Does the 5-Aminosalicylate Concentration Correlate with the Efficacy of Oral 5-Aminosalicylate and Predict Response in Patients with Inflammatory Bowel Disease? A Systematic Review

Oral 5-aminosalicylic acid (5-ASA, mesalazine) is the first choice therapeutic agent for treating mild-to-moderate ulcerative colitis (UC). Unfortunately a significant group of patients fail to respond. Therapeutic drug monitoring might help to maintain or induce remission by providing a tool for optimization of 5-ASA therapy. However, plasma and urine concentrations of 5-ASA reflect systemic uptake and are not useful to evaluate therapeutic effect.  To explore if mucosal and faecal 5-ASA values correlate with disease activity and/or therapeutic effects in patients with inflammatory bowel disease, especially UC.  We identified studies that analysed 5-ASA in faeces or mucosa of humans using an oral 5-ASA formulation, using PubMed and Embase.  In total, 39 studies (n = 939) were included, 27 on faecal 5-ASA, 9 on mucosal concentrations, and 3 on both faecal and mucosal values. We included 33 cross-sectional studies, 3 randomised clinical trials, 2 longitudinal cohorts and 1 randomized cross-over study. Mucosal 5-ASA concentrations in healthy subjects and patients on equivalent doses of 5-ASA were not found to differ remarkably. In the sub-analysis of mucosal 5-ASA concentrations in patients with active or quiescent UC, a higher concentration was seen during remission. Faecal concentrations were associated with 5-ASA doses but not with disease activity. Differences in faecal or mucosal 5-ASA values could not be ascribed to different 5-ASA formulations.  An increase of the mucosal 5-ASA concentrations was observed during remission in patients with UC. No clear relationship between the faecal 5-ASA excretion and the therapeutic efficacy was identified.

Related papers:

title: Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies
abstract: Inflammatory bowel disease is a global disease in the 21st century. We aimed to assess the changing incidence and prevalence of inflammatory bowel disease around the world.



We searched MEDLINE and Embase up to and including Dec 31, 2016, to identify observational, population-based studies reporting the incidence or prevalence of Crohn's disease or ulcerative colitis from 1990 or later. A study was regarded as population-based if it involved all residents within a specific area and the patients were representative of that area. To be included in the systematic review, ulcerative colitis and Crohn's disease needed to be reported separately. Studies that did not report original data and studies that reported only the incidence or prevalence of paediatric-onset inflammatory bowel disease (diagnosis at age <16 years) were excluded. We created choropleth maps for the incidence (119 studies) and prevalence (69 studies) of Crohn's disease and ulcerative colitis. We used temporal trend analyses to report changes as an annual percentage change (APC) with 95% CI.



We identified 147 studies that were eligible for final inclusion in the systematic review, including 119 studies of incidence and 69 studies of prevalence. The highest reported prevalence values were in Europe (ulcerative colitis 505 per 100 000 in Norway; Crohn's disease 322 per 100 000 in Germany) and North America (ulcerative colitis 286 per 100 000 in the USA; Crohn's disease 319 per 100 000 in Canada). The prevalence of inflammatory bowel disease exceeded 0·3% in North America, Oceania, and many countries in Europe. Overall, 16 (72·7%) of 22 studies on Crohn's disease and 15 (83·3%) of 18 studies on ulcerative colitis reported stable or decreasing incidence of inflammatory bowel disease in North America and Europe. Since 1990, incidence has been rising in newly industrialised countries in Africa, Asia, and South America, including Brazil (APC for Crohn's disease +11·1% [95% CI 4·8-17·8] and APC for ulcerative colitis +14·9% [10·4-19·6]) and Taiwan (APC for Crohn's disease +4·0% [1·0-7·1] and APC for ulcerative colitis +4·8% [1·8-8·0]).



At the turn of the 21st century, inflammatory bowel disease has become a global disease with accelerating incidence in newly industrialised countries whose societies have become more westernised. Although incidence is stabilising in western countries, burden remains high as prevalence surpasses 0·3%. These data highlight the need for research into prevention of inflammatory bowel disease and innovations in health-care systems to manage this complex and costly disease.

title: Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
abstract: The newer 5-ASA preparations were intended to avoid the adverse effects of SASP while maintaining its therapeutic benefits. The efficacy and safety of 5-ASA preparations have been evaluated in numerous clinical trials that have often lacked sufficient statistical power to arrive at definitive conclusions. Previously, it was found that newer 5-ASA drugs in doses of at least 2g/day, were more effective than placebo but no more effective than SASP in inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the effectiveness, dose-responsiveness, and safety of 5-ASA preparations in terms of more precise outcome measures.



To assess the efficacy, dose-responsiveness and safety of the newer release formulations of 5-aminosalicylic acid (5-ASA) compared to placebo or sulfasalazine (SASP) for the induction of remission in active ulcerative colitis.


SEARCH STRATEGY
A computer-assisted literature search for relevant studies (1981-2003) was performed using MEDLINE, BIOS, the Cochrane Controlled Trials Register, the Cochrane IBD group specialized trials register and the Science Citation Index, followed by a manual search of reference lists from previously retrieved articles, review articles, symposia proceedings, and abstracts from major gastrointestinal conferences.



Studies were accepted for analysis if they were randomized, double-blinded, and controlled clinical trials of parallel design, with treatment durations of a minimum of four weeks.



Based on an intention to treat principle, the outcomes of interest in the treatment of active disease were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, or endoscopic improvement.



5-ASA was superior to placebo with regard to all measured outcome variables. For the failure to induce global/clinical improvement or remission, the pooled Peto odds ratio was 0.51 (95% CI, 0.35 to 0.76). A dose-response trend for 5-ASA was also observed. When 5-ASA was compared to SASP, the pooled Peto odds ratio was 0.87 (CI, 0.63 to 1.21) for the failure to induce global/clinical improvement or remission, and 0.66 (CI, 0.42 to 1.04) for the failure to induce endoscopic improvement. SASP was not as well tolerated as 5-ASA.



The newer 5-ASA preparations were superior to placebo and tended towards therapeutic benefit over SASP. However, considering their relative costs, a clinical advantage to using the newer 5-ASA preparations in place of SASP appears unlikely. This review updates the existing review of oral 5-aminosalicylic acid for induction of remission in ulcerative colitis which was published in the Cochrane Library (Issue 2, 2003).

title: Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study
abstract: The introduction of anti tumour necrosis factor-α (anti-TNFα) therapy might impact healthcare expenditures, but there are limited data regarding the costs of inflammatory bowel diseases (IBD) following the introduction of these drugs. We aimed to assess the healthcare costs and productivity losses in a large cohort of IBD patients.  Crohn's disease (CD) and ulcerative colitis (UC) patients from seven university hospitals and seven general hospitals were invited to fill-out a web-based questionnaire. Cost items were derived from a 3 month follow-up questionnaire and categorised in outpatient clinic, diagnostics, medication, surgery and hospitalisation. Productivity losses included sick leave of paid and unpaid work. Costs were expressed as mean 3-month costs per patients with a 95% CI obtained using non-parametric bootstrapping.  A total of 1315 CD patients and 937 UC patients were included. Healthcare costs were almost three times higher in CD as compared with UC, €1625 (95% CI €1476 to €1775) versus €595 (95% CI €505 to €685), respectively (p<0.01). Anti-TNFα use was the main costs driver, accounting for 64% and 31% of the total cost in CD and UC. Hospitalisation and surgery together accounted for 19% and <1% of the healthcare costs in CD and 23% and 1% in UC, respectively. Productivity losses accounted for 16% and 39% of the total costs in CD and UC.  We showed that healthcare costs are mainly driven by medication costs, most importantly by anti-TNFα therapy. Hospitalisation and surgery accounted only for a minor part of the healthcare costs.

title: Cyclooxygenase-2-dependent and -independent inhibition of proliferation of colon cancer cells by 5-aminosalicylic acid.
abstract: The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway may have a pathogenic role in colorectal cancer (CRC). Recent studies suggest that 5-aminosalicylic acid (5-ASA) reduces the risk of inflammatory bowel disease-related CRC, but the mechanism by which 5-ASA interferes with CRC cell growth remains unknown. In this study, we have examined whether the negative effect of 5-ASA on CRC cells is dependent on COX-2/PGE2 axis inhibition. We show that 5-ASA down-regulates both constitutive and TNF-alpha or IL-1beta-induced COX-2 in HT-115 and HT-29 cells. Inhibition of COX-2 by 5-ASA occurs at the RNA and protein level, and is associated with a significant decrease in PGE2 synthesis, arrest of growth and enhanced death of CRC cells. However, exogenous PGE2 does not revert the 5-ASA-mediated CRC cell proliferation block. 5-ASA also inhibits the growth of DLD-1, a COX-deficient CRC cell line, thus suggesting that the anti-proliferative effect of 5-ASA on CRC cells is not strictly dependent on the inhibition of COX-2/PGE2. Taken together our data indicate that 5-ASA causes both a COX-2-dependent and -independent inhibition of CRC cell growth.

title: Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor kappaB activation in mouse colonocytes.
abstract: Derivatives of 5-aminosalicylic acid (mesalamine) represent a mainstay in inflammatory bowel disease therapy, yet the precise mechanism of their therapeutic action is unknown. Because tumor necrosis factor (TNF)-alpha is important in the pathogenesis of inflammatory bowel disease, we investigated the effect of mesalamine on TNF-alpha-regulated signal transduction and proliferation in intestinal epithelial cells.



Young adult mouse colon cells were studied with TNF-alpha, epidermal growth factor, or ceramide in the presence or absence of mesalamine. Proliferation was studied by hemocytometry. Mitogen-activated protein (MAP) kinase activation and IkappaBalpha expression were determined by Western blot analysis. Nuclear transcription factor kappaB (NF-kappaB) nuclear translocation was determined by confocal laser immunofluorescent microscopy.



The antiproliferative effects of TNF-alpha were blocked by mesalamine. TNF-alpha and ceramide activation of MAP kinase were inhibited by mesalamine, whereas epidermal growth factor activation of MAP kinase was unaffected. TNF-alpha-stimulated NF-kappaB activation and nuclear translocation and the degradation of Ikappa-Balpha were blocked by mesalamine.



Mesalamine inhibits TNF-alpha-mediated effects on intestinal epithelial cell proliferation and activation of MAP kinase and NF-kappaB. Therefore, it may function as a therapeutic agent based on its ability to disrupt critical signal transduction events in the intestinal cell necessary for perpetuation of the chronic inflammatory state.

title: Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1
abstract: Graphical abstract (a) PAK1 orchestrates mesalamine activity, (b) mesalamine inhibits PAK1; increases membranous E-cadherin and β-catenin; modulates cell adhesion

title: 5-Aminosalicylic acid is a potent inhibitor of interleukin 1 beta production in organ culture of colonic biopsy specimens from patients with inflammatory bowel disease.
abstract: Interleukin 1 beta in biopsy specimens from inflamed colonic mucosa of patients with active inflammatory bowel disease was studied. Compared with normal colonic mucosal biopsy specimens, a significantly greater amount of interleukin 1 beta was present in rectal mucosa before (median (range) 4.3 (2.0-11.8) v 119.2 (30.1-286.8) pg/mg; p less than 0.01) and produced during organ culture (39.1 (9.4-106.8) v 97.6 (28.2-991.6) pg/mg; p less than 0.01). Values of interleukin 1 beta after culture correlated with concentrations of thromboxane B2. Organ culture of inflamed biopsy specimens in the presence of 5 aminosalicylic acid and dexamethasone reduced the amount of interleukin 1 beta detected. At the doses studied, 5 aminosalicylic acid also reduced the amount of leukotriene B4 detected after culture.

title: 5-Aminosalicylic acid prevents oxidant mediated damage of glyceraldehyde-3-phosphate dehydrogenase in colon epithelial cells
abstract: Reactive oxygen and nitrogen derived species produced by activated neutrophils have been implicated in the damage of mucosal proteins including the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the active inflammatory lesion in patients with inflammatory bowel disease (IBD). This study investigated the efficacy of currently used IBD therapeutics to prevent injury mediated by reactive oxygen and nitrogen derived species. Methods GAPDH activity of human colon epithelial cells was used as a sensitive indicator of injury produced by reactive oxygen and nitrogen derived species. HCT116 cells (106/ml phosphate buffered saline; 37°C) were incubated in the presence of 5-aminosalicylic acid (5-ASA), 6-mercaptopurine, methylprednisolone, or metronidazole before exposure to H2O2, HOCl, or NO in vitro. HCT116 cell GAPDH enzyme activity was determined by standard procedures. Cell free reactions between 5-ASA and HOCl were analysed by spectrophotometry and fluorimetry to characterise the mechanism of oxidant scavenging. Results GAPDH activity of HCT116 cells was inhibited by the oxidants tested: the concentration that produced 50% inhibition (IC50) was 44.5 (2.1) μM for HOCl, 379.8 (21.3) μM for H2O2, and 685.8 (103.8) μM for NO (means (SEM)). 5-ASA was the only therapeutic compound tested to show efficacy (p<0.05) against HOCl mediated inhibition of enzyme activity; however, it was ineffective against H2O2 and NO mediated inhibition of GAPDH. Methylprednisolone, metronidazole, and the thiol-containing 6-mercaptopurine were ineffective against all oxidants. Studies at ratios of HOCl:5-ASA achievable in the mucosa showed direct scavenging to be the mechanism of protection of GAPDH activity. Mixing 5-ASA and HOCl before addition to the cells resulted in significantly greater protection of GAPDH activity than when HOCl was added to cells preincubated with 5-ASA. The addition of 5-ASA after HOCl exposure did not restore GAPDH activity.  Therapies based on 5-ASA may play a direct role in scavenging the potent neutrophil oxidant HOCl, thereby protecting mucosal GAPDH from oxidative inhibition. These findings suggest that strategies for the further development of new HOCl scavenging compounds may be useful in the treatment of IBD.

title: Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator–activated receptor-γ
abstract: 5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator–activated receptor-γ (PPAR-γ) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-γ+/− mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-γ expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element–driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-γ as a target of 5-ASA underlying antiinflammatory effects in the colon.

title: Pharmacokinetics of 5-aminosalicylic acid in man following administration of intravenous bolus andper os slow-release formulation
abstract: The fate of 5-aminosalicylic acid (5-ASA), which is used in the treatment of chronic inflammatory bowel diseases, was studied in six healthy volunteers receiving doses of 100 mg and 250 mg intravenous bolus as well as 250 mgper os (slow release). Following intravenous administration, the drug was rapidly eliminated with a plasma half-life of about 40 min, mainly due to rapid metabolism. No parent drug was recovered in feces, and the total recovery following oral administration (30%) was significantly lower than following the intravenous doses (77% and 72%). Nonlinear pharmacokinetics were suggested as the 2.5-fold increase in intravenous dose was followed by a significant relative increase (>2.5) in the renal elimination of 5-ASA, as well as a significant decrease (<2.5) in the elimination of the metaboliteN-acetyl-5-ASA. There was also a trend towards a decreasing total body clearance and metabolic ratio. The present study confirms earlier findings on the pharmacokinetics of 5-ASA and suggests a possible saturation of theN-acetylating system in the dose range studied. This may be of interest in the design of controlled-release formulations and dosage regimes for the treatment of diseases of the small-bowel, where 5-ASA is easily absorbed. Further, for the first time, a marked difference in the intestinal fate compared to the systemic fate of the drug is demonstrated, suggesting alternative presystemic metabolism of 5-ASA, which may bear relevance to its mode of action. Further studies on the pharmacokinetics of 5-ASA, preferably in patients, are warranted.

title: Dose loading with delayed-release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters.
abstract: Tissue concentrations of 5-aminosalicylic acid (5ASA) and its metabolites may influence the clinical course of inflammatory bowel disease. Since the factors that determine tissue drug concentrations are unknown we have studied the relationships between the oral dose of delayed-release mesalazine, rectal tissue drug concentrations and standard pharmacokinetic parameters.



Twelve healthy volunteers were studied following 7 days treatment with 1.2, 2.4 and 4.8 g of delayed-release mesalazine daily. 5-aminosalicylic acid and N-acetyl 5-aminosalicylic acid concentrations were measured in serum, urine, stool and rectal tissue biopsies.



Serum concentrations and 24 h urinary excretion of 5ASA and N-acetyl 5ASA increased as the oral dose of mesalazine was increased from 1.2 g through 2.4 g to 4.8 g daily (serum area under curve (AUC):5ASA = 3. 9, 15.4 and 46.8 microg ml-1 h, P < 0.0001; N-acetyl 5ASA = 17.2, 30. 9 and 57.8 microg ml-1 h, P < 0.0001: urinary excretion: 5ASA = 1.8, 85.5 and 445 mg, P < 0.0001; N-acetyl 5ASA = 250, 524 and 1468 mg, P < 0.0001, respectively). Faecal 5ASA excretion increased as the oral dose increased from 1.2 g to 2.4 g but did not increase further with 4.8 g daily dosing whereas faecal N-acetyl 5ASA excretion was similar at all three doses. Rectal tissue concentrations of 5ASA increased markedly, and N-acetyl 5ASA increased modestly, as the dose of oral mesalazine increased from 1.2 g to 2.4 g daily but neither increased further with 4.8 g daily dosing.



The relationship between the ingested dose of delayed-release mesalazine and rectal tissue drug concentrations is complex. Factors other than dose are likely to be important determinants of rectal tissue drug concentrations.

title: Intestinal metabolism and transport of 5-aminosalicylate.
abstract: The purpose of this study was to determine the characteristics of intestinal absorption and metabolism of 5-aminosalicylic acid (5ASA). Regional perfusions of 5ASA in the anesthetized rat resulted in the appearance of N-acetyl-5-aminosalicylic acid in the intestinal lumen. Lumenal metabolite appearance was proportional to 5ASA permeability, which was 5-fold higher in the jejunum than in the ileum. Intestinal elimination significantly decreases 5ASA absorption at low lumenal drug concentrations and this process is saturated at high drug concentrations. Metabolite levels in intestinal tissue were higher than plasma levels at low perfusion drug concentrations, whereas the reverse was observed at high concentrations. Transport and metabolism of 5ASA was studied in Caco-2 monolayers. At low drug concentrations, 5ASA was preferentially transported in the basolateral (BL) to apical (AP) direction. With 5ASA incubation in either the AP or BL chamber, the N-acetyl metabolite appeared only in the AP compartment. Transport of N-acetyl-5-aminosalicylic acid was also exclusively observed in the BL to AP direction. Clinical data indicate that anti-inflammatory response to oral 5ASA correlates with the amount of 5ASA delivered to the intestinal tissue. This study shows that at lumenal levels below 200 microg/ml (concentrations that are typically achieved by controlled release dosage forms), intestinal secretion of 5ASA accounts for more than 50% of the total elimination and can significantly affect tissue levels and, therefore, may be an important factor in determining the response to 5ASA therapy.

title: Mesalazine preparations for the treatment of ulcerative colitis: Are all created equal?
abstract: Oral mesalazine (also known as mesalamine) is a 5-aminosalicylic acid compound used in the treatment of mild to moderate ulcerative colitis, with high rates of efficacy in induction and maintenance of remission. The therapeutic effect of mesalazine occurs topically at the site of diseased colonic mucosa. A myriad of oral mesalazine preparations have been formulated with various drug delivery methods to minimize systemic absorption and maximise drug availability at the inflamed colonic epithelium. It remains unclear whether different oral mesalazine formulations are bioequivalent. This review aims to evaluate the differences between mesalazine formulations based on the currently available literature and explore factors which may influence the selection of one agent above another.

title: Ulcerative Colitis Remission Status After Induction With Mesalazine Predicts Maintenance Outcomes: the MOMENTUM Trial
abstract: This study assessed the efficacy of maintenance treatment with multimatrix mesalazine following achievement of complete or partial remission after induction treatment with high-dose multimatrix mesalazine.  In this phase 3b/4, open-label, multicentre, prospective, single-arm study, patients with mild-to-moderate ulcerative colitis were treated with multimatrix mesalazine 4.8g/day once daily for 8 weeks [induction phase]. At Week 8, those who achieved complete or partial remission, based on predefined clinical and endoscopic criteria, were eligible to receive 12 months of multimatrix mesalazine 2.4g/day once daily maintenance therapy. The primary endpoint was the proportion of patients in complete remission at Month 12.  A total of 717 patients received induction treatment; 25.9% and 39.3% of patients achieved complete and partial remission, respectively, at Week 8. A total of 461 patients entered the maintenance phase. The likelihood of remaining in/achieving complete remission at Month 12 was higher for patients who entered the maintenance phase in complete remission compared with those who began maintenance in partial remission [47.8% vs 26.0%; p < 0.001]. At Month 12, mucosal healing [endoscopy score ≤ 1] was demonstrated in 76.4% [139/182] and 63.5% [176/277] of those who were in complete and partial remission, respectively, at the end of induction.  Patients achieving complete remission before dose reduction were more likely to remain in remission at Month 12.

title: Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis.
abstract: It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC.



A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment.



The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events.



Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.

title: Five-Aminosalicylic Acid: An Update for the Reappraisal of an Old Drug
abstract: Inflammatory bowel disease (IBD) comprises several conditions with chronic or recurring immune response and inflammation of the gastrointestinal apparatus, of which ulcerative colitis and Crohn's disease are the commonest forms. This disease has a significant prevalence and it is of an unknown aethiology. Five-aminosalicylic acid (5-ASA) and its derivatives are among the oldest drugs approved for the treatment of the IBD. In this review we reapprise aspects of 5-ASA mechanism of action, safety, and efficacy that in our opinion make it a valuable drug that can be fruitfully tailored in personalised treatments as a therapeutic option alongside other immune-modifying agents.

title: Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches.
abstract: Intestinal microbiota are involved in the pathogenesis of Crohn's disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD-either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment.

title: Therapeutic drug monitoring for tomorrow
abstract: Therapeutic drug monitoring (TDM) represents an early approach to personalised medicine. It helps the clinician to individualise drug treatment and guide dosage to reach systemic drug concentrations associated with therapeutic efficacy and/or to reduce the risk of concentration-dependent adverse effects. Well into the fifth decade of TDM as a service to healthcare, this concept is still expanding, and new areas for clinical implementation continue to emerge. The aim of this overview is to discuss promising new therapeutic areas in future TDM services, how to improve the clinical interpretation of single drug measurements and how recent technology development opens the doors to research and new applications.

title: Clinical Pharmacokinetics in the 21st Century
abstract: Clinical pharmacokinetics emerged as a clinical discipline in the late 1960s and early 1970s. Clinical pharmacokinetic monitoring (CPM) helped many pharmacists to enter the clinical arena, but the focus was more on the pharmacists and tools. With the widespread acceptance of pharmaceutical care and patientfocused pharmacy, we now must take a sobering look at how clinical pharmacokinetics fits into the pharmaceutical care process.The existing literature is laden with articles that evaluate the effect of CPM on surrogate end-points. Many pharmacists have also had personal experiences that attest to the usefulness of CPM. Decreased mortality, decreased length of treatment, decreased length of hospital stay, decreased morbidity, and decreased adverse effects from drug therapy have been examined in an effort to measure and evaluate the impact of CPM on patient outcomes. While many of these studies demonstrated significant positive outcomes, several showed that CPM did not have a significant impact on specific patient outcomes. A few studies even found a negative impact on specific patient outcomes. Ultimately, there is good evidence in only a few specific patient groups to support the benefit of CPM.Despite the limitations of data supporting the routine use of CPM in managing drug therapy in diverse populations, many pharmacists continue to expend considerable time and effort in this activity. We need to define those patients who are most likely to benefit from CPM and incorporate this into our provision of pharmaceutical care, while minimising the time and money spent on CPM that provides no value.In redefining the patients who will benefit from CPM, we need to critically re-evaluate clinical studies on the relationship between drug concentration and response. Similarly, we need to pay special attention to recent studies evaluating the impact of CPM on outcomes in specific subpopulations. In the absence of specific studies demonstrating the value of CPM in particular patients, we propose that a more comprehensive decision-making process be undertaken that culminates in the quintessential question: ‘Will the results of the drug assay make a significant difference in the clinical decision-making process and provide more information than sound clinical judgement alone?’ We also need to consider opportunities to expand the use of CPM for new drugs and where new evidence suggests benefit.Even when there is strong evidence that CPM is useful in managing therapy in particular patient groups, clinicians need to remember that the therapeutic range is no more than a confidence interval and, therefore, we need to ‘treat the patient and not the level’. We need to incorporate the patient-specific and outcome-oriented principles of pharmaceutical care into our CPM, even as we utilise CPM as an essential tool in pharmaceutical care.

title: Review article: delivery and efficacy of topical 5‐aminosalicylic acid (mesalazine) therapy in the treatment of ulcerative colitis
abstract: 2011; 33: 996–1009

title: Systemic absorption of 5-aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine
abstract: To compare the systemic load of 5-aminosalicylic acid (5-ASA) as a basis for potential long-term toxicity during treatment in usual dosage with olsalazine (Dipentum) and one controlled-release mesalazine preparation (Salofalk) in patients with inactive ulcerative colitis.  Open, randomized, crossover study. Treatment schedule: Olsalazine 500 mg twice daily for 7 days and mesalazine 500 mg thrice daily for 7 days consecutively.  Fifteen patients (12 males/3 females) aged between 18–70 years with ulcerative colitis in endoscopically confirmed remission for at least one month.  A morning predose plasma sample and a 24-h urine collection on days 6 and 7 of each course were obtained from all patients for quantitative determination of 5-ASA and acetyl-5-ASA (Ac-5-ASA) concentrations. High performance liquid chromatography was used and all analyses were performed blindly on coded samples.  Treatment with mesalazine compared with olsalazine gave significantly higher levels of 5-ASA and Ac-5-ASA in plasma and urine. Maximum values and ranges of all variables were higher in the mesalazine group than in the olsalazine group. It is noteworthy that there was clear discriminance in the range of urine 5-ASA and Ac-5-ASA concentrations after mesalazine and olsalazine treatment.  1. The mesalazine preparation used, in comparison with olsalazine given in usual dosages, causes significantly higher levels of 5-ASA and Ac-5-ASA in plasma and urine in patients with inactive ulcerative colitis. 2. The lower systemic load of 5-ASA may reduce the potential risk of adverse events and in particular of nephrotoxicity. European Journal of Gastroenterology & Hepatology 1996,

title: Review article: 5‐aminosalicylate formulations for the treatment of ulcerative colitis – methods of comparing release rates and delivery of 5‐aminosalicylate to the colonic mucosa
abstract: Many oral 5‐aminosalicylic acid (5‐ASA) formulations are designed to maximize 5‐ASA release in the colon where it acts topically on the colonic mucosa. Delayed‐release formulations and azo‐prodrugs minimize 5‐ASA absorption in the upper gastrointestinal (GI) tract.

title: The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro‐drugs used in the management of ulcerative colitis
abstract: To quantify through systematic review the pharmacokinetic profiles of the oral delayed release and sustained release mesalazine (5‐aminosalicylate, 5ASA) formulations (Asacol, Salofalk, Mesasal, Claversal, Pentasa) and pro‐drugs (sulfasalazine, olsalazine, balsalazide) used in the management of ulcerative colitis.

title: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
abstract: David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses

title: Distribution studies of salicylazosulfapyridine and its metabolites.
abstract: Previous studies in the rat have indicated that the initial reaction of salicylazosulfapyridine (SAS) metabolism, reduction of the azo bond, can be attributed exclusively to the action of the intestinal bacteria. This finding raises questions concerning the amount of intact SAS that reaches its possible site of action within the lumen in inflammatory disease of the lower intestine. Accordingly, a study of the distribution of SAS and its metabolites in the rat and in man has been undertaken. In both species only small amounts of SAS were recovered in the urine. The drug was not recovered in the feces of rats but small amounts were found in the feces of 4 of 11 human subjects. In both species a consistent finding was high levels of sulfapyridine in the urine and high levels of 5-aminosalicylate in the feces. Indeed the level of 5aminosalicylate in rat feces greatly exceeded that found when an equimolar amount of 5-aminosalicylate itself was fed orally to the rats. These studies indicate that SAS is almost completely metabolized in both human subjects and rats and that there is a tendency for its metabolite 5-aminosalicylate to reach relatively high levels in the feces.

title: Distribution and metabolism in healthy volunteers of disodium azodisalicylate, a potential therapeutic agent for ulcerative colitis.
abstract: A series of experiments has been performed in healthy male volunteers to investigate the disposition of orally administered disodium azodisalicylate, a potentially useful drug for the treatment of ulcerative colitis. The drug was given by mouth in doses of up to 2 g a day for six weeks and there were no adverse effects. Serum concentrations of the intact compound were low and the serum half-time was 4-12.8 days, probably because of a combination of a low clearance rate and a high apparent volume of distribution. Less than 5% of the ingested dose was excreted unchanged in the urine. Circulating concentrations of 5-ASA and N-acetyl-5-ASA were low and 30% of the equivalent daily dose was excreted in the urine, predominantly as N-acetyl-5-ASA. In most subjects more than 30% of the equivalent daily dose of 5-ASA was recovered from the faeces, either as 5-ASA itself or as the acetylated derivative. As 5-ASA has been shown to be the active therapeutic moiety of sulphasalazine, disodium azodisalicylate appears to be suitable for therapeutic trial in ulcerative colitis.

title: Colonic azodisalicylate metabolism determined by in vivo dialysis in healthy volunteers and patients with ulcerative colitis.
abstract: Azodisalicylate, a second generation drug of sulfasalazine, delivers twice the amount of 5-aminosalicylic acid to the colonic lumen on a molar basis when split by bacterial azoreductases. In 6 patients with inactive ulcerative colitis, the colonic metabolism of sulfasalazine and azodisalicylate was studied by equilibrium in vivo dialysis of feces to measure the therapeutically relevant concentrations of their metabolites (5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid) in free fecal water. After oral intake of sulfasalazine (2 g/day) the total luminal concentrations of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid determined by high-performance liquid chromatography were higher (median 14 mmol/L) than previously reported and almost doubled (median 25 mmol/L, p less than 0.05) when sulfasalazine was replaced by the same dose of azodisalicylate. In contrast, the corresponding serum concentrations were negligible. After administration of azodisalicylate to 12 healthy volunteers, a similar distribution of the metabolites was found. In nearly all cases, the concentrations of azodisalicylate in fecal dialysates were below the detection limit (6 mumol/L). We conclude, therefore, that oral azodisalicylate is a highly effective means of delivery of 5-aminosalicylic acid to the colonic mucosa. In addition, determination of the active metabolites in free fecal water seems important for the interpretation of results obtained in vitro concerning the mode of drug action.

title: Simple method for the determination of 5-aminosalicylic and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies.
abstract: We describe a sensitive high-performance liquid chromatographic method for the determination of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies. Samples were derivatised using propionic anhydride and proteins were precipitated with methanol. A Supelcosil ABZ column (150x4.6 mm I.D., 5 microm silica particles) was used with a mobile phase comprising 0.1 M acetic acid, acetonitrile and triethylamine (1600:114:6, v/v/v). Fluorescence detection was employed and detection limits were 0.2 ng/mg tissue at a signal-to-noise ratio of three (measured concentration: 5-aminosalicylic acid, 0.254 (0.228-0.286) ng/mg, C.V. 10.7%; N-acetyl-5-aminosalicylic acid, 0.18 (0.154-0.198) ng/mg, C.V 9.8%). This assay was validated for use with serum, urine and faecal samples for which it proved to be both precise and accurate (C.V.<10%, measured concentration within 10%).

title: Mesalazine release from coated tablets: effect of dietary fibre.
abstract: Delayed-release mesalazine formulations relay on pH-dependent coat dissolution to ensure delivery of 5-aminosalicylic acid (5-ASA) to the colon. As dietary fibre acidifies the colonic lumen we have studied the effect of fibre supplementation in 10 patients with quiescent colitis. Greater intake of dietary fibre was associated with a decrease in stool pH and an increase in stool frequency and faecal mass. However, the 24 h faecal and urinary excretion of 5-ASA and N-acetyl-5-ASA was unchanged. The percentage of total faecal ASA excreted as N-acetyl-5-ASA correlated with whole-gut transit time, suggesting that prolonged transit may be disadvantageous to patients with colitis as N-acetyl-5-ASA appears to be inactive.

title: Influence of intestinal transit time on azo-reduction of salicylazosulphapyridine (Salazopyrin).
abstract: During a normal and an accelerated intestinal transit, in seven healthy volunteers, the recoveries of salicylazosulphapyridine (SASP) and its split products sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) were determined in urine and faeces. The azo-reduction of SASP and consequently the recovery of 5-ASA in the faeces was found to be substantially decreased during an accelerated intestinal transit. In addition, in 18 patients with inflammatory disease of the colon during maintenance therapy of SASP it could be demonstrated that the serum SP levels were related to the diarrhoeal state and did not correlate with disease activity. As recent studies have reported that 5-ASA is possibly the active therapeutic moiety of SASP, the ineffectiveness of SASP therapy in patients with active colitis may be ascribed to the reduced azo reduction of SASP as the result of profuse diarrhoea.

title: Longterm olsalazine treatment: pharmacokinetics, tolerance and effects on local eicosanoid formation in ulcerative colitis and Crohn's colitis.
abstract: To examine pharmacokinetics and tolerance of long term administration of olsalazine (azodisalicylate), increasing doses of the drug were given for one year to 31 patients with ulcerative colitis (UC) and nine patients with Crohn's colitis (CC), refractory to, or intolerant of sulphasalazine, until sustained remission was obtained or a maximum of 4 g/day was reached. Colonic drug metabolism was studied by equilibrium in vivo dialysis of faeces. Complete azoreduction occurred in most cases. Concentrations of 5-aminosalicylic acid, but not N-acetyl-5-aminosalicylic acid, in faecal dialysates increased dose dependently. Serum concentrations disclosed no cumulation in the long term and olsalazine was well tolerated, although loose stools occurred transiently in some patients with extensive disease: this was associated with a larger proportion of unsplit olsalazine in the faecal dialysates. Patients with ulcerative colitis having a high prostaglandin E2 concentration (greater than ng/ml) determined by equilibrium dialysis of rectum, were less likely to benefit from treatment. Olsalazine is a very effective means of delivery of 5-aminosalicylic acid to the colonic mucosa in active disease. Use of the drug in controlled trials may be considered safe even in prolonged high dosage.

title: Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man
abstract: One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 μg · ml−1 and 1.33 μg · ml−1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.

title: Olsalazine in the Treatment of Active Ulcerative Colitis: A Placebo Controlled Clinical Trial and Assessment of Drug Disposition
abstract: The efficacy, safety and disposition of olsalazine was assessed in patients with left-sided ulcerative colitis or proctitis in a double-blind placebo controlled trial. Thirty patients with a mild-to-moderate attack of ulcerative colitis were randomly allocated to olsalazine capsules, 1 g b.d., or placebo for 6 weeks. Good clinical response was found in six patients receiving olsalazine and in two receiving placebo. Improvement in sigmoidoscopic findings and histological appearance of rectal biopsies was also seen more often in olsalazine-treated patients. Plasma concentrations of olsalazine were significantly higher in patients who improved. Olsalazine showed an advantage over placebo which needs to be confirmed by further studies; it was safe in sulphasalazine-sensitive patients but appeared to cause watery diarrhoea in two patients.

title: Is 5-Aminosalicylic Acid Delivered Directly to the Colon by Olsalazine?
abstract: The aims of this investigation were to determine the amount of olsalazine which is delivered to the colon and the amount biotransformed to 5-ASA and N-acetyl-5-ASA, and to study the effect of concomitant food intake on the availability of 5-ASA and acetyl-5-ASA after olsalazine, 1 g. Studies in 10 subjects who received a single 1 g oral dose showed that olsalazine is transported intact to the colon and that less than 3% is absorbed. Olsalazine is, therefore, biologically transformed to 5-ASA and acetyl-5-ASA in the large intestine. The small amount of olsalazine absorbed has a short β half-life of 56 minutes. The simultaneous intake of food in a study involving eight healthy volunteers slightly diminished the low absorption of olsalazine, though the effect was not significant, and no effect was seen on the absorption of 5-ASA.

title: Su1081 A Novel Method to Investigate Local Concentrations of Mesalamine in the Gastrointestinal Tract of Healthy Volunteers
abstract: Recent observatory studies suggest that non-adherence to 5-ASA therapy during remission is a main factor for relapse in ulcerative colitis (UC) (1). Patient education may improve adherence. We investigated demographic and clinical parameters associated with non-adherence and influence of patient education on 5-ASA adherence in a randomized, prospective clinical trial.  247 patients with inactive or mildly active UC (CAI 60 yrs: 30.2%; 13/43). High levels of non-adherence were associated with short duration of disease (2-5 yrs: 55.9%; 57/102 vs. 5-10 yrs: 52.2%; 35/67, 10-15 yrs: 51.2%; 21/41 and >15 yrs: 44.7%; 17/38). A trend for a relationship between non-adherence and low education levels was seen (low education (only basic school): 63.8%, 30/47 vs. higher education levels (trade school): 41.8 %, 28/67 and "Abitur"/university: 58%, 65/ 112).  Although >25% of the population were not in remission throughout the study no relationship between disease activity and adherence was seen. Non adherence was associated with younger age, short duration of disease and lower education levels. While a structured intervention using a patient education program failed to improve adherence in this particular group, efforts should be maximized to motivate this high-risk population for adherence. Lit :(1) Khan et al., Aliment Pharmacol Therap 2012

title: 5-ASA colonic mucosal concentrations resulting from different pharmaceutical formulations in ulcerative colitis.
abstract: To compare the mucosal concentrations of 5-aminosalicylic acid (5-ASA) resulting from different pharmaceutical formulations and analyse the influence of inflammation on the mucosal concentrations.



The study included 130 inflammatory bowel disease (IBD) patients receiving 5-ASA as pH-dependent-release formulations (73 patients), time-dependent-release formulations (11 patients), or pro-drugs (18 patients). In addition, 28 patients were receiving topical treatment (2-4 g/d) with pH-dependent-release formulations. Endoscopic biopsies were obtained from the sigmoid region during the colonoscopy. The 5-ASA concentrations (ng/mg) were measured in tissue homogenates using high-pressure liquid chromatography with electrochemical detection. The t test and Mann-Whitney test, when appropriate, were used for statistical analysis.



Patients receiving pH-dependent-release formulations showed significantly higher mucosal concentrations of 5-ASA (51.75 ± 5.72 ng/mg) compared with patients receiving pro-drugs (33.35 ± 5.78 ng/mg, P = 0.01) or time-dependent-release formulations (38.24 ± 5.53 ng/mg, P = 0.04). Patients with endoscopic remission had significantly higher mucosal concentrations of 5-ASA than patients with active disease (60.14 ± 7.95 ng/mg vs 35.66 ± 5.68 ng/mg, P = 0.02). Similar results were obtained when we compared patients with the histological appearance of remission and patients with active histological inflammation (67.53 ± 9.22 ng/mg vs 35.53 ± 5.63 ng/mg, P < 0.001). Significantly higher mucosal concentrations of 5-ASA were detected in patients treated with both oral and topical treatments in combination compared with patients who received oral treatment with pH-dependent-release formulations alone (72.33 ± 11.23 ng/mg vs 51.75 ± 5.72 ng/mg, P = 0.03).



IBD patients showed significant variability in mucosal 5-ASA concentrations depending on the type of formulation, and the highest mean concentration was achieved using pH-dependent-release formulations.

title: Measurement of Colonic Mucosal Concentrations of 5-Aminosalicylic Acid Is Useful for Estimating Its Therapeutic Efficacy in Distal Ulcerative Colitis: Comparison of Orally Administered Mesalamine and Sulfasalazine
abstract: ObjectivesOral 5-aminosalicylic acid (5-ASA) preparations have been used frequently in the treatment of ulcerative colitis. However, there have been few reports investigating the relationship between colonic mucosal concentrations of 5-ASA and its clinical efficacy when oral sulfasalazine or 5-ASA compounds were administered. The aim of this study is to compare the mucosal concentrations of 5-ASA ensured by sulfasalazine or mesalamine, and to define the clinical significance of the measurement of 5-ASA concentrations in the treatment of distal ulcerative colitis. Materials and MethodsBiopsies were taken from the rectum and sigmoid colon of the oral sulfasalazine group (n = 13) and the slow-release 5-ASA (mesalamine) group with (n = 5) or without (n = 11) rectal administration of 5-ASA. High-pressure liquid chromatography was used to measure the tissue concentrations of 5-ASA and its metabolites. We compared the 5-ASA concentrations of the sulfasalazine group with the mesalamine group. Furthermore, we analyzed the relationship between tissue 5-ASA concentrations and the Disease Activity Index (DAI). ResultsThe concentrations of 5-ASA and acetyl-5-ASA in the sulfasalazine group were higher than those in the group taking oral mesalamine alone (p < 0.01). The concentration of 5-ASA was much higher in the patients who received oral and rectal mesalamine in an enema than in the patients who had oral mesalamine alone. There was a significant inverse correlation between the DAI and concentrations of 5-ASA in the rectum (r = 0.712, p < 0.001). ConclusionsWe demonstrated that the colonic mucosal concentration of 5-ASA was significantly higher in the sulfasalazine group than in the mesalamine group. Furthermore, the concentrations of mucosal 5-ASA may be a good marker for the estimation of its efficacy in the treatment of ulcerative colitis.

title: Mucosal 5-aminosalicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis
abstract: The treatment of ulcerative colitis (UC) with 5-aminosalicylic acid (5-ASA) does not have the same therapeutic effect in all patients. We tested the hypothesis that the effectiveness of the drug is related to its mucosal concentration.  Twenty one UC patients receiving oral 5-ASA (2.4–3.2 g/day) were enrolled in the study. Four were also receiving topical treatment (2 g/day).  Six endoscopic biopsies were taken from the rectum for measurement of 5-ASA concentrations (ng/mg) by HPLC; soluble interleukin 2 receptor (sIL-2R) concentrations (U/ml) were measured by ELISA and histology. Endoscopic and histological appearance was graded on a four point scale (0–3). The Wilcoxon's rank test and Pearson's correlation coefficient were used for statistical analysis.  Mucosal concentrations of 5-ASA were significantly higher (p=0.03) in patients with endoscopic scores of 0–1 compared with those with scores of 2–3 (16.1 (range 10.2–45) v 5.5 (3.5–17.4), respectively) and in patients with lower histological inflammation compared with those with more severe scores (17.4 (10.5–45)v 8.9 (3.5–17.2), respectively) (p<0.01). In contrast, mucosal sIL2-R concentrations were significantly lower in patients with slight endoscopic and histological lesions than in those with more severe disease. A significative inverse correlation (r=−0.85) was found between 5-ASA and sIL-2R mucosal concentrations (p=0.00008).  In patients with UC, in the same area of the intestinal tract, we found that the higher the 5-ASA mucosal concentrations, the lower the IL-2R levels and endoscopic and histological scores. We hypothesise that maintenance of high mucosal 5-ASA concentrations in all colonic segments could contribute to improve clinical outcome in UC patients.

title: Once versus divided daily dosing with delayed‐release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters
abstract: Delayed‐release mesalazine is traditionally taken as three divided doses. However, it is well‐recognized that dosing frequency has a significant impact on compliance and that once daily dosing is preferable.

title: High-performance liquid chromatographic assay for the determination of 5-aminosalicylic acid and acetyl-5-aminosalicylic acid concentrations in endoscopic intestinal biopsy in humans.
abstract: A high-performance liquid chromatographic method for the simultaneous determination of 5-amino-salicylic acid (5-ASA) and N-acetyl-5-ASA (Ac-5-ASA) concentrations in endoscopic mucosal biopsy homogenates is presented. The mean recoveries of 5-ASA and Ac-5-ASA from spiked blank biopsy homogenates ranged from 95.9 to 120% and from 92.5 to 100%, respectively. The coefficients of variation for 5-ASA and Ac-5-ASA were 0.7-8.6% and 1.4-12.9%, respectively. This method is useful for direct determination of topical availability of 5-ASA and Ac-5-ASA and probably an accurate parameter of drug bioavailability.

title: Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion.
abstract: To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.

title: Disposition of 5-aminosalicylic acid from 5-aminosalicylic acid-delivering drugs during accelerated intestinal transit in healthy volunteers.
abstract: In eight healthy volunteers accelerated intestinal transit time was induced with bisacodyl, and urinary and faecal excretion of sulphasalazine, olsalazine, 5-aminosalicylic acid (5-ASA), and acetyl-5-ASA was studied after a single oral dose of 3.3 mmol sulphasalazine, olsalazine, Pentasa, and Salofalk and 2.6 mmol of Asacol. The faecal and urinary excretion of acetyl-5-ASA was lowest after intake of sulphasalazine and olsalazine and highest after intake of Pentasa and Salofalk. The figures for Asacol were intermediate. This indicates insufficient release of 5-ASA from sulphasalazine and olsalazine. When the results of this study are compared with those of a previous study without accelerated transit time, the disposition of 5-ASA from all the 5-ASA-delivering drugs is influenced unfavourably by an accelerated gut transit but most pronounced in the case of sulphasalazine, olsalazine, and Asacol. The impaired release from the azo compounds sulphasalazine and olsalazine is a result of far less complete splitting of the diazo bond.

title: Pharmacokinetics and safety of single and multiple doses of Asacol tablets in Japanese healthy volunteers
abstract: IntroductionThe pharmacokinetics and safety of Asacol® (Tillotts Pharma AG, Ziefen, Switzerland), which has been used worldwide to treat ulcerative colitis and Crohn’s disease, were studied in Japanese healthy male volunteers.MethodsDrug plasma concentrations and urinary and fecal excretions after a single dose (400–4800 mg) and multiple doses (3600 mg/day for 7 days) were investigated.ResultsAll adverse events were “not serious.” The peak plasma concentration (Cmax) was reached at 12.3–18.0 hours after a single dose, and the Cmax and area under the plasma concentration-time curve (AUC) of mesalazine and its N-acetyl metabolite were proportional to the doses. The Cmax and AUC in non-Japanese subjects reported in the literature were closely correlated to findings in Japanese subjects, and external excretions were also similar in the Japanese and non-Japanese subjects.ConclusionsAsacol was safe and well tolerated in this Japanese population, and the non-Japanese clinical data could be extrapolated to the Japanese population.

title: Disposition of disodium azodisalicylate in healthy subjects. A possible new drug for inflammatory bowel disease.
abstract: The disposition of disodium azodisalicylate and salicylazosulfapyridine was studied in 6 healthy volunteers. After a single oral dose (1.0 g disodium azodisalicylate; 2.3 g salicylazosulfapyridine) maximum serum concentrations of the intact compound ranged between 1.4 and 6.8 mumol/L and 32 and 114 mumol/L, respectively. Mean residence time and serum half-life of disodium azodisalicylate were considerably longer than those of salicylazosulfapyridine, probably because of a higher apparent volume of distribution. Both compounds were largely split by colonic bacteria and comparable amounts of the active moiety, (acetyl-)5-aminosalicylic acid, were recovered in feces. During long-term ingestion of disodium azodisalicylate (1.0 g/day) it took 6-19 days to reach a steady state. Serum concentrations of disodium azodisalicylate at steady state were low: 2.2-8.4 mumol/L. The serum half-life was 6-10 days. It is concluded that the disposition of disodium azodisalicylate is similar, in important respects, to that of salicylazosulfapyridine. Disodium azodisalicylate, therefore, deserves therapeutic trial.

title: Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea.
abstract: The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum) and from the slow-release mesalazine drugs Pentasa, Asacol, and Salofalk was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from all these drugs except Pentasa.

title: Bioavailability of 5-aminosalicylic acid from slow release 5-aminosalicylic acid drug and sulfasalazine in normal children
abstract: The bioavailability of a controlled release 5-aminosalicylic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration ofN-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicylic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid andN-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.

title: Pharmacokinetics of a 5‐aminosalicylic acid enteric‐coated tablet and suppository dosage form
abstract: An Eudragit‐L coated oral 5‐aminosalicylic acid (5‐ASA; mesalazine) product (Mesasal), has been formulated to deliver 5‐ASA to the distal small intestine and colon for the treatment of inflammatory bowel disease. The purpose of this study was to compare the pharmacokinetic profile of this product to sulphasalazine (SASP; Salazopyrin) and to assess the pharmacokinetics of a suppository 5‐ASA dosage form.

title: Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study
abstract: Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC.  A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks.  Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026).  In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.

title: Mesalazine vanishing time from rectal mucosa following its topical administration.
abstract: To investigate how long and how much Mesalazine (M) is available inside the rectal mucosa following its topical instillation, in patients (pts) with Ulcerative Colitis (UC). Two rectal biopsies for M concentration were obtained from 45 UC pts in clinical remission and on oral M treatment (OT), before a 4g enema randomly given to consentient pts every day (Group A, 15 pts), every 2 days (Group B, 15 pts) and every 3 days (Group C, 15 pts). Two additional biopsies were taken 1, 2 and 3 days after the last enema in group A, B and C respectively, at least 10 days later. All biopsies were immediately frozen at -80°C for later assay by means of high-performance light chromatography (HPLC). Data were analyzed using Student's t-test. Mean values±standard deviation of M mucosal concentration (ng/mg of tissue) were 1.32±1.41, 56.1±39.2, 9.65±6.60, and 6.39±5.03 in pts receiving OT alone, groups A, B and C, respectively. Values in Group A were statistically higher (p<0.001) than those in Groups B and C while no differences were found between Groups B and C. Values of OT were lower than groups A, B and C. M mucosal concentration rapidly decreases 2 days after a 4g enema, but after three days is still higher than OT alone. These results may provide data which would be useful to plan topical therapy and improve adherence to treatment.

title: Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract.
abstract: As an orally administered, locally acting gastrointestinal drug, mesalamine products are designed to achieve high local drug concentration in the gastrointestinal (GI) tract for the treatment of ulcerative colitis. The aim of this study was to directly measure and compare drug dissolution of three mesalamine formulations in human GI tract and to correlate their GI concentration with drug concentration in plasma. Healthy human subjects were orally administered Pentasa, Apriso, or Lialda. GI fluids were aspirated from stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum regions. Mesalamine (5-ASA) and its primary metabolite acetyl-5-mesalamine (Ac-5-ASA) were measured using LC-MS/MS. GI tract pH was measured from each GI fluid sample, which averaged 1.82, 4.97, 5.67, 6.17, and 6.62 in the stomach, duodenum, proximal jejunum, middle jejunum, and distal jejunum, respectively. For Pentasa, high levels of 5-ASA in solution were observed in the stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum from 1 to 7 h. Apriso had minimal 5-ASA levels in stomach, low to medium levels of 5-ASA in duodenum and proximal jejunum from 4 to 7 h, and high levels of 5-ASA in distal jejunum from 3 to 7 h. In contrast, Lialda had minimal 5-ASA levels from stomach and early small intestine. A composite appearance rate (CAR) was calculated from the deconvolution of individual plasma concentration to reflect drug release, dissolution, transit, and absorption in the GI tract. Individuals dosed with Pentasa had high levels of CAR from 1 to 10 h; individuals dosed with Apriso had low levels of CAR from 1 to 4 h and high levels of CAR from 5 to 10 h; Lialda showed minimal levels of CAR from 0 to 5 h, then increased to medium levels from 5 to 12 h, and then decreased to further lower levels after 12 h. In the colon region, Pentasa and Apriso showed similar levels of accumulated 5-ASA excreted in the feces, while Lialda showed slightly higher 5-ASA accumulation in feces. However, all three formulations showed similar levels of metabolite Ac-5-ASA in the feces. These results provide direct measurement of drug dissolution in the GI tract, which can serve as a basis for investigation of bioequivalence for locally acting drug products.

title: Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations.
abstract: Intramucosal 5-aminosalicylic acid (5-ASA) and acetylated 5-ASA (Ac-5-ASA) concentrations were determined in ileocolonic biopsy specimens from 61 patients with irritable bowel syndrome treated for one week with near equimolar doses of different slow release preparations of 5-ASA (Claversal, Asacol, or Pentasa) or azo-bound drugs (Salazopyrin, Dipentum). The transit time in these patients was accelerated by a laxative, metoclopramide, and colonic lavage. The presence of 5-ASA in the mucosa was confirmed by autofluorescence. The highest concentrations of 5-ASA were obtained after Asacol (mean (SEM), 298.5 (37.3) ng/mg wet wt), followed by Claversal 500 mg (108.8 (11.7) ng/mg wet wt) and Pentasa (25.7 (2.2) ng/mg wet wt). Very low concentrations only were observed after Claversal 250 mg (0.3 (0.03) ng/mg wet wt), Salazopyrine (1.2 (0.1) ng/mg wet wt), and Dipentum (11.0 (3.2) ng/mg wet wt). The results for Ac-5-ASA were similar but the concentrations were generally lower. Serum concentration-time curves over eight hours were obtained from 34 healthy volunteers after a single oral dose of 400 to 500 mg of the different drugs. For the slow release forms, an apparently inverse relationship was found between the area under the curve of the serum concentrations and the intramucosal concentrations, supporting the importance of the local availability of the drug. This inverse relationship was absent for the azo-bound drugs. Colonic washout induced mechanical removal of intraluminal 5-ASA with a secondary disturbance in absorption resulting in a rapid decline in the serum concentrations. However, only for Dipentum did this result in significantly lower 5-ASA mucosal concentrations. This is the first reported attempt to evaluate the mucosal availability of 5-ASA after different oral preparations. It shows that where transit time is accelerated higher mucosal concentrations occur after slow release preparations (except for Claversal 250 mg) than after azo-bound drugs. Additional studies are necessary to correlate these concentrations with clinical effects.

title: Anastomotic configuration and mucosal 5-aminosalicyclic acid (5-ASA) concentrations in patients with Crohn's disease: a GISC study. Gruppo Italiano per lo Studio del Colon e del Retto.
abstract: Recurrence of Crohn's disease quite inevitably occurs after resection of distal small bowel and proximal colon, involving the neoterminal ileum close to the anastomosis. Oral 5-aminosalicylic acid (5-ASA) administered soon after surgery delays recurrence and reduces its severity. We recently observed that in operated patients submitted to prophylactic treatment with oral 5-ASA the rate of recurrence was significantly higher in those with end-to-end anastomosis than in those with other types of anastomosis (end-to-side, side-to-side). The hypothesis investigated in the present study was that patients with end-to-side or side-to-side anastomosis would benefit from a higher mucosal concentration of 5-ASA with respect to patients with end-to-end anastomosis. Therefore, the mucosal 5-ASA concentration was measured in the perianastomotic area of both groups.



The study was carried out in 19 patients submitted to radical surgery for Crohn's ileitis or ileocolitis, under oral prophylactic treatment with 5-ASA (Asacol). All patients were on regular endoscopic follow-up and were free of recurrence. Two biopsies were collected 3 cm from the anastomosis, in the neoterminal ileum, and two biopsies were collected at the colonic site 3 cm below the anastomosis. 5-ASA concentrations (ng/mg) were measured in tissue homogenates by high-performance liquid chromatography (HPLC) with electrochemical detection.



The mucosal concentration of 5-ASA in the neoterminal ileum was significantly lower in patients with end-to-end anastomosis than in those with other types of anastomosis (median values: 29.4 ng/mg vs 92.9 ng/mg respectively; p < 0.001). Six of 10 patients (60%) with end-to-end anastomosis, but none of the nine patients with other types of anastomosis, showed 5-ASA mucosal concentrations <40 ng/mg at the neoterminal ileum. On the contrary, no patients with end-to-end anastomosis showed mucosal concentrations of 5-ASA >90 ng/mg, compared with the 57% of patients in the group with other types of anastomosis. No differences were observed for colonic biopsies.



The different mucosal concentrations in these two groups may be explained by the difference in segmental transit time induced by the different anastomotic configurations. A slower preanastomotic transit time, demonstrated in patients with end-to-side or side-to-side anastomosis, could offer a prolonged contact time between the intestinal content and the mucosa, resulting in an increase in drug absorption.

title: Steady-state kinetics of 5-aminosalicylic acid and sulfapyridine during sulfasalazine prophylaxis in ulcerative colitis.
abstract: Fifteen adult and 19 pediatric outpatients with ulcerative colitis were studied to determine the steady-state kinetics of 5-aminosalicylic acid (5-ASA) released from salazosulfapyridine (SASP). Results of excretion in adults (mean 24-h recovery of 5-ASA, 21% in urine and 57% in feces) were compatible with those of healthy volunteers. Since mean SASP dose/kg body weight (about 50 mg/kg) and compliance (reflected in sulfapyridine recovery) were equal in adults and pediatric patients, the results of the patient groups could be compared. Near-complete azo reduction of SASP occurs in children. Absorption and excretion of 5-ASA and metabolism to acetyl-5-ASA did not differ statistically between pediatric and adult patients. However, the fecal excretion of the drug and its metabolites was significantly lower in young patients, although fecal concentrations were the same. The present results demonstrate that SASP is an excellent sustained-release drug for the delivery of 5-ASA to the lower part of the bowel system and provide a reference for comparison of 5-ASA kinetics after treatment with newer 5-ASA preparations.

title: Stability of disodium azodisalicylate (olsalazine) and metabolites in urine and faeces stored at different temperatures.
abstract: The stability of disodium azodisalicylate, 5-aminosalicylic acid and acetyl-5-aminosalicylic acid dissolved in distilled water and in urine or mixed with faeces to which HgCl2 was added, was studied at -20 degrees C, 4 degrees C and room temperature.



In water, no marked differences were found between the three storage regimens. In urine, disodium azodisalicylate and acetyl-5-aminosalicylic acid were stable, while the 5-ASA concentration decreased when stored at 4 degrees C and room temperature. In faeces stored during seven days, a marked decrease in 5-aminosalicylic acid concentration to about zero was found when it was kept at 4 degrees C and room temperature. No marked change in the concentration of disodium azodisalicylate and 5-aminosalicylic acid added to the faeces-HgCl2-mixtures appeared.

title: Release of 5-aminosalicylic acid from Pentasa during normal and accelerated intestinal transit time.
abstract: The influence of intestinal transit time on the release of 5-aminosalicylic acid (5-ASA) from a peroral, slow-release preparation (Pentasa) was studied at steady state in seven healthy volunteers. Daily dose was 1500 mg Pentasa, normal transit time (NTT) was 24 h (16-26 h) and accelerated transit time (ATT), caused by a laxative, was 5 h (4-9 h). Median total recovery (24 h, 5-ASA + acetyl-5-ASA) was 87% (61-129%) (NTT) and 81% (56-100%) (ATT), respectively, (P greater than 0.10). The total faecal excretion of 5-ASA (per cent of dose) increased from 16%, (9-21%) (NTT) to 29%, (16-38%) (ATT) (P less than 0.02). Free 5-ASA rose from 12% (4-19%) to 17% (10-25%), the retained part (in granules) from 4% (2-5%) to 12% (4-24%). Urinary excretion decreased correspondingly from 32% (19-59%) to 21% (11-38%), predominantly as Ac-5-ASA (P less than 0.05). Mean plasma Ac-5-ASA concentration decreased from 1.42 micrograms ml-1 to 0.86 microgram ml-1 (P less than 0.05). An almost complete release of 5-ASA from Pentasa takes place during NTT. At ATT conditions about 88% is released, indicating Pentasa to be an acceptable source of 5-ASA in diarrhoeal states.

title: Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs
abstract: Measurements of luminal pH in the normal gastrointestinal tract have shown a progressive increase in pH from the duodenum to the terminal ileum, a decrease in the caecum, and then a slow rise along the colon to the rectum. Some data in patients with ulcerative colitis suggest a substantial reduction below normal values in the right colon, while limited results in Crohn's disease have been contradictory. Determinants of luminal pH in the colon include mucosal bicarbonate and lactate production, bacterial fermentation of carbohydrates and mucosal absorption of short chain fatty acids, and possibly intestinal transit. Alterations in these factors, as a result of mucosal disease and changes in diet, are likely to explain abnormal pH measurements in inflammatory bowel disease (IBD). It is conceivable that reduced intracolonic pH in active ulcerative colitis impairs bioavailability of 5-aminosalicylic acid from pH dependent release formulations (Asacol, Salofalk) and those requiring cleavage by bacterial azo reductase (sulphasalazine, olsalazine, balsalazide), but further pharmacokinetic studies are needed to confirm this possibility. Reports that balsalazide and olsalazine may be more efficacious in active and quiescent ulcerative colitis, respectively, than Asacol suggest that low pH may be a more critical factor in patients taking directly pH dependent release than azo bonded preparations. Reduced intracolonic pH also needs to be considered in the development of pH dependent colonic release formulations of budesonide and azathioprine for use in ulcerative and Crohn's colitis. This paper reviews methods for measuring gut pH, its changes in IBD, and how these may influence current and future therapies.

title: Epithelial barrier defects in ulcerative colitis: characterization and quantification by electrophysiological imaging.
abstract: In ulcerative colitis (UC), the epithelial barrier is impaired by erosion/ulcer-type lesions and epithelial apoptosis causing local leaks, and generalized tight junction alterations increasing the basal permeability. We quantified the contribution of these mechanisms to the increased colonic ion permeability.



Sigmoid colon was stripped, and the spatial distribution of current clamped across the viable epithelium was recorded by a microelectrode probe, using the conductance scanning method. Local leaks (circumscribed conductive peaks) were marked, and structural changes were studied in H&E-stained series sections.



Overall conductivity increased from 8.4 +/- 0.7 mS/cm(2) (mean +/- SEM) in controls to 11.7 +/- 0.6 in specimens with mild inflammation (i.e., with intact epithelium) and 34.4 +/- 6.2 mS/cm(2) in moderate-to-severe inflammation (i.e., with visible epithelial lesions). Only in part this was caused by a generalized increase in basal conductivity (12.2 +/- 1.5 mS/cm(2) in moderate-to-severe UC vs. 8.3 +/- 0.7 in controls). More importantly, the spatial distribution of conductivity, which was even in controls, showed dramatic leaks in UC. Leaks found in mild inflammation without epithelial lesion turned out to be foci of epithelial apoptosis. In moderate-to-severe inflammation, leaks correlated with epithelial erosion/ulcer-type lesions or crypt abscesses.



In early UC, but not in controls, seemingly intact epithelium comprises leaks at apoptotic foci. With more intensive inflammation, erosion/ulcer-type lesions are highly conductive, even if covered with fibrin. Local leaks contribute 19% to the overall epithelial conductivity in mild and 65% in moderate-to-severe inflammation.

title: The association between the gut microbiota and the inflammatory bowel disease activity: a systematic review and meta-analysis
abstract: The pathogenesis of inflammatory bowel diseases (IBD) involves complex interactions between the microbiome and the immune system. We evaluated the association between the gut microbiota and disease activity in IBD patients.  Systematic review of clinical studies based on a published protocol. Included patients had ulcerative colitis (UC) or Crohn’s disease (CD) classified as active or in remission. We selected bacteria assessed in at least three studies identified through electronic and manual searches (November 2015). Bias control was evaluated with the Newcastle Ottawa scale (NOS). Results of random-effects meta-analyses were presented as mean differences (MD).  Three prospective and seven cross-sectional studies (NOS score 6–8) were included. Five studies included patients with CD (231 patients) and eight included patients with UC (392 patients). Compared to patients in remission, patients with active IBD had lower abundance of Clostridium coccoides (MD = −0.49, 95% CI: −0.79 to −0.19), Clostridium leptum (MD = −0.44, 95% CI: −0.74 to −0.14), Faecalibacterium prausnitzii (MD = −0.81, 95% CI: −1.23 to −0.39) and Bifidobacterium (MD = −0.37, 95% CI: −0.56 to −0.17). Subgroup analyses showed a difference in all four bacteria between patients with UC classified as active or in remission. Patients with active CD had fewer C. leptum, F. prausnitzii and Bifidobacterium, but not C. coccoides.  This systematic review suggests that dysbiosis may be involved in the activity of IBD and that there may be differences between patients with CD and UC.