic acid may be mainly mediated by a colonic mucosal enzyme and only to a small extent by fecal (bacterial) processes.     

Lupus-like syndrome caused by 5-aminosalicylic acid in patients with inflammatory bowel disease.

BACKGROUND: Although 5-aminosalicylic acid (5-ASA) preparations used to treat inflammatory bowel disease are reported to have fewer side effects than sulphasalazine, increased clinical use of these compounds has resulted in increased reports of significant side effects. OBJECTIVE: To report four patients with antinuclear antibody-positive migratory arthralgias and acute inflammation unrelated to the underlying inflammatory bowel disease, fulfilling the criteria of a drug-induced lupus-like syndrome. SETTING: A university-affiliated teaching hospital. INTERVENTION: Cessation of treatment with 5-ASA compounds. RESULTS: The cases described constitute a drug-induced lupus-like syndrome. All patients improved rapidly after discontinuation of 5-ASA compounds. CONCLUSIONS: Reversible lupus-like syndrome appears to be a rare but significant side effect of 5-ASA compounds. Patients treated with 5-ASA compounds who experience acute inflammatory symptoms or clinical deterioration not related to their gastrointestinal disease should be screened to rule out a lupus-like reaction.     

Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease

Despite the advent of biological products,such as antitumor necrosis factor-αmonoclonal antibodies(infliximab and adalimumab),for treatment of moderate to severe cases of inflammatory bowel disease(IBD),most patients depend upon aminosalicylates as the conventional treatment option.In recent years,the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin,omega-3 fatty acids,probiotics and innovative formulations such as high-dose,oncedaily multi-matrix mesalamine,which are designed to minimize the inflammatory process through inhibition of different targets.Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid(ASA)in the form of sulfasalazine,balsalazide,olsalazine and ipsalazine,but rarely for its positional isomer 4-ASA-a wellestablished antitubercular drug that is twice as potent as 5-ASA against IBD,and more specifically,ulcerativecolitis.The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD.The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD.     

Possible protective effect of 5-aminosalicylic acid on Helicobacter pylori infection in patients with inflammatory bowel disease

GOALS: To evaluate the prevalence of (Hp) infection in a group of inflammatory bowel disease (IBD) outpatients and the possible influence of treatment. BACKGROUND: The low prevalence of Hp infection in these patients is usually attributed to environmental factors; the role of drugs has not been fully investigated. STUDY: Seventy-two consecutive outpatients underwent a C13-urea breath test for Hp: 32 with Crohn's disease (13 men; mean age, 48 years; range, 20-72 years) and 40 with ulcerative colitis (25 men; mean age, 49 years; range, 25-71 years). Thirty-one patients were treated with sulfasalazine and 41 with 5-ASA. The control group consisted of 72 age- and sex-matched subjects. RESULTS: The prevalence of Hp infection was 47% in the IBD patients and 61% in the controls (p = 0.089; odds ratio = 0.55; 95% CI = 0.283-1.089) with a statistically significant increase for each year of age ( p= 0.044; odds ratio = 1.02; 95% CI = 1.001-1.052). Among the IBD patients, age and gender, the type, activity, duration, extent of the disease, or the calendar year of diagnosis, had no influence on Hp infection. was detected in 65% of the patients treated with sulfasalazine and in 34% treated with 5-ASA (p = 0.017). CONCLUSIONS: Although low, the prevalence of Hp infection in our patients was not significantly different from that in the controls. 5-ASA, and not sulfasalazine, may have a protective effect against Hp infection.     

Oral 5-aminosalicylic acid preparations in treatment of inflammatory bowel disease an update

Therapeutic efficacy of 5-aminosalicylic acid (5-ASA) preparations is reviewed. In the acute treatment of Crohn's disease, Pentasa and Salofalk seem to be more effective than placebo. When it is given in an equimolar 5-ASA regimen, Salofalk appears to be at least as effective as sulfasalazine (SAS) in the treatment of both Crohn's disease and ulcerative colitis. Asacol and SAS are equally effective in maintenance therapy of ulcerative colitis. Dipentum was more efficient than placebo. There was only a low incidence of side effects from oral 5-ASA preparations, but larger-scale trials may be needed for a more accurate profile of adverse reactions.     

Cancer prevention in inflammatory bowel disease and the chemoprophylactic potential of 5-aminosalicylic acid

The risk of colorectal cancer is increased in ulcerative colitis and Crohn's colitis. Regular dysplasia surveillance colonoscopy in chronic colitis generally has been adopted as a strategy to prevent colorectal cancer or at least to diagnose it in an earlier stage. This has not been proven to reduce mortality, but it does provide the clinician and the patient with some confidence that they are participating in an active strategy to deal with the problem of colorectal cancer in chronic colitis. Disease extent and duration have long been held to be risk factors for colorectal cancer in chronic colitis, and recently some special risk groups have been identified which may require either more intensive surveillance or alternative approaches to cancer prevention. These include patients with primary sclerosing cholangitis, patients with first-degree relatives with sporadic colon cancer, and possibly, patients with backwash ileitis. There is an emerging interest in potential chemopreventative strategies in both sporadic and colitis-associated colorectal cancer. There also have been suggestive data that chronic maintenance 5-aminosalicylate use might reduce the risk of developing colorectal cancer. Recent data have suggested some potential preventative benefit of using ursodeoxycholic acid in patients with ulcerative colitis and primary sclerosing cholangitis. The scientific rationale for using these agents is sound but clinical data are lacking to fully support these approaches as chemoprevention in chronic colitis at present.     

Retrograde spread of 5-aminosalicylic acid enemas in patients with active ulcerative colitis

In an attempt to know the exact retrograde spread of high-dosage 5-aminosalicylic acid enemas, we have studied eight patients with active left-sided colitis, by adding a small amount of barium sulfate to the enemas and by checking the spread radiologically after 15 minutes, 1 hour, and 6 hours. Four grams of 5-aminosalicylic acid in 100-ml enemas and 4 gm in 200-ml enemas were used. The same experiment was repeated in a subsequent attack, with enemas labeled with technetium-99m and checked by scintiscans in five of these patients. We always have observed a volume-dependent spread of enemas but, interestingly, in the patients studied with technetium-99m there was always a wider spread than that which was detected with barium enemas. In all five patients, 100-ml enemas reached the splenic flexure. In two patients with total colitis, a progression of 100-ml technetium-99m enemas was performed in the transverse colon, but the maximum opacity remained in the left side. We can conclude that 4 gm of 5-aminosalicylic acid in 100-ml enemas can be suitable for treating patients with left-sided colitis, and will represent a valid addition for patients with more extensive colitis.     

Retrograde spread of therapeutic enemas in patients with inflammatory bowel disease

Little is known about the factors that determine the extent of dispersion of enema solutions in the colon. To unravel some of the determinants we evaluated a consecutive series of patients with left-sided colitis. 40 ml enema solutions, viscosity 0.062 Pa.s (62 cP) at 37 degrees C were labelled with 10 MBq 99m-technetium human serum albumin microcolloid. Scintigraphic imaging was performed in 35 patients until 2 hours after administration of the enema. In 8 of the 16 patients with limited retrograde spread the study was repeated after doubling the volume (80 ml). We conclude that the extent of dispersion of an enema 0.062 Pa.s solution is highly variable. The basic fluid component for therapeutic 40 ml enemas (viscosity 0.062 Pa.s) reaches the affected area in patients with left sided colitis only in 40% of the cases. Increasing the volume of the enema can be an effective way to increase the retrograde spread up to the affected area in patients with limited retrograde spread. Scintigraphic imaging is a simple and reliable method of checking whether an enema conforms to the requirements of medical treatment. Scintigraphic imaging lasting for 1 hour after administration of the enema appears to suffice.     

Efficacy of 5-aminosalicylic acid enemas versus hydrocortisone enemas in ulcerative colitis

A controlled trial has been carried out in order to compare the efficacy of enemas containing a high dosage of 5-ASA (4g) versus enemas containing hydrocortisone 100 mg. The trial was conducted on 86 patients, 44 of whom received 5-ASA and 42 received hydrocortisone. The results were favorable in terms of clinical, sigmoidoscopic, and histologic criteria for 5-ASA treatment. Other aspects have been investigated, such as retrograde spread of enemas which have been shown to reach the left colon. No nephrotoxicity was detected. The long term experience confirmed the preliminary positive results.     

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.     

Microproteinuria in patients with inflammatory bowel disease:TS it associated with the disease activity or the treatment with 5-aminosalicylic acid?

AIM: To investigate whether microproteinuria in patients with inflammatory bowel disease (IBD) is associated with the disease activity or the treatment with 5-aminosalicylic acid (5-ASA).METHODS: We prospectively studied microproteinuria in 86 consecutive patients with IBD, 61 with ulcerative colitis (UC) and 25 with Crohn's disease (CD), before as well as 2 and 6 months after their inclusion in the study.Forty-six patients received 5-ASA for a period of 28.8months (range 1-168 mo). Microalbuminuria (mALB) and urine levels of the renal tubular proteins β2-microglobulin (β2mGLB) and β-N-acetyl-D-glucosamidase (β-NAG) as well as the creatinine clearance were determined in a 12-h overnight urine collection. Tumor necrosis factor-α(TNF-α) serum levels were also measured.RESULTS: A totalof 277 measurements (194 in UC patients and 83 in CD patients) were performed. The prevalence of abnormal microproteinuria in UC and CD patients was 12.9% and 6.0% for mALB, 22.7% and 27.7% for β2mGLB, and 11.3% and 8.4% for β-NAG,respectively. mALB was not associated with IBD activity.β2mGLB and β-NAG urine levels were correlated to UC activity (UCAI:P＜0.01; UCEI: P＜0.005). mALB in UC patients and β-NAG urine levels in CD patients were related to TNF-a serum levels. An association was noticed between microproteinuria and smoking habit.Treatment with 5-ASA was not correlated to the severity of microproteinuria or to the changes of creatinine clearance.CONCLUSION: Microproteinuria is mainly associated with UC and its activity but not affected by 5-ASA.     

No dose-dependent tubulotoxicity of 5-aminosalicylic acid: a prospective study in patients with inflammatory bowel diseases

BACKGROUND AND AIMS: Elevated levels of renal tubular markers in the urine are found in 20-30% of patients with chronic inflammatory bowel diseases. We investigated whether this reflects a dose-dependent tubulotoxicity of 5-aminosalicylic acid (5-ASA). PATIENTS AND METHODS: In an open, prospective, multicenter study 18 patients with Crohn's disease and 29 with ulcerative colitis were treated with 3 g 5-ASA or more daily as the sole drug for 6 weeks. Clinical activity (CDAI, CAI) and renal tubular markers [beta-N-acetyl-D-glucosaminidase (beta-NAG) and other proteins in urine] were monitored. We examined whether the proportion of patients with elevated beta-NAG is more than 15% higher (absolute difference) than that prior to treatment. RESULTS: The proportion decreased from 19.2% to 12.8% in the intention-to-treat analysis (n=47) and from 24.3% to 13.5% in the per-protocol analysis (n=37), which was not more than 15% higher than at baseline. Mean CDAI decreased from 222 to 146 and mean CAI from 7.3 to 3.1 (intention-to-treat analysis). Response to therapy was shown by 61% of patients with Crohn's disease and 66% of patients with ulcerative colitis. The cumulative dose of 5-ASA was not correlated with beta-NAG level in the urine. CONCLUSION: This study largely rules out that 5-ASA at 3 g or higher per day for 6 weeks induces renal tubular damage. Elevated renal tubular markers reflect inflammatory activity or an extraintestinal manifestation of inflammatory bowel diseases.     

Optimum dosage of 5-aminosalicylic acid as rectal enemas in patients with active ulcerative colitis.

5-Aminosalicylic acid (5-ASA), the active moiety of sulphasalazine (SASP), was given as a rectal enema to patients with mild to moderate distal ulcerative colitis to determine the minimum effective dosage. A double blind study was carried out using enemas containing 1, 2, or 4 g or 5-ASA or placebo for a one month treatment period. One hundred and thirteen patients with ulcerative colitis attending our outpatient clinic volunteered to participate. Clinical, sigmoidoscopic, and histological assessments were carried out at the beginning of the study and after 15 and 30 days of treatment. All patients who received 5-ASA enemas showed significantly better results than those who received a placebo enema (p less than 0.001) but no difference was detected among the patients receiving differing concentrations of 5-ASA. This study suggests that 1 g 5-ASA (in a 100 ml enema) is a sufficient dosage for patients with a mild to moderate attack of ulcerative colitis.     

Idiopathic acute pancreatitis in patients with inflammatory bowel disease: A multicenter cohort study

BackgroundIdiopathic acute pancreatitis (IAP) in patients with inflammatory bowel disease (IBD) is not well characterized. Our purpose was to better understand this condition and its natural history.MethodsRetrospective cohort study conducted at nine Spanish IBD referral centers. Patients with IBD and a first episode of acute pancreatitis (AP) between 1998 and 2018 were included. Patients with a previous episode of AP or a diagnosis of chronic pancreatitis were excluded. IAP and non-IAP were compared by multivariate logistic regression and survival analysis.ResultsWe identified 185 patients with IBD (68.7% Crohn’s disease) and a first episode of AP. Thirty-eight of those 185 (20.6%) fulfilled criteria for IAP. There were no severe cases of IAP. On multivariate analysis, AP before IBD diagnosis (21.1% vs. 3.4%, p = 0.04) and ulcerative colitis (52.6% vs. 23.1%, p = 0.002) were significantly more common in IAP. Further work-up was performed in 16/38 (42%) IAP patients, and a cause was identified in 6/16 (37.5%). Median time from AP to the end of follow-up was 6.3 years (3.1–10). Five-year risk of AP recurrence was significantly higher in IAP group (28% vs. 5.1%, log-rank p = 0.001), with a median time to first recurrence of 4.4 months (2.9–12.2).ConclusionsIAP represents the second cause of AP in patients with IBD. It is more frequent in ulcerative colitis, and presents a high risk of recurrence. Additional imaging work-up after a first episode of IAP in IBD patients is highly advisable, as it identifies a cause in more than one-third of cases.     

6-Mercaptopurine-related pancreatitis in 2 patients with inflammatory bowel disease

Two patients with inflammatory bowel disease who developed acute pancreatitis within 21 days of commencing treatment with 6-mercaptopurine are presented. Both were inadvertently reexposed to the drug and developed recurrent pancreatitis within 3 hr of a single dose.     

Tolerance of nonsteroidal antiinflammatory drugs in patients with inflammatory bowel disease

OBJECTIVE: We sought to examine whether use of nonsteroidal antiinflammatory drugs (NSAIDs) in an outpatient inflammatory bowel disease (IBD) population is associated with an increased likelihood of active disease. METHODS: We reviewed records of initial outpatient visits of IBD patients to the principal author from June 1995 to December 1997, with regard to use of aspirin and other NSAIDs and disease activity. RESULTS: Of 40 Crohn's patients seen with active disease, three (7.5%) were using NSAIDs; 14 of 72 (19.4%) Crohn's patients seen with inactive disease were using NSAIDs. Fifty-eight ulcerative colitis patients were seen with active disease, with eight (13.7%) using NSAIDs. Among 21 UC patients initially seen while in remission, five (23.8%) were using NSAIDs. CONCLUSIONS: Among this group of outpatients, NSAID use was not associated with a higher likelihood of active IBD. NSAID use in IBD deserves further study before recommending that patients refrain from their use under all circumstances.