Bile Acid Sequestrants in Microscopic Colitis: Clinical Outcomes and Utility of Bile Acid Testing.

BACKGROUND & AIMS: Bile acid sequestrants (BAS) may be a treatment in microscopic colitis (MC), but efficacy data are limited. We evaluated the effectiveness of BAS in MC and assessed the utility of bile acid testing to predict response. METHODS: Adults with MC treated with BAS (2010-2020) at Mayo Clinic were identified. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing using previously validated cutoffs. Response was defined at 12 ± 4 weeks after BAS initiation as: complete (resolution of diarrhea), partial (≥50% improvement in diarrhea), nonresponse (<50% improvement), and intolerance (discontinuation due to side effects). Logistic regression was used to identify predictors of response to BAS. RESULTS: We identified 282 patients (median age, 59 years [range, 20-87 years]; 88.3% women) with median follow-up of 4.5 years (range, 0.4-9.1 years). Patients were treated with the following BAS: 64.9% cholestyramine, 21.6% colesevelam, and 13.5% colestipol. Clinical outcomes were: 49.3% complete response, 16.3% partial response, 24.8% nonresponse, and 9.6% intolerance. There were no differences in outcomes between those on BAS alone or BAS combined with other medications (P = .98). The dose of BAS was not associated with response (P = .51). Bile acid testing was done in 31.9% of patients, and 56.7% were positive. No predictors of response to BAS were identified. After BAS discontinuation, 41.6% had recurrence at a median of 21 weeks (range, 1-172 weeks). CONCLUSION: In one of the largest cohorts evaluating BAS treatment in MC, nearly two-thirds had a partial or complete response. Additional research is needed to determine the role of BAS and bile acid malabsorption in MC.

Prevalence of biliary acid malabsorption in patients with chronic diarrhoea of functional characteristics: a prospective study.

BACKGROUND: Bile acid malabsorption occurs in up to one third of patients with chronic diarrhoea of functional characteristics. The gold standard test for its diagnosis is the 75Selenium homocholic acid taurine (75SeHCAT) test. The aim of this work is to confirm previous data suggesting that bile acid malabsorption, diagnosed by 75Se-HCAT test, is the underlying cause of diarrhoea in a significant proportion of patients previously diagnosed with a functional disorder. In addition, we have analysed the clinical response of bile acid sequestrants in those patients with a bile acid diarrhoea diagnosis. METHODS: This is a prospective, single-centre study including consecutive adult patients diagnosed with chronic diarrhoea of unknown origin and with functional characteristics; systematic rule out of common causes of chronic diarrhoea was performed before bile acid malabsorption evaluation by 75SeHCAT scanning. A retention percentage less than 10% was considered positive. Clinical response to cholestyramine was further evaluated in those patients with a positive diagnosis of bile acid diarrhoea RESULTS: 38 patients (20 male, mean age 37.5 years) were finally included. Twenty (52.6%) patients included had a positive 75SeHCAT test. Median body mass index was significantly higher in those patients. We did not find significant differences in other clinical or biochemical variables 75SeHCAT-positive and 75SeHCAT-negative groups. Only 6 of 17 (35.3%) patients responded to cholestyramine treatment; 10 patients did not have response or withdraw the drug due to adverse events. Logistic regression analysis showed that none of the included variables was a predictor of clinical response to cholestyramine. CONCLUSIONS: Bile acid malabsorption occurs in a high proportion of patients suffering from chronic diarrhoea with functional characteristics. Systematic investigation of bile acid malabsorption should be included in the diagnostic algorithms of patients with chronic watery diarrhoea in the routine clinical practice. Absence of response to cholestyramine does not rule out bile acid diarrhoea.

Acute teriflunomide overdose with relatively mild symptoms: A case report.

WHAT IS KNOW AND OBJECTIVE: Teriflunomide is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis. CASE SUMMARY: We present a rare intoxication with a high dose (672 mg) of teriflunomide. According to its product label, the only known treatment is the administration of colestyramine and activated carbon (charcoal). No serious adverse events occurred during the time the patient was admitted (<24 h). No long-term overdose-related symptoms or complaints were reported. WHAT IS NEW AND CONCLUSION: The fact that after the acute overdose both adverse events and laboratory parameters were acceptable, prescribing colestyramine and activated carbon, as well as monitoring of laboratory parameters such as full blood count, liver and kidney values and QTc, seems sufficient during the early stage (<24 h after intake) of teriflunomide overdose.

The Role of Bile Acids in Chronic Diarrhea.

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.

Adjusting for adherence in randomized trials when adherence is measured as a continuous variable: An application to the Lipid Research Clinics Coronary Primary Prevention Trial.

BACKGROUND: Clinicians and patients may be more interested in per-protocol effect estimates than intention-to-treat effect estimates from randomized trials. However, per-protocol effect estimates may be biased due to insufficient adjustment for prognostic factors that predict adherence. Adjustment for this bias is possible when appropriate methods, such as inverse probability weighting, are used. But, when adherence is measured as a continuous variable, constructing these weights can be challenging. METHODS: In the placebo arm of the Lipid Research Clinics Coronary Primary Prevention Trial, we estimated the 7-year cumulative incidence of coronary heart disease under 100% adherence and 0% adherence to placebo. We used dose-response discrete-hazards models with inverse probability weighting to adjust for pre- and post-randomization covariates. We considered several continuous distributions for constructing the inverse probability weights. RESULTS: The risk difference estimate for 100% adherence compared with 0% adherence ranged from -7.7 to -6.1 percentage points without adjustment for baseline and post-baseline covariates, and ranged from -1.8 to 2.2 percentage points with adjustment using inverse probability weights, depending on the dose-response model and inverse probability weight distribution used. CONCLUSIONS: Methods which appropriately adjust for time-varying post-randomization variables can explain away much of the bias in the "effect" of adherence to placebo. When considering continuous adherence, investigators should consider several models as estimates may be sensitive to the model chosen.

Pharmacological interventions for treating intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013. OBJECTIVES: To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy. DATA COLLECTION AND ANALYSIS: The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy. AUTHORS' CONCLUSIONS: When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).

Current and innovative emerging therapies for porphyrias with hepatic involvement.

Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.

Clinical evaluation and treatment of chronic bowel symptoms following cancer in the colon and pelvic organs.

Background: Chronic gastrointestinal symptoms are common among patients surviving surgery and/or radio-/chemotherapy for cancer in the pelvic organs. However, little is known about the pathophysiology behind symptoms or the effect of treatment. The aim of the present study was to present the results of clinical evaluation and treatment of patients with chronic bowel symptoms after treatment for cancer in the colon or pelvic organs. Material and methods: All patients referred to our department of gastroenterology between May 2016 and June 2018 with chronic bowel symptoms after treatment for cancer in the colon or pelvic organs were prospectively evaluated. Results: In total, 60 patients had been referred. The patients were treated for cancer in the right colon (n = 31), sigmoid colon (n = 1), rectum (n = 14), anal canal (n = 4), cervix uteri (n = 5), corpus uteri (n = 2), ovary (n = 2), and prostate (n = 1). The median time from cancer treatment to referral was 5.5 (range 1-36) years. Symptoms mainly included frequent bowel movements (65%), loose stools (87%), urgency for defecation (57%), and fecal incontinence (50%). A specific cause of bowel dysfunction was found in 48 (80%) of the patients and 21 (35%) had more than one cause of bowel symptoms. Bile acid malabsorption was present in 35 patients and small intestinal bacterial overgrowth was detected in 32. Treatment included bile acid sequestrants (n = 36), antibiotics (n = 33), loperamide (n = 21), and dietary intervention (n = 20). Major improvement in bowel symptoms was reported by 23 (38%) patients, while another 27 (45%) reported some improvement. Conclusion: Most patients with chronic bowel symptoms following cancer in the colon or pelvic organs will benefit from expert clinical evaluation and targeted treatment.

INTRAVENOUS LIPID EMULSION TREATMENT REDUCES SYMPTOMS OF BREVETOXICOSIS IN TURTLES (TRACHEMYS SCRIPTA).

Harmful algal blooms (HABs) occur when excess nutrients allow dinoflagellates to reproduce in large numbers. Marine animals are affected by blooms when algal toxins are ingested or inhaled. In the Gulf of Mexico, near annual blooms of Karenia brevis release a suite of compounds (brevetoxins) that cause sea turtle morbidity and mortality. The primary treatment at rehabilitation facilities for brevetoxin-exposed sea turtles is supportive care, and it has been difficult to design alternative treatment strategies without an understanding of the effects of brevetoxins in turtles in vivo. Previous studies using the freshwater turtle as a model species showed that brevetoxin-3 impacts the nervous and muscular systems, and is detoxified and eliminated primarily through the liver, bile, and feces. In this study, freshwater turtles (Trachemys scripta) were exposed to brevetoxin (PbTx-3) intratracheally at doses causing clear systemic effects, and treatment strategies aimed at reducing the postexposure neurological and muscular deficits were tested. Brevetoxin-exposed T. scripta displayed the same behaviors as animals admitted to rehabilitation centers for toxin exposure, ranging from muscle twitching and incoordination to paralysis and unresponsiveness. Two treatment regimes were tested: cholestyramine, a bile acid sequestrant; and an intravenous lipid emulsion treatment (Intralipidt) that provides an expanded circulating lipid volume. Cholestyramine was administered orally 1 hr and 6 hr post PbTx-3 exposure, but this regime failed to increase toxin clearance. Animals treated with Intralipid (100 mg/kg) 30 min after PbTx-3 exposure had greatly reduced symptoms of brevetoxicosis within the first 2 hr compared with animals that did not receive the treatment, and appeared fully recovered within 24 hr compared with toxin-exposed control animals that did not receive Intralipid. The results strongly suggest that Intralipid treatment for lipophilic toxins such as PbTx-3 has the potential to reduce morbidity and mortality in HAB-exposed sea turtles.

Lipid-Lowering Agents and High HDL (High-Density Lipoprotein) Are Inversely Associated With Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. METHODS: The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women's Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. RESULTS: Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47-0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93-0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23-0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure-response curve between HDL levels and risk of aneurysmal rupture was obtained. CONCLUSIONS: Higher HDL values and the use of lipid-lowering agents are significantly inversely associated with ruptured intracranial aneurysms.

Diagnosis and Management of Microscopic Colitis.

Microscopic colitis (MC) is a relatively common cause of chronic watery diarrhea, especially in older persons. Associated symptoms, including abdominal pain and arthralgias, are common. The diagnosis is based upon characteristic histological findings in the presence of diarrhea. The two types of MC, collagenous and lymphocytic colitis, share similar clinical features, with the main difference being the presence or absence of a thickened subepithelial collagen band. There are several treatment options for patients with MC, although only budesonide has been well studied in multiple controlled clinical trials. This review will describe the clinical features, epidemiology, pathophysiology, diagnostic criteria, and treatment of patients with MC.

Interventions for treating lymphocytic colitis.

BACKGROUND: Lymphocytic colitis is a cause of chronic diarrhea. It is a subtype of microscopic colitis characterized by chronic, watery, non-bloody diarrhea and normal endoscopic and radiologic findings. The etiology of this disorder is unknown.Therapy is based mainly on case series and uncontrolled trials, or by extrapolation of data for treating collagenous colitis, a related disorder. This review is an update of a previously published Cochrane review. OBJECTIVES: To evaluate the efficacy and safety of treatments for clinically active lymphocytic colitis. SEARCH METHODS: The MEDLINE, PUBMED and EMBASE databases were searched from inception to 11 August 2016 to identify relevant papers. Manual searches from the references of included studies and relevant review articles were performed.Abstracts from major gastroenterological meetings were also searched to identify research submitted in abstract form only. The trial registry web site www.ClinicalTrials.gov was searched to identify registered but unpublished trials. Finally, the Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies. SELECTION CRITERIA: Randomized controlled trials assessing medical therapy for patients with biopsy-proven lymphocytic colitis were considered for inclusion DATA COLLECTION AND ANALYSIS: Data was independently extracted by at least two authors. Any disagreements were resolved by consensus. Data were analyzed on an intention-to-treat (ITT) basis. The primary outcome was clinical response as defined by the included studies. Secondary outcome measures included histological response as defined by the included studies, quality of life as measured by a validated instrument and the occurrence of adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. Data were combined for analysis if they assessed the same treatments. Dichotomous data were combined using a pooled RR along with corresponding 95% CI. A fixed-effect model was used for the pooled analysis. MAIN RESULTS: Five RCTs (149 participants) met the inclusion criteria. These studies assessed bismuth subsalicylate versus placebo, budesonide versus placebo, mesalazine versus mesalazine plus cholestyramine and beclometasone dipropionate versus mesalazine. The study which assessed mesalazine versus mesalazine plus cholestyramine and the study which assessed beclometasone dipropionate versus mesalazine were judged to be at high risk of bias due to lack of blinding. The study which compared bismuth subsalicylate versus us placebo was judged as low quality due to a very small sample size and limited data. The other 3 studies were judged to be at low risk of bias. Budesonide (9 mg/day for 6 to 8 weeks) was significantly more effective than placebo for induction of clinical and histological response. Clinical response was noted in 88% of budesonide patients compared to 38% of placebo patients (2 studies; 57 participants; RR 2.03, 95% CI 1.25 to 3.33; GRADE = low). Histological response was noted in 78% of budesonide patients compared to 33% of placebo patients (2 studies; 39 patients; RR 2.44, 95% CI 1.13 to 5.28; GRADE = low). Forty-one patients were enrolled in the study assessing mesalazine (2.4 g/day) versus mesalazine plus cholestyramine (4 g/day). Clinical response was noted in 85% of patients in the mesalazine group compared to 86% of patients in the mesalazine plus cholestyramine group (RR 0.99, 95% CI 0.77 to 1.28; GRADE = low). Five patients were enrolled in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks versus placebo). There were no differences in clinical (P=0.10) or histological responses (P=0.71) in patients treated with bismuth subsalicylate compared with placebo (GRADE = very low). Forty-six patients were enrolled in the trial studying beclometasone dipropionate (5 mg/day or 10 mg/day) versus mesalazine (2.4 g/day). There were no differences in clinical remission at 8 weeks (RR 0.97; 95% CI 0.75 to 1.24; GRADE = low) and 12 months of treatment (RR 1.29; 95% CI 0.40 to 4.18; GRADE = very low). Although patients receiving beclometasone dipropionate (84%) and mesalazine (86%) achieved clinical remission at 8 weeks, it was not maintained at 12 months (26% and 20%, respectively). Adverse events reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, hyperhidrosis and headache. Nausea and skin rash were reported as adverse events in the mesalazine study. Adverse events in the beclometasone dipropionate trial include nausea, sleepiness and change of mood. No adverse events were reported in the bismuth subsalicylate study. AUTHORS' CONCLUSIONS: Low quality evidence suggests that budesonide may be effective for the treatment of active lymphocytic colitis. This benefit needs to be confirmed by a large placebo -controlled trial. Low quality evidence also suggests that mesalazine with or without cholestyramine and beclometasone dipropionate may be effective for the treatment of lymphocytic colitis, however this needs to be confirmed by large placebo-controlled studies. No conclusions can be made regarding bismuth subsalicylate due to the very small number of patients in the study, Further trials studying interventions for lymphocytic colitis are warranted.

Interventions for treating collagenous colitis.

BACKGROUND: Collagenous colitis is a cause of chronic diarrhea. This updated review was performed to identify therapies for collagenous colitis that have been assessed in randomized controlled trials (RCTs). OBJECTIVES: The primary objective was to assess the benefits and harms of treatments for collagenous colitis. SEARCH METHODS: We searched CENTRAL, the Cochrane IBD Group Specialized Register, MEDLINE and EMBASE from inception to 7 November 2016. SELECTION CRITERIA: We included RCTs comparing a therapy with placebo or active comparator for the treatment of active or quiescent collagenous colitis. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two authors. The primary outcome was clinical response or maintenance of response as defined by the included studies. Secondary outcome measures included histological response, quality of life and the occurrence of adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The Cochrane risk of bias tool was used to assess bias. The overall quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: Twelve RCTs (476 participants) were included. These studies assessed bismuth subsalicylate, Boswellia serrata extract, mesalamine, cholestyramine, probiotics, prednisolone and budesonide therapy. Four studies were low risk of bias. One study assessing mesalamine and cholestyramine was judged to be high risk of bias due to no blinding. The other studies had an unclear risk of bias for random sequence generation (five studies) allocation concealment (six studies), blinding (one study), incomplete outcome data (one study) and selective outcome reporting (one study). Clinical response occurred in 100% (4/4) of patients who received bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks) compared to 0% (0/5) of patients who received placebo (1 study; 9 participants; RR 10.80, 95% CI 0.75 to 155.93; GRADE = very low). Clinical response occurred in 44% (7/16) of patients who received Boswellia serrata extract (three 400 mg/day capsules for 8 weeks) compared to 27% (4/15) of patients who received placebo (1 study; 31 participants; RR 1.64, 95% CI 0.60 to 4.49; GRADE = low). Clinical response occurred in 80% (24/30) of budesonide patients compared to 44% (11/25) of mesalamine patients (1 study; 55 participants; RR 1.82, 95% CI 1.13 to 2.93; GRADE = low). Histological response was observed in 87% (26/30) of budesonide patients compared to 44% (11/25) of mesalamine patients (1 study, 55 participants; RR 1.97, 95% CI 1.24 to 3.13; GRADE = low). There was no difference between the two treatments with respect to adverse events (RR 0.69, 95% CI 0.43 to 1.10; GRADE = low), withdrawals due to adverse events (RR 0.09, 95% CI 0.01 to 1.65; GRADE = low) and serious adverse events (RR 0.12, 95% CI 0.01 to 2.21; GRADE = low). Clinical response occurred in 44% (11/25) of mesalamine patients (3 g/day) compared to 59% (22/37) of placebo patients (1 study; 62 participants; RR 0.74, 95% CI 0.44 to 1.24; GRADE = low). Histological response was observed in 44% (11/25) and 51% (19/37) of patients receiving mesalamine and placebo, respectively (1 study; 62 participants; RR 0.86, 95% CI 0.50 to 1.47; GRADE = low). There was no difference between the two treatments with respect to adverse events (RR 1.26, 95% CI 0.84 to 1.88; GRADE = low), withdrawals due to adverse events (RR 5.92, 95% CI 0.70 to 49.90; GRADE = low) and serious adverse events (RR 4.44, 95% CI 0.49 to 40.29; GRADE = low). Clinical response occurred in 63% (5/8) of prednisolone (50 mg/day for 2 weeks) patients compared to 0% (0/3) of placebo patients (1 study, 11 participants; RR 4.89, 95% CI 0.35 to 68.83; GRADE = very low). Clinical response occurred in 29% (6/21) of patients who received probiotics (2 capsules containing 0.5 x 1010 CFU each of L. acidophilus LA-5 and B. animalis subsp. lactis strain BB-12 twice daily for 12 weeks) compared to 13% (1/8) of placebo patients (1 study, 29 participants, RR 2.29, 95% CI 0.32 to 16.13; GRADE = very low). Clinical response occurred in 73% (8/11) of patients who received mesalamine (800 mg three times daily) compared to 100% (12/12) of patients who received mesalamine + cholestyramine (4 g daily) (1 study, 23 participants; RR 0.74, 95% CI 0.50 to 1.08; GRADE = very low). Clinical response occurred in 81% (38/47) of patients who received budesonide (9 mg daily in a tapering schedule for 6 to 8 weeks) compared to 17% (8/47) of placebo patients (3 studies; 94 participants; RR 4.56, 95% CI 2.43 to 8.55; GRADE = low). Histological response was higher in budesonide participants (72%, 34/47) compared to placebo (17%, 8/47) (RR 4.15, 95% CI 2.25 to 7.66; GRADE = low). Clinical response was maintained in 68% (57/84) of budesonide patients compared to 20% (18/88) of placebo patients (3 studies, 172 participants, RR 3.30 95% CI 2.13 to 5.09; GRADE = low). Histological response was maintained in 48% (19/40) of budesonide patients compared to 15% (6/40) of placebo patients (2 studies; 80 participants; RR 3.17, 95% CI 1.44 to 6.95; GRADE = very low). No difference was found between budesonide and placebo for adverse events (5 studies; 290 participants; RR 1.18, o95% CI 0.92 to 1.51; GRADE = low), withdrawals due to adverse events (5 studies, 290 participants; RR 0.97, 95% CI 0.43 to 2.17; GRADE = very low) or serious adverse events (4 studies, 175 participants; RR 1.11, 95% CI 0.15 to 8.01; GRADE = very low). Adverse effects reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, excessive sweating and headache. Adverse effects reported in the mesalamine studies included nausea and skin rash. Adverse effects in the prednisolone study included abdominal pain, headache, sleep disturbance, mood change and weight gain. AUTHORS' CONCLUSIONS: Low quality evidence suggests that budesonide may be effective for inducing and maintaining clinical and histological response in patients with collagenous colitis. We are uncertain about the benefits and harms of therapy with bismuth subsalicylate, Boswellia serrata extract, mesalamine with or without cholestramine, prednisolone and probiotics. These agents and other therapies require further study.

Use of a Cholestyramine Washout in a Patient With Septic Shock on Leflunomide Therapy: A Case Report and Review of the Literature.

Patients presenting with infections while receiving disease-modifying antirheumatic agents (DMARD) may be predisposed to a higher degree illness due to immunosuppression. This can be particularly problematic in patients who are receiving DMARDs with prolonged pharmacokinetic profiles. Leflunomide is a DMARD that has a prolonged half-life due to enterohepatic recirculation. We report a case of a patient with severe septic shock secondary to a prosthetic joint infection in which therapeutic levels of leflunomide were discovered, despite the patient ceasing therapy several weeks prior to admission. An orogastric cholestyramine washout was given to the patient to expedite the removal of the drug. Serum levels rapidly declined over the next several days, corresponding with resolution of her sepsis. A review of the literature relevant to the incidence of DMARD-related infections was conducted as well as discussion regarding the role of leflunomide drug monitoring and cholestyramine-facilitated removal of the drug in episodes of acute infectious syndromes.

Effect of anti-hyperlipidemia drugs on the alpha-tocopherol concentration and their potential for murine malaria infection.

The current preventions of malaria are protection against mosquito bites and taking chemoprophylactic anti-malarial drugs. However, drug therapies are usually associated with adverse events and emergency of drug-resistant malaria parasites. Previous study showed that host plasma alpha-tocopherol deficiency enhanced resistance against malaria infection in mice. Here, we report a new prevention strategy against malaria by using anti-hyperlipidemia drugs, ezetimibe, berberine, cholestyramine, and probucol to modify the host plasma alpha-tocopherol concentration. The drugs were mixed with diet and fed to C57BL/6J mice for 2 weeks. Although all drugs reduced plasma alpha-tocopherol concentration after 2 weeks of feeding, probucol-treated mice showed 90 % reduction and it was the lowest alpha-tocopherol concentration among the four drugs. Ezetimibe, berberine, and combination of ezetimibe and berberine pretreatment for 2 weeks were not effective against infection of Plasmodium yoelii XL17, a lethal strain, for survival and parasitemia in mice. Two-week pretreatment and 1-week treatment after infection of cholestyramine had also no effect on malaria infection. Survival rates of cholestyramine, ezetimibe, and/or berberine treated mice were 0-22 %. However, probucol caused significant decrease in parasitemia and increased in mice survival following 2-week pretreatment and 1-week treatment after infection. All control mice died while all probucol treated mice survived during the course of infection. Thus, probucol which reduced plasma alpha-tocopherol concentration was effective in enhancing the host to resist malaria infection in mice. Our finding indicates that plasma alpha-tocopherol reducing drugs like probucol might be a candidate for beneficial prevention strategy for travelers from malaria-free area.

Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy.

Although recognised as a cause of chronic diarrhoea for over forty years, diagnostic tests and treatments for bile acid malabsorption (BAM) remain controversial. Recent National Institute for Health and Care Excellence (NICE) guidelines highlighted the lack of evidence in the field, and called for further research. This retrospective study explores the BAM subtype and severity, the use and response to bile acid sequestrants (BAS) and the prevalence of abnormal colonic histology. 264 selenium-75-labelled homocholic acid conjugated taurine (SeHCAT)-tested patient records were reviewed and the severity and subtype of BAM, presence of colonic histopathology and response to BAS were recorded. 53% of patients tested had BAM, with type-2 BAM in 45% of patients with presumed irritable bowel syndrome. Colonic histological abnormalities were similar overall between patients with (29%) or without (23%) BAM (p = 0.46) and between BAM subtypes, with no significant presence of inflammatory changes. 63% of patients with BAM had a successful BAS response which showed a trend to decreased response with reduced severity. Colestyramine was unsuccessful in 44% (38/87) and 45% of these (17/38) were related to medication intolerance, despite a positive SeHCAT. 47% (7/15) of colestyramine failures had a successful colesevelam response. No patient reported colesevelam intolerance. Quantifying severity of BAM appears to be useful in predicting BAS response. Colesevelam was better tolerated than colestyramine and showed some efficacy in colestyramine failures. Colestyramine failure should not be used to exclude BAM. Colonic histology is of no relevance.

Treatments of faecal incontinence: recommendations from the French national society of coloproctology.

Faecal incontinence is common and significantly affects quality of life. Its treatment involves dietary manipulation, medical treatments, perineal rehabilitation or surgery. In this paper, the French National Society of Coloproctology offers recommendations based on the data in the current literature, including those on recently developed treatments. There is a lack of high quality data and most of the recommendations are therefore based either on grade of recommendation B or expert recommendation (Level 4). However, the literature supports the construction of an algorithm based on the available scientific evidence and expert recommendation which may be useful in clinical practice. The French National Society of Coloproctology proposes a decision-making algorithm that includes recent developments of treatment. The current recommendations support sacral nerve modulation as the key treatment for faecal incontinence. They do not support the use of sphincter substitutions except in certain circumstances. Transanal irrigation is a novel often successful treatment of faecal incontinence due to neurological disorders.

Persistent diarrhea: 15 years experience at a tertiary care hospital.

OBJECTIVE: To determine the risk factors, causative enteric pathogens, final diagnosis and treatment outcomes of persistent diarrhea in children. MATERIAL AND METHOD: A retrospective study of the patients who had diarrheal symptoms for at least 14 days diagnosed as persistent diarrhea (PD) and admitted at QSNICH during January 1997 and December 2011. Demographic data, risk factors, causative enteric pathogens, management and outcome were reviewed. RESULTS: The review included 79 PD patients. Excluded were patients who were HIV seropositive, had GI anomalies and/or other underlying immune deficiencies. The demographic data showed mean age 11.42 months and male:female 56:23 (2.43:1). Feeding with infant formula before admission was 43% compared to exclusive breastfeeding that was only 10%. Normal nutritional status was found in half of the cases (52.1%) and protein energy malnutrition (PEM) was present in 42.3%. Stool for enteropathogens was positive only in 49.4% and the most common being mixed enteropathogens. Secondary lactase deficiency was the cause of PD in half (50%) of the patients. Management consisted of rehydration, intravenous antibiotics 53%, and other adjuvant therapies such as cholestyramine, zinc and probiotics. Along with rehydration, all patients received aggressive nutritional management upon admission. The diarrhea subsided in less than 7 days in about 70% of the patients. CONCLUSION: The present study supports that important risk factors for PD are very young age group (especially under 1 year old), lack of breastfeeding and malnutrition. Enteropathogens were found in only about half of the patients and the most common cause of PD was secondary lactase deficiency. Most of the diarrhea subsided in less than 7 days of admission with proper management and aggressive nutrition upon admission.

[Drugs and diarrhea]. / Arzneistoffe und Diarrhoe.

Drug induced diarrhea is a frequent adverse event. The pathophysiological mechanisms include intraluminal accumulation of osmotically active substances, increased secretion or impaired resorption of gastrointestinal fluids, stimulation of gastrointestinal motility, or inflammation of gastrointestinal mucosa. For many drugs, however, the causative mechanism is unknown. A careful drug history, including non-prescription drugs and additives that frequently cause diarrhea, is essential for the identification of potential causative substances. The clinical course of drug-induced diarrhea in many cases is mild and self-limited. In severe cases fluid-and electrolyte substitution, symptomatic and in certain cases specific therapy can be necessary. Symptomatic treatment primarily includes opioids and intraluminal adsorbents. In special cases octreotide or scopolamine can be used.

Progressive familial intrahepatic cholestasis type 4: a case report.

BACKGROUND: Progressive familial intrahepatic cholestasis is an autosomal recessive genetic disorder that manifests primarily with jaundice and pruritus and can progresses from persistent cholestasis to cirrhosis and late childhood liver failure. Classically, progressive familial intrahepatic cholestasis is classified into three subtypes: 1, 2, and 3 and results from a defect in a biliary protein responsible for bile formation and circulation in the liver. In the last decade and with the increased use of genetic testing, more types have been known. CASE PRESENTATION: A 6-month-old Afrocentric boy presented with progressive jaundice and pruritus that started since the age of 2 months. He was thoroughly investigated to be finally diagnosed as progressive familial intrahepatic cholestasis type 4. A low-fat diet, ursodeoxycholic acid, fat-soluble vitamins, and cholestyramine were started. He showed initial improvement then had refractory pruritus and impaired quality of life. He underwent surgical biliary diversion at the age of 1 year with marked improvement of manifestations. CONCLUSION: Owing to the increased technology of genetic testing, more clinical subtypes of progressive familial intrahepatic cholestasis were diagnosed other than the classical three types. Surgical management using biliary diversion could be beneficial and delays or may even obviate the need for liver transplantation.