The aminosalicylate - folate connection.

Two aminosalicylate isomers have been found to possess useful pharmacological behavior: p-aminosalicylate (PAS, 4AS) is an anti-tubercular agent that targets M. tuberculosis, and 5-aminosalicylate (5AS, mesalamine, mesalazine) is used in the treatment of ulcerative colitis (UC) and other inflammatory bowel diseases (IBD). PAS, a structural analog of pABA, is biosynthetically incorporated by bacterial dihydropteroate synthase (DHPS), ultimately yielding a dihydrofolate (DHF) analog containing an additional hydroxyl group in the pABA ring: 2'-hydroxy-7,8-dihydrofolate. It has been reported to perturb folate metabolism in M. tuberculosis, and to selectively target M. tuberculosis dihydrofolate reductase (mtDHFR). Studies of PAS metabolism are reviewed, and possible mechanisms for its mtDHFR inhibition are considered. Although 5AS is a more distant structural relative of pABA, multiple lines of evidence suggest a related role as a pABA antagonist that inhibits bacterial folate biosynthesis. Structural data support the likelihood that 5AS is recognized by the DHPS pABA binding site, and its effects probably range from blocking pABA binding to formation of a dead-end dihydropterin-5AS adduct. These studies suggest that mesalamine acts as a gut bacteria-directed antifolate, that selectively targets faster growing, more folate-dependent species.

Congestive ischemic colitis successfully treated with anti-inflammatory therapy: A case report.

BACKGROUND: Congestive ischemic colitis is a rare subtype of ischemic colitis with an unknown pathophysiology. Excluding conservative management, such as fasting, no established treatment exists; therefore, surgical intervention should be considered in some cases if symptoms worsen. Current literature suggests that anti-inflammatory agents may effectively treat congestive ischemic colitis. CASE SUMMARY: We present the case of a 68-year-old female patient who underwent laparoscopic left hemicolectomy for transverse colon cancer 3 years ago. Postoperatively, follow-up included an annual colonoscopy and abdominal computed tomography (CT) at a local clinic. However, progressive erythema and edema of the sigmoid colon were observed 1 year postoperatively. Upon admission to our hospital, she complained of abdominal pain and diarrhea. Abdominal CT showed thickening of the sigmoid colon walls, and colonoscopy revealed erythema, edema, and multiple ulcers with exudate in the sigmoid colon. CT angiography showed engorgement of the sigmoid vasa recta without any vascular abnormalities. The diagnosis was congestive ischemic colitis, and we treated the patient with anti-inflammatory agents. After 2 mo of glucocorticoid therapy (20 mg once daily) and 7 mo of 5-aminosalicylate therapy (1 g twice daily), the ulcers completely healed. She has not experienced any recurrence for 2 years. CONCLUSION: Anti-inflammatory therapy, specifically glucocorticoids and 5-aminosalicylate, has demonstrated promising efficacy and introduces potential novel treatment options for congestive ischemic colitis.

New genetic biomarkers predicting 5-aminosalicylate-induced adverse events in patients with inflammatory bowel diseases.

Background: Notably, 5-aminosalicylates (5-ASA) are vital in treating inflammatory bowel diseases (IBD). The adverse events of 5-ASA rarely occur but they could be fatal. Objectives: We aimed to discover new genetic biomarkers predicting 5-ASA-induced adverse events in patients with IBD. Design: This was a retrospective observational study. Methods: We performed a genome-wide association study on patients with IBD in South Korea. We defined subset 1 as 39 all adverse events and 272 controls; subset 2 as 20 severe adverse events and 291 controls (mild adverse events and control); subset 3 as 20 severe adverse events and 272 controls; and subset 4 as 19 mild adverse events and 272 controls. Logistic regression analysis was performed and commonly found associated genes were determined as candidate single-nucleotide polymorphisms predicting 5-ASA adverse events. Results: Patients with Crohn's disease (CD) were significantly negatively associated with the development of adverse events compared to patients with ulcerative colitis (UC) (5.3% versus 22.9%). However, sex and age at diagnosis were unassociated with the adverse events of 5-ASA. rs13898676 [odds ratio (OR), 20.33; 95% confidence interval (CI), 5.69-72.67; p = 3.57 × e-6], rs12681590 (OR, 7.35; 95% CI, 2.85-19.00; p = 3.78 × e-5), rs10967320 (OR, 4.51; 95% CI, 2.18-9.31; p = 4.72 × e-5), and rs78726924 (OR, 3.54; 95% CI, 1.69-7.40; p = 7.96 × e-5) were genetic biomarkers predicting 5-ASA-induced severe adverse events in patients with IBD. Conclusion: The adverse events of 5-ASA were more common in patients with UC than those with CD in our study. We found that novel rs13898676 nearby WSB2 was the most significant genetic locus contributing to 5-ASA's adverse event risk.

Inflammatory Bowel Diseases in Renal Transplantat Recipients: A Case Series and Review of the Literature.

Inflammatory bowel diseases are autoimmune disorders affecting the gastrointestinal tract and producing a wide variety of extraintestinal manifestations. Kidneys are a rare target organ of their extraintestinal activity, but if affected, renal function could deteriorate to end-stage kidney disease, which is curable only by organ transplantation. Renal calculi are the most common pathological kidney manifestation in IBD patients, followed by tubulointerstitial nephritis, glomerulonephritis, and other kidney pathologies. The liver is the most commonly transplanted organ in IBD patients (primary sclerosing cholangitis and autoimmune hepatitis), and a scarcity of literature on kidney recipients is present to date regarding the incidence of renal insufficiency, kidney transplantations, post-transplant IBD course and further complications such as graft rejection or infections in this specific group of patients. De novo IBD is a paradoxical entity in the setting of rigorous post-transplant immunosuppression. In this case series, we present three patients who underwent kidney transplantation with a history of an IBD and one patient who developed de novo Crohn's disease after the deceased donor organ transplant was performed.

Classification and clinical features of adverse drug reactions in patients with ulcerative colitis treated with 5-aminosalicylate acid: a single-center, observational study.

BACKGROUND: 5-Aminosalicylate acid (5-ASA) is a crucial drug for ulcerative colitis (UC) patients. 5-ASA has several side effects. However, the types of side effects vary and are sometimes severe. METHODS: A single-center, retrospective cohort study was conducted from September 2001 to June 2020. We surveyed consecutive UC patients who visited our hospital and investigated adverse drug reactions (ADRs) related to 5-ASA formulations. We grouped patients into four subgroups: (1) lupus-like symptoms, (2) blood test abnormalities, (3) mimicking IBD exacerbation and (4) others. Their clinical courses were evaluated. RESULTS: We surveyed 288 consecutive UC patients, 35 of whom developed ADRs of any grade (12.9%), and analyzed 27 patients. The median age and 5-ASA doses were 43 years and 4000 mg, respectively, and 48% were male. The ADR triggers were the first use of 5-ASA (n = 17, 63%), 5-ASA switch (n = 9, 33%) and 5-ASA dose escalation (n = 1, 3.7%). The median time to ADR was 15 days (IQR: 7, 63). Ten patients (37%) had grade 3/4 ADRs. Fever was the most common ADR (n = 6, 23%), followed by hyperamylasemia and headache (n = 4, 15%). Lupus-like symptoms accounted for 56% (n = 15), blood test abnormalities for 26% (n = 7), mimicking IBD exacerbation for 15% (n = 4) and others for 3.7% (n = 1). The time to ADR was shorter in the mimicking IBD exacerbation group (median 11 days) than in the lupus-like symptoms (22 days) and blood test abnormalities (55 days) groups. CONCLUSION: Classification of ADRs related to 5-ASA into four groups might lead to early recognition of ADRs.

Identification of a new azoreductase driven prodrug from bardoxolone methyl and 5-aminosalicylate for the treatment of colitis in mice.

For local treatment of ulcerative colitis, a new azoreductase driven prodrug CDDO-AZO from bardoxolone methyl (CDDO-Me) and 5-aminosalicylate (5-ASA) was designed, synthesized and biologically evaluated. It is proposed that orally administrated CDDO-AZO is stable before reaching the colon, while it can also be triggered by the presence of azoreductase in the colon to fragment into CDDO-Me and 5-ASA, generating potent anti-colitis effects. Superior to olsalazine (OLS, a clinically used drug for ulcerative colitis) and CDDO-Me plus 5-ASA, CDDO-AZO significantly attenuated inflammatory colitis symptoms in DSS-induced chronic colitis mice, which suggested that CDDO-AZO may be a promising anti-ulcerative colitis agent.

Key Strategies to Optimize Outcomes in Mild-to-Moderate Ulcerative Colitis.

Mesalamine (5-ASA) is the mainstay therapy in patients with mild-to-moderate active ulcerative colitis (UC). However, non-adherence to therapy and practice variability among gastroenterologists represent long-standing barriers, leading to poor outcomes. Additionally, targets to treat in UC are increasingly evolving from focusing on clinical remission to achieving endoscopic and histological healing. To date, systemic steroids are still recommended in non-responders to 5-ASA, despite their well-known side effects. Importantly, with the advent of new therapeutic options such as oral corticosteroids with topical activity (e.g., budesonide multimatrix system (MMX)), biologics, and small molecules, some issues need to be addressed for the optimal management of these patients in daily clinical practice. The specific positioning of these drugs in patients with mild-to-moderate disease remains unclear. This review aims to identify current challenges in clinical practice and to provide physicians with key strategies to optimize treatment of patients with mild-to-moderate UC, and ultimately achieve more ambitious therapeutic goals.

Induction of DNA damage, apoptosis and cell cycle perturbation mediate cytotoxic activity of new 5-aminosalicylate-4-thiazolinone hybrid derivatives.

Modulation of several targets in cancer cells enhances the effect of anti-cancer drugs. This can be achieved by using combinations of anti-cancer drugs or by designing new drugs with novel pharmacophore structures that target different molecules within cancer cells. We developed a panel of such compounds by accommodating two chemical entities (5-Aminoslicylic acid and thiazolin-4-one) known to have anti-cancer activities into a single framework structure. Using a panel of 7 cancer cell lines, two compounds (HH3 and HH13) showed efficient cytotoxic effects on some types of cancer comparable to the standard anti-cancer drug doxorubicin with tumor specificity and minimal effects on normal fibroblasts. Investigating the molecular mechanisms of the two compounds revealed (i) induction of DNA damage, (ii) cell cycle arrest in G2/M phase and (iii) induction of apoptosis as indicated by annexin-V staining and activation of caspases. These effects were more prominent in HH compounds-sensitive cells (with IC50 < 0.5µM) than -resistant or normal cells (with IC50 > 1µM). Moreover, both compounds modulate the expression and activity of several factors in the DNA damage response pathway (γ-H2AX, ATM, ATR, CHK1, CHK2), cyclins/cyclin dependent kinases and CDC25 phosphatase. Altogether, our results show that both HH3 and HH13 compounds are good candidates as anti-cancer drug leads for certain types of cancer and worth further detailed investigations of their safety and effectiveness on animal/xenograft models.

British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

Novel Gene Encoding 5-Aminosalicylate 1,2-Dioxygenase from Comamonas sp. Strain QT12 and Catalytic Properties of the Purified Enzyme.

The 1,125-bp mabB gene encoding 5-aminosalicylate (5ASA) 1,2-dioxygenase, a nonheme iron dioxygenase in the bicupin family that catalyzes the cleavage of the 5ASA aromatic ring to form cis-4-amino-6-carboxy-2-oxohexa-3,5-dienoate in the biodegradation of 3-aminobenzoate, was cloned from Comamonas sp. strain QT12 and characterized. The deduced amino acid sequence of the enzyme has low sequence identity with that of other reported ring-cleaving dioxygenases. MabB was heterologously expressed in Escherichia coli cells and purified as a His-tagged enzyme. The optimum pH and temperature for MabB are 8.0 and 10°C, respectively. FeII is required for the catalytic activity of the purified enzyme. The apparent Km and Vmax values of MabB for 5ASA are 52.0 ± 5.6 µM and 850 ± 33.2 U/mg, respectively. The two oxygen atoms incorporated into the product of the MabB-catalyzed reaction are both from the dioxygen molecule. Both 5ASA and gentisate could be converted by MabB; however, the catalytic efficiency of MabB for 5ASA was much higher (∼70-fold) than that for gentisate. The mabB-disrupted mutant lost the ability to grow on 3-aminobenzoate, and mabB expression was higher when strain QT12 was cultivated in the presence of 3-aminobenzoate. Thus, 5ASA is the physiological substrate of MabB.IMPORTANCE For several decades, 5-aminosalicylate (5ASA) has been advocated as the drug mesalazine to treat human inflammatory bowel disease and considered the key intermediate in the xenobiotic degradation of many aromatic organic pollutants. 5ASA biotransformation research will help us elucidate the microbial degradation of these pollutants. Most studies have reported that gentisate 1,2-dioxygenases (GDOs) can convert 5ASA with significantly high activity; however, the catalytic efficiency of these enzymes for gentisate is much higher than that for 5ASA. This study showed that MabB can convert 5ASA to cis-4-amino-6-carboxy-2-oxohexa-3,5-dienoate, incorporating two oxygen atoms from the dioxygen molecule into the product. Unlike GDOs, MabB uses 5ASA instead of gentisate as the primary substrate. mabB is the first reported 5-aminosalicylate 1,2-dioxygenase gene.

Efficacy of topical 5-aminosalicylate monotherapy in patients with ulcerative proctitis with skip inflammation.

BACKGROUND AND AIM: In some patients with ulcerative proctitis (UP), skip inflammation is noted in the right side of the colon, but little is known about its clinical course. The aim of this study was to evaluate the clinical course of UP with skip inflammation and the efficacy of topical 5-aminosalicylate (5-ASA) monotherapy. METHODS: This study reviewed the data of 388 patients with an initial diagnosis of UP from January 2005 to October 2015. This study matched each UP patient with skip inflammation 1:2 with controls who had UP without skip inflammation; to reduce bias, this study matched the controls with the cases by age, gender, and initial disease activity. RESULTS: During the follow-up period (median: 69.5 months), the overall progression rates for the control group (n = 192) and the skip inflammation group (n = 96) were 24.0% and 32.9% at 10 years, respectively (log-rank P = 0.71). In the skip inflammation group, the progression rates were not significantly different between the 5-ASA combination group and the topical group, 33.4% and 26.6% at 10 years, respectively (log-rank P = 0.96). The overall acute exacerbation rates for the control and skip inflammation groups were 17.2% and 26.8% at 10 years, respectively (log-rank P = 0.68). In the skip inflammation group, the exacerbation rates were also not significantly different between the combination and topical treatment groups, 26.6% and 23.6% at 10 years, respectively (log-rank P = 0.88). CONCLUSION: The clinical course of UP with skip inflammation was not different from that of typical UP, and topical 5-ASA monotherapy for maintaining remission was as effective as 5-ASA combination therapy irrespective of the presence of skip lesions.

Inhibitory Potency of Marketed Drugs for Ulcerative Colitis and Crohn's Disease on PEPT1.

We investigate the inhibitory effect of marketed drugs for treatment of inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) on the uptake transporters of peptide transporter 1 (PEPT1), which are up-regulated under the inflamed condition. The uptake transport of glycylsarcosine, a typical substrate for PEPT1, was reduced to 60% only by 5-aminosalicylate at the clinically relevant concentration among tested marketed drugs in PEPT1 transfected HEK293 cell lines. These findings suggest that the inhibition of PEPT1, which were up-regulated in inflamed or non-inflamed site on UC and CD patients, contribute to the clinical effect of commercially available drugs for IBD patients through the inhibition of uptake of antigenic proinflammatory oligopeptides such as formyl-methionine (Met)-leucine (Leu)-phenylalanine (Phe) via PEPT1.

5-Aminosalicylates to maintain remission in Crohn's disease: Interpreting conflicting systematic review evidence.

5-Aminosalicylates are a class of anti-inflammatory agents that have been used for decades in inflammatory bowel disease. Whilst they are first line for induction and an option for maintenance of remission in ulcerative colitis, the picture in Crohn's disease is variable. For maintenance of remission, key Cochrane systematic reviews have found conflicting results between the medical and surgical induced contexts. In this piece, the possible reasons for this are considered. It is proposed that clinicians should consider 5-aminosalicylates agents an option to maintain remission post-surgery. Future primary research is needed in the medical induced remission setting which considers the length of remission on enrolment and endoscopic or histological disease scores. Additionally, secondary research to rank the various treatment options in the post-surgical setting could be achieved through the use of network meta-analysis and will guide policy makers in the future.

5-Aminosalicylate intolerance causing exacerbation in pediatric ulcerative colitis.

BACKGROUND: 5-Aminosalicylate (5-ASA) is widely used as the first-line drug for ulcerative colitis (UC). 5-ASA is mostly a safe and effective drug, but it can bring about exacerbation due to 5-ASA intolerance. 5-ASA intolerance can be confusing and it can mislead physicians into considering unnecessary treatment escalation, including corticosteroid (CS), biologics, or even surgery. In spite of the clinical importance of 5-ASA intolerance, there have been few studies on its incidence, clinical features, and diagnosis. METHODS: In order to evaluate the incidence, characteristic symptoms, disease course, and laboratory data of children with 5-ASA intolerance, we retrospectively reviewed the medical records of 80 children with UC. RESULTS: Eleven of 80 children (13.8%) with UC were diagnosed with 5-ASA intolerance. The median time between the initiation of 5-ASA and the onset of 5-ASA intolerance was 10 days (range, 4-20 days) in patients not receiving CS. Drug-induced lymphocyte stimulation test (DLST) was performed in 10 patients, and was positive in eight. C-reactive protein (CRP) increased significantly when exacerbation of colitis symptoms occurred. CONCLUSIONS: The incidence of 5-ASA intolerance was relatively high. Besides the challenge test, elevation of CRP and positive DLST appeared to support the diagnosis of 5-ASA intolerance.

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy.

BACKGROUND & AIMS: The management of inflammatory bowel disease (IBD) poses a particular challenge during pregnancy because the health of both the mother and the fetus must be considered. METHODS: A systematic literature search identified studies on the management of IBD during pregnancy. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. RESULTS: Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti-tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohn's disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy. CONCLUSIONS: Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes.

Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus.

BACKGROUND & AIMS: The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS: A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS: The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS: Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.

Pharmacological intervention based on fecal calprotectin levels in patients with ulcerative colitis at high risk of a relapse: A prospective, randomized, controlled study.

BACKGROUND: Targeted therapy, using biomarkers to assess disease activity in ulcerative colitis (UC), has been proposed. OBJECTIVE: The objective of this study was to evaluate whether pharmacological intervention guided by fecal calprotectin (FC) prolongs remission in patients with UC. METHODS: A total of 91 adults with UC in remission were randomized to an intervention group or a control group. Analysis of FC was performed monthly, during 18 months. A FC value of 300 µg/g was set as the cut-off for intervention, which was a dose escalation of the oral 5-aminosalicylate (5-ASA) agent. The primary study end-point was the number of patients to have relapsed by month 18. RESULTS: There were relapses in 18 (35.3%) and 20 (50.0%) patients in the intervention and the control groups, respectively (p = 0.23); and 28 (54.9%) patients in the intervention group and 28 (70.0%) patients in the control group had a FC > 300 µg/g, of which 8 (28.6%) and 16 (57.1%) relapsed, respectively (p < 0.05). CONCLUSION: Active intervention significantly reduced relapse rates, although no significant difference was reached between the groups overall. Thus, FC-levels might be used to identify patients with UC at risk for a flare, and a dose escalation of their 5-ASA agent is a therapeutic option for these patients.

Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis.

BACKGROUND & AIMS: Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. METHODS: We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 µg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC <50 µg/g. Secondary outcomes were continued remission with FC <100 µg/g or <200 µg/g (among patients with pre-randomization values above these levels). RESULTS: The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P = .0496). More patients in the dose escalation group reduced FC to below 100 µg/g (P = .04) and 200 µg/g (P = .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 µg/g compared with those with FC <200 µg/g (P = .01). CONCLUSIONS: Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145.

Polymorphism p.Val231Ile alters substrate selectivity of drug-metabolizing arylamine N-acetyltransferase 2 (NAT2) isoenzyme of rhesus macaque and human.

Arylamine N-acetyltransferases (NATs) are polymorphic enzymes mediating the biotransformation of arylamine/arylhydrazine xenobiotics, including pharmaceuticals and environmental carcinogens. The NAT1 and NAT2 genes, and their many polymorphic variants, have been thoroughly studied in humans by pharmacogeneticists and cancer epidemiologists. However, little is known about the function of NAT homologues in other primate species, including disease models. Here, we perform a comparative functional investigation of the NAT2 homologues of the rhesus macaque and human. We further dissect the functional impact of a previously described rhesus NAT2 gene polymorphism, causing substitution of valine by isoleucine at amino acid position 231. Gene constructs of rhesus and human NAT2, bearing or lacking non-synonymous polymorphism c.691G>A (p.Val231Ile), were expressed in Escherichia coli for comparative enzymatic analysis against various NAT1- and NAT2-selective substrates. The results suggest that the p.Val231Ile polymorphism does not compromise the stability or overall enzymatic activity of NAT2. However, substitution of Val231 by the bulkier isoleucine appears to alter enzyme substrate selectivity by decreasing the affinity towards NAT2 substrates and increasing the affinity towards NAT1 substrates. The experimental observations are supported by in silico modelling localizing polymorphic residue 231 close to amino acid loop 125-129, which forms part of the substrate binding pocket wall and determines the substrate binding preferences of the NAT isoenzymes. The p.Val231Ile polymorphism is the first natural polymorphism demonstrated to affect NAT substrate selectivity via this particular mechanism. The study is also the first to thoroughly characterize the properties of a polymorphic NAT isoenzyme in a non-human primate model.

Peripheral T-cell lymphoma mimicking 5-aminosalicylate hypersensitivity in ulcerative colitis.

5-aminosalicylates (5-ASA) remain an important strategy in the induction and maintenance of remission of inflammatory bowel diseases especially in ulcerative colitis. The prototypical drug of this class, sulfasalazine is generally well tolerated with severe hypersensitivity reactions and hepatotoxicity also described within the literature. When approaching a patient with an adverse reaction to 5-ASA, it can be difficult to differentiate clinically between a sulfa allergy versus a 5-ASA allergy versus a malignancy. We report on a case with initial signs and symptoms suggestive of a sulfa/5-ASA allergy that was subsequently found to be malignant in nature.