Expanding Applications: The Potential Usage of 5-Aminosalicylic Acid in Diverticular Disease

Diverticular disease is a common bowel condition, the pathogenesis of which is incompletely understood. Acute exacerbations of diverticular disease usually require dietary changes, antibiotic therapy, and may necessitate urgent surgery. Approximately 25–33% of patients experience symptomatic and acute inflammatory disease recurrence, suggesting that current long-term management is inadequate. Because inflammatory complications of diverticular disease, including diverticulitis, are similarities to inflammatory bowel diseases, evidence suggests that patients may respond to anti-inflammatory therapies used in these conditions. Here, we explore the rationale and evidence for use of inflammatory bowel disease treatment, namely 5-aminosalicylic acid (5-ASA; mesalamine), in diverticular disease, and review clinical data on the efficacy of mesalamine either alone or in combination with other agents for the treatment of diverticular disease. PubMed and conference abstracts were searched for clinical studies examining the use of mesalamine in treating diverticular disease. Studies were evaluated for treatment efficacy in symptom reduction, recurrence prevention, or improving quality of life. The results of our search suggest that single-agent mesalamine can reduce diverticular disease symptoms and improve quality of life more effectively than antibiotic treatment alone. Mesalamine in combination with antibiotics can also reduce symptoms and improve quality of life with greater efficacy than either treatment alone. Combining mesalamine and probiotics treatments may reduce recurrent attacks of diverticular disease. Further randomized, well-controlled studies are required for validation; however, it seems that mesalamine is an important agent in future diverticular disease management.     

Safety of Topical 5-Aminosalicylic Acid in Pregnancy

Objectives: To assess the safety and efficacy of topical 5-aniinosalicylic acid preparations for therapy of distal colitis during pregnancy. Methods : Nineteen pregnancies in sixteen consecutive patients with proven distal colitis were identified prospectively at a tertiary care center. All patients were given trials of weaning off medication and all failed. All subjects were on maintenance topical 5-aminosalicylic acid therapy at the time of conception. They were followed throughout their pregnancy and thereafter. Their children were also closely examined and followed by a pediatrician. Results : The mean age at delivery was 25.8 yr, and the mean duration of illness was 4.6 yr. After taking topical therapy, there were no relapses during the pregnancy. There were 19 successful full-term pregnancies with no fetal abnormalities. The mothers and children were followed for more than 6 months. Conclusion : In this series, topical 5-aniinosali-cylic acid appears safe, effective, and well tolerated in the management of pregnant patients with distal colitis.     

Effectiveness of 5-Aminosalicylic Acid for Maintaining Remission in Patients with Crohn's Disease: A Meta-Analysis

Objective: We conducted a meta-analysis of the published randomized clinical trials to evaluate the effectiveness of 5-aminosalicylic acid (5–ASA) for maintaining remission in inactive Crohn's disease. Methods: The trials were identified by standard computerized techniques for literature search. All studies included in the meta-analysis were aimed at evaluating the effectiveness of 5-ASA in comparison with a control group receiving either no treatment or placebo. Results: Our meta-analysis of five clinical trials published as full-length articles indicates that 5-ASA significantly reduces the relapse frequency in patients with inactive Crohn's disease [odds-ratios (95% CI): 0.56 (0.37–0.84) at 6 months, 0.47 (0.33–0.67) at 12 months, 0.53 (0.38–0.73) at 24 months]. The pooled relapse-free rates in the treatment group were 9t% at 6 months, 84% at 12 months, and 72% at 24 months; the corresponding rates in the control group were 77%, 60%, and 52%. A second meta-analysis, conducted using the additional information deriving from four randomized trials published as abstracts, gave essentially the same results. Conclusions: Whereas our meta-analysis shows that the effectiveness of 5-ASA is statistically significant, a simple pharmacoeconomic assessment indicates that the cost for preventing each relapse can lie between $4,000 and $10,000. This cost compares favorably with the average cost for treating a relapse.     

5-Aminosalicylic Acid Enemas in Patients with Active Ulcerative Colitis

Enemas containing 1000 mg 5-ASA were administered to patients with active distal colitis in three separate studies: as a single dose in a neutral solution (pH 7.4); as a single dose in a slightly acidic, buffered suspension (pH 4.8); and as multiple doses once a day for 10 days with the acidic enema. 5-ASA was relatively rapidly absorbed from the neutral solution, resulting in plasma concentrations of 5-ASA sometimes two to three times higher than those found after peroral salazosulfapyridine (SASP) treatment. In contrast, absorption from the acidic enema was reduced and/or prolonged, giving plasma concentrations similar to those found during oral SASP treatment. After repeated doses of the acidic enema, plasma concentrations after an enema resembled those seen after the single dose. Urinary excretion was significantly lower, suggesting a reduced fraction of absorption at steady-state conditions. No side effects were observed, and no local irritation was reported. An acidic buffer suspension with 5-ASA seems to be safe for use as enema and deserves further clinical testing for treatment of distal ulcerative colitis.     

5-Aminosalicylic Acid Enemas in Refractory Distal Ulcerative Colitis: Long-Term Results

In this trial, we examined the role of 4-g 5-aminosalicylic acid (5-ASA) enema in the long-term management of patients with previously refractory distal ulcerative colitis. Of 20 such patients treated with nightly 5-ASA enemas, 16 improved symptomatically, with 15 achieving clinical remission and 14 achieving sigmoidoscopic remission within 3 to 5 wk. An attempt was made to maintain clinical remission with 5-ASA enemas in these 16 by successively decreasing the frequency of administration to every other night and then every third night, as long as remission was maintained. Relapses were treated by reinstituting nightly 5-ASA enema administration followed by another attempt at tapering the frequency of administration. Follow-up has ranged from 5 to 16 months. Nine patients were rapidly tapered to every third night administration, but six relapsed. Of these six, four were brought into remission with reinitiation of nightly enemas and tapered to every three nights, whereas one ultimately required enemas every two nights for control and one required enemas nightly (with mild symptoms). Six other patients relapsed when the enemas were tapered to every two nights, and after retreatment on a nightly regimen, four could be maintained on an every third night regimen while two have required every second night administration. One patient has required nightly administration from the outset. Currently, one patient is off all medication, while eight are on an every third night, three are on an every second night, and three are on a nightly schedule. We conclude that in patients with distal ulcerative colitis refractory to conventional therapy but responsive to 5-ASA enemas, relapse is common as the frequency of 5-ASA enema administration is decreased, although some patients may be maintained on a less than nightly schedule. The optimal maintenance regimen remains to be determined.     

5-氨基水杨酸在炎症性肠病及其相关性结直肠癌中的作用新机制

炎症性肠病（IBD）包括溃疡性结肠炎（UC）和克罗恩病（CD）,5-氨基水杨酸（5-ASA）是IBD治疗中最经典的抗炎剂。IBD患者结直肠癌（CRC）的发病率较正常人群明显增高,长期使用5-ASA可减少IBD患者发生CRC的风险。5-ASA传统的抗炎机制是通过影响抑制前列腺素合成、调节各种细胞因子的产生而发挥抗炎作用的,新近研究发现5-ASA可能通过氧化物酶体增殖物激活受体（PPAR）-γ途径发挥抗炎和抗瘤作用。本文就5-ASA的作用新机制作一简要概述。     

Niclosamide Modulates the Cellular and Humoral Immune Response in Balb/c Mice

Background: Niclosamide, a STAT3 inhibitor, is widely under investigation due to its anti-cancer properties. STAT3 also exhibits an exciting role in the immune responses. Objective: This study aimed to evaluate the impact of niclosamide on immune response of mice. Methods: Niclosamide was administered to balb/c mice. To evaluate cell-mediated immune response, a contact-hypersensitivity (CHS) test, cyclophosphamide-induced neutropenic assay, and carbon clearance test were performed, whereas a humoral immune response was evaluated by hemagglutination assay (HA) and mice lethality test. The concentration of TGF-β1 was determined by enzyme-linked immunosorbent assay (ELISA) on murine peritoneal macrophages. Results: In the CHS test, niclosamide caused a decrease in skin thickness, significantly exhibiting a decrease in inflammation. A highly significant decrease in overall leukocyte count (lymphocytes and neutrophils) was observed before and after cyclophosphamide injection as compared with the control group. However, only a highly significant decrease in the neutrophil percentage was observed. Niclosamide has decreased the phagocytic process immensely compared with the control. In the HA titer, niclosamide was found to reduce the antibodies' titer compared with the negative control group. In the mice lethality test, the treatment groups have shown an increase in the percentage of mortality. TGF-β1 elevated in peritoneal macrophages when treated with niclosamide, in a dose-dependent manner. Conclusion: Niclosamide exerts potent immunomodulatory effects by significantly suppressing cell-mediated and humoral immune responses and increasing the levels of TGF-β1 in mice. Niclosamide might be added as an adjuvant to immunosuppressive drugs for the treatment of autoimmune diseases.     

A Case of Diversion Colitis Treated with 5-Aminosalicylic Acid Enemas

An 85-yr-old female presented with diversion colitis after surgery with a resultant colostomy and excluded rectal segment. Treatment with 5-aminosalicylic acid (Rowasa) enemas resulted in both endoscopic and histological resolution. This is the first case of diversion colitis treated with 5-aminosalicylic acid enemas.     

The Protein Kinase Receptor Modulates the Innate Immune Response against Tacaribe Virus

The New World (NW) mammarenavirus group includes several zoonotic highly pathogenic viruses, such as Junin (JUNV) or Machupo (MACV). Contrary to the Old World mammarenavirus group, these viruses are not able to completely suppress the innate immune response and trigger a robust interferon (IFN)-I response via retinoic acid-inducible gene I (RIG-I). Nevertheless, pathogenic NW mammarenaviruses trigger a weaker IFN response than their nonpathogenic relatives do. RIG-I activation leads to upregulation of a plethora of IFN-stimulated genes (ISGs), which exert a characteristic antiviral effect either as lone effectors, or resulting from the combination with other ISGs or cellular factors. The dsRNA sensor protein kinase receptor (PKR) is an ISG that plays a pivotal role in the control of the mammarenavirus infection. In addition to its well-known protein synthesis inhibition, PKR further modulates the overall IFN-I response against different viruses, including mammarenaviruses. For this study, we employed Tacaribe virus (TCRV), the closest relative of the human pathogenic JUNV. Our findings indicate that PKR does not only increase IFN-I expression against TCRV infection, but also affects the kinetic expression and the extent of induction of Mx1 and ISG15 at both levels, mRNA and protein expression. Moreover, TCRV fails to suppress the effect of activated PKR, resulting in the inhibition of a viral titer. Here, we provide original evidence of the specific immunomodulatory role of PKR over selected ISGs, altering the dynamic of the innate immune response course against TCRV. The mechanisms for innate immune evasion are key for the emergence and adaptation of human pathogenic arenaviruses, and highly pathogenic mammarenaviruses, such as JUNV or MACV, trigger a weaker IFN response than nonpathogenic mammarenaviruses. Within the innate immune response context, PKR plays an important role in sensing and restricting the infection of TCRV virus. Although the mechanism of PKR for protein synthesis inhibition is well described, its immunomodulatory role is less understood. Our present findings further characterize the innate immune response in the absence of PKR, unveiling the role of PKR in defining the ISG profile after viral infection. Moreover, TCRV fails to suppress activated PKR, resulting in viral progeny production inhibition.     

Immune Phenotype of Chronic Liver Disease

Immune disorders in chronic liver disease mayreflect common host propensities or diseasespecificfactors. Our aim was to determine the principal basesfor these expressions. Four hundred fifty-one patients with various chronic liver diseases wereassessed prospectively for concurrent immune disorders.Individuals with immune diseases were more frequentlywomen (73% vs 60%, P = 0.02) and they had HLA DR4 more often than counterparts with other HLA(46% vs 23%, P = 0.000008). The association between HLADR4 and immune disease was apparent within individualliver diseases and within different categories of liver disease. Women with HLA DR4 had ahigher frequency of immune disease than women withoutHLA DR4 (52% vs 22%, P 0.000001), and they also hadimmune diseases more commonly than DR4-positive men (52% vs 31%, P = 0.03). DR4-positive men,however, had higher frequencies of immune disease thanDR4-negative men, especially in the nonimmune types ofliver disease (26% vs 4%, P = 0.002). We conclude that HLA DR4 and female gender constitute animmune phenotype that is an important basis forautoimmune expression in chronic liverdisease.     

Absorption, Enterohepatic Circulation, and Excretion of 5-Aminosalicylic Acid in Rats

After oral administration of sulfasalazine, the majority of the administered dose reaches the colon, where it is split into 5-aminosalicylic acid (5-ASA) and sulfapyridine. 5-ASA is believed to be the effective component in the treatment of inflammatory bowel disease. After intraduodenal administration of 5-ASA (20 mg) in rats, 91% of the drug was absorbed in the proximal small intestine. Peak serum 5-ASA concentration (55 μg/ml) was reached in 1 h. Approximately 61 and 6% of the administered dose were excreted in the urine and bile, respectively, in 24 h, almost exclusively in the acetylated form. When sulfapyridine (20 mg) was administered in addition to 5-ASA, 70% of the sulfapyridine was absorbed in the small intestine, peak serum concentration (50 jug/ml) was reached in 1 b, and 30% of the administered dose was excreted in the urine in 24 b. The results indicate that after oral administration of 5-ASA, a therapeutically significant concentration of the drug is not expected in the terminal ileum which is a common site of involvement in Crohn's disease. The therapeutic implications of these findings are discussed herein.     

Search for Chronic Beryllium Disease Among Sarcoidosis Patients in Ontario,Canada

Chronic beryllium disease (CBD) is clinically similar to other granulomatous diseases such as sarcoidosis. It is often misdiagnosed if a thorough occupational history is not taken. When appropriate, a beryllium lymphocyte proliferation tests (BeLPT) need to be performed. We aimed to search for CBD among currently diagnosed pulmonary sarcoidosis patients and to identify the occupations and exposures in Ontario leading to CBD. Questionnaire items included work history and details of possible exposure to beryllium. Participants who provided a history of previous work with metals underwent BeLPTs and an ELISPOT on the basis of having a higher pretest probability of CBD. Among 121 sarcoid patients enrolled, 87 (72%) reported no known previous metal dust or fume exposure, while 34 (28%) had metal exposure, including 17 (14%) with beryllium exposure at work or home. However, none of these 34 who underwent testing had positive test results. Self-reported exposure to beryllium or metals was relatively common in these patients with clinical sarcoidosis, but CBD was not confirmed using blood assays in this population.     

Diurnal Levels of Immunoreactive Erythropoietin in Normal Subjects and Subjects with Chronic Lung Disease

S ummary . Serum levels of immunoreactive erythropoietin (Ep) were measured in 48 normal male and female volunteers, ages 20-60 years, to establish a control value for Ep of 18·5±5·0 ( SD) mU/ml. Levels of the hormone were also measured sequentially over a 24 h period of time in an additional 17'normal'volunteers with no diurnal variation. Diurnal levels of immunoreactive Ep were also measured in 30 subjects with chronic lung disease. These patients, in contrast to normal subjects, exhibited a diurnal variation in the level of immunoreactive Ep with peak levels occurring at midnight. The only variable measured which correlated with the serum immunoreactive Ep level in subjects with chronic lung disease was the level of carboxyhaemoglobin ( P <0·02).     

Ursodeoxycholic Acid in the Treatment of Chronic Liver Disease

Recent data have suggested that ursodeoxycholic acid (UDCA) is useful in the treatment of a variety of chole-static and chronic liver diseases. Symptomatic and biochemical improvement have heen ohserved in diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and cystic fibrosis, but data on histological improvement and survival are limited. The purpose of this article is to review the proposed mechanisms of action of UDCA and to critically evaluate the existing literature reporting a heneficial therapeutic effect of UDCA in the treatment of chronic liver disease.