Keiko Shiratori

Clinical evaluation of oral administration of a cholecystokinin-A receptor antagonist (loxiglumide) to patients with acute, painful attacks of chronic pancreatitis: a multicenter dose-response study in Japan.

Introduction Cholecystokinin (CCK)–receptor antagonists have been found to markedly reduce the severity of pancreatitis and improve survival in experimental animal models of acute pancreatitis. CCK appears to play an important role in the development and progression of acute pancreatitis, and the recent development of CCK antagonists has provided a new approach to the treatment of acute pancreatitis in humans. Aims The therapeutic efficacy of a CCK-A receptor antagonist, loxiglumide, in patients with painful acute attacks of chronic pancreatitis was evaluated. Methodology A multicenter dose–response controlled trial was conducted at 110 institutions in Japan from June 1993 to December 1994. Chronic pancreatitis was diagnosed for all patients on the basis of the Japanese criteria for chronic pancreatitis. Two-hundred seven patients were randomized to oral treatment with loxiglumide (300, 600, and 1,200 mg/d) or placebo for 4 weeks. The efficacy of treatment was evaluated on the basis of clinical symptoms, physical signs, and serum pancreatic enzyme levels. The groups were comparable with respect to age, sex, etiology, complications, and previous treatment. Results The improvement rate of the abdominal and/or back pain was 46% in the loxiglumide 300-mg group, 59% in the 600-mg group, and 52% in the 1,200-mg group, and it was 36% in the placebo group (600 mg versus placebo:p < 0.05). The physical signs evaluated—abdominal tenderness and resistance—improved in all three loxiglumide groups, and the serum pancreatic amylase and trypsin levels decreased significantly in the 600-mg group (p < 0.05). The overall clinical improvement rate was 46% in the 300-mg loxiglumide group, 58% in the 600-mg group, and 52% in the 1,200-mg group, and it was 34% in the placebo group. Conclusion These results indicate that oral administration of loxiglumide may be useful in the treatment of patients with acute, painful attacks of chronic pancreatitis, and 600 mg/d is recommended as a beneficial dosage.

Engulfment of necrotic acinar cells by pancreatic stellate cells inhibits pancreatic fibrogenesis.

Objectives: We have previously reported that pancreatic stellate cells (PSCs) have a phagocytic function. The aim of the present study was to investigate whether engulfment of necrotic acinar cells affects pancreatic fibrogenesis. Methods: Rat pancreatic acinar cells were incubated for 48 hours to induce necrosis, and PSCs were allowed to interact with them for 12 to 48 hours. Annexin V and propidium iodide staining or detection of DNA fragmentation was used to identify cell death. Results: A large number of necrotic acinar cells were engulfed by PSCs. When PSCs were exposed to necrotic acinar cells for 12 hours, the number of living PSCs was significantly lower than among the control PSCs, which were not exposed to necrotic acinar cells. DNA degradation was observed in PSCs that had ingested necrotic acinar cells, and they were Annexin V and propidium iodide positive, suggesting that engulfment of necrotic acinar cells induced PSC death. There was no difference between the concentrations of transforming growth factor-&bgr; in the medium of the PSCs that had engulfed acinar cells and the medium of the control PSCs. Conclusions: Engulfment of necrotic acinar cells by PSCs induces PSC death, suggesting that engulfment of necrotic acinar cells may inhibit the progression of fibrogenesis.

Expression of cholecystokinin in the pancreas during development

We have reported that cholecystokinin-like immunoreactivity (CCK-LI) and its transcripts are expressed in rat pancreatic islets (Endocrinology 1998;139:389-96). The purpose of this study was to elucidate the ontogeny of CCK during pancreatic development in the rat. Fetal rats from day 13 (E13) to 20 (E20) and postnatal (P) rats from day 1 to adulthood were used in this study. Immunohistochemical studies of rat pancreas were carried out with rabbit antisera against CCK-8 and gastrin-17. The absorption studies were performed by using CCK-8 antiserum incubated with excess CCK-8 or gastrin-17. In situ hybridization was performed to demonstrate the CCK and gastrin transcripts in the pancreas. CCK and gastrin were first detected at E15, and they were distributed in the periphery of the islets in the fetal and neonatal pancreas. The mirror sections for CCK revealed positive cells with characteristics identical to those that stained positive for gastrin. The CCK-LI in early development was completely abolished by preabsorption with excess gastrin but not with CCK-8. These findings indicated that the CCK-LI in the fetal and neonatal pancreas was crossreacting gastrin rather than CCK-8. From weaning (P21) through adulthood, on the other hand, CCK-LI was expressed diffusely in pancreatic islets, but there were no gastrin-positive cells after weaning. In situ hybridization showed that CCK messenger RNA (mRNA) was present in rat pancreatic islets in adults but not in early development. Although CCK-positive cells were not detected in fetal and neonatal pancreatic islets, CCK was expressed in islets during and after weaning through adulthood, indicating that CCK in pancreatic islets might be developmentally regulated.

Clinical Significance of Serum Ornithine Carbamoyltransferase in Liver Diseases – Is the Ratio of OCT/ALT a New Tumor Marker?

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer-related mortality (World Health Organization. Mortality database, 2010). According to the most recent nationwide Japanese registration data, primary liver cancer ranks fourth for men and sixth for women as cause of death from malignant neoplasm (Journal of Health and Welfare Statistics. Health and Welfare Statistics Association, 2009).