Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

There is an unmet need for effective pharmacological therapies for constipation, a symptom that significantly deteriorates patients' quality of life and impacts health care. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor and has been shown to exert prokinetic effects on gastrointestinal (GI) motility via the vagus and pelvic nerves. The pharmacological potential of ghrelin is hampered by its short half-life. Ghrelin receptor (GRLN-R) agonists with enhanced pharmacokinetics were thus developed. Centrally penetrant GRLN-R agonists stimulate defecation and improve impaired lower GI transit in animals and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other GRLN-R analogs which are in preclinical or clinical stages of development for the management of disorders with underlying GI hypomotility, like constipation

Recurrent acute pancreatitis prevention by the elimination of alcohol and cigarette smoking (REAPPEAR): protocol of a randomised controlled trial and a cohort study

Background/objectives Acute recurrent pancreatitis (ARP) due to alcohol and/or tobacco abuse is a preventable disease which lowers quality of life and can lead to chronic pancreatitis. The REAPPEAR study aims to investigate whether a combined patient education and cessation programme for smoking and alcohol prevents ARP. Methods and analysis The REAPPEAR study consists of an international multicentre randomised controlled trial (REAPPEAR-T) testing the efficacy of a cessation programme on alcohol and smoking and a prospective cohort study (REAPPEAR-C) assessing the effects of change in alcohol consumption and smoking (irrespective of intervention). Daily smoker patients hospitalised with alcohol-induced acute pancreatitis (AP) will be enrolled. All patients will receive a standard intervention priorly to encourage alcohol and smoking cessation. Participants will be subjected to laboratory testing, measurement of blood pressure and body mass index and will provide blood, hair and urine samples for later biomarker analysis. Addiction, motivation to change, socioeconomic status and quality of life will be evaluated with questionnaires. In the trial, patients will be randomised either to the cessation programme with 3-monthly visits or to the control group with annual visits. Participants of the cessation programme will receive a brief intervention at every visit with direct feedback on their alcohol consumption based on laboratory results. The primary endpoint will be the composite of 2-year all-cause recurrence rate of AP and/or 2-year all-cause mortality. The cost-effectiveness of the cessation programme will be evaluated. An estimated 182 participants will be enrolled per group to the REAPPEAR-T with further enrolment to the cohort

Measurement of Silver Nanolayer Absorption by the Body in an in Vivo Model of Inflammatory Gastrointestinal Diseases

Layers of silver particles are used in the studies on pathophysiology and treatment of diseases, both in pre-clinical and clinical conditions. Silver layers can be formed using different techniques and on different substrates. Deposition by magnetron sputtering on glass beads was used in this study. Silver absorption by the body was estimated by calculating the difference in thickness of the silver nanolayer deposited on a bead and measured before and after application of the bead in an animal model of gastrointestinal inflammation. Recommendations for the minimal thickness of silver nanolayer deposited on glass beads were worked out for further studies

Dietary Interventions in Inflammatory Bowel Disease

Inflammatory bowel disease, which primarily includes ulcerative colitis and Crohn’s disease, is a group of chronic diseases of the gastrointestinal tract. Mainly affecting young people, it is characterized by periods of exacerbation and remission. In recent years, there has been an increase in the prevalence of inflammatory bowel disease worldwide, including Poland. The potential impact of nutrition and selected dietary components that are directly or indirectly involved in the pathogenesis of intestinal lesions in IBD is not fully clear. Evaluating the impact of diet on the course of IBD is very complex due to the fact that regardless of a dietary model adopted, each one is based on consumption of many different food groups which affect one another. However, the growing need to produce dietary recommendations for these patients has prompted the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) to develop nutrition guidelines for the patients. The present paper characterizes the dietary models most commonly discussed in research studies and their potential impact on IBD activity

Efficacy, Safety and Future Perspectives of JAK Inhibitors in the IBD Treatment

Although development of biologics has importantly improved the effectiveness in inducing and maintaining remission in inflammatory bowel disease (IBD), biologic therapies still have several limitations. Effective, low-cost drug therapy with good safety profile and compliance is therefore a substantial unmet medical need. A promising target for IBD treatment strategies are Janus kinase (JAK) inhibitors, which are small molecules that interact with cytokines implicated in pathogenesis of IBD. In contrast to monoclonal antibodies, which are able to block a single cytokine, JAK inhibitors have the potential to affect multiple cytokine-dependent immune pathways, which may improve the therapeutic response in some IBD patients. Tofacitinib, inhibiting signaling via different types of JAKs, has been already approved for ulcerative colitis, and several other small-molecule are still under investigation. However, one of the main concerns about using JAK inhibitors is the risk of thromboembolic events. Moreover, patients with COVID-19 appear to have an increased susceptibility for immunothrombosis. Therefore, thrombotic complications may become a serious limitation in the use of JAK inhibitors in the SARS-CoV-2 pandemic. As many questions about safety and efficacy of small molecules still remain unclear, in our review we present the current data regarding approved JAK inhibitors, as well as those in clinical development for the treatment of IBD

AdipoRon, an Orally Active, Synthetic Agonist of AdipoR1 and AdipoR2 Receptors Has Gastroprotective Effect in Experimentally Induced Gastric Ulcers in Mice

Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. Methods: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. Results: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. Conclusions: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers