Rifaximin-α reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial.

BACKGROUND & AIMS: Rifaximin-α is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-α reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE. METHODS: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-α (550 mg BID) or placebo for 90 days. PRIMARY OUTCOME: 50% reduction in neutrophil oxidative burst (OB) at 30 days. SECONDARY OUTCOMES: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis. RESULTS: Patients were well-matched: median MELD (11 rifaximin-α vs. 10 placebo). Rifaximin-α did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-α. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-α (TNF-α) (p <0.001). Rifaximin-α suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α- and interleukin-17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96). CONCLUSION: Rifaximin-α led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflammation. Rifaximin-α plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02019784. LAY SUMMARY: In this clinical trial, we examined the underlying mechanism of action of an antibiotic called rifaximin-α which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). We show that rifaximin-α suppresses gut bacteria that translocate from the mouth to the intestine and cause the intestinal wall to become leaky by breaking down the protective mucus barrier. This suppression resolves encephalopathy and reduces inflammation in the blood, preventing the development of infection.

Preoperative Serum Vedolizumab Levels Do Not Impact Postoperative Outcomes in Inflammatory Bowel Disease.

BACKGROUND: Vedolizumab has been proposed to lead to fewer postoperative complications because of its gut specificity. Studies, however, suggest an increased risk of surgical site infections, yet the data are conflicting. OBJECTIVE: This study aimed to assess the effect of vedolizumab drug levels on postoperative outcomes in patients undergoing major abdominal surgery for IBD. DESIGN: This was a retrospective study of a prospectively maintained database. SETTING: Patients were operated on by a single surgeon at an academic medical center. PATIENTS: A total of 72 patients with IBD undergoing major abdominal surgery were included. INTERVENTIONS: Patients were exposed preoperatively to vedolizumab. MAIN OUTCOME MEASURES: The primary outcome measured was the postoperative morbidity in patients who had IBD with detectable vs undetectable vedolizumab levels. RESULTS: A total of 72 patients were included in the study. Thirty-eight patients had detectable vedolizumab levels (>1.6 µg/mL), and 34 had undetectable vedolizumab levels. The overall rate of complications was 39%, and ileus was the most common complication. There were no significant differences in clinical variables between the detectable and undetectable vedolizumab level patient groups except for the time between the last dose and surgery (p < 0.01). There were 42 patients in the ulcerative colitis cohort; 48% had an undetectable vedolizumab level and 52% had a detectable vedolizumab level. There were no differences in any postoperative morbidity between ulcerative colitis groups. The Crohn's cohort had 27 patients; 48% had an undetectable vedolizumab levels and 52% had a detectable vedolizumab level. There was a significantly lower incidence of postoperative ileus in patients who had Crohn's disease with detectable vedolizumab levels compared with patients with an undetectable vedolizumab level (p < 0.04). LIMITATIONS: Limitations include a low overall patient population and a high rate of stoma formation. CONCLUSIONS: Serum vedolizumab levels do not influence postoperative morbidity in IBD. Vedolizumab may reduce the incidence of postoperative ileus in patients with Crohn's disease. See Video Abstract at http://links.lww.com/DCR/B574. LOS NIVELES DE VEDOLIZUMAB EN SUERO PREOPERATORIO, NO AFECTAN LOS RESULTADOS POSTOPERATORIOS EN LA ENFERMEDAD INFLAMATORIA INTESTINAL: ANTECEDENTES:Se ha propuesto que el vedolizumab presenta menos complicaciones postoperatorias debido a su especificidad intestinal. Sin embargo, estudios sugieren un mayor riesgo de infecciones en el sitio quirúrgico, aunque los datos son contradictorios.OBJETIVO:Evaluar el efecto en los niveles del fármaco vedolizumab, en resultados postoperatorios de pacientes sometidos a cirugía mayor abdominal, por enfermedad inflamatoria intestinal.DISEÑO:Estudio retrospectivo de una base de datos mantenida prospectivamente.ENTORNO CLÍNICO:Pacientes intervenidos por un solo cirujano en un centro médico académico.PACIENTES:Un total de 72 pacientes con enfermedad inflamatoria intestinal sometidos a cirugía mayor abdominal.INTERVENCIONES:Exposición preoperatoria a vedolizumab.PRINCIPALES MEDIDAS DE VALORACIÓN:Morbilidad postoperatoria en pacientes con enfermedad inflamatoria intestinal, con niveles detectables versus no detectables de vedolizumab.RESULTADOS:Se incluyó en el estudio a un total de 72 pacientes. Treinta y ocho pacientes tuvieron niveles detectables de vedolizumab (> 1,6 mcg / ml) y 34 con niveles no detectables de vedolizumab. La tasa global de complicaciones fue del 39% y el íleo fue la complicación más común. No hubo diferencias significativas en las variables clínicas entre los grupos de pacientes con niveles detectables y no detectables de vedolizumab, excepto por el intervalo de tiempo entre la última dosis y la cirugía (p <.01). La cohorte de colitis ulcerosa tuvo 42 pacientes, el 48% con un nivel no detectable de vedolizumab y el 52% un nivel detectable de vedolizumab. No hubo diferencias en ninguna morbilidad postoperatoria entre los grupos de colitis ulcerosa. La cohorte de Crohn tuvo 27 pacientes, 48% con niveles no detectables de vedolizumab y el 52% con niveles detectables de vedolizumab. Hubo una incidencia significativamente menor de íleo postoperatorio en pacientes de Crohn con niveles detectables de vedolizumab, comparados con los pacientes con un nivel no detectable de vedolizumab (p <0,04).LIMITACIONES:Las limitaciones incluyen una baja población general de pacientes y una alta tasa de formación de estomas.CONCLUSIONES:Los niveles séricos de vedolizumab no influyen en la morbilidad postoperatoria de la enfermedad inflamatoria intestinal. Vedolizumab puede reducir la incidencia de íleo postoperatorio en pacientes de Crohn. Consulte Video Resumen en http://links.lww.com/DCR/B574.

Alterations in microbiota and their metabolites are associated with beneficial effects of bile acid sequestrant on icteric primary biliary Cholangitis.

Background: Increasing data suggests an interaction between bile acids and intestinal microbiota in the pathogenesis of primary biliary cholangitis (PBC). Bile acid sequestrants are widely used to bind bile acids in the intestinal lumen and are therefore posited to impact gut bacteria. Herein we aimed to investigate the effects of cholestyramine on the bile acid profile and gut microbiome in a cohort of icteric PBC patients.Results: Thirty-three PBC patients were treated with cholestyramine, serum and stool samples were collected at baseline, 4 and 16 weeks. Shotgun metagenomic sequencing and targeted metabolomic profiling were performed. Following cholestyramine administration, patients exhibited a high interpersonal variability in remission of cholestasis, and were therefore dichotomized according to the decrease of total bilirubin. Gut microbial co-abundance networks showed distinct taxa interactions between subjects with superior remission (SR) and those with inferior remission (IR) at baseline. After treatment, compositional shifts of the microbiome in the SR group were characterized with enrichment of two Lachnospiraceae species, typically producing short-chain fatty acids (SCFAs). In contrast, Klebsiella pneumonia, a commensal pathobiont, was only increased in the IR group. Correspondingly, metabolome analysis demonstrated that patients with SR, but not IR, were marked by elevations of SCFAs including valeric acid and caproic acid. Finally, integrative analysis identified robust associations between the variations of microbiota, metabolites, and inflammatory cytokines in SR group, indicating potential mechanistic links.Conclusions: Beneficial responses caused by cholestyramine were closely related with compositional and functional alterations in gut commensal, highlighting the possibility of exploring bile acid-microbiota interactions for treating PBC.

Improving the Gastrointestinal Stability of Linaclotide.

High susceptibility to proteolytic degradation in the gastrointestinal tract limits the therapeutic application of peptide drugs in gastrointestinal disorders. Linaclotide is an orally administered peptide drug for the treatment of irritable bowel syndrome with constipation (IBS-C) and abdominal pain. Linaclotide is however degraded in the intestinal environment within 1 h, and improvements in gastrointestinal stability might enhance its therapeutic application. We therefore designed and synthesized a series of linaclotide analogues employing a variety of strategic modifications and evaluated their gastrointestinal stability and pharmacological activity at its target receptor guanylate cyclase-C. All analogues had substantial improvements in gastrointestinal half-lives (>8 h vs linaclotide 48 min), and most remained active at low nanomolar concentrations. This work highlights strategic approaches for the development of gut-stable peptides toward the next generation of orally administered peptide drugs for the treatment of gastrointestinal disorders.

Discovery of 3-(4-(2-((1H-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease.

TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound 14l exhibited acceptable TYK2 inhibition with an IC50 value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of 14l were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, 14l reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, 14l was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.

Preventive Effects of Continuous Betaine Intake on Cognitive Impairment and Aberrant Gene Expression in Hippocampus of 3xTg Mouse Model of Alzheimer's Disease.

BACKGROUND: The deposition of amyloid-ß (Aß) and hyperphosphorylation of tau are well-known as the pathophysiological features of Alzheimer's disease (AD), leading to oxidative stress and synaptic deficits followed by cognitive symptoms. We already demonstrated that betaine (glycine betaine) prevented cognitive impairment and hippocampal oxidative stress in mice intracerebroventricularly injected with an active fragment of Aß, whereas the effect of betaine in chronic models of AD remains unknown. OBJECTIVE: Our objective was to investigate the effects of chronic betaine intake on cognitive impairment and aberrant expression of genes involved in synapse and antioxidant activity in the hippocampus of a genetic AD model. METHODS: We performed cognitive tests and RT-PCR in the hippocampus in 3xTg mice, a genetic AD model. RESULTS: Cognitive impairment in the Y-maze and novel object recognition tests became evident in 3xTg mice at 9 months old, and not earlier, indicating that cognitive impairment in 3xTg mice developed age-dependently. To examine the preventive effect of betaine on such cognitive impairment, 3xTg mice were fed betaine-containing water for 3 months from 6 to 9 months old, and subsequently subjected to behavioral tests, in which betaine intake prevented the development of cognitive impairment in 3xTg mice. Additionally, the expression levels of genes involved in synapse and antioxidant activity were downregulated in hippocampus of 3xTg mice at 9 months old compared with age-matched wild-type mice, which were suppressed by betaine intake. CONCLUSION: Betaine may be applicable as an agent preventing the progression of AD by improving the synaptic structure/function and/or antioxidant activity.

Differences in In Vitro Properties of Pancreatin Preparations for Pancreatic Exocrine Insufficiency as Marketed in Russia and CIS.

BACKGROUND: Pancreatic enzyme-replacement therapy (PERT), provided as pancreatin to patients with pancreatic exocrine insufficiency (PEI), is considered an essential substitute for the pivotal physiological function the pancreas fulfills in digestion. PEI involves a reduction in the synthesis and secretion of pancreatic enzymes (lipase, protease, amylase), which leads to an inadequate enzymatic response to a meal and consequently to maldigestion and malabsorption of nutrients. The efficacy of PERT is strongly dependent on enzyme activity, dissolution, and pancreatin particle size. OBJECTIVE: The physiological properties of eight pancreatin preparations (nine batches; five different brands) available in Russia and CIS (Commonwealth of Independent States: Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyzstan, Moldova, Russia, Tajikistan, Uzbekistan) were investigated. METHODS: The lipase activity, dissolution, and particle size distribution of samples from multiple batches of pancreatin of different strengths were measured. RESULTS: Regarding lipase activities, all pancreatin preparations except Micrazim® matched the labeled content. Considerable differences were observed in particle size and dissolution. CONCLUSION: Pancreatin preparations available in Russia and CIS demonstrate product-to-product and batch-to-batch variability regarding the measured properties of lipase activity, dissolution, and particle size. This may impact the efficacy of PERT and therefore clinical outcomes.

Exploiting disease-induced changes for targeted oral delivery of biologics and nanomedicines in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic and progressive disorder with destructive inflammation in the gastrointestinal tract (GIT). Biologics have changed the management of IBD, but have serious limitations, which is associated with their systemic administration via injection. Oral administration is the most accepted route of drug administration. However, the physiological barriers of the GIT pose significant challenges for oral administration of biologics, making this route of administration currently unavailable. The status of tissue barriers to oral drug delivery is altered in IBD. This may bring more challenges, but also present opportunities for oral delivery of biologics. This article provides an overview of disease-induced alterations of GIT barriers in IBD and discusses challenges, opportunities and commonly-utilised strategies for oral delivery of complex therapeutics, including biologics and nanomedicines.

Amelioration of muscular spasm-induced pain of Guangtongxiao recipe in a non-everted gut sac in vitro model.

BACKGROUND: The modern study of the traditional Chinese medicine (TCM) compound recipes is a complex issue because of the large number of components in the recipes that would produce several metabolites after entering the body. The TCM compound recipes are known to have the advantage of synergistic treatment by multiple targets due to diverse components. Therefore, a research method that can reflect the overall effect of compounds with multi-components is essential. The pharmacological studies of the classic TCM compound recipes mainly use the sero-pharmacological method. It is a semi-in vivo study method, and the drug to be tested in the in vitro experiment is the drug-containing serum from the model animals (the drug to be tested is a mixed drug system containing the prototype drugs in animal bodies that have pharmacodynamic effects and the metabolites). Herein, a safe and effective external TCM recipe was used to develop another semi-in vivo experimental method to reflect the overall effects of TCM. AIM: To observe the effects of in-vitro intestinal absorption liquid of aqueous extracts of the TCM compound recipe-Guangtongxiao foam aerosol (Guangtongxiao)-on the tension of isolated rectal rings of mouse and investigate the underlying mechanisms of antispasmodic and amelioration of muscular spasm-induced pain. METHODS: Intestinal absorption liquid of the Guangtongxiao aqueous extract at the five time points (30, 45, 75, 105, and 120 min) was prepared using a non-everted gut sac method. The isolated rectal rings of mice were prepared by pre-contraction using potassium chloride (KCl) or acetylcholine chloride (ACh) to make steady contraction. The intestinal absorption liquid were added cumulatively to the sink with the constricted rectal rings. The effects of the five groups of the intestinal absorption liquid with different drug concentration were observed on the tension of the isolated rectal rings. Then the ex vivo perfusion of the mouse rectal ring was performed as same as Guangtongxiao intestinal absorption liquid experiments, and the effects of two major components of Guangtongxiao, paeoniflorin (Pae) and tetrahydropalmatine (THP), on the rectal ring pre-treated with high concentration of KCl and ACh to induce contraction were studied. RESULTS: The relaxation rate of the five groups of the intestinal canals increased significantly with 3200 µL cumulative sample volume as compared to the blank group (P < 0.01). It suggested that the relaxation activity of the intestinal absorption liquid enhanced significantly with the prolongation of the interaction between isolated rectal rings and intestinal absorption liquid in a time-dependent manner. Also, significant differences were detected while comparing between the 120-min intestinal absorption liquid group and the blank group with respect to various cumulative sampling volumes (P < 0.01). In addition, the intestinal relaxation rate elevated gradually with the increase in sampling volume, indicating that the concentrations of active substances in the intestinal absorption liquid prepared by the non-everted gut sac model increased and the intestinal relaxation activity was enhanced with the prolongation of the absorption time in a dose-dependent manner. And Pae and THP in a concentration-dependent manner caused relaxation of the rectal ring, which is pretreated with high K+(KCl) and ACh to induce contraction. The EC50 of Pae and THP was 8.67 × 10-5 M (6.68 × 10-5-1.13 × 10-4) and 1.41 × 10-4 M (1.24 × 10-4-1.61 × 10-4) in the contraction model induced by KCl, and was 6.15 × 10-5 M (4.47 × 10-5-8.45 × 10-5), and 1.31 × 10-4 M(1.22 × 10-4-1.42 × 10-4) in the model induced by ACh, respectively. CONCLUSION: The intestinal absorption liquid of Guangtongxiao exerted a remarkable relaxation activity for the rectal rings, and relaxation of the smooth muscle tension might be one of the antispasmodic mechanisms of Guangtongxiao compound recipe. Also, adopting a semi-in-vivo experimental method to study the efficacy of topical external TCM recipe medicine is optimal.

OPTICORE™, an innovative and accurate colonic targeting technology.

Inflammatory bowel disease (IBD) is a debilitating condition, estimated to affect 7 million people worldwide. Current IBD treatment strategies are substandard, relying on colonic targeting using the pH gradient along the gastrointestinal tract. Here, we describe an innovative colonic targeting concept, OPTICORE™ coating technology. OPTICORE™ combines two release triggers (pH and enzyme: Phloral™) in the outer layer, with an inner layer promoting a release acceleration mechanism (Duocoat™). The technology comprises an inner layer of partially neutralized enteric polymer with a buffer agent and an outer layer of a mixture of Eudragit® S and resistant starch. 5-aminosalicylic acid (5-ASA) tablets were coated with different inner layers, where the type of polymer, buffer salt concentration and pH of neutralization, were investigated for drug release acceleration. Buffer capacity of polymethacrylate neutralized polymer significantly contributes to the buffer capacity of the inner layer formulation, while buffer salt concentration is a major contributor to dispersion buffer capacity in the case of hypromellose enteric polymer formulations. An interplay between buffer capacity, pH and ionic strength contributes to an accelerated drug release. Resistant starch does not impact the enteric properties but allows for drug release mediated by colonic bacterial enzymes, ensuring complete drug release. Therefore, OPTICORE™ technology is designed to offer significant advantages over standard enteric coatings, particularly allowing for more accurate colonic drug delivery in ulcerative colitis patients.

The tissue distribution and excretion study of mosapride and its active des-p-fluorobenzyl and 4'-N-oxide metabolites in rats by ultra-high performance liquid chromatography-tandem mass spectrometry method.

1. Mosapride is a potent gastroprokinetic agent, and des-p-fluorobenzyl mosapride (M1) and mosapride-N-oxide (M2) are its two major active metabolites.2. The validated ultra-high performance liquid chromatography-tandem mass spectrometry method was successfully applied to the distribution and excretion of mosapride and its two active metabolites.3. Mosapride and its metabolites were distributed widely and rapidly in various tissues. The highest concentration of mosapride and M2 in both male and female rats was found in the duodenum, followed by cecum.4. The excretion study showed that a total of 71.8% (37.6, 22.4 and 11.8% for urine, feces and bile, respectively) and 66.3% (35.7, 22.8 and 7.8% for urine, feces and bile) of administered dose was recovered from male and female excreta. M1 was excreted in the largest dose percentage, followed by mosapride and M2, and the total cumulative excretion amounts were about 36.9, 28.1 and 11.6% in male rat, while 24.3, 25.9 and 16.2% in female rat. The results demonstrated for the first time that M2 is one of the important excretion forms of mosapride, which is much higher than that of mosapride in urine.5. This work could provide valuable information for further pharmacological and clinical studies of mosapride.

Pharmacological and computational evaluation of fig for therapeutic potential in hyperactive gastrointestinal disorders.

BACKGROUND: Ficus palmata (Fig), are distributed in different parts of the world, and are used in traditional medicine to treat various ailments including inflammation, tumor, epilepsy, jaundice, influenza and bacillary dysentery. The present study aimed to evaluate the antidiarrheal, antisecretary, antispasmodic, antiulcer and anti motility properties of Ficus palmata. METHODS: In-vivo, in-vitro and in-silico techniques were used to investigate various gastrointestinal effects of Ficus palmata. Antidiarrheal, antisecretary, antispasmodic, antiulcer, anti motility and molecular docking were performed using castor oil induced diarrhea and fluid accumulation, isolated tissue preparations, ethanol-HCl induced ulcer assay, charcoal meal transit time and Auto Doc Vina. RESULTS: Ficus palmata crude extract (Fp.Cr) exhibited protection against castor oil-induced diarrhea in mice and dose-dependently inhibited intestinal fluid secretions. Fp.Cr caused relaxation of spontaneous and K+ (80 Mm)-induced contractions in isolated rabbit jejunum preparations. It showed protective effect against gastric ulcers induced by ethanol-hydrochloric acid in rats. Fp.Cr reduced distance travelled by charcoal meal in the gastrointestinal transit model in mice. The plant constituents: psoralenoside and bergapten showed high binding affinities (E-value ≥ - 6.5 Kcal/mol) against histaminergic H1, calmodulin and voltage gated L-type calcium channels, while showed moderate affinities (E-value ≥7 Kcal/mol) against dopaminergic D2, adrenergic α1, muscranic M3, mu-opioid, whereas revealed lower affinities (E-value ≥9.5 Kcal/mol) vs. muscranic M1, histaminergic H2 and H+/K+ ATPase pump. Germanicol acetate and psoralene exhibited weak affinities against aforementioned targets. CONCLUSION: This study reveals that Ficus palmata possesses anti-diarrheal, anti-secretory, anti-spasmodic, anti-motility and anti-ulcer activities. The various constituents reveal different binding affinities against target proteins, which mediate the gastrointestinal functions.

Gastrin secretion in normal subjects and diabetes patients is inhibited by glucagon-like peptide 1: a role in the gastric side effects of GLP-1-derived drugs?

Background: Randomized and controlled trials of glucagon-like peptide-1 (GLP-1) derived drugs have shown that the most frequent adverse symptoms are gastrointestinal. Some of the side effects such as dyspepsia, nausea and upper abdominal pain may well be of gastric origin. Since the antral hormone gastrin regulates gastric secretion of acid and enzymes and contributes to the regulation of gastric motility, we examined the effect of GLP-1 on the secretion of gastrin in normal subjects and diabetes patients.Method: Plasma was sampled from ten healthy subjects and ten patients with diabetes mellitus type 1 with glucose clamped between 6 and 9 mM. GLP-1 or saline were infused for 4 h during and after a meal. Plasma concentrations of gastrin and GLP-1 were measured using specific radioimmunoassays.Results: Basal plasma concentrations of gastrin were similar in controls and patients. After the meal, the gastrin concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of gastrin significantly, most pronounced in the diabetes patients.Conclusions: The results show that GLP-1 infusion suppresses the postprandial secretion of gastrin in normal subjects and even more so in the diabetes patients. The results may therefore shed further light on the upper gastrointestinal side effects of GLP-1-derived drugs in diabetic patients.

Lactulose: Patient- and dose-dependent prebiotic properties in humans.

Lactulose is a disaccharide used in clinical practice since 1957 and has since been tested in the treatment of many human disorders, including chronic constipation, hepatic encephalopathy, and chronic kidney disease. Its mode of action is based on the lactulose fermentation by intestinal microbiota. Based on in silico, in vitro and in vivo studies we comprehensively review here the impact of lactulose on human gut/fecal and vaginal microbiota composition and both fecal and blood metabolomes. However, both in vitro and in vivo studies summarized in this review have revealed that the effects of lactulose on human microbiota composition are both patient- and dose-dependent. This highlights the need of heterogeneity indication in clinical trials.

New Zealand Society of Gastroenterology Guidelines on Therapeutic Drug Monitoring in Inflammatory Bowel Disease.

The incidence of inflammatory bowel disease (IBD) in New Zealand has increased over the last several decades. The management of IBD has been transformed since the introduction of monoclonal antibody drugs. Other medications used in the treatment of IBD include amino-salicylates, steroids, thiopurines and methotrexate. Therapeutic drug monitoring (TDM) involves the measurement of serum drug levels or active metabolites and anti-drug antibodies. TDM is essential for a personalised approach to the management of patients with IBD and is used to optimise drug efficacy and reduce the risk of toxicity. In IBD, TDM can be used for checking adherence, evaluating drug toxicity, identifying hypermethylators, assessing loss of response and in decisions regarding treatment escalation or de-escalation. Management decisions in patients on a thiopurine are facilitated by checking TPMT enzyme activity and thiopurine metabolite levels. Measurement of drug trough levels and anti-drug antibodies can result in individualised treatment decisions in patients on biologics. In addition to using TDM in patients who fail therapy, proactive TDM can potentially facilitate early treatment decisions, albeit more work is needed in this area. The clinical benefits of reactive TDM are well documented and this has been shown to be cost effective. Studies have shown that combination therapy in patients on a biologic leads to better clinical outcomes. Effective use of drugs in the treatment of IBD is even more imperative in the New Zealand setting due to relatively fewer options of funded treatment, and the limitations on the use of available drugs. This document represents the current guidelines of the New Zealand Society of Gastroenterology on TDM in IBD.

Vitamin A and inflammatory bowel diseases: from cellular studies and animal models to human disease.

INTRODUCTION: Vitamin A (VA) and metabolites such as Retinoic Acid (RA) and all-trans-RA (at-RA) are crucial in the modulation of the immune system and may be determinative in the balance of the immune responses. Inflammatory bowel diseases (IBD) consist of chronic relapsing and heterogeneous disorders with not well-known etiology. Due to its role in inflammatory processes, VA may be helpful in the treatment of IBD. Area covered: As VA plays a significant role in the inflammatory processes, this review aims to show the potential role of this vitamin in IBD, searching for cellular studies, animal models, and studies with humans. Expert commentary: Many studies have described the importance of alternative therapeutic approaches for IBD. Due to its role in the immune system, VA may also exert an indispensable role in the IBD. Nevertheless, some authors have shown that these compounds could stimulate the release of pro-inflammatory cytokines. For these reasons, more studies should be performed to establish the precise mechanisms of VA and its metabolites in systemic and intestinal inflammation.

Developments in bile salt based therapies: A critical overview.

Bile acids, amphipathic molecules known for their facilitating role in fat absorption, are also recognized as signalling molecules acting via nuclear and membrane receptors. Of the bile acid-activated receptors, the Farnesoid X Receptor (FXR) and the G protein-coupled bile acid receptor-1 (Gpbar1 or TGR5) have been studied most extensively. Bile acid signaling is critical in the regulation of bile acid metabolism itself, but it also plays a significant role in glucose, lipid and energy metabolism. Activation of FXR and TGR5 leads to reduced hepatic bile salt load, improved insulin sensitivity and glucose regulation, increased energy expenditure, and anti-inflammatory effects. These beneficial effects render bile acid signaling an interesting therapeutic target for the treatment of diseases such as cholestasis, non-alcoholic fatty liver disease, and diabetes. Here, we summarize recent findings on bile acid signaling and discuss potential and current limitations of bile acid receptor agonist and modulators of bile acid transport as future therapeutics for a wide-spectrum of diseases.

Identification and structural characterization of hydrolytic degradation products of alvimopan by LC/QTOF/MS/MS and NMR studies.

Alvimopan (ALV), a peripherally acting mu-opioid receptor (PAM-OR) antagonist used for the treatment of postoperative ileus, was examined for its degradation behaviour under different stress conditions. A total of five degradation products (DP1-DP5) were formed and identified using high-performance liquid chromatography (HPLC) method. Primarily, complete fragmentation pathways of the protonated drug and its degradation products (DP1-DP5) were elucidated by using liquid chromatography-mass spectrometry (LC/MS) and high-resolution mass spectrometry (HRMS) studies. Subsequently, three major degradation products (DP1-DP3) formed under acid hydrolytic stress conditions were isolated by preparative-high performance liquid chromatography (prep-HPLC) and subjected to nuclear magnetic resonance (NMR) experiments (1D and 2D NMR) for further confirmation of their structures. All the spectral data from LC/QTOF/MS/MS and NMR studies were used for the identification and structural characterization of degradation products (DP1-DP5).

[S-methylmethionin (vitamin U): experimental studies and clinical perspective].

Vitamin-like compound S-methyl-L-methionine (SMM, historically called vitamin U) is a metabolic agent, affects metabolic processes, which causes a wide variety of effects. The data of the studies demonstrating gastroprotective effect, hypolipidemic and antioxidant effect, participation in regulation of adipocyte function, homocysteine exchange are presented. SMM is involved in all methylation reactions in which another activated form of methionine, S-adenosylmethionine, normally participates. The results of the observed studies indicate a possible expansion of the clinical use of S-methylmethionine.