Update on treatment of abdominal pain in irritable bowel syndrome: A narrative review.

The objectives of this narrative review are to update readers on the current state-of-the-art regarding diverse approaches for the treatment of pain, global symptoms, or adequate relief in irritable bowel syndrome (IBS). The article appraises medications, dietary interventions including low fermentable oligosaccharides, disaccharides, and monosaccharides and polyols (FODMAP) diet, fecal microbial transplantation (FMT), electrical approaches, and behavioral therapies including cognitive behavioral therapy (CBT), gut-directed hypnotherapy (GDH), mindfulness, and open-label placebo. Current evidence demonstrates only modest benefit in global IBS symptoms and pain relief. A future approach that identifies pathophysiological mechanisms of IBS through validated biomarkers has the potential to individualize treatment of patients rather than sequential therapeutic trial and error approaches.

Diet as a therapeutic tool in chronic gastrointestinal disorders: Lessons from the FODMAP journey.

BACKGROUND AND AIM: Diet is a powerful tool in the management of gastrointestinal disorders, but developing diet therapies is fraught with challenge. This review discusses key lessons from the FODMAP diet journey. METHODS: Published literature and clinical experience were reviewed. RESULTS: Key to designing a varied, nutritionally adequate low-FODMAP diet was our accurate and comprehensive database of FODMAP composition, made universally accessible via our user-friendly, digital application. Our discovery that FODMAPs coexist with gluten in cereal products and subsequent gluten/fructan challenge studies in nonceliac gluten-sensitive populations highlighted issues of collinearity in the nutrient composition of food and confirmation bias in the interpretation of dietary studies. Despite numerous challenges in designing, funding, and executing dietary randomized controlled trials, efficacy of the low-FODMAP diet has been repeatedly demonstrated, and confirmed by real-world experience, giving this therapy credibility in the eyes of clinicians and researchers. Furthermore, real-world application of this diet saw the evolution of a safe and effective three-phased approach. Specialist dietitians must deliver this diet to optimize outcomes as they can target and tailor the therapy and to mitigate the key risks of compromising nutritional adequacy and precipitating disordered eating behaviors, skills outside the gastroenterologist's standard tool kit. While concurrent probiotics are ineffective, specific fiber supplements may improve short-term and long-term outcomes. CONCLUSIONS: The FODMAP diet is highly effective, but optimal outcomes are contingent on the involvement of a gastroenterological dietitian who can assess, educate, and monitor patients and manage risks associated with implementation of this restrictive diet.

Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet versus traditional dietary advice for functional dyspepsia: a randomized controlled trial.

BACKGROUND AND AIM: Prospective trials evaluating efficacy of specific diet restriction in functional dyspepsia (FD) are scarce. We aimed to assess efficacy of low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet in FD, compared with traditional dietary advice (TDA). METHODS: In this prospective, single-blind trial, patients with FD (Rome IV) were randomized into low FODMAP diet (LFD) and TDA groups, for 4 weeks (phase I). In phase II (4-12 weeks), LFD group was advised systematic re-introduction of FODMAPs. Symptom severity and quality of life were assessed using "Short-Form Nepean Dyspepsia Index (SF-NDI)." Primary outcome was symptomatic response (symptom score reduction of ≥ 50%), at 4 weeks. Study was registered with CTRI (2019/06/019852). RESULTS: Of 184 patients screened, 105 were randomized to LFD (n = 54) and TDA (n = 51) groups. At 4 weeks, both groups showed significant reduction in SF-NDI symptom scores compared with baseline, with no significant difference in inter-group response rates [LFD: 66.7% (36/54); TDA: 56.9% (29/51); P = 0.32]. On sub-group analysis, patients with postprandial distress syndrome or bloating had significantly better symptomatic response with LFD (P = 0.04). SF-NDI quality of life scores improved significantly in both groups. On multivariate analysis, factors predicting response to LFD were bloating and male gender. Incidences of adverse events (minor) were similar in both groups. CONCLUSIONS: In patients with FD, LFD and TDA lead to significant symptomatic and quality of life improvement. Patients with postprandial distress syndrome or bloating respond significantly better to LFD. Therefore, dietary advice for FD should be individualized according to FD subtype.

An evaluation of ferric derisomaltose as a treatment for anemia.

Introduction: Originally approved in Europe in 2009, ferric derisomaltose is the most recently authorized intravenous iron compound in the United States of America (2020). Ferric derisomaltose given as a rapid high-dose infusion can allow complete iron repletion in a single dose and it is now widely used in the treatment of iron deficiency. Areas covered: The chemistry, pharmacodynamics and pharmacokinetics of ferric derisomaltose are reviewed. Results from phase II, III and IV trials regarding efficacy and safety are presented. Mechanisms behind minor infusion reactions, hypersensitivity and hypophosphatemia are discussed. The economic impact of ferric derisomaltose use is presented. Data pertaining to the use of ferric derisomaltose in iron deficiency anemia, chronic kidney disease, inflammatory bowel disease, chronic heart failure, perioperative care and other patient groups are comprehensively covered. Expert opinion: Ferric derisomaltose is an effective intravenous iron formulation with a good safety profile, providing rapid, cost-effective iron repletion. Ferric derisomaltose releases low quantities of labile iron relative to older compounds. Anaphylaxis is extremely rare, and 'Fishbane' reactions are uncommon. Hypophosphatemia following ferric derisomaltose administration is infrequent in comparison to other intravenous irons such as ferric carboxymaltose. The scope of ferric derisomaltose use is growing with increasing research in these areas.

N-acetylcysteine modulates effect of the iron isomaltoside on peritoneal mesothelial cells.

Intravenous (i.v.) iron supplementation is used in patients on chronic peritoneal dialysis (pd). Iron induced intraperitoneal inflammation observed in our previous studies with iron sucrose may deteriorate the function of the peritoneum as the dialysis membrane. We evaluated effect iron compound, iron-isomaltoside-100 (IIS) on the peritoneal mesothelial cells (MC). We studied the effect of iv treatment with IIS ± N-acetylcysteine (NAC) on the dialysate parameters and function of MC. In 7 uremic pd patients IIS 200 mg was infused i.v. ± NAC 600 mg. Afterward, a 4 hours exchange was performed with Dianeal 1.5%. As a control dialysate exchange preceding IIS treatment was used. Inflammatory parameters of the drained dialysates as well as the dialysates and IIS effects on MC were evaluated in ex vivo experiments. Intravenous infusion of IIS resulted in an increase of the dialysate Fe (+147%, P < 0.01). Concentrations of the dialysates inflammatory mediators were increased: interleukin-6 (IL-6) +39%, P < 0.02, monocyte chemoattractant protein-1(MCP1) +50%, P < 0.02, and hyaluronan (HA) +64%, P < 0.02. Simultaneous i.v. infusion of NAC prevented increase of the dialysate inflammatory mediators. Dialysates collected after IIS treatment induced oxidative stress in MC (+29%, P < 0.05) and stimulated IL-6 synthesis (+64%, P < 0.05) in MC; no such effect was seen in dialysates obtained after simultaneous IIS and NAC i.v. treatment. IIS used as the additive to culture medium stimulated synthesis in MC of IL6 (+76%, P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) (28%, P < 0.001) whereas synthesis of tissue plasminogen activator (t-PA) was reduced (-16%, P < 0.001). These changes were prevented in the presence of NAC 1 mmol/L. Intravenous administration of IIS results in the mild stimulation of intraperitoneal inflammation. IIS changes MC phenotype to the inflammatory one with reduced fibrinolytic activity. These effects are prevented by NAC.

Incidence of hypophosphatemia in patients with inflammatory bowel disease treated with ferric carboxymaltose or iron isomaltoside.

BACKGROUND: Iron deficiency and iron deficiency anaemia are common complications in inflammatory bowel disease (IBD). In patients with moderate-to-severe anaemia, oral iron intolerance or ineffectiveness of oral iron, ferric carboxymaltose and iron isomaltoside are widely used. Hypophosphatemia is a side effect of both preparations. AIMS: To investigate the occurrence of hypophosphatemia in IBD patients with iron deficiency/iron deficiency anaemia treated with high-dose intravenous iron. METHODS: A prospective observational study of adult IBD patients with iron deficiency/iron deficiency anaemia was conducted at two study sites where patients received 1000 mg of ferric carboxymaltose or iron isomaltoside. At baseline, weeks 2 and 6, blood and faecal samples were collected. The primary endpoint was to determine the incidence of moderate-to-severe hypophosphatemia. Secondary endpoints included the total incidence of hypophosphatemia, possible risk factors for hypophosphatemia, and response to single-dose intravenous iron. RESULTS: One hundred and thirty patients were included. In the per-protocol set, 52 patients received ferric carboxymaltose and 54 patients received iron isomaltoside. Ferric carboxymaltose treatment had a significantly higher incidence of moderate-to-severe hypophosphatemia compared with iron isomaltoside at week 2 (56.9% vs 5.7%, P < 0.001) and a higher incidence at week 6 (13.7% vs 1.9%, P = 0.054).The overall incidence of hypophosphatemia was significantly higher with ferric carboxymaltose compared with iron isomaltoside treatment at weeks 2 (72.5% vs 11.3%, P < 0.001) and 6 (21.6% vs 3.7%, P = 0.013). CONCLUSIONS: In IBD patients with iron deficiency/iron deficiency anaemia, ferric carboxymaltose was associated with higher incidence, severity and persistence of hypophosphatemia compared with iron isomaltoside. The presence of moderate-to-severe hypophosphatemia beyond 6 weeks is a clinical concern that requires further investigation.

Effect of Oral Nutritional Supplements with Sucromalt and Isomaltulose versus Standard Formula on Glycaemic Index, Entero-Insular Axis Peptides and Subjective Appetite in Patients with Type 2 Diabetes: A Randomised Cross-Over Study.

Oral diabetes-specific nutritional supplements (ONS-D) induce favourable postprandial responses in subjects with type 2 diabetes (DM2), but they have not been correlated yet with incretin release and subjective appetite (SA). This randomised, double-blind, cross-over study compared postprandial effects of ONS-D with isomaltulose and sucromalt versus standard formula (ET) on glycaemic index (GI), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and SA in 16 individuals with DM2. After overnight fasting, subjects consumed a portion of supplements containing 25 g of carbohydrates or reference food. Blood samples were collected at baseline and at 30, 60, 90, 120, 150 and 180 min; and SA sensations were assessed by a visual analogue scale on separate days. Glycaemic index values were low for ONS-D and intermediate for ET (p < 0.001). The insulin area under the curve (AUC0-180 min) (p < 0.02) and GIP AUC (p < 0.02) were lower after ONS-D and higher GLP-1 AUC when compared with ET (p < 0.05). Subjective appetite AUC was greater after ET than ONS-D (p < 0.05). Interactions between hormones, hunger, fullness and GI were found, but not within the ratings of SA; isomaltulose and sucromalt may have influenced these factors.

A prospective, multi-center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON-IDA trial.

Iron deficiency anemia (IDA) is prevalent, and intravenous iron, especially if given in a single dose, may result in better adherence compared with oral iron. The present trial (FERWON-IDA) is part of the FERWON program with iron isomaltoside 1000/ferric derisomaltose (IIM), evaluating safety and efficacy of high dose IIM in IDA patients of mixed etiologies. This was a randomized, open-label, comparative, multi-center trial conducted in the USA. The IDA patients were randomized 2:1 to a single dose of 1000 mg IIM, or iron sucrose (IS) administered as 200 mg intravenous injections, up to five times. The co-primary endpoints were adjudicated serious or severe hypersensitivity reactions, and change in hemoglobin from baseline to week eight. A total of 1512 patients were enrolled. The frequency of patients with serious or severe hypersensitivity reactions was 0.3% (95% confidence interval: 0.06;0.88) vs 0.4% (0.05;1.45) in the IIM and IS group, respectively. The co-primary safety objective was met, and no risk difference was observed between groups. The co-primary efficacy endpoint of non-inferiority in hemoglobin change was met, and IIM led to a significantly more rapid hematological response in the first two weeks. The frequency of cardiovascular events was 0.8% and 1.2% in the IIM and IS group, respectively (P = .570). The frequency of hypophosphatemia was low in both groups. Iron isomaltoside administered as 1000 mg resulted in a more rapid and more pronounced hematological response, compared with IS, which required multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions and cardiovascular events.

Comparison of hypersensitivity reactions of intravenous iron: iron isomaltoside-1000 (Monofer® ) versus ferric carboxy-maltose (Ferinject® ). A single center, cohort study.

AIMS: Intravenous iron supplementation is widely used to treat iron deficiency and iron deficiency anemia when oral iron administration is ineffective or poorly tolerated. Hypersensitivity reactions (HSRs) during infusions are rare, but can be life-threatening. This study aimed to compare the risk for HSRs with the intravenous administration of iron isomaltoside-1000 and ferric carboxymaltose for the treatment of iron deficiency and iron deficiency anemia. METHODS: This was a single-centre cohort study. Nurses and physicians were instructed to fill out an HSR registration form with every administration of intravenous iron. HSRs were distinguished into serious and non-serious HSRs using the Ring and Messmer classification. RESULTS: HSRs occurred in 18/836 (2.1%) ferric carboxymaltose and 43/496 (8.7%) iron isomaltoside-1000 administrations. The crude risk for HSRs was 75% lower after ferric carboxymaltose treatment (RR = 0.248, 95% CI: 0.145-0.426, P < 0.0001). The risk for grade II HSRs was 88% lower after ferric carboxymaltoside (RR = 0.123, 95% CI: 0.051-0.294). The likelihood of HSRs was 3.4 times higher after the administration of iron isomaltoside-1000 (95% CI: 1.910-6.093, P < 0.0001). Regardless of the type of intravenous iron, patients with comorbidities have a factor 3.6 higher risk (95% CI: 1.899-6.739, P < 0.0001). CONCLUSIONS: Ferric carboxymaltose is associated with a 75% lower risk for HSRs compared with iron isomaltoside-1000 in our population. The presence of a comorbidity raises the likelihood of an HSR by a factor of three regardless of the type of intravenous iron infusion. Further research is needed to clarify the underlying mechanism in various patient groups.

When the low FODMAP diet does not work.

Irritable bowel syndrome (IBS) is heterogeneous. Patients need proper assessment and explanation of IBS pathophysiology and appropriate therapies. A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet effectively reduces symptoms in 75% of patients. Best treatment for those nonresponsive will depend on the pathophysiological basis for symptom genesis, with the following possible abnormalities: (i) Visceral hypersensitivity and/or enhanced gut-brain communication: a low FODMAP diet is mainly targeted for this patient group. A dietitian may also recommend antispasmodic agents, including peppermint oil. Another dietary treatment is a low food chemical diet, although this diet is often extremely limited, and therefore, not suited for some populations. Psychological therapies are also clinically beneficial. (ii) Altered motility: in patients with fast transit, a dietitian may recommend a reduction in all FODMAPs or targeted monosaccharides and disaccharides, which are more osmotic in nature. If not effective, patients may benefit from psyllium, which has an exceptional water-holding capacity aimed to promote more formed stools. Patients with slow or uncoordinated transit are often more difficult to treat. Dietary interventions have some success and usually comprise a combination of adequate fiber and fluid, osmotic laxatives, and stimulating agents such as caffeine, senna, and exercise. (iii) Altered microbiome: supplementary probiotics and prebiotics have weak evidence of efficacy with some notable exceptions. A dietitian may trial supplementary Bifidobacterium infantis or oligosaccharides, usually as an adjunct therapy. Guidance from a dietitian will encompass dietary methods to treat IBS but additionally identify where dietary treatment is not indicated to ensure that diet is correctly used and patients are not nutritionally or psychologically compromised.

Prebiotic inulin-type fructans and galacto-oligosaccharides: definition, specificity, function, and application in gastrointestinal disorders.

Prebiotics are non-digestible selectively fermented dietary fibers that specifically promote the growth of one or more bacterial genera in the gastrointestinal tract and thus provide health benefit to the host. The two most investigated prebiotics being the inulin-type fructans and galacto-oligosaccharides. Prebiotic specificity is mediated through species-specific gene clusters within saccharolytic bacteria controlled by signaling sensors for various substrates. Prebiotic health benefits are attributed to immune regulation and bacterial metabolite production. In humans, prebiotic supplementation leads to increased growth of specific gut microbiota (e.g., bifidobacteria), immune modulation, and depending on the bacterial augmentation, short-chain fatty acid production. Irritable bowel syndrome and Crohn's disease are gastrointestinal disorders associated with reductions in some gut bacteria and greater mucosal inflammation. Prebiotic supplementation studies have shown some promise at low doses for modulation of the gut bacteria and reduction of symptoms in IBS; however, larger doses may have neutral or negative impact on symptoms. Studies in Crohn's disease have not shown benefit to bacterial modulation or inflammatory response with prebiotic supplementation. Dietary restriction of fermentable carbohydrates (low FODMAP diet), which restricts some naturally occurring prebiotics from the diet, has shown efficacy in improving symptoms in irritable bowel syndrome, but it lowers the numbers of some key gut microbiota. Further research is required on the effect of prebiotics in gastrointestinal disorders and, in particular, on their use in conjunction with the low FODMAP diet.

Choice of High-Dose Intravenous Iron Preparation Determines Hypophosphatemia Risk.

BACKGROUND: Ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) are increasingly used because they allow correction of severe iron deficiency in a single infusion. A transient decrease in serum phosphate concentrations is a frequent side effect of FCM. AIM: To characterize this adverse event and search for its predictors in a gastroenterology clinic patient cohort. METHODS: Electronic medical records of patients attending the University Hospital of Innsbruck were searched for the keywords ferric carboxymaltose or iron isomaltoside. Eighty-one patients with documented administration of FCM or IIM with plasma phosphate concentrations before and after treatment were included. RESULTS: The prevalence of hypophosphatemia (<0.8 mmol/L) increased from 11% to 32.1% after treatment with i.v. iron. The hypophosphatemia risk was greater after FCM (45.5%) compared with IIM (4%). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after FCM (32.7%). The odds for hypophosphatemia after i.v. iron treatment were independently determined by baseline phosphate and the choice of i.v. iron preparation (FCM vs. IIM-OR = 20.8; 95% CI, 2.6-166; p = 0.004). The median time with hypophosphatemia was 41 days, but prolonged hypophosphatemia of ≥ 2 months was documented in 13 of 17 patients in whom follow-up was available. A significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation. CONCLUSION: Treatment with FCM is associated with a high risk of developing severe and prolonged hypophosphatemia and should therefore be monitored. Hypophosphatemia risk appears to be substantially lower with IIM.

High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anaemia without profound changes in phosphate or fibroblast growth factor 23.

OBJECTIVE: Iron isomaltoside (Monofer(®)) is a high-dose intravenous iron preparation with good tolerability and efficacy in inflammatory bowel disease (IBD) patients with iron deficiency anaemia (IDA). This trial evaluates the safety and efficacy, including effect on intact fibroblast growth factor 23 (iFGF23) of a high single dose and cumulative doses of iron isomaltoside in IBD patients with IDA. MATERIALS AND METHODS: The trial was a prospective, open-label, multi-centre trial conducted in IBD patients with IDA. Based upon haemoglobin (Hb) levels at baseline and weight, the patients received 1500, 2000, 2500 or 3000 mg of iron isomaltoside infused in single doses up to 2000 mg. The outcome measurements included adverse drug reactions (ADRs) and changes in haematology and biochemistry parameters. RESULTS: Twenty-one IBD patients with IDA were enrolled, receiving 1500 (seven patients), 2000 (eight patients), 2500 mg (four patients) or 3000 (two patients) mg of iron. No serious ADRs were observed. Four patients experienced nine mild to moderate ADRs (hypersensitivity, pyrexia, vomiting, constipation, abdominal pain, dyspepsia (two events) and eye allergy (two events)). In total, 15 (75%) patients had an increase in Hb of ≥2.0 g/dL during the trial, with normalisation of ferritin. No changes in iFGF23 or clinically significant hypophosphataemia were found. CONCLUSION: Rapid infusions of high-dose iron isomaltoside, administered as single doses up to 2000 mg and cumulative doses up to 3000 mg, were without safety concerns and were efficacious in increasing Hb levels in IBD patients. Iron isomaltoside did not induce profound phosphate wasting via increased iFGF23 levels.

Management of Hepatic Encephalopathy: A Primer.

OBJECTIVE: To review the management of hepatic encephalopathy (HE), including lifestyle modifying strategies and pharmacological interventions. DATA SOURCES: A literature search of PubMed through March 2016 was conducted utilizing the keywords hepatic encephalopathy, ammonia, and cirrhosis All published articles evaluating treatments for HE were considered. STUDY SELECTION AND DATA EXTRACTION: Available English-language data from reviews, abstracts, presentations, and clinical trials of the treatment of HE in humans were reviewed; relevant clinical data were selected and included. DATA SYNTHESIS: HE is a prevalent complication of portal hypertension and cirrhosis that results in altered mental status and neuropsychiatric impairment. Although the pathogenesis has not been elucidated, numerous treatment options exist. This review will explore the role of dietary interventions and supplements, including use of zinc, acetyl-l-carnitine, and probiotics, in the management of HE. Additionally, the use of various ammonia-lowering agents will be evaluated. The nonabsorbable disaccharides represent first-line therapies for the management and prophylaxis of HE; rifaximin use has been demonstrated to be effective for both treatment and prophylaxis of HE symptoms, with use relegated to those patients who fail to respond to or tolerate the nonabsorbable disaccharides. In light of toxicities associated with the use of neomycin and metronidazole, recent guidelines recommend both as alternatives for the treatment of HE, with the use of vancomycin discouraged. CONCLUSION: Although numerous treatment options are available, management of HE remains a clinical challenge. Additional research is needed to explore the pathogenesis and better understand the role of pharmacotherapy in managing this condition.

Food allergy in adolescence and adulthood.

In young children, food allergy is usually acquired via the gastrointestinal tract and directed toward egg and milk. Adolescent and adult patients, however, mainly acquire food allergy via primary sensitization to inhalant allergens on the basis of cross-reactivity between proteins in inhalant sources and in food. This type of food allergy is frequently mediated by sensitization to broadly represented allergens, or so-called panallergens. Food allergic reactions in adult patients - similar to those in children - range in severity from very mild and local symptoms, as in contact urticaria of the oral mucosa, to systemic symptoms involving distal organs, to a fatal outcome. Plant foods, such as fruits, nuts, and vegetables, are the most prevalent allergenic foods in this age group.

[Safety aspects of parenteral iron supplementation therapies in patients with chronic kidney disease]. / Sicherheitsaspekte parenteraler Eisentherapien bei Patienten mit chronischer Niereninsuffizienz.

Iron deficiency often occurs in patients with chronic kidney disease and can be effectively treated with parenteral supplementation of iron. In these patients, prompt application of iron therapy can help to reduce the dependence of erythropoietin-stimulating agents and effectively treat anemia. Correct evaluation of iron metabolism in CKD patients can be difficult. Duration of and response to therapy should always be considered while planning parenteral supplementation of iron. The main safety aspects of parenteral iron preparations relate to their possible anaphylactic potential and the potential induction of oxidative stress due to the release of free iron. However, parenteral iron supplementation is usually safe and without major side effects. Regarding current data, none of the iron preparations is showing definitive superiority. Although uncommon, iron preparations containing dextran can lead to severe side effects, therefore these preparations appear to have an inferior safety profile. Due to limited data, a comparison of third-generation iron preparations with previous preparations is not possible. Recently, for the first time, the third generation iron preparation ferumoxytol has been directly compared to iron sucrose. From this data and others, it remains unclear whether third generation iron preparations show safety-relevant superiority.

Iron isomaltoside 1000: a new intravenous iron for treating iron deficiency in chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) often suffer from iron deficiency anemia necessitating treatment with intravenous iron. This study was designed to assess the safety of iron isomaltoside 1000 (Monofer) in CKD patients. The secondary objective was to assess its effect on iron deficiency anemia. METHODS: This open-label, noncomparative, multicenter trial assigned 182 patients with CKD (n=161 in dialysis and n=21 in predialysis) to iron isomaltoside 1000 either as 4 intravenous bolus injections of 100-200 mg iron per dose or as a fast high-dose infusion at baseline. Patients were generally undergoing erythropoiesis-stimulating agent (ESA) treatment (82%), and the dosage was to be kept constant during the trial. They were either switched from an existing parenteral maintenance therapy (n=144) or were not currently being treated with parenteral iron (n=38). Frequency of adverse events (AEs) and changes in markers of iron deficiency anemia were measured during 8 weeks from baseline. RESULTS: Nineteen treatment-related AEs occurred in 13 patients (7.1%) and after 584 treatments (3.3%). No anaphylactic or delayed allergic reactions were observed. There were no clinically significant changes in routine clinical laboratory tests or vital signs. Hemoglobin increased from 99.2 g/L (SD=9.0) at baseline to 111.2 g/L (SD=14.7) at week 8 in patients not currently treated with parenteral iron (p<0.001) and increased slightly or stabilized in patients in maintenance therapy. S-Ferritin, s-iron and transferrin saturation increased significantly at all visits. CONCLUSIONS: Iron isomaltoside 1000 was clinically well tolerated, safe and effective. This new intravenous iron may offer a further valuable choice in treating the anemia of CKD.

Pharmacotherapy for hepatic encephalopathy.

Hepatic encephalopathy (HE) is a challenging clinical complication of liver dysfunction with a wide spectrum of neuropsychiatric abnormalities that range from mild disturbances in cognitive function and consciousness to coma and death. The pathogenesis of HE in cirrhosis is complex and multifactorial, but a key role is thought to be played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia. Therapeutic treatment options for HE are currently limited and have appreciable risks and benefits associated with their use. Management of HE primarily involves avoidance of precipitating factors, limitation of dietary protein intake, and administration of various ammonia-lowering therapies such as non-absorbable disaccharides and select antimicrobial agents. Non-absorbable disaccharides, such as lactulose, have traditionally been regarded as first-line pharmacotherapy for patients with HE. However, multiple adverse events have been associated with their use. In addition, recent literature has questioned the true efficacy of the disaccharides for this indication. Neomycin, metronidazole and vancomycin may be used as alternative treatments for patients intolerant or unresponsive to non-absorbable disaccharides. Antimicrobials reduce bacterial production of ammonia and other bacteria-derived toxins through suppression of intestinal flora. Neomycin has been reported to be as effective as lactulose, and similar efficacy has been reported with vancomycin and metronidazole for the management of HE. However, the adverse effects frequently associated with these antimicrobials limit their use as first-line pharmacological agents. Neomycin is the most commonly used antimicrobial for HE and, although poorly absorbed, systemic exposure to the drug in sufficient amounts causes hearing loss and renal toxicity. Long-term neomycin therapy requires annual auditory testing and continuous monitoring of renal function. Long-term use of metronidazole has been associated with neurotoxicity in patients with cirrhosis, including dose-dependent peripheral neuropathy. Vancomycin may be a safer option for HE in patients with chronic liver disease; however, limited experience, possible bacterial overgrowth and risk for enteric bacteria resistance preclude the routine use of vancomycin for HE. Rifaximin is a novel antimicrobial agent with a wide spectrum of activity that has shown promise as an alternative antimicrobial treatment option for HE. Several clinical trials have compared rifaximin to the disaccharides, lactulose and lactitol, and the antimicrobial neomycin. Rifaximin appears to be at least as effective as conventional drug therapy and has been associated with fewer adverse effects due to its limited systemic absorption. The available clinical data appear to support a favourable benefit-risk ratio for rifaximin, which has shown efficacy with an improved tolerability profile. Future studies are needed in order to truly characterize its cost effectiveness in today's healthcare environment. Other less frequently utilized alternative treatment options include administration of benzodiazepine receptor antagonists, branched-chain amino acids, ornithine aspartate, zinc supplementation, sodium benzoate, dopamine receptor agonists, acarbose and probiotics. Presently, there is relatively limited clinical data supporting their routine use in HE.

Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose.

The purpose of these studies was to gain insight into the pathophysiology of pure osmotic diarrhea and the osmotic diarrhea caused by carbohydrate malabsorption. Diarrhea was induced in normal volunteers by ingestion of polyethylene glycol (PEG), which is nonabsorbable, not metabolized by colonic bacteria, and carries no electrical charge. In PEG-induced diarrhea, (a) stool weight was directly correlated with the total mass of PEG ingested; (b) PEG contributed 40-60% of the osmolality of the fecal fluid, the remainder being contributed by other solutes either of dietary, endogenous, or bacterial origin; and (c) fecal sodium, potassium, and chloride were avidly conserved by the intestine, in spite of stool water losses exceeding 1,200 g/d. Diarrhea was also induced in normal subjects by ingestion of lactulose, a disaccharide that is not absorbed by the small intestine but is metabolized by colonic bacteria. In lactulose-induced diarrhea, (a) a maximum of approximate 80 g/d of lactulose was metabolized by colonic bacteria to noncarbohydrate moieties such as organic acids; (b) the organic acids were partially absorbed in the colon; (c) unabsorbed organic acids obligated the accumulation of inorganic cations (Na greater than Ca greater than K greater than Mg) in the diarrheal fluid; (d) diarrhea associated with low doses of lactulose was mainly due to unabsorbed organic acids and associated cations, whereas with larger doses of lactulose unmetabolized carbohydrates also played a major role; and (e) the net effect of bacterial metabolism of lactulose and partial absorption of organic acids on stool water output was done dependent. With low or moderate doses of lactulose, stool water losses were reduced by as much as 600 g/d (compared with equimolar osmotic loads of PEG); with large dose, the increment in osmotically active solutes within the lumen exceeded the increment of the ingested osmotic load, and the severity of diarrhea was augmented.