Search

Cheng T Tee1,2 Katharina Wallis1,3 Simon M Gabe1,41Lennard-Jones Intestinal Failure Unit, St Mark's Hospital and Academic Institute, Harrow, UK; 2Antigen Presentation Research Group, Imperial College London, Northwick Park and St Mark's Campus, Harrow, UK; 3West Hertfordshire Hospitals NHS Trust, Watford, UK; 4Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Imperial College Healthcare, London, UKIntroduction: Current medical management of short bowel syndrome (SBS) involves the use of lifelong parenteral nutrition (PN). Glucagon-like peptide-2 (GLP-2), an important intestinotrophic growth factor has been shown to increase intestinal absorption in SBS through augmentation of post-resection intestinal adaptation. This may lead to the reduction of PN dependence in patients with SBS.Areas covered in review: Advancing research of GLP-2 physiology has spurred the growing understanding of the diverse effects of GLP-2. The development of the degradation resistant GLP-2 analog, teduglutide (GattexTM, NPS Pharmaceuticals, Bedminster, NJ), has allowed its exploration as a therapeutic agent in a variety of clinical settings. Recent multicenter, placebo-controlled studies of GLP-2 in SBS patients demonstrate meaningful reductions in PN requirements with good safety profiles. The reparative and immunomodulatory effects of teduglutide may also be beneficial in patients with inflammatory bowel disease (IBD). Safety concerns about possible carcinogenic properties during long-term use require ongoing evaluation.Summary: GLP-2 appears to offer a novel adjuvant treatment modality for SBS. Promise for its use in other clinical settings like IBD has been shown in small pilot studies.Keywords: glucagon-like peptide-2, intestinal failure, intestinal adaptation, parenteral nutrition

Background & Aims: Clinical studies showed teduglutide to increase urine production and reduce need for parenteral support volume in patients with short bowel syndrome (SBS) with intestinal failure, increasing intestinal wet weight absorption and reducing diarrhea. However, the effects of teduglutide on parenteral support vary among patients. We performed a post hoc analysis of a phase III placebo-controlled study to identify characteristics of patients in whom teduglutide has the largest effects on parenteral support volume response., Methods: We collected data from 85 patients with SBS with intestinal failure, according to the European Society for Clinical Nutrition and Metabolism classification system, who received teduglutide or placebo between November 25, 2008, and January 4, 2011, at 27 sites in 10 countries. Changes in parenteral support volume were evaluated according to baseline parenteral support volume, bowel anatomy (group 1, jejunostomy/ileostomy; group 2, ≥50% colon-in-continuity without stoma; and group 3, other colon anatomies), and disease features (with inflammatory bowel disease, mesenteric vascular diseases, or other conditions). Correlation analyses were conducted using simple linear regression models, with unadjusted r 2 values reported. Two-sided t tests were used for comparisons between treatment groups., Results: We correlated parenteral support volume reduction with teduglutide treatment and baseline parenteral support volume (y = -0.3870x + 90.0279, r 2  = 0.61; P < .0001). The effects of teduglutide on absolute parenteral support volume were significantly greater in group 1 patients (reduction of 919 ± 644 mL/d), not only compared with patients given placebo (reduction of 340 ± 436 mL/d; P = .0112) but also compared with teduglutide-treated patients in group 2 (reduction of 355 ± 306 mL/d; P = .0066). Teduglutide had an intermediate effect on patients in group 3. A minority of patients with SBS and inflammatory bowel diseases had colon-in-continuity (10.5% [n = 2/19]), whereas most patients with SBS and vascular or other diseases had colon-in-continuity (84.4% [n = 27/32] and 67.6% [n = 23/34], respectively)., Conclusions: In a post hoc analysis of data from a phase III study of the effects of teduglutide on patients with SBS, we associated reduced parenteral support volume with baseline parenteral support volume, bowel anatomy, and SBS features. These findings may inform initial parenteral support volume adjustments and management of these severely disabled patients. ClinicalTrials.gov no: NCT00798967; ClinicalTrialsRegister.eu no: 2008-006193-15., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Tumour necrosis factor alpha (TNF-α) is a cytokine elevated in inflammatory bowel disease enterocutaneous fistula (IBD ECF). Dendritic cells are antigen presenting cells that orchestrate the immune responses and regulate the production of cytokines by immune cells including T cells. No study to date has assessed the level of TNF-α or the presence of dendritic cells in non-IBD ECF. The aim of this study was to assess the inflammatory activity, with a particular emphasis on TNF-α in non-IBD ECF when compared with control small bowel tissue., Methods: Tissue biopsies were obtained from ECF at operation from non-IBD patients and from terminal ileum in normal colonoscopy control patients. After overnight culture, accumulation of intracellular TNF-α was measured by flow cytometry in cells treated with monensin to assess the on-going cytokine production. Data were acquired using FACS Canto II. Unpaired Student's t-test was used to compare variables between groups and p < 0.05 was regarded as significant., Results: The on-going production of TNF-α from dendritic cells (p = 0.0007), putative monocyte and B cell populations (p = 0.04) and CD3 + T cells (p = 0.04) was significantly higher in non-IBD ECF tissue than that from control tissue., Conclusions: This study reveals results which provide evidence for the potential use of anti-TNF-α agents in the treatment of non-IBD ECF. A pilot study to evaluate this treatment as an alternative option in an already surgically challenging group of patients is planned. Positive findings would be a major medical advance with a new use for anti-TNF-α agents., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Objectives: In the pivotal 24-week, phase III, placebo-controlled trial, teduglutide significantly reduced parenteral support (PS) requirements in patients with short bowel syndrome (SBS). STEPS-2 was a 2-year, open-label extension of that study designed to evaluate long-term safety and efficacy of teduglutide., Methods: Enrolled patients had completed 24 weeks of either teduglutide (TED/TED) or placebo (PBO/TED) in the initial placebo-controlled study or qualified for that study, but were not treated (NT/TED) because of full enrollment. Patients received subcutaneous teduglutide 0.05 mg/kg/day for up to 24 months (NT/TED and PBO/TED) or up to 30 months (TED/TED). Clinical response was defined as 20-100% reduction from baseline in weekly PS volume; baseline was considered the beginning of teduglutide treatment in the initial placebo-controlled study (TED/TED) or STEPS-2 (NT/TED and PBO/TED). Descriptive statistics summarized changes in efficacy and safety variables., Results: Of 88 enrolled patients, 65 (74%) completed STEPS-2. The most common treatment-emergent adverse events were abdominal pain (34%), catheter sepsis (28%), and decreased weight (25%). Mean weight, body mass index, and serum albumin remained stable. In patients who completed the study, clinical response was achieved in 28/30 (93%) TED/TED, 16/29 (55%) PBO/TED, and 4/6 (67%) NT/TED patients. Mean PS volume reductions from baseline were 7.6 (66%), 3.1 (28%), and 4.0 (39%) l/week in the TED/TED, PBO/TED, and NT/TED groups, respectively. Thirteen patients achieved full enteral autonomy., Conclusions: In patients with SBS, long-term teduglutide treatment resulted in sustained, continued reductions in PS requirements. Overall health and nutritional status was maintained despite PS reductions.

Background/objectives: Patients with a short bowel and receiving parenteral nutrition (PN) have an increased risk of chronic cholestasis (CC). Restoration of bowel continuity after a mesenteric infarction results in PN requirements being reduced or stopped. This study aimed to determine the prevalence of CC and whether restoring bowel continuity reduced the risk of CC., Subjects/methods: A retrospective review of patients with a short bowel owing to mesenteric infarction from 2000 to 2012. CC was defined as two of bilirubin, alkaline phosphatase and gamma-glutamyl transferase being 1.5 times the upper limit of normal for >6 months., Results: We identified 104 (55 females, median age 54 years) patients. Seventy-three (70%) patients had restoration of bowel continuity; of these, 25 (34%) had abnormal liver biochemistry (liver function test (LFT)), with 15 (21%) having CC. Following restoration of bowel continuity, 8 (53%) of 15 patients with CC and 10 (100%) of 10 patients with abnormal LFT but not CC had a return of liver function within normal range within a year. Univariate analysis showed restoring bowel continuity (P=0.002) and cessation of PN (P=0.006) were associated with a reduction in prevalence of CC. Multivariate analysis showed that cessation of PN was a significant factor in reducing CC (P=0.02)., Conclusions: The prevalence of CC is 29% for patients with a short bowel receiving PN following a mesenteric infarction. CC resolves in 53% after continuity is restored, and this is most likely due to stopping or reducing the PN.

We investigated the relationship between preoperative comorbidity and postoperative survival after intestinal transplantation. Each patient received a score for preoperative comorbidity. Each comorbidity was given a score based on the degree it impaired function (score range 0-3). A total score was derived from the summation of individual comorbidity scores. Patients (72 adults (M : F, 33 : 39)) received an isolated intestinal graft (27) or a cluster graft (45). Mean (standard deviation) survival was 1501 (1444) days. The Kaplan-Meier analysis revealed a significant inverse association between survival and comorbidity score (logrank test for trend, P < 0.0001). Patients grouped into comorbidity scores of 0 and 1, 2 and 3, 4 and 5, 6, and above had hazard ratios (95% confidence intervals) for death (compared to group 0 + 1), which increased with comorbidity scores: 1.945 (0.7622-5.816), 5.075 (3.314-36.17), and 13.77 (463.3-120100), respectively, (P < 0.0001). Receiver-operator curves at 1, 3, 5, and 10 years postoperative had "C" statistics of 0.88, 0.85, 0.88, and 0.92, respectively. When evaluating patients for transplantation, the degree of comorbidity should be considered as a major factor influencing postoperative survival.

Background: Enterocutaneous fistulas (ECF) are debilitating and usually result following complex abdominal surgery. While there is an association with inflammatory bowel disease (IBD), a large number of fistulas occur after surgery not related to IBD. The consequences of ECF include short bowel syndrome and the need for long term parenteral nutrition.ECF can heal spontaneously and in the case of IBD can be cured by medical therapy in some instances. Those that do not resolve spontaneously have to be cured by surgery which is complex and associated with a high morbidity. It is not considered traditional treatment to use the same medical therapy as in IBD to cure ECF caused by other conditions.A small case series has reported three patients with persistent ECF not related to IBD to have healed following use of Infliximab which is the treatment commonly used for ECF caused by IBD. Infliximab acts by inhibiting the activity of the inflammatory cytokine TNF- alpha. It is not known if this cytokine is present in ECF tissue in the absence of IBD.The aim of this study is to demonstrate the presence of inflammatory markers in tissue surrounding non-IBD ECF and in particular to quantify the presence of the cytokine TNF- alpha. We hypothesise that TNF - alpha levels are raised in non-IBD ECF., Methods/design: Tissue and serum from ECF of IBD and non-IBD patients will be prospectively collected at St. Mark's Hospital Intestinal Failure Unit. The control group will consist of patients undergoing colonoscopy for bowel cancer screening, with normal findings. Biopsies of the terminal ileum will be obtained from this group during colonoscopy. The fistula tract and serum cytokine profiles of interleukins (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, TNF- alpha, IFN-y, MCP-1, EGF and VEGF will be assessed., Discussion: This study aims to assess the presence or absence of TNF- alpha expression in the ECF tissue in non-IBD origin. If our hypothesis is correct we would then be able to study the use of the TNF- alpha inhibitor Infliximab as a therapeutic option in the treatment of non-IBD ECF. Secondary aims include assessing the spectrum of inflammatory cytokines and markers present in tissue and serum of non-IBD ECF when compared with IBD ECF and normal controls., Trial Registration: ISRCTN44000447.

Introduction: Current medical management of short bowel syndrome (SBS) involves the use of lifelong parenteral nutrition (PN). Glucagon-like peptide-2 (GLP-2), an important intestinotrophic growth factor has been shown to increase intestinal absorption in SBS through augmentation of post-resection intestinal adaptation. This may lead to the reduction of PN dependence in patients with SBS., Areas Covered in Review: Advancing research of GLP-2 physiology has spurred the growing understanding of the diverse effects of GLP-2. The development of the degradation resistant GLP-2 analog, teduglutide (Gattex(TM), NPS Pharmaceuticals, Bedminster, NJ), has allowed its exploration as a therapeutic agent in a variety of clinical settings. Recent multicenter, placebo-controlled studies of GLP-2 in SBS patients demonstrate meaningful reductions in PN requirements with good safety profiles. The reparative and immunomodulatory effects of teduglutide may also be beneficial in patients with inflammatory bowel disease (IBD). Safety concerns about possible carcinogenic properties during long-term use require ongoing evaluation., Summary: GLP-2 appears to offer a novel adjuvant treatment modality for SBS. Promise for its use in other clinical settings like IBD has been shown in small pilot studies.

Liver dysfunction is common in individuals receiving parenteral nutrition (PN) and particularly in neonates and infants. Abnormalities of liver function tests in patients receiving short term PN are usually transient but in individuals receiving long term PN, substantial liver damage and ultimately end stage liver disease may occur. The aetiology is complex, involving a large number of patient related and nutrition related factors. The terminology intestinal failure associated liver disease (IFALD) is therefore more appropriate than PN associated liver disease. Effort should be made to prevent liver dysfunction by managing sepsis, avoiding parenteral overfeeding, employing cyclical parenteral feeding and encouraging enteral nutrition where possible. Intake of soybean based parenteral lipid emulsions should be reduced in individuals with established IFALD, possibly to be replaced by lipid emulsions containing medium chain triacylglycerol, monounsaturated fatty acids or fish oil although larger clinical studies are needed. Similarly, evidence supporting the widespread use of parenteral choline and taurine supplementation in the prevention or treatment of IFALD remains limited. There are more data to support the use of oral antibiotics to treat bacterial overgrowth and oral ursodeoxycholic acid in neonates. Ultimately, severe IFALD may necessitate referral for small intestine and/or liver transplantation., Competing Interests: Competing interests: None.

Background: Most studies of enterocutaneous fistula report management and outcome. Few studies examine factors predicting healing and mortality., Aim: To identify factors predicting healing and mortality in patients with ECF managed either with a definitive attempt at surgical closure or conservatively., Methods: The case notes of 277 patients with enterocutaneous fistula, treated at our institution over a 10 year period, were retrospectively reviewed. Patients were divided into those managed operatively or conservatively. Eleven factors were examined for their relationship to fistula healing and fistula-related mortality., Results: For patients treated operatively, successful enterocutaneous fistula closure related only to the complexity of the fistula (multiple fistula or presence of an internal abscess cavity) (P = 0.03), whereas fistula-related mortality related only to the presence of comorbidity (P = 0.02). In patients managed conservatively, a decreased likelihood of enterocutaneous fistula closure was associated with a high fistula output (P = 0.01), comorbidity (P = 0.03) and being referred from an external institution (P < 0.001). Fistula related-mortality in this group was related to a high output (P = 0.003) and an increased age (P = 0.001)., Conclusion: In patients managed operatively, fistula healing and fistula-related mortality are each associated with only one factor, whereas in patients managed conservatively healing and mortality are predicted by three and two factors, respectively.

Objective: Studies suggest clinical benefit of glutamine-supplemented parenteral nutrition. The aim was to determine if the inclusion of 10 g of glutamine as part of the nitrogen source of home parenteral nutrition (HPN) reduces infectious complications., Subjects/methods: Thirty-five patients on HPN were recruited and 22 completed the study. Patients were randomized to receive either standard HPN or glutamine-supplemented HPN. Patients were assessed at randomization, 3 and 6 months later then they were crossed over to the alternative HPN and reassessed at 3 and 6 months. Assessments included plasma amino acid concentrations, intestinal permeability and absorption, nutritional status, oral and parenteral intake, quality of life, routine biochemistry and haematology., Results: No difference was seen between the groups at randomization. No difference was detected between the treatment phases for infective complications (55% in the standard treatment phase and 36% in the glutamine-supplemented phase P=0.67). There were no differences in nutritional status, intestinal permeability, plasma glutamine concentrations or quality of life., Conclusion: Although limited by the sample size, the study has shown that glutamine as part of the nitrogen source of parenteral nutrition can be given to patients on HPN for 6 months without any adverse effects.

Background: Chronic biochemical cholestasis has been shown to be associated with a fivefold increase in histologically advanced liver disease in patients receiving home parenteral nutrition., Aims: To investigate prevalence of chronic biochemical cholestasis in home parenteral nutrition patients and examine factors influencing its occurrence., Methods: Records of all patients receiving home parenteral nutrition for >6 months treated at a single centre were reviewed and plasma biochemistry recorded. Logistic regression analysis was employed to identify factors associated with prevalence of chronic biochemical cholestasis., Results: Records of 113 patients were reviewed. The point prevalence of chronic biochemical cholestasis was 24%, increasing to 28% if patients receiving parenteral fluid and electrolytes only were excluded. In multivariate analysis, presence of colon in continuity was associated with a significantly lower prevalence of chronic biochemical cholestasis, while total parenteral calorie intake was associated with a higher prevalence of chronic biochemical cholestasis. No association was seen between small intestinal lengths or between parenteral lipid intake and chronic biochemical cholestasis in multivariate analysis., Conclusions: Chronic biochemical cholestasis is common in patients receiving home parenteral nutrition. High parenteral calorie intake and lack of a colon in continuity with small intestine are independently associated with an increased risk of chronic biochemical cholestasis.

Parenteral nutrition is life saving in patients with intestinal failure but liver dysfunction is commonly encountered, especially in neonates. Although abnormal liver function tests associated with short-term parenteral nutrition are usually benign and transient, liver dysfunction in both children and adults receiving long-term parenteral nutrition can progress to end-stage liver disease and liver failure. The aetiology of parenteral nutrition-associated liver disease is complex and multifactorial, with a range of patient, disease and nutrition-related factors implicated. Sepsis is of particular importance, as is the lack of enteral nutrition and overfeeding with intravenous glucose and/or lipid. Deficiencies of a number of amino acids including choline and taurine have also been implicated. Management of hepatic dysfunction in parenteral nutrition should initially focus on preventing its occurrence. Sepsis should be managed appropriately, enteral nutrition should be encouraged and maximised where possible and parenteral overfeeding should be avoided. Provision of parenteral lipid should be optimised to prevent the adverse effects of both deficiency and excess, and cyclical rather than continuous parenteral feeding should be administered. There is some evidence of benefit in neonates from oral antibiotics to prevent intestinal bacterial overgrowth and from oral ursodeoxycholic acid, but less to support their use in adults. Similarly, data to support widespread use of parenteral choline or taurine supplementation are lacking at present. Ultimately, severe parenteral nutrition-associated liver disease may necessitate referral for small intestine and/or liver transplantation.

Background: Home parenteral nutrition (HPN) is the standard treatment for severe intestinal failure in the United Kingdom., Aim: To review long-term survival and ongoing HPN dependence of patients receiving HPN treated at a specialist UK referral centre., Methods: Medical records of patients commenced on HPN between 1979 and 2003 were reviewed retrospectively. Regression analysis was employed to identify factors associated with poor prognosis., Results: Case notes of 188 patients were reviewed. Overall probability of survival was 86%, 77%, 73% and 71% at 1, 3, 5 and 10 years after starting treatment. In multivariate analysis, association was seen between mechanism of intestinal failure and survival: short bowel syndrome associated with a favourable prognosis, and intestinal dysfunction, dysmotility and obstruction with poorer prognoses. There was an association between increasing age and poor prognosis, but increased mortality was also seen in the youngest age groups. Only 9% of deaths were due to complications of HPN. Continued HPN dependence was 89%, 87%, 84% and 84% at 1, 3, 5 and 10 years in survivors., Conclusions: Long-term survival of patients receiving HPN remains better than that reported after intestinal transplantation. Mortality predominantly relates to underlying disease rather than complications of HPN.

Parenteral nutrition is an expensive therapeutic modality that is used to treat patients with intestinal failure. The benefit it offers in terms of life prolongation needs to be weighed against its risks and burdens. Through the use of descriptive clinical vignettes, this article illustrates the ethical and legal principles that underpin decisions to administer and, more importantly, to withhold or withdraw parenteral nutrition.

Tissue engineering of the small intestine offers an alternative to long-term intravenous nutrition and transplantation in patients with intestinal failure. Initial work, although encouraging, is limited by the volume of neonatal tissue required to produce a small neomucosal cyst. Our novel approach is to implant tubular poly-lactide-co-glycolide (PGLA) foam scaffolds subcutaneously. The aim of this study was to investigate whether these scaffolds would support growth of intestinal neomucosa. PGLA scaffolds were implanted subcutaneously into 8 Lewis rats; after 5 weeks, 'organoid units' were injected into the lumens. Tissue was assessed histologically after harvesting and quantitative immunohistochemistry was performed using antibodies against vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGF-R2), fibroblast growth factor basic (bFGF) and fibroblast growth factor receptor 2 (FGF-R2). At 4 weeks post organoid unit implantation, clearly recognisable mucosa and submucosa was present on the luminal surface of the scaffold. Densities of VEGF and VEGF-R2 positive cells increased with time post organoid unit implantation. This pilot study demonstrates that it is possible to tissue engineer small intestinal neomucosa using subcutaneously implanted PLGA scaffolds. The yield of the process compares favourably to the published literature. Further work is required to optimise the technique.

Sufficient neovascularization of neotissue is currently a limiting factor for the engineering of large tissue constructs. 45S5 Bioglass has been investigated extensively in bone tissue engineering but there has been relatively little previous research on its application to soft-tissue engineering. The objectives of this study were to investigate the use of 45S5 Bioglass in soft-tissue engineering scaffolds using in vitro and in vivo models. A fibroblast cell line (208F) was used for in vitro evaluation of surfaces coated with 45S5 Bioglass. Increased proliferation of fibroblasts was observed after growth on polystyrene surfaces coated with low concentrations (0.01-0.2%wt/vol) of 45S5 Bioglass for 24 h in vitro, determined as a change in total cell number by measuring lactate dehydrogenase. At higher concentrations of 45S5 Bioglass and longer periods of incubation (48 and 72 h) on coated surfaces, cell proliferation was reduced. Light microscopy revealed that the morphology of fibroblasts grown on 45S5 Bioglass-coated surfaces was not altered at low concentrations, but at higher concentrations fibroblasts became vacuolated. Enzyme-linked immunosorbent assay of conditioned culture medium collected from fibroblasts grown for 24 h on surfaces coated with low concentrations of 45S5 Bioglass (0.01%wt/vol) was found to contain significantly higher concentrations of vascular endothelial growth factor. Histological examination of polyglycolic acid (PGA)/45S5 Bioglass composite scaffolds that had been implanted subcutaneously into rats revealed that 45S5 Bioglass-coated meshes were well tolerated. Light microscopy revealed that neovascularization into 45S5 Bioglass-coated meshes was significantly increased at 28 and 42 days. Electron microscopy revealed fibroblasts adhering closely to the PGA mesh but not to 45S5 Bioglass particles. The apparent ability of 45S5 Bioglass incorporated into scaffolds to increase neovascularization would be extremely beneficial during the engineering of larger soft-tissue constructs.

Polylactide-co-glycolide (PLGA) foams of tubular shape were assessed for their use as soft-tissue engineering scaffolds in vitro and in vivo. Porous membranes were fabricated by a thermally induced phase separation process of PLGA solutions in dimethylcarbonate. The parameters investigated were the PLGA concentration and the casting volume of solution. Membranes produced from 5 wt/v % polymer solutions and a 6 ml casting volume of polymer solution were selected for fabricating tubes of 3 mm diameter, 20 mm length and a nominal wall thickness of 1.5 mm. Scanning electron microscopy revealed that the structure of the tubular foams consisted of radially oriented and highly interconnected pores with a large size distribution (50-300 microm). Selected tubes were implanted subcutaneously into adult male Lewis rats. Although the lumen of the tubes collapsed within one week of implantation, histological examination of the implanted scaffolds revealed that the foam tubes were well tolerated. Cellular infiltration into the foams, consisting mainly of fibrovascular tissue, was evident after two weeks and complete within eight weeks of implantation. The polymer was still evident in the scaffolds after eight weeks of implantation. The results from this study demonstrate that the PLGA tubular foams may be useful as soft-tissue engineering scaffolds with modification holding promise for the regeneration of tissues requiring a tubular shape scaffold such as intestine.

Background & Aims: The maintenance of the intestinal mucosal barrier may be energy dependent. Tacrolimus is a potent immunosuppressive drug that decreases mitochondrial adenosine triphosphate production and increases intestinal permeability in animals., Methods: Twelve liver graft recipients receiving tacrolimus, 9 healthy volunteers, and 5 liver graft recipients not receiving immunosuppression underwent a combined absorption-permeability-mitochondrial function test using 5 g lactulose, 1 g L-rhamnose, 0.5 g D-xylose, 0.2 g 3-O-methyl-D-glucose, 1 mg/kg 2-keto[1-13C]isocaproic acid ([13C]KICA), and 20 mg/kg L-leucine. The respiratory quotient and resting energy expenditure were measured by indirect calorimetry. Tacrolimus pharmacokinetic profiles and levels of endotoxin and IgM and IgG endotoxin core antibodies were determined., Results: Tacrolimus inhibited the decarboxylation of [13C]KICA, the resting energy expenditure, and the respiratory quotient in an exposure-dependent manner, suggesting an inhibition of mitochondrial respiration. Tacrolimus inhibited intestinal absorptive capacity in an exposure-dependent manner. Tacrolimus-treated patients had an increased intestinal permeability and significantly higher endotoxin levels compared with healthy volunteers., Conclusions: Tacrolimus inhibits cellular energy production in humans at clinically relevant doses. This is associated with an increased intestinal permeability, endotoxemia, and an impaired intestinal absorptive capacity.

Background: This study determines the efficacy and safety of a 1-week triple therapy regimen of lansoprazole, clarithromycin and metronidazole in an area with a high prevalence of pre-treatment metronidazole-resistant strains of Helicobacter pylori., Methods: Seventy-five H. pylori positive patients with gastritis or duodenal ulcer were entered into an open study of lansoprazole 30 mg o.m., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. H. pylori status was determined by CLOtest, histology, culture and by 13C-urea breath test (repeated > or = 28 days after treatment)., Results: Seventy-one patients completed the treatment and returned for follow-up. H. pylori was eradicated in 61 of 71 (86%) patients by per-protocol analysis, and in 61 of 75 (81%) patients by intention-to-treat analysis. H. pylori was eradicated in 12 of 16 (75%) patients with metronidazole-resistant strains compared with 22 of 24 (92%) in patients with metronidazole-sensitive strains of H. pylori (P = 0.14). Fourty-five patients reported at least one adverse event, and three patients stopped treatment due to them (two with headaches and one with diarrhoea)., Conclusions: A 1-week course of lansoprazole 30 mg o.m., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. eradicates H. pylori in up to 86% of patients. It is of proven benefit in patients with pre-treatment metronidazole-resistant strains of H. pylori.