Background: Necrotizing enterocolitis (NEC) is the leading gastrointestinal cause of death of premature neonates. We have previously shown that this hyperinflammatory state persists even post-recovery. We hypothesize that recovered patients with NEC will have a decreased hyperinflammatory response when the anti-inflammatory medication mesalamine (5-ASA) is administered even when exposed to in vitro NEC induction. Methods: Enteroids were generated and subjected to in vitro NEC induction. One half were subjected to 5-ASA treatment. Tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL-8) were evaluated via RT-qPCR. Mice underwent in vivo NEC induction, one group was given 5-ASA 50 mg/kg 12 h before the start of NEC induction. The intestine was harvested and assessed for hyperinflammatory markers and histological grading was performed. Results: Recovered NEC enteroids treated with 5-ASA during NEC induction show a significant decrease in inflammatory markers compared with control (p = 0.0014 TNF-α, downtrend IL-8). Active NEC enteroids treated with 5-ASA during in vitro NEC induction show a significant decrease in TNF-α RT-qPCR (p = 0.0443) and IL-8 RT-qPCR (p = 0.0265). In mice that received 5-ASA 50 mg/kg before in vivo NEC induction, there is a significant decrease in both TNF-α (p = 0.0114) and IL-8 (p = 0.0051). Conclusion: Enteroids and mice exposed to 5-ASA have a significant decrease in inflammatory markers. This decrease despite NEC induction in both enteroids and mice may demonstrate the impact that anti-inflammatory agents could have on treatment for NEC. This could be important given the robust hyperinflammatory response to a second hit after recovery and may impact the trajectory of an illness post-recovery from NEC.

Aminosalicylates have been used for the prevention and treatment of radiation enteritis (RE) for more than 50 years. However, their effectiveness in acute radiation enteritis (ARE) has been controversial. We conducted a meta-analysis to clarify the clinical efficacy of aminosalicylates in controlling the symptoms of ARE.

We searched PubMed, Cochrane Library, Embase, and Web of Science for studies published before January 2020. Eligible randomized controlled trials (RCTs) comparing the incidence of diarrhea, abdominal pain, constipation, tenesmus, and hematochezia between the aminosalicylates and control groups were included. Subgroup analyses were conducted based on different drugs and doses. Publication bias was assessed using funnel plots.

Seven RCTs with 613 patients were included. Aminosalicylates reduced the incidence of mild to moderate diarrhea (P < 0.05), while total diarrhea, severe diarrhea, abdominal pain, hematochezia, tenesmus, and constipation showed no significant differences from the control group. Subgroup analysis showed that sulfasalazine (SASP) reduced mild to moderate diarrhea (P < 0.05), whereas 5-aminosalicylic acid (5-ASA) increased total and severe diarrhea (P < 0.05). Additionally, when aminosalicylate doses exceeded 2 g/d, diarrhea incidence increased (P < 0.05).

SASP is a safe and effective treatment for mild to moderate diarrhea, while 5-ASA may increase diarrhea incidence in ARE patients. Aminosalicylates at ≤2 g/d are safe for ARE, but higher doses may worsen diarrhea.

The term inflammatory bowel disease (IBD) refers principally to two major categories of chronic relapsing inflammatory intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). In the United States, it is currently estimated that about 1.5 million people suffer from IBD, causing considerable suffering, mortality and economic loss every year. Yet the cause of IBD is unknown, and until we understand more, prevention or cure will not be possible. There is a lot of variation in the incidence and prevalence of CD based on geographic region, environment, immigrant population, and ethnic groups. The annual incidence of CD in North America is reported to be 3.1-20.2 per 100,000 with a prevalence of 201 per 100,000 population. Based on the epidemiological, genetic and immunological data, CD is considered to be a heterogeneous disorder with multifactorial etiology in which genetics and environment interact to manifest the disease. Several genes have been studied so for with respect to CD, but thus far the strong and replicated associations have been identified with NOD2, IL23R and ATG16L1 genes. The risk factors implicated with CD include smoking, low fiber- high carbohydrate diet, altered microbiome and medications such as non-steroidal anti-inflammatory drugs. CD is typically characterized by transmural inflammation of the intestine and could affect any part of the gastrointestinal tract from mouth to perianal area. In terms of distribution of the disease 25% of the patients have colitis only, 25% is ileitis only and 50% have ileocolitis. The Montreal classification is based on the age at diagnosis (<16, 17-40, > 40), disease location (Ileal, colonic, Ileocolonic) and the disease behavior (nonstricturing/nonpenetrating, stricturing, penetrating). The key features for diagnosing CD comprises a combination of radiographic, endoscopic and pathological findings demonstrating focal, asymmetric, transmural or granulomatous features. Abdominal Computed tomography (CT) enterography is the most preferred first-line radiologic study used in the assessment of small bowel CD. The diagnostic accuracy of magnetic resonance enterography/enteroclysis is similar to that of CT scans and also prevents exposure to ionizing radiation. Endoscopic scores are considered to be the gold standard tool to measure the activity of CD and they are used more commonly in the clinical trials to measure the efficacy of various drugs on inducing and maintaining mucosal healing. The most common scoring systems used to measure clinical disease activity include Crohn's Disease Activity Index (CDAI), HBI- Harvey-Bradshaw index (HBI), short inflammatory bowel disease questionnaire (SIBDQ) and Lehmann score. Management of Crohn's disease has been seen as an evolving challenge owing to its widely heterogeneous manifestations, overlapping characteristics with other inflammatory disorders, often elusive extraintestinal manifestations and uncertain etiology. Therapeutic interventions are tailored to address symptomatic response and subsequent tolerance of the intervention. Chronology of treatment should favor treatment dose acute disease or "induction therapy", followed by maintenance of adequate response or remission, i.e. "maintenance therapy". The medications which are highly effective in inducing remission include steroids and Tumor Necrosis Factor (TNF) inhibitors. Medications used to maintain remission include 5-aminosalicyclic acid products, immunomodulators (Azathioprine, 6-mercaptopurine, methotrexate) and TNF inhibitors (infliximab, adalimumab, certolizumab and golimumab). Surgical interventions like bowel resection, stricturoplasty or drainage of abscess is required in up to two thirds of CD patients during their lifetime. The most common indications for surgical resection are medically refractory disease, perforation, persisting or recurrent obstruction, abscess not amenable to percutaneous drainage, intractable hemorrhage, dysplasia or cancer. Endoscopic recurrence in postoperative CD patients, as defined by Rutgeers score i2-i4 occur in 30-90% of the patients at the neoterminal ileum within 12 months of surgery and almost universally by 5 years. Treating CD requires a comprehensive care team including the patient, primary care provider, and gastroenterologist. In summary CD is a chronic inflammatory condition with a remitting and relapsing course primarily affecting relatively younger population with significant socioeconomic effects.

5-aminosalicylic acid (5-ASA) is a classic anti-inflammatory drug for the treatment of ulcerative colitis. N-acetyltransferase (NAT) enzymes convert 5-ASA to its metabolite N-acetyl-5-ASA, and it is unresolved whether 5-ASA or N-acetyl-5-ASA is the effective therapeutic molecule. We previously demonstrated that colonic production of N-acetyl-5-ASA (NAT activity) is decreased in dextran sulfate sodium-induced colitis. Our hypothesis is that 5-ASA is the therapeutic molecule to improve colitis, with the corollary that altered NAT activity affects drug efficacy. Since varying clinical effectiveness of 5-ASA has been reported, we also ask if NAT activity varies with inflammation in pediatric or adult patients.

Acute colonic inflammation was induced in C57BL/6 NAT wild-type (WT) or knockout mice, using 3.5% dextran sulfate sodium (w/v) concurrent with 5-ASA treatment. Adult and pediatric rectosigmoid biopsies were collected from control or patients with ulcerative colitis. Tissue was analyzed for NAT and myeloperoxidase activity.

Dextran sulfate sodium-induced colitis was of similar severity in both NAT WT and knockout mice, and NAT activity was significantly decreased in NAT WT mice. In the setting of colitis, 5-ASA significantly restored colon length and decreased myeloperoxidase activity in NAT knockout but not in WT mice. Myeloperoxidase activity negatively correlated with NAT activity in pediatric patients, but correlation was not observed in adult patients.

Inflammation decreases NAT activity in the colon of mice and human pediatric patients. Decreased NAT activity enhances the therapeutic effect of 5-ASA in mice. A NAT activity assay could be useful to help predict the efficacy of 5-ASA therapy.

This is an update of a Cochrane review first published in 2002, and previously updated in 2007. Late radiation rectal problems (proctopathy) include bleeding, pain, faecal urgency, and incontinence and may develop after pelvic radiotherapy treatment for cancer.

To assess the effectiveness and safety of non-surgical interventions for managing late radiation proctopathy.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2015); MEDLINE (Ovid); EMBASE (Ovid); CANCERCD; Science Citation Index; and CINAHL from inception to November 2015.

We included randomised controlled trials (RCTs) comparing non-surgical interventions for the management of late radiation proctopathy in people with cancer who have undergone pelvic radiotherapy for cancer. Primary outcomes considered were: episodes of bowel activity, bleeding, pain, tenesmus, urgency, and sphincter dysfunction.

Study selection, 'Risk of bias' assessment, and data extraction were performed in duplicate, and any disagreements were resolved by involving a third review author.

We identified 1221 unique references and 16 studies including 993 participants that met our inclusion criteria. One study found through the last update was moved to the 'Studies awaiting classification' section. We did not pool outcomes for a meta-analysis due to variation in study characteristics and endpoints across included studies.Since radiation proctopathy is a condition with various symptoms or combinations of symptoms, the studies were heterogeneous in their intended effect. Some studies investigated treatments targeted at bleeding only (group 1), some investigated treatments targeted at a combination of anorectal symptoms, but not a single treatment (group 2). The third group focused on the treatment of the collection of symptoms referred to as pelvic radiation disease. In order to enable some comparison of this heterogeneous collection of studies, we describe the effects in these three groups separately.Nine studies assessed treatments for rectal bleeding and were unclear or at high risk of bias. The only treatments that made a significant difference on primary outcomes were argon plasma coagulation (APC) followed by oral sucralfate versus APC with placebo (endoscopic score 6 to 9 in favour of APC with placebo, risk ratio (RR) 2.26, 95% confidence interval (CI) 1.12 to 4.55; 1 study, 122 participants, low- to moderate-quality evidence); formalin dab treatment (4%) versus sucralfate steroid retention enema (symptom score after treatment graded by the Radiation Proctopathy System Assessments Scale (RPSAS) and sigmoidoscopic score in favour of formalin (P = 0.001, effect not quantified, 1 study, 102 participants, very low- to low-quality evidence), and colonic irrigation plus ciprofloxacin and metronidazole versus formalin application (4%) (bleeding (P = 0.007, effect not quantified), urgency (P = 0.0004, effect not quantified), and diarrhoea (P = 0.007, effect not quantified) in favour of colonic irrigation (1 study, 50 participants, low-quality evidence).Three studies, of unclear and high risk of bias, assessed treatments targeted at something very localised but not a single pathology. We identified no significant differences on our primary outcomes. We graded all studies as very low-quality evidence due to unclear risk of bias and very serious imprecision.Four studies, of unclear and high risk of bias, assessed treatments targeted at more than one symptom yet confined to the anorectal region. Studies that demonstrated an effect on symptoms included: gastroenterologist-led algorithm-based treatment versus usual care (detailed self help booklet) (significant difference in favour of gastroenterologist-led algorithm-based treatment on change in Inflammatory Bowel Disease Questionnaire-Bowel (IBDQ-B) score at six months, mean difference (MD) 5.47, 95% CI 1.14 to 9.81) and nurse-led algorithm-based treatment versus usual care (significant difference in favour of the nurse-led algorithm-based treatment on change in IBDQ-B score at six months, MD 4.12, 95% CI 0.04 to 8.19) (1 study, 218 participants, low-quality evidence); hyperbaric oxygen therapy (at 2.0 atmospheres absolute) versus placebo (improvement of Subjective, Objective, Management, Analytic - Late Effects of Normal Tissue (SOMA-LENT) score in favour of hyperbaric oxygen therapy (HBOT), P = 0.0019) (1 study, 150 participants, moderate-quality evidence, retinol palmitate versus placebo (improvement in RPSAS in favour of retinol palmitate, P = 0.01) (1 study, 19 participants, low-quality evidence) and integrated Chinese traditional plus Western medicine versus Western medicine (grade 0 to 1 radio-proctopathy after treatment in favour of integrated Chinese traditional medicine, RR 2.55, 95% CI 1.30 to 5.02) (1 study, 58 participants, low-quality evidence).The level of evidence for the majority of outcomes was downgraded using GRADE to low or very low, mainly due to imprecision and study limitations. 

Although some interventions for late radiation proctopathy look promising (including rectal sucralfate, metronidazole added to an anti-inflammatory regimen, and hyperbaric oxygen therapy), single small studies provide limited evidence. Furthermore, outcomes important to people with cancer, including quality of life (QoL) and long-term effects, were not well recorded. The episodic and variable nature of late radiation proctopathy requires large multi-centre placebo-controlled trials (RCTs) to establish whether treatments are effective. Future studies should address the possibility of associated injury to other gastro-intestinal, urinary, or sexual organs, known as pelvic radiation disease. The interventions, as well as the outcome parameters, should be broader and include those important to people with cancer, such as QoL evaluations.

We found the first evidence of the efficacy of a herbal treatment with myrrh, dry extract of chamomile flowers, and coffee charcoal for ulcerative colitis (UC). However, the impact of the herbal treatment on the CD4+ T-cell compartment, which is essential for both the induction of UC and the maintenance of tolerance in the gut, is not well understood.

To analyze the frequency and functional phenotype of CD4+ T cells and of immune-suppressive CD4+CD25high regulatory T cells (Tregs) in healthy control subjects, patients with UC in remission, and patients with clinical flare of UC.

Patients in clinical remission were treated with either mesalazine or the herbal preparation for 12 months. The frequencies of whole CD4+ T cells, CD4+CD25med effector T cells, and Tregs and the expression of Foxp3 within the CD4+CD25hig Tregs were determined by flow cytometry at 6 time points. We determined the suppressive capability of Tregs from healthy control subjects and from patients in remission or clinical flare.

A total of 79 patients (42 women, 37 men; mean age, 48.5 years; 38 with clinical flare) and 5 healthy control subjects were included in the study. At baseline the frequencies of whole CD4+ T cells, CD4+CD25med effector cells, and Tregs did not differ between the two treatment groups and the healthy control subjects. In addition, patients with UC in sustained clinical remission showed no alteration from baseline after 1, 3, 6, 9, or 12 months of either treatment. In contrast, CD4+ T cells, CD4+CD25med effector T cells, and Tregs demonstrated distinctly different patterns at time points pre-flare and flare. The mesalazine group showed a continuous but not statistically significant increase from baseline to pre-flare and flare (p = ns). In the herbal treatment group, however, the percentage of the CD4+ T cells was lower at pre-flare than at baseline. This decrease was completely reversed after flare, when a significant increase was seen (CD4+CD25med pre-flare/flare p = 0.0461; CD4+CD25high baseline/flare p = 0.0269 and pre-flare/flare p = 0.0032). In contrast, no changes in the expression of Foxp3 cells were detected within the subsets of CD4+CD25high regulatory T cells. Of note, no alterations were detected in the suppressive capability of CD4+CD25high regulatory T cells isolated from the peripheral blood of healthy donors, from patients in remission, or from patients with clinical flare.

In patients with UC experiencing acute flare, the CD4+ T compartment demonstrates a distinctly different pattern during treatment with myrrh, chamomile extract, and coffee charcoal than during treatment with mesalazine. These findings suggest an active repopulation of regulatory T cells during active disease.

EU Clinical Trials Register 2007-007928-18/DE.

Pharmacotherapy based on 5-aminosalicylic acid (5-ASA) is a preferred treatment for ulcerative colitis, but variable patient response to this therapy is observed. Inflammation can affect therapeutic outcomes by regulating the expression and activity of drug-metabolizing enzymes; its effect on 5-ASA metabolism by the colonic arylamine N-acetyltransferase (NAT) enzyme isoforms is not firmly established. We examined if inflammation affects the capacity for colonic 5-ASA metabolism and NAT enzyme expression. 5-ASA metabolism by colonic mucosal homogenates was directly measured with a novel fluorimetric rate assay. 5-ASA metabolism reported by the assay was dependent on Ac-CoA, inhibited by alternative NAT substrates (isoniazid, p-aminobenzoylglutamate), and saturable with Km (5-ASA) = 5.8 μM. A mouse model of acute dextran sulfate sodium (DSS) colitis caused pronounced inflammation in central and distal colon, and modest inflammation of proximal colon, defined by myeloperoxidase activity and histology. DSS colitis reduced capacity for 5-ASA metabolism in central and distal colon segments by 52 and 51%, respectively. Use of selective substrates of NAT isoforms to inhibit 5-ASA metabolism suggested that mNAT2 mediated 5-ASA metabolism in normal and colitis conditions. Western blot and real-time RT-PCR identified that proximal and distal mucosa had a decreased mNAT2 protein-to-mRNA ratio after DSS. In conclusion, an acute colonic inflammation impairs the expression and function of mNAT2 enzyme, thereby diminishing the capacity for 5-ASA metabolism by colonic mucosa.

Ulcerative colitis (UC) is an inflammatory disease of the colon characterized by periods of active disease and remission. The pathogenesis of this disease is likely a complex interaction of genetic predisposition, environmental factors, and immune system dysregulation, and is not completely understood. A Multi-MatriX (MMX®) system formulation of mesalamine, MMX mesalamine (SPD476; Lialda®; Mesavancol®; Mezavant®), allows for high-dose, once-daily dosing for patients with mild-to-moderate UC. Mesalamine is a topically active agent with anti-inflammatory properties.

Available literature regarding MMX mesalamine is extensively reviewed in this article, covering its chemical makeup, mechanism of action, pharmaceutics and pharmacokinetics, clinical efficacy, and safety and tolerability.

A dose of 2.4 and 4.8 g was used in large Phase III clinical trials and was efficacious for induction of clinical and endoscopic remission in UC. MMX mesalamine was also efficacious in large multicenter maintenance studies for the maintenance of clinical and endoscopic remission. The introduction of the first once-daily mesalamine has given practitioners and patients more flexibility in dosing administration, which will ultimately lead to higher satisfaction and improved clinical outcomes.

5-Aminosalicylic Acid (5-ASA) has been used for over 50 years in the treatment of inflammatory bowel disease in the pro-drug form sulphasalazine (SASP). SASP is also used to treat rheumatoid arthritis. However whether the therapeutic properties of SASP are due to the intact molecule, the 5-ASA or sulphapyridine components is unknown. Several mechanisms of action have been proposed for 5-ASA and SASP including interference in the metabolism of arachidonic acid to prostaglandins and leukotrienes, scavenging,of reactive oxygen species, effects on leucocyte function and production of cytokines. However, it is unlikely that the anti-inflammatory properties of SASP and 5-ASA are due to several different properties but more likely that a single property of 5-ASA explains the theraapeutic effects of 5-ASA and SASP. Reactive oxygen species (ROS) are involved in the metabolism of prostaglandins and leukotrienes and can act as second messengers, and so the scavenging of ROS may be the single mechanism of action of 5-ASA that gives rise to its antiinflammatory effects in both inflammatory bowel disease and rheumatoid arthritis.

Ulcerative colitis (UC) is a disease of unknown etiology characterized by inflammation of the mucosa and occasionally the submucosa of the colon. Conventional drug therapy for UC involves use of aminosalicylates, corticosteroids, azathioprine/6-mercaptopurine, cyclosporine and anti-tumor necrosis factor therapy. Alternative therapies include probiotics, nicotine and fish oil. Drugs like tacrolimus, rosiglitazone and Trichuris suis ova are being evaluated for use in UC patients. With the new biologic agents, new treatment options for UC continue to evolve. In this article we will discuss the conventional drugs, the alternative therapies and the management strategies according to the severity and extent of UC.

Although a variety of pharmaceutical preparations of aminosalicylate are commonly used in the clinic for the control of inflammatory bowel disease, the mechanisms underlying their therapeutic actions remain unclear. Recent in vivo and in vitro studies have demonstrated that 5-aminosalicylic acid (5-ASA), regarded as the active moiety in aminosalicylate preparations such as sulfasalazine, can induce the heat shock protein, heme oxygenase-1 (HO-1) and up-regulate HO enzyme activity in the colon. As HO-1 can produce endogenous anti-oxidant and anti-inflammatory moieties such as bilirubin and carbon monoxide (CO), these findings suggest a novel mechanism of action for aminosalicylates, acting as anti-colitic agents through the up-regulation of HO-1 enzyme expression and activity.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn disease (CD), is a disorder characterized by diffuse inflammation of the gastrointestinal tract. The immune response and inflammation are mediated by polyunsaturated fatty acids and influenced by dietary fats and lipid metabolism. This study examined the qualitative and quantitative fat intake of IBD patients and healthy controls on plasma phospholipid and erythrocyte membrane phospholipid (EMP) fatty acid content. Measurement of the fatty acid composition of plasma phospholipid and EMP were performed in 29 UC patients, 20 CD patients, and 31 healthy controls. Anthropometric characteristics and data on dietary intake were also collected. We observed significantly lower lipid intake in UC and CD patients vs controls. The UC and CD patients had significantly higher levels of linoleic acid in their EMP than did controls. There were no significant differences in the levels of n-3 polyunsaturated fatty acids, but there were significantly higher levels of the n-6 in the EMP of UC and CD patients compared with controls. The significant differences persisted after the data were adjusted for potential confounders and lipid intake. Higher levels of linoleic acids and n-6 fatty acids, which are involved in production of proinflammatory mediators, were found in IBD patients compared with controls, thereby implicating n-6 fatty acids in the pathophysiology of the disease.

Diverticular disease (DD) of the colon is common. This paper reviews the evidence supporting the role of some of the conventional medical therapies such as fiber and nonabsorbable antibiotics in the treatment of DD. More importantly, it will review the emerging body of evidence supporting the use of 5-aminosalicylic acid and probiotics for symptomatic or complicated DD. Possible mechanisms supporting the role of 5-aminosalicylates will also be discussed. On the basis of strength of the evidence supporting each medical intervention, recommendations will be graded in an evidence-based fashion. Finally, an evidence-based algorithmic approach is proposed for the medical management of DD. This paper does not discuss the use of absorbable antibiotics such as ciprofloxin and metronidazole, which are discussed in all standard textbooks. The purpose of this paper is to discuss newer recommendations.

The mechanism of action of 5-aminosalicylic acid (5-ASA), the active therapeutic moiety of a number of clinically used anti-colitic agents, is unclear. The present study investigates whether the beneficial effects in vivo could involve induction of the heat shock protein, heme oxygenase-1 (HO-1), known to provide endogenous anti-oxidant and anti-inflammatory moieties which can modulate colonic inflammation. The effects of 5-ASA on the colonic expression and activity of HO-1 along with its effect on the inflammatory damage have been evaluated in the colitis provoked by instillation of trinitrobenzene sulphonic acid (TNBS) over 48 h in the rat. Intracolonic administration of 5-ASA (8, 25 and 75 mg/kg/day) dose-dependently reduced the TNBS-provoked macroscopic colonic inflammatory injury, myeloperoxidase (MPO) activity and TNF-alpha levels, while also dose-dependently increasing colonic heme oxygenase enzyme activity. Colonic HO-1 protein expression, determined by Western blot analysis in this colitis model, was likewise further induced by 5-ASA. Intracolonic administration of 5-ASA alone under unchallenged conditions also induced colonic HO-1 protein expression and stimulated heme oxygenase enzyme activity. Administration of zinc protoporphyrin (50 micromol/kg/day, s.c.), which prevented the increase in colonic heme oxygenase activity, abolished the anti-colitic effect of 5-ASA. These results suggest that 5-ASA may exert its colonic anti-oxidant and anti-inflammatory effects in vivo in part through the up-regulation of HO-1 enzyme expression and activity.

Nutrition may play an important role in the pathogenesis and treatment of ulcerative colitis. Several studies suggest an association between dietary factors and the onset of ulcerative colitis; however, only few studies have examined the relationship between dietary intake and relapse of ulcerative colitis. The aim of this study was to assess the dietary intake and antioxidative capacity of ulcerative colitis patients and to elucidate the efficacy of dietary therapy for ulcerative colitis. Dietary intake, fatty acid composition of phospholipids in plasma and neutrophils, serum fat-soluble vitamin levels, and oxygen radical absorbance capacity were analyzed in 29 ulcerative colitis patients (7 males and 22 females), who were treated at the Department of Gastroenterology, Okayama University Hospital. Total fat intake, fat energy ratio and linoleic acid intake were significantly lower, while protein and carbohydrate intakes were significantly higher, in the patients than age- and sex-matched controls. In the neutrophil phospholipids of ulcerative colitis patients, significantly higher levels of linoleic aicd and arachidonic acid and a lower level of eicosapentaenoic acid were observed. The concentrations of serum retinol and beta-carotene but not alpha-tocopherol were significantly lower and serum oxygen radical absorbance capacity was also lower than in the controls. Significant correlations between serum oxygen radical absorbance capacity and retinol (r = 0.567, p = 0.0031), alpha-tocopherol (r = 0.560, p = 0.0036) and beta-carotene (r = 0.440, p = 0.0279) concentrations were observed in the ulcerative colitis patients. A diet restricting the intake of linoleic acid and supplemented with eicosapentaenoic acid and antioxidative vitamins may be recommendable for the nutritional management of ulcerative colitis patients.

NV-52, a synthetic flavonoid derivative, is a selective thromboxane synthase (TXS) inhibitor that is being developed as a treatment for inflammatory bowel disease. NV-52 selectively inhibits TXS in vitro in physiological relevant concentrations, causing a reduction in thromboxane B(2) of </= 40% in association with an increase in prostaglandin E(2). NV-52 is effective in suppressing colonic inflammation in a murine model of inflammatory bowel disease. NV-52 has not demonstrated any toxicity in in vitro and animal toxicological studies, and has been administered to normal volunteers in a Phase I clinical trial without detectable adverse effects. NV-52 is well absorbed and a single dose of 400 mg p.o. produced a plasma concentration that is comparable with the concentrations that have been shown to produce significant TXS inhibition in vitro.

Chronic inflammation is a complex biologic process which involves immune as well as non-immune cells including the microvasculature and its endothelial lining. Growing evidence suggests that the microvasculature plays an integral role in the pathophysiology of inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). The microvasculature contributes to chronic inflammation through altered leukocyte recruitment, impaired perfusion, and angiogenesis leading to tissue remodeling. These diverse areas of IBD microvascular biology represent therapeutic targets that are currently undergoing investigation.

5-Aminosalicylic acid (5-ASA) is the mainstay of therapy for inflammatory bowel disease (IBD), particularly ulcerative colitis. 5-ASA is the active moiety in sulfasalazine, which was initially developed for the treatment of rheumatoid arthritis more than 60 years ago, by linking 5-ASA with sulfapyridine Because many of the side effects related to sulfasalazine were found to be due to sulfapyridine, several drugs that contain 5-ASA, and lack the side-effect profile of sulfasalazine, have been developed during the last 2 decades. These drugs have proven to be quite effective in treating mild-to-moderate symptoms of IBD, as well as inducing and maintaining remission. Although they exert anti-inflammatory effects, their exact mechanism of action remains elusive. Nonetheless, their success in treating IBD has led to studies using this class of drugs for novel indications. Several recent studies have evaluated the use of 5-ASA drugs (mesalamine) for the treatment of uncomplicated acute diverticulitis. In this review, we will briefly discuss the development of 5-ASA releasing drugs, their metabolism, side effects, indications, mechanisms of action, and the rationale for the clinical use of mesalamine in colonic diverticulitis.

This review has focused on evidence regarding intestinal perfusion of inflammatory bowel disease (IBD). Basic investigation has defined an altered microvascular anatomy in the affected IBD bowel, which corresponds with diminished mucosal perfusion in the setting of chronic, long-standing inflammation. Diminished perfusion is linked to impaired wound healing, and may contribute to the continued refractory mucosal damage, which characterizes IBD. Alterations in vascular anatomy and physiology in IBD suggests additional possible mechanisms by which micro-vessels may contribute to the initiation and perpetuation of IBD. This begs the following questions: will angiogenesis within the gut lead to sustained inflammation, does the growing vasculature generate factors that transform the surrounding tissue and does angiogenesis generate vascular anastomosis within the gut, with shunting of blood away from the mucosal surface, impairment of metabolism and potentiation of gut damage? Further studies are required to define the mechanisms that underlie the vascular dysfunction and its role in pathophysiology of IBD.

We evaluated changes in gastric and colonic mucosal prostanoid contents in rats treated with cisplatin. We also determined effects of gamma-glutamylcysteine ethyl ester (GCE), a pro-drug of glutathione, on cisplatin-induced changes in prostanoid concentrations. Rats were divided into three groups--the control: 0.5 ml of physiological saline was administered intraperitoneally (i.p.); the cisplatin group: 0.5 ml of cisplatin, 10 mg/kg, was administered i.p.; the GCE + cisplatin group: GCE, 30 min before cisplatin injection. In each group, rat gastric and colonic mucosa were isolated and their prostanoid concentrations were determined using high-performance liquid chromatography. 6-Keto-PGF1 alpha, PGF2 alpha, PGE2 were detected in gastric mucosa. In addition to these prostaglandins (PGs), thromboxane (TX) B2 was also detected in the colonic mucosa. In the cisplatin group, gastric mucosal 6-keto-PGF1 alpha concentration decreased significantly 24 h after administration, while PGE2 and PGD2 concentrations were increased significantly after 12 and 24 h, respectively. In colonic mucosa, cisplatin increased PGE2 and PGD2 concentrations, while it decreased TXB2 concentration. 6-Keto-PGF1 alpha concentration was not affected by cisplatin in colonic mucosa. GCE canceled out these changes in prostanoid concentrations in both gastric and colonic mucosa. Changes in prostanoid concentrations might be implicated in the adverse gastrointestinal effects of cisplatin, and clinical application of GCE could be expected.

1. This study was designed to elucidate the effects of guar gum, a dietary fibre, on changes in prostanoid contents induced by 1,2-dimethylhydrazine, a carcinogenic agent, in rat colonic mucosa. 2. Prostanoid contents were determined using high performance liquid chromatography; five prostanoids, namely 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, prostaglandin D2 and thromboxane B2, were detected. 3. Four subcutaneous injections of dimethylhydrazine, 60 mg/kg every 6 days, increased the mucosal concentrations of prostaglandin E2 and thromboxane B2 by approximately 50%. Other prostanoids did not change significantly throughout the experiments. 4. In rats treated with dimethylhydrazine and a fibre diet a significant increase in thromboxane B2 content was not observed, although a significant increase in prostaglandin E2 content was observed. These effects were observed in rats fed with fibre diet over 20 days but not observed in rats fed with fibre diet over 10 days. 5. From these results and the report that aspirin use at low doses is effective in the reduction of the risk of fatal colonic cancer, inhibiting thromboxane B2 synthesis by fibre diet might be involved in the protective effect against the occurrence of colonic cancer.

Sulphasalazine is an effective drug for the treatment of rheumatoid arthritis in adults. In paediatric patients, the drug has been used to treat inflammatory bowel disease and is currently under investigation for the treatment of juvenile chronic arthritis. Although sulphasalazine has a rather low incidence of serious side effects, one of the most common is skin rash, thought to be an allergic reaction. In adults, sulphasalazine desensitization programmes have proven to be effective for the treatment of this side effect. We present the case of a 7-year-old boy suffering from HLA-B 27 positive juvenile chronic arthritis. After initiation of treatment with sulphasalazine he developed an allergic skin rash, but tolerated the drug well after completion of a desensitization programme. To our knowledge, this is the first report of a paediatric patient with juvenile chronic arthritis successfully desensitized with sulphasalazine.

Delivery of 5-aminosalicylic acid to the colon by sulphasalazine, other azo-bonded compounds and controlled-release preparations is introduced in the context of metabolism by epithelial cells and therapeutic efficacy in ulcerative colitis. Potential modes of action are then reviewed, including actions on luminal bacteria, epithelial cell surface receptors, cellular events (such as nitric oxide release or butyrate oxidation), electrolyte transport and epithelial permeability. Evidence for an influence of salicylates on circulating and lamina propria inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides and inflammatory mediators, such as eicosanoids, platelet-activating factor, cytokines or reactive oxygen metabolites. The precise mechanism will remain uncertain as long as the aetiology of ulcerative colitis is unknown, but a pluripotential mode of action of salicylates is an advantage when influencing the network of events that constitute chronic inflammation.

A new, orally active de-N-acetylated lysoglycosphingolipid (WILD20) was evaluated as antiinflammatory agent using a model of chemically-induced inflammatory bowel disease (IBD) in the rat to mimic human ulcerative colitis and Chron's disease. IBD was induced by hapten trinitrobenzenesulphonic acid (TNB). WILD20, orally administered as preventive or curative, was demonstrated to be efficacious at daily dosages of 0.1-1 mg/kg for 4-5 days. Damage scores, body weight, spleen weight, colonic tissular levels of LTB4, myeloperoxidase (MPO) and malondialdehyde (MDA) are influenced and brought into parameters of normality. Histological observation demonstrated quicker healing, better repair, reduced inflammation, and poor eosinophil degranulation. The mechanisms underlying WILD20 antiinflammatory effects were investigated: whereas WILD20 fails to show a direct effect on PKC, it reduces PKC translocation to the membrane; cellular PLA2 was consequently greatly reduced through this mechanism and thought to be responsible for WILD20 efficacy towards chemically-induced IBD.

Recent work suggests that thromboxanes may play a major pathogenic role in inflammatory bowel disease. Thromboxanes are produced in excess not only in inflamed mucosa but also in Crohn's disease, by uninflamed bowel and by isolated intestinal and peripheral blood mononuclear cells. Their cellular source is likely to include platelets, neutrophils, endothelial and epithelial cells as well as mononuclear cells, possible stimuli to their overproduction being chemotactic peptides, lipopolysaccharide, leukotrienes, platelet activating factor, interleukin-1, bradykinin and angiotensin II. The pro-inflammatory effects of thromboxanes are both direct (diapedesis and activation of neutrophils, mucosal ulceration, reduction of suppressor T-cell activity) and indirect (vasoconstriction, platelet activation). Although corticosteroids and aminosalicylates inhibit thromboxane synthesis, this action does not necessarily explain their therapeutic effect in inflammatory bowel disease. Selective thromboxane synthesis inhibitors and receptor antagonists, however, ameliorate experimental colitis in animals. Picotamide and ridogrel are dual thromboxane pathway blockers already used in man. Drugs of this type could prove useful not only for the prevention of systemic thrombo-embolism but also for suppressing intestinal mucosal inflammation in patients with inflammatory bowel disease.

Sulphasalazine and other 5-aminosalicylic acid (5-ASA)-containing drugs are used in the treatment of acute inflammatory bowel disease and in the maintenance of clinical remission. Despite their use for over 50 years, the mechanism of action of this class of drugs remains uncertain, although a number of possibilities are discussed in this review. It seems likely that the aminosalicylates are important free radical scavengers, can reduce leukotriene production and can inhibit the cellular release of interleukin-1, all of which are likely to be important in reducing the acute inflammatory response in inflammatory bowel disease. The effects of these drugs on prostaglandin production are more contentious, but it appears that 10(-5) to 10(-4) M concentrations stimulate production of prostaglandins which may be cytoprotective, while higher doses of these drugs inhibit prostaglandin production. The aminosalicylates may maintain remission in inflammatory bowel disease by preventing leucocyte recruitment into the bowel wall. The drugs inhibit the chemotactic response to leukotriene B4, reduce the synthesis of platelet activating factor and also inhibit leucocyte adhesion molecule upregulation.

Sulphasalazine is an effective treatment for diarrhoea occurring during pelvic radiotherapy. We report the results of a trial to assess the value of its active moiety, 5-aminosalicylic acid, (5-ASA) in a prophylactic setting. Seventy-three patients planned for external beam radiotherapy to the pelvis were randomized on a double-blind basis to receive prophylactic 5-ASA or placebo. The severity of the acute radiation bowel reaction was documented by a weekly questionnaire. Surprisingly, diarrhoea occurred in a higher proportion of patients in the 5-ASA arm than the placebo arm (91.2% versus 73.7%, P = 0.070). The maximum change in both the severity of diarrhoea and the number of days per week on which diarrhoea occurred (from pre-radiotherapy level to the worst level at any time during treatment) were both significantly greater in patients taking 5-ASA than those taking placebo (P = 0.014 and P = 0.026, respectively). The average change (the sum of the weekly scores divided by the number of weeks of treatment, minus the pre-radiotherapy score) for both severity and days per week of diarrhoea were again greater in the 5-ASA than the placebo arm, but failed to reach statistical significance (P = 0.095 and P = 0.079, respectively). The use of anti-diarrhoeal medicines was significantly greater in the 5-ASA arm (P = 0.011). Constipation was more common in the placebo arm but this did not reach significance (P = 0.20). 5-ASA thus has no protective effect against acute radiation enteritis and appears to worsen it. Possible reasons for this surprising finding are discussed.

In parallel studies, the effects of 5-aminosalicylic acid (5-ASA) and acetyl-5-aminosalicylic acid (acetyl-5-ASA) on peroxidation of red-cell membrane lipids and production of prostaglandins by peripheral blood mononuclear cells were assessed. 5-ASA at concentrations of 10(-5), 10(-4) and 10(-3) M significantly inhibited erythrocyte lipid peroxidation, measured as malondialdehyde production, by 20%, 56% and 63%, respectively, (P < 0.05, P < 0.002, P < 0.001, respectively) while acetyl-5-ASA had no effect. 10(-5) and 10(-4) M 5-ASA significantly increased production by stimulated peripheral blood mononuclear cells of PGE2 (by 31% and 30%, P < 0.01, P < 0.05, respectively) and PGF2 alpha (by 30% and 25%, P < 0.05, P < 0.01, respectively). 10(-4) M 5-ASA also significantly stimulated prostacyclin production measured as 6KF1 alpha by 10% (P < 0.05). At 10(-3) M 5-ASA there were significant falls in 6KF1 alpha (by 37%) PGE2 (by 45%) and PGF2 alpha (by 47%) (P < 0.01, P < 0.001, P < 0.001, respectively) although this was accompanied by a decrease in cell viability. Acetyl-5-ASA had little effect upon prostaglandin production. 5-ASA scavenges free radicals and stimulates production of cytoprotective prostaglandins.

Whatever initiates inflammation, the final message mediating cellular invasion is chemical. This consideration allows rational development of anti-inflammatory treatments. Two main classes of chemotactic mediator are recognised. Water-soluble peptides, e.g. cytokines derived from macrophages and other cells, play an important integrating part in the early recruitment of neutrophils and mononuclear cells, and in the amplification of immune responses. Lipid-soluble mediators, of which leukotriene B4 is the most highly chemotactic for neutrophils, are important in secondary amplification. In inflammatory bowel disease, we have shown evidence of increased synthesis of cytokines interleukin 1, 6 and 8. These are associated with activation of circulating monocytes in active Crohn's disease, of lamina propria macrophages in relapse of both ulcerative colitis and Crohn's disease, and development of adhesion molecules on vascular endothelium. Our studies show that interleukin 6 is selectively increased in Crohn's disease, whilst preliminary findings suggest that enhanced synthesis of interleukin 8 is particularly characteristic of ulcerative colitis. Patterns of cytokine synthesis may, therefore, be of diagnostic value. They also offer the potential for therapeutic strategies since cytokine antagonists are becoming available. We have also demonstrated increased synthesis of leukotrienes in active inflammatory bowel disease. Since leukotriene B4 is quantitatively the main chemotactic signal in the mucosa in inflammatory bowel disease during relapse, we investigated the therapeutic effect of suppressing leukotriene B4 synthesis by treating patients with fish oil (as Hi-EPA), giving 4.5 g daily of eicosapentaenoic acid. This competes for the 5-lipoxygenase enzymes, inhibiting leukotriene B4 and promoting synthesis of the less chemotactic product, LTB5.(ABSTRACT TRUNCATED AT 250 WORDS)

Although it has been proposed that sulphasalazine (SASP) and its metabolite 5-aminosalicylic acid (5-ASA) act therapeutically by inhibiting production of vasoactive and immunoregulatory prostaglandins (PGs), in previous in vitro studies these drugs have both inhibited and promoted PG production. This study demonstrates that SASP and 5-ASA promote or inhibit peripheral blood mononuclear cell PG production depending upon the PG measured, the concentration of the drug, and whether the cells were stimulated. Sulphapyridine, the other constituent of SASP, only inhibited production. At high concentrations of SASP and 5-ASA the viability of mononuclear cells was reduced. The enhancement of PG production and toxicity was greater with SASP than 5-ASA, while the PGs most affected by SASP were not those most affected by 5-ASA. Thus, in vitro SASP may possess properties other than those of 5-ASA and this may explain the different therapeutic properties of these two compounds.

We investigated the action of the new aminosalicylate olsalazine (disodium azodisalicylate) on arachidonic acid metabolism in comparison with 5-aminosalicylic acid (5-ASA) and sulphasalazine (SASP) by in vitro incubation of cellular homogenates from human polymorphonuclear (PMNL) and mononuclear (MNL) leukocytes with 14C-labelled arachidonic acid. Olsalazine reduced the synthesis of leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (5-HETE), 11-HETE, 12-HETE, and 15-HETE in PMNL and MNL slightly less than SASP. 5-ASA was significantly less inhibitory than olsalazine and SASP on the formation of lipoxygenase products in PMNL and on LTB4 synthesis in MNL. In contrast, in MNL the formation of 5-HETE was unaffected, and the production of 11-HETE, 12-HETE, and 15-HETE was even slightly activated by 5-ASA. Total prostaglandin synthesis was dose-dependently reduced by the aminosalicylates (SASP greater than olsalazine greater than 5-ASA), but only SASP markedly altered the prostaglandin (PG) profile, with an increase in PGE2 and PGF2 alpha at the expense of other cyclooxygenase products. It may be concluded that olsalazine resembled SASP with regard to the inhibition of the lipoxygenase but had effects intermediate between the other salicylates on cyclooxygenase. Furthermore, the alteration of the prostaglandin profile by SASP points to an overlying cofactor effect of this drug.

Atrophie blanche can be a chronic condition for which there is no satisfactory treatment. Two patients with atrophie blanche who had not responded to various therapeutic modalities were given a trial of sulfasalazine 1 g three times daily. The ulcers healed within 3 months in both cases. In view of these positive results, patients should be treated with sulfasalazine to determine the efficacy of this drug in atrophie blanche.

Topical 5-ASA Agents. Observations that 5-ASA may be the clinically active component of sulfasalazine have stimulated extensive pharmaceutical efforts to develop a new class of agents for the treatment of the inflammatory bowel diseases. Both oral and rectal forms of 5-ASA have been designed, tested, and released for use in Europe and Canada. Only one rectal 5-ASA formulation is now commercially available in the United States. Studies with topical 5-ASA have demonstrated that this formulation is safe and effective for distal colitis, even in patients with disease refractory to standard therapy. Adverse effects of topical 5-ASA are minimal. However, optimal treatment doses have not been defined, relapse is common after withdrawal of therapy, and issues regarding maintenance regimens are not yet resolved. Other disadvantages include the expense and inconvenience of enema therapy. However, rectally administered 5-ASA is an appropriate initial therapy for the treatment of distal ulcerative colitis, or as a therapeutic option for refractory distal colitis. Data are insufficient to make recommendations regarding the use of topical 5-ASA in Crohn's disease. Whether this class of agents will be of benefit for Crohn's proctitis or for perineal disease must await further clinical trials. Oral 5-ASA Agents. There appears to be a well-substantiated benefit equivalent to that of sulfasalazine achieved by the new oral formulations of 5-ASA when used for the treatment of acute mild to moderate ulcerative colitis, and as maintenance treatment of ulcerative colitis in remission. Adverse reactions to these agents are uncommon, usually mild, and infrequently require withdrawal of therapy. The major problem reported with these agents is watery diarrhea, most commonly associated with olsalazine, but the practical importance of this adverse effect is disputed. Rare occurrences of reversible pericarditis and acute pancreatitis have been encountered during clinical application of these agents. As more experience is obtained, these agents may become the initial therapy of choice for the treatment of mild to moderate ulcerative colitis and for maintenance in inactive disease. Currently available data have defined a role for these agents as an important alternative for the treatment of patients intolerant or allergic to sulfasalazine. As with sulfasalazine, these agents should not be used as the sole treatment for severely active ulcerative colitis. Many unanswered questions remain regarding therapy with these agents for ulcerative colitis. Still undefined are optimal drug dosages, appropriate dosing intervals, and the necessary duration of therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of olsalazine, an analogue of sulphasalazine, consisting of two molecules 5-aminosalicylic acid linked by an azobond has been investigated for the treatment of ulcerative colitis. In a randomised double blind trial we compared 2 g olsalazine with placebo for four weeks. Of the 105 patients, with mild to moderate ulcerative colitis, entered in the trial 52 received olsalazine, and 53 placebo. Treatment had to be terminated prematurely because of untoward effects of olsalazine (mainly diarrhoea) in three patients and treatment failure--that is, increased rectal bleeding in four patients (olsalazine group: one placebo group: three). After four weeks' treatment, a statistically significant improvement in the endoscopic findings in rectum and a positive trend in the reduction of rectal mucus and blood discharge was observed in the patients treated with olsalazine. No statistically significant difference was found for other factors, including stool frequency, consistency, urge to defecate, abdominal pain, and biopsy findings. A comparison between these clinical and endoscopic parameters at study entry and those at study completion (within drug evaluation) showed significant improvement in six of 10 parameters during treatment with olsalazine and in two of 10 during placebo treatment. This difference suggests the significant effect of olsalazine. We conclude that 2 g olsalazine was tolerated as well as placebo, apart from causing diarrhoea in some patients and was slightly superior to placebo during four weeks' treatment of mild to moderate ulcerative colitis. A study with 3 or 4 g olsalazine per day may show a more definite effect.

Immune effector mechanisms are central to the disease process in inflammatory bowel disease, but it is not clear whether the mucosal or systemic immunological abnormalities are primary phenomena, or are secondary to disease activity. Corticosteroid drugs remain the most effective treatment for active disease, but there is no evidence that they are useful for maintenance therapy. Some patients, however, are dependent on low-dose corticosteroids, and relapse when the drug is withdrawn. These drugs have widespread actions on the immune response, and monocytes are particularly sensitive to corticosteroids. In contrast, sulphasalazine and 5-aminosalicylic acid are effective in maintenance therapy, but do not act primarily by immunosuppressive mechanisms. They are effective in maintenance therapy of ulcerative colitis, and mild relapses of ulcerative colitis and colonic Crohn's disease. New preparations of 5-aminosalicylic acid have reduced side effects, many of which are due to sulphapyridine. Azathioprine and 6-mercaptopurine are used less widely: in Crohn's disease there is reasonable evidence for benefit in chronic active disease unresponsive to corticosteroids, and maintenance of remission. In ulcerative colitis, the position is less clearcut. Overall, trials favour an effect in chronic active disease, and there are pointers to an effect in maintenance of remission. Because of their side effects, in particular marrow suppression, these drugs should be reserved for second-line therapy. Similarly, other cytotoxic drugs are not used because of their side effects. More recently, cyclosporin A, with its selective action on interleukin-2 release and/or synthesis, and inhibition of helper T cell function, has been shown to be helpful in Crohn's disease. At present it should only be used in controlled trials, for patients with unresponsive disease in whom surgery is contraindicated. Renal toxicity may limit long term use. There is little data for cyclosporin A in ulcerative colitis. On the basis that there may be an underlying immune defect in Crohn's disease leading to mucosal inflammation, immunostimulant therapy has been used, but there is no evidence for benefit from treatment with BCG or levamisole in active disease or in maintenance therapy. 7S-Immunoglobulin, plasmapheresis or T-lymphocyte apheresis have been used in acute relapse, but evidence is anecdotal, and does not support their use except as a desperate measure to avoid surgery. Further well-designed controlled trials are needed to define the role of all these drugs, and further research into the mechanism of action on the immune response may shed light on the pathogenesis of inflammatory bowel disease.

1. The effects of anti-inflammatory drugs on eicosanoid formation and colonic damage in a chronic model of inflammatory bowel disease (IBD) in the rat were investigated. 2. A single colonic instillation of the hapten, trinitrobenzene sulphonic acid (TNB) resulted in ulceration and inflammation which persisted for 3 weeks. 3. The macroscopic colonic damage, present 3 weeks after TNB, was correlated with an increase in immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene B4 (LTB4) synthesis by the rat colon. 4. Anti-inflammatory drugs were administered 2 weeks after TNB, when there was substantial colonic damage, and continued for a week. The experimental drug BW755C inhibited the increased formation of 6-keto-PGF1 alpha and LTB4 by the inflamed colon. Indomethacin and aspirin markedly inhibited prostanoid formation in both inflamed and control colon. Sulphasalazine or prednisolone also inhibited the formation of 6-keto-PGF1 alpha but the effects were less marked. 5. None of the anti-inflammatory drugs significantly reduced the colonic damage induced by TNB. 6. The results suggest that eicosanoids, including LTB4, have only a minor role in maintaining the chronic macroscopic damage induced in the rat colon by TNB. The role of such eicosanoids in the underlying infiltration and activity of inflammatory cells in this model of IBD, however, is not known.

Sulfasalazine and, to a lesser extent, 5-aminosalicylic acid and N-acetyl-aminosalicylic acid, were found to block production of 5-hydroxy-6,8,11,14-eicosatetraenoic acid, leukotriene B4 (LTB4), and LTB4 stereoisomers from both exogenous and endogenous [14C]arachidonic acid (14C-AA) in ionophore A23187 (1 microgram/ml)-stimulated human neutrophils. Lipids were assessed by thin-layer chromatography and reverse-phase high-pressure lipid chromatography. Sulfasalazine blocked the synthesis of these metabolites from both exogenous and endogenous AA, but was more effective in blocking the metabolism of exogenous than endogenous AA. The IC50 for sulfasalazine in blocking the synthesis of LTB4 was 0.8 mM when exogenous AA was the substrate and 2.8 mM when endogenous AA was the substrate. N-Acetyl-aminosalicylic acid showed a similar pattern, but was less effective than sulfasalazine (IC50 for exogenous AA was 5.4 mM, and for endogenous AA was 8.0 mM). 5-Aminosalicylic acid had similar effects with an IC50 of 6.0 and 6.4 mM respectively. Sulfasalazine but not 5-aminosalicylic acid inhibited the incorporation of arachidonic acid into phospholipids and triglycerides. Sulfasalazine, but not its metabolites, inhibited the release of 14C-AA from membrane phospholipids in a dose-dependent manner (46.0% inhibition with 4 mM sulfasalazine). Sulfasalazine also blocked the metabolism of exogenously added LTB4 to 20-OH LTB4 and 20-COOH LTB4 with an IC50 of 2 mM. Our findings suggest that under physiologic conditions, with endogenous AA as a substrate, sulfasalazine acts as an inhibitor of lipoxygenase, of phospholipase A2 and of LTB4 metabolism, whereas 5-aminosalicylic acid and N-acetyl-aminosalicylic acid inhibit only lipoxygenase.