Eriko Hosomi

The efficacy of intensive granulocyte and monocyte adsorption apheresis in a patient with Crohn's disease complicated by extensive subcutaneous aseptic neutrophilic abscesses

BACKGROUND AND AIMS Subcutaneous aseptic abscess is one phenotype of neutrophilic dermatitis. We were interested to see if a case of steroid refractory Crohns disease (CD) complicated by subcutaneous aseptic neutrophilic abscesses responds to intensive granulocyte/monocyte adsorptive apheresis (GMA). METHODS The patient was a 21-year-old male with worsening severe CD while on oral prednisolone (30 mg/day). His symptoms included fever, bloody diarrhoea and multiple painful subcutaneous nodules throughout his body. Skin biopsy showed chronic panniculitis with neutrophilic infiltrates. Further, colonoscopy showed oedematous sigmoid colon, while colonic biopsy showed non-caseous granuloma. Because biologics were feared to increase the risk of bacteraemia as the result of germ culture on his pus was not known at the time, we decided to treat this case with GMA. Five GMA sessions with the Adacolumn over 5 consecutive days (daily GMA) were initiated. RESULTS On admission, his CD activity index (CDAI) was 355, C-reactive protein (CRP) 11.2 mg/dL. After 5 GMA sessions, CDAI decreased to 170, and CRP fell to 5.0 mg/dL, with no fever. GMA was restarted at 2 sessions/week (total 10 sessions). The patients CDAI fell to <150, and the skin lesions re-epithelialized. CONCLUSIONS In this CD case complicated by subcutaneous aseptic neutrophilic abscesses, GMA appeared to be effective. Our impression is that when biopsy reveals neutrophil infiltrate is a major feature of the lesions, GMA should be considered. As GMA appears to have no safety concerns, a frequent GMA protocol, like daily followed by 2 to 3 times/week should be preferred over the routine weekly GMA.

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model.

Functional dyspepsia (FD) is one of the most common disorders of gastrointestinal (GI) diseases. However, no curable treatment is available for FD because the detailed mechanism of GI dysfunction in stressed conditions remains unclear. We aimed to clarify the association between endogenous acylated ghrelin signaling and gastric motor dysfunction and explore the possibility of a drug with ghrelin signal‐enhancing action for FD treatment.

Ghrelin and Functional Dyspepsia

Food consumption is supposed to affect the onset of functional gastrointestinal disorder (FGID), particularly functional dyspepsia (FD). Many secretory fluids and digestive enzymes are secreted from digestive organs in response to food consumption and are then combined with the crushed and mixed food and transported, thereby inducing gastrointestinal motility. Gastrointestinal hormones are active substances that promote these digestive and absorptive functions. Furthermore, in recent years, many gastrointestinal hormones were found to have appetite-regulatory activity, and the abnormal secretion of gastrointestinal hormones and changes in their physiological activity have been suggested to contribute to FD onset. Although some gastrointestinal hormones have anorexic effects, only ghrelin have an orexigenic action and it also stimulates gastric motility. This short review presents the physiological activity of ghrelin as well as the regulatory mechanisms underlying appetite, acid secretion, and gastric motility via the brain–gut axis. In this review, we present the action of ghrelin on the secretion of gastric acid and its mechanism. We found that histamine mediates the stimulatory action of ghrelin on acid secretion through the mechanism based on brain–gut axis. Furthermore, we discussed the relationship between FD and ghrelin, and pathophysiology for FD in the state of stress that was simulated through animal experiments with intracerebroventricular (icv) injection of stress-related peptide urocortin 1 (UCN1). Our study has elucidated that UCN1 decreases plasma ghrelin level through CRF receptor 2. The inhibition of ghrelin secretion is mediated by sympathetic nerve through α2-adrenergic receptor in periphery. The mechanism may explain pathophysiology for FD inducing dyspepsia symptoms such as abdominal distension, fullness, and anorexia.

Open Label Trial of the Efficacy and Safety Profile of Rikkunshito used for the Treatment of Gastrointestinal Symptoms in Patients with Parkinson’s Disease: A Pilot Study

Background Patients with Parkinson’s disease (PD) usually experience distress related not only to motor dysfunction, but also to nonmotor symptoms, including gastrointestinal dysfunction. Objective The purpose of this pilot study was to evaluate the efficacy and safety profile of a traditional Japanese medicine, rikkunshito (RKT), used for the treatment of gastrointestinal symptoms, associated with anorexia and dyspepsia, in patients with PD. Methods Patients were randomly assigned to either Group A (4-week treatment period with 7.5 g/d RKT followed by a 4-week off-treatment period) or Group B (4-week off-treatment period followed by a 4-week treatment period with 7.5 g/d RKT). Appetite, quality of life for gastrointestinal symptoms, and depression were assessed using a visual analog scale, the Gastrointestinal Symptom Rating Scale and the Self-Rating Depression Scale, respectively. The gastric emptying examination and assay of plasma acylated ghrelin level were performed using the 13C-acetate breath test and commercially available assay kits, respectively. Results RKT treatment produced a significant increase in the appetite score (1.84 [2.34]; P < 0.05), compared to a decrease in the score over the off-treatment period (−1.36 [2.94]). The mean score for abdominal pain, on the Gastrointestinal Symptom Rating Scale, and for self-reported depression, on the Self-Rating Depression Scale, also decreased significantly with RKT treatment (P < 0.05), compared with the off-treatment period scores. No effect of RKT on plasma acylated ghrelin level and rate of gastric emptying was identified. Conclusions RKT may improve anorexia in patients with PD. The positive effects of RKT on depression and anorexia may improve the overall quality of life of these patients. The benefits of RKT identified in our pilot study will need to be confirmed in a randomized, double-blind, controlled trial. UMIN Clinical Trial Registry identifier: UMIN000009626.

Sa2021 The Stress Hormone Urocortin 1 Induces Gastric Dysfunction by α2-Adrenergic Receptor-Mediated Decrease in Ghrelin Signal in Rats

Background/Aim: Excessive stress in modern society is associated with development of functional dyspepsia, which presents with symptoms of epigastric pain, early satiety and postprandial fullness. The central neural peptides, members of the corticotropin-releasing factor family, play key roles in response to stress. We previously reported that urocortin1 (UCN1) suppressed feeding behavior in fasted rats through an α2-adrenergic receptor (α2AR) activation, which decreases ghrelin secretion (DDW 2014). However, the influence of UCN1 on gastrointestinal (GI) function remains unclear. To elucidate this, we investigated the changes in gastric emptying and GI motility in UCN1-treated rats. Methods: UCN1 (300 pmol/rat) or phosphate-buffered saline (PBS) were intracerebroventricularly (ICV) injected to Sprague-Dawley rats, and gastric emptying and plasma ghrelin levels 2 h after oral administration of test meal were measured. The α2-AR antagonist, yohimbine (5 mg/kg) 15 min before ICV were intraperitoneal(IP) administered to UCN1-treated rats. Furthermore, ghrelin (3 nmol/rat, intravenous (IV)) were administered to UCN1-treated rats. In another set of experiment, the effects of co-administration of rikkunshito (RKT; 1000 mg/kg, which is an endogenous ghrelin enhancer) and with the ghrelin receptor antagonist ([D-Lys3] GHRP-6; 4 μmol/kg IV) was investigated. GI motility was investigated to determine the effects of ghrelin or RKT to UCN1-treated rats using a strain gauge force transducer in free-moving condition. Results: UCN1-treated rats exhibited significantly delayed gastric emptying. Administration of yohimbine improved gastric emptying (UCN1: 22.9±6.5 %, UCN1+yohimbine: 58.5±7.6 %, p<0.05) and significantly increased plasma ghrelin levels (UCN1:47.2±3.6 fmol/mL, UCN1+yohimbine: 81.9±7.8 fmol/mL, p<0.05). Exogenous administration of ghrelin restored delayed gastric empting. Administration of RKT significantly prevented delayed gastric empting and decreased plasma ghrelin levels. The gastric function of RKT was blocked by co-administration of the ghrelin receptor antagonist. ICV injection of UCN1 decreased the amplitude of contraction in the stomach while increasing the amplitude in the duodenum. Motility index of the stomach, but not the duodenum, was significantly reduced by treatment with UCN1 (PBS: 92.1 ± 10.1%, UCN1: 62.8 ± 4.7%), which was improved by the administration of ghrelin or RKT (99.03 ± 7.95%, p<0.05). Conclusions UCN1-induced gastric motility dysfunction with decrease in plasma ghrelin levels wasmediated byα2-AR activation. Disturbance in endogenous ghrelin dynamics play an important role in the functional abnormality of the upper GI tract under stressful conditions.

Su1253 Abnormal Dynamics of Endogenous Acylated Ghrelin Mediates Decreases in Gastric Phase III-Like Contraction, Leading to Delayed Gastric Emptying in Urocortin1-Induced Stress Rats

INTRODUCTION: Gastric acid suppression is justified to prevent severe gastro esophageal reflux (GER) disease related complications. However, it does not reduce the total amount and proximal extent of GER in the esophagus and non-acid components are able to induce (extra-esophageal) GER symptoms as well. No data on the composition of gastric juice (GJ) in children using gastric acid suppression exists. We therefore aimed to assess whether the composition of gastric juice in children using proton pump inhibitors (PPIs) differs, compared to that of their controls. METHODS: Infants and children (0-18 years) on proton pump inhibitors (PPIs) for at least six weeks and a control group not using anti reflux medication, were included. GJ was obtained through an existing nasogastric or a percutaneous endoscopic gastrostomy tube/ Mic-key gastrostomy. In the collected GJ (5 ml), pH, pepsin activity, bile salts and endotoxin (LPS) levels were determined. Pepsin was measured using a fluorometric assay using 4-Methyl-Coumaryl-7-Amide (MCA) substrate with/without pepstatin. Concentrations of deconjugated and taurine/glycine-conjugated bile salts were assessed by reversephase HPLC. Levels of LPS were determined using the spectrophotometric Limulus Amebocyte Lysate assay. RESULTS: GJ was analyzed from 16 children with (median: 3.8 yrs, range: 17.6 years) and 16 children (4.0 yrs, range: 16.0) without PPI therapy. Median duration of PPI treatment was 24 weeks (range: 514 weeks). Gastric pH was 5.0 (range: 5.0) and 1.0 (range: 4.5) in the PPI and control group respectively (p <0.001). Pepsin, unconjugated bile salts, and endotoxin were not significantly different in the two groups. Total taurine conjugated bile salts, and specifically taurocholate, was significantly higher in the PPI group (p=0.01 and p=0.005). pH and concentration of deconjugated bile and conjugated bile salts were significantly associated (p=0.006 and p=0.02). Endotoxin and bile salts were not significantly associated. CONCLUSION: Taurine conjugated bile acids are significantly higher in children chronically using PPIs compared to controls. Moreover acidity of gastric pH correlated negatively with deconjugated and conjugated bile salts. These findings imply that GJ under chronic proton pump inhibition contains nonacid components potentially harmful to esophageal mucosa and bronchial tissue.